Australian Public Assessment Report for Retapamulin Proprietary Product Name: Altargo Sponsor: GlaxoSmithKline Australia Pty Ltd November 2013 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 <http://www.tga.gov.au>. About AusPARs · An Australian Public Assessment Record (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, in that it will provide 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 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]>. AusPAR Retapamulin; Altargo; GlaxoSmithKline Australia Pty Ltd; PM-2012-01489-3-2 Page 2 of 68 Date of Finalisation 11 November 2013 Therapeutic Goods Administration Contents I. Introduction to product submission _____________________________________ 5 Submission details ____________________________________________________________________ 5 Product background __________________________________________________________________ 6 Regulatory status _____________________________________________________________________ 6 Product Information __________________________________________________________________ 6 II. Quality findings _____________________________________________________________ 6 Drug substance (active ingredient) _________________________________________________ 6 Drug product __________________________________________________________________________ 7 Biopharmaceutics_____________________________________________________________________ 8 Advisory committee considerations ________________________________________________ 8 Quality summary and conclusions __________________________________________________ 8 III. Nonclinical findings _______________________________________________________ 8 Introduction ___________________________________________________________________________ 8 Pharmacology _________________________________________________________________________ 8 Pharmacokinetics ___________________________________________________________________ 13 Toxicology ___________________________________________________________________________ 17 Nonclinical summary and conclusions ____________________________________________ 22 Recommendation ___________________________________________________________________ 24 IV. Clinical findings __________________________________________________________ 25 Introduction _________________________________________________________________________ 25 Pharmacokinetics ___________________________________________________________________ 32 Pharmacodynamics _________________________________________________________________ 33 Efficacy ______________________________________________________________________________ 34 Safety ________________________________________________________________________________ 37 First round benefit-risk assessment_______________________________________________ 40 Clinical questions ___________________________________________________________________ 41 Recommendation regarding authorisation _______________________________________ 41 V. Pharmacovigilance findings ____________________________________________ 41 Risk management plan _____________________________________________________________ 41 VI. Overall conclusion and risk/benefit assessment __________________ 45 Quality _______________________________________________________________________________ 46 Nonclinical __________________________________________________________________________ 47 Clinical _______________________________________________________________________________ 47 Risk Management Plan _____________________________________________________________ 57 AusPAR Retapamulin; Altargo; GlaxoSmithKline Australia Pty Ltd; PM-2012-01489-3-2 Page 3 of 68 Date of Finalisation 11 November 2013 Therapeutic Goods Administration Risk-benefit analysis _______________________________________________________________ 58 Outcome _____________________________________________________________________________ 67 Attachment 1. Product Information ____________________________________ 67 Attachment 2. Extract from the Clinical Evaluation Report ________ 67 AusPAR Retapamulin; Altargo; GlaxoSmithKline Australia Pty Ltd; PM-2012-01489-3-2 Page 4 of 68 Date of Finalisation 11 November 2013 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New Chemical Entity Decision: Approved Date of decision: 19 July 2013 Active ingredient: Retapamulin Product name: Altargo Sponsor’s name and address: GlaxoSmithKline Australia Pty Ltd Level 4, 436 Johnston Street Abbotsford VIC 3067 Dose form: Topical ointment Strength: 1% weight/weight Container: Tube Pack sizes: 2.5, 5, 10 and 15 g Approved therapeutic use: Altargo is indicated for the short term treatment of superficial skin infections (including impetigo, infected small lacerations, abrasions, sutured wounds, and secondarily infected dermatoses) in adults, adolescents, children and infants aged from 9 months, in the absence of abscess formation and infections due to methicillin-resistant Staphylococcus aureus (MRSA). The in vitro susceptibility to antibiotics varies geographically and with time; the local situation must always be considered when selecting antibiotic therapy. Route of administration: Topical A thin layer of ointment should be applied to the affected area Dosage (abbreviated): twice daily for five days. The area treated may be covered with sterile bandage or gauze dressing if desired. Patients not showing a clinical response within three to four days should be re-evaluated. Safety and efficacy has not been established in secondarily infected traumatic lesions more than 10 cm in length or 100 cm2 in surface area, or in secondarily infected dermatoses or primary impetigo affecting more than 100 cm2 in surface area (or exceeding 2% of body surface area in paediatric patients). For topical application only. ARTG number: 198947 AusPAR Retapamulin; Altargo; GlaxoSmithKline Australia Pty Ltd; PM-2012-01489-3-2 Page 5 of 68 Date of Finalisation 11 November 2013 Therapeutic Goods Administration Product background Retapamulin is an antibacterial agent with a novel structure and a distinct mode of action. It is a member of a new chemical class of antibacterial agents for human use known as pleuromutilins. Retapamulin is a semisynthetic derivative of the compound pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus. Retapamulin selectively inhibits bacterial protein synthesis by interacting with the 50s subunit of the bacterial ribosome in a way that is distinct from that of other non-pleuromutilin antibiotics that interact with the ribosome. This AusPAR describes the application by GlaxoSmithKline Australia Pty Ltd (the sponsor) to register retapamulin as a 1% weight/weight (w/w) topical ointment (Altargo) for the following indications in adults, children and infants aged nine months and over: Altargo is indicated for the topical treatment of the following bacterial skin and skin structure infections (SSSI): · primary impetigo · secondarily infected traumatic lesions e.g. small lacerations, abrasions, sutured wounds · secondarily infected dermatoses including infected psoriasis, infected