Australian Public Assessment Report for Misoprostol Proprietary Product Name: GyMiso Sponsor: MS Health October 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. • 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 <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 2012 This work is copyright. 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AusPAR GyMiso Misoprostol Marie Stopes International Australia Page 2 of 100 PM-2011-01625-3-5 Final 2 October 2012 Therapeutic Goods Administration Contents Introduction to product submission __________________________________________________ 4 Submission details ____________________________________________________________________ 4 Product background __________________________________________________________________ 4 Regulatory Status _____________________________________________________________________ 5 Product Information__________________________________________________________________ 5 II. Quality findings _______________________________________________________________________ 5 Drug Substance _______________________________________________________________________ 5 Drug Product __________________________________________________________________________ 6 Conclusion ____________________________________________________________________________ 8 III. Nonclinical findings _________________________________________________________________ 8 Introduction ___________________________________________________________________________ 8 Pharmacology _________________________________________________________________________ 8 Pharmacokinetics _____________________________________________________________________ 9 Toxicology ____________________________________________________________________________ 10 Nonclinical Summary and Conclusions ____________________________________________ 12 IV. Clinical findings ____________________________________________________________________ 13 Introduction __________________________________________________________________________ 13 Pharmacokinetics ____________________________________________________________________ 15 Pharmacodynamics__________________________________________________________________ 23 Efficacy _______________________________________________________________________________ 27 Safety _________________________________________________________________________________ 46 First Round Benefit-Risk Assessment ______________________________________________ 63 List of Questions _____________________________________________________________________ 65 Second Round Benefit-Risk Assessment ___________________________________________ 65 V. Pharmacovigilance findings _______________________________________________________ 66 Risk Management Plan ______________________________________________________________ 66 Summary of Recommendations ____________________________________________________ 74 VI. Overall conclusion and risk/benefit assessment _____________________________ 75 Quality ________________________________________________________________________________ 75 Nonclinical ___________________________________________________________________________ 76 Clinical ________________________________________________________________________________ 77 Risk Management Plan ______________________________________________________________ 82 Risk-benefit analysis ________________________________________________________________ 83 Outcome ______________________________________________________________________________ 89 Appendix 1. Clinical References _____________________________________________________ 89 Attachment 1. Product Information ____________________________________________ 99 AusPAR GyMiso Misoprostol MS Health Page 3 of 100 PM-2011-01625-3-5 Final 2 October 2012 Therapeutic Goods Administration Introduction to product submission Submission details Type of Submission Extension of indications (New formulation, new indication) Decision: Approved Date of Decision: 7 August 2012 Misoprostol Active ingredient(s): Product Name(s): GyMiso Sponsor’s Name and Address: MS Health1l, GPO Box 1635, Melbourne VIC Dose form(s): Tablet (uncoated, not scored) Strength(s): 200 µg Container(s): Blister pack Pack size(s): 4 x tablets Approved Therapeutic use: GyMiso® is indicated in females of childbearing age for the medical termination of a developing intrauterine pregnancy in sequential combination with a mifepristone 200 mg tablet, up to 49 days of gestation. Route(s) of administration: Oral (PO) or buccal Dosage: 800 µg (4 tablets) ARTG Number (s) 188015 Product background Misoprostol is a prostaglandin E1 analogue. This AusPAR describes an application to register GyMiso, misoprostol 200 µg tablets, which is linked to a related application to register Mifepristone Linepharma 200 mg tablet. A single dose of 800 GyMisio is proposed to be used in combination with the 200 mg mifepristone tablets to achieve termination of pregnancy in women who are up to 49 days of gestation/daysμg of amenorrhoea (DA). The 200 mg mifepristone dose is to be taken 36 to 48 h before the misoprostol dose. Cytotec misoprostol 200 µg tablets are currently registered for use in Australia (ARTG R 63983) for the treatment of acute duodenal and gastric ulcers and for the prevention of stress induced upper gastrointestinal mucosal bleeding and lesions in post surgical patients in intensive care units. GyMiso is new formulation of misoprostol for a new indication. GyMiso is not proposed as a generic medicine with respect to Cytotec and no gastrointestinal indications are proposed for GyMiso. 1 The Applicant Marie Stopes International Australia has transferred sponsorship of the registered product to MS Health. AusPAR GyMiso Misoprostol MS Health Page 4 of 100 PM-2011-01625-3-5 Final 2 October 2012 Therapeutic Goods Administration The approved regimen for Cytotec® for gastrointestinal indications involves a total daily longer. dose of 800 μg, taken in divided doses for periods of 14 days up to 12 months or even The sponsor proposed the following indication for GyMiso: In adults and adolescents of childbearing age for the medical termination of a developing intrauterine pregnancy in sequential combination with Mifepristone Linepharma 200mg tablet, up to 49 days of gestation. Cytotec® has been widely used off-label internationally and in Australia for many years for this and related gynaecological indications. Other prostaglandins are registered in Australia for obstetric and gynaecological indications as follows: • Gemeprost (Cervagem®; vaginal pessary): For the softening and dilatation of the cervix uteri prior to transcervical, intrauterine operative procedures in the first trimester of pregnancy. Therapeutic termination of pregnancy in patients in the second trimester of gestation. • Dinoprostone (Cervidil®; vaginal pessary): Cervical ripening in patients, at or near term, who have favourable induction features and in whom there is a medical or obstetrical indication for induction of labour. • Dinoprostone (Prostin® E2; vaginal pessary): Induction of labour