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

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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.

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Federal Institute for Drugs and Medical Devices The drug products consist of pink, round, film-coated tablets, packed into PVC foil/aluminium blisters as containers. The development of the drug product has been described, the choice of excipients is justified and their functions explained. Drug product manufacture and control of excipients are described sufficiently. Comparative in-vitro dissolution and impurity profile studies between the bio batches (test and reference product) have been presented, and as a consequence of the dissolution profiles the dissolution acceptance criteria have been specified adequately. The composition of the pharmaceutical product and route of manufacture of the finished product is described sufficiently. In-process-controls which cover the critical steps of the manufacturing process are described. The product specifications cover appropriate parameters for this dosage form and comprise the relevant quality characteristics. The control tests and specifications for drug product are adequately chosen with exception of the dissolution specification. Validation of the analytical methods has been presented. The results demonstrate that the methods used are qualified as stability indicating methods. Batch analysis has been performed. The batch analysis results show that the finished product meets the proposed specifications to date. The batch analyses data together with the results obtained from the stability testing and analytical validation studies provide evidence that the quality of the finished product is properly controlled by the analytical methods. The results of batch analyses demonstrate the reproducibility of the manufacturing process for the drug product On the basis of the submitted stability data and according to the Guideline on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products, a shelf-life of 18 months can be granted for the finished products Gammadinone, Betadinone, Lamour, Xidinone and Epsilondinone 2 mg/0.03 mg FCT.

III.2 Nonclinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of ethinyl estradiol and chlormadinone acetate are well known. As ethinyl estradiol and chlormadinone acetate are widely used, well-known active substances, no further studies are required. A nonclinical overview was presented, dated 9 Dec 2008 and including 45 publications up to year 2008. This is considered adequate. There are no objections to approval of Gammadinone from a non-clinical point of view.

III.3 Clinical aspects Pharmacokinetics The Applicant has submitted the results of one bioequivalence study. Study EHN-P8-408 is titled ”Single dose crossover comparative bioavailability study of ethinyl estradiol/chlormadinone acetate 0.03 mg/ 2 mg tablets in healthy female volunteers/fasting state.” The study was designed as a single center randomized, single dose, laboratory-blinded, 2-period, 2 sequence, crossover study. A single oral dose was administered under fasting conditions in each study period. The drug administrations were separated by a wash-out of 28 days. The primary objective was to evaluate and compare relative bioavailability and therefore the bioequivalence of two different formulations of ethinyl estradiol/ chlormadinone acetate after a single oral dose administration under fasting conditions.

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Federal Institute for Drugs and Medical Devices The clinical part was conducted at Algorithme Pharma Inc., Quebec, Canada. The clinical part was performed between 26/06/2008 and 03/10/2008. The final study report is dated 27.11.2008. The Test product used was Chlormadinone acetate 2mg/ Ethinylestradiol 0.03 mg tablets, one single dose of 1 tablet for oral administration, Batch No. H0460, Re-test date October 2010. The Reference product used was Belara, Grünenthal GmbH, Germany, Chlormadinone acetate 2mg /Ethinylestradiol 0.03 mg tablets, one single dose of 1 tablet for oral administration, Batch No. 430L18, Re-test date 03/2010. Forty-two healthy female subjects were planned for inclusion and 40 subjects were enrolled, 10 of these subjects dropped-out. Given the unexpected number of drop-out during the study, in addition to the first group “A” (n=40) a second group “B” of 14 subjects was enrolled in order to complete the study with at least 36 subjects. The mean age of the women included was 32 years (19-51 yrs), The mean weight was 63.0 kg (48.7 to 84.0 kg) and the mean BMI was 23.5 kg/m²(18.8 to 29.2 kg/m²). Statistical inference of ethinyl estradiol and chlormadinone based on a bioequivalence approach using the following standards: - The ratio of geometric LSmeans with corresponding 90 % confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameters Cmax, AUC-t and AUC∞ were all to be within the 80 to 125 % bioequivalence range. Based on the hypotheses used to generate the sample size (theoretical ratio of 95%, expected intra- subject CV of 29% and a sample size of 42), the expected 90% confidence interval around the ratio was expected to go from 85.8 to 105.2%. Taken together the subjects of both study groups A and B, fifty-four (54) healthy female subjects were included in the study. Of these fifty-four (54) subjects, forty-three (43) subjects completed the crossover design and received a single oral dose of the assigned formulation on day 1 and day 29. Overall, there were 43 subjects analysed and considered in the statistical analysis. The number of drop-outs is very high with about 25% (n=10) of the subjects originally being enrolled in the study (n=40). There were 4 subjects who had “abnormal haemoglobin values”. There was one subject dropped out “due to clinical events and haematological test results”. The results for the two components were as follows: Ethinyl estradiol

The mean Cmax were respectively 68.09 pg/mL and 68.04 pg/mL for the Test and Reference formulation. The Test to Reference Cmax ratio of geometric LSmeans was 100.25 % (90 % CI: 95.64 to 105.08 %). 90 % confidence interval of the relative Cmax geometric LSmeans of the Test to Reference formulation is within the pre-specified 80 to 125% bioequivalence range. The mean AUCT were respectively 608.67 pg·h/mL and 606.02 pg·h/mL for the Test and Reference formulation. The Test to Reference AUCT ratio of geometric LSmeans was 100.37% (90%CI: 96.50 to 104.39 %). This result thus demonstrates that the 90% confidence interval of the relative AUCT geometric LSmeans of the Test to Reference formulation is within the pre-specified 80 to 125% bioequivalence range. The mean AUC∞ were respectively 644.89 ng·h/mL and 645.46 ng·h/mL for the Test and Reference formulation. The Test to Reference AUC∞ ratio of geometric LSmeans was 99.74% (90 % CI: 96.36 to

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Federal Institute for Drugs and Medical Devices 103.25 %). This result thus demonstrates that the 90% confidence interval of the relative AUC∞ geometric LSmeans of the Test to Reference formulation is within the pre-specified 80 to 125% bioequivalence range.

The median Tmax was 1.75 and 1.50 hours for the Test and Reference formulations, respectively. The mean AUCT over AUC∞ individual ratio (AUCT/∞) were respectively 94.03% and 93.51% for the Test and Reference formulation. This implies that the blood sampling schedule was defined adequately to characterize at least 80% of the area under the curve for both products. Chlormadinone acetate The mean Cmax were respectively 3731.66 pg/mL and 3567.67 ng/mL for the Test and Reference formulation. The Test to Reference Cmax ratio of geometric LSmeans was 104.53% (90%CI: 97.34 to 112.25 %). This result thus demonstrates that the 90% confidence interval of the relative Cmax geometric LSmeans of the Test to Reference formulation is within the pre-specified 80 to 125% bioequivalence range. The median Tmax was 1.25 and 1.50 hours for the Test and Reference formulations, respectively. The mean AUCT were respectively 23213.18 pg·h/mL and 23479.23 ng·h/mL for the Test and Reference formulation. The Test to Reference AUCT ratio of geometric LSmeans was 98.53% (90%CI: 94.45 to 102.78 %). This result thus demonstrates that the 90 % confidence interval of the relative AUCT geometric LSmeans of the Test to Reference formulation is within the pre-specified 80 to 125% bioequivalence range. The mean AUC∞ were respectively 26382.18 ng·h/mL and 26953.97 ng·h/mL for the Test and Reference formulation. The Test to Reference AUC∞ ratio of geometric LSmeans was 97.90 % (90 % CI: 93.74 to 102.24%). This result thus demonstrates that the 90% confidence interval of the relative AUC∞ geometric LSmeans of the Test to Reference formulation is within the pre-specified 80 to 125% bioequivalence range. Study results for group A and additional group B The Applicant has presented the study results including all patients enrolled in group A and B. For both components, the ratios of test (treatment A, test) versus reference (treatment B, reference) for the primary PK parameters AUCτ and Cmax and for AUC∞ resulted to be within the predefined acceptance range of 80-125 %. The Applicant has declared that no interim analysis was performed and no bioanalytical investigation of plasma samples was performed before the second study group of subjects was enrolled. The Applicant has performed an additional analysis separately for each treatment group as requested by the RMS and CMS IT. Bioequivalence could be demonstrated for the pooled groups A and B and also for group A and B separately. The differences between the two groups seen in the intra-subject variance are most probably due to the smaller number of subjects in group B. A second test performed by the Applicant, the study-by treatment interaction did not show significant differences for any of the main study parameters. The Applicant has submitted the requested data. Bioequivalence could also be shown for both groups separately. The bioequivalence study is now accepted. Pharmacodynamics N/A Clinical efficacy N/A

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Federal Institute for Drugs and Medical Devices Clinical Safety The safety analysis included the fifty-four (54) subjects who entered the study and received at least one of the treatments. Forty-one (41) of the fifty-four (54) subjects experienced a total of ninety-six (96) adverse events during the study. Fifty-four adverse events (29 different types) were reported after the single dose administration of the Test product and forty-two adverse events (23 different types) were reported after the single dose administration of the Reference product. Twenty-eight (28) subjects (55%) reported adverse events after the administration of the Test formulation and twenty-eight (28) subjects (60%) reported adverse events after the administration of the Reference formulation. The most commonly reported adverse events were headache (n=10, 7 Test, 3 Reference respectively), somnolence (n=8, 4 Test, 4 Reference respectively), fatigue (n=5, 4 Test, 1 Reference respectively), nausea (n=5, 3 Test, 2 Reference respectively) abdominal pain (n=5, 2 Test, 3 Reference respectively) and abdominal distension (n=3, 1 Test, 2 Reference respectively) Eight (8) events that were judged possibly related to the study drugs were unexpected: (neutrophil count increased, somnolence (8 episodes), fatigue (5 episodes), dysgeusia, back pain, dyspepsia, lymphocyte count decreased and upper respiratory tract infection). No serious adverse events (SAEs) were recorded in this study. The safety profile of ethinylestradiol and chlormadinone acetate is well known. The most commonly reported adverse events like headache, abdominal pain, nausea and fatigue are potentially expected for this combined oral contraceptive and are already reflected in the proposed SPC. Pharmacovigilance system The RMS considers that the Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan No risk management plan is required for this application as the combination of CMA and EE is well known and already licensed for more than 10 years.

IV BENEFIT RISK ASSESSMENT The benefit-risk profile of EE and CMA containing combined oral contraceptive is well known. The originator product Belara, used as reference product in this application, is licensed on the German market for more than 10 years. The applicant has performed an additional analysis separately for each treatment group as requested by the RMS and CMS IT. The Applicant has submitted the requested data. Bioequivalence could also be shown for both groups A and B separately. The bioequivalence study is now accepted. The Applicant has further discussed the differences seen in intra-individual variance No new safety concerns have been identified from the bioequivalence study. From a clinical point of view, approval is now recommended. Concerning quality, approval is now also recommended.

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