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Public Assessment Report Scientific discussion LADYBON tibolone CZ/H/0131/001/MR Applicant: Zentiva a.s., Prague, Czech Republic This module reflects the scientific discussion for the approval of Ladybon. The procedures were finalised at 25-09-2006. INTRODUCTION The application was submitted as abridged application according to article 10.1 (a)(iii) of Directive 2001/83/EC, claiming essential similarity to the original products Livial tablets, N.V.Organon, The Netherlands authorised in the Czech Republic since 1991, marketing authorisation number 54/249/91- C. The first Mutual Recognition Procedure was finished on 25.9.2006 with Estonia, Hungary, Latvia, Lithuania and Slovak Republic as CMS. Originally this medicinal product was approved nationally in the Czech Republic on 23.02.2006. 2nd wave of Mutual Recognition Procedure was finished on 16th July 2008, the Concerned Member State was Poland. The product contains the active ingredient Tibolone, a synthetic steroid that has estrogenic, progestagenic and androgenic properties. It is used for hormone replacement therapy (HRT) in the treatment of menopausal vasomotor symptoms and prevention of postmenopausal osteoporosis. The usual dose is 2,5 mg daily. QUALITY ASPECTS Introduction Ladybone is presented in the form of uncoated tablets containing 2.5 mg of tibolone. The excipients are lactose monohydrate, potato starch, ascorbyl palmitate and magnesium stearate. The product is packed into blisters made of thermoformed PVC/PVDC transparent foils laminated with aluminium foils. Blisters are placed, together with a package leaflet, into a paper folding box. Drug substance The active substance tibolone is not described in the European Pharmacopoeia. Tibolone is a white or almost white crystalline powder, soluble in acetone, methanol and ethanol, slightly soluble in water, melting point is165 to 169°C, tibolone presents 6 chiral centers and exhibits two crystalline forms and also an amorphous form. At this time the quality of the drug substance corresponds to the European Pharmacopoeia. This change of specifications has been approved. Starting material for the manufacturing of the active substance is purchased from one manufacturer, other manufacturer and six testing facilities are involved in manufacturing of tibolone. The DMF and Letter of Access were submitted. The specification was proposed in accordance with ICH Q6A guideline. Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the stated specification. All components of the primary packaging for the active substance are in line with Directive 2002/72/EC and with Ph.Eur. monographs. Based on stability results the re-test period (date) was set for 2 years. Medicinal Product The development of medical product has been sufficiently described; the essential similarity, based on comparison of dissolution profiles, impurity profiles and bioequivalence with brand leader Livial, has been documented. Tablets are formulated using excipients described in the current Ph Eur. The content of the anti-oxidant ascorbyl palmitate is justified. Certificates of analysis have been provided. Lactose monohydrate is the only material of animal origin used in manufacture of the tablets. TSE risk is minimised in line with EMEA/CPMP/571/02. The manufacturing process has been presented with its critical steps and with in process controls. The validation of manufacturing process confirms that the process is reproducible, and demonstrates accordance with the specification. The tests and limits are considered appropriate to justified the quality of the medicinal product. The analytical methods have been sufficiently described and validated. Batch analysis data have demonstrated compliance with the proposed release specification The safety of proposed packaging material has been documented. Stability studies under ICH conditions have been performed and data presented. Based on the result obtained from this stability study and evaluation of stability data, the shelf life of 2 years can be approved for Ladybon 2,5 mg when stored at temperature bellow 25°C in the original package (blister) with the precaution ”Keep blister in the outer carton” to protect the product from light and air humidity. STEPS TAKEN AFTER AUTHORISATION – SUMMARY Application type and scope Variation IA/11a: Change in batch size of active substance – up to 10-fold. Variation IB/7c: Replacement of or additional manufacturing site for part or all of the manufacturing process of the finished product – all other manufacturing operations except batch release. Variation IA/38a: Change in test procedure of the finished product – Minor change to an approved test procedure. Variation IB/38c: Change in the test procedure of the finished product – Other changes to a test procedure Variation IA/37a: Change in the specification of the finished product – Tightening of specification limits. Variation IB/25a1: Change of specification(s) of a former non-Eur. Pharmacopoeial substance to comply with Ph.Eur. – Active Substance. Variation IA/12a: Change in the specification of the active substance – Tightening of specification limits. Variation IA/4: Change in the name of a manufacturer of the active substance where no Ph.Eur. certificate of suitability is available. Variation IB/33: Minor change in the manufacture of the finished product. Variation II: Change to Module 2 (Update of the Clinical Overview). Variation IA/13a: Change in test procedure for active substance – Minor changes to an approved test procedure. CLINICAL ASPECTS Based on the review of data on quality, safety and efficacy, the RMS considered that the application for Ladybon, tablets, in the treatment of estrogen deficiency symptoms in women and in prevention of osteoporosis in postmenopausal women with a high risk of future fractures, could be approved. This is an abridged application. The applicant claims essential similarity, under article 10.1 (a)(iii) 1st par.of Directive 2001/83/EC, to Livial, tablets, N.V.Organon, Oss, Netherlands, authorised for more than 10 years in Europe. Livial has been authorised in the Czech Republic since 1991 (MANo 54/249/91-C, marketing authorisation holder N.V.Organon, Oss, Netherlands). Tibolone is a synthetic steroid that acts on estrogen, progesterone, and androgen receptors either directly or indirectly through its metabolites, with a different pattern according to the target tissue. Tibolone is used in the treatment of estrogen deficiency symptoms, prevents bone loss as second line therapy for prevention of osteoporosis in postmenopausal women (who are intolerant to other medicinal products), and reduces menopausal symptoms (including vasomotor complaints, depressed mood, decreased libido) without causing estrogen-like stimulation of the endometrium and breast. No new preclinical studies and no clinical studies were conducted, which is acceptable given that the applications were based on essential similarity to a product that has been licensed for more than 10 years. The application contains an adequate review of published clinical data. One single-dose bioequivalence study at fasted state has been conducted for 2,5 mg strength. Essential similarity has been sufficiently proven by the bioequivalence study that complies with current requirements and by comparison of dissolution and impurity profiles. Quality of the product Ladybon tablets and GMP standards of manufacture have been sufficiently demonstrated. The SmPC of product Ladybon tablets corresponds to the SmPC of reference product. The Package leaflet has been shown to provide the tested consumers with all required information in a clear and comprehensive form and the Readability testing was performed according to the guidelines. The quality of the product Ladybon, tablets, is satisfactory in relation to its safety and efficacy. The data have demonstrated the efficacy and safety of Ladybon tablets, to the extent that the overall risk/benefit of the products is favourable for the proposed indications. To support the application, the applicant has submitted as report one bioequivalence study. A single-dose, randomized, two-period, two-treatment, two-sequence, crossover bioequivalence study on tibolone preparations Ladybon 2.5 mg tablets (Zentiva a.s., Czech Republic) versus Livial 2.5 mg tablets (N.V. Organon, The Netherlands) in healthy postmenopausal women. Investigator: I. Ulč, M.D.,Ph.D., Site of the clinical and analytical parts: Cepha s.r.o., Pilsen, CZ; January/ February 2005; Study code: CPA 221-04/Zentiva 16/04/TIB/BSD, EudraCT No.: 2004-004132-31; Sponsor: Zentiva a.s., Prague 10, CZ The objective of the study was to compare bioavailability of two tibolone formulations on the request of Zentiva a.s., Prague: Ladybon 2.5 mg tablets with Livial 2.5 mg tablets (Organon, NL). This was an open (laboratory blind), single-dose, randomised, two-way cross-over study. The assessment of bioequivalence was based on pharmacokinetic parameters derived from 3-hydroxytibolone, 3-hydroxytibolone and tibolone concentrations analysed in individual plasma samples. After a 10.5 hour fasting period, each subject was administered orally a single dose (one 2.5 mg tablet) of one of the two tibolone formulations with 200 ml water. The fasting period continued 4 hours after the dosing. 21 blood samples were taken predose and up to 30.0 hours after dosing. The subjects were confined at the study centre from the evening prior to each study phase until collection of the 30-hour blood sample. There was a six-day washout period between doses. Vital signs were measured before dosing and at 1, 3, 8, 12, 24, and 30 hours after drug administration. The total twenty-four (24) + four (4) alternates healthy female volunteers initiated and completed the study. Their ages ranged from 48 to 65 years (median age 55 years), and their body weight was between 56.9 and 81.3 kg (median 66.5 kg). Plasma samples for 3-hydroxytibolone, 3-hydroxytibolone, and tibolone concentrations were planned to be analysed by means of validated HPLC-MS/MS method in CEPHA bioanalytical laboratory. The lower limit of quantification was 0.20 ng/mL for 3hydroxytibolone, and 0.19 ng/mL for 3-hydroxytibolone. The determination of parent drug tibolone has been performed after the Clinical Study Report and was issued as a Supplement to Clinical Study Report. Tibolone plasma levels were determined in CEPHA bioanalytical laboratory by the validated HPLC-MS/MS method with the lower limit of quantitation 0.30 ng/ml. Bioequivalence of tibolone products, assessed in this study, was based on the pharmacokinetic parameters of active drug metabolite 3-hydroxytibolone as a primary parameter and 3hydroxytibolone and parent drug tibolone as a secondary parameters, analysed in individual plasma samples. Based on the pharmacokinetic parameters of of the active metabolites 3-hydroxytibolone and 3hydroxytibolone and the parent drug tibolone, the reference and test 2.5 mg tablet formulations are bioequivalent with respect to the extent and rate of absorption. The 90% confidence intervals calculated for AUC (0-last), AUC (0-inf) and Cmax were within the range of acceptability. Based on the presented bioequivalence study, Ladybon 2.5 mg tablets is considered bioequivalent to Livial 2.5 mg tablets.