Public Assessment Report. Scientific discussion. Hunogidon. Desogestrel/Ethinylestradiol

Transcription

1 Public Assessment Report Scientific discussion Hunogidon 150/20 μg film-coated tablets Desogestrel/Ethinylestradiol This module reflects the scientific discussion for the approval of Hunogidon. The procedure was finalised on 5 September For information on changes after this date please refer to the module Update. 1/6

2 I. INTRODUCTION This assessment report concerns a generic version of desogestrel/ethinylestradiol 150/20 μg filmcoated tablets approved through DCP on 5 September 2008 with Denmark acting as RMS. Based on the review of the data and the Applicant s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS and CMS have approved the application for desogestrel/ethinylestradiol 150/20 μg film-coated tablets indicated for oral contraception. The application is submitted according to Article 10(1) generic application of Directive 2001/83/EEC as amended. The originator product is Mercilon tablets 150/20 μg by N.V. Organon, which was licensed for the Danish market in December In Denmark the Brand Leader is Mercilon tablets 150/20 μg by N.V. Organon. Desogestrel/ethinylestradiol 150/20 μg film-coated tablets are fixed-combination tablets which combine potent synthetic derivatives of the natural estrogen estradiol and the progestogen desogestrel. It is indicated in women as oral hormonal contraceptive. 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 that acceptable standards of GMP are in place at those sites. II. QUALITY ASPECTS II.1 Introduction The chemical-pharmaceutical documentation and Expert Report in relation to desogestrel/ethinylestradiol film-coated tablets are of sufficient quality in view of the present European regulatory requirements. The finished product is presented as film-coated tablets in the strength of 150/20 μg desogestrel/ethinylestradiol packed in PVC/PVDC-Aluminium blisters of 21 tablets per calendar blister strip available in packs containing 1x21, 3x21, 6x21 or 13x21 tablets. The tablet core consists of: Potato starch; Stearic acid; All-rac-alpha-tocopherol; Lactose monohydrate; Magnesium stearate; Silica colloidal anhydrous; Povidone K 30; Quinoline yellow (E 104); Cellulose, microcrystalline; Lactose monohydrate; Magnesium stearate and Silica, colloidal anhydrous. The tablet coating consists of: Hypromellose; Macrogol 6000 and Propylene glycol. II.2 Drug Substance The documentation on the drug substances is presented as a CEP. The control tests and specifications for drug substance are adequately drawn up. Re-test periods are accepted for ethinylestradiol and desogestrel according to CEPs referred to. 2/6

3 II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on production scale batches of each strength. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 36 months with store below 30 C in the original packaging for the drug product is considered acceptable. III. NON-CLINICAL ASPECTS III.1 Introduction Specific non-clinical studies have not been performed, as the application is submitted in accordance with Article 10(1) of Directive 2001/83/EEC as amended. Pharmacodynamic, pharmacokinetic and toxicological properties of desogestrel and ethinylestradiol are well known. As desogestrel and ethinylestradiol are widely used, well-known active substances, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. The report refers 18 publications up to year IV. CLINICAL ASPECTS IV.1 Introduction No specific clinical studies have been performed, as the application is submitted in accordance with Article 10(1) of Directive 2001/83/EEC as amended. The legal basis of the application as a generic application according to Article 10(1) has been justified. The clinical overview presents a satisfactory overview of clinical pharmacology, efficacy and safety. The clinical overview is adequate. The report refers 34 publications up to year To support the application, the Applicant has submitted as report one single dose bioequivalence study. IV.2 Pharmacokinetics General description Desogestrel Desogestrel is metabolised rapidly and completely in the liver and in the gut wall. It is metabolised to 3-keto-desogestrel (via cytochrome P450), which mediates its progestogenic effects, and it is not metabolised further to any other progesterone. The serum concentration of 3-keto-desogestrel reaches 3/6

4 maximum plasma levels after within 1.5 hours (1.5-3 hours) after administration and is subsequently cleared with a half-life of 31 hours (24-38 hours). In steady state conditions serum level of 3-ketodesogestrel is elevated by two to three folds. Sexual hormones are metabolised via the liver cytochrome P 450 enzyme thus other drugs being metabolised via this enzyme may be influence the efficacy of contraception. Desogestrel has however no significant influence or inhibitory effect on metabolism of ethinylestradiol. Ethinylestradiol Absorption from the gastro intestinal tract is rapid and generally complete with 40% bioavailability due to first pass metabolism. Peak plasma levels are reached after 1.5 hours. EE is highly protein bound, but unlike naturally occurring sex hormones (bound to SHBG (sex hormone binding globuline)) it is principally bound to albumin. AUC and Cmax may be expected to rise slightly over time. It is metabolised in the liver via cytochrome P450 enzymes. The primary hydroxylated metabolite is 2-hydroxy-ethinylestradiol, but small amounts are of 6-hydroxy-ethinylestradiol and 16- hydroxy-ethinylestradiol is excreted in the urine, bile and faeces (urine / faeces 1:1). Metabolites enter the enterohepatic circulation. The elimination half-life of EE is about 29 hours (24-38 h). In steady state condition serum drug level is about 30-40% higher than after single dose administration. Bioequivalence To support the application, the applicant has submitted as report one single dose bioequivalence study. Study design The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way crossover, single-dose bioavailability study conducted under fasting with a wash out period of 4 weeks between the two administrations. 600 μg desogestrel and 80μg ethinylestradiol (~ 4 tablets) was administered in each period. Blood samples were collected pre-dosing and at time-points up to 72.0 hours post administration of a single-dose (~ 4 tablets) with 200 ml of water for the analyses of ethinylestradiol and 3-ketodesogestrel. Day of administration was on 4 th, 5 th or 6 th day of the menstrual cycle. Test and reference products The test product (150/20 μg) has been compared to Mercilon (150/20 μg), Organon from the French market. Satisfactory certificates of analysis of the test and reference product are presented. Population(s) studied 41 healthy pre-menopausal Caucasian female subjects (19-35 years) participated in the study. 36 subjects completed the study and results from 36 subjects were analysed. Drop-outs: 5 (subjects 2, 6, 12, 28 and 34). Subject 28 became pregnant, subject 2 and 34 were non-compliant/not available at prefixed sample points and subjects 6 and 12 refused follow-up examinations or did not show up for planned visits. A total number of at least 36 subjects were calculated for an 80% power of the study. Analytical methods The blood samples were analyzed by GC/MS method for detection of ethinylestradiol and by HPLC/MS for detection of 3-keto-desogestrel. Pharmacokinetic Variables Method of assessment of pharmacokinetic parameters: ANOVA was tested by use of SAS for Windows software. Non-parametric (by Hauschke et al.) evaluation of t max was done. Choice of primary variables and secondary PK variables: The parameters calculated were AUC 0-t, AUC 0-, C max, t max MRT and t½. 4/6

5 Primary variables: AUC 0- and C max Statistical methods ANOVA was performed on the ln-transformed C max, AUC 0-t and AUC 0-. The ANOVA model included sequence, subject nested within sequence, period and treatment. Nonparametric test was carried out on t max. Criteria for conclusion of bioequivalence: AUC 0- : % CI C max : % CI Results Results of the BE study fall within the normally acceptable confidence intervals %. The extrapolated AUC was not below 20% for all subjects, treatments and analytes, which is why evaluation of both AUC0-t and AUC0-inf have been statistically evaluated. The main reason for this higher extrapolated area is the high sensitivity of the analytical methods applied which also result in longer elimination half-lives than reported when analytical methods with lower sensitivity are applied. No pre-dose levels were reported for any of the tested analytes and t max values were not identified at any of the 1 st post-dose sample points. Safety evaluation 4 adverse events were observed in 4 volunteers after test drug dosing and 6 adverse events were observed after reference drug dosing. Subjects all fully recovered after short duration of AEs. 7 of 10 AEs were related to vaginal bleeding and 2 cases of headache were observed. Both test and reference products were well tolerated. Pharmacokinetic conclusion The application contains an adequate review of published clinical data and the bioequivalence has been shown. 5/6

6 V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the generic products and the innovator is interchangeable. The benefit risk is, therefore, considered to be positive. The following commitment has been made during the procedure: The applicant commits to conduct user testing evaluation on the proposed PIL mock-up and submit the results as a type II variation for approval before market launch of the product. 6/6