Public Assessment Report Scientific discussion. Metoprolol ratiopharm (metoprolol succinate) SE/H/0760/ /DC

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1 Public Assessment Report Scientific discussion Metoprolol ratioparm (metoprolol succinate) SE/H/0760/ /DC Tis module reflects te scientific discussion for te approval of Metoprolol ratioparm. Te procedure was finalised at For information on canges after tis date please refer to te module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Pone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION ratioparm GmbH as applied for a marketing autorisation for Metoprolol ratioparm, prolonged-release tablets, 25, 50, 100 and 200 mg claiming essential similarity to Seloken ZOC prolonged-release tablets, 25, 50, 100 and 200 mg marketed in Sweden by AstraZeneca Te product contains metoprolol succinate as active substance. For approved indications see te Summary of Product Caracteristics. Te reference product used in te bio-equivalence study is Beloc-Zok forte marketed by AstraZeneca GmbH in Germany. II. II.1 QUALITY ASPECTS Introduction Metoprolol ratioparm is presented in te form of prolonged release tablets containing metoprolol succinate corresponding to 25, 50, 100 and 200 mg of metoprolol tartrate. Te excipients are sugar speres (containing sucrose and maize starc), macrogol, etyl acrylatemetyl metacrylate copolymer, talc, povidone, microcrystalline cellulose, magnesium stearate, colloidal anydrous silica, ypromellose and titanium dioxide. Te tablets are packed in Al/Al blisters or HDPE bottles. II.2 Drug Substance Metoprolol succinate as a monograp in te P Eur. Metoprolol succinate is a wite, crystalline powder wic is freely soluble in water. Te structure of metoprolol succinate as been adequately proven and its pysico-cemical properties sufficiently described. Relevant information on polymorpism and cirality is presented. Te route of syntesis as been adequately described and satisfactory specifications ave been provided for starting materials, reagents and solvents. Te active substance specification includes relevant tests and te limits for impurities/degradation products ave been justified. Te analytical metods applied are suitably described and validated. Stability studies under ICH conditions ave been conducted and te data provided are sufficient to confirm te retest period. II.3 Medicinal Product Metoprolol ratioparm prolonged-release tablets are formulated using excipients described in te current P Eur. All raw materials used in te product are of vegetable origin. Te product development as taken into consideration te pysico-cemical caracteristics of te active substance. Te manufacturing process as been sufficiently described and critical steps identified. Results from te process validation studies confirm tat te process is under control and ensure bot batc to batc reproducibility and compliance wit te product specification. 2/6

3 Te tests and limits in te specification are considered appropriate to control te quality of te finised product in relation to its intended purpose. Stability studies under ICH conditions ave been performed and data presented support te self life claimed in te SPC, wen stored below 25 C. III. III.1 NON-CLINICAL ASPECTS Discussion on te non-clinical aspects Since tis product as been sown to be essentially similar and refer to a product approved based on a full application wit regard to preclinical data, no furter suc data ave been submitted or are considered necessary. IV. IV.1 CLINICAL ASPECTS Parmacokinetics Te applications was supported by tree clinical studies to demonstrate te bioequivalence between te generic product and te originator, eac study testing te igest tablet strengt (190 mg metoprolol succinate) in ealty subjects. Te studies were two single-dose studies in fasted and fed state, respectively, and a repeat-dose study in fasted state. All studies were open-label, balanced, and randomised, two-treatment, two-period, two-sequence, crossover, comparative oral bioavailability studies. In eac period of te fasted single-dose study, subjects were administered 190 mg metoprolol succinate in te morning after an overnigt fast and continued to fast for 4 ours post-dose. In te fed study, te tablet was administered witin 30 minutes after te subjects ad been served a ig-fat, ig-calorie breakfast. Blood sampling was performed for 48 ours post-dose. In te multiple-dose study, in eac period metoprolol 190 mg tablets were administered once daily for 6 days in te fasted state. Predose blood samples were collected on all dosing days and post-dose samples for 24 ours after dose 6. Te concentrations of metoprolol in plasma were analysed by an LC-MS/MS metod. Bioequivalence was to be based on C max, AUC 0-t, and AUC 0- in te single-dose studies and C max-ss, C min-ss, and AUC τ, in te multiple-dose study. Te acceptance criteria for bioequivalence of AUC values were defined as confidence intervals (CIs) for te test/reference ratio witin 80.00% to %. For C max and, in te multiple-dose study, C min, te acceptance criteria were defined as CIs for te test/reference ratio witin 75.00% to %. Te study package and te primary parmacokinetic parameters for evaluation were appropriate for studying bioequivalence between two metoprolol prolonged-release formulations. Te widening of te acceptance range for C min was acceptable since te Applicant demonstrated tat te intra-individual, day-to-day variability in C min for te reference formulation was >30% at steady state in te multiple-dose bioequivalence study. As te 90% CIs for C max fell witin te normal acceptance range in all tree studies (see below), widening of te acceptance range for C max was not an issue for tis application. Te parmacokinetic results of te tree bioequivalence studies are sown in Tables /6

4 Table 1. Parmacokinetic parameters of metoprolol after administration of a single dose of 190 mg metoprolol in te fasted state (non-transformed values; aritmetic mean ± SD, t max as median, range) Treatment AUC 0-t AUC 0- C max Test 1602 ± ± ± ± 0.98 Reference 1700 ± ± ± ± 0.86 *Ratio (%) % CI AUC 0- AUC 0-t C max T max T 1/ 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 *ln-transformed values t max T 1/2 - - Table 2. Parmacokinetic parameters of metoprolol after administration of a single dose of 190 mg metoprolol in te fed state (non-transformed values; aritmetic mean ± SD, t max as median, range) Treatment AUC 0-t AUC 0- C max Test 2365 ± ± ± ±1.23 Reference 2259 ± ± ± ± 1.3 *Ratio (%) % CI 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 t max T 1/2 - - Table 3. Parmacokinetic parameters of metoprolol at steady-state (day 6) after dosing wit 190 mg metoprolol daily for 6 days in te fasted state (non-transformed values; aritmetic mean ± SD, T max median) Treatment AUC 0-τ ng*r/ml C max, ss Test 3167 ± ± C min, ss a) T max (r) PTF% 79.2 ± ± 45.0 Reference 3006 ± ± ± ± 50.8 Ratio (%) % CI AUC 0-τ area under te plasma concentration-time curve during te 24-r dose interval C max maximum plasma concentration C min minimum plasma concentration (24-r concentration) T max refers to te wole dosing period (day 1-6) wit dose 6 given at 120 r PTF% fluctuation index a) C min-ss is te concentration in te 24-r sample after dose 6 % - - 4/6

5 Bioequivalence between te test and reference formulation was demonstrated for C max and AUC witin te normal acceptance criteria of % in all tree studies. Bioequivalence between te test and reference formulation was demonstrated for C min in te multiple-dose study using te wider acceptance criteria of %. Te Applicant also provided bioequivalence analysis of te peak-to-troug fluctuation (PTF) in te multiple-dose study, demonstrating tat te test and reference formulations are bioequivalent (witin te % limits) in tis respect. Tus, te generic product was concluded to be bioequivalent wit te originator. IV.2 Discussion on te clinical aspects Since tis product as been sown to be essentially similar and refer to a product approved based on a full application wit regard to clinical efficacy/safety data, no furter suc data ave been submitted or are considered necessary. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION User testing of te package leaflet as been performed and is acceptable. Te results of te conducted bioequivalence studies can be extrapolated to oter strengts since te criteria for biowaiver for additional strengts are fulfilled according to te Note for Guidance on te Investigation of Bioavailability and Bioequivalence. Te risk/benefit ratio is considered positive and Metoprolol ratioparm, prolonged-release tablets, 25, 50, 100 and 200 mg is recommended for approval. VI. APPROVAL Te Decentralised procedure for Metoprolol ratioparm, prolonged-release tablets, 25, 50, 100 and 200 mg was successfully finalised on /6

6 Public Assessment Report Update Scope Procedure number Product Information affected Date of start of te procedure Date of end of procedure Approval/ non approval Assessment report attaced Y/N (version) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Pone: +46 (0) Fax: +46 (0) Internet: Template version: