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

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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.

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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

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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. monograph of Dienogest. Drug Product The medicinal drug product 2 mg DNG tablet is formulated as an immediate release tablet. The product composition is described sufficiently. In general, the physico-chemical characteristics of the drug substances and the choice of the excipients have been satisfactorily described. Different trials were done in order to adjust the process and formulation in order to obtain in-vitro dissolution profiles of the proposed product that are similar to the reference product Visanne. However, the development of the generic medicinal product is sufficiently described. The bioequivalence study was performed with a reference medicinal product marketed in DE: Visanne (2 mg Dienogest tablets). Information on the clinical batch used in the bioequivalence studies is provided. Comparative in-vitro dissolution between the test product (batch no. 16002) and the reference product used in the clinical BE study are provided. The manufacturing process is a direct compression at both manufacturing sites. The critical steps of the manufacturing process are discussed. The manufacturing processes are sufficiently described for both sites. The manufacturing process at the two manufacturing sites differs from one another but the applicant could demonstrate that the in vitro dissolution profiles of the validation batches from one manufacturer are similar with the in vitro dissolution profile of the clinical test batch for which the applicant claims bioequivalence with the reference product. The drug product is a specialized product as the dienogest content 2 mg in a tablet is very low (≤2 % of tablet mass), only and thus manufacture of the proposed drug is be critical in terms of blend homogeneity of the final blend before tableting and subsequent content uniformity of tablets.

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Therefore, the RMS blend homogeneity during the manufacturing process iscontrolled routinely by IPCs. The suitability of the excipients has been proven. A bulk holding time for the tablets can be granted. The release and shelf life specification are acceptable The limits of impurities are acceptable. All analytical procedures used for drug testing at release and shelf life have been well described. The validation data submitted are in accordance with the requirements of the relevant ICH guidelines and are therefore accepted. The methods used for assay and impurities are stability indicating. The batch analyses data demonstrate batch to batch consistency; no out of specification results have been reported. The packaging materials are sufficiently described and specified. Based on the stability data provided a shelf-life of 36 months with the storage conditions “Store in the original package in order to protect from light” as proposed by the applicant could be accepted for both sites.

III.2 Non clinical aspects

The pharmacodynamic, pharmacokinetic and toxicological properties of Dienogest are well known. As Dienogest is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. An overview based on a literature review is, thus, appropriate.

Environmental Risk Assessment (ERA) The product is a generic with the active pharmaceutical ingredient dienogest, which is a potent hormone. An increase in consumption of the active substance was shown in the CMS Italy, Poland and Spain in the last 4 years according to IMS Market Data (IMS Health) provided by the applicant. The applicant was asked to provide an ERA for the active substance Dienogest according to the EMA guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2*, June 2006) . As the active ingredient has an endocrine mode of action, a tailored risk assessment addressing the specific properties of the substance is necessary.

The applicant committed to update the current ERA in the dossier of Dienogest Aristo 2mg Tabletten by July 2021.

Conclusions on studies: We consider that a final conclusion on potential risk of the active substance dienogest to the environment cannot be drawn based on the available data yet.

III.3 Clinical aspects

One bioequivalence study was submitted (Protocol Identification Code: 724B15; Version 1.0, Date 2016/01/29). The study was an open-label, laboratory-blinded, randomized, single dose, two-period, two-treatment cross-over bioequivalence study in healthy female subjects under fasting conditions with a wash out period of 7 days between two administrations. A single dose study in fasting condition is adequate and in line with the recommendations of the Guideline on the investigation of Bioequivalence [CPMP/EWP/QWP/1401/98 Rev. 1/Corr** (BE-GL)], as the SmPC recommends intake irrespectively of food intake. Beside others, subjects with of hypersensitivity to the study drug or any related drugs or to any of the excipients, presence of any clinically significant cardiovascular, pulmonary, hepatobiliary, renal,

Dienogest Aristo 2 mg Tabletten DE/H/5431/001/DC Public Assessment Report Page 7/11 haematological, gastrointestinal, endocrinologic, immunologic, dermatologic, neurological, psychiatric, metabolic, musculoskeletal, or malignant disease, unwillingness or inability to comply with the study protocol or study-related procedures (e.g. difficulty to stay fasting, consume the standard meals, or swallow tablets; difficult venous access), have been excluded. The study population included healthy female volunteers aged 18-55 years, with a body mass index (BMI) ≥ 18.5 and ≤ 30 kg/m2. Each subject received one (1) 2 mg tablet of the test product or one (1) 2 mg tablet of the reference product in each study period. The subjects fasted overnight (at least 10 hours). Each dose was taken concomitantly with 240 mL of water. A thorough oral cavity check was performed immediately after drug administration to ensure that the study drug was swallowed. A standard lunch was taken 4 hours after dosing and 10 hours after dosing a standard afternoon dinner was consumed. The posture and physical activity after administration of the study drug were standardised in line with the requirements of the BE-GL. The reference product Visanne® 2 mg Tabletten, batch no. WEL8WF, expiry date 06/2020, source: DE (EU market). The applicant confirmed that the test product used in the BE study is identical to the product intended for marketing. A total of 40 subjects were screened in this study and, after randomization, 24 subjects (100%) received the Test and 24 subjects (100%) received the Reference. No subjects (0%) discontinued the study. Plasma samples of all (24) subjects were analysed and included in the pharmacokinetic and statistical analysis. During the trial three (5) subjects (1.2%) received concomitant medication (acetaminophen). No relevant effect of this concomitant medication on bioequivalence assessment (including bioanalytics) is to be expected as assay specificity in the presence of concomitantly administered acetaminophen has been shown. Only minor sampling time violations occurred and actual sampling times were used for bioequivalence parameter calculations. No effect on bioequivalence assessment would be expected. No further protocol deviations were documented. Bioanalytics The analytical method to quantify dienogest concentrations in plasma by using a LC-MS/MS method was developed and validated for dienogest at ACC GmbH Analytical Clinical Concepts, Leidersbach according to SOP 10-P-306. The method used has been described in detail. The validation is performed according to the Guideline on bioanalytical method validation, EMEA/CHMP/EWP/192217/2009. The levels of DNG were determined in 960 plasma samples by a validated HPLC-MS/MS method which covered the range 0.500 ng/ml – 200.000 ng DNG/mL. The performance of the analytical method was successfully demonstrated in the validation reports and also during in-study method performance. From the results of the validation, it can be concluded that the method used has adequate sensitivity, precision, accuracy, and specificity to determine DNG at the concentration levels expected in real samples.

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Results The main pharmacokinetic parameters of dienogest are displayed in the following table:

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range)

Treatment AUC0-t AUC0-∞ Cmax tmax ng/ml/h ng/ml/h ng/ml h Test 708.08 730.43 53.57 1.17 (0.67-4.00) ±200.49 ±207.65 ±11.57 Reference 684.40 706.90 50.06 1.84 (1.00-5.00) ±186.55 ±193.93 ±8.29 *Ratio (90% CI) 103.5 (100.4-106.8) 103.4 (100.3-106.6) 106.1 (101.3-111.2) %CVres(%) 6.2 6.2 9.4 AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t (72h). AUC0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t Cmax Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values Based on the submitted bioequivalence study 724B15 Dienogest Aristo is considered bioequivalent with Visanne (Jenapharm). Regarding the safety in the limited safety population no new signals or concerns became obvious. The informative texts of the SmPC and PL including the therapeutic indication are in line with the originator Visanne 2 mg tablets and acceptable.

Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan The applicant has provided a RMP (revision 2) version 0.2 with the data lock point 25.10.2017 and the sign off date 28.06.2018 covering one medicinal product with the proposed brand name “Dienogest Aristo 2mg Tabletten” within a decentralised marketing authorisation application for generic products.

Safety specification: The following summary of safety concerns have been proposed by the applicant, which is considered acceptable.

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Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMP The submitted Risk Management Plan, version 0.2 signed 28.06.2018 is considered acceptable.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.

• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.

• In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

Common renewal date The common renewal date is 10.10.2024.

Legal status Medicinal product subject to medical prescription.

User Test The results of this test indicate that the PIL provides a set of comprehensible information enabling the use of the medicinal product safely and appropriately.

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IV BENEFIT RISK ASSESSMENT

The application contains an adequate review of published clinical data.

Based on the submitted bioequivalence study, bioequivalence was demonstrated between the test product Dienogest Aristo and the reference product Visanne (Jenapharm).

The SmPC and PIL are in line with the current versions of the Originator and acceptable.

The application for Dienogest Aristo is approvable from a clinical point of view.

From the quality point of view the application is approvable.

RMP version 0.2 signed 28.06.2018 is approvable.

The application is approved. For intermediate amendments see current product information.

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