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Australian Public Assessment Report for Ezetimibe and Atorvastatin

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Australian Public Assessment Report for Ezetimibe and Atorvastatin Australian Public Assessment Report for Ezetimibe and Atorvastatin Proprietary Product Names: Atozet, Zeteze Sponsor: Merck Sharp & Dohme Australia Pty Ltd August 2015 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 <https://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 2015 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 Atozet/Zeteze Ezetimibe and Atorvastatin Merck Sharp & Dohme Australia Pty Ltd PM-2013-03231-1-3 Page 2 of 75 Date of Finalisation 7 August 2015 Therapeutic Goods Administration Contents List of the most common abbreviations used in this AusPAR _________ 5 I. Introduction to product submission _____________________________________ 8 Submission details ____________________________________________________________________ 8 Introduction ___________________________________________________________________________ 9 Regulatory status ____________________________________________________________________ 11 Product Information_________________________________________________________________ 12 II. Quality findings ___________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 12 Biopharmaceutics ___________________________________________________________________ 13 Quality summary and conclusions _________________________________________________ 16 III. Nonclinical findings _____________________________________________________ 16 Introduction __________________________________________________________________________ 16 Pharmacodynamics__________________________________________________________________ 16 Pharmacokinetics ____________________________________________________________________ 16 Toxicology ____________________________________________________________________________ 17 Nonclinical summary and conclusions _____________________________________________ 17 IV. Clinical findings __________________________________________________________ 18 Pharmacokinetics ____________________________________________________________________ 20 Pharmacodynamics__________________________________________________________________ 22 Dosage selection for the pivotal studies ___________________________________________ 25 Efficacy _______________________________________________________________________________ 26 Safety _________________________________________________________________________________ 28 First round benefit-risk assessment _______________________________________________ 30 First round recommendation regarding authorisation ___________________________ 38 Clinical questions ____________________________________________________________________ 38 Second round evaluation of clinical data submitted in response to questions _ 39 Second round benefit-risk assessment ____________________________________________ 39 Second round recommendation regarding authorisation ___________ 39 V. Pharmacovigilance findings ____________________________________________ 40 Risk management plan ______________________________________________________________ 40 VI. Overall conclusion and risk/benefit assessment __________________ 44 Product background _________________________________________________________________ 44 Quality ________________________________________________________________________________ 50 Nonclinical ___________________________________________________________________________ 50 AusPAR Atozet/Zeteze Ezetimibe and Atorvastatin Merck Sharp & Dohme Australia Pty Ltd PM-2013-03231-1-3 Page 3 of 75 Date of Finalisation 7 August 2015 Therapeutic Goods Administration Clinical ________________________________________________________________________________ 51 Risk management plan ______________________________________________________________ 61 Risk-benefit analysis ________________________________________________________________ 61 Outcome ______________________________________________________________________________ 74 Attachment 1. Product Information ______________________________________ 74 Attachment 2. Extract from the Clinical Evaluation Report __________ 74 AusPAR Atozet/Zeteze Ezetimibe and Atorvastatin Merck Sharp & Dohme Australia Pty Ltd PM-2013-03231-1-3 Page 4 of 75 Date of Finalisation 7 August 2015 Therapeutic Goods Administration List of the most common abbreviations used in this AusPAR Abbreviation Meaning ACPM Advisory committee for prescription medicines ADRs Adverse drug reactions AE Adverse event/experience (used interchangeably) ALT Alanine aminotransferase ALP Alkaline phosphatase ANCOVA Analysis of covariance APaT All Patients as Treated Apo Apolipoprotein API active pharmaceutical ingredient AST Aspartate aminotransferase Atorva Atorvastatin AUC area under the plasma concentration time curve BE bioequivalence CER Clinical Evaluation Report CHD Coronary heart disease CI Confidence interval CIOMS The Council for International Organizations of Medical Sciences CK Creatine kinase or creatine phosphokinase Cmax Maximum concentration CSR Clinical study report CTD Common technical document dL deci litre EMA European Medicines Agency EZ Ezetimibe AusPAR Atozet/Zeteze Ezetimibe and Atorvastatin Merck Sharp & Dohme Australia Pty Ltd PM-2013-03231-1-3 Page 5 of 75 Date of Finalisation 7 August 2015 Therapeutic Goods Administration Abbreviation Meaning FAS Full Analysis Set FDA Food and Drug Administration FDC fixed dose combination GCP Good Clinical Practice GGT Gamma glutamyl transferase GM Geometric mean GMR Geometric mean ratio HDL-C High-density lipoprotein cholesterol HeFH heterozygous familial hypercholesterolaemia HMG-CoA Hydroxymethylglutaryl coenzyme A (3 hydroxy–3-methyl methylglutaryl coenzyme A) HoFH homozygous familial hypercholesterolaemia hs-CRP High-sensitivity C-reactive protein ICH International Conference on Harmonisation LFT Liver function test LDL-C Low-density lipoprotein cholesterol LS Least squares MSD Merck Sharp & Dohme NCEP National Cholesterol Education Program Adult Treatment Program III PDCO EMEA Paediatric Committee Ph.Eur European Pharmacopeia PP Per-Protocol PVC polyvinyl chloride RMP Risk management plan Rosuva Rosuvastatin SAE Serious adverse event AusPAR Atozet/Zeteze Ezetimibe and Atorvastatin Merck Sharp & Dohme Australia Pty Ltd PM-2013-03231-1-3 Page 6 of 75 Date of Finalisation 7 August 2015 Therapeutic Goods Administration Abbreviation Meaning SD Standard deviation SDH succinate dehydrogenase SE Standard error SmPC Summary of product characteristics SOC System Organ Class TG triglyceride TGA Therapeutic Goods Administration Tmax The time after administration of a drug when the maximum plasma concentration is reached Total-C Total cholesterol UK United Kingdom ULN Upper limit of normal USP-NF United States Pharmacopeia and The National Formulary AusPAR Atozet/Zeteze Ezetimibe and Atorvastatin Merck Sharp & Dohme Australia Pty Ltd PM-2013-03231-1-3 Page 7 of 75 Date of Finalisation
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