Australian Public Assessment Report for Netupitant / Palonosetron (As Hydrochloride)
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Australian Public Assessment Report for Netupitant / palonosetron (as hydrochloride) Proprietary Product Name: Akynzeo Sponsor: Specialised Therapeutics Australia Pty 1 Ltd October 2016 1 Post registration the sponsorship for Akynzeo has changed to Mundipharma Pty Ltd, GPO Box 5214, Sydney NSW 2001. 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 2016 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 Akynzeo Netupitant/palonosetron Specialised Therapeutics Australia Pty Ltd Page 2 of 88 PM-2014-00341-1-4 Final 28 October 2016 Therapeutic Goods Administration Contents About AusPARs _______________________________________________________________ ii Common abbreviations _____________________________________________________ 5 I. Introduction to product submission ____________________________________ 9 Submission details ______________________________________________________________________ 9 Product background __________________________________________________________________ 10 Regulatory status _____________________________________________________________________ 10 Product Information __________________________________________________________________ 12 II. Quality findings _________________________________________________________ 12 Introduction ___________________________________________________________________________ 12 Drug substance (active ingredient) _________________________________________________ 12 Drug product __________________________________________________________________________ 12 Biopharmaceutics _____________________________________________________________________ 13 Advisory committee considerations ________________________________________________ 13 Quality summary and conclusions __________________________________________________ 14 III. Nonclinical findings ___________________________________________________ 14 Introduction ___________________________________________________________________________ 14 Pharmacology _________________________________________________________________________ 14 Pharmacokinetics _____________________________________________________________________ 19 Pharmacokinetic drug interactions _________________________________________________ 19 Toxicology _____________________________________________________________________________ 20 Genotoxicity ___________________________________________________________________________ 25 Paediatric use _________________________________________________________________________ 28 Nonclinical summary _________________________________________________________________ 28 IV. Clinical findings ________________________________________________________ 30 Clinical rationale ______________________________________________________________________ 30 Pharmacokinetics _____________________________________________________________________ 31 Population pharmacokinetics _______________________________________________________ 37 Efficacy _________________________________________________________________________________ 42 Safety ___________________________________________________________________________________ 44 First round benefit-risk assessment ________________________________________________ 47 First round recommendation regarding authorisation ___________________________ 50 Clinical questions _____________________________________________________________________ 50 Second round evaluation of clinical data submitted in response to questions _ 51 Second round benefit-risk assessment _____________________________________________ 51 AusPAR Akynzeo Netupitant/palonosetron Specialised Therapeutics Australia Pty Ltd Page 3 of 88 PM-2014-00341-1-4 Final 28 October 2016 Therapeutic Goods Administration V. Pharmacovigilance findings ___________________________________________ 51 Risk management plan _______________________________________________________________ 51 Summary of recommendations ______________________________________________________ 65 VI. Overall conclusion and risk/benefit assessment__________________ 65 Quality __________________________________________________________________________________ 65 Nonclinical _____________________________________________________________________________ 66 Clinical _________________________________________________________________________________ 66 Risk management plan _______________________________________________________________ 76 Risk-benefit analysis __________________________________________________________________ 76 Attachment 1. Product Information _____________________________________ 87 Attachment 2. Extract from the Clinical Evaluation Report _________ 87 AusPAR Akynzeo Netupitant/palonosetron Specialised Therapeutics Australia Pty Ltd Page 4 of 88 PM-2014-00341-1-4 Final 28 October 2016 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning 5-HT3 Serotonin 5-HT3 RA 5-HT3 receptor antagonist AC anthracycline-cyclophosphamide ADR adverse drug reaction AE adverse event ALT Alanine aminotransferase APD action potential duration ASCO American Society of Clinical Oncology AST Aspartate aminotransferase AUC area under the concentration time curve AUCinf area under the concentration versus time curve up to infinity AUC0- area under the concentration versus time curve up to infinity ∞ AUC0-t area under the concentration-time curve from time zero to time t AUC0-tz area under the concentration-time data profile from administration until the last sampling point (tz) equal or above LLOQ. BA bioavailability BCRP breast cancer resistance protein BD twice daily BE bioequivalence BP British Pharmocopeia bpm beats per minute CHMP Committee for Medicinal Products for Human Use CI Confidence interval CINV Chemotherapy induced nausea and vomiting CL/F apparent clearance AusPAR Akynzeo Netupitant/palonosetron Specialised Therapeutics Australia Pty Ltd Page 5 of 88 PM-2014-00341-1-4 Final 28 October 2016 Therapeutic Goods Administration Abbreviation Meaning CLCR Creatinine clearance Cmax peak drug concentration CNS central nervous system CTZ chemoreceptor trigger zone CYP Cytochrome P450 CYP3A4 Cytochrome P450 isoenzyme 3A4 ECG Electrocardiogram ED50 Median (50%) effective dose EMA European Medicines Agency EPAR European public assessment reports EviQ Evidence based cancer treatments (online) ESMO European Society for Medical Oncology EU European Union FAS Full Analysis Set FDA Food and Drug Administration FDC fixed dose combination G-CSF granulocyte colony-stimulating factor GD gestation day GDH glutamate dehydrogenase GGT gamma-glutamyl transpeptidase GLP Good Laboratory Practice GM-CSF granulocyte macrophage colony-stimulating factor h hour/s Hb haemoglobin HEC highly emetogenic chemotherapy hERG human Ether-à-go-go Related Gene AusPAR Akynzeo Netupitant/palonosetron Specialised Therapeutics Australia Pty Ltd Page 6 of 88 PM-2014-00341-1-4 Final 28 October 2016 Therapeutic Goods Administration Abbreviation Meaning IV Intravenous MASCC Multinational