Australian Public Assessment for Armodafinil
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Australian Public Assessment Report for Armodafinil Proprietary Product Name: Nuvigil Sponsor: Teva Pharmaceuticals Australia Pty Ltd May 2016 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 Nuvigil Teva Pharmaceuticals Australia Pty Ltd PM-2014-01922-1-1 Page 2 of 124 Final 26 May 2016 Therapeutic Goods Administration Contents About AusPARs _______________________________________________________________ ii Common abbreviations _____________________________________________________ 5 I. Introduction to product submission ____________________________________ 8 Submission details ______________________________________________________________________ 8 Product background ____________________________________________________________________ 9 Regulatory status _______________________________________________________________________ 9 Product Information __________________________________________________________________ 11 II. Quality findings _________________________________________________________ 11 Introduction ___________________________________________________________________________ 11 Drug substance (active ingredient) _________________________________________________ 11 Drug product __________________________________________________________________________ 13 Biopharmaceutics _____________________________________________________________________ 14 Quality summary and conclusions __________________________________________________ 16 III. Nonclinical findings ___________________________________________________ 16 Introduction ___________________________________________________________________________ 16 Pharmacology _________________________________________________________________________ 17 Pharmacokinetics _____________________________________________________________________ 18 Toxicology _____________________________________________________________________________ 20 Nonclinical summary and conclusions _____________________________________________ 29 IV. Clinical findings ________________________________________________________ 31 Introduction ___________________________________________________________________________ 31 Pharmacokinetics _____________________________________________________________________ 32 Pharmacodynamics ___________________________________________________________________ 38 Dosage selection for the pivotal studies ____________________________________________ 40 Efficacy _________________________________________________________________________________ 41 Safety ___________________________________________________________________________________ 50 First round benefit-risk assessment ________________________________________________ 56 First round recommendation regarding authorisation ___________________________ 64 Clinical questions _____________________________________________________________________ 64 Second round evaluation _____________________________________________________________ 66 Second round benefit-risk assessment _____________________________________________ 80 Second round recommendation regarding authorisation ________________________ 80 V. Pharmacovigilance findings ___________________________________________ 80 Risk management plan _______________________________________________________________ 80 VI. Overall conclusion and risk/benefit assessment__________________ 89 AusPAR Nuvigil Teva Pharmaceuticals Australia Pty Ltd PM-2014-01922-1-1 Page 3 of 124 Final 26 May 2016 Therapeutic Goods Administration Quality __________________________________________________________________________________ 89 Nonclinical _____________________________________________________________________________ 90 Clinical _________________________________________________________________________________ 91 Risk management plan ______________________________________________________________ 118 Risk-benefit analysis _________________________________________________________________ 119 Outcome_______________________________________________________________________________ 123 Attachment 1. Product Information ____________________________________ 123 Attachment 2. Extract from the Clinical Evaluation Report ________ 123 AusPAR Nuvigil Teva Pharmaceuticals Australia Pty Ltd PM-2014-01922-1-1 Page 4 of 124 Final 26 May 2016 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ACPM Advisory Committee on Prescription Medicines ACSOM Advisory Committee on the Safety of Medicines AE adverse event AO asymmetric oxidation ARTG Australian Register of Therapeutic Goods AUC area under the plasma drug concentration-time curve BFI Brief Fatigue Inventory Cmax maximum concentration of drug in serum CDR Cognitive Drug Research CGI Clinical Global Impression CGI-C Clinical Global Impression of Change CGI-S Clinical Global Impression of Severity CHMP Committee for Medicinal Products for Human Use CL/F apparent clearance CPAP continuous positive airways pressure DAT dopamine transporter DDI drug-drug interaction EMA European Medicines Agency ESS Epworth Sleepiness Scale FAS full analysis set IC50 half maximal inhibitory concentration ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICSD International Classification of Sleep Disorders IP intraperitoneal AusPAR Nuvigil Teva Pharmaceuticals Australia Pty Ltd PM-2014-01922-1-1 Page 5 of 124 Final 26 May 2016 Therapeutic Goods Administration Abbreviation Meaning IV intravenous Ki inhibitory constant KSS Karolinska Sleepiness Scale MRHD Maximum Recommended Human Dose MSLT Multiple Sleep Latency Test MWT Maintenance of Wakefulness Test NOAEL no observed adverse effect level NOEL no observed effect level OSA Obstructive Sleep Apnoea OSAHS Obstructive Sleep Apnoea/Hypopnoea Syndrome PADER Periodic Adverse Drug Experience Report PD pharmacodynamic PI Product Information PK pharmacokinetic PO per os (oral) PPK population pharmacokinetic PSG polysomnography PVT Psychomotor Vigilance Task QD quaque die (once daily) RMP Risk Management Plan SAE serious adverse event SE sleep efficiency SJS Steven-Johnson Syndrome SWSD Shift Work Sleep Disorder Tmax amount of time a drug is present at the maximum concentration in serum AusPAR Nuvigil Teva Pharmaceuticals Australia Pty Ltd PM-2014-01922-1-1 Page 6 of 124 Final 26 May 2016 Therapeutic Goods Administration Abbreviation Meaning V/F volume of distribution WASO wake after sleep onset AusPAR Nuvigil Teva Pharmaceuticals Australia Pty Ltd PM-2014-01922-1-1 Page 7 of 124 Final 26 May 2016 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New chemical entity Decision: Approved Date of decision: 24 November 2015 Date of entry onto ARTG 26 November 2015 Active ingredient: Armodafinil Product name: Nuvigil Sponsor’s name and address: Teva Pharmaceuticals Australia Pty Ltd Level 2, 37 Epping