PUBLIC ASSESSMENT REPORT Decentralised Procedure Dienogest Aristo 2 mg Tabletten Procedure Number: DE/H/5431/001/DC Active Substance: Dienogest Dosage Form: Tablet Marketing Authorisation Holder in the RMS, Germany: Aristo Pharma GmbH Publication: 18.12.2019 This module reflects the scientific discussion for the approval of Dienogest Aristo 2 mg Tabletten. The procedure was finalised on 10.10.2019. TABLE OF CONTENTS I INTRODUCTION ......................................................................................................................... 4 II EXECUTIVE SUMMARY .......................................................................................................... 4 II.1 PROBLEM STATEMENT............................................................................................................... 4 II.2 ABOUT THE PRODUCT ................................................................................................................ 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER ............................................................... 5 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES ........................................................................................................................................... 5 III SCIENTIFIC OVERVIEW AND DISCUSSION .................................................................... 6 III.1 QUALITY ASPECTS .................................................................................................................... 6 III.2 NON CLINICAL ASPECTS ........................................................................................................... 7 III.3 CLINICAL ASPECTS ................................................................................................................... 7 IV BENEFIT RISK ASSESSMENT ............................................................................................. 11 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Dienogest Aristo 2 mg Tabletten product in the RMS Name of the drug substance (INN Dienogest name): Pharmaco-therapeutic group G03DB08 (ATC Code): Pharmaceutical form(s) and Tablet strength(s): Reference Number(s) for the DE/H/5431/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: AT,CZ,ES,IT,PL and SE Legal basis of application: Generic Art 10.1 Dir 2001/83/EC Aristo Pharma GmbH Marketing Authorisation Holder Wallenroder Str. 8-10 (name and address) 13435 Berlin Germany Aristo Pharma GmbH Names and addresses of all proposed Wallenroder Str. 8-10 manufacturer(s) responsible for 13435 Berlin batch release in the EEA Germany Dienogest Aristo 2 mg Tabletten DE/H/5431/001/DC Public Assessment Report Page 3/11 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Dienogest Aristo, in the treatment of endometriosis, is approved. II EXECUTIVE SUMMARY II.1 Problem statement For a generic application, this section is not applicable. II.2 About the product Mode of action: The active ingredient, dienogest is a nonethinylated progestogen. It is reported to have anti- androgenic properties. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo. Pharmacological classification: G03DB08, progestogens Claimed indication: Treatment of endometriosis Claimed posology: The dosage of dienogest is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. The tablet can be taken with or without food. Tablets must be taken continuously without regard to vaginal bleeding. When a pack is finished the next one should be started without interruption. There is no experience with dienogest treatment >15 months in patients with endometriosis. Treatment can be started on any day of the menstrual cycle. Any hormonal contraception needs to be stopped prior to initiation of dienogest. If contraception is required, non-hormonal methods of contraception should be used (e.g. barrier method). Management of missed tablets: The efficacy of dienogest may be reduced in the event of missed tablets, vomiting and/or diarrhea (if occurring within 3-4 hours after tablet taking). In the event of one or more missed tablets, the woman should take one tablet only, as soon as she remembers, and should then continue the next day at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by one tablet. Paediatric population: Dienogest is not indicated in children prior to menarche The safety and efficacy of dienogest was investigated in an uncontrolled clinical trial over 12 months in 111 adolescent women (12-<18) with clinically suspected or confirmed endometriosis. Geriatric population: There is no relevant indication for use of dienogest in the Geriatric population. Dienogest Aristo 2 mg Tabletten DE/H/5431/001/DC Public Assessment Report Page 4/11 Patients with hepatic impairment: Dienogest is contraindicated in patients with present or past severe hepatic disease. Patients with renal impairment: There are no data suggesting the need for a dosage adjustment in patients with renal impairment. II.3 General comments on the submitted dossier This decentralised application concerns a generic version of dienogest, under the name Dienogest Aristo. With Germany as the Reference Member State in this Decentralized Procedure, Aristo Pharma GmbH applied for the Marketing Authorisations for Dienogest 2 mg tablets in the Czech Republic, Italy, Poland, Spain and Sweden. Legal basis: These applications concern Article 10(1) generic applications with Visanne 2 mg tablets (Marketing authorisation holder Jenapharm GmbH & Co. KG). The medicinal reference product is approved for more than 8 years in the EU (date of authorization in EEA Germany: 26 January 2010), thus the data protection has expired. Therefore, this legal basis is considered justified. Reference product use in the member states: The reference product used in DE and the CMS is Visanne 2 mg from the marketing authorization holder: Bayer or Jenapharm. No ERP was used. Reference product use in the bioequivalence studies: The reference product, which was used, was Visanne 2 mg tablets, from Jenapharm (Germany). Summary justification applicant for essentially similarity claim: This marketing authorization application is based upon the Article 10(1) of directive 2001/83/EC as a generic application (essentially similar products i.e. generics). The essential similarity of the innovator product Visanne®, 2 mg Dienogest tablets (Jenapharm GmbH & Co. KG, Jena, Germany) and the generic product, Dienogest 2 mg tablets (Lindopharm GmbH, Germany (bulk and secondary packaging); Idifarma Desarrollo Farmacéutico, S.L., Spain (primary packaging)), was evaluated on the basis of dissolution profiles and clinical bioequivalence. Bioequivalence studies: A bioequivalence study has been conducted with Dienogest 2 mg tablets (Test) and with Visanne® 2 mg tablets manufactured by Jenapharm GmbH & Co. KG, Jena, Germany (Reference) when given in equal doses. Study reference number: 724B15 No scientific advice was given for this application. A Risk Management Plan has been submitted. There is no need for paediatric development or development in other special populations. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification Dienogest Aristo 2 mg Tabletten DE/H/5431/001/DC Public Assessment Report Page 5/11 that acceptable standards of GMP are in place at those sites. GMP active substance Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU. A statement on the application of appropriate GCP standards in the submitted study has been provided. A signed QAU Statement indicating that the study was regularly audited was provided. The clinical trial site and/or the bioanalytical facilities have been inspected by competent authorities/EU inspectors. During the assessment, no concerns regarding GCP compliance were identified. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Introduction The generic application concerns the following product: Dienogest Aristo (2 mg Dienogest tablets). The chemical-pharmaceutical documentation is not yet of sufficient quality in view of the present European regulatory requirements. Drug Substances Dienogest (DNG) is the international non-proprietary name (INN) of the drug substance. DNG is described in the Ph.Eur. (04/2016:2732). For the quality of DNG the applicant refers to an ASMF of the manufacturer Industriale Chimica Meanwhile a CEP was granted for the ASMF from Industriale Chimica S.r.l. and thus the ASMF could be accepted without further evaluation as according to EDQM the un-micronized Dienogest described in the ASMF can be controlled by the current Ph. Eur.