zilongwang/ReadingBank huggingface dataset:
84) Weighted mean percent sputum eosinophil levels (Day 0 to 84 or last day with available eosinophil data prior to Day 84) w/v (%) Weight/Volume (Percentage) I. Introduction to product submission Submission details Type of submission: New biological entity Decision: Approved Date of decision: 25 January 2016 Date of entry onto ARTG 02 February 2016 Active ingredient(s): Mepolizumab (rch) Product name(s): Nucala Sponsor’s name and address: GlaxoSmithKline Australia Pty Ltd (GSK) PO Box 18095 Melbourne VIC 8003, Australia Dose form(s): Powder for injection Strength(s): 100 mg Container(s): Vial Pack size(s): One single-use vial per pack (WFI not included) Approved therapeutic use: Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in patients aged 12 years and over see Clinical Trials) of administration: Subcutaneous (SC) injection Dosage: 100 mg every 4 weeks ARTG number: 232028 Product background This AusPAR describes the application by the sponsor to register a new biological entity, mepolizumab (Nucala) for the following proposed indication: Nucala is indicated as an add-on treatment for severe eosinophilic asthma in patients aged 12 years and over identified by either a blood eosinophil count ≥ 150 cells/L at
19: Effects of single dose aprepitant on AUC of CYP3A4 substrates Fold increase in AUC Substrate Day 1 Day 2 Day 3 Day 4 Day 8 Aprepitant single dose (Day 1) Study Dexamethasone 8 mg Days 1, 2, 3 1.96 2.29 1.61 - - 250 mg fasted P155 Dexamethasone 12 mg Day 1, 8 mg Days 2, 3, 4 2.09 2.33 1.42 1.06 - 200 mg fed* P175 Midazolam 2 mg Day 1 1.63 - - - 0.69 250 mg fasted P155 Midazolam 2 mg Days 1, 4, 8 3.15 - - 1.24 0.65 200 mg fed* P175 * standard light breakfast
The adverse events reported with mifepristone and a prostaglandin analogue such as GyMiso®, classified according to frequency and system organ class, are summarised as shown in Table 1. Table 1: Adverse Events for the Combined Use of Mifepristone and Misoprostol MedDRA Adverse events (frequency) System Organ Class Very common > 1/10 Common > 1/100 to < 1/10 Uncommon > 1/1000 to < 1/100 Rare > 1/10000 to < 1/1000 and very rare (< 1/10000)* Infections and infestations Infection shock syndrome Neoplasms benign, malignant and unspecified Elevated alpha-foeto protein Elevated carcinoembryonic antigen Blood and lymphatic system disorders Thrombotic thrombocytopenic purpura Thrombocytopenia Induced systemic lupus erythematosus Psychiatric disorders Mania Nervous system disorders Headache Epilepsy Neurogenic tinnitus Eye disorders Ophthalmoplegia Cardiac disorders Myocardial infarction Induced syndrome Vascular disorders Hot flush Hypotension (0.25%) Superficial thrombophlebitis Respiratory, thoracic and mediastinal disorders Bronchospasm Induced bronchial asthma
Gastrointestinal disorders Nausea Vomiting Diarrhoea Gastric discomfort Abdominal pain Cramping, light or moderate Gastric bleeding Hepatobiliary disorders Abnormal liver function tests Hepatic failure Hepatorenal failure Skin and subcutaneous tissue disorders Skin rash / pruritus Urticarial reaction epidermal necrolysis Erythema nodosum Angioedema* Musculoskeletal and connective tissue disorders Limb spasm Renal and urinary disorders Renal failure Pregnancy, puerperium and perinatal conditions Very common uterine contractions or cramping (10 to 45%) in the following prostaglandin intake. Heavy bleeding occurs in about 5% of the cases and may require haemostatic curettage in up to 1.4% of the cases. Hydatiform mole Ectopic pregnancy Amniotic band syndrome Gestational trophoblastic tumor Uteroplacental apoplexy Reproductive system and breast disorders Vaginal bleeding Uterine Prolonged bleeding Spotting Severe haemorrhage Endometritis Breast tenderness bleeding Haemorrhagic shock Salpingitis Bilateral adnexal mass Intrauterine adhesion Ovarian cyst rupture Breast abscess Haematosalpynx Uterine rupture
Copyright © Commonwealth of Australia 2012 This work is copyright. You may reproduce the whole 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 sponsor should provide an assurance that the Targeted Data questionnaires for all the specified important potential risks will be submitted to the TGA when they become available. Consequently these should be included in the RMP and/or the ASA when these documents are next updated. The sponsor has now provided copies of the Targeted Data questionnaires for the important identified risks: ‘Increased heart rate and tachycardia’ & ‘Hypersensitivity reactions’; the important potential risks: ‘QT prolongation’, ‘Increased blood pressure’ & ‘Embryo-fetal toxicity’; and the important missing information: ‘Decreased lymphocytes’ according to the update of the EU-RMP. This is acceptable. The sponsor should provide compelling justification as to why the long-term observational studies required by the US FDA as post-marketing commitments have not been included in the PP. Alternatively, if the sponsor decides to include these studies within the PP, the relevant sections of the RMP and/or the ASA will need to be updated accordingly and at least draft protocols for these studies should be submitted to the TGA for review. The sponsor has now added a planned safety study (PASS) to address cardiovascular safety, especially in elderly patients, in the PP of the updated AU-RMP and EU-RMP. This is acceptable, although it is suggested Sections of the EU-RMP be reworked to provide the required information in relation to the planned PASS, particularly in regard to reporting milestones, when this document is next updated. The ASA refers to routine pharmacovigilance activities rather than routine risk minimisation activities. Nevertheless the sponsor’s conclusion that no additional risk minimisation activities are needed is consistent with assessment of the US FDA and it is agreed the specified ongoing safety concerns would not appear to warrant additional risk minimisation activities. The sponsor has now changed the wording in Section 3 of the ASA. This is acceptable.
The sponsor’s proposed application of routine risk minimisation activities would appear to be reasonable and therefore acceptable. The sponsor this comment. N/A In regard to the proposed routine risk minimisation activities, the draft PI document is considered satisfactory. The sponsor notes this comment. N/A In regard to the proposed routine risk minimisation activities, the draft Consumer Medicine Information (CMI) document is considered satisfactory. The sponsor this comment. N/A
Evaluator conclusion The study included a small number of patients with short duration of treatment. There was no evidence of significant difference in efficacy in the defined terms which is not to say that significant difference has been ruled out. Statistical approach was neither superiority nor non-inferiority in design begging the question, was the approach decided post-hoc. The inclusion of the word superiority in the title is considered misleading. Li et al. 2011 – MMF vs. tacrolimus vs. IVC - Jadad score 1 Methods Country: Setting: Not specified design: Randomised controlled trial Blinding: No ITT: Yes Participants 60 patients aged between 16 – 64 years in three groups of 20 participants 87% female. Classes III, IV, V or combination and chronic index ≤ 3 with urinary protein excretion ≥1.0 g/24 h and/or a recent deterioration in renal function. Interventions MMF: 1.5g – 2g/day Tacrolimus: 0.08 – 01 mg/kg/day IVC: 0.5 – 0.75 g/m2/ month Prednisolone 0.8 – 1 mg/kg/day to max 60 mg reducing to minimum 10 mg/day over 4 months Outcomes Assessed at 24 Primary outcome: Complete remission or partial remission Complete remission: Urinary protein excretion < 0.3 g/24 h, with normal urine sediment, serum albumin concentration of > 35 g/L and stabilization (15%) or improvement in serum creatinine at 24 weeks. Partial remission: Urinary protein excretion between 0.3 and 2.9 g/24h, having decreased by ≥50% from baseline values, with serum albumin concentration ≥30 g/L and stabilization (30%) in serum creatinine. Notes Imbalance of baseline demographics noted with MMF group including patients with lower median age, lower median serum creatinine, higher creatinine clearance and higher serum albumen. Random sequence generation (selection bias) No details
Interventions Treatment sequences (A-B or B-A). Treatment A: EC-MPS 720 mg 12 hour for 21 days. Treatment B MMF 1000 mg 12 hourly for 21 days. Drugs were administered one hour before meals. Cyclosporine and prednisone doses were kept constant over the course of the study and were taken concomitantly with the study medication, whereas other co medications were ingested four hours apart. Drug administration prior to PK testing drugs was after a 12 hour fast. Outcomes MPA plasma levels were measured over the seven consecutive days at 1, 0, 1, 2, and 3 h after the morning MPA dose using validated high performance liquid chromatography method. Random sequence generation (selection bias) Unclear Allocation concealment (selection bias) Unclear Blinding (performance bias and detection bias) Self-reported outcomes Unclear Blinding (performance and detection bias) Objective outcomes Unlikely Incomplete outcome data (attrition bias) Unlikely Selective reporting (reporting bias) No for PK. Possibly for AEs Other bias (include funding) Novartis study Ethics and GCP The trial was performed in accordance with the amended Declaration of Helsinki.
Neutropenia < 2.0 x 109/L < 0.5 x 109/L 80 9 82 22 Thrombocytopenia < 100 x 109/L < 50 x 109/L 2 <1 3 <1 Anaemia < 110 g/L < 80 g/L 33 1 25 <1 Infections 24 20 Neutropenic sepsis <1 <1 Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactione All 4 12 Severef 0 2 Cardiovascular Sign Changesg Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsf 3 4 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Peripheral Neuropathy Any Symptoms 71 56 Severe Symptomsf 10 2 Table 7: Frequencya of Important Treatment Emergent Adverse Effects in Metastatic Breast Cancer in the Randomised Study on an Every-3-Weeks Schedule, Continued Percent of Patients ABRAXANE 260/30minb (n=229) Solvent-based paclitaxel 175/3hc,d (n=225) Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsf 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention / Oedema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any Symptoms 30 22
each system organ class grouping, adverse reactions are presented in order of decreasing frequency. The frequency estimates for adverse reactions are defined as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000); and Not known (cannot be estimated from available data – spontaneous reports). Table 9: Adverse Reactions Reported in ≥5% of Patients in Non-Small Cell Lung Cancer Clinical Trial (by MedDRA System Organ Class and Preferred Term) System Organ Class Frequency Preferred Term ABRAXANE (100 mg/m2/week) and carboplatin (N=514) Solvent-based paclitaxel (200 mg/m2 every 3 weeks) and carboplatin (N=524) All Grades Toxicity2 (%) Grade 3 or Higher Toxicity3 (%) All Grades Toxicity2 (%) Grade 3 or Higher Toxicity3 (%) Blood and lymphatic system disorders1 Very Common Anaemia1 97 27 91 7 Leukopenia1 89 24 83 23 Neutropenia1 84 47 83 58 Thrombocytopenia1 67 18 55 9 Skin and subcutaneous tissue disorders Very Common Alopecia 56 <1 60 0 Rash 10 0 8 <1 Nervous system disorders Very Common Peripheral neuropathy4 48 3 64 12 Common Dysgeusia 7 0 6 0 Headache 7 <1 4 <1 Dizziness 6 0 4 <1 General disorders and administration site conditions Very Common Fatigue 25 4 23 4 Asthenia 16 3 15 4 Oedema peripheral 10 0 4 <1 Common Pyrexia 9 0 8 0 Chest pain 5 <1 4 <1 disorders Very Common Nausea 27 <1 25 <1 Constipation 16 <1 13 <1 Diarrhoea 15 <1 11 0 Vomiting 12 <1 12 <1 Common Stomatitis 6 0 4 0 Respiratory thoracic and mediastinal disorders Very Common Dyspnoea 12 3 12 3 Common Cough 9 <1 7 0 Epistaxis 7 0 2 0 Haemoptysis 4 <1 5 0 9: Adverse Reactions Reported in ≥5% of Patients in Cell Lung Cancer Clinical Trial (by MedDRA System Organ Class and Preferred Term) (Continued) intestinal
First round benefit-risk assessment First round assessment of benefits See Table 4. Table 4: First round assessment of benefits Indication Benefits Strengths and Uncertainties Compared with placebo, weight based dosing with nadroparin at recommended doses significantly lowers incidence of DVT by 45%; Nadroparin showed comparable efficacy to UFH in preventing DVT and PE (Harenberg, 1996). Requires once daily administration compared to thrice daily with UFH. Enoxaparin, nadroparin and certoparin were found to be similar in preventing PE and DVT in hospitalised medical patients, with similar rates of major and minor bleeding. Similar or better safety profile in terms of haemorrhagic side effects compared to UFH Reduction in DVT was modest; the difference in incidence of total DVT was barely statistically significant (nadroparin versus placebo: 13 versus 23, p=0.045). The distribution of proximal (3 versus 7, p=1.00) and distal (10 versus 17, p > 0.05) thrombi was not statistically different between groups. No PE was reported in this pivotal study mainly due to lack of objective testing. Interpretation was limited by low incidence of primary endpoint and lack of details (95% CI not presented). Furthermore, incidence of deaths was higher in the nadroparin treatment group.. This was on indirect evidence from a MTC (Dooley, 2014) and there is lack of studies which directly compare one LMWH against another. LMWHs are not clinically interchangeable and so the general evidence provided for heparin (UFH and LMWH) and for all LMWHs cannot be extrapolated as evidence for efficacy/ safety of nadroparin for proposed new indication of thromboprophylaxis of medical patients bedridden due to acute illness. Compared to UFH, significantly lower rate of withdrawals, thrombocytopenia, haematomas and local reactions (Forette, 1995).
III. Nonclinical findings Introduction The range of studies submitted was adequate, and relevant studies were Good Laboratory Practice (GLP) compliant. A notable feature of the submission which detracted from its overall quality was that a large number of the studies, including many of the pivotal studies, dated back to around the 1980s. The quality of reporting was often poorer than what is expected today, and in some instances the study designs reflected the era, with toxicokinetic data, in particular, being limited. However, several more recent studies were conducted to rectify some of the deficiencies from the earlier studies. These issues are discussed in further detail under the relevant sections below. In many of the study reports, the exact nature of the test compound (base, hydrochloride salt or hydrochloride dihydrate) and how the dose/concentration was expressed was not clear. The molecular weight (MW) difference between the base and hydrochloride salt is ~11% and between the base and the hydrochloride dihydrate is ~21%. Where available, the missing information was provided in the Section 31 response; the remaining gaps in the data were considered to have little/no impact on study interpretation/conclusions. Pharmacology Primary pharmacology Table 6 shows binding affinity for nalmefene and its metabolites at the µ, δ and κ opioid receptors. 6a: Binding affinity: Ki values (nM) for nalmefene and its metabolites at the µ, δ and κ opioid receptors. Study (receptor source) 054-884-2011 (cloned receptors, human unless noted) 12 (guinea pig brain) Compound Nalmefene Nalmefene Nalmefene glucuronide Nornalmefene µ receptor 0.2 1.3 0.73 810 18.7 δ receptor 16 53 9.3 5,064 279 κ receptor 0.31 (rat receptor) 1.1 0.64 4.7 ~10,000 917 Table 6b: Binding affinity: Ki values (nM) for nalmefene and its metabolites at the µ, δ and κ opioid receptors. Study (receptor source) 056-884-2011 (cloned receptors, human unless noted) 053-884-2011 (cloned receptors, human unless noted)
Second round CER: September 2015 AusPAR Attachment 2 Extract from the Clinical Evaluation Report for naloxegol oxalate Proprietary Product Name: Movantik Sponsor: AstraZeneca 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 a more detailed evaluation 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], where they appear in this document, indicate that confidential information has been deleted.
Sponsor response The TGA’s comment regarding the duration of treatment of Ilevro is The following statement has been included in the Precautions section of the PI: Post marketing experience with topical NSAIDs also suggest that use for more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk and severity of corneal adverse events. In addition, the ‘Dosage and Administration’ section of the draft PI has been revised to reflect the change in duration of treatment. The following statement is proposed: For the prevention and treatment of pain and inflammation, the dose is 1 drop of Ilevro in the conjunctival sac of the affected eye(s) once a day beginning 1 day to cataract surgery, continued on the day of surgery and up to 14 days of the postoperative period, as directed by the clinician. An additional drop should be administered 30 to 120 minutes prior to surgery. The revised PI is included (Proposed Australian PI and package insert.). The CMI will be revised in alignment with the approved PI. Evaluator’s comment The sponsor’s response is acceptable from an RMP perspective. Recommendation #3 in RMP evaluation report In the header of the EU-RMP, it is stated “Version 8.0” however elsewhere the version is listed as 6.1. The sponsor should confirm the correct version number. Sponsor response The discordance is due to the use of an electronic system for handling documents where every time a new version is made effective the version number in the header rolls out to the following number. The version of the RMP under evaluation is the version 06.1 (EU-RMP-NEVANAC-06.1) as described throughout the document. This version corresponds to the eighth electronic version (effective date: 20 September 2013). The applicant did not find the technical possibility to harmonise paper version and electronic versions. Evaluator’s comment The sponsor’s response is noted. Recommendation #4 in RMP evaluation report The sponsor notes that on account of the low systemic absorption of the drug and its active metabolite… both known and potential risks are limited to local effects. The sponsor should provide justification for this statement and for not considering systemic absorption as a potential risk. Sponsor response The sponsor has provided the requested justification (see Section 31 response). Evaluator’s comment The sponsor’s response is acceptable from an RMP perspective.
Comment: The sponsor's rational for the armodafinil clinical development program is acceptable. Contents of the clinical dossier Scope of the clinical dossier The submission contained the following clinical information: 11 Phase I clinical pharmacology studies, including pharmacokinetic data with or without pharmacodynamic data (9 in healthy subjects, 1 in patients with schizophrenia, and 1 in patients with OSAHS). 1 population pharmacokinetic report, 1 pharmacokinetic/pharmacodynamic modelling and simulation report. 4 pivotal III, double-blind, placebo controlled studies (2 in patients with OSAHS, 1 in patients with narcolepsy, 1 in patients with SWSD). 2 Phase III, open-label studies each including patients with narcolepsy, OSAHS or SWSD. 2 Phase IIIb studies (1 double-blind, placebo-controlled study in patients with SWSD, 1 open-label study in patients with OSAHS or narcolepsy). 4 in vitro bioanalytical reports; 2 human biomaterial reports. Literature references. Paediatric data The sponsor has not applied to the European for a waiver relating to the submission of paediatric studies for the treatment of OSAHS, narcolepsy or SWSD. The FDA (USA) has granted a waiver for paediatric studies in patients from birth to 17 years of age in OSAHS "on the basis that studies are highly impractical because the number of patients is so small or non-existent", and in SWSD "on the basis that very few, if any, paediatric patients experience excessive sleepiness associated with" this condition. The FDA granted a partial waiver for the paediatric study requirement for patients aged less than 6 years with narcolepsy "on the basis that studies are highly impractical because the number of patients is so small or non-existent". However, the FDA deferred the paediatric study requirement for patients aged 6 to 17 years with narcolepsy until November 2017 "on the basis that the other paediatric groups are subject to a waiver request". Good clinical practice The sponsor states that the clinical studies were undertaken in compliance with the principles of Good Clinical Practice.
‘VasoKINOX is indicated in conjunction with ventilator support and other appropriate active substances for the treatment of: Newborn infants ≥ 34 gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation. Perioperative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0-17 in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve left ventricular function and oxygenation by increasing the pulmonary flow.’ Product Information The Product Information (PI) approved with the submission which is described in this AusPAR can be found as Attachment 1. , please refer to the TGA website at <https://www.tga.gov.au/product-information-pi>. II. Registration Timeline Table 2: Registration timeline Description Date Submission dossier accepted and 1st round evaluation commenced 31 2015 1st round evaluation completed 11 September 2015 Sponsor provides responses on questions raised in 1st round evaluation 31 October 2015 2nd evaluation completed 30 November 2015 Delegate’s overall risk-benefit assessment and request for Advisory Committee advice 4 January 2016 Sponsor’s pre-Advisory Committee meeting response 18 January 2016 Advisory Committee meeting 26 February 2016 Registration decision 18 March 2016 Entry onto ARTG 16 January 2017 Number of TGA working days from submission dossier acceptance to registration decision * 197 * Target timeframe for standard applications: 220 working days trial
All SAEs (regardless of causality) 49.1 36.5 51.6 31.9 47.8 36.5 48.6 35.8 Drug-related SAEs 7.2 7.2 11.0 9.9 11.6 7.9 10.4 8.0 All AEs leading to (regardless of causality) 12.6 3.0 24.2 13.2 17.7 11.1 17.3 9.3 Drug-related AEs leading to 6.6 3.0 14.3 8.8 7.6 4.7 8.3 4.8 Deaths and other serious adverse events A summary of deaths and other SAEs from the dose ranging studies is given in Table 56, below. Table 56. Summary of deaths and SAEs in patients with advanced RCC receiving nivolumab monotherapy ID: CA902010* CA902009 CA902025 All RCC Patient % Patient number % Patient number % Patient % Patient number 167 91 406 664 Deaths 112 43.7 39 42.9 181 44.6 293 44.1 Within 30 days NA 4 4.4 19 4.7 23 3.5 Within 100 days NA 14 15.4 56 13.8 70 10.5 of death Due to Study Drug Toxicity 0 0.0 0 0.0 0 0.0 0 0.0 Due to disease progression 103 41.9 33 36.3 162 39.9 265 39.9 Unknown/other 9 1.8 6 6.6 19 4.7 28 4.2 SAEs
cholestasis Nervous system disorders Very common headache Common peripheral neuropathy, headache, dizziness peripheral neuropathy, dizziness Uncommon Polyneuropathy, autoimmune neuropathy (including facial and abducens paresis) Guillain-Barré syndrome, polyneuropathy, neuritis, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitisb Rare Guillain-Barré syndrome, demyelination, myasthenic syndrome Eye disorders Common dry eye uveitis, blurred vision Uncommon Uveitis, blurred vision Cardiac disorders Common tachycardia Uncommon tachycardia arrhythmia (including ventricular arrhythmia)a, atrial fibrillation, myocarditisa,e Rare arrhythmia (including ventricular arrhythmia), myocarditis a,e, atrial fibrillation Vascular disorders Common hypertension hypertension Uncommon vasculitis Respiratory, thoracic and mediastinal disorders Common pneumonitisa,c, dyspnoea, cough pneumonitisa,c dyspnoea, cough Uncommon pleural effusion pleural effusion Rare lung infiltration Gastrointestinal disorders Very common diarrhoea, nausea colitis, diarrhoea, vomiting, nausea, abdominal pain Common colitis, stomatitis, vomiting, abdominal pain, constipation, dry mouth stomatitis, gastritis, constipation, dry mouth Uncommon Pancreatitis, gastritis pancreatitis, intestinal perforation, duodenitis Rare duodenal ulcer Skin and subcutaneous tissue disorders Very common pruritus rashd, pruritus Common vitiligo, dry skin, erythema, alopecia vitiligo, dry skin, erythema, alopecia, urticaria Uncommon erythema multiforme, psoriasis, rosacea, urticaria psoriasis
Copyright © Commonwealth of Australia 2012 This work is copyright. You may reproduce the whole 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 <>.
Year of PID diagnosis 2004 2003 20. Study 07-42. Trough Serum IgG Concentrations, interim analysis Wash in/wash out Period Efficacy Period Visit 0 3 6 Month 9 12 Month Patient1 IgG trough concentration (g/L) 6.8 10.4 11.8 10.6 Patient2 IgG trough concentration (g/L) 13.3 13.4 12.6 14.2 The conclusion drawn by CSL regarding efficacy is that the interim analysis of data from two paediatric patients showed that trough serum IgG concentrations were maintained by weekly doses. Paediatric Patients. Combined Studies 05-23 and 07-42 In Study 05-23, a total of 5 children under the age of 12 years were enrolled. A 13 year old paediatric patient from this was considered by the TGA to be eligible for analysis in the paediatric population. An additional two children were enrolled into the 07-42 trial. Results for a total of eight paediatric patients were separately summarised in the sponsor’s current Australian submission. These patients comprised the Paediatric population for the Efficacy Period. Six (75%) patients were male and two (25%) were female and all were White (100%). The mean age was 9.85 (median 10.20, range: 5.9 to13.4) years and the mean weight was 35.25 (median 34.40, range: 20.2 to 64.5) kg. Demographic and baseline data are summarised in Table 21 below. Table 21. Combined paediatric demographics and baseline information, paediatric population. Baseline Characteristics Paediatric population N=8 Age (years) n Mean (SD) Median Min, Max 8 9.85 (2.22) 10.20 5.9, 13.4 Sex, n (%) Male Female 6 (75.0%) 2 (25.0%) Race, n (%) White 8 (100.0%) Screening weight (kg) n 8 35.25 (13.98)
profile of patients > 18 years. Longitudinal natural history studies in a research agreement with the Alliance to expand current registries to include nusinersen treatment information. The Global SMA Patient Registry consists of 26 national patient registries representing 29 countries (20 countries in genetically confirmed patients across the spectrum of SMA. Data are self-reported and/or provided by healthcare professionals. More than 5000 SMA patients worldwide have been enrolled in associated registries. Missing information: safety profile in patients with low or higher SMN2 copy number and/or different disease severity from the majority of patients in the nusinersen clinical programme Type IV SMA); safety profile of patients > 18 years Ongoing Updates to be provided in PSURs. 11: Long term safety and efficacy studies short name and title Rationale and study objectives/study design Due Date(s) Study CS11 (SHINE) An open label extension study for patients with spinal muscular atrophy who previously participated in investigational studies of ISIS 396443 (nusinersen). This is an open label extension study in subjects with SMA who previously participated in investigational studies of nusinersen. The primary purpose of this study is to gather First patient dosed 17 November 2015 Last patient dosed Q3 2017 Last patient completed Q3 2022
In the Per-protocol analysis population (PP) in which additional patients were censored at end study therapy, tumour progression or tumour-related death was observed in 19 and 38 Sandostatin LAR and placebo recipients, respectively (HR = 0.24; 95% CI, 0.13 to 0.45; p-value =0.0000036). Figure 1 Kaplan-Meier estimates of TTP comparing Sandostatin LAR with placebo (conservative ITT population) Table 1 TTP results by analysis populations TTP Events Median TTP months [95% C.I.] HR [95% C.I.] p-value * Sandostati n LAR Placebo Sandostatin LAR Placebo ITT 26 41 NR NR 0.32 [95% CI, 0.19 to 0.55] P=0.000015 cITT 26 40 14.3 [95% CI, 11.0 to 28.8] 6.0 [95% CI, 3.7 to 9.4] 0.34 [95% CI, 0.20 to 0.59] P=0.000072 PP 19 38 NR NR 0.24 [95% CI, 0.13 to 0.45] P =0.0000036
Hypertension severity: AEs were observed at similar rates in subjects with mild to moderate and severe hypertension.The small number of subjects with severe hypertension limits interpretation of data in this subgroup (Table 32, below). 32: Overview of Adverse Events – Number (%) of Subjects by Period II Treatment Group – Hypertension Severity Subgroup –Safety Set 2 (CS8635-A-E303) Mild or Moderate Hypertension N = 746 Severe Hypertension N = 60 TEAE n (%) Peripheral oedema URTI 107 (14.3%) 15 (2.0) 11 ( 1.5) 8 (13.3%) 2 (3.3) 1 ( 1.7) Drug-related TEAE n (%) 40 (5.4%) 3 (5.0%) Deaths n (%) 0 (0.0) 0 (0.0) SAE n (%) 4 (0.5%) 1 (1.7%) Discontinued due to AE n (%) 10 (1.3%) 0 (0.0) Diabetic Status: AEs were observed at similar in subjects with and without diabetes.The small number of subjects with diabetes limits interpretation of data in this subgroup (Table 33). Table 33: Overview of Adverse Events – Number (%) of Subjects by Period II Treatment Group – Diabetic Status Subgroup –Safety Set 2 (CS8635-A-E303) With Diabetes N = 104 Without Diabetes N = 702 TEAE n (%) Peripheral oedema URTI Bronchitis Hyperglycaemia 13 (12.5%) 1 (1.0) 0 (0.0) 2 (1.9) 4 (3.8) 102 (14.5%) 16 (2.3) 12 (1.7) 5 (0.7) 1 (0.1) Drug-related TEAE n (%) 3 (2.9%) 40 (5.7%) Deaths n (%) 0 (0.0) 0 (0.0) SAE n (%) 2 (1.9%) 3 (0.4%) Discontinued due to AE n (%) 1 (1.0%) 9 (1.3%) Safety related to drug-drug interactions and other interactions None reported in the submitted data.
In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft consumer medicine information document be revised to adequately reflect any changes made to the Australian PI as a result of the above recommendations. The sponsor states: ‘None of the above recommendations are actually warranting any changes to the draft consumer medicine information’. This is acceptable. Summary of recommendations It is considered that the sponsor’s response to the TGA has adequately addressed all of the issues identified in the RMP evaluation report. Nevertheless an updated ASA should be submitted to the TGA, preferably before this application is approved. Outstanding issues Issues in relation to the RMP In regard to the proposed routine risk minimisation activities for the important identified risk: ‘Churg Strauss Syndrome (CSS) / Hypereosinophilic Syndrome’, the sponsor has advised that the wording in the Precaution section of the draft Australian PI is the same as that in the current EU SmPC. This is acceptable, although Table 1: ‘Details by safety concern of information included in the Australia Product Information and EU SmPC and justification for any differences’ and Table 2: ‘Summary of safety specification, pharmacovigilance plan and planned risk minimisation measures in Australia’ of the ASA only state: ‘Adverse effects, Post-marketing observations Respiratory, thoracic and mediastinal disorders: Allergic granulomatous angiitis (i.e. Churg Strauss syndrome) is listed as a post-marketing observation’. Consequently these tables of the ASA should be updated with this information, preferably before this application is approved. In addition the ASA states that the release date for the EU-RMP (Version: 10) is 8 July 2015, while the document itself states the date for final sign-off is 5 March 2015. The sponsor should clarify this discrepancy and amend the ASA if required. Advice from the Advisory Committee on the Safety of Medicines (ACSOM) ACSOM advice was not sought for this submission. Key changes to the updated RMP In response to the TGA the sponsor provided an updated EU-RMP (Version 10.0, dated 5 March 2015) with an updated ASA (Version 5.0, dated 13 August 2015). Key changes from the versions evaluated in the first round are summarised below in Table 15.
Ear and labyrinth disorders Common vertigo Eye disorders Uncommon visual impairment Gastrointestinal disorders Common abdominal pain, constipation, diarrhoea, dry dyspepsia, nausea, vomiting Uncommon flatulence Not known eructation General disorders and application site conditions Common asthenic conditions, fatigue Uncommon chest pain, chills, drug withdrawal syndrome, malaise, peripheral oedema, thirst Hepatobiliary disorders Uncommon hepatic enzymes increased Immune system disorders Uncommon hypersensitivity Injury, poisoning and procedural complications Uncommon injuries from accidents Metabolism and nutrition disorders Common decreased appetite Musculoskeletal and connective tissue disorders Uncommon muscle spasms, muscle twitching, myalgia Nervous system disorders Common dizziness, headache, somnolence Uncommon disturbance in attention, dysgeusia, speech disorder, tremor, convulsion (particularly in persons with epileptic disorder or predisposition to convulsions), syncope, lethargy Not known sedation, paraesthesia Psychiatric disorders Common insomnia Uncommon anxiety, confusional state, depression, nervousness, restlessness, abnormal thinking Rare drug dependence (see PRECAUTIONS, Drug dependence) Not nightmares, euphoric mood, hallucinations Renal and urinary disorders Uncommon micturition urgency Not known urinary retention trial
Reproduction system and breast disorders Not known erectile dysfunction Respiratory, thoracic and mediastinal disorders Uncommon dyspnoea Not known respiratory depression Skin and subcutaneous tissue disorders Common hyperhidrosis, pruritus, rash Vascular disorders Common hot flush Uncommon increase in blood pressure, decrease in blood pressure The following additional adverse events are known for oxycodone: Due to its pharmacological properties, oxycodone may cause respiratory depression, miosis, bronchial spasm, and spasms of non-striated muscles as well as suppress the cough reflex. Ear and labyrinth disorders Uncommon tinnitus Eye disorders Uncommon miosis Gastrointestinal disorders Common gastritis, hiccup Uncommon colic, dysphagia, gastrointestinal disorder, ileus, stomatitis Not known dental caries General disorders and administration site conditions Common fever Uncommon facial flushing, lymphadenopathy, neck pain, oedema, drug tolerance Not known drug withdrawal syndrome neonatal Hepatobiliary disorders Uncommon biliary Not known cholestasis Immune system disorders Uncommon allergic reaction, anaphylactoid reaction Not known anaphylactic reaction Metabolism and nutrition disorders Uncommon dehydration, hyponatraemia Rare: increased appetite Musculoskeletal and connective tissue disorders Uncommon involuntary muscle contractions, muscular rigidity
free survival (PFS) benefit observed in PALOMA-1 study. Continued approval for this indication is contingent upon verification and description of clinical benefit in PALOMA-2 study. Submitted 29 November 2016 For the treatment of hormone receptor (HR) HER2 negative advanced or metastatic breast cancer: -in combination with an aromatase inhibitor as initial endocrine- based therapy in postmenopausal women Singapore Approved 21 July 2016 Ibrance in combination with letrozole for the treatment of postmenopausal women with ER+, advanced breast cancer as initial endocrine-based therapy for their metastatic disease Switzerland Approved 31 January 2017 Ibrance is indicated for the treatment of hormone receptor (HR)-positive, epidermal growth factor receptor 2 advanced or metastatic breast cancer in combination with fulvestrant in pre-/peri- (combined with LHRH analogs) or postmenopausal women who have received prior endocrine therapy Submission First quarter 2017 Ibrance is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 advanced or metastatic breast cancer in combination with letrozole in pre-/peri- (combined with LHRH analogs) or postmenopausal women New Zealand Under evaluation (granted Full Priority Review) Abbreviated NMA ref. EU consent submitted 31 October 2016 Ibrance is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 locally advanced or metastatic breast cancer: in combination with an aromatase inhibitor; in combination with fulvestrant in women who have received prior endocrine therapy. trial negative negative
HOMA-IR normalized measure of insulin resistance HOMA-%B normalized measure of beta-cell function IDMC Independent Data Monitoring Committee IR immediate-release ITT intent-to-treat LAI long-acting injectable LDL low-density lipoprotein MA maintenance MedDRA Medical Dictionary for Regulatory Activities mg eq. milligram equivalents mITT Modified intent-to-treat NMS neuroleptic malignant syndrome OL open-label P-gp P-glycoprotein PANSS positive and negative syndrome PK pharmacokinetic(s) PP1M paliperidone palmitate 1-month formulation PP3M paliperidone palmitate 3-month formulation linear derived method for calculation of heart rate-corrected QT interval QTcB Bazett method for calculation of corrected QT interval QTcF Fridericia method for calculation of corrected QT interval SAE serious adverse event SAS Simpson Angus rating scale SBP systolic blood pressure SCS summary of clinical safety SOC system class trial
Table 56: Percentages of patients will have levels below 7.5 ng/mL predose (that is potentially sub-therapeutic concentrations) early in treatment in those patients who have ceased taking medication that is with no recent prior medication Second injection Predose Day 8 Predose Day10 Predose Day 12 On Day 8 16 On Day 10 15 On Day 12 13 Table 57: Percentages of patients will have levels below 7.5 ng/mL predose (that is potentially sub-therapeutic concentrations) late in the first treatment cycle in those patients who have ceased taking medication that is with no recent prior medication Second injection Day 22 Day 29 Day 36 Day 4 8 13 16 Day 6 7 12 15 Day 8 4 11 15 Table 58: Maximum exposure (Cmax) in patients on oral paliperidone PR 6 mg for 5days (that is as per PI for patients not previously exposed) using the upper 90% limit for plasma concentration as pre dose level at initial injection Second injection Cmax ng/mL On Day 4 49.34 On Day 6 47.95 on Day 8 46.22 Prev max from 150/150a 49.34 From R092670-PSY-1008 and -3006 150/150 mg eq on Day 1/Day 8 Second evaluation of clinical data submitted in response to questions Sponsor response: The PP1M population PK as published by Samtani et al. and described in the submitted PP1M population PK report should then be considered the representative description of paliperidone PK after PP1M administration. Therefore, the PK simulations performed using that model, including those mentioned by the evaluator should be still considered valid.
Psychiatric disorders Sleep disorder, Blunted affect, Nightmare Confusional state, Libido decreased, Anorgasmia, Nervousness Nervous system disorders Parkinsonismc, Sedation/somnolence, Tremor Tardive dyskinesia, Dystonia, Dizziness postural, Disturbance in attention, Dizziness, Dyskinesia, Hypoesthesia Neuroleptic malignant syndrome, Cerebral ischemia, Unresponsive to stimuli, Loss of consciousness, Depressed level of consciousness, Diabetic coma, Convulsion, Syncope, Psychomotor hyperactivity, Balance disorder, Coordination abnormal, Dysarthria, Head titubation, Paresthesia Eye disorders Vision blurred, Lacrimation increased Glaucoma, Eye movement disorder, Eye rolling, Photophobia, Conjunctivitis, Dry eye, Ocular hyperemia Ear and labyrinth disorders Vertigo, Tinnitus Ear pain Cardiac disorders Tachycardiac Atrioventricular Conduction disorder, Electrocardiogram QT prolonged, Bradycardia, Electrocardiogram abnormal, Palpitations Postural orthostatic tachycardia syndrome, Sinus arrhythmia Vascular disorders Hypotension, Orthostatic hypotension Pulmonary embolism, Ischemia, Flushing Respiratory, thoracic and mediastinal disorders Dyspnea, Pharyngolaryngeal pain, Epistaxis, Nasal congestion Hyperventilation, Pneumonia aspiration, Pulmonary congestion, Respiratory congestion, Rales, Wheezing, Dysphonia Gastrointestinal disorders Nausea Abdominal pain, Abdominal discomfort, Vomiting, Constipation, Gastroenteritis, Dysphagia, Dyspepsia, Dry mouth, Toothache, Flatulence Intestinal obstruction, Swollen tongue, incontinence, Fecaloma, Cheilitis Hepatobiliary disorders Transaminases increased Gamma-glutamyltransferase increased, Hepatic enzyme increased Skin and subcutaneous tissue disorders Pruritus, Rash, Eczema Drug eruption, Urticaria, Hyperkeratosis Dry skin, Erythema, Skin discoloration, Acne, Seborrheic dermatitis, Dandruff
Diabetes mellitus and hyperglycaemia-related adverse events Weight gain Seizures Somnolence Priapism Cerebrovascular accident Venous thromboembolism Leukopenia Agranulocytosis Thrombocytopenia Rhabdomyolysis Elevated plasma concentrations in patients with renal disease Injection site reactions (injectable formulations only) Hypersensitivity reactions (injectable formulations only) Important potential risks Carcinogenicity (pituitary adenomas, endocrine pancreas tumours, breast cancer) Overall increased mortality in elderly patients with dementia Cerebrovascular adverse events in elderly patients with dementia Cognitive and motor impairment Body temperature dysregulation Suicidality Depression in patients with affective disorders (INVEGA only) Increased sensitivity to antipsychotics in patients with Parkinson's disease or Dementia with Lewy bodies Gastrointestinal obstruction (in patients with pre-existing severe gastrointestinal narrowing [pathologic or iatrogenic] or in patients with dysphagia or significant difficulty in swallowing tablets) (INVEGA only) Decreased bone mineral density/osteoporosis Missing information Use in haemodialysis patients Exposure during pregnancy Exposure via breastfeeding Pharmacovigilance plan The sponsor is proposing routine pharmacovigilance activities for all specified safety concerns.
17.5 70 5 20 Cmax (ng/mL) AUC0-28d (ng.d/mL) AUC0-84d (ng.d/mL) Cav,τ Cmax / Cτ 17.6 278 378 4.5 25 68.3 1067 1888 23 8.6 9.77 111 314 4.0 5.1 68.1 682 1740 24 7.0
HBsAg hepatitis B surface antigen HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HIV immunodeficiency virus ICH International Conference on Harmonisation IEC Independent Ethics Committee IgG immunoglobulin G IgM immunoglobulin M IL28B interleukin 28B IP-10 interferon gamma-induced protein 10 IRT interactive response technology ITT intent-to-treat IU international units LCB lower bound of the 95% confidence interval LLN lower limit of normal LLOD lower limit of detection LLOQ lower limit of quantitation MedDRA Medical Dictionary for Regulatory Activities MEMS Medication Event Monitoring System mRNA messenger RNA NS3 non-structural protein 3 NS4A non-structural protein 4A NS5A non-structural protein 5A NS5B non-structural protein 5B