Attachment 2: Extract from the Clinical Evaluation Report for Tadafil

AusPAR Attachment 2 Extract from the Clinical Evaluation Report for tadalafil Proprietary Product Name: Cialis Sponsor: Eli Lilly Australia Pty Ltd First round CER: 6 June 2012 Second round CER: 26 September 2012 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing, 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 <http://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 <http://www.tga.gov.au/hp/information-medicines-pi.htm>. Copyright © Commonwealth of Australia 2013 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-2011-03166-3-3 Extract from the Clinical Evaluation Report for Cialis Page 2 of 163 Therapeutic Goods Administration Contents List of abbreviations ________________________________________________________ 5 1. Clinical rationale ______________________________________________________ 9 2. Contents of the clinical dossier ____________________________________ 10 2.1. Scope of the clinical dossier _________________________________________________ 10 2.2. Paediatric data _______________________________________________________________ 10 2.3. Good clinical practice ________________________________________________________ 10 3. Pharmacokinetics ____________________________________________________ 10 3.1. Studies providing pharmacokinetic data ___________________________________ 10 3.2. Summary of pharmacokinetics _____________________________________________ 11 3.3. Evaluator’s overall conclusions on pharmacokinetics ____________________ 14 4. Pharmacodynamics __________________________________________________ 15 4.1. Studies providing pharmacodynamic data _________________________________ 15 4.2. Summary of pharmacodynamics ___________________________________________ 15 4.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 17 5. Dosage selection for the pivotal studies __________________________ 17 6. Clinical efficacy _______________________________________________________ 19 6.1. Treatment of the signs and symptoms of BPH in adult men ______________ 19 6.2. Treatment of ED and the signs and symptoms of BPH in adult men _____ 72 7. Clinical safety _________________________________________________________ 79 7.1. Studies providing evaluable safety data ____________________________________ 79 7.2. Pivotal studies that assessed safety as a primary outcome _______________ 82 7.3. Patient exposure ____________________________________________________________ 101 7.4. Adverse events ______________________________________________________________ 102 7.5. Laboratory tests _____________________________________________________________ 132 7.6. Post-marketing experience_________________________________________________ 142 7.7. Safety issues with the potential for major regulatory impact ___________ 143 7.8. Other safety issues __________________________________________________________ 146 7.9. Evaluator’s overall conclusions on clinical safety ________________________ 147 8. First round benefit-risk assessment ____________________________ 148 8.1. First round assessment of benefits ________________________________________ 148 8.2. First round assessment of risks ____________________________________________ 148 8.3. First round assessment of benefit-risk balance __________________________ 149 9. First round recommendation regarding authorisation ______ 149 10. Clinical questions __________________________________________________ 150 Submission PM-2011-03166-3-3 Extract from the Clinical Evaluation Report for Cialis Page 3 of 163 Therapeutic Goods Administration 10.1. Additional expert input ___________________________________________________ 150 10.2. Clinical questions __________________________________________________________ 150 11. Second round evaluation of clinical data submitted in response to questions __________________________________________________________________ 151 12. Second round benefit-risk assessment _________________________ 158 12.1. Second round assessment of benefits ____________________________________ 158 12.2. Second round assessment of risks _______________________________________ 158 12.3. Second round assessment of benefit-risk balance ______________________ 158 13. Second round recommendation regarding authorisation ___ 158 14. References __________________________________________________________ 159 Submission PM-2011-03166-3-3 Extract from the Clinical Evaluation Report for Cialis Page 4 of 163 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning 5-ARI 5-alpha reductase inhibitor ABPM ambulatory blood pressure monitoring ADR(s) adverse drug reaction(s) AE(s) adverse event(s) ALT alanine transaminase ANCOVA analysis of covariance ANOVA analysis of variance ARGPM Australian Regulatory Guidelines for Prescription Medicines AST aspartate transaminase AUA American Urological Association AUC area under the curve AUC area under the plasma concentration time curve for the dosing interval τ AUC 0- area under the plasma concentration time curve from zero to infinity ∞ BII Benign Prostatic Hyperplasia (BPH) Impact Index BCI Bladder Contractility Index BMI Body Mass Index BP blood pressure BPM beats per minute BOOI Bladder Outlet Obstruction Index BPH benign prostatic hyperplasia BPH-LUTS lower urinary tract symptoms associated with benign prostatic hyperplasia BVE bladder voiding efficiency Submission PM-2011-03166-3-3 Extract from the Clinical Evaluation Report for Cialis Page 5 of 163 Therapeutic Goods Administration Abbreviation Meaning CABG coronary artery bypass graft (surgery) CCDS Company Core Data Sheet CGI-I Clinician Global Impression of Improvement CIOMS Council for International Organisations of Medical Sciences cGMP cyclic guanosine monophosphate CI confidence interval CL/F apparent clearance Cmax maximum observed drug concentration CNS central nervous system DBP diastolic blood pressure ECG electrocardiogram ED erectile dysfunction EMA European Medicines Agency ERG electroretinogram EU European Union FAD female (sexual) arousal disorder FDA US Food and Drug Administration GCP Good Clinical Practice IC351 tadalafil IIEF International Index of Erectile Function IPSS International Prostate Symptom Score ITT intention-to-treat IVRS interactive voice response system IC710 unconjugated methylcatechol LHRH luteinising hormone-releasing hormone Submission PM-2011-03166-3-3 Extract from the Clinical Evaluation Report for Cialis Page 6 of 163 Therapeutic Goods Administration Abbreviation Meaning LLQ lower limit of quantification LOCF last observation carried forward LS least squares LUT lower urinary tract LUTS lower urinary tract symptoms LUTS-GAQ lower urinary tract symptoms-global assessment question LY450190 tadalafil MedDRA Medical Dictionary for Regulatory Activities MI myocardial infarction mIPSS Modified International Prostate Symptom Score ms millisecond NAION nonarteritic ischemic optic neuropathy NO nitric oxide NYHA New York Heart Association OAB over active bladder PAH pulmonary arterial hypertension PDE5 phosphodiesterase type 5 pdetQmax detrusor pressure at peak urinary flow rate PGI-I patient global impression of improvement PI Product Information PK pharmacokinetic PSA prostate-specific antigen PSUR Periodic Safety Update Report PVR post-void residual (volume) PVRcath post-void

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