Public Assessment Report

Scientific discussion

Flow 15 µg / 60 µg film-coated tablets , Gestodene

AT/H/0506/001/MR

This module reflects the scientific discussion for the approval of Flow. The procedure was finalised on 20.12.2013.

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I. INTRODUCTION

This MRP concerned a generic version of a combined oral contraceptive (COC), containing 15 micrograms ethinylestradiol/60 micrograms gestodene under the trade name Flow 15µg/60µg film- coated tablets. Ethinylestradiol (EE) is a synthetic , which is used as a component of most COCs. Gestoden is a C-19 nortestosterone derivate, an orally active synthetic of the 3rd generation that is used in combination with EE for oral contraception.

II. QUALITY ASPECTS

II.1 Introduction Flow is a film-coated tablet which is presented in a PVC/aluminium blister.

II.2 Drug Substance The active substances in Flow are ethinylestradiol and gestodene. The specification of the active substances meets the current scientific requirements. The adequate quality of the active substances has been shown by submitting the appropriate control data. The stability of the active substances has been tested under ICH conditions. The results of the stability studies support the established retest-period.

II.3 Medicinal Product Flow contains the following excipients: Active film-coated tablets: Tablet core: Lactose monohydrate (46.725 mg), Microcrystalline cellulose, Polacrilin potassium, Glyceryl distearate Film coating AquaPolish (yellow 024.15 MS) consisting of: hypromellose, hydroxypropylcellulose, talc, cottonseed oil (hydrogenated), titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172) Inactive film-coated tablet: Tablet core Lactose monohydrate (46.67 mg), Microcrystalline cellulose, Polacrilin potassium, Glyceryl distearate. Film coating AquaPolish (white 018.03 MS) consisting of: hypromellose, macrogol, cottonseed oil (hydrogenated), modified starch, titanium dioxide (E171)

The manufacturer responsible for batch release is Merckle GmbH, DE. The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 36 months.

The pharmaceutical quality of Flow has been adequately shown.

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II.4 Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics.

III. NON-CLINICAL ASPECTS

Pharmacodynamic, pharmacokinetic and toxicological properties of EE/gestodene are well known. As EE/gestodene is a widely used, well-known active substance (the reference product is Melodia 0.015mg/0.060 mg, Bayer Santé. FR) the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.

III.1 Ecotoxicity/environmental risk assessment Since Flow is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

IV. CLINICAL ASPECTS

IV.1 Introduction Flow is a single-phase oestrogen-progestogen combination. One tablet is to be taken daily for 28 consecutive days without a tablet-free interval between the individual blister strips, one active yellow film-coated tablet for the first 24 days and one white inactive film-coated tablet for the next 4 days.

IV.2 Pharmacokinetics Ethinylestradiol: Absorption Ethinylestradiol is rapidly and completely absorbed after oral ingestion. Following administration of 15 μg, peak plasma concentrations of 30 pg/ml are reached after 1-1.5 hours. Ethinylestradiol undergoes a marked first-pass effect which displays large interindividual differences. Absolute bioavailability is approximately 45%.

Distribution Ethinylestradiol has a volume of distribution of 15 L/kg and is about 98% bound to plasma proteins. Ethinylestradiol induces the hepatic synthesis of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). During administration of 15 μg ethinylestradiol, the plasma concentration of SHBG increases from 86 to about 200 nmol/L.

Biotransformation Ethinylestradiol is completely metabolised (metabolic clearance is approximately 10 ml/min/kg). The metabolites formed are excreted with the urine (40%) and faeces (60%).

Elimination The elimination half-life of ethinylestradiol is approximately 15 hours. Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a ratio of 4:6 (urine: bile).

Steady state Steady state is reached in the second half of the cycle, with plasma levels of ethinylestradiol accumulating by a factor of approximately 1.4-2.1. 3

Gestodene: Absorption Following oral administration, gestodene is rapidly and completely absorbed. Absolute bioavailability is approximately 100%. After oral ingestion of a single dose of 60 μg, peak plasma concentrations of 2 ng/ml are reached after about 60 minutes. Plasma concentrations are highly dependent on the SHBG concentration.

Distribution After a single dose of 60 μg, gestodene has a volume of distribution of 1.4 L/kg. It is 30% bound to albumin and 50 to 70% bound to SHBG.

Biotransformation Gestodene is almost completely metabolised via the usual pathways of metabolism. Metabolic clearance after a single dose of 60 μg is approximately 0.8 ml/min/kg. Non-active metabolites are excreted with the urine (60%) and faeces (40%).

Elimination The elimination half-life of gestodene is about 13 hours. It is prolonged to 20 hours when co- administered with ethinylestradiol.

Steady state After multiple dosing in combination with ethinylestradiol, the plasma concentration increases by a factor of about 2 to 4.

IV.3 Pharmacodynamics Pharmacotherapeutic group: and oestrogens, fixed combination ATC code: G03AA10 (urogenital system and sex hormones). The contraceptive efficacy of ethinylestradiol/gestodene is based on three complimentary modes of action: - Ovulation is inhibited at the level of the hypothalamic-pituitary axis. - Cervical mucus becomes impassable to sperm. - The endometrium becomes unsuitable for implantation.

IV.4 Bioequivalence study The applicant submitted the following bioequivalence (BE) study: Randomised, open-label, 2-way crossover, bioequivalence study of ethinylestradiol/gestoden 0.015 mg/0.060 mg tablets (test) and Melodia 0.015 mg/0.060 mg tablets (reference) following a 0.015 mg/0.060 mg dose in female healthy subjects under fasting conditions. 28 healthy female volunteers received one single oral dose of either test or reference product in each study period. The treatment phases were separated by a washout period of 28 days. EE and gestodene were determined in human plasma samples. Of the 28 subjects who were dosed, all completed the study. In accordance with the study protocol, data from all subjects who completed the study and for whom the pharmacokinetic profile was adequately characterised were used for the pharmacokinetic and statistical analysis (n=28). The bioequivalence between the test and the reference product has been shown appropriately.

IV.5 Clinical safety The safety results of the BE study do not suggest new safety concerns with regard to the test product.

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Overall, there is vast clinical experience with EE/gestodene containing COCs, indicating a good tolerability and well known safety of the active substances. COCs are known to have potential serious side effects, including an increased risk of venous thromboembolism, stroke, and myocardial infarction. Recently all available data on the risk of VTE with COCs containing EE/gestodene (among others) were under review in an Article 31 referral. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of combined hormonal contraceptives (CHCs) in preventing unwanted pregnancies continue to outweigh their risks, and that the well-known risk of VTE with all CHCs is small. The European Commission adopted a legally binding decision to update the product information of all CHCs throughout the EU, to ensure that clear and up-to-date information is provided.

IV.6 Discussion on the clinical aspects

This abridges application (“so called generic”) refers to the reference product Melodia comprimé pelliculé, 15µ/60µ, Bayer Santé, FR. For generics bioequivalence studies are pivotal (see above), repetitive tests on animals and humans are needless. The application contains an adequate review of published non-clinical and clinical data and based on the submitted bioequivalence study Flow 15µ/60µ film-coated tablets are considered bioequivalent with Melodia comprimé pelliculé, 15µ/60µ, Bayer Santé, FR.

V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

The benefit-risk ratio of Flow is considered favourable. The pharmaceutical quality of Flow has been adequately shown.

User consultation The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was German. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

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Public Assessment Report

Update

Flow 15 µg / 60 µg film-coated tablets Ethinylestradiol, Gestodene

AT/H/0506/001/MR

This module reflects the procedural steps and scientific information after the finalisation of the initial procedure.

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Procedure number* Scope Product Information Date of end Approval/ Summary/ Justification for affected of procedure non approval refuse

AT/H/0506/001/IB/001 Adaption of product information due to finalisation of article 31 referral yes 23.03.2014 approval - on combined hormonal contraceptives AT/H/0506/001/IB/003 Introduction of, or change(s) to, the obligations and conditions of a no 29.08.2014 approval - marketing authorisation, including the risk management plan AT/H/0506/001/IB/005 To update SmPC and PIL as an outcome of CMDh report of meeting yes 07.04.2016 approval - held on 23-25 March 2015. AT/H/0506/001/R/001 Renewal yes 04.11.2016 approval - *Only procedure qualifier, chronological number and grouping qualifier (when applicable)

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