AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Armodafinil Proprietary Product Name: Nuvigil Sponsor: Teva Pharmaceuticals Australia Pty Ltd First Round CER report: 4 December 2014 Second Round CER report: 26 April 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 the Extract from the Clinical Evaluation Report • This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities. • The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted. • For the most recent Product Information (PI), please refer to the TGA website <https://www.tga.gov.au/product-information-pi>. 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]>. Submission PM-2014-01922-1-1 Extract from the Clinical Evaluation Report for Nuvigil 2 / 153 Therapeutic Goods Administration Contents List of abbreviations ________________________________________________________ 5 1. Introduction ___________________________________________________________ 8 1.1. Submission type __________________________________________________________________8 1.2. Drug class and therapeutic indication _________________________________________8 1.3. Dosage forms and strengths ____________________________________________________8 1.4. Dosage and administration______________________________________________________8 2. Clinical rationale ______________________________________________________ 9 3. Contents of the clinical dossier ____________________________________ 10 3.1. Scope of the clinical dossier ___________________________________________________ 10 3.2. Paediatric data __________________________________________________________________ 10 3.3. Good clinical practice __________________________________________________________ 10 4. Pharmacokinetics ____________________________________________________ 11 4.1. Studies providing pharmacokinetic data ____________________________________ 11 4.2. Summary of pharmacokinetics _______________________________________________ 12 4.3. Evaluator's overall conclusions on pharmacokinetics _____________________ 36 5. Pharmacodynamics __________________________________________________ 39 5.1. Study 103 - Healthy young men undergoing acute sleep deprivation ____ 39 5.2. PK/PD modelling and simulations - Report Cephalon CP-05-001 ________ 41 5.3. Evaluator's overall conclusions on pharmacodynamics ___________________ 41 6. Dosage selection for the pivotal studies __________________________ 42 7. Clinical efficacy _______________________________________________________ 42 7.1. Overview of the studies________________________________________________________ 42 7.2. OSAHS ___________________________________________________________________________ 44 7.3. Narcolepsy ______________________________________________________________________ 64 7.4. Shift Work Sleep Disorder (SWSD) ___________________________________________ 74 7.5. Evaluator's conclusions on efficacy ________________________________________ 100 8. Clinical safety _______________________________________________________ 107 8.1. Studies providing evaluable safety data ___________________________________ 107 8.2. Overall extent of exposure __________________________________________________ 108 8.3. Adverse events _______________________________________________________________ 109 8.4. Laboratory tests ______________________________________________________________ 115 8.5. Electrocardiography _________________________________________________________ 118 8.6. Vital signs _____________________________________________________________________ 119 8.7. Polysomnography ____________________________________________________________ 121 Submission PM-2014-01922-1-1 Extract from the Clinical Evaluation Report for Nuvigil 3 / 153 Therapeutic Goods Administration 8.8. Other safety issues ___________________________________________________________ 122 8.9. Post marketing experience __________________________________________________ 123 8.10. Evaluator's overall conclusions on clinical safety _______________________ 124 9. First round benefit-risk assessment ____________________________ 128 9.1. OSAHS _________________________________________________________________________ 128 9.2. Narcolepsy ____________________________________________________________________ 130 9.3. SWSD __________________________________________________________________________ 132 9.4. First round assessment of risks ____________________________________________ 133 9.5. First round assessment of benefit-risk balance ___________________________ 135 10. First round recommendation regarding authorisation ______ 136 11. Clinical questions __________________________________________________ 136 11.1. Pharmacokinetics ___________________________________________________________ 136 11.2. Safety _________________________________________________________________________ 137 12. Second round evaluation of clinical data _______________________ 137 12.1. Pharmacokinetics ___________________________________________________________ 137 12.2. Safety _________________________________________________________________________ 146 13. Second round benefit-risk assessment _________________________ 152 13.1. Second round assessment of benefits ____________________________________ 152 13.2. Second round assessment of risks ________________________________________ 152 13.3. Second round assessment of benefit-risk balance ______________________ 152 14. Second round recommendation regarding authorisation ___ 152 Submission PM-2014-01922-1-1 Extract from the Clinical Evaluation Report for Nuvigil 4 / 153 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning ALT alanine aminotransferase (SGPT) ANC absolute neutrophil count ANCOVA analysis of covariance ANOVA analysis of variance AST aspartate aminotransferase (SGOT) BFI Brief Fatigue Inventory BMI body mass index BP blood pressure bpm beats per minute BUN blood urea nitrogen CDR Cognitive Drug Research (system) CFR Code of Federal Regulations CGI-C Clinical Global Impression of Change CGI-S Clinical Global Impression of Severity of Illness Cmax maximum observed plasma concentration Ctrough plasma trough concentration CMH Cochran-Mantel-Haenzel CRF case report form CRO contract research organization DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th Edition ECG electrocardiography, electrocardiogram ESS Epworth Sleepiness Scale FDA Food and Drug Administration GCP Good Clinical Practice Submission PM-2014-01922-1-1 Extract from the Clinical Evaluation Report for Nuvigil 5 / 153 Therapeutic Goods Administration Abbreviation Meaning GGT gamma-glutamyl transpeptidase HEENT head, eyes, ears, nose, and throat ICH International Conference on Harmonisation ICSD International Classification of Sleep Disorders IEC Independent Ethics Committee IRB Institutional Review Board LLN lower limit of normal range LS least square max maximum MedDRA Medical Dictionary for Regulatory Activities min minimum MSLT Multiple Sleep Latency Test MWT Maintenance of Wakefulness Test OSAHS obstructive sleep apnea/hypopnea syndrome OTC over-the-counter PSG polysomnography RBC red blood cell REM rapid eye movement SD standard deviation SE standard error SOP standard operating procedure SSRI selective serotonin reuptake inhibitor SWSD shift work sleep disorder ULN upper limit of the normal range WBC white blood cell Submission PM-2014-01922-1-1 Extract from the