zilongwang/ReadingBank huggingface dataset:
In the ‘Interaction with other medicines’ section, the PI should include examples of drugs that inhibit (such as tacrolimus, cyclosporine, diltiazem, amiodarone, carvedilol, nifedipine, verapamil, ketoconazole, itraconazole, quinidine, ritonavir, saquinavir, nelfinavir, ranolazine valspodar, and isradipine) to assist clinicians referring to this section. [recommendation repeated accidentally] [recommendation repeated accidentally] In the ‘Interaction with other medicines’ section, the PI should include examples of substances transported by or other transporters to assist clinicians referring to this section. Appropriate PI changes were made by the sponsor. This was considered acceptable. In the ‘Interaction with other medicines’ section, the PI should include examples of cytoreductive therapies to assist clinicians referring to this section. Appropriate PI changes were made by the sponsor. This was considered acceptable. In the ‘Adverse events’ section, the sponsor should include increased systolic blood pressure. Appropriate PI changes were made by the sponsor. This was considered acceptable. In the ‘Dosage and administration’ section, the sponsor should include more detailed dosing recommendations for patients with thrombocytopaenia to assist prescribers with dose adjustments. Appropriate PI changes were made by the sponsor. This was considered acceptable. In the ‘Dosage and administration’ section, the sponsor should add information on dose modification on response. Appropriate PI changes were made by the sponsor. This was considered acceptable.
Duration of Treatment median (range) mths 7.8 (2.6-13.6) 7.1 (1.1-13.4) - % Subjects with ≥ 35% reduction in spleen volume at Week 24 41.9% 0.7% 41.3% [33.2%, 49.2%]1 p<0.00012 Duration of reduction in spleen volume median weeks3 48.1 Not applicable - % Subjects with ≥ 50% reduction in symptom score4 at Week 24 45.9% 5.3% 40.6% [?, ?] p<0.00015 EORTC QLQ-C30 score – mean change at Week 24 +12.3 -3.4 15.76 [?, ?] 1 Newcombe-Wilson method without continuity correction – CE R1, p.68. 2 Fisher’s exact test.3 estimate in subjects with ≥ 35% reduction in spleen volume at week 24. 4 Night sweats, itch, abdominal discomfort, pain under left ribs, feeling of fullness, muscle bone pain scored 0-10 daily from Week -1 to Week 24 using Modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 developed by the sponsor and agreed with the US FDA. 5 χ2 test. 6 Difference < 10 not clinically significant. ? Sponsor requested to provide data in Pre-ACPM Response. 23: #352 Results – Intent-to-Treat Population Ruxolitinib n=144 BAT n=72 Difference [95% CI] Duration of Treatment median (range) months 11.8 (0.5-17.3) 10.4 (0.03-15.4) - % Subjects with ≥ 35% reduction in spleen volume at Week 48 28.5% 0.0% 28.5% [?, ?] p<0.00011 % Subjects with ≥ 35% reduction in spleen volume at Week 24 31.9% 0.0% 31.9% [?, ?] p<0.00011 Duration of reduction in spleen volume median weeks3 48 Not assessable - EORTC QLQ-C30 quality-of-life score – mean change at Week 48 ? ? ?4 [?, ?]
Table 7: Summary of the proposed summary of safety concerns and their associated risk monitoring and mitigation strategies Summary of safety concerns (ASA v3.0) Pharmacovigilance Risk Minimisation Routine Additional Routine Additional Important identified risks Serious infections § Hypersensitivity reactions* * § * * Important potential risks Increased risk of infection secondary to neutropaenia § Thrombocytopaenia and potential risk of bleeding § Clinically evident hepatic injury § Impact on cardiovascular (CV) outcome (major adverse cardiac event (MACE)) secondary to low density lipoprotein (LDL) elevation § Gastrointestinal (GI) perforations § Malignancy - Clinical consequences of immunogenicity - - Demyelinating disorders* * -* x* -* Missing information Use in pregnant and lactating women - Use in paediatric patients - - Use in patients with hepatic impairment* - - Use in patients with renal impairment* -* * -* Long term use* * * x* -* Use in patients switching to/from other drugs in the anti-IL-6R class* * -* x* -*
Information regarding use in patients with chronic infection. 9. As there is very limited information available about the safety of the product for women who are breastfeeding, this patient group should be added as missing information in the table of ongoing safety concerns as missing information. Novartis does not consider it necessary to add ‘women who are breastfeeding’ to the missing information in the table of ongoing safety concerns of the proposed RMP. This position is based on the appropriate wording provided in the current proposed Product Information as shown below. The RMP evaluator maintains the opinion that ‘women who are breastfeeding’ should be added as missing information in the table of ongoing safety concerns. 10. As there is very limited information available about the safety of the product for very elderly patients (aged >75 years), this patient group should be added as missing information in the table of ongoing safety concerns. Novartis does not consider it necessary to add ‘elderly patients (aged>75 years)’ as missing information in the table of ongoing safety concerns of the proposed RMP. The secukinumab clinical program included: Over 5,044 patients, including 4,498 patients who were treated with secukinumab in blinded and open-label clinical studies in various indications (plaque psoriasis and other autoimmune conditions) in 39 clinical studies. Psoriasis Program: 4,546 patients were studied to support the that secukinumab is safe and effective in adults with moderate to severe plaque psoriasis in 10 Phase II/III studies. This represents the largest registration program for a biologic for the treatment of psoriasis to date. Across the psoriasis trials, the majority of patients were < 65 years of age. Of the 3,430 plaque psoriasis patients exposed to secukinumab in clinical studies, a total of 230 were 65 years of age or older and 32 patients were 75 years of age or older. This is a significant number of elderly patients for a new psoriasis product. From an efficacy perspective, this product is effective in the elderly population, as stated in the sponsor’s summary of clinical efficacy. This is considered acceptable.
I. Introduction to product submission Submission details Type of Submission New Biological Entity Initial Decision: Rejected Final Decision: Date of Initial Decision: Date of Final Decision: Approved 17 February 2012 6 July 2012 Active ingredient(s): Belimumab Product Name(s): Benlysta Sponsor’s Name and Address: GlaxoSmithKline Australia Pty Ltd PO Box 168, Boronia VIC 3155 Dose form(s): Lyophilized powder for intravenous infusion in sterile single-use vials, light. Two configurations of the FDP are available to accommodate dosing Strength(s): 400 mg/vial 5mL deliverable configuration 120 mg/vial 1.5mL deliverable configuration Container(s): Glass flint tubing vial with rubber stopper Pack size(s): 1 vial Approved Therapeutic use: Benlysta is indicated as add-on therapy for reducing disease activity in adult patients with active, autoantibody-positive systemic lupus erythematosus with a high degree of disease activity (e.g. ANA titre ≥ 1:80 and/or titre ≥30 IU/mL) despite standard therapy. The safety and efficacy of Benlysta have not been evaluated in patients with severe active nephritis or severe active central nervous system lupus. of administration: Intravenous (IV). ARTG Numbers: 173078 and 173077 Product background This AusPAR describes the application by GlaxoSmithKline Australia Pty Ltd to register a powder for IV infusion containing belimumab, a new, fully human immunoglobulin (IgG1λ) monoclonal antibody. Belimumab was designed to specifically neutralise soluble B
Metabolism and Nutrition Disorders 8.2 2.6 Musculoskeletal and Connective Tissue Disorders Muscle spasms Pain in extremity 5.5 4.1 3.8 7.7 Nervous System Disorders Dizziness Headache 8.2 4.1 3.8 5.1 Respiratory, Thoracic and Mediastinal Disorders Cough 5.5 3.8 The most frequently occurring (≥ 2% of patients) undesirable effects possibly or probably related to sevelamer were mainly in the gastrointestinal disorders system organ class (Table 6). Most of these adverse reactions were mild to moderate in intensity. Table 6 Adverse Reactions in Studies GD3-163-201 (N=73), SVCARB00205 (N=31), and SVCARB00105 (N=49) in CIOMS format System Organ Class Common (≥ 1/100 to <1/10 ) Nausea Constipation Vomiting Gastrointestinal Disorders Abdominal pain upper Diarrhoea
General Disorders and Administration Site Conditions Fatigue 1.4 5.1 Infections and Infestations Urinary tract infection 8.2 1.3 Injury, Poisoning and Procedural Complications fistula site complication fistula site haemorrhage fistula thrombosis 6.8 5.5 4.1 1.3 2.6 11.5 Investigations Carbon dioxide decreased 5.5 5.1 Metabolism and Nutrition Disorders 8.2 2.6 Musculoskeletal and Connective Tissue Disorders Muscle spasms Pain in extremity 5.5 4.1 3.8 7.7
PRODUCT INFORMATION SEVELAMER CARBONATE WINTHROP AUSTRALIAN NAME Sevelamer carbonate CHEMICAL STRUCTURE The structure is presented in Figure 1. Figure 1 Structure of sevelamer carbonate The primary amine groups shown in the structure are derived directly from poly (allylamine hydrochloride). The cross - linking groups consist of two secondary amine groups derived from poly (allylamine hydrochloride) and one molecule of epichlorohydrin. Molecular Formula: (C3H7N.nH2CO3)810z (C9H18N2O.nH2CO3)95z where z = a large number Chemical Name: poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. CAS 845273-93-0 Sevelamer Carbonate Winthrop contains sevelamer, a non-absorbed phosphate binding polymer, free of metal and calcium. Sevelamer is a white to off-white powder comprising of a partial carbonate salt with approximately 40 % amine carbonate and 60 % free base. Sevelamer carbonate is amorphous, hygroscopic and hydrophilic, but insoluble in water with a pH range of 8-10.5 as a 1% aqueous slurry. Each Sevelamer Carbonate Winthrop film-coated tablet contains 800 mg of sevelamer carbonate on an anhydrous basis. Sevelamer Carbonate Winthrop tablets contain the following excipients:
Injury, Poisoning and Procedural Complications fistula site complication fistula site haemorrhage fistula thrombosis 6.8 5.5 4.1 1.3 2.6 11.5 Investigations Carbon dioxide decreased 5.5 5.1 Metabolism and Nutrition Disorders 8.2 2.6 Musculoskeletal and Connective Tissue Disorders Muscle spasms Pain in extremity 5.5 4.1 3.8 7.7 Nervous System Disorders Dizziness Headache 8.2 4.1 3.8 5.1 Respiratory, Thoracic and Mediastinal Disorders Cough 5.5 3.8
are not part of the planned pharmacovigilance activities in the RMP. The sponsor describes that a request was submitted to the EMA in August 2013 to request the French registry to be discontinued. It is recommended that the sponsor provides an update on the outcome of the assessment this request by the EMA. If the status of this registry has changed since submission of the dossier, then the RMP should be updated accordingly. The EMA assessment has been completed and agreement has been reached that the risk of peritonitis in peritoneal dialysis patients will be removed from the RMP. This will be reflected in the updated scheduled to be available in the first quarter of 2015. The sponsor will continue to monitor peritonitis in the PSUR. A revised ASA was provided reflecting the changes described above. This is considered acceptable. The sponsor should provide information in the Australian PI/CMI to address the missing information of ‘Data on use in hyperphosphataemic CKD patients on PD’ and ‘Data on use in hyperphosphataemic CKD patients not on dialysis with serum phosphorus ≥1.78 mmol/L’. Of note information to address the missing information is provided in the European Summary of Product Characteristics (SmPC). The risk minimisation plan in the ASA should be updated accordingly. As per response to Point 2, these risks are no longer considered missing information and the ASA has been updated accordingly. No further information relating to these patient groups has therefore been added to the Australian PI. Pending the Delegate’s approval this is considered acceptable. It is recommended that the potential risk of ‘Arteriovenous fistula (AVF) Complications’ be addressed by routine-risk minimisation in the Australian PI. The ASA should be updated accordingly. AVF site complications are a well-recognised comorbidity in haemodialysis patients secondary to the patient’s underlying disease and/or the complexity of the surgical procedure. A direct causal association with administration of sevelamer is not evident from the clinical safety data or from post marketing safety surveillance. Therefore information relating to AVF is not included in the Australian Renvela PI. Based on the latest PSUR, the sponsor has proposed to remove the potential risk of arteriovenous fistula (AVF) site complications in haemodialysis patients from the RMP, and this will be This is considered acceptable.
Second Evaluation: 29 April 2014 AusPAR Attachment 1 Extract from the Clinical Evaluation Report for Sevelamer hydrochloride Proprietary Product Name: Sevelamer GPPL, Sevelamer GxP, Sevelam, Sevlar, Apotex-sevelamer, Chemmart sevelamer, Genrx sevelamer, Terry White sevelamer Sponsor: Generic partners 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 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 <>. the Extract from the Clinical Evaluation Report
The Langmuir binding constants – affinity constant (k1) and capacity constant (k2) were the outcomes reported for the 2 shows the log-transformed data for the generic and reference products. The test/reference (T/R) ratio of the geometric least squares means of the affinity constant was 76.4 (%CV4.4) without acid pre-treatment. The capacity constant T/R ratio was 97.25% (90% CI 95.17 – 99.38) which was within the pre-specified 80 – 125% set down in the guidance document.
relevance for the RMP, and any specific information needed to address this issue in the RMP. For any safety considerations so raised, the sponsor should provide information that is relevant and necessary to address the issue in the RMP. gastrointestinal tract’ as an ongoing safety concern and give consideration to appropriate pharmacovigilance and risk minimisation activities. Such revision should be reflected in an amended ASA before this application is approved. 2. It is recommended that the following be added to the list of potential safety concerns: ‘Potential Off-label use’. The sponsor has replaced the important missing information: ‘Paediatric patients’ with ‘Potential off-label use, including paediatric patients’ to be monitored by routine pharmacovigilance activities with routine risk minimisation applied. This is acceptable. 3. The safety and efficacy of this product has not been established in patients below the age of 18 years and this is mentioned in the PI. However, there has been significant off-label use of sevelamer in paediatric patients in USA. The Delegate may wish to update the Australian PI to strengthen the wording (that is, ‘Sevelamer is not recommended in children below the age of 18 years’) in order to discourage the use of sevelamer in paediatric patients. The sponsor does not appear to make any direct response to this recommendation to the Delegate. This recommendation to the Delegate regarding revision to the PI is open for consideration. 4. The Delegate may wish to update the Australian PI to strengthen the wording in order to discourage the use of sevelamer in pre-dialysis patients. The sponsor does not appear to make any direct response to this recommendation to the Delegate. This recommendation to the Delegate regarding revision to the PI is still open for consideration.
IFN interferon IgM immunoglobulin IIV inter-individual variability IL interleukin INR international normalised ratio ITT intent to treat IWRS/IVRS Interactive Web Response System/Interactive Voice Response System Ka absorption rate constant LDL low density lipoprotein LH luteinizing hormone LLOQ lower limit of quantification LOCF last observation carried forward LR likelihood ratio LS least squares MedDRA medical dictionary for regulatory activities METAVIR a scoring system for liver biopsies that assigns two standardised numbers: one to represent the degree of inflammation and the other the degree of fibrosis. MRI Magnetic Resonance Imaging MS metavir score MTD maximum tolerated dose Na sodium NK natural killer no observed adverse effect NtRTI nucleotide reverse transcriptase inhibitor PBMC peripheral blood mononuclear cell trial
Primary Pharmacology Effect on activity C201 Dose-dependency of effect using 4 dosing regimens Effect on sustained virological response C205 Sustained virologic response at Week 72 in HCV infected subjects C206 Proportion of treatment-experienced, HCV-infected subjects achieving SVR24 Secondary Pharmacology Effect on QTc C117 Thorough QT study Effect on photosensitivity C125 Cutaneous photosensitizing potential of multiple doses PD Interactions Norethindrone and ethinylestradiol C124 Effect of simeprevir on hormone levels after co-administration of norethindrone and ethinylestradiol Atorvastatin and simvastatin HPC1006 HMG-CoA reductase inhibitory activity in the presence and absence of simeprevir Methadone C110 PD effects of concurrent use of simeprevir and methadone TMC647055 HPC1001 Anti-viral activity following the of TMC647055 and simeprevir Population PD and PK-PD analyses Target population PPD Multivariate analysis of prognostic factors * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. ‡ And adolescents if applicable. None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Summary of pharmacodynamics The information in the following summary is derived from conventional pharmacodynamic studies in humans unless otherwise stated. Mechanism of action Simeprevir is an inhibitor of the HCV NS3/4A protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively.
HPC1006 Atorvastatin and simvastatin C112 Escitalopram C110 Methadone C120 Cyclosporine and tacrolimus HPC1001 TMC647055 C123 Efavirenz and raltegravir C105 Rifampin C108 Digoxin and rosuvastatin GS-5885 Population PK analyses Simeprevir Global PPK Study Population PK meta-analysis C205-C206 PPK Bayesian estimation C208 PPK Bayesian estimation C216 PPK Bayesian estimation HPC3007 PPK Bayesian estimation C212 PPK Bayesian estimation HPC3011 PPK Bayesian estimation C201-C205 PPK Effect of bilirubin C215 PPK Effect of bilirubin * Indicates the primary aim of the study. † Bioequivalence of different formulations. § Subjects who would be eligible to receive the drug if approved for the proposed indication. Evaluator’s summary and conclusions on pharmacokinetics Pharmacokinetics in healthy subjects Following single, PO, 200 mg doses of either the Phase IIa (F007) or IIb (F020) capsule formulations in healthy subjects the median Tmax of simeprevir was 6.0 h and the mean t½ values were 10.5 h to 10.94 h, respectively. The absolute bioavailability of simeprevir is not known at this time.
individual. Therefore, the sponsor does not consider it warranted to add acute hypersensitivity reactions as an Important Potential Risk in the simeprevir RMP. The Sponsor should add the following important missing information: Off-label use, including use in the absence of pegIFN and/or RBV, or with interferon drugs other than PegIFNα. Use in HCV genotypes Patient’s with previous triple therapy simeprevir/PegIFN/ RBV treatment failure Long term therapy Exposure in patients with psychiatric disorders Use in patients of Aboriginal and Torres Strait Islander descent Use in patients with HIV co-infection Details of sponsor’s full response and justification are not included here. The OPR evaluator acknowledges the sponsor’s response regarding the inclusion of these areas of missing information. However, the recommendation remains to include the following two areas of important missing information: Use in HCV genotypes Use in patients of Aboriginal and Torres Strait Islander descent The following important identified risks are known to be associated with pegIFN and RBV treatment (as agreed by the sponsor in the RMP): Psychiatric disorders Diabetes mellitus Thyroid disorders Specific skin disorders (cutaneous leukocytoclastic vasculitis, lichen planus, polyarteritis nodosa, porphyria cutanea As mentioned above, identified risks of PegIFN and/or RBV which are not attributable to simeprevir, are not listed as important identified risk or important potential risk in the simeprevir RMP. The safety of simeprevir cannot be separated from that of pegIFN and RBV as these products are dosed together as part of triple therapy. This of including important risks related to pegIFN and RBV treatment is deferred to the Delegate for consideration.
full-length rFVIII BHK 0.38 0.09 OS Simoctocog alfa 0.37 0.11 0.97 0.859, 1.088 full-length rFVIII BHK 0.38 0.11
Start Phase I * All 26 a 1.834 0.409 1.845 Aged 2-5 13 1.871 0.270 1.822 Aged 6-12 13 a 1.796 0.521 1.916 Start Phase II * All 30 b 1.568 0.509 1.586 Aged 2-5 14 b 1.446 0.457 1.563 Aged 6-12 16 1.676 0.542 1.602 3 Months All 55 d 1.698 0.402 1.682 Aged 2-5 28 1.549 0.330 1.604 Aged 6-12 27 c 1.852 0.418 1.805 6 months All 53 e 1.765 0.464 1.760 Aged 2-5 26 c 1.672 0.396 1.709 Aged 6-12 27 c 1.854 0.512 1.826 Note: a = data not available for 1 patient; b = data not available for 2 patients; c = data not available for 3 patients; d = data not available for 4 patients; e = data not available for 6 patients; data were not available for 2 patients (6–12 years) at 3 and 6 months due to premature withdrawal from the study; other missing IVR values were not evaluable. * = Phase I includes all patients who underwent PK analysis in Cycles 1 and 2; Phase II specifies recovery at start of open treatment phase and therefore includes only patients who did not undergo PK analysis. Comment: In patients aged 2-12 years (ITT population), based on the CHR assay mean IVR values over time were above 1.5% per IU/kg, and ranged from 1.568% to 1.834% per IU/kg. The mean IVR values over time (ITT population) ranged from 1.446% to
A new AusPAR will be developed to reflect changes to indications and/or variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2012 This work is copyright. You may reproduce the or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>.
The following tables describe the safety results reported in study 02CLLIII of 161 previously-untreated patients with Binet Stage B or C CLL requiring treatment. Table 6: Adverse events occurring in at least 5% of patients in either treatment group by system organ class and preferred term – safety population System Class Preferred Term BEN (N = 161) CLB (N=151) Total (N=312) Blood & lymphatic system disorders Neutropaenia Thrombocytopaenia Anaemia Leukopaenia Lymphopaenia 44 (27.3%) 40 (24.8%) 35 (21.7%) 28 (17.4%) 10 (6.2%) 21 (13.9%) 31 (20.5%) 21 (13.9%) 5 (3.3%) 1 (0.7%) 65 (20.8%) 71 (22.8%) 56 (17.9%) 33 (10.6%) 11 (3.5%) Gastrointestinal disorders Nausea Vomiting Diarrhoea 31 (19.3%) 25 (15.5%) 16 (9.9%) 21 (13.9%) 10 (6.6%) 6 (4.0%) 52 (16.7%) 35 (11.2%) 22 (7.1%) General disorders & administration site conditions Pyrexia Asthenia Fatigue Chills 40 (24.8%) 14 (8.7%) 14 (8.7%) 9 (5.6%) 8 (5.3%) 7 (4.6%) 7 (4.6%) 2 (1.3%) 48 (15.4%) 21 (6.7%) 21 (6.7%) 11 (3.5%) Immune system disorders Hypersensitivity 8 (5.0%) 3 (2.0%) 11 (3.5%) Infections & infestations Nasopharyngitis Infection 11 (6.8%) 10 (6.2%) 11 (7.3%) 2 (1.3%) 22 (7.1%) 12 (3.8%)
Number of adverse events possible, probable or definite to the study medication (including missing relationship) was higher in the bendamustine arm than in the chlorambucil arm. Especially blood and lymphatic system disorders, gastrointestinal disorders and pyrexia occurred more frequently under bendamustine than under chlorambucil. 8: Drug related adverse events by CTC category in at least 5% of patients in either treatment group by system organ class and preferred term – safety population System Organ Class Preferred Term BEN (N=161) CLB (N=151) (N=312) Blood & lymphatic system disorders Neutropaenia Thrombocytopaenia Anaemia Leukopaenia Lymphopaenia 43 (26.7%) 37 (23.0%) 28 (17.4%) 28 (17.4%) 10 (6.2%) 21 (13.9%) 27 (17.9%) 15 (9.9%) 5 (3.3%) 1 (0.7%) 64 (20.5%) 64 (20.5%) 43 (13.8%) 33 (10.6%) 11 (3.5%) Gastrointestinal disorders Nausea Vomiting Diarrhoea 31 (19.3%) 24 (14.9%) 13 (8.1%) 21 (13.9%) 9 (6.0%) 4 (2.6%) 52 (16.7%) 33 (10.6%) 17 (5.4%) General disorders & administration site conditions Pyrexia Asthenia Fatigue Chills 34 (21.1%) 12 (7.5%) 10 (6.2%) 8 (5.0%) 3 (2.0%) 7 (4.6%) 4 (2.6%) 2 (1.3%) 37 (11.9%) 19 (6.1%) 14 (4.5%) 10 (3.2%) Infections & infestations Infection 8 (5.0%) 1 (0.7%) 9 (2.9%) Metabolism & nutrition disorders Hyperuricaemia 9 (5.6%) 1 (0.7%) 9 (2.9%)
mmol/L millimoles per litre NOAEL No observable adverse effect PDE Permitted Daily Exposure PXRD Powder X-ray diffraction QD once daily QTc corrected QT interval on ECG RAAS renin-angiotensin aldosterone system SAE serious adverse event SK serum potassium SPS sodium polystyrene sulfonate TEAE treatment-emergent adverse TDS three times daily ZS sodium zirconium cyclosilicate I. Introduction to product submission Submission details Type of submission: New chemical entity Decision: Withdrawn Date of decision: 13 2017 Date of entry onto ARTG NA Active ingredient: Sodium zirconium cyclosilicate hydrate Product name: Lokelma Sponsor’s name and address: AstraZeneca Pty Ltd PO Box 131 North Ryde NSW 1670 Dose form: Powder, oral Strengths: 5 g and 10 g
Blood and Lymphatic System Disorders lymphopenia leucopoenia neutropenia anaemia thrombocytopenia Immune system Disorders anaphylactic reaction hypersensitivity reactions (including skin reactions and urticaria) Endocrine Disorders hypothyroidism hyperthyroidism Metabolism and Nutrition Disorders anorexia hypophosphataemia hypocalcaemia hypokalemia hyponatraemia dehydration Psychiatric Disorders depression Nervous System Disorders peripheral sensory neuropathy dysgeusia reversible posterior leukoencephalopathy* Ear and Labyrinth Disorders tinnitus Cardiac Disorders congestive heart failure* myocardial ischaemia and/or infarction* QT prolongation Vascular Disorders haemorrhage (inc. gastrointestinal*, respiratory tract* and cerebral haemorrhage*) hypertension flushing hypertensive crisis* Respiratory, Thoracic and Mediastinal Disorders rhinorrhoea dysphonia interstitial lung disease-like events* (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation)
Gastrointestinal Disorders diarrhoea nausea vomiting constipation stomatitis (including dry mouth and glossodynia) dyspepsia dysphagia gastrooesophageal reflux disease pancreatitis gastritis gastrointestinal perforations* Hepato-biliary Disorders increase in bilirubin and jaundice, cholecystitis, cholangitis drug induced hepatitis* Skin and Subcutaneous Tissue Disorders dry skin rash alopecia hand foot skin reaction** erythema pruritus keratoacanthoma/ squamous cell cancer of skin dermatitis exfoliative acne skin desquamation hyperkeratosis eczema erythema multiforme Musculoskeletal, Connective Tissue and Bone Disorders arthralgia myalgia muscle spasms Renal and Genitourinary Disorders renal failure proteinuria nephrotic syndrome Reproductive System and Breast Disorders erectile dysfunction gynaecomastia General Disorders and Administration Site Conditions fatigue pain (including mouth, abdominal, bone, tumour pain and headache) asthenia influenza like illness mucosal inflammation Investigations weight decreased increased amylase increased lipase transient increase in transaminases transient increase in blood alkaline phosphatase INR abnormal, prothrombin level abnormal * The adverse reactions may have a life-threatening or outcome. ** palmar plantar erythrodysaesthesia syndrome in MedDRA
regimen; no./time TT087190 Rat (SD); 6 over 0.5–24 h; = 3 ♀ Embryofetal development 30 30.9 2.2 150 279 19.5 1000 853 59.7 TT107100 Rat (SD); 6 over 0.5–24 h; n = 6 ♀ Embryofetal development Suvorexant 30 76.8 5.4 80 230 16.1 325 794 55.5 Embryofetal development M9 30 6.16 0.6 80 11.3 1.2 325 24.0 2.5 TT087200 Rabbit (DB); 6 over 0.5–24 h; n = 3 ♀ Embryofetal development 40 29.9 2.1 100 95.7 6.7 300 255 17.8 TT107090 Rabbit (DB); 6 over 0.5–24 h; n = 6 ♀ Embryofetal development Suvorexant 50 46.6 3.3 150 361 25.2 325 647 45.2 Embryofetal development M9 50 57.6 6.0 150 234 24 325 314 33 TT117220 Rat (SD); 6 over 0.5–24 h; n = 6 ♀ Pre/postnatal development Suvorexant 200 447 31.3 Pre/postnatal development M9 200 20.6 2.2 Human (healthy volunteers) Steady state 40 mg 14.3# M9: 9.55& ^ = animal: human plasma AUC0–24 h for suvorexant and M9 # = Module 2.7.2, Summary of Clinical Pharmacology Studies, Tables 38-40 & = Reference P003, Day 14 data
1241/030 39 weeks IV – 1 1.44 0.319 54 44 – – 10 12.6 3.10 474 431 – 1241/012 Monkey 4 weeks topical ocular (single eye; twice daily) 0.3 0.067–0.1 – – 6# 4# 0.7 3 0.67–1 – – 56# 43# 7 30 6.7–10 7.51 1.53 565 425 67 1241/020 13 weeks 0.3 0.075–0.1 – – 6# 4# 0.7 3 0.75–1 0.74 – 56 39# 7 30 7.5–10 5.81 1.39 437 386 67 1241/034 52 weeks 0.3 0.075–0.1 – – 4# 3.4# 0.7 3 0.75–1 0.54 – 41 34# 7 30 7.5–10 4.38 1.23 329 342 67 Human [MRHD, 900 ng] topical ocular 0.45 0.018 0.0266 0.0072 – – – * = of tafluprost acid (active metabolite); a = calculated as animal:human Cmax multiplied by dosing frequency; b = calculated as animal:human AUC0–t multiplied by dosing frequency; c = calculated as animal:human ocular dose/day; – = not detected/not calculated/not applicable; # = estimate based on linear extrapolation; once daily administration for SC and IV routes; Note that exposure ratios in the monkey studies refer to a 24 h period, ratios after each dose are half the given value; MRHD = maximum recommended human dose (based on once daily bilateral use with 30 μL drop volume); Human body weight of 50 kg assumed. Table 2. Relative exposure in reproductive toxicity studies Study Species Type Route Dose (μg/kg/day) Cmax* (ng/mL) AUC0–t* (ng∙h/mL) Relative exposurea Cmax AUC 1241/32 Rat (SD) fertility IV 10 26.8¶ 1.70¶ 1008 236 30 108.8¶ 6.30¶ 4090 875 100 379.4¶ 26.4¶ 14263 3667
1241/29 embryofetal development IV 3 9.13 – 343 227# 10 62.4 5.45 2346 757 30 136.9 5.59 5147 776 MP04098 pre-/postnatal development IV 0.3 – – 34# 23# 1 – – 114# 76# 3 9.13† – 343 227# 10 62.4† 5.45† 2346 757 1241/28 Rabbit (NZW) embryofetal development IV 0.03 – – 3# – 0.1 0.26 – 10 – 0.3 1.18 – 44 – 1241/35 IV 0.001 <0.02 – <0.75 – 0.003 0.01 77551 [MRHD, 900 ng] topical ocular 0.018 0.0266 0.0072 – – * = of tafluprost acid (active metabolite); – = not detected/not calculated/not applicable; a = calculated as animal:human Cmax or AUC0–t; ¶ = based on data in the 4-week IV rat study (1241/018); † = based on data from the embryofetal development study (1241/29); # = estimate based on linear extrapolation; Reported pharmacokinetic parameters are for GD17 (rat) or GD19 (rabbit); MRHD = maximum recommended human dose (based on once daily bilateral use; 30 μL drop). Acute toxicity In single-dose toxicity studies, neither oral (PO) administration of tafluprost at dose levels up to 100 mg/kg nor IV administration at up to 3 mg/kg produced significant signs of toxicity in rats. In dogs, single IV administration at ≥3 μg/kg produced salivation, vomiting, moderate miosis, irregular respiration and increased heart rate. At 30 µg/kg, the miosis was severe and blood pressure was also increased. No adverse effects were noted at 0.3 µg/kg IV, associated with a Cmax for tafluprost acid estimated to be ~24 times the level in humans at the maximum recommended clinical dose.
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Product Information Viread (tenofovir disoproxil fumarate) 300 mg Tablets NAME OF THE MEDICINE VIREAD 300 mg tablets The active substance in VIREAD is tenofovir disoproxil fumarate Tenofovir disoproxil fumarate is a salt of a prodrug of tenofovir. Tenofovir disoproxil fumarate is designated chemically as fumarate (1:1). Chemical structure: Molecular formula: C23H34O14N5P Molecular mass: 635.52 CAS number: 202138-50-9 DESCRIPTION Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25°C. The partition coefficient (log P) for tenofovir disoproxil is 1.25 and the pKa is 3.75. The active pharmaceutical product is a single enantiomer that does not undergo racemisation either in vitro or in vivo. VIREAD tablets contain the following ingredients as excipients: Core: microcrystalline cellulose (E460), pregelatinised maize starch, croscarmellose sodium, lactose and magnesium stearate (E572). Coating: Opadry II Y-30-10671-A-(ARTG3968). Each VIREAD tablet is light blue and almond-shaped. Each tablet is debossed on one side with the markings “” and “4331” and on the other side with the marking “300”. The tablets are supplied in bottles with screw cap closures. PHARMACOLOGY Pharmacokinetics
sample of HIV-1 infected paediatric patients PBPK simulations of the effect of potent CYP3A4 inhibitors on COBI exposure GS-US-183-1004 - A Phase I, Multiple Dose Study to Evaluate the Pharmacokinetics of Cobicistat-Boosted Elvitegravir in Subjects with Decreased UGT1A1 Activity The sponsor should provide at least an electronic copy of the draft protocols for these studies to the TGA for review if they have not already been initiated. If they are not yet available the sponsor should provide an assurance that draft protocols for these studies will be provided to the TGA when they become available. sponsor should provide an assurance that draft protocols for these studies will be provided to the TGA when they become available. 5. The ‘Potential for Medication Errors’ section of the AU-RMP previously accepted for Stribild has been removed from the updated AU-RMP. The sponsor’s handling of this matter using routine pharmacovigilance, routine risk minimisation and additional risk minimisation activities was previously considered satisfactory. Consequently the sponsor should reinstate such a section in a revised AU-RMP, which relates to the important identified risk: ‘Renal toxicity’, including updating this section with post marketing data. The sponsor states: “Gilead has reinstated the ‘Potential for Medication Errors’ section of the AU-RMP within Section 6, Additional Requirements for the Safety Specification”. This is acceptable. 6. The sponsor’s correspondence, dated 16 January 2013, states: (information relating to additional risk minimisation activities for the important identified risk: ‘Renal The sponsor states: “Gilead has updated Table 1-1.Risk Minimisation Measures for Important Identified Risks within Part V of This is acceptable, although it is noted that Annex 9. ‘Details of additional risk minimisation measures’ has been added rather than Table 1-2. ‘Risk Minimisation Measures for
1 : 2 5% ≥2 prior 10 (A) NR 50 22 / 14 (38%) NR 50 % 5% ≥2 prior 11 (A) Median 70 53 28 : 16 (36%) 11 : 5 Median of 2 treatments 12 (A) NR 42 11 : 10 (48%) NR Median of 3 prior treatments 276 / 108 (28%) *: Publication or Abstract AA: Anaplastic Astrocytoma, AO: Anaplastic Oligoastrocytoma Pooled response rates were reported for all the groups except for group 10, which only reported PFS and OS. More than 5% of patients in the pooled analysis obtained a CR compared with < 1% in the 349 historic controls (Wong et al) (Table 14). Table 14 Summary of response efficacy data for Patient Groups 5-12 Patient Group (A or P) Number Response Rates (combined Grade III and IV n (all) Grade III n (%) CR PR SD PD ORR CR+PR (Grade III) 5 (P) 61 24 (40%) AA = 15 AO = 9 7/53 PR 32/55 SD 11/55 PD 3/55 NR 6 (P) 55 22 (40%) AG = 21 Other = 1 1/55 PR 25/55 SD 25/55 PD 3/55 NR 7 (P) 27 15 (55%) Gd III = 9 0/27 PR 12/27 SD 11/27 NR trial
Probability of disability progression at Week 108 20.2% 27.3% HRc (95% CI): 0.70 (0.51, 0.97) 0.0279b MRI Endpoint Burden of disease (mL) Mean (SD) change from baseline at Week 108 Mean (SD) [LSM (SE)] change in absolute of cubic root transformed BOD from baseline at Week 108 0.723 (7.59) 0.045 (0.30) [0.043 (0.02)] 2.208 (7.00) 0.111 (0.31) [0.132 (0.02)] LSM mean difference (SE) from placebo: -0.089 (0.025) 0.0003b Number of T1 lesion per MRI scan at Week 108 0.261 1.331 RRa (95% CI): 0.196 (0.120, 0.321) <0.0001b
Risk minimisation activities The sponsor proposes routine and additional risk minimisation activities (development and distribution of educational materials to Consumers and Healthcare Professionals prepared in accordance with Medicines Australia Code of Conduct Guidelines) for all the ongoing safety concerns. The sponsor’s evaluation of the need for risk minimisation activities was considered to be satisfactory. Reconciliation of issues outlined in the RMP report Table 8 summarises the OPR’s first round evaluation of the RMP, the sponsor’s responses to issues raised by the OPR and the OPR’s evaluation of the sponsor’s responses. Table 8. Reconciliation of issues outlined in the RMP report Recommendation in RMP evaluation report Sponsor’s response OPR evaluator’s comment ‘Drug abuse in weight loss’ has been listed as an identified safety risk in the pharmacovigilance and risk minimisation plan in the proposed RMP. The sponsor should include this risk in the ‘Summary of Safety Concerns’. RMP has been updated regarding ‘Drug abuse in weight loss’. Based on estimated patient exposure of approximately 224 million patient-years for the 100 microgram daily dose and 148 million patient-years for the 150 microgram daily dose for the post-authorisation period, and the potential for drug abuse with levothyroxine is considered to be low. Hence all reference to drug abuse in weight loss has been removed from the RMP. The sponsor’s response was considered to be acceptable. The sponsor proposes a specific adverse reaction form for the identified risks ‘in order to gather more accurate information on patient status, change of dosage, change of brand, latest hormonal levels, new concomitant drugs’, the sponsor should provide a sample of such form to the TGA for evaluation. The following 2 ICSR Follow-Up Questionnaires had been agreed and were submitted to the TGA. Cardiac Adverse Events Potential Hypo- or – Thyroidism or Treatment Imbalance. The sponsor’s response was considered to be acceptable. The evaluator agrees that the introduction of more strengths will help minimise the potential for some medication errors as the sponsor has stated. However, eleven different The risk of medication errors can be reduced by packaging with the judicious use of different colours to distinguish different strengths on the carton pack and inclusion of unique embossing on each and every strength of the tablet. The sponsor’s response was considered to be acceptable.
The prepared infusion solution of ACTEMRA is physically and chemically stable in 0.9% w/v sodium chloride solution at 30ºC for 24 To reduce microbiological hazard, the prepared infusion should be used immediately. If storage is necessary, hold at 2ºC – 8ºC for not more than 24 hours. Do not use after the expiry date (EXP) shown on the pack. Disposal of Medicines The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal. POISON SCHEDULE Prescription Only Medicine (S4) SPONSOR Roche Products Pty Limited ABN 70 000 132 865 Dee Why NSW 2099 Customer enquiries: 1800 233 950 Distributed in by: Roche Products () Limited Penrose 1642 Customer enquiries: 0800 656 464 DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG) 21 May 2009 DATE OF MOST RECENT AMENDMENT 4 October 2013
skeletal growth, immune function and sexual maturation Immunogenicity Observed with TCZ; clinical relevance needs further evaluation Malignancies Based on increased risk in RA and with other biological DMARDs; no imbalance noted for TCZ CYP450 enzyme normalisation Hypothetical risk – of greater relevance to agents with a narrow therapeutic index which are subject to regular monitoring or effect or concentration, & dosage adjustment, as standard clinical practice. Risk applies at initiation and withdrawal of TCZ treatment Important missing information Elderly No clinical evidence of increased risk; no difference in PK Paediatric patients Paediatric program ongoing (PIP approved) Effects during pregnancy Use in pregnancy not recommended Hepatic impairment Caution to be exercised in this subgroup; TCZ not subject to hepatic metabolism Renal impairment No dose adjustment required; TCZ not subject to renal elimination. No effect of mild renal impairment noted with TCZ. No formal study in patients with mild to moderate renal impairment. Combination of biologics Study ongoing: rituximab + TCZ Vaccinations Efficacy of proteinaceous and polysaccharide vaccines to be studied in comcomitant use with TCZ. Increased mortality in the Japanese PMS compared to clinical study population Observation likely to reflect population being exposed. Patients are elderly with significant concurrent medical disease and multiple concomitant medications.
while others will generate data that will provoke applications to amend the Australian registration details. To this end it is suggested that the sponsor should provide an attachment to the ASA setting out all the forthcoming studies and the anticipated dates for their submission in Australia. Planned Studies in the Post-Authorisation Pharmacovigilance Development Plan. This section does not include anticipated dates for their submission in Australia, but rather refers to the table for estimated timelines for data availability. The sponsor states that following availability of data from these studies, the results will be assessed and if deemed necessary, the company Core Data Sheet (CDS) will be updated. Any relevant safety updates to the company CDS, will result in applications to amend the PI. 2013 and Q4 2013 respectively. Consequently it is reiterated that the anticipated dates for the submission in Australia of studies referenced in the pharmacovigilance plan should be included in this section of a revised ASA before this application is approved. The ‘RMP submission history table’ of the ASA should state that the guided questionnaires erroneously associated with the important missing information: ‘Effects during pregnancy’ and ‘Hepatic Impairment’ have now been removed in the ASA Version: 3.0. In the revised ASA provided, the ‘Change history of RMPs submitted to TGA’ tables notes that Guided Questionnaires erroneously associated with the Important Missing information ‘Effects during pregnancy’ and ‘Hepatic Impairment’ in ASA v1.0 have been removed from the ASA. This is acceptable. The sponsor should provide an update on the status of the unnamed paediatric patient registry and provide an assurance that if it is still not yet initiated at least a draft protocol will be submitted to the TGA for review once it becomes available. A draft protocol for the pJIA paediatric patient registry is now available and has been provided in Annex 5 of the updated ASA. The protocol has been submitted to EMA and FDA for review and therefore is considered a draft. This is acceptable. RMP
EU (Centralised procedure). Rapporteur: Germany; Co-rapporteur: Hungary. Submitted: 17 November 2016 Positive CHMP opinion: 20 July 2017 EU registration: 18 September 2017 ‘RoActemra is indicated for the treatment of Giant Cell Arteritis (GCA) in adult patients.’ USA Submitted: 22 November 2016 Approved: 22 May 2017 Breakthrough Therapy Designation was granted by FDA for Actemra for giant cell arteritis. The application was evaluated under Priority Review. ‘Adult patients with giant cell arteritis.’ Canada Submitted: 30 2017 Approved: 27 October 2017 Actemra is indicated for the treatment of giant cell arteritis (GCA) in adult patients. New Zealand Submitted: 9 December 2016 Approved: 1 June 2017 ‘Actemra is indicated for the treatment of giant cell arteritis (GCA) in adult patients.’ Switzerland Submitted: 6 January 2017 Under evaluation Product Information The Product Information (PI) approved with the submission which is described in this AusPAR can be found as Attachment 1. For the most recent PI, please refer to the TGA website at <>. II. Registration timeline Table 2: Registration timeline for Submission PM-2016-03548-1-4 Description Date Submission dossier accepted and 1st round evaluation commenced 3 January 2017 First round evaluation completed 29 May 2017 Sponsor provides responses on questions raised in round evaluation 3 July 2017 Second round evaluation completed 9 August 2017 Request for Advisory Committee advice and/or Delegate’s Overview 4 September 2017