Public Assessment Report. Scientific discussion. Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets. (Ethinylestradiol/Drospirenone)

Transcription

1 Public Assessment Report Scientific discussion Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets (Etinylestradiol/Drospirenone) NL/H/2890/ /DC Date: 18 June 2014 Tis module reflects te scientific discussion for te approval of Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets. Te procedure was finalised on 21 November For information on canges after tis date please refer to te module Update.

2 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te Member States ave granted a marketing autorisation for Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets from Laboratorios Liconsa S.A. Te product is indicated for oral contraception. A compreensive description of te indication and posology is given in te SmPC. Tis decentralised procedure concerns a generic application claiming essential similarity wit te innovator products Yasminelle, film-coated tablets 0.02/3 mg (NL/H/0701/001/MR, registered since 4 August 2005) and Yasmin, film-coated tablets 0.03/3 mg (NL/H/0215/001/MR, registered since 7 Marc 2000). Te concerned member state (CMS) involved in tis procedure was Italy. Te marketing autorisation as been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Orlyelle 0.02 mg/3 mg is a pink, round film-coated tablet of 5.7 mm diameter. Eac film-coated tablet contains 0.02 mg of etinylestradiol and 3 mg of drospirenone. Orlyelle 0.03 mg/3 mg is a yellow round film-coated tablets of 5.7 mm diameter. Eac film-coated tablet contains 0.03 mg of etinylestradiol and 3 mg of drospirenone. Te film-coated tablets are packed in clear to sligtly opaque transparent PVC/PVDC/Al blister containing 21 tablets. Te excipients are: Tablet core - lactose monoydrate, maize starc, pregelatinised starc (maize), crospovidone type B, povidone K-30 (E1201), polysorbate 80 (E433), magnesium stearate (E470b) Coating - poly (vinyl alcool), titanium dioxide (E171), macrogol 3350, talc (E553b), yellow iron oxide (E172), red & black iron oxide (E172) (only 0.02/3 mg strengt) II.2 Drug Substances Etinylestradiol Te active substance etinylestradiol is an establised active substance, described in te European Parmacopoeia (P.Eur.). It is a wite or sligtly yellowis-wite crystalline powder, wic is practically insoluble in water and freely soluble in alcool. It dissolves in dilute alkaline solutions. Etinylestradiol exibits only one not solvated polymorpic form. Te CEP procedure is used for te active substance etinylestradiol. Under te official Certification Procedures of te EDQM of te Council of Europe, manufacturers or suppliers of substances for parmaceutical use can apply for a certificate of suitability concerning te control of te cemical purity and microbiological quality of teir substance according to te corresponding specific monograp, or te evaluation of reduction of Transmissible Spongiform Encepalopaty (TSE) risk, according to te general monograp, or bot. Tis procedure is meant to ensure tat te quality of substances is guaranteed and tat tese substances comply wit te European Parmacopoeia. Manufacturing process A CEP as been submitted; terefore no details on te manufacturing process ave been included. Quality control of drug substance Te drug substance specification is in line wit te P.Eur. and te CEP. An additional test for one residual solvent is included. Te specification is acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data ave been provided. 2/10

3 Stability of drug substance Te active substance is stable for 5 years wen stored under te stated conditions. Assessment tereof was part of granting te CEP and as been granted by te EDQM. Drospirenone Te active substance drospirenone is an establised active substance, described in te P.Eur. It is a wite or almost wite powder. Water solubility is 10.9 mg/l. Drospirenone does not sow polymorpic forms. Te CEP procedure is used for tis active substance. Manufacturing process A CEP as been submitted; terefore no details on te manufacturing process ave been included. Quality control of drug substance Te drug substance specification is based on te P.Eur. monograp and te CEP wit additional tests for one residual solvent. Te specifications are acceptable in view of te route of syntesis and te P.Eur. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided for two batces. Stability of drug substance Te active substance is stable for 4 years wen stored under te stated conditions. No special storage conditions are required. Te assessment was part of granting te CEP and as been granted by te EDQM. II.3 Medicinal Product Parmaceutical development Te development of te product as been described, te coice of excipients is justified and teir functions explained. Te product development objective was to develop film-coated tablets tat would be bioequivalent to te medicinal products Yasminelle and Yasmin, aving te same qualitative and quantitative composition in drug substances per tablet and te same parmaceutical form. Development of te drospirenone 3 mg/etinylestradiol 0.03 mg was simultaneous to tat of te drospirenone 3 mg/etinylestradiol 0.02 mg. Terefore, a common development strategy was followed for bot formulations. Te formulation wit lower concentration of etinylestradiol (i.e mg) was selected for testing. A water based wet granulation process was tried and experimental batces were tested and dissolution profiles were compared to te dissolution profile of te reference product. Dissolution profiles at tree different ph values were determined for test and reference batces used in te bioequivalence studies. Additionally, a comparison of tree industrial validation batces against te bioequivalence pilot batc and bot reference products was performed. It was sown tat all profiles are comparable. Sufficient in-vitro data ave been presented. A compatibility study was performed to describe potential interactions between te individual excipients and te active drug substances. Te container closure system (PVC-PVdC/aluminium blisters) is usual for tis type of dosage form. Manufacturing process Te drug product is manufactured by wet granulation. Te process consists of blending, granulation, drying, milling, tablet compression and coating. Te in-process controls for te manufacturing process of te active tablets are acceptable. Te manufacturing process as been adequately validated according to relevant European Guidelines. Control of excipients All excipients are tested in accordance wit teir respective P.Eur. monograp, except for Opadry II Pink and Opadry II Yellow, wic are tested according to in-ouse procedures. Te specifications are acceptable. Quality control of drug product Te active drug product specification includes tests for appearance, identification (release only), dissolution, assay, related substances, content uniformity (release only), residual solvents (release only) and microbial control. For appearance, dissolution, drospirenone assay, drospirenone related substances and microbial control, te self-life specifications are te same as te release specifications. For assay of etinylestradiol, te self-life specification is wider tan te release specification, wic is supported by stability data. 3/10

4 Te analytical metods ave been adequately described and validated. Te HPLC metods for assay and related substances are considered to be stability indicating. Batc analytical data for two pilot batces and tree industrial batces of eac of te strengts of te drug product ave been provided, demonstrating compliance wit te release specifications. Stability of drug product Stability data on te drug product ave been provided on two pilot-scale and tree commercial-scale batces of eac strengt. Te batces were stored at 25 C/60% RH (36 monts for te pilot-scale and 12 monts for te commercial-scale batces), 30 C/65% RH (12 monts for two commercial scale batces) and 40 C/75%RH (6 monts for all batces). Te conditions used in te stability studies are according to te ICH stability guideline. Te batces were stored in PVC/PVdC-Al blisters. A potostability study in compliance wit te NfG on Potostability Testing as been performed, wic sows tat te product is not sensitive to ligt. In view of te provided stability data, te claimed selflife of 36 monts and te proposed storage conditions Store below 30ºC were granted. Specific measures concerning te prevention of te transmission of animal spongiform encepalopaties TSE declarations ave been provided for lactose monoydrate and lactose anydrous, as tey are of animal origin. II.4 Discussion on cemical, parmaceutical and biological aspects Based on te submitted dossier, te member states consider tat Orlyelle film-coated tablets ave a proven cemical-parmaceutical quality. Sufficient controls ave been laid down for te active substance and finised product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Orlyelle tablets are intended for generic substitution, tis will not lead to an increased exposure to te environment. An environmental risk assessment is terefore not deemed necessary. III.2 Discussion on te non-clinical aspects Tis products is a generic formulations of Yasmin and Yasminelle, wic are available on te European market. Reference is made tot te preclinical data obtained wit te innovator product. A non-clinical overview on te parmacology, parmacokinetics and toxicology as been provided, wic is based on up-to-date and adequate scientific literature. Te overview justifies wy tere is no need to generate additional non-clinical parmacology, parmacokinetics and toxicology data. Terefore, te member states agreed tat no furter non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Drospirenone and etinylestradiol are well-known active substances wit establised efficacy and tolerability. A clinical overview as been provided, wic is based on scientific literature. Te overview justifies wy tere is no need to generate additional clinical data. Terefore, te member states agreed tat no furter clinical studies are required. For tis generic application, te MAH as submitted two bioequivalence studies, wic is discussed below. IV.2 Parmacokinetics 4/10

5 Te MAH conducted two bioequivalence studies in wic te parmacokinetic profile of te test products Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg (Laboratorios Liconsa S.A., Spain) is compared wit te parmacokinetic profile of te reference products Jasminelle 3.0 mg/0.02 mg and Jasmine 3.0 mg/0.03 mg film-coated tablets (Scering S.A.S, France). Te coice of te reference product Te coice of te reference products in te bioequivalence studies as been justified by comparison of dissolution results and compositions of reference products in different member states. Te formula and preparation of te bioequivalence batc is identical to te formula proposed for marketing. Analytical/statistical metods Te analytical metods ave been adequately validated and are considered acceptable for analysis of te plasma samples. Te metods used in tis study for te parmacokinetic calculations and statistical evaluation are considered acceptable. Bioequivalence studies Bioequivalence study I 3 mg/0.02 mg strengt Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 34 ealty females of cildbearing potential, aged years old. Eac subject received a single dose of tree tablets (3 x 3 mg/0.02 mg) of one of te 2 drospirenone/etinylestradiol formulations. Te tablets were orally administered wit 240 ml water after a fasting period of at least 10 ours. Tere were 2 dosing periods, separated by a wasout period of 28 days. Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 ours after administration of te products. Te design is acceptable for tis kind of application, te was-out of 28 days is sufficient and te sampling period long enoug. Furtermore, te sampling sceme is adequate to estimate parmacokinetic parameters. Te administration of 3 tablets was considered necessary to acieve measurable plasma etinylestradiol levels and justified by dose-linearity of drospirenone (1 10 mg) and Etinylestradiol (20 60 μg). Tis is acceptable. Results Two subjects witdrew and did not sow up for te second period of te study. Terefore a number of 32 subjects completed te study. However, one subject was excluded from te analysis since predose concentrations of >5% of C max were observed in bot periods for bot compounds. Statistical analysis was performed wit 31 subjects. Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of drospirenone under fasted conditions. Treatment AUC 0-t AUC 0- C max t max t 1/2 N=31 µg./ml µg./ml ng/ml Test 1.3 ± ± ± Reference 1.3 ± ± ± *Ratio (90% CI) 1.00 ( ) 1.00 ( ) 1.01 ( ) CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values 5/10

6 Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of etinylestradiol under fasted conditions. Treatment AUC 0-t AUC 0- C max t max t 1/2 N=31 ng./ml ng./ml pg/ml Test 1.4 ± ± ± Reference 1.5 ± ± ± *Ratio (90% CI) 0.95 ( ) 0.95 ( ) 0.96 ( ) CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values Te 90% confidence intervals calculated for AUC 0-t, AUC 0- and C max are in agreement wit tose calculated by te MAH and are witin te bioequivalence acceptance range of Based on te parmacokinetic parameters of drospirenone and etinylestradiol under fasted conditions, it can be concluded tat Orlyelle 0.02 mg/3 mg and Jasminelle, 3.0 mg/0.02 mg, film-coated tablets are bioequivalent wit respect to rate and extent of absorption, and fulfil te bioequivalence requirements outlined in te relevant CHMP Note for Guidance. A significant treatment effect was observed for te AUC (0- ) of etinylestradiol and a significant period effect for te AUC (0-t) and AUC (0- ) of drospirenone. Te observed treatment effect is considered due to te ig power of te study and terefore clinically not relevant since bioequivalence as been sown. Te period effect for drospirenone is neiter judged to influence te conclusion of te study since only 1 case of a pre-dose level was detected and terefore no carry-over effect could be concluded. Bioequivalence study II 3 mg/0.03 mg strengt Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 46 ealty females of cildbearing potential, aged years old. Eac subject received a single dose of two tablets (2 x 3 mg/0.03 mg) of one of te 2 drospirenone/etinylestradiol formulations under fasted conditions. Tere were 2 dosing periods, separated by a wasout period of 28 days. Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 ours after administration of te products. Te design is acceptable for tis kind of application, te was-out of 28 days is sufficient and te sampling period long enoug. Furtermore, te sampling sceme is adequate to estimate parmacokinetic parameters. Te administration of 2 tablets was considered necessary to acieve measurable plasma etinylestradiol levels. Results A total of 43 subjects finised bot treatment periods of te study; a total of 3 subjects discontinued before te start of te 2nd treatment period. One of tem discontinued because of fainting before dosing, anoter due to disallowed concomitant medication during te was-out period and a tird subject due to difficulty wit blood collection during period 1. Table 3. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of drospirenone under fasted conditions. Treatment N=43 AUC 0-t µg./ml AUC 0- µg./ml C max ng/ml t max t 1/2 6/10

7 Test 0.9 ± ± ± ( ) 32.7 Reference 0.9 ± ± ± ( ) 31.9 *Ratio (90% CI) 1.05 ( ) 1.06 ( ) 1.01 ( ) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values Table 4. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of etinylestradiol under fasted conditions. Treatment AUC 0-t AUC 0- C max t max t 1/2 N=43 ng./ml ng./ml ng/ml Test 1.3 ± ± ± ( ) 32.7 Reference 1.3 ± ± ± ( ) 31.9 *Ratio (90% CI) 1.05 ( ) 1.05 ( ) 1.01 ( ) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values Te 90% confidence intervals calculated for AUC 0-t, AUC 0- and C max are in agreement wit tose calculated by te MAH and are witin te bioequivalence acceptance range of Based on te parmacokinetic parameters of drospirenone and etinylestradiol under fasted conditions, it can be concluded tat Orlyelle 0.03 mg/3 mg and Jasmine 3.0 mg/0.03 mg, film-coated tablets are bioequivalent wit respect to rate and extent of absorption, and fulfil te bioequivalence requirements outlined in te relevant CHMP Note for Guidance. Tere were no pre-dose levels. A treatment effect was observed for AUC 0-t and AUC 0- for bot etinylestradiol and drospirenone. For drospirenone alone a significant period effect was observed for AUC 0-t and AUC 0-. Te observed treatment effect is considered due to te ig power of te study and terefore clinically not relevant since bioequivalence as been sown. Drospirenone/etinylestradiol may be taken witout reference to food intake. From te literature it is known tat food does not interact wit te absorption of te active substances. Terefore, a food interaction study is not deemed necessary. Te bioequivalence study under fasting conditions is in accordance wit CPMP/EWP/QWP/1401/98 Note for Guidance on te investigation of bioavailability and bioequivalence. Te MEB as been assured tat te bioequivalence studies ave been conducted in accordance wit 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 Te MAH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to 7/10

8 identify, caracterise, prevent or minimise risks relating to Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets. Summary table of safety concerns as approved in RMP Important identified risks Venous tromboembolism, Arterial tromboembolism Breast cancer Benign and malignant liver tumours Disturbances of liver function Pancreatitis Increased blood pressure Effect on ereditary angioedema Important potential risks Cervical cancer Worsening of endogenous depression Cron s disease and ulcerative colitis Insulin resistance Hyperkalemia Important missing information - Te safety concerns included in te RMPs are considered appropriate. Te member states agreed tat routine parmacovigilance activities and routine risk minimisation activities are considered sufficient for tis product. IV.4 Discussion on te clinical aspects For tis autorisation, reference is made to te clinical studies and experience wit te innovator products Yasminelle and Yasmin. No new clinical studies were conducted. Te MAH demonstrated troug a bioequivalence study tat te parmacokinetic profile of te two products is similar to te parmacokinetic profile of tese reference products. Risk management is adequately addressed. Tese generic medicinal products can be used instead of te reference products. V. USER CONSULTATION Te package leaflet as not been evaluated via a user consultation study. For te PLs a bridging report as been provided referring to te user test conducted for te PL approved in procedure NL/H/2632/002/DC: etinylestradiol/drospirenone 0.03/3 mg 28 (21 active and 7 inert tablets). In te bridging report differences between Daugter and Parent PL are presented along wit an analysis and evidence wic adequately sow tat tese differences ave little material impact on te readability. Separate user testing is not required. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets ave a proven cemical-parmaceutical quality and are generic forms of Yasminelle, film-coated tablets 0.02/3 mg and Yasmin, film-coated tablets 0.03/3 mg. Yasmin and Yasminelle are well-known medicinal products wit an establised favourable efficacy and safety profile. Bioequivalence as been sown to be in compliance wit te requirements of European guidance documents. Te MAH as provided written confirmation tat systems and services are in place to ensure compliance wit teir parmacovigilance obligations. Te SmPC is consistent wit tat of te reference product. Te SmPC, package leaflet and labelling are in te agreed templates. Te Board followed te advice of te assessors. 8/10

9 Tere was no discussion in te CMD(). Agreement between member states was reaced during a written procedure. Te member states, on te basis of te data submitted, considered tat essential similarity as been demonstrated for Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finised on 21 November Orlyelle 0.02 mg/3 mg and 0.03 mg/3 mg film-coated tablets were autorised in te Neterlands on 26 Marc /10

10 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of te procedure Date of end of te procedure Approval/ non approval Assessment report attaced 10/10