C B G M E B Public Assessment Report Scientific discussion Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets (desogestrel/ethinylestradiol) NL/H/3146/001-002/DC Date: 26 August 2016 This module reflects the scientific discussion for the approval of Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets. The procedure was finalised on 8 June 2015. For information on changes after this date please refer to the ‘steps taken after finalisation’ at the end of this PAR. C B G M E B List of abbreviations ASMF CEP CHMP CMD(h) CMS EDMF EDQM EEA ERA ICH MAH Ph.Eur. PL RH RMP SmPC TSE Active Substance Master File Certificate of Suitability to the monographs of the European Pharmacopoeia Committee for Medicinal Products for Human Use Coordination group for Mutual recognition and Decentralised procedure for human medicinal products Concerned Member State European Drug Master File European Directorate for the Quality of Medicines European Economic Area Environmental Risk Assessment International Conference of Harmonisation Marketing Authorisation Holder European Pharmacopoeia Package Leaflet Relative Humidity Risk Management Plan Summary of Product Characteristics Transmissible Spongiform Encephalopathy 2/11 C I. B G M E B INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets from Stada Arzneimittel AG. The product is indicated for oral contraception. A comprehensive description of the indications and posology is given in the SmPC. For the lowest strength the MAH claimed essential similarity with Mercilon 0.15/0.02 mg, tablets (NL License RVG 11508) which has been registered in the Netherlands by N.V. Organon since 19 November 1987. For the 150/30 micrograms strength, essential similarity is claimed with the innovator product Marvelon 0.15/0.03 mg tablets (NL License RVG 08859) which has been registered in the Netherlands by N.V. Organon since 29 May 1981. In addition, reference is made to Mercilon and Marvelon authorisations in the individual member states (reference product). The concerned member states (CMS) involved in this procedure were Czech Republic and Spain. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Desogestrel/Ethinylestradiol STADA 150/20 mcg is a white to off-white, round, biconvex, uncoated tablet. It contains 20 microgram ethinylestradiol and is debossed with ‘141’ on one side. Desogestrel/Ethinylestradiol STADA 150/30 mcg is a white to off-white, round, biconvex, uncoated tablet. It contains 30 microgram ethinylestradiol and is debossed with ‘142’ on one side. The tablets are packed in clear transparent PVC/PVDC-Al blisters in tri-laminated pouches, with or without a molecular sieve. The excipients are: anhydrous lactose, potato starch, povidone K30 (E1201), stearic acid (E570), αTocopherol (E370), colloidal silicon dioxide (E551). II.2 Drug Substances Desogestrel The active substance desogestrel is an established active substance described in the European Pharmacopoeia (Ph.Eur.). Desogestrel is a white or almost white powder or crystals. It is slightly soluble in ethanol (96%) and in ethyl acetate, sparingly soluble in n-Hexane and practically insoluble in water. Desogestrel has six chiral centres. It exhibits polymorphism. Because the drug substance is dissolved before the manufacture of the drug product, information on polymorphism and particle size distribution is not considered necessary. The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. 3/11 C B G M E B Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The active substance specification is considered adequate to control the quality. It meets the requirements of the monograph in the Ph.Eur. with additional tests on residual solvents. Batch analytical data demonstrating compliance with this specification have been provided for 6 batches. Stability of drug substance For one supplier The MAH submitted stability testing results in support of a retest period of 5 years without any special storage conditions. For the other supplier no retest period was included on the CEP. Ethinylestradiol The active substance is ethinylestradiol, an established active substance described in the European Pharmacopoeia (Ph.Eur.). Ethinylestradiol is a white to practically white powder. It is freely soluble in dioxane, diethyl ether, acetone and ethanol; soluble in chloroform and practically insoluble in water. Ethinylestradiol has five chiral centres and does not exhibit polymorphism. The CEP procedure is also used for this active substance. Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The active substance specification is considered adequate to control the quality It meets the requirements of the monograph in the Ph.Eur. with additional tests on residual solvents, visible particles, heavy metals, any other impurity and particle size distribution. Batch analytical data demonstrating compliance with this specification have been provided for one production batch. Stability of drug substance A retest period of 5 years is applied, when stored under the stated conditions. Assessment thereof was part of granting the CEP and has been granted by the EDQM. II.3 Medicinal Product Pharmaceutical development The development of the product has been adequately described, the choice of excipients is justified and their functions explained. The pharmaceutical development of the product has been adequately performed. The development of the clinical batches is discussed, comparative dissolution profiles at different pHs are provided. The dissolution profiles of desogestrel do not fully support bioequivalence, however, the in vivo data prevail. Equivalence of the reference product used in the bioequivalence studies with the innovator products from all member states has been demonstrated. Manufacturing process The drug product is manufactured by a wet non-aqueous granulation process. The active substances and some excipients are mixed together. The premix is further mixed, granulated, then air dried and sifted. The final blend is compressed and packed. The provided in-process controls are deemed acceptable. The manufacturing process has been adequately validated according to relevant European guidelines. The product is manufactured using conventional manufacturing techniques, but given the low concentration of active substance in the drug product, the process can be considered as nonstandard. Full-scale process validation results have been provided. Control of excipients The excipients are tested in accordance with their respective Ph. Eur. Monograph. The specifications are acceptable. 4/11 C B G M E B Quality control of drug product The drug product specifications includes tests for appearance, identification, identification and assay of vitamin E, dissolution, assay, related substances, uniformity of dosage units (content uniformity), residual isopropyl alcohol, microbiological requirements and water content. The shelf-life specifications are the same as the release specification, with the exception of the limit for assay of ethinylestradiol, related substances and vitamin E content. The analytical methods have been adequately described and validated. Batch analytical data from the proposed production site have been provided on three pilot scaled batches of each tablet strength, demonstrating compliance with the release specifications. Stability of drug product Stability data on the product have been provided for three pilot scale batches for each tablet strength . The data cover up to 24 months stored at 25°C/60%RH and 6 months stored at 40°C/75%RH. The conditions used in the stability studies are according to the ICH stability guideline. The batches were stored in clear transparent PVC/PVDC-Al blisters in tri-laminated pouches; sub batches of each batch for a packaging with molecular sieve and without the molecular sieve. The accelerated conditions demonstrate that the drug product is slightly sensitive to elevated temperatures. However, it stayed well within the specifications and no restrictive storage temperatures are required. Under all conditions, a decrease in assay and dissolution and an increase in impurities are observed. As demonstrated by forced degradation studies the product is light sensitive and moisture sensitive. An in-use stability study demonstrated that the packaging is adequate to protect the product from light and moisture. The shelf-life of 24 months with the storage conditions “Store in the original package in order to protect from moisture and light” when stored in clear transparent PVC/PVDC-Al blisters in trilaminated pouches; with or without the molecular sieve can be granted. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies Lactose anhydrous is the only excipient of animal origin. A TSE declaration has been provided. The excipient magnesium stearate is of vegetable origin. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the member states consider that Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg have a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substances and finished product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg tablets are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.2 Discussion on the non-clinical aspects These products are generic formulations of Mercilon and Marvelon, tablets which are available on the European market. Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-to-date and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required. 5/11 C IV. IV.1 B G M E B CLINICAL ASPECTS Introduction Desogestrel and ethinylestradiol are well-known active substances with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required. For this generic application, the MAH has submitted two bioequivalence studies, one for each tablet strength, which are discussed below. IV.2 Pharmacokinetics Study 1 – 150/30 micrograms The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product Desogestrel/Ethinylestradiol STADA 150 mcg/30 mcg Tablets (Stada Arzneimittel AG, Germany) is compared with the pharmacokinetic profile of the reference product Marvelon 0.15 mg/0.03 mg tablets (N.V. Organon, the Netherlands). The choice of the reference product The choice of the reference product in the bioequivalence study has been justified. The formula and preparation of the bioequivalence batch is identical to the formula proposed for marketing. Design A open label, balanced, single-dose, randomised, two-period, two-treatment, two-sequence, crossover, comparative bioequivalence study was carried out under fasted conditions in 34 healthy female subjects. Each subject received a single dose (2 x 150 mcg/30 mcg) of one of the 2 desogestrel/ethinylestradiol formulations. The tablet was orally administered after an overnight fasting period of at least 10 hours. There were 2 dosing periods, separated by a washout period of 29 days. Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose after administration of each dose. The design of the study under fasted conditions is acceptable. The plasma samples were analysed for 3-ketodesogestrel (etonogestrel) and ethinylestradiol. The measurement of the active metabolite 3ketodesogrestrel is agreed as desogestrel is rapidly absorbed and completely converted into 3ketodesogestrel. Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Results Nine subjects discontinued from the study on medical grounds (vomiting). One subject withdrew from the study of her own accord. A total of 24 subjects completed both study periods and were eligible for pharmacokinetic analysis. The number of drop out subjects is high. The reasons for discontinuation were given for all subjects and were according to protocol; therefore the high number of drop out subjects was accepted. 6/11 C Table 1. B G M E B Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, range)) of 3-ketodesogestrel under fasted conditions. Treatment N=24 Test Reference *Ratio (90% CI) AUC0-t AUC0-∞ Cmax tmax pg*h/ml pg*h/ml pg/ml h h 39783 ± 15176 54748 ± 21563 2978 ± 1253 1.5 (1.0 – 4.0) 57 ± 22 37193 ± 15674 50558 ± 23684 3243 ± 1395 56 ± 21 1.09 (0.99 - 1.20) 1.10 (0.99 – 1.22) 0.95 (0.83 – 1.09) 2.0 (1.0 - 3.5) -- 20 21 27 -- -- CV (%) t1/2 -- AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration tmax time for maximum concentration t1/2 half-life CV coefficient of variation *ln-transformed values Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, range)) of ethinylestradiol under fasted conditions. Treatment N=24 Test Reference *Ratio (90% CI) AUC0-t AUC0-∞ Cmax tmax pg.h/ml pg.h/ml pg/ml h h 1849 ± 650 1906 ± 665 153 ± 47 1.5 (1.0-3.5) 17 ± 3 1896 ± 625 1946 ± 637 166 ± 49 16 ± 3 0.97 (0.95 – 0.99) 0.97 (0.95 – 1.00) 0.91 (0.88 – 0.96) 1.5 (1.0-2.5) -- 5 5 9 -- -- CV (%) t1/2 -- AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration tmax time for maximum concentration half-life t1/2 CV coefficient of variation *ln-transformed values Study 2 – 150/20 micrograms The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product Desogestrel/Ethinylestradiol STADA 150 mcg/20 mcgTablets (Stada Arzneimittel AG, Germany) is compared with the pharmacokinetic profile of the reference product Mercilon 0.15 mg/0.02 mg tablets (N.V. Organon, the Netherlands). The choice of the reference product The choice of the reference product in the bioequivalence study has been justified. The formula and preparation of the bioequivalence batch is identical to the formula proposed for marketing. Design A open label, balanced, single-dose, randomised, two-period, two-treatment, two-sequence, crossover, comparative bioequivalence study was carried out under fasted conditions in 34 healthy 7/11 C B G M E B female subjects. Each subject received a single dose (2 x 150 mcg/20 mcg) of one of the 2 desogestrel/ethinylestradiol formulations. The tablets were orally administered with 240 ml water after an overnight fasting period of at least 10 hours. There were 2 dosing periods, separated by a washout period of 28 days. Blood samples were collected 0.0 (pre-dose) and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose after administration of each dose. The design of the study under fasted conditions is acceptable. The plasma samples were analysed for 3-ketodesogestrel (etonogestrel) and ethinylestradiol. The measurement of the active metabolite 3ketodesogrestrel is agreed as desogestrel is rapidly absorbed and completely converted into 3ketodesogestrel. Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Results Three subjects discontinued on the grounds of protocol deviation. One subject withdrew on medical grounds (fever) and one subject discontinued of her own accord. A total of 30 subjects were eligible for pharmacokinetic analysis. Table 3. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, range)) of 3-Ketodesogestrel under fasted conditions. Treatment N=30 Test Reference *Ratio (90% CI) CV (%) AUC0-t AUC0-∞ Cmax tmax t1/2 pg.h/ml pg.h/ml pg/ml h h 55045 ± 16642 73744 ± 21683 4703 ± 1751 1.5 (1.0 – 3.5) 57434 ± 18628 78100 ± 28858 5124 ± 2321 0.96 (0.90 – 1.03) 0.95 (0.87 – 1.04) 0.93 (0.93 – 1.03) 1.5 (1.0 – 2.5) -- -- 19 26 30 -- -- AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration tmax time for maximum concentration t1/2 half-life CV coefficient of variation *ln-transformed values Table 4. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, range)) of ethinylestradiol under fasted conditions. Treatment N=30 Test Reference *Ratio (90% CI) CV (%) AUC0-t AUC0-∞ Cmax tmax pg.h/ml pg.h/ml pg/ml h h 935 ± 391 1021 ± 406 101 ± 34 1.5 16 ± 6 938 ± 392 1009 ± 407 96 ± 32 1.5 14 ± 5 1.01 (0.95 – 1.07) 1.03 (0.97 – 1.08) 1.05 (0.99 – 1.12) -- -- -- -- -- -- -- 8/11 t1/2 C B G M E B AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration tmax time for maximum concentration t1/2 half-life CV coefficient of variation *ln-transformed values Conclusion on bioequivalence studies In both studies the 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax of 3Ketodesogestrel and ethinylestradiol are within the bioequivalence acceptance range of 0.80 – 1.25. Based on the submitted bioequivalence studies Desogestrel/ Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tabletsare considered bioequivalent with respectively Mercilon and Marvelon tablets. The MEB has been assured that the bioequivalence studies have been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.3 Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets. - Summary table of safety concerns as approved in RMP Important identified risks Venous thromboembolism Arterial thromboembolism Benign and malign liver tumours Breast cancer, Cervical cancer Effect on hereditary angioedema Disturbance of liver function Pancreatitis Increased blood pressure Important potential risks Worsening of endogenous depression/depressed mood Crohn’s disease and ulcerative colitis Important missing information none The member states agreed that routine pharmacovigilance activities and routine risk minimisation measures are sufficient for the risks and areas of missing information. IV.4 Discussion on the clinical aspects For this authorisation, reference is made to the clinical studies and experience with the innovator products Mercilon and Marvelon tablets. No new clinical studies were conducted. The MAH demonstrated through bioequivalence studies that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of this reference product. Risk management is adequately addressed. This generic medicinal product can be used instead of the reference product. V. USER CONSULTATION Due to the usage of the already tested and approved package leaflet texts of another Desogestrel/Ethinylestradiol 150/20 mcg and 150/30 mcg tablet product of STADA (NL/H/2236+2246/001-002/DC) and implementation of the user-tested STADA layout, the MAH considers that the proposed package leaflet is compliant with Article 59(3) of Directive 2001/83/EC and therefore, an additional user-test is not required. The minor differences in wording and word order 9/11 C B G M E B in the proposed package leaflet as compared to already tested and approved package leaflet are due to the new QRD template. These differences do not affect readability. This conclusion is agreed. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets have a proven chemicalpharmaceutical quality and are generic forms of Mercilon and Marvelon 150/20 mcg and 150/30 mcg. Mercilon and Marvelon tablets are a well-known medicinal products with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The Board followed the advice of the assessors. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 8 June 2015. 10/11 C B G M E B STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification 11/11 Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached
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