AusPAR Attachment 1 Extract from the Clinical Evaluation Report for Bosentan Proprietary Product Name: Tracleer Sponsor: Actelion Pharmaceuticals Australia Pty Ltd First round report: 25 October 2016 Second round report: 3 February 2017 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 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]> . Attachment 2 TRACLEER - Bosentan - Actelion Pharmaceuticals Australia Pty Ltd - PM-2015-04745-1-3 Page 2 of 142 Extract from the Clinical Evaluation Report – FINAL 25 June 2018 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Introduction _______________________________________________________________ 9 1.1. Submission type _____________________________________________________________ 9 1.2. Drug class and therapeutic indication _____________________________________ 9 1.3. Dosage forms and strengths ________________________________________________ 9 1.4. Dosage and administration _______________________________________________ 10 1.5. Information on the condition being treated _____________________________ 11 1.6. Current treatment options ________________________________________________ 11 2. Clinical rationale _______________________________________________________ 12 2.1. Formulation ________________________________________________________________ 14 2.1. Evaluator’s commentary on the background information______________ 14 3. Contents of the clinical dossier ______________________________________ 15 3.1. Scope of the clinical dossier _______________________________________________ 15 Paediatric data ______________________________________________________________________ 16 3.2. Good clinical practice ______________________________________________________ 17 3.3. Evaluator’s commentary on the clinical dossier ________________________ 17 4. Pharmacokinetics ______________________________________________________ 18 4.1. Studies providing pharmacokinetic information ________________________ 18 4.1. Summary of pharmacokinetics ___________________________________________ 19 4.2. Evaluator’s overall conclusions on pharmacokinetics __________________ 37 5. Pharmacodynamics ____________________________________________________ 40 5.1. Studies providing pharmacodynamic information ______________________ 40 5.2. Summary of pharmacodynamics _________________________________________ 40 5.3. Evaluator’s overall conclusions on pharmacodynamics ________________ 40 6. Dosage selection for the pivotal studies ___________________________ 40 7. Clinical efficacy _________________________________________________________ 40 7.1. Pivotal or main efficacy studies___________________________________________ 41 7.2. Other efficacy studies _____________________________________________________ 55 7.3. Analyses performed across trials: pooled and meta analyses __________ 69 7.4. Evaluator’s conclusions on clinical efficacy ______________________________ 69 8. Clinical safety ___________________________________________________________ 70 8.1. Studies providing evaluable safety data _________________________________ 70 8.2. Studies that assessed safety as the sole primary outcome _____________ 70 8.3. Patient exposure ___________________________________________________________ 90 Attachment 2 TRACLEER - Bosentan - Actelion Pharmaceuticals Australia Pty Ltd - PM-2015-04745-1-3 Page 3 of 142 Extract from the Clinical Evaluation Report – FINAL 25 June 2018 Therapeutic Goods Administration 8.4. Adverse events _____________________________________________________________ 94 8.5. Evaluation of issues with possible regulatory impact _________________ 109 8.6. Other safety issues ________________________________________________________ 119 8.7. Post marketing experience_______________________________________________ 120 8.8. Evaluator’s overall conclusions on clinical safety ______________________ 124 9. First round benefit-risk assessment _______________________________ 124 9.1. First round assessment of benefits ______________________________________ 124 9.2. First round assessment of risks _________________________________________ 125 9.3. First round assessment of benefit-risk balance ________________________ 126 10. First round recommendation regarding authorisation ______ 127 11. Clinical questions ___________________________________________________ 127 11.1. General ____________________________________________________________________ 127 11.2. Pharmacokinetics _________________________________________________________ 127 11.3. Efficacy ____________________________________________________________________ 128 11.4. Safety ______________________________________________________________________ 128 11.5. PI and CMI _________________________________________________________________ 128 12. Second round evaluation of clinical data submitted in response to questions _____________________________________________________________________ 128 12.1. General ____________________________________________________________________ 128 12.2. Pharmacokinetics _________________________________________________________ 129 12.3. Efficacy ____________________________________________________________________ 134 12.4. Safety ______________________________________________________________________ 136 12.5. PI and CMI _________________________________________________________________ 138 13. Second round benefit-risk assessment _________________________ 139 13.1. Second round assessment of benefits ___________________________________ 139 13.2. Second round assessment of risks_______________________________________ 139 13.1. Second round assessment of benefit-risk balance _____________________ 141 14. Second round recommendation regarding authorisation ___ 141 Attachment 2 TRACLEER - Bosentan - Actelion Pharmaceuticals Australia Pty Ltd - PM-2015-04745-1-3 Page 4 of 142 Extract from the Clinical Evaluation Report – FINAL 25 June 2018 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning AaDO2 Alveolar-arterial oxygen difference ABG Arterial blood gas AE Adverse event AI Accumulation index ALT Alanine aminotransferase ANCOVA Analysis of covariance ARGPM Australian Regulatory Guidelines for Prescription Medicines ASA Australian Specific Annexe AST Aspartate aminotransferase AUC Area under the curve AUC0-24C Corrected AUC AUC0-24CN AUC dose normalised to 1 mg per day AUCτ AUC during a dosing interval BCS Biopharmaceutic Classification System BD Twice daily BMI Body mass index BP Blood pressure bpm Beats per minute CHD Congenital heart disease CHMP Committee for Medicinal Products for Human Use CI Confidence interval CL Confidence limits CL/f Apparent total body clearance Attachment 2 TRACLEER - Bosentan - Actelion Pharmaceuticals Australia Pty Ltd - PM-2015-04745-1-3 Page 5 of 142 Extract from the Clinical Evaluation Report – FINAL 25 June 2018 Therapeutic Goods Administration Abbreviation Meaning Cmax Maximum observed concentration CmaxC Corrected Cmax CMI Consumer Medicines Information CPMP Committee for Proprietary