Public Assessment Report

Public Assessment Report

Scientific discussion

TORVACARD 10

TORVACARD 20

TORVACARD 40

Atorvastatin

CZ/H/0108/001

CZ/H/0108/002

CZ/H/0108/003

Applicant: Zentiva, a.s., Prague, Czech Republic

This module reflects the scientific discussion for the approval of Torvacard 10, 20 and 40mg. The procedures were finalised at 30-06-2005.

INTRODUCTION

This is an abridged application. The applicant claims essential similarity, under article 10.1 (a)(iii) of Directive 2001/83/EC, to Sortis 10mg, 20mg, 40mg /10mg, 20mg, 40mg of atorvastatin/, film coated tablets, which contains the same amount of active substance in the same pharmaceutical form. The marketing authorisation holder for reference product Sortis 10mg, 20mg, 40mg, which has been authorized in the Czech Republic since 1999, is Pfizer s.r.o., Czech Republic.

Torvacard 10, 20, 40 mg film-coated tablets are generic medicinal products containing atorvastatin calcium as the active substance.

The applications were submitted under § 24 paragraph 6 of Czech Act No. 79/1997 on Pharmaceuticals, as amended, as generic applications of product that is not registered in another country (so called “generic application”), in accordance with Directive 2001/83/EC, Article 10.1. (a)(iii) first paragraph.

Original products authorized for not less than 6 years in the EEA are Sortis 10, 20 and 40 mg tablets from Parke-Davis (Pfizer) – first authorization was granted in Germany in 1996. The same products have been marketed in the Czech Republic since 1999 and therefore can be taken as reference medicinal products. Also for bioequivalence studies the product Sortis (Sortis 40 mg) is used.

Active ingredient is contained in medicinal products registered in the world for more than 5 years.

Atorvastatin calcium is a serum lipid lowering agent known as HMG-CoA reductase inhibitor which reduces cholesterol. The product is used for decreasing of cholesterol level in patients with primary hypercholesterolemia and combined hyperlipidemy as well as with higher level of triglycerides and with dysbetalipopoproteinemy.

All three strengths are presented in three types of containers, either PP/COC/PP aluminium blisters (with 30 or 90 tablets), Al/Al blisters (with 30 or 90 tablets) or glass bottles with screw caps (with 30 and 90 tablets).

QUALITY ASPECTS

Introduction

Torvacard contains atorvastatin calcium as the active substance; excipients are magnesium oxide, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, colloidal anhydrous silica, magnesium stearate, hypromellose, macrogol 6000, titanium dioxide, talc.

One film-coated tablet contains 10.340 (20.680, 41.360) mg of atorvastatin calcium equivalent to 10 (20, 40) mg of atorvastatin.

The proposed product shelf life is 2 years without special storage conditions.

Active Substance

The active substance atorvastatin calcium (chemical name: R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt) is a white to yellowish powder. Physical-chemical properties have been adequately described. There have been literature reports of polymorphism for this active substance. Atorvastatin calcium exists in number of polymorphic forms and amorphous form which can be distinguished by X-ray powder diffraction and 13C CP/MAS NMR.

There are two chiral centers with four enantiomers. Atorvastatin is manufactured from R, R-enantiomer and during manufacture chiral centers are not changed. Optical rotation, measured in dimethyl sulphoxide (1% solution) is - 6.5 to – 8.5°.

Cis-trans isomerism and threo-erythro isomerism are not applicable to this molecule.

The chemical structure was sufficiently characterized.

The scientific information has been submitted in a frame of an Active Substance Master File.

The manufacture has been described in details.

The applicant has provided an in-house monograph because atorvastatin calcium is not described in any pharmacopoeia. Satisfactory specification is provided. Appropriate discussion has been presented on organic and inorganic impurities including residual solvents.

Certificates of analysis have been provided for pilot and full scale batches. Results comply with the proposed specification and confirm the consistency of the process.

The container closure for Atorvastatin calcium drug substance is described as follows: LDPE bag is bound with a cotton string. The bags (primary packaging material) comply with the provisions of Ph.Eur.

The bags are placed inside a polyethylene bag coated with aluminium layer and sealed by heating. Substance is stored at -18 ºC with the re-test period of one year.

Appropriate stability studies have been carried out. Results showed no significant change and remained within the specification. Therefore the proposed re-test period is justified based on the stability results when substance is kept in the proposed packaging.

Atorvastatin calcium is not a very stable substance; it decomposes under all stress conditions with the exception of light. Under an acid exposition the main degradant atorvastatin lactone arised. From lactone atorvastatin methyl ester is formed in methanol by esterification. In basic ambiance there is presence of only one degradant while with under of influence of peroxide a mixture of degradants is observed. Also sensitivity to increasing temperature is evident.

Medicinal Product

Atorvastatin calcium is presented as a film-coated tablet (immediate-release) intended for once-daily oral administration. Each tablet contains 10 mg, 20 mg, or 40 mg of drug substance. The tablets are white to off-white, film-coated, oval, and biconvex

Pharmaceutical Development

The objective was to obtain atorvastatin calcium film-coated tablets achieving pharmaceutical equivalence and bioequivalence with the product of reference Sortis 10, 20, and 40 mg film-coated tablets.

The active substance is compatible with most of the commonly used excipients – this has been either described in the literature or has been observed in stability tests of the finished product. For development of the new medicinal product an amorphous form of atorvastatin was used.

All of used excipients with the exception of Low-substituted hydroxypropyl cellulose are the subject of monographs in the Ph. Eur. Low-substituted hydroxypropyl cellulose is referred to the USP.

Satisfactory Certificates of analysis of all excipients have been provided.

Whereas magnesium stearate is obtained from plant sources, lactose monohydrate is produced from milk used for human consumption. The current requirements with respect to TSE are met. Information on the safety of excipients is described in the dossier.

There is no material containing a genetically modified organism (GMO) within the meaning of Article 2 of Council Directive 90/220/EEC.

In order to demonstrate the equivalence of the Torvacard and the reference product Sortis, comparative dissolution data between the proposed and reference products (all three strengths) have been provided including the biobatches.

The impurity profile comparison of proposed product with reference product from different EU markets has been provided with comparable results.

Manufacturing of the product

The manufacturing process can be considered as a standard one. The manufacture and in-process controls are fully described in the dossier. Results of process validation for all three strengths have been submitted and showed the process is adequately controlled and reproducible. A satisfactory validation plan has been presented for the validation of the process on commercial batches.

Product specification

The approved proposed specifications are acceptable. Satisfactory control tests are applied at time of release and during the shelf-life. Release and shelf life limits for the assay of atorvastatin calcium are in line with batch and stability data. Limits for related substances comply with ICH guidelines.

Analytical methods have been satisfactorily described and validated in accordance to regulatory requirements.

Results of analysis for several pilot batches for every strength were given in documentation. All results complied with the specifications.

The packaging material is the same as specified in the Introduction of this report.

The materials comply with the Ph.Eur. and with EU directives.

Stability of the product

The stability of the drug product was tested and evaluated in several stability studies in accordance with the predefined individual stability protocols.

Based on the data, proposed shelf life and storage conditions were accepted.

Discussion on chemical and pharmaceutical aspects

Information on development, manufacture and control of the drug substance and drug product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics, and these in turn lead to the conclusion that the product should have a satisfactory and uniform performance in the clinic.

STEPS TAKEN AFTER AUTHORISATION – SUMMARY

Variation IB/14a
Change in the manufacturer of API where no Ph.Eur. is available
Variation IA/36b
Change in shape or dimensions of the container or closure – other products
Variation II
In M3 – addition of manufacturer of API’s intermediate
Variation IA/11a
Change in the batch size of active substance
Variation IA/4
Change in the name and/or address of a manufacturer of the active substance where no European Pharmacopoeia certificate of suitability is available
Variation IA/13a
Change in the test procedure for active substance or starting material, intermediate, or reagent used in the manufacturing process of the active substance- minor changes to an approved method
Variation IA/42a
Change in shelf-life
Variation IA/32a
Change in the batch size of the finished products
Variation IA/9
deletion of manufacturing site
Variation II
in Module 3 – addition of excipient source
Variation II
in Module 3 – addition of 2nd excipient source
Variation II
in Module 3 – change in API specification
Variation II
in Restricted Part of DMF
Variation II
in Module 1 – addition of Risk management plan
Variation II
in Module 1 – harmonization of SPC after EMEA referral and addition of readability

CLINICAL ASPECTS

Torvacard is indicated simultaneously with a suggested diet to reduce elevated levels of total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolemia, including familial hypercholesterolemia (the heterozygous form), or with mixed (combined) hyperlipidaemia (corresponding to type IIa or type IIb according to Fredrickson) if the diet and other non-pharmacological measures have not resulted in a sufficient effect.Torvacard is also indicated to lower the total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia, as an adjuvant therapy to other hypolipidemic treatment , or in cases when these therapeutic methods are not available.

Prior to commencement of Torvacard treatment, the patient should be advised to follow the standard low-cholesterol dietary regimen and maintain it also for the whole duration of treatment with Torvacard. The treatment is usually commenced with 10 mg of atorvastatin given once a day. Modification of subsequent dosage is individualized according to the starting values of LDL-cholesterol in comparison with the targeted levels of LDL-cholesterol, and according to the patient’s response to the treatment. The adjustment of dosage should be carried out at an interval of 4 weeks or more. The maximum dose is 80 mg of atorvastatin at one daily dose. The product may be used irrespectively of daytime or food intake.

The applicant has submitted the bioequivalence study of the 40 mg tablets, in support of the application. The study was audited by experienced auditor of sponsor and declared to have been performed in accordance with ICH GCP standards.

Bioequivalence Study

A single dose, randomized, two-period, two-treatment, two-sequence, crossover bioequivalence study on atorvastatin 40 mg film-coated tablets Torvacard 40 versus Sortis 40 mg in healthy volunteers.

Forty-eight healthy male and female volunteers including four alternates initiated Study period 1.One subject was withdrawn for emerging exclusion criterion before Period 2 commencement. Forty-seven subjects completed all study procedures. Consequently, one subject was excluded from the pharmacokinetic and statistical analyses in accordance with the study protocol to keep the group sequence-balanced In each period, subjects were housed from the evening before dosing until after the 24-hour blood draw. Atorvastatin bioequivalence was evaluated in 46 subjects. The median age was 27.5 years and median weight 70.8 kg.

Each overnight fasting subject was administered orally a single dose (two tablets, i.e.80 mg of atorvastatin) of one of the two atorvastatin formulations with 200 mL water. Blood samples were collected before dosing and at 0.25 0.5, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours after dosing. Subjects fasted for 4 hours after the drug administration; standard identical meals for both periods were provided thereafter. Sitting blood pressure and heart rate were measured before dosing and at approximately 1, 3, 5, 8, 12, 24, 36, 48 and 72 hours post-dose.

The individual plasma levels as well as the calibration and quality control data were tabulated together with the descriptive statistics data for 46 subjects.

The pharmacokinetic parameters, characterizing the rate and extent of the absorption of atorvastatin and the rate of its metabolism and elimination, were calculated and statistically evaluated using both parametric and non-parametric approach, whichever appropriate. The following parameters derived from the plasma concentration versus time profiles were extracted: AUC(0-inf.), AUC(0-t), the ratio AUC(0-t)/AUC(0-inf.), Cmax (both linear and ln-transformed), tmax, kel and t½ (all linear). Analyses of variance using sequence, formulation, and period as fixed effects and subject nested within sequence as a random effect were performed on ln-transformed main pharmacokinetic parameters. Consistent with the two one-sided t-tests for bioequivalence, 90% confidence intervals for the difference between drug formulation least square means were derived from the analyses on the ln-transformed individual parameters AUC(0-t), AUC(0-inf.), and Cmax. Non-parametric analysis of tmax was performed. The intrasubject variability for the AUC(0-inf.), AUC(0-t), and Cmax parameters was derived as a major determinant of sample size, power, and the width of confidence intervals for crossover studies.

The tolerance of the study products was good. No adverse event, severe adverse event, unexpected adverse drug reaction or other clinically significant adverse event occurred.

The primary objective was to establish bioequivalence for the atorvastatin in plasma after administration of two 40 mg tablets of test and reference products. The pharmacokinetic parameters of atorvastatin and 2-hydroxyatorvastatin are presented in the following tables. The mean T/R ratios (log normal distribution) for the main atorvastatin parameters AUC(0-t) were 111.88% (90% C.I.: (105.22-118.96%)), AUC0-¥ 111.35% (105.05-118.04%), and Cmax 111.65%, (100.56-123.97%) respectively. The median tmax values for the test and reference products were 0.75 hours and 0.51 hours, respectively. The mean T/R ratios (log normal distribution) for the 2-hydroxy-atorvastatin parameters AUC(0-t) were 113.01% (90% C.I. (105.04-121.57%), AUC0-¥ 110.53% ((103.59-117.95%)), and Cmax 112.30% (101.72-123.98%), respectively. The median tmax values for the test and reference products were 1.0 hours and 1.0 hours, respectively.