Australian Public Assessment Report for Ranolazine Proprietary Product Name: Ranexa Sponsor: A Menarini Australia Pty Ltd March 2018 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 Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. · An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2018 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 RANEXA ranolazine – A Menarini Australia Pty Ltd PM-2015-00423-1-3 FINAL Page 2 of 96 20 February 2018 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission ___________________________________ 11 Submission details ___________________________________________________________________ 11 Product background _________________________________________________________________ 12 Regulatory status ____________________________________________________________________ 12 Product Information_________________________________________________________________ 13 II. Registration timeline ____________________________________________________ 13 III. Quality findings __________________________________________________________ 14 Introduction __________________________________________________________________________ 14 Drug substance (active ingredient) ________________________________________________ 15 Drug product _________________________________________________________________________ 15 Biopharmaceutics ___________________________________________________________________ 17 Quality summary and conclusions _________________________________________________ 21 IV. Nonclinical findings _____________________________________________________ 21 Introduction __________________________________________________________________________ 21 Nonclinical report for submission PM-2009-03573-3-3 _________________________ 22 Pharmacology ________________________________________________________________________ 22 Pharmacokinetics ____________________________________________________________________ 27 Toxicology ____________________________________________________________________________ 31 Nonclinical summary and conclusions (from submission PM-2009-03573-3-3)37 Nonclinical report for submission PM-2015-00423-1-3 _________________________ 39 V. Clinical findings ___________________________________________________________ 42 Introduction __________________________________________________________________________ 42 Pharmacokinetics ____________________________________________________________________ 44 Pharmacodynamics__________________________________________________________________ 47 Dosage selection for the pivotal studies ___________________________________________ 49 Efficacy _______________________________________________________________________________ 49 Safety _________________________________________________________________________________ 54 First round benefit-risk assessment _______________________________________________ 61 First round recommendation regarding authorisation ___________________________ 64 Clinical questions and second round evaluation of clinical data submitted in response to questions _______________________________________________________________ 64 Second round benefit-risk assessment ____________________________________________ 64 Second round recommendation regarding authorisation ________________________ 65 VI. Pharmacovigilance findings ___________________________________________ 65 AusPAR RANEXA ranolazine – A Menarini Australia Pty Ltd PM-2015-00423-1-3 FINAL Page 3 of 96 20 February 2018 Therapeutic Goods Administration Risk management plan ______________________________________________________________ 65 VII. Overall conclusion and risk/benefit assessment _________________ 75 Quality ________________________________________________________________________________ 76 Nonclinical ___________________________________________________________________________ 77 Clinical ________________________________________________________________________________ 78 Risk management plan ______________________________________________________________ 86 Delegate’s considerations ___________________________________________________________ 87 Outcome ______________________________________________________________________________ 95 Attachment 1. Product Information ______________________________________ 95 Attachment 2. Extract from the Clinical Evaluation Report __________ 95 AusPAR RANEXA ranolazine – A Menarini Australia Pty Ltd PM-2015-00423-1-3 FINAL Page 4 of 96 20 February 2018 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning 5-HT Serotonin ACE Angiotensin converting enzyme ACS Acute coronary syndrome ACTH Adrenocorticotrophic hormone ADME Absorption, Distribution, Metabolism, and Excretion AE Adverse event AF Atrial fibrillation AP Action potential APD Action potential duration AST Aspartate aminotransferase ATX-II Anemone Toxin II AUC Area under the plasma concentration-time curve over one dosing interval AUC0-inf Area under the plasma concentration-time curve from time 0 to infinity AUC0-t Area under the plasma concentration-time curve from time 0 to last measurable time-point AUC Area under the plasma concentration versus time curve over the τ dosing interval AV Atrioventricular BCRP Breast cancer resistance protein BCS Biopharmaceutical Classification System BD Twice daily BE Bioequivalence BP Blood pressure CAD Coronary artery disease CCDS Core company data sheet AusPAR RANEXA ranolazine – A Menarini Australia Pty Ltd PM-2015-00423-1-3 FINAL Page 5 of 96 20 February 2018 Therapeutic Goods Administration Abbreviation Meaning CEC Clinical Events Committee CHF Congestive heart failure CHMP Committee for Medicinal Products for Human Use CI Confidence interval CL/F Oral clearance Cmax Maximum plasma concentration Cmax,ss steady-state Cmax Cmin minimum plasma concentration CNS Central nervous system COPD Chronic obstructive pulmonary disease CV coefficient of variation CVT CV Therapeutics, Inc. CYP Cytochrome P450 DMA or Dimethylaniline, or 2,6-xylidine DMA 2,6 DSM DSM Pharmaceuticals EAD Early after depolarization ECG Electrocardiogram ER Extended-release ETT Exercise treadmill (tolerance) testing EU European Union FAS Full analysis set GLP Good laboratory practice GI Gastrointestinal GVP good pharmacovigilance practices h Hour/s AusPAR RANEXA ranolazine – A Menarini Australia Pty Ltd PM-2015-00423-1-3 FINAL Page 6 of 96 20 February 2018 Therapeutic Goods Administration Abbreviation Meaning HbA1c Haemoglobin A1c hERG Human ether-à-go-go-related gene encoding pore-forming protein -subunits of the human potassium channel responsible for IKr representing α HFpEF Heart failure with preserved ejection fraction HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A HPLC High performance liquid chromatography HR Heart rate IARC International agency for research on cancer IC50 50% inhibitory concentration (measurement of relative potency of inhibition) ICa Inward calcium current through L-type calcium channels IK Total delayed