Public Assessment Report. Scientific discussion. (Atorvastatin calcium) SE/H/757/01-03/DC

Transcription

1 Public Assessment Report Scientific discussion Atovans 10mg, 20mg and 40mg film coated tablets (Atorvastatin calcium) SE/H/757/01-03/DC Tis module reflects te scientific discussion for te approval of Atovans. Te procedures were 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 Jacobsen Parma AS as applied for a marketing autorisation for Atovans, film coated tablets, 10 mg, 20 mg and 40 mg claiming essential similarity to Lipitor, film coated tablets 10 mg, 20 mg and 40 mg marketed in Sweden by Pfizer AB. Te product contains Atorvastatin calcium as active substance. For approved indications see te Summary of Product Caracteristics. Te reference product used in te bio-equivalence study is Sortis 40 mg marketed by Pfizer in Germany. II. QUALITY ASPECTS II.1 Introduction Atovans is presented in te form of tablets containing 10.36, or 41,44 mg of atorvastatin calcium wic corresponds to 10, 20 and 40 mg, respectively, of te atorvastatin. Te excipients are lactose monoydrate, microcrystalline cellulose, ydroxypropylcellulose, croscarmellose sodium, crospovidone, sodium laurilsulfate, sodium ydroxide, magnesium stearate and Opadry II HP wite 85F Te tablets are packed in OPA/Al/PVC-aluminium blisters. II.2 Drug Substance Atorvastatin calcium does not ave a monograp in te P Eur. Atorvastatin calcium is a wite or sligtly wite powder sparingly soluble in DMSO, soluble in metanol, practically insoluble in water and 10% HCl. Te structure of Atorvastatin calcium as been adequately proven and its pysico-cemical properties sufficiently described. Te substance is amorpous and sows non-crystallinic properties. 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 Atovans film coated tablets, 10 mg, 20 mg and 40 mg are formulated using excipients described in te current P Eur. Only lactose monoydrate is of animal origin and compliance wit Commission Directive 2003/63/EC and te NfG on Minimising te risk of transmitting Animal Spongiform Encepalopaty Agents via uman and veterinary medicinal products (EMEA/410/01) as been demonstrated. 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. Te tests and limits in te specification are considered appropriate to control te quality of te finised product in relation to its intended purpose. 2/6

3 Stability studies under ICH conditions ave been performed and data presented support te self life claimed in te SPC, wen stored in te original package in order to protect from ligt and moisture. III. NON-CLINICAL ASPECTS III.1 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. CLINICAL ASPECTS IV.1 Parmacokinetics One bioequivalence study comparing te parmacokinetic profiles of Atovans 40 mg tablets wit Sortis 40 mg tablets, Pfizer was performed. Te study design was an open, 2 periods, 2- way crossover study performed in ealty, adult, male uman subjects under fasting conditions. Plasma samples were analyzed for atorvastatin, ortoydroxy atorvastatin (2-OHatorvastatin) and paraydroxy atorvastatin (4-OH-atorvastatin) by a validated LC-MS/MS metod. Parmacokinetic parameters were calculated using conventional non-compartmental metods. ANOVA was performed on te ln-transformed C max, AUC 0-t and AUC 0-. Parmacokinetic results are sown in te tables 1-3 below. Table 1. Atorvastatin parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max median, range) Treatment AUC 0-t AUC 0- C max t max ng/ml/ ng/ml/ ng/ml Test 111.7± ± ± ( ) Reference 99.97± ± ± ( ) *Ratio (90% CI) NS ( ) ( ) ( ) 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 alf-life NS no statistically significant difference *ln-transformed values 12.2± ±4.2 3/6

4 Table 2. 2-OH-atorvastatin parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max median, range) Treatment AUC 0-t AUC 0- C max t max ng/ml/ ng/ml/ ng/ml Test 102.0± ± ± ( ) Reference 94.48± ± ± ( ) *Ratio (90% 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 alf-life *ln-transformed values 13.2± ±5.2 Table 3. 4-OH-atorvastatin parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max median, range) Treatment AUC 0-t AUC 0- C max t max ng/ml/ ng/ml/ ng/ml Test 13.5± ± (5.0-36) Reference 12.7± ± ( ) *Ratio (90% 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 alf-life *ln-transformed values Bioequivalence between te two products, in terms of rate (Cmax) and extent of absorption (AUC), was adequately demonstrated. 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. Te SPC, package leaflet and labelling are acceptable 4/6

5 Te results of te conducted bioequivalence study 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 Atovans, 10 mg, 20 mg and 40 mg film coated tablets, are recommended for approval. VI. APPROVAL Te Decentralised procedures for Atovans, film coated tablets, 10 mg, 20 mg and 40 mg were 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: