Federal Institute for Drugs and Medical Devices PUBLIC ASSESSMENT REPORT Decentralised Procedure Scientific discussion during the initial procedure Gammadinone Betadinone Lamour Xidinone Epsilondinone Active Substance : Ethinylestradiol/Chlormadinone acetate Dosage Form : Film-coated tablets Procedure number DE/H/1606, 1607, 2349, 2374, 2375/001/DC Marketing authorisation holder in the Reference Member State, Germany : Helm Pharmaceuticals GmbH Nordkanalstr.28 20097 Hamburg, Germany Date: 25.02.2015 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/8 Public AR TABLE OF CONTENTS I RECOMMENDATION .......................................................................................................... 3 II EXECUTIVE SUMMARY .................................................................................................... 3 II.1 Problem statement ..................................................................................................................... 3 II.2 About the product ..................................................................................................................... 3 II.3 General comments on the submitted dossier............................................................................. 3 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. ....... 4 III SCIENTIFIC OVERVIEW AND DISCUSSION................................................................. 4 III.1 Quality aspects .......................................................................................................................... 4 Introduction ............................................................................................................................... 4 Drug substance .......................................................................................................................... 4 Drug Product ............................................................................................................................. 4 III.2 Nonclinical aspects ................................................................................................................... 5 III.3 Clinical aspects ......................................................................................................................... 5 Pharmacokinetics ...................................................................................................................... 5 Ethinyl estradiol ........................................................................................................................ 6 Chlormadinone acetate.............................................................................................................. 7 Study results for group A and additional group B .................................................................... 7 Pharmacodynamics ................................................................................................................... 7 Clinical efficacy ........................................................................................................................ 7 Clinical Safety ........................................................................................................................... 8 Pharmacovigilance system ........................................................................................................ 8 Risk Management Plan ............................................................................................................. 8 IV BENEFIT RISK ASSESSMENT ........................................................................................... 8 DE/H/1606/-07/2349/2374/2375/001/DC 2/8 Public AR Federal Institute for Drugs and Medical Devices I RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Betadinone, with the indication “hormonal contraception” is approvable.. II EXECUTIVE SUMMARY II.1 Problem statement This decentralised application concerns a generic version of a combined oral contraceptive containing 2 mg chlormadinone acetate (CMA) and 0.03 mg ethinylestradiol (EE) per film-coated tablets, under the trade names Betadinone, Epsilodinone, Gammadinone, Lamour and Xidinone. The trade name Betadinone will be used in this Overview. II.2 About the product The contraceptive effect of the combination of CMA and EE is based on the interaction of various effects, the most important of which may be seen as the inhibition of ovulation and the changes in the cervical secretion. The progestational component of Betadinone, CMA, is an antiandrogenic progestogen which is structurally related to cyproterone acetate. The second component, Ethinylestradiol (EE), which is known since more than 60 years, is a synthetic steroid with high oral estrogenic potency and is used as the estrogen in most currently marketed combined oral contraceptives. The preparation applied for is a monophasic COC, given once daily at a fixed dose over the treatment cycle of 21 days followed by a 7-day “pill free” period. The therapeutic indication applied for is hormonal contraception and is identical with the indication licensed for the originator product, Belara. II.3 General comments on the submitted dossier The application is submitted under article 10 (1), generic application of Council Directive 2001/83/EC, as amended, claiming to be a generic to the reference product Belara 0.3 mg/2 mg film- coated tablets, Grünenthal Laboratories; Germany. Belara also contains 2 mg CMA and 0.03 mg EE per tablet and was approved in Germany on 30.11.1998 (MA no. 36579.00.00). The clinical overview describes and discusses pharmacodynamics, pharmacokinetics, efficacy and safety aspects of ethinylestradiol/chlormadinone acetate containing combinded oral contraceptives (COCs) based on published data. The list of literature cited gives an extensive overview of published articles dated from 1979 to 2008 concerning the components EE and CMA and oral contraception. Furthermore, the clinical overview summarizes the bioequivalence study. The results of one bioequivalence study have been submitted. The reference product used in this study was Belara, approved in Germany, manufactured by Grünenthal Laboratories, Germany. The bioequivalence study was performed in accordance with the CPMP Note for Guidance on Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98). No further clinical studies have been submitted and are not required for this type of application. The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 3/8 Public AR Federal Institute for Drugs and Medical Devices Together with the submitted documentation the information given in the submitted dossier is sufficient for this generic application. Additional data to be submitted as requested in the list of questions should be summarized and discussed in the Applicant´s responses and not only submitted as annexes including only the original statistical results without any table of contents or Applicant´s comment. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 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 that acceptable standards of GMP are in place at those sites. For both active substances declarations from the Qualified Persons of the manufacturing holders in Section 2.5.1, responsible for batch release, are attached which confirm that all active substance manufacturers referred to in Section 2.5.3 operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. The Applicant declares that this study was performed in compliance with good clinical practice (GCP), including the archiving of essential documents. There is no hint for non-compliance with GCP. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Introduction The generic applications concern medicinal products containing 2 mg of EE and 0.03 mg CMA (FCT). The products are formulated as immediate release film coated tablets and are packaged in PVC/PVDC/Al blister. The documentation is of sufficient quality in view of the present European regulatory requirements. Drug substance The active substances CMA and EE are well known substances. The particle sizes are specified for both substances. The active drug substance CMA is described in French Pharmacopoeia (FPX) and Japanese Pharmacopoeia (JP). The manufacturer have submitted Active Substance Master Files (ASMF), based on the FPX and the JP monographs. The drug substance is controlled sufficiently. The control tests are adequately drawn up and the validation data are plausible. The available data show that CMA is stable for at least 5 years, if the samples are packed in a double polyethylene bag inside a fibre container. The quality of the drug substance EE is controlled in compliance with the recently implemented monograph of the European Pharmacopoeia (Ph. Eur.). For the EE manufacturer a Certificate of Suitability is presented documenting that the EE monograph is suitable to control the active substance purity. The micronisation step is discussed adequately. Drug Product The finished products Gammadinone, Betadinone, Lamour, Xidinone and Epsilondinone, film-coated tablets, contain 2 mg of CMA and 0.03 mg EE per film-coated tablet as drug substances each. The BfArM is a Federal Institute within the portfolio