Australian Public Assessment Report for alprostadil Proprietary Product Name: Proshaeos Sponsor: Commercial Eyes Pty Ltd June 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 Proshaeos Commercial Eyes Pty Ltd PM-2014-03512-1-3 Page 2 of 91 Final 9 June 2016 Therapeutic Goods Administration Contents About AusPARs _________________________________________________________________ ii Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 7 Submission details ____________________________________________________________________ 7 Product background __________________________________________________________________ 7 Regulatory status _____________________________________________________________________ 8 II. Quality findings ___________________________________________________________ 10 Introduction __________________________________________________________________________ 10 Drug substance (active ingredient) ________________________________________________ 10 Drug product _________________________________________________________________________ 11 Advisory committee considerations _______________________________________________ 12 Quality summary and conclusions _________________________________________________ 13 III. Nonclinical findings _____________________________________________________ 13 Introduction __________________________________________________________________________ 13 Pharmacology ________________________________________________________________________ 13 Pharmacokinetics ____________________________________________________________________ 14 Toxicology ____________________________________________________________________________ 15 Nonclinical summary and conclusions _____________________________________________ 24 IV. Clinical findings __________________________________________________________ 26 Introduction __________________________________________________________________________ 26 Pharmacokinetics ____________________________________________________________________ 28 Pharmacodynamics__________________________________________________________________ 29 Dosage selection for the pivotal studies ___________________________________________ 30 Efficacy _______________________________________________________________________________ 31 Safety _________________________________________________________________________________ 40 First round benefit-risk assessment _______________________________________________ 49 First round recommendation regarding authorisation ___________________________ 50 Clinical questions ____________________________________________________________________ 51 Second round evaluation ____________________________________________________________ 54 Second round recommendation regarding authorisation ________________________ 55 V. Pharmacovigilance findings ____________________________________________ 56 Risk management plan ______________________________________________________________ 56 VI. Overall conclusion and risk/benefit assessment __________________ 68 Quality ________________________________________________________________________________ 68 Nonclinical ___________________________________________________________________________ 69 AusPAR Proshaeos Commercial Eyes Pty Ltd PM-2014-03512-1-3 Page 3 of 91 Final 9 June 2016 Therapeutic Goods Administration Clinical ________________________________________________________________________________ 70 Risk management plan ______________________________________________________________ 78 Risk-benefit analysis ________________________________________________________________ 79 Outcome ______________________________________________________________________________ 90 Attachment 1. Extract from the Clinical Evaluation Report __________ 90 AusPAR Proshaeos Commercial Eyes Pty Ltd PM-2014-03512-1-3 Page 4 of 91 Final 9 June 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 ASA Australian Specific Annex Cmax maximum plasma concentration of a drug after administration CMI Consumer Medicines Information DDAIP dodecyl-2-N, N-dimethylaminopropionate ECG electrocardiogram ED erectile dysfunction EF Erectile Function (score) from International Index of Erectile Function ER exposure ratio FDA Food and Drug Administration HCl hydrochloride IC50 inhibitory concentration 50% ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IIEF International Index of Erectile Function ITT Intention to Treat IV intravenous LD50 lethal dose 50% mcg microgram (µg) MHRA Medicines and Healthcare Products Regulatory Agency (UK) PD pharmacodynamic/s PGE0 prostaglandin E0 PGE1 prostaglandin E1 AusPAR Proshaeos Commercial Eyes Pty Ltd PM-2014-03512-1-3 Page 5 of 91 Final 9 June 2016 Therapeutic Goods Administration Abbreviation Meaning Ph. Eur European Pharmacopoeia PI Product Information PIL Patient Information Leaflet PK pharmacokinetic/s PP Per Protocol PSUR Periodic Safety Update Report RMP Risk Management Plan SAE serious adverse event SC subcutaneous SEP Sexual Encounter Profile SPC Summary of Product Characteristics STD sexually transmitted disease STI sexually transmitted infection TEAE treatment emergent adverse event USP United States Pharmacopeia AusPAR Proshaeos Commercial Eyes Pty Ltd PM-2014-03512-1-3 Page 6 of 91 Final 9 June 2016 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: Major variation (new dosage form, new dose, new strength and new route of administration) Decision: Withdrawn Active ingredient: Alprostadil Product name: Proshaeos Sponsor’s name and address: Commercial Eyes Pty Ltd Level 11 500 Collins Street Melbourne VIC 3000 Dose form: Cream Strengths: 0.2% w/w (200 µg) and 0.3% w/w (300 µg) Container: AccuDose Dispenser placed into a foil laminate pouch and packed into a box Pack size: 4 dispensers Route of administration: Topical Dosage: Used as needed; patients should be initiated with the 300 µg dose and titrated down to 200 µg dose based on patient tolerance Product background This AusPAR describes the application by Commercial Eyes Pty Ltd, on behalf of Montrose Pharma Pty Ltd, to register a new dosage form of alprostadil. The cream will be available in 200 and 300 µg strengths and are proposed to be registered under the trade name Proshaeos. 1 Erectile dysfunction (ED) is a common problem, with physiological and psychological (sometimes mixed) aetiologies. It is more frequent in patients with increasing age, and in the setting of diabetes, vascular disease or neurological disorders. The strategies for management include treatment of any underlying disorder