Australian Public Assessment Report for Aclidinium bromide Proprietary Product Name: Bretaris Genuair Sponsor: A Menarini Australia Pty Ltd September 2014 Therapeutic Goods Administration 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 decision- making, 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 <http://www.tga.gov.au>. About AusPARs · An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. · An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2014 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 <[email protected]>. AusPAR Bretaris Genuair Aclidinium bromide A Menarini Australia Pty Ltd PM-2012-04170-1-5 Page 2 of 86 Final 8 September 2014 Therapeutic Goods Administration Contents List of abbreviations commonly used in this AusPAR ___________________ 5 I. Introduction to product submission ___________________________________ 10 Submission details ___________________________________________________________________ 10 Product background _________________________________________________________________ 10 Regulatory status ____________________________________________________________________ 11 Product Information_________________________________________________________________ 12 II. Quality findings ___________________________________________________________ 12 Introduction __________________________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 13 Quality summary and conclusions _________________________________________________ 13 III. Nonclinical findings _____________________________________________________ 13 Introduction __________________________________________________________________________ 13 Pharmacology ________________________________________________________________________ 13 Pharmacokinetics ____________________________________________________________________ 15 Toxicology ____________________________________________________________________________ 18 Nonclinical summary ________________________________________________________________ 25 IV. Clinical findings __________________________________________________________ 27 Introduction __________________________________________________________________________ 27 Pharmacokinetics ____________________________________________________________________ 29 Pharmacodynamics__________________________________________________________________ 32 Dosage selection for the pivotal studies ___________________________________________ 33 Efficacy _______________________________________________________________________________ 34 Safety _________________________________________________________________________________ 40 Safety issues with the potential for major regulatory impact ____________________ 44 First round benefit-risk assessment _______________________________________________ 48 First round recommendation regarding authorisation ___________________________ 51 Clinical questions ____________________________________________________________________ 51 Efficacy _______________________________________________________________________________ 51 Safety _________________________________________________________________________________ 52 Second round evaluation of clinical data submitted in response to questions _ 52 Second round benefit-risk assessment ____________________________________________ 53 Second round recommendation regarding authorisation ________________________ 54 V. Pharmacovigilance findings ____________________________________________ 54 Risk management plan ______________________________________________________________ 54 AusPAR Bretaris Genuair Aclidinium bromide A Menarini Australia Pty Ltd PM-2012-04170-1-5 Page 3 of 86 Final 8 September 2014 Therapeutic Goods Administration VI. Overall conclusion and risk/benefit assessment __________________ 60 Quality ________________________________________________________________________________ 60 Nonclinical ___________________________________________________________________________ 61 Clinical ________________________________________________________________________________ 62 Risk management plan ______________________________________________________________ 79 Risk-benefit analysis ________________________________________________________________ 79 Outcome ______________________________________________________________________________ 85 Attachment 1. Product Information ______________________________________ 85 Attachment 2. Extract from the Clinical Evaluation Report __________ 85 AusPAR Bretaris Genuair Aclidinium bromide A Menarini Australia Pty Ltd PM-2012-04170-1-5 Page 4 of 86 Final 8 September 2014 Therapeutic Goods Administration List of abbreviations commonly used in this AusPAR Abbreviation Meaning ADME Absorption, distribution, metabolism and excretion ADR Adverse Drug Reaction Ae Amount of unchanged drug excreted into urine AEs Adverse events ALT alanine aminotransferase Am Amount of metabolite excreted into urine Am1 Amount of LAS34850 excreted into urine Am2 Amount of LAS34823 excreted into urine ANCOVA Analysis of covariance AST aspartate aminotransferase ATS American Thoracic Society AUC Area-under-the-curve AUC0-t Area under the concentration-time curve from time zero up to the last measurable concentration AUCo- Area under the concentration-time curve from time zero to infinity ∞ Area under the concentration-time curve during a dosing interval AUCτ AUC ,SS Area(τ) under the concentration-time curve during dosing interval τ state BChE Butyrylcholinesterase(τ) at steady BDI Baseline Dyspnoea Index BD Twice daily BLQ Below the lower limit of quantification BMI body mass index BP blood pressure bpm beats per minute AusPAR Bretaris Genuair Aclidinium bromide A Menarini Australia Pty Ltd PM-2012-04170-1-5 Page 5 of 86 Final 8 September 2014 Therapeutic Goods Administration Abbreviation Meaning BUN Blood urea nitrogen CI Confidence interval CL Total body clearance from plasma CL/f Total body clearance from plasma after extravascular administration CLcr Creatinine clearance CLR Renal clearance Cmax Maximum observed plasma concentration Cmax,SS Maximum observed plasma concentration at steady state Cmin Minimum observed plasma concentration Cmin,SS Minimum observed plasma concentration at steady state COPD Chronic obstructive pulmonary disease CV Coefficient of variation CYP450 Cytochrome P450 DPI Dry powder inhaler ECG Electrocardiogram EMA European Medicines Agency ENR expanded normal range E-RS Exacerbations of COPD Tool – Respiratory Symptoms EXACT Exacerbations of Chronic Obstructive Pulmonary Disease Tool FDC fixed-dose combination fe Percentage of dose excreted in urine FEV1 AUC0- Normalised area under the FEV1 versus time curve from 0 to 24 24/24h hours post-dose FEV1 Forced expiratory volume in 1 second FEV1 Forced expiratory volume in 1 second FRC Forced residual capacity AusPAR Bretaris Genuair Aclidinium bromide A Menarini Australia Pty Ltd PM-2012-04170-1-5 Page 6 of 86 Final 8 September 2014 Therapeutic Goods Administration Abbreviation Meaning FRC Functional residual capacity FVC AUC0- Normalised area under