zilongwang/ReadingBank huggingface dataset:
Important potential risks Immune mediated adverse events For haematological malignancies: increased risk of severe complications of allogenic stem cell transplantation in patients who have previously received pembrolizumab X - Immunogenicity – Missing information Safety in patients with moderate or severe hepatic impairment – – Safety in patients with severe renal impairment – – Safety in patients with active systemic autoimmune disease – – Safety in patients with HIV or Hepatitis B or Hepatitis C – – Safety in paediatric patients - - Reproductive and lactation data * - Safety in various ethnic groups - ‘n/a’ - Potential pharmacodynamic interaction with systemic immunosuppressants - - Missing information: ‘Long term safety’ has been deleted by the sponsor without adequate justification. Key: * Enhanced routine pharmacovigilance with the use of structured targeted follow-up questionnaires X Risk minimisation content in PI/CMI considered to be inadequate ‘n/a’ Listed by the sponsor in the ASA as ‘n/a’ ‘n/a’ Listed by the sponsor in the ASA as ‘n/a’; however, listed in the adverse events section of PI. Pharmacovigilance activities Routine pharmacovigilance is proposed for all concerns, with the use of targeted follow up questionnaires for all the important identified risks and for the important potential risk: ‘Myasthenic syndrome’. Monitoring and analysis of safety data from the ongoing trials is listed as additional pharmacovigilance for all safety concerns; this includes monitoring of immunogenicity which will be assessed in anti-drug antibody assessments. No paediatric investigation plan is described in the Core-RMP with ASA. Risk minimisation activities Routine and additional risk minimisation activities are implemented to mitigate all the important identified risks, including:
The ACPM advised that implementation by the sponsor of the recommendations outlined above to the satisfaction of the TGA, in addition to the evidence of efficacy and safety provided would support the safe and effective use of this product. Outcome on a review of quality, safety and efficacy, TGA approved the registration of Harvoni (ledipasvir/sofosbuvir 90 mg/400 mg) indicated for: Harvoni (ledipasvir/sofosbuvir dose combination) is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. Specific conditions of registration applying to these goods The EU RMP (Version: 0.2, dated 19 August 2014) with an ASA (Version: 0.1, dated February 2015) must be implemented for the Harvoni (ledipasvir/sofosbuvir 90 mg/400 mg) tablet. Attachment 1. Product Information The PI approved for Harvoni at the time this AusPAR was published is at Attachment 1. For the most recent PI, please refer to the TGA website at <>. Attachment 2. Extract from the Clinical Evaluation Report
Pharmacovigilance plan The sponsor proposes routine and additional pharmacovigilance activities (as stated above). The additional pharmacovigilance activities are provided and include the following studies as shown in Table 4. Table 4: Ongoing studies proposed or in progress Study Objectives Safety concerns addressed Status (planned, started) Date for submission of Interim of reports (planned or actual) To evaluate the relative bioavailability and safety of an age-appropriate paediatric SOF formulation in healthy adult volunteers safety of age appropriate paediatric SOF formulation planned April 2016 To evaluate the PK efficacy and safety of LDV/SOF for 12 weeks in adolescents and children safety in children planned final study report 2019 To evaluate the safety, efficacy and PKs of treatment with SOF + RBV for 24 weeks in subjects with chronic genotype 1 or 3 HCV infection and severe renal impairment safety in patients with severe renal impairment or end stage renal disease started final study report July 2017 To evaluate the safety and efficacy of treatment with LDV/SOF ± RBV in subjects with HCV/HIV safety in patients with HCV/HIV started March 2017 To evaluate the safety and efficacy of one cohort will provide safety information in started June 2016 GS-US-337-
Effects of age, gender and genetic polymorphism Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily, age, sex, weight, or race (Japanese versus other, Caucasian versus other) had no significant effects on clearance Paediatric patients have not been studied. Effects of food Food does not affect the extent of absorption, but slows the rate of absorption. When given with food to healthy subjects, peak plasma concentrations are delayed by 2 h. Summary of bioavailability and bioequivalence studies Three biopharmaceutic/bioavailability/bioequivalence studies have been presented in the dossier. Table 1 summarises the studies performed, and indicates which studies have been fully evaluated or summarised. Table 1. Summary of bioavailability and bioequivalence studies. Number Primary objectives Formulations Evaluation To compare the bioavailability of a 10-mg capsule formulation with the 10-mg tablet formulation of E7080 10-mg capsule E7080 10-mg tablet Summary only To determine the effect of food on the bioavailability of following administration of E7080 with and without a high fat meal E7080 10-mg capsule Full evaluation To determine whether two test lots of 10-mg capsules that vary by the of lenvatinib crystal form were bioequivalent to a reference lot of capsules. E7080 10-mg capsules with low, medium and high crystal form Summary only The different formulations and their relation to the final proposed commercial formulation and the clinical study phases are summarised below in Table 2. Table 2. Different formulations and clinical study phases. E7080-A001-003 has been fully evaluated as it provides an estimate of the food effect for the capsules. Evaluation of crossover multiple dose PK Study E7080-E044-101 which included a food effect arm was not required as it was performed on tablets, which have had very limited use and were not used in pivotal studies. Trial
Study 203 (DB extension) 78 48 - 78(1) Study 203 (open extension) - - 79 79(1) Monotherapy Study 303 107 107 - 107 305 - - 143(1) 143(1) Study 202 (core period) 96 27 - 96 Study 202 (open extension) - - 50(1) 50(1) Total gout subjects 1799(2) TOTAL 1438 770 1183 2586(2) (1) A proportion of subjects had also received lesinurad in the preceding controlled study. (2) Unique subjects Adverse events An overall summary of the incidence of AEs in the pivotal studies 301, 302 and 304 is shown in Table 15. Table 15. Studies 301, 302 and 304 – Overall summary of AEs. All adverse events (irrespective of relationship to study treatment) Pivotal studies (301, 302 and 304) The overall incidence of any AE was 77.7% with lesinurad and 70.3% with placebo. Common AEs (those occurring with an incidence of ≥ 2% in either lesinurad group) are summarised in Table 16. Comment: Creatinine increases were reported more frequently as AEs (6.1% with lesinurad vs. 2.3% with placebo). The incidence was dose related (4.3% at 200 mg vs. 7.8% at 400 mg). Blood urea increases were also more commonly reported with lesinurad (1.4% vs. 0.6%). Headache, dizziness and hypertension were also slightly more common with lesinurad. Table 16. Studies 301, 302 and 304 – Common AEs (incidence ≥ 2%). Most of the AEs were as mild or moderate in severity (Table 17). Table 17. Studies 301, 302 and 304 – AEs by severity.
Pituitary apoplexy Medication errors Apart from medication errors, there was no new information received during the reporting period for identified or potential risks. Important potential risk Cardiovascular diseases Missing information Use in patients with renal impairment Use in patients with hepatic impairment Use in children Summary of post-marketing data The PBRER concluded that the adverse event profile of leuprorelin acetate has been well established in both clinical studies and in post marketing experience. The product has not been withdrawn or suspended for a safety reason in any country. The safety data remains in accordance with the previous cumulative experience and with the current RSI (CCDS). The content of the report does not change the current positive benefit risk assessment of ELIGARD in its various presentation forms. The report represents information on 238,874 patient years of exposure, and consists of 31 serious ADEs collected from clinical trials and 2,415 ADEs from post marketing sources. This report therefore adds significant support to the assessment of the safety and risk benefit profile of this medicine. The CCDS was in effect at the start of this reporting period included both the palliative treatment indication currently registered in Australia, as well as the extension of indication proposed in this application. The PBRER therefore provides additional information relevant to both the safety and risk benefit of Eligard when used in the extension of indication proposed in this application. Apart from lack of efficacy due to the wrong administration technique, there was no new information relevant to these important identified or potential risks detected during the current reporting period. The conclusion provided in Benefit-Risk Analysis Evaluation section of the PBRER adequately reflects the impact of the information provided in this report on the risk benefit profile of Eligard. The overall appraisal of the benefit risk profile for ELIGARD remains favourable for the approved indication and population (including the proposed extension of indication for Australia). Review of safety data from worldwide sources during the period covered by the revealed no new clinically significant safety signals that warrant an immediate change to the reference safety information (RSI). All known AEs with leuprorelin acetate are listed in the current CCDS and there are no new risks identified other than those currently listed in the CCDS of ELIGARD dated 20 May 2014. The proposed Australian PI reflects the information contained in the CCDS.
daily for 9 months. RT after androgen max (median 4.7mo) Solberg 2011 of Widmark 2009 Biopsy at 45 months follow-up. Assessed 3/12 for 1 year then 6/12 death or Feb 2008. Locally cancer. Residual cancer in 66% (n=41) endocrine only patients and 22% (12) ADT+RT patients; p<0.0001. Use of adjuvant ADT appears to have decreased rate of residual cancer in an population. Stone 2000 (n=296) (dose 3 months before and after brachy implant. 750mg daily 3 months before and after implant. + brachy implant. N/A 2 years. Assessed every 6/12 and at 2 years after implant. cancer (note not specific 30 (10%) had post implant biopsies. 4 were positive in who received hormone blockade, while 26 were positive in those who had not (p=0.002) Again the role of ADT in reducing positive biopsy. Link to clinical outcomes. Only benefited high-risk in sub analysis. Stone 1999 (n=145) (dose 3 months before and after brachy implant. 750mg daily 3 N/A 4 years. Assessed 3 and 6 months and 6 month intervals thereafter. Biopsy at 2 years. cancer. Prostate volume, freedom from PSA-defined failure. Mean PV reduction 35% (R2-62). actuarial freedom from PSA failure the reduction in prostate volume achieved. What proportion due to ADT or RT unknown.
Widmark 2009 cancer burdens in those receiving combination treatment. Berg 2009 (n=86) 3.75mg equiv. monthly for 3 months. 750mg daily until or death +3D conf. RT 3/12 of ADT. N/A 5 years Locally cancer Evaluated HRQoL and hormonal changes in those who’d used ADT for 5 years, adjuvant to RT. Compared with NORM, patients scored statistically (p < 0.05) and clinically (effect size ≥ 0.4) lower on sexual domains, and statistically (p < 0.05) lower on physical function and vitality. Estimated free testosterone and measured serum oestradiol had increased from baseline in most patients, but did not correlate with HRQoL outcomes 5 years after the start of treatment. Kohutek 2016 (n=2011) EBRT, or both + 7.5mg monthly EBRT or or both. At least 5 years assessed for first 5 years, then annually. T1-T3 cancer ADT at time of RT: significantly higher 10 year incidence of cardiovascular events (CE: 19.6%; 95% CI 17.0-22.6%) Although low level data, a large population studied. A long-term safety item to consider
List of abbreviations Abbreviation Meaning AE Adverse event BMI Body mass index CMPH (CHMP) Committee for Medicinal Products for Human Use formerly known as Committee for Proprietary Medicinal Products - a European Medicines Agency committee FAS Full analysis set FDA US Food and Drugs Administration ICH International Committee on Harmonisation IUS Intrauterine Device In vitro–In vivo Correlation LCS 12 To be marketed as Jaydess in Australia LNG levonorgestrel
Complicated Association, ‘administration of prophylactic antibiotics solely to prevent endocarditis is not recommended for patients who undergo genitourinary tract procedures, including insertion or removal of IUDs’. cardiomyopathy. Limited indirect evidence from noncomparative studies did not demonstrate any cases of arrhythmia or infective endocarditis in women with cardiac disease who used IUDs. Separate category for women with peripartum myocardiopathy (Category 2), comment: IUD insertion might induce cardiac arrhythmias in healthy women; women with peripartum cardiomyopathy have a high incidence of cardiac arrhythmias UK MEC (2016) Valvular and congenital heart disease: Complicated 1 (Uncomplicated), 2 (Complicated) ‘Prophylaxis against bacterial endocarditis is no longer indicated for women with artificial heart valves or previous endocarditis when inserting or removing IUS. However, this does not necessarily mean that there is no risk’. Congenital disease including Aortic stenosis; Atrial septal defects; septal defect; Cardiomyopathy (hypertrophic or dilated); Coarctation of the Aorta; Complex Transposition of the Great Arteries; Ebstein’s Anomaly; Eisenmenger Syndrome: Patent Ductus Arteriosus; Pulmonary Atresia; Pulmonary Stenosis; Tetralogy of Fallot; Total Anomalous Pulmonary Venous Connection; Tricuspid Atresia; Truncus Arteriosus; Ventricular Septal Defect WHO MEC 201511 Valvular heart disease: Complicated 1 (Uncomplicated), 2 (Complicated) Prophylactic antibiotics to prevent endocarditis are advised
sulfonylurea;...” (see FDA Product Label page 2). The proposed Australian PI does not include this information. infection’ was not considered as listed event. As the USPI displayed the algorithm for the side effect identification, the term was subsequently added. The term ‘urinary tract infection’ is not considered to be listed, therefore no updated was carried out for the EU SmPC or other labels (including the Australian PI). 8. The important potential risk ‘Worsening of renal function’ is not assigned any risk minimisation activities. The FDA Product Label and EU SmPC also do not include any information on this potential risk. Boehringer Ingelheim, supports the RMP evaluator's recommendation that the important potential risk 'Worsening of renal function' is not assigned any risk minimisation activities. As supported by Study 1218.43 [U11-3170-01], the use of linagliptin as add-on to anti-diabetic therapy, the reported safety and laboratory results were comparable between linagliptin and placebo with no distinct safety concerns observed. A statistically significant and clinically relevant reduction in the change from baseline in HbA1c of -0.72% after 52 weeks of treatment was observed for linagliptin compared to placebo. The reduction in HbA1c observed for the linagliptin treatment group was sustained throughout the 52 weeks of the study. This study supports the assumption that renal impairment would not significantly alter the exposure of linagliptin and that no dose adjustment would be required in patients with any degree of renal impairment. This was considered acceptable. SmPC=Summary of Product Characteristics
Other special population: renal impairment, hepatic impairment, and elderly The available nonclinical data do not indicate any risk associated with use of linagliptin to renal or hepatic function [U10-1492]. Metformin is contraindicated in renal impaired and hepatic insufficient patients [R10-5537]. Because of the metformin component of the fixed dose combination, linagliptin/metformin will be contraindicated in renal impaired and hepatic insufficient patients. Data of the individual compounds do not indicate an increased risk for elderly [U07-1910, U08-1185, R10-5239]. Therefore, no additional nonclinical data for linagliptin/metformin will be obtained. [Part I section 1.1.2 “Specification of need for additional non-clinical data if the product is to be used in special population”] Boehringer Ingelheim proposes to update the Australian Product Information to include “Hepatic insufficiency, acute alcohol intoxication, alcoholism (due to the metformin component)” in the Contraindication section, and a statement in the Dosage and Administration section related to Hepatic impairment. Therefore “hepatic impaired patients” is not required to be included as an “Important potential risk” in the linagliptin and metformin RMP. 2) Include use with insulin as an area of important missing information It was noted the sponsor proposes a precautionary PI statement “The use of TRAJENTA DUO in combination with insulin has not been adequately studied.” It was recommended to the Delegate that the sponsor: Australian educational programme: Expand this programme to include the Important identified risk - lactic acidosis, which may occur due to the metformin component of the fixed dose combination. The Australian Specific Annex has been amended to include lactic acidosis as an identified safety concern (section 3a). Boehringer Ingelheim as part of the Australian education programme is developing a diabetes CME program which will include information on Trajenta Duo. Although the sponsor concludes in the RMP routine risk minimisation activities are sufficient and no risk minimisation plan is needed, they provide details of an educational programme for Australian healthcare professionals (specialist physicians and general practitioners) in the Australian Specific Annex.
The potency of this medicinal product should not be compared to the potency of another pegylated or non-pegylated protein of the same therapeutic class. For more information, refer to the PHARMACOLOGY. Pharmacotherapeutic group: Immunostimulants, Colony stimulating factors, ATC code: L03AA14 Pharmacological Actions Mechanism of action Human G-CSF is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. Filgrastim is an un-glycosylated recombinant methionyl human G-CSF. Lipegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Lipegfilgrastim binds to human the G-CSF receptor like filgrastim and pegfilgrastim. Pharmacodynamics effects Lipegfilgrastim and filgrastim induced a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. These results suggest that the G-CSF moiety of lipegfilgrastim confers the expected activity of this growth factor: stimulation of proliferation of haematopoietic progenitor cells, differentiation into mature cells and release into the peripheral blood. This effect includes not only the neutrophil lineage but extends to other single lineage and multilineage progenitors and pluripotent haematopoietic stem cells. G-CSF also increases the antibacterial activities of neutrophils including the phagocytosis. Pharmacokinetics Absorption Following initial sc administration of lipegfilgrastim in healthy subjects, a lag in absorption of approximately 1 hour is observed with maximum serum concentrations being attained at approximately 35 hours after dose administration. Given its molecular weight, lipegfilgrastim is believed to be primarily absorbed via the lymphatic system then drained into the vascular system. Following repeated administration in patients 4), mean serum concentrations of lipegfilgrastim are consistently lower than after a single dose. Maximum serum concentrations after repeat doses were attained earlier (8 to 24 hours after dose
Haemodynamically unstable PE patients is a new item of missing information directly relating to the proposed indications. The approved US product label includes a related precaution. It is recommended that a similar precaution is included in the Australian PI as routine risk minimisation for the missing information Haemodynamically unstable PE patients. This should be appropriately reflected in the EU-RMP and/or ASA. The sponsor has updated the Product Information. This is acceptable from a RMP standpoint subject to final consideration by the Delegate. The EU and US product labels include a precaution regarding temporary discontinuation of apixaban and the associated increased risk of thrombosis. The corresponding precaution in the Australian PI focuses more on the increased risk of stroke when transitioning from apixaban to warfarin. Consideration should be made for inclusion of similar advice to the EU Summary of Product Characteristics (SmPC) regarding temporary discontinuation in general. The sponsor has updated the Product Information in line with the recommendation in the US product information. This is acceptable from a RMP standpoint subject to final consideration by the Delegate. The proposed PI contains advice on switching between apixaban and anticoagulants. It is noted that the US product label contains the following useful statement regarding measuring INR when switching from apixaban to warfarin: Eliquis affects INR, so that INR measurements during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. It is recommended that a similar statement is included in the Australian PI. The sponsor has updated the Product Information. This is acceptable from a RMP standpoint subject to final consideration by the Delegate. Changes made to the PI in response to the evaluation The sponsor provides an assurance that any changes This is acceptable.
Australian Public Assessment Report for liraglutide Proprietary Product Name: Saxenda Sponsor: Novo Nordisk Pharmaceuticals Pty Ltd About the Therapeutic Goods Administration (TGA) The Therapeutic Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. The TGA administers the Therapeutic Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. The work of the TGA is based on applying scientific and clinical expertise to to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. To report a problem with a medicine or medical device, please see the information on the TGA website <>. AusPARs An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. AusPARs are prepared and published by the TGA. An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Trial Trial
Fully informing patients of the limitations of Saxenda use will ensure that the right patients are using Saxenda for the right reasons and that they will be appropriately monitored. Attachment 1. Product Information The PI approved for Saxenda at the time this AusPAR was published is at Attachment 1. For the most recent PI, please refer to the TGA website at <>. Attachment 2. Extract from the Clinical Evaluation Report
Introduction Lisdexamfetamine is a centrally acting sympathomimetic. It is a prodrug of dexamphetamine, which is a central nervous system stimulant. The lisdexamfetamine parent compound does not bind to the sites responsible for the reuptake of noradrenaline and dopamine in vitro and is not thought to contribute to the pharmacological effects. After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and hydrolysed primarily in whole blood to d-amphetamine, which is thought to be responsible for all of the drug’s activity. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action of amphetamine in Attention Deficit Hyperactivity Disorder (ADHD) is not fully established. However it is thought to be due to its ability to block the reuptake of noradrenaline and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The proposed indication is: Vyvanse is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in: Children Adolescents Adults Clinical rationale ADHD is a common condition in childhood and has a significant burden through interference with regular activities and with socialisation. Lisdexamfetamine is proposed to have PK properties similar to a controlled release formulation. The advantage of such properties is that of once daily dosing with improved compliance and decreased stigmatisation. Formulation The formulation proposed for marketing is that used in the Pivotal studies. Contents of the clinical dossier of the clinical dossier The submission contained the following clinical information: Module 5 15 clinical pharmacology studies, including 13 that provided pharmacokinetic data and a further two that provided pharmacodynamic data. No population pharmacokinetic analyses. Nine pivotal efficacy/safety studies. Four other efficacy/safety studies. Three integrated summaries Module 1
Rabbit (NZW); Adderall Embryofetal development (GD 19) 2 89.9 0.1 6 377 0.3 16 1464 1.0 20 2578 1.8 Rat (SD); Adderall Pre-/postnatal development (mean GD 6 and PPD 20) Amphetamine 2 674 0.5 6 2173 1.5 10 4247 2.9 Human$ d-amphetamine^^ steady [70 mg] 1453** NA LDX@ steady state [70 mg] 61.1 NA # = animal:human plasma AUC0–24 h; * doses of LDX refer to the salt, doses of Adderall refer to total damphetamine base; ^ males/females; ^^ study NRP104.104 conducted in healthy adults aged 18-55 years; $ day 7 data; ** AUC0-∞; NA = not applicable Impurities Related substances do not exceed the ICH thresholds, and two impurities with genotoxic potential have been controlled in the drug substance to levels below the Threshold of Toxicological Concern. Nonclinical summary and conclusions Shire Australia Pty Ltd has applied to register a new chemical entity, LDX (Vyvanse) which is a prodrug of d-amphetamine covalently linked to llysine by an amide bond. Vyvanse is proposed for the treatment of ADHD in adults, adolescents and children. The maximum recommended dose is 70 mg/day. amphetamine is a well-characterised medicine, an abridged program of nonclinical studies was conducted focusing on identifying any characteristics of the prodrug that are not related to d-amphetamine. This is appropriate and an adequate set of studies was submitted, with all pivotal studies being GLP compliant. LDX appears to be pharmacologically inactive and lacks affinity for the dopamine and noradrenaline transporters that mediate the actions of d-amphetamine, as well as for a range of other receptors, transporters and ion channels. The active moiety, is a well-known sympathomimetic psychostimulant, and its primary amphetamine,
In the ‘Adverse Effects’ section, stroke, myocardial infarction, sudden hypertension, and growth suppression should be included in the table provided. These adverse events are already mentioned in the proposed PI in the ‘Precautions’ section, but should be repeated in the table shown in the ‘Adverse Events’ section for the purpose of completeness. ‘As noted above stroke, myocardial infarction, sudden death, hypertension, and growth suppression are listed in the Precautions sections as adverse events that have been reported or associated with amphetamines. The adverse drug reaction section of the PI contains adverse drug reactions that have been determined by the MAH to have sufficient evidence to be an adverse drug reaction with lisdexamfetamine. To date the MAH does not consider stroke, myocardial infarction, sudden death, hypertension and growth retardation as adverse drug reactions related to LDX.’ This is considered acceptable.
Annualised Spontaneous Bleeding Rate (AsBR) Median (IQR*) 0 (0–2.4) 11.73 (2.8–36.5) 0 (0–2.2) 31.76 (0–42.7) Number of subjects with zero bleeding episodes requiring treatment 63 (43.2%) 1 (3.7%) 21 (26.3%) 0 * IQR = interquartile range, 25th percentile to 75th percentile. Control and prevention of bleeding episodes in the perioperative setting Thirteen subjects in the adult/adolescent study underwent a total of 16 surgical procedures. Overall, investigators assessed haemostatic efficacy of AFSTYLA® in surgical prophylaxis as excellent in 15 of 16 surgeries and as good in 1 of 16 surgeries (see Table 6). Median factor consumption on the day of surgery was 89.4 IU/kg (range 40.5–108.6 IU/kg). Table 6: Efficacy of AFSTYLA® in surgical prophylaxis Procedure Efficacy Evaluation* Factor Consumption (IU/kg) (pre- and intra-operatively) Extraction of wisdom Excellent 51.09 Abdominal hernia repair Excellent 47.89 Elbow replacement Excellent 108.58 Ankle arthroplasty Excellent 76.83 Knee replacement (5) Excellent (4), Good (1) 92.49 100.9 67.26 105.79 86.09 Cholecystectomy and Lengthening of the Achilles tendon combined with: Straightening of the right toes Excellent Excellent 105.95 Circumcision (3) Excellent (3) 99.04 92.74 81.5 Open reduction internal fixation (ORIF) right ankle Excellent 89.36 Hardware removal, right ankle Excellent 40.45
Octocog alfa (bhk) Kogenate FS For the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital Factor VIII deficiency). It may also be used in patients with Factor VIII inhibitors (neutralising antibodies) who continue to respond to infused Factor VIII. Kogenate FS does not contain von Willebrand Factor and is not indicated in von Willebrand’s disease. CSL Behring Octocog alfa (bhk) Kovaltry Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Kovaltry can be used for all age groups. (See Clinical Trials section). Kovaltry does not contain von Willebrand factor and is not indicated in von Willebrand disease. Bayer Octocog alfa (rch) For use in haemophilia A (classical haemophilia) for the prevention and control of haemorrhagic episodes. Patients with haemophilia A may be treated with Recombinate as perioperative management. Recombinate is not indicated in von Willebrand’s disease. Baxalta Moroctocog alfa Xyntha For the control and prevention of haemorrhagic episodes in patients with haemophilia A, including control and prevention of bleeding in surgical settings. Xyntha does not contain von Willebrand factor and should not be used by patients with von Willebrand’s disease. Pfizer Turoctocog alfa NovoEight For the treatment and prophylaxis of bleeding episodes in patients with haemophilia A, including control and prevention of bleeding in surgical settings. Novo Nordisk Simoctocog alfa Nuwiq Treatment and prophylaxis of bleeding (also during and after surgery) in previously treated paediatric (> 2 years) and adult patients with haemophilia A (congenital factor VIII deficiency). Nuwiq does not contain von Willebrand Factor and is thus not indicated to treat von Willebrand's Disease.
Musculoskeletal and connective tissue disorders Joint swelling Arthralgia Bone pain Myalgia Musculoskeletal pain Muscular weakness Muscle spasms Pain in extremity Sensation of heaviness Renal and urinary disorders Proteinuria Renal failure Cystitis noninfective Micturition disorder Haematuria Leukocyturia Reproductive system and breast disorders Menstrual disorder General disorders and administration site conditions Pyrexia Oedema Mucosal inflammation Malaise General physical health deterioration Pain Feeling of body temperature change Xerosis Investigations Hepatic enzyme increased Blood alkaline phosphatase increased Weight decreased creatinine increased Electrocardiogram QT prolonged International normalised ratio increased Activated partial thromboplastin time prolonged urea increased Blood lactate dehydrogenase increased Protein total decreased C-reactive protein increased Haematocrit decreased a. Different MedDRA preferred terms that were considered clinically similar have been grouped into a single term. b. Fatal cases have been reported. c. Hand-foot skin reaction. Rare and very rare events reported in the Phase III (RECOURSE) clinical could not be estimated from the available data due to the limited number of patients exposed to LONSURF. Elderly Patients aged ≥ 65 years who received LONSURF had a higher incidence of the following events compared to patients aged < 65 years: Grade 3 or 4 neutropenia (48% v 30%), Grade 3 anaemia (26% v 12%), Grade 3 or 4 leucopenia (26% v 18%) and Grade 3 or 4 thrombocytopenia (9% v 2%). Infections
Rimas M, Kjellman NI, Blychert LO, Bjorksten B. “Topical levocabastine protects better than sodium cromolygate and placebo in conjunctival provocation tests”. Allergy Vol.45: pp18-21, 1990.
Date of second round CER: November 2013 AusPAR Attachment 2 Extract from the Clinical Evaluation Report for lurasidone hydrochloride Proprietary Product Name: Latuda Sponsor: Commercial Eyes Pty Ltd About the Therapeutic Goods Administration (TGA) The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices. The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. The work of the TGA is based on applying scientific and clinical expertise to to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. To report a problem with a medicine or medical device, please see the information on the TGA website <>. About the Extract from the Clinical Evaluation Report This document provides more detail of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities. The words [Information redacted] indicate confidential information has been deleted. For the most recent Product Information (PI), please to the TGA website <>. trial
xi) Overdosage Otezla was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg twice daily) for 4.5 days without evidence of dose limiting toxicities. Patients should be managed by symptomatic and supportive care should there be an overdose. Contact the Poisons Advisory Centre on 13 11 26 for advice on management. xii) Presentation and storage conditions Presentation# A two-week titration pack (4 x 10 mg, 4 x 20 mg and 5 x 30 mg for the first week for dose titration and 14 x 30 mg tablets for the second week). A four-week pack (56 x 30 mg tablets) A 12 week pack (168 x 30 mg tablets) # Not all pack sizes are marketed in Australia Otezla 10 mg Tablets: Pink, diamond shaped 10 mg film-coated tablet with “APR” engraved on one side and “10” on the opposite side. Otezla 20 mg Tablets: Brown, diamond shaped 20 mg film-coated tablet with “APR” engraved on one side and “20” on the opposite side. Otezla 30 mg Tablets: Beige, diamond shaped 30 mg film-coated tablet with “APR” engraved on one side and “30” on the opposite side. Composition Active Apremilast Excipients See Description section, for a list of the excipients. Storage conditions Store below 30C. Container type The tablets are provided in polyvinylchloride (PVC) blisters with push through aluminium foil. Name and address of the sponsor Sponsored in Australia by: Celgene Pty Limited 7, 607 St Kilda Road, Melbourne, VIC 3004, Australia. Telephone: 1800 CELGENE (1800 235 4363)
The results from Study D1001054 on healthy subjects showed that food had a significant effect on lurasidone levels compared with the fasted state. The results from D1050294 showed that medium fat meal resulted in smaller increase in levels compared to a high fat/high calorie meal. The PSC noted the lack of absolute bioavailability and the lack of a justification for not providing such a study. The sponsor had been asked for a justification but this was unavailable for the meeting. The absence of an absolute bioavailability study may be permissible, as long as this was supported by sound justification. The sponsor has not provided such a justification at the present time. It appears that 14C-labelled oral doses have been administered. Although from the information presented in the summaries presented to the PSC it is impossible to tell if they might provide some measure of bioavailability. Population pharmacokinetics The PSC advised that detailed population PK analysis showed liner PK. Non linearity in the different dosing might be due to the different point estimate and the limited number of subjects. PSC discussion There might be an issue with one of the proposed packaging (Al/Al). Product Information (PI) The PSC advised that the food effect demonstrated should be included in the PI. PSC recommendation The PSC resolved to recommend to the Advisory Committee on Prescription Medicines (ACPM) and the TGA that: The PSC endorsed all the questions raised by the TGA in relation to the quality and biopharmaceutic aspects of the submission by Commercial Eyes Pty Ltd to register Latuda film coated tablets containing 20 mg, 40 mg and 80 mg of lurasidone (as hydrochloride). The PSC advised that all outstanding issues should be addressed to the satisfaction of the TGA. There is no requirement for this submission to be reviewed again by the PSC before it is presented for consideration by the ACPM. Quality summary and conclusions There are no objections in respect of Chemistry, Manufacturing, Controls and Biopharmaceutics to registration of these products.
Age 18 to 64 Macitentan 3mg N=210 Macitentan 10mg N=209 Macitentan N=419 Placebo N=198 Number of subjects with at least 1 AE (%) 200 (95.2%) 196 (93.8%) 396 (94.5%) 189 (95.5%) Most commonly reported AE (by PT) in combined macitentan pulmonary arterial hypertension, n (%) 57 (27.1%) 43 (20.6%) 100 (23.9%) 68 (34.3%) URTI, n (%) 44 (21.0%) 33 (15.8%) 77 (18.4%) 29 (14.6%) Age ≥ 65 years Macitentan 3mg N=33 Macitentan 10mg N=27 Total Macitentan N=60 Placebo N=44 Number of subjects with at least 1 AE (%) 33 (100.0%) 27 (100.0%) 60 (100.0%) 44 (100.0%) Most commonly reported AE (by PT) in combined macitentan group pulmonary arterial hypertension, n (%) 14 (42.4%) 9 (33.3%) 23 (38.3%) 15 (34.1%) oedema peripheral, n (%) 10 (30.3%) 7 (25.9%) 17 (28.3%) 8 (18.2%) Subgroup by gender Males Macitentan 3mg N=61 Macitentan 10mg N=48 Total Macitentan N=109 Placebo N=65 Number of subjects with at least 1 AE (%) 57 (93.4%) 48 (100.0%) 105 (96.3%) 61 (93.8%) Most commonly reported AE (by PT) in combined macitentan group pulmonary arterial hypertension, n (%) 19 (31.1%) 11 (22.9%) 30 (27.5%) 26 (40.0%)
right ventricular failure, n (%) 11 (18.0%) 8 (16.7%) 19 (17.4%) 16 (24.6%) Females Macitentan 3mg N=189 Macitentan 10mg N=194 Total Macitentan N=383 Placebo N=184 Number of subjects with at least 1 AE (%) 183 (96.8%) 181 (93.3%) 364 (95.0%) 179 (97.3%) Most commonly reported AE (by PT) in combined macitentan group pulmonary arterial hypertension, n (%) 56 (29.6%) 42 (21.6%) 98 (25.6%) 61 (33.2%) urti, n (%) 40 (21.2%) 33 (17.0%) 73 (19.1%) 28 (15.2%) Subgroup by WHO FC at baseline Baseline WHO FC I or II Macitentan 3mg N=138 Macitentan 10mg N=121 Total Macitentan N=259 Placebo N=130 Number of subjects with at 1 AE (%) 131 (94.9%) 117 (96.7%) 248 (95.8%) 123 (94.6%) Most commonly reported AE (by PT) in combined macitentan group pulmonary arterial hypertension, n (%) 35 (25.4%) 20 (16.5%) 55 (21.2%) 31 (23.8%) urti, n (%) 33 (23.9%) 22 (18.2%) 55 (21.2%) 19 (14.6%) Baseline WHO FC III or IV Macitentan 3mg N=112 Macitentan 10mg N=121 Macitentan N=233 Placebo N=119 Number of subjects with at least 1 AE (%) 109 (97.3%) 112 (92.6%) 221 (94.8%) 117 (98.3%) Most commonly reported AE (by PT) in combined macitentan group pulmonary arterial 40 (35.7%) 33 (27.3%) 73 (31.3%) 56 (47.1%)
Elderly: there is limited experience in patients >65 years of age, therefore caution should be exercised when administering CELSENTRI in elderly patients (see PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS). Renal impairment: Table 13 provides dosing recommendations for patients based on renal function and concomitant medications Table 13: Recommended dosing regimens based on renal function Concomitant Medications* CELSENTRI dose on Renal Function Normal Mild Moderate Severe End Stage Renal Disease (ESRD) CrCl >80 mL/min CrCl >50 mL/min and ≤ 80-mL/min CrCl >30 mL/min and ≤ 50-mL/min CrCl ≤ On Regular Haemodialysis Potent inhibitors (with or without CYP3A inducer)* 150 mg twice daily 150 mg twice daily 150 mg twice daily NR NR Other concomitant medications* 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily# 300 mg daily# Potent CYP3A inducers (without CYP3A inhibitor)* 600 mg twice daily 600 mg twice daily 600 mg twice daily NR NR NR = not recommended *See Table 7 for list of concomitant medications # The CELSENTRI dose should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension (see PRECAUTIONS, Renal Impariments) Hepatic impairment: limited data in mild and moderately hepatically impaired patients demonstrated increase in the mean Cmax of maraviroc, suggesting no dose adjustment is required. However, CELSENTRI should be used with caution in patients with hepatic impairment (see PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS). Race: no dosage adjustment is necessary on the basis of race (see PHARMACOLOGY, Pharmacokinetics). Gender: no dosage adjustment is necessary on the of gender (see PHARMACOLOGY, Pharmacokinetics). OVERDOSAGE The highest dose administered in clinical studies was 1200 mg. The dose limiting adverse reaction was postural hypotension.
Table 8. Summary of proposed pharmacovigilance activities for potential risks and risk minimisation activities Safety concern Proposed pharmacovigilance activities (routine and additional) Proposed risk minimisation activities (routine* and additional) Important identified risks: (and complications such as Febrile Seizure) Routine PV for fever but enhanced PV for febrile seizure PI and Consumer Medicine Information (CMI) for the management of the fever Important potential risks: Syndrome Enhanced pharmacovigilance with questionnaire and adjudication by NVD SMT** PI and CMI Acute disseminated encephalomyelitis Enhanced pharmacovigilance with questionnaire and adjudication by NVD SMT PI and CMI Anaphylaxis and Anaphylactic Routine pharmacovigilance PI indicates that vaccine should not be given to persons with history of allergic reactions to the vaccine or its components. Kawasaki Disease Enhanced pharmacovigilance with questionnaire and adjudication by expert panel PI and CMI Seizure and febrile seizure Enhanced pharmacovigilance with questionnaire and adjudication by NVD SMT PI and CMI Chronic Fatigue Syndrome Routine pharmacovigilance PI and CMI Important missing information: Vaccine failure Enhanced pharmacovigilance with SMT adjudication on criteria PI and CMI Safety of vaccine during pregnancy or lactation, Pregnancy registry PI and CMI Vaccine effectiveness Vaccine effectiveness study PI and CMI Strain/serotype replacement Carriage PI and CMI *The PI and CMI, respectively, are used in place of ‘SPC’ (Summary of Product Characteristics) and ‘Patient leaflet’ that appear originally in the sponsor’s RMP summary table. ** NVD SMT: Novartis Vaccines and Diagnostics Safety Management Team Table 9 summarises the OPR’s evaluation of the RMP, the sponsor’s responses to issues raised by the OPR, and the second round OPR evaluation of the sponsor’s responses.
Australian Public Assessment Report for Apremilast Proprietary Product Name: Otezla Sponsor: Celgene Pty Ltd About the Therapeutic Goods Administration (TGA) The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. The work of the TGA is based on applying scientific and clinical expertise to to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. To report a problem with a medicine or medical device, please see the information on the TGA website <>. About AusPARs An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. AusPARs are prepared and published by the TGA. An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. An AusPAR is a static document, in that it will provide information that relates to a submission at a particular in time. A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. trial
VAS Visual analogue scale V1 Volume of central compartment V2 Volume of peripheral compartment V2/F Apparent volume of the central compartment V3/F Apparent volume of the peripheral compartment WFI Water for injection wmeaneos(0–Day 84) Weighted mean absolute blood eosinophil levels (Day 0 to 84) wmeaneos(84–Day 140) Weighted mean absolute blood eosinophil levels (Day 84 to 140) wmeaneos(0–tlast) Weighted mean absolute blood eosinophil levels (Day 0 to last quantifiable measurement) 84) Weighted mean percent sputum eosinophil levels (Day 0 to 84 or last day with available eosinophil data prior to Day 84)
Inclusion: YES n 121 130 146 Exacerbation rate/year 1.64 1.13 0.94 Comparison versus placebo Rate ratio (mepolizumab/placebo) 0.69 0.57 95% CI 0.49, 0.98 0.41, 0.80 ≥ demonstrated at screening Inclusion: No n 21 30 35 Exacerbation rate/year 1.31 1.23 1.20 Comparison versus placebo Rate ratio (mepolizumab/placebo) 0.94 0.91 95% CI 0.43, 2.07 0.44, 1.90 Inclusion: Yes n 167 155 155 Exacerbation rate/year 1.75 0.81 0.67 Comparison versus placebo Rate ratio (mepolizumab/placebo) 0.46 0.38 95% CI 0.33, 0.64 0.27, 0.53 ≥ in previous 12 months OR ≥ at screening2 ≥ documented in the previous 12 months n 23 34 39 Exacerbation rate/year 1.52 1.62 1.25 Comparison versus placebo