Public Assessment Report Scientific discussion Gestoden/Etinylestradiol 75/20 Stragen Gestoden/Etinylestradiol 75/30 Stragen 75/20 micg and 75/30 micg coated tablets Gestodene/Etinylestradiol DK/H/1149/001-002/DC Tis module reflects te scientific discussion for te approval of Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen. Te procedure was finalised on 13 August 2008. For information on canges after tis date please refer to te module Update. 1/7
I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te Member States ave granted a marketing autorisation for of Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen coated tablets, from Stragen Nordic A/S. Te product is indicated for oral contraception. Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen coated tablets are fixed-combination tablets of wic combine potent syntetic derivatives of te natural estrogen estradiol and te progestogen gestodene. Te tablets are monopasic oral contraceptives containing etinylestradiol 20 micg/30 micg and gestodene 75 micg as active ingredients. Te monopasic combination of etinylestradiol and gestodene inibits ovulation via a negative feedback mecansim on te ypotalamus, wic alters te normal pattern of gonadotropin secretion of folliclestimulationg ormone and luteinizing ormone by te anterior pituitary. In addition, te combination oral contraceptive modifies cervical secretions, producing an unfavourable environment for implantation. Te product is indicated in women as oral ormonal contraceptive. An gestodene/etinylestradiol terapy consists in a single dose of 75/20 or 30 micg given once daily, for 21 days, starting on te first day of te menstrual cycle. No medication is taken during te 7-day menses period. Tis repeat use procedure concerns a generic application claiming essential similarity wit te reference products Meloden 75/20 micg coated tablets and Gynera 75/30 micg coated tablets by Scering. Te reference products ave been registered in Denmark since 1995 and 1988, respectively. Te marketing autorisation is granted based on article 10.1 of Directive 2001/83/EC. II. II.1 QUALITY ASPECTS Introduction Eac Gestoden/Etinylestradiol 75/20 Stragen coated tablet contains 75 micrograms gestodene and 20 micrograms etinylestradiol. Eac Gestoden/Etinylestradiol 75/30 Stragen coated tablet contains 75 micrograms gestodene and 30 micrograms etinylestradiol. Te tablets are wite, round, biconvex sugar coated tablets, bot sides are witout imprinting. Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen is packed in blister packs (PVC/aluminium) in pack sizes of 1 x 21 tablets; 3 x 21 tablets, and 6 x 21 tablets. However, not all pack sizes may be marketed. Te excipients in te tablet core are: Magnesium stearate; povidone K-25; maize starc and lactose monoydrate. Te coating consists of: Povidone K-90; macrogol 6000; talc; calcium carbonate; sucrose and wax montan glycol. Compliance wit Good Manufacturing Practice Te RMS as been assured tat acceptable standards of GMP (see Directive 2003/94/EC) are in place for tis product type at all sites responsible for te manufacturing of te active substance as well as for te manufacturing and assembly of tis product prior to granting its national autorisation. 2/7
II.2 Drug Substance Te active substance gestodene is not described in te European Parmacopoeia. It is a wite or yellowis crystalline powder. It is practically insoluble in water, soluble in metylene cloride, sligtly soluble in etanol and metanol. It is optically active. It as six asymmetric carbon atoms. It consists of only one crystalline form. Te documentation on te active substance is presented as a European Drug Master File/Active Substance Master File (DMF) (in CTD-format). Te Applicant s Part of te DMF as been forwarded by te Applicant. Te Applicant s and Restricted Part plus a LoA as been forwarded by te ASM. Te active substance etinylestradiol is described in te European Parmacopoeia. It is a wite or sligtly yellowis-wite, crystalline powder. It is practically insoluble in water, freely soluble in alcool. It dissolves in dilute alkaline solutions. It is optically active. Te manufacturer of te active substance as obtained a Certificate of Suitability, a copy of wic is presented in te documentation. Te control tests and specifications for bot drug substances gestodene and etinylestradiol are adequately drawn up. Based on te stability data presented, appropriate retest periods ave been set. II.3 Medicinal Product Te finised product is wite round biconvex coated tablets, to be marketed in PVC/Alu blister packaging. Eac tablet core contains less tat 5 % of te active substance gestodene and less tan 5 % of te active substance etinylestradiol. Te development of te product as been described, te coice of excipients is justified and teir functions explained. Te product specifications cover appropriate parameters for tis dosage form. Validations of te analytical metods ave been presented. Batc analysis as been performed on 6 batces of eac strengt. Te batc analysis results sow tat te finised products meet te specifications proposed. Te conditions used in te stability studies are according to te ICH stability guideline. Te control tests and specifications for drug product are adequately drawn up. Te proposed self-life of 24 monts wit do not store above 30 C for te drug product is considered acceptable. III. NON-CLINICAL ASPECTS Tis product is a generic formulation of Meloden and Gynera coated tablets, wic are available on te European market. No new preclinical data ave been submitted, and terefore te application as not undergone preclinical assessment. Tis is acceptable for tis type of application since parmacodynamic, parmacokinetic and toxicological properties of gestodene and etinylestradiol are well known. Overview based on literature review is, tus, appropriate. Environmental risk assessment Te product is intended as a substitute for oter identical products on te market. Te approval of tis product will not result in an increase in te total quantity of gestodene/etinylestradiol released into 3/7
te environment. It does not contain any component, wic results in an additional azard to te environment during storage, distribution, use and disposal. IV. CLINICAL ASPECTS IV.1 Introduction Gestodene and etinylestradiol are well-known active substances wit establised efficacy and tolerability. For tis generic application, te MAH as submitted one single-dose bioequivalence study under fasting conditions in wic te parmacokinetic profile of te test product Gestoden/Etinylestradiol 75/30 Stragen is compared wit te parmacokinetic profile of te reference product Moneva 75/30 micg coated tablets, Scering, France. Te study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way crossover, single-dose bioavailability study conducted under fasting conditions wit a was out period of 28 days between te two administrations. Gestodene is igly bound to SHBG wic is wy 28 days was cosen to allow SHBG to return to normal levels before Period 2. 2 tablets of Gestoden/Etinylestradiol 75/30 Stragen were administered in eac period (~2x30 micg etinylestradiol and 2x75 micg gestodene). 2 tablets were dosed to meet bioanalytial assay requirements altoug te product labelling specifies a dose of one tablet per day. Blood samples were collected pre-dosing and at time points up to 96 ours for gestodene and up to 72 ours for etinylestradiol post administration of a single-dose of 2x75 micg gestodene/30 micg etinylestradiol fixed combination tablets wit 240 ml of water for te analyses of gestodene and etinylestradiol. 48 ealty post-menopausal, non-smoking, Caucasian female subjects (49-63 years) were enrolled and participated in te study. 48 subjects completed te study. Statistical analysis was carried out on te first 46 subjects to complete te study according to study protocol. Te parmacokinetic parameters calculated were AUC 0-t, AUC 0-, C max, t max, K el t ½ el and residual area. Primary variables were AUC 0-t, AUC 0- and C max. Te applicant would conclude bioequivalence if 90% CI were witin 80-125% for ln-transformed AUC 0-t, AUC 0-inf and ln-transformed C max according to te study protocol. 4/7
Table 1. Parmacokinetic parameters of gestodene under fasted conditions. Treatment N=46 Test AUC 0-t AUC 0- C max t max t 1/2 pg/ml 52794.80 57546.47 5662.99 0.894 25.87 Reference 52553.32 57701.88 5831.59 0.844 25.74 Ratio 1 100.44 % 99.94 % 96.22 % 90% Geometric C.I. 2 Intra-Subject CV AUC 0- AUC 0-t C max t max t 1/2 95.82 % to 105.29 % 95.49 % to 104.59 % 92.35 % to 100.24 % 13.45 % 13.00 % 11.70 % area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life 1 Calculated using least-squares means according to te formula e (Etinylestradiol-Gestodene (A)-Moneva (B)) x 100 2 90% Geometric Confidence Interval using ln-transformed data Table 2. Parmacokinetic parameters of etinylestradiol under fasted conditions. Treatment N=46 Test AUC 0-t AUC 0- C max t max t 1/2 pg/ml 1367.86 1553.45 141.24 1.51 16.79 Reference 1281.11 1456.75 136.14 1.50 16.45 Ratio 1 106.97 % 107.02 % 104.28 % 90% Geometric C.I. 2 Intra-Subject CV AUC 0- AUC 0-t C max t max t 1/2 103.79 % to 110.25 % 104.06 % to 110.07 % 101.21 % to 107.43 % 8.59 % 7.99 % 8.49 % area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life 1 Calculated using least-squares means according to te formula e (Etinylestradiol-Gestodene (A)-Moneva (B)) x 100 2 90% Geometric Confidence Interval using ln-transformed data 5/7
Te 90% confidence intervals for te ln-transformed AUC 0-t, AUC 0- and C max are witin te acceptance range of 80-125%. Based on te submitted bioequivalence study Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen coated tablets are considered bioequivalent wit Meloden 75/20 micg coated tablets and Gynera 75/30 micg coated tablets, respectively, wit respect to rate and extent of absorption of gestodene and etinylestradiol. Tolerability of te test product is acceptable and not significantly different from reference product. Te 75/20 micg strengt is dose proportional wit te 75/30 micg strengt. Te parmacokinetics of te active substances are linear in te dose range. Te results of te bioequivalence study performed wit te 75/30 micg strengt terefore apply to te 75/20 micg strengt. Te RMS as been assured tat te bioequivalence study as 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.2 Risk management plan & Parmacovigilance system Te combination gestodene/etinylestradiol was first approved in 1995 (75/20 micg) and 1986 (75/30 micg), respectively, and tere is now more tan 10 years post-autorisation experience wit te combination of active substances. Te safety profile of gestodene/etinylestradiol can be considered to be well establised and no product specific parmacovigilance issues were identified pre- or postautorisation wic are not adequately covered by te current SPC. Additional risk minimisation activities ave not been identified for te reference medicinal product. Te MAH as a parmacovigilance system at teir disposal, wic is based on te current European legislation. Te Parmacovigilance system described fulfils te requirements and provides adequate evidence tat te applicant as te services of a qualified person responsible for parmacovigilance and as te necessary means for te identification and notification of any a potential risks occurring eiter in te Community or in a tird country. V. PRODUCT INFORMATION SmPC and Package leaflet Te content of te SmPC and package leaflet approved during te decentralised procedure is in general in accordance wit tat accepted for Gestinyl (DK/H/0926/001-002/DC, Day 210: 26 January 2007), marketed by Stragen Nordic A/S. Readability test Te package leaflet as been evaluated via a user consultation study in accordance wit te requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. Te language used for te purpose of user testing te package leaflet was Danis. Te test consisted of a pilot test wit 3 participants, followed by two rounds wit 10 participants eac. Te questions covered te following areas sufficiently: traceability, compreensibility and applicability. Te results sow tat te package leaflet meets te criteria for readability as set out in te Guideline on te readability of te label and package leaflet of medicinal products for uman use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION 6/7
Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen coated tablets ave a proven cemical-parmaceutical quality and are generic forms of Meloden 75/20 micg coated tablets and Gynera 75/30 micg coated tablets by Scering. Meloden and Gynera 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, package leaflet and labelling are in te agreed templates and are in agreement wit tat accepted for Gestinyl (DK/H/0926/001-002/DC, Day 210: 26 January 2007), marketed by Stragen Nordic A/S. Agreement between Member States was reaced during a written procedure. Tere was no discussion in te CMD(). Te Concerned Member States, on te basis of te data submitted, considered tat essential similarity as been demonstrated for Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised on 13 August 2008. Gestoden/Etinylestradiol 75/20 Stragen /Gestoden/Etinylestradiol 75/30 Stragen was autorised in Denmark on 2 October 2008. A European armonised birt date as been allocated (1995-03-17 (75/20 micg) and 1986-07-09 (75/30 micg)) and subsequently te first PSUR will be submitted wit a DLP of 2009-03 (75/20 micg) and 2009-08 (75/30 micg), respectively, after wic te PSUR submission cycle is 3 years. Te date for te first renewal will be: 13 August 2013. Te following post-approval commitments ave been made during te procedure: Te Applicant commits to reconsider limits for total impurities in te self-life specification at te end of stability studies i.e. 36 monts. 7/7