Direction de l’Evaluation des Médicaments et des Produits Biologiques
PUBLIC ASSESSMENT REPORT Scientific Discussion SIMVASTATIN TEVA 5/10/20/40/80 mg, film coated tablets simvastatin FR/H/307/01-05/MR Applicant: TEVA Classics
Date of the PAR: December 2007
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 1 of 7
Information about the initial procedure: Application/Legal Basis Active substance Pharmaceutical form Strength Applicant EU-Procedure number End of procedure
1.
Generic 10(1) Simvastatin Film coated tablet 5, 10, 20, 40 and 80 TEVA Classics FR/H/307/01-05/MR 25/07/2007
INTRODUCTION
Based on review of the quality, safety and efficacy data, the Afssaps has granted a marketing authorisation (MA) for Simvastatin Teva 5mg, 10mg, 20mg, 40mg, 80mg film-coated tablets from Teva Classics on March 14, 2005. The product is indicated for: « Hypercholesterolaemia Treatment of primary hypercholesterolaemia and mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. physical exercise, weight reduction) is inadequate. Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipidlowering treatments (e.g. low-density lipoprotein [LDL] apheresis) or if such treatments are not appropriate. Cardiovascular prevention Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1). » A comprehensive description of the indications and doses is given in the SPC. The generic application for marketing authorisation concerns Simvastatin Teva film-coated tablets in the strengths 5mg, 10mg, 20mg, 40mg, 80mg. The medicinal products are claimed to be essentially similar to Zocor 5mg, 10mg, 20mg, 40mg and 80mg tablets marketed in France by Merck Sharp Dohme Ltd The applicant has submitted two bioequivalence studies. The reference products used in the bioequivalence studies are ZOCOR 40mg, tablets marketed by MSD Ltd in UK. No new preclinical or clinical studies were conducted, which is acceptable for this kind of application. During the procedure, no potential serious risk to public health concerns was raised. 2.
QUALITY ASPECTS
2.1 Introduction Simvastatin Teva is presented in the form of film-coated tablets containing 5mg, 10mg, 20mg, 40mg or 80mg of simvastatin. The excipients are described in the current Ph. Eur.: lactose monohydrate, pregelatinised starch, microcrystalline cellulose, citric acid monohydrate, ascorbic acid, butylhydroxyanisole, magnesium stearate. The tablets are packed in white opaque PVC/PE/PVDC - Aluminium blister.
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 2 of 7
2.2 Drug substance The drug substance, simvastatin is supplied by TEVA Pharmaceuticals-TEVA API Division Israel (holder) and is manufactured by TEVA Pharmaceuticals Works Private Limited Company (Hungary) which has been granted a certificate of suitability granted. Simvastatin is practically insoluble in water. The powder is micronised. The drug substance is controlled according to the current version of the monograph Simvastatin n° 1563 of the Ph. Eur. with the following supplemented specifications: any other impurity than those mentioned in the monograph and detected by the test for related substances of the monograph, test for residual butyl hydroxyl toluene, test for residual methanol and particle size. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the retest period. 2.3 Medicinal product Simvastatin Teva 5mg, 10mg, 20mg, 40mg, 80mg film-coated tablets are presented as colored, standard convex or capsules shaped film-coated tablet. The formulation contains excipients described in the current Ph Eur. All raw materials used in the product have demonstrated compliance with Commission Directive 2003/63/EC and the NfG on Minimising the risk of transmitting Animal Spongiform Encephalopathy Agents via human and veterinary medicinal products (EMEA/410/01). The development is sufficiently described in accordance with the relevant European guidelines. Comparative in vitro dissolution profiles and impurities profiles of the generic product and the reference product support the essentially similar character. The biobatches used for the bioequivalence study are considered as representative of the production. The manufacturing process is a wet granulation. It is satisfactorily described, main operating parameters are set and type of equipment is presented. Process validation reports for the 10, 20, 40 & 80 strengths are presented on three batches per strength. Batches were investigated according to a detailed validation protocol. The same validation scheme will be used for the validation of the 5mg strength. The process is under control and ensures both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed. The data support the shelf life claimed in the SPC, 24 months with storage condition “store below 25°C”. 3.
NON-CLINICAL ASPECTS
3.1 Discussion on the non-clinical aspects This product is a generic formulation of ZOCOR® on the European market. Therefore, no new preclinical data have been submitted in the dossier, and no preclinical assessment has been performed. 4.
CLINICAL ASPECTS
4.1 Introduction After oral administration simvastatin is well absorbed from GI tract and extensively up-taken by the liver (target organ) by first-pass effect. Its absolute bioavailability is poor (about 4 %). In the liver simvastatin is converted into different active and inactive metabolites. β-hydroxy acid metabolite is the major active moiety. No significant deviation from linearity has been reported for the pharmacokinetics of this drug.
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 3 of 7
Simvastatin is rapidly eliminated from plasma. Its elimination half-life is about 2 hours. Comparatively to fasted state, the concomitant food intake doesn’t modify significantly the bioavailability of simvastatin and the systemic exposure to related active derivatives. Simvastatin is a lactone pro-drug. Following oral administration the parent simvastin is extensively hydrolysed in the liver to form numerous active and inactive metabolites. Among them the β-hydroxy acid metabolite is a potent inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This hepatic enzyme catalyses an early key step in the biosynthesis of cholesterol. The therapeutic indication of Simvastatin is: “Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1)”. This drug is also indicated for the treatment of “primary hypercholesterolaemia and mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. physical exercise, weight reduction) is inadequate” and the “Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. low-density lipoprotein [LDL] apheresis) or if such treatments are not appropriate”. 4.2 Discussion on the clinical aspects The bioequivalence of the product in comparison with the adequate comparators could be considered as demonstrated. Taking into account the pharmaceutical characteristics of the products subject of the application (five different strengths of an immediate release pharmaceutical form), bioequivalence testing was performed with the 40 mg and 80 mg tablets at single dose, and under fasting conditions. Waiver from bioequivalence testing was validly claimed for the lower 20, 10 and 5 mg strengths. As simvastatin TEVA is a generic version of the already approved and well known ZOCOR (brand leader in France), no new clinical studies were conducted and the bioequivalence studies have been considered as a valid surrogate for efficacy and safety demonstration. 4.3 Pharmacokinetics In support of this application, two bioequivalence have been submitted. The first study (protocol n° 200-773) has investigated the 40 mg strength under fasting conditions. The second study (protocol n° 020080) has investigated the 80 mg strength under fasting conditions as well. In both studies, the reference products were the brand leaders in the UK, ZOCOR 40 and ZOCOR 80 mg tablets marketed by MSD Ltd. These products have the same quantitative and qualitative composition than ZOCOR 40 and 80 on the French market and thus, could be accepted as valid and adequate comparators for an application in France. In both studies, an open label, two-period, two-sequence and two-treatment crossover design was followed. The investigational products were administered as a single-dose after an overnight fast and 23 blood samples were subsequently collected up to 36 hours post-dose. A 7 days washout period was observed between the first and the second period. Sixty healthy volunteers were included in each study. In the study with the lowest strength (40 mg) all subjects have finished all the study periods and thus analyzed. In the study with the highest strength (80 mg), 59 subjects have completed all study periods and thus, were analyzed (one subject was withdrawn due to a mild adverse event). Plasma concentrations of the parent drug (simvastatin) and the major active metabolite (β-Hydroxyacid-simvastatin) were monitored in the plasma samples by the means of fully validated LC-MS-MS analytical technique. The primary PK parameters investigated in the study were: AUC0-t, AUC0-inf, Cmax and Tmax. The outcome of these studies is tabulated below.
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 4 of 7
First Study: Tablet 40 mg (single-dose under fasting conditions): • Parent drug: simvastatin: Pharmacokinetic parameters (log-transformed values; arithmetic mean ± SD, tmax median, range)
Treatment
AUC0-t
AUC0-∞
Cmax
hr.ng/ml
hr.ng/ml
ng/ml
tmax h
Test (S.D.) Reference (S.D.) *Ratio (90% CI) Point estimate
38.1 (22.4) 36.9 (19.5) [90;109] % 99.3 %
40.4 (24.7) 38.7 (20.1) [88; 107] % 97.2 %
8.95 (5.80) 9.39 (5.42) [87;103]% 94.5 %
1.17 (0.67-6) 1.00 (0.67-5.5)
Intra-subject CV (%)
31.2 %
32.5 %
29.1 %
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration Tmax time for maximum concentration *log-transformed values •
Active metabolite: β-OH-acid-simvastatin: Pharmacokinetic parameters (log-transformed values; arithmetic mean ± SD, tmax median, range) Treatment
AUC0-t
AUC0-∞
Cmax
hr.ng/ml
hr.ng/ml
ng/ml
tmax h
Test (S.D.) Reference (S.D.) *Ratio (90% CI) Point estimate
20.8 (16.6) 17.9 (10.2) [101;118]% 109 %
22.2 (18.3) 19.4 (10.6) [99; 118]% 108.3%
2.50 (1.7) 2.24 (1.12) [99;117]% 107.5 %
4.5 (3.5-10) 4.5 (2-10)
Intra-subject CV (%)
26.1 %
25.8 %
27.6 %
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration Tmax time for maximum concentration *log-transformed values
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 5 of 7
Second Study : Tablet 80 mg: (single-dose under fasting conditions): •
Parent drug: simvastatin: Pharmacokinetic parameters (log-transformed values; arithmetic mean ± SD, tmax median, range)
Treatment
AUC0-t
AUC0-∞
Cmax
hr.ng/ml
hr.ng/ml
ng/ml
tmax h
Test (S.D.) Reference (S.D.) *Ratio (90% CI) Point estimate
93.2 (64.9) 89.6 (52.9) [90;111] % 99.9 %
100.5 (73.4) 94.4 (53.3) [89; 112] % 99.9 %
18.17 (12.4) 18.37 (12.60) [88;108]% 97.7 %
1 (0.5-6) 1.25 (0.5-6)
Intra-subject CV (%)
35.7 %
37 %
34.4 %
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration Tmax time for maximum concentration *log-transformed values •
Active metabolite: β-OH-acid-simvastatin: Pharmacokinetic parameters (log-transformed values; arithmetic mean ± SD, tmax median, range)
Treatment
AUC0-t
AUC0-∞
Cmax
tmax
hr.ng/ml
hr.ng/ml
ng/ml
h
Test (S.D.) Reference (S.D.) *Ratio (90% CI) Point estimate
40.5 (21.2) 41.7 (27.4) [92;108]% 99.7 %
46.4 (28.8) 45.2 (29.8) [93; 113]% 102.3%
4.45 (2.67) 4.59 (3.36) [90;106]% 97.6 %
4.5 (1.25-12) 4.5 (2.5-10)
Intra-subject CV (%)
26.1 %
30.5 %
26.8 %
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration Tmax time for maximum concentration *log-transformed values The bioequivalence of the 40 mg and 80 mg tablets to respective reference products was demonstrated. Waiver from BE study was claimed by the applicant for the lower strengths: 20-10 and 5 mg. This claim was accepted as all the requirements were fulfilled: • All the tablet strengths are manufactured by the same manufacturer following the same process; • The drug input has been shown to be linear over the therapeutic dose range; • The qualitative composition of the different strengths is the same; • The ratio between amounts of active substance and excipients is the same for the 80, 40, 20, 10 strengths. For the lowest strength (5 mg), the concentration of the active substance is low (less than 5 %) and the ratio between the amounts of excipients is similar;
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 6 of 7
•
5.
The dissolution profiles are similar under identical conditions for the 5, 10 and 20 strengths and the 40 and 80 mg bio-batches. OVERALL DISCUSSION , BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
The chemical-pharmaceutical quality of Simvastatin Teva 5mg, 10mg, 20mg, 40mg, 80mg film-coated tablets is demonstrated. The products are generic forms of Zocor 5mg, 10mg, 20mg, 40mg and 80mg tablets marketed in France which is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the European guidance documents. The SPC is consistent with that of the reference product. The SPC, Package Leaflet (PL) and Labelling are in the agreed template. The Member States mutually recognised the French evaluation of the marketing authorisation. There was no discussion in the CMD(h). Agreement between Member States was reached through a written procedure. The following post-approval commitments were made during the procedure: - The applicant commits to perform validation of the 5 mg tablets before launch according to the validation protocol presented in module 3.2.R. - The applicant commits to investigate the stability of three consecutive commercial batches of the 5 and 80 mg.
PUBLIC ASSESSMENT REPORT - simvastatin - clean - 14-12
Page 7 of 7
