Public Assessment Report. Scientific discussion. Atorvastatin DK/H/1744/ /DC

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1 Public Assessment Report Scientific discussion Atorvastatin Orifarm 10 mg 20 mg, 40 mg and 80 mg film-coated tablets Atorvastatin DK/H/1744/ /DC This module reflects the scientific discussion for the approval of Atorvastatin Orifarm. The procedure was finalised on 22 September For information on changes after this date please refer to the module Update. 1/8

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Atorvastatin Orifarm 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets, from Orifarm Generics A/S. The product was authorised in Denmark on 5 November The product is indicated for: Hypercholesterolaemia Atorvastatin is indicated as an adjunct to diet for lowering elevated total cholesterol, LDLcholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolaemia, including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (corresponding to types IIa and IIb of the Frederickson classification) when response to diet and other non-pharmacological measures is inadequate. Atorvastatin is also indicated for lowering total-c and LDL-C in patients with homozygous familial hypercholesterolaemia, as an adjunct to other lipid-lowering treatments (such as LDL apheresis) or if such treatments are unavailable. Prevention of cardiovascular disorders Prevention of cardiovascular events in patients expected to be at high risk of a first cardiovascular event, as an addition to correction of other risk factors. Atorvastatin calcium is a synthetic lipid-lowering agent. It is a selective, competitive inhibitor of 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Zarator 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets, which has been registered in Denmark since May 1997 (10 mg, 20 mg and 40 mg) and February 2002 (80 mg) by Pfizer ApS. The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC. II. II.1 QUALITY ASPECTS Introduction Each film-coated tablet contains 10 mg, 20 mg, 40 mg and 80 mg atorvastatin (as atorvastatin calcium propylene glycol solvate), respectively. The 10 mg tablets are white, oval, biconvex film coated tablets with APO engraved on one side and A10 on the other side. The 20 mg tablets are white, oval, biconvex film coated tablets with APO engraved on one side and ATV20 on the other side. The 40 mg tablets are white, oval, biconvex film coated tablets with APO engraved on one side and ATV40 on the other side. The 80 mg tablets are white, oval, biconvex film coated tablets with APO engraved on one side and ATV80 on the other side. The tablets are packed in Aluminium-OPA-PVC/Aluminium blisters of 28, 30, 49, 50, 56, 98 and 100 tablets and in HDPE bottles with PP cap of 30, 50, 90, 100, 150, 200, 250, 300, 500 and 1000 tablets. However, not all pack sizes may be marketed. 2/8

3 The excipients in the tablet core are: Calcium acetate; Silica, colloidal anhydrous; Croscarmellose sodium; Magnesium stearate (E572); Microcrystalline cellulose (E460) and Sodium carbonate anhydrous. The tablet coat consists of: Hydroxypropylcellulose (E463); Hypromellose (E464); Polyethylene glycol 8000 and Titanium dioxide (E171). Compliance with Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. II.2 Drug Substance Common name: Atorvastatin calcium propylene glycol solvate Chemical name(s): (3R, 5R)-7-{2-(4-flurophenyl)-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1h-pyrrole-1-yl}-3,5-dihydroxy-1-heptanoic acid, calcium salt (2:1), propylene glycol solvate Molecular Formula: C 66 H 68 CaF 2 N 4 O 10 C 3 H 8 O 2 Molecular Weight: g/mol Structural Formula: Atorvastatin calcium propylene glycol solvate is a white to off-white solid. The documentation for the active substance is presented as a European drug master file (DMF). The starting material has been redefined and further information on the steps in the upstream synthesis has been provided. The applicant has provided additional information about the active substance in order to justify the similarity in physico-chemical characteristics between atorvastatin calcium trihydrate and atorvastatin calcium propylene glycol solvate and thereby their equivalency, since the latter is used in the finished product as compared to atorvastatin calcium trihydrate which is used in the reference product. Several issues concerning control tests and specifications for the active substance have been clarified also due to the additional information on the synthesis of the active substance. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period and storage conditions have been found acceptable. 3/8

4 II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and their functions explained. Compatibility studies of the excipients with the active substance have been performed revealing that the product is moisture sensitive. The product specifications cover appropriate parameters for this dosage form; and the limits applied for degradants are considered qualified although some of the limits should be reviewed once supportive data are available. Satisfactory validations of the analytical methods have been presented. Batch analysis has been performed on 3 batches of each strength demonstrating compliance with the proposed specifications. Validation of the manufacturing process has been performed on pilot batches and satisfactory validation protocols are presented for validation of production scale batches. The conditions used in the stability studies are according to the ICH stability guideline. The proposed shelf-life is 18 months which is supported by the 18 months stability data. The SPC has been supplemented with the storage conditions Store in the original package. Keep the container tightly closed to protect from moisture. since the product is moisture sensitive. Satisfactory results from in-use stability studies have been presented. Because of the moisture sensitivity dose dispensing cannot be recommended. III. NON-CLINICAL ASPECTS This product is a generic formulation of Zarator, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application. Environmental risk assessment The product is intended as a substitute for other identical products on the market. The approval of this product will not result in an increase in the total quantity of atorvastatin released into the environment. It does not contain any component, which results in an additional hazard to the environment during storage, distribution, use and disposal. IV. CLINICAL ASPECTS IV.1 Introduction Atorvastatin is a well-known active substance with established efficacy and tolerability. For this generic application, the MAH has submitted one single dose bioequivalence study in which the pharmacokinetic profile of the test product Atorvastatin Orifarm 80 mg film-coated tablets is compared with the pharmacokinetic profile of the reference product Lipitor 80 mg film-coated tablets, Pfizer Ireland Pharmaceuticals, from the UK market. The application concerns 4 dosage strengths, 10, 20, 40 and 80 mg. The study was carried out with the 80 mg strength. Justification for biowaiver for the 10, 20 and 40 mg strength has been provided. The results from the 80 mg film-coated tablet can be extrapolated to the other strengths, according to 4/8

5 conditions in Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4. The study was an open-label, randomized, three-treatment, three sequence, three-period, three-way crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period of 7 days between the two administrations. 80 mg was administered in each period. Blood samples were collected pre-dosing and at various time-points post administration of a singledose 80 mg film-coated tablets with 240 ml of water for the analyses of atorvastatin and 2-hydroxy atorvastatin. 102 healthy male subjects participated in the study in two groups. 92 subjects completed the study. Two subjects dropped out voluntarily due to family emergency (before period 2 and in period 3, respectively), five subjects were withdrawn due to non-compliance (all before or in period 2) and three subjects were withdrawn due to adverse events (all before period 2), subsequently these 10 subjects were excluded from the pharmacokinetic/statistical analysis. The pharmacokinetic parameters calculated were AUC 0-t, AUC0-, C max, t max, K el and t½ el. Primary variables were AUC 0-t, AUC 0- and C max. The 90% confidence interval of the relative mean AUC 0-t and AUC 0- of the test (T) to reference (R1) formulation should be within 80 to 125% in order for bioequivalence to be concluded. The 90% confidence interval of the relative mean measured C max of the test (T) to reference (R1) formulation should be within % for atorvastatin and 2-hydroxy atorvastatin. This wider confidence interval was justified a priori in the protocol. The applicant s justification is based on the effect of atorvastatin and the relation to the plasma concentration. Results Table 1. Atorvastatin tmax range T: h. tmax range R1: h. Table 2. 2-Hydroxy-atorvastatin 5/8

6 t max range T: h t max range R1: h. A widening of the 90% CI acceptance range for C max to % is proposed in the protocol. This is not considered adequately justified. However, since all results are within the normal acceptance range of %, no concerns have been raised on this issue. The pharmacokinetic parameters have been adequately calculated, summarised and analysed. The residual areas are acceptable. The 90% CV of AUC 0-t and C max demonstrate bioequivalence between the test product, Atorvastatin Orifarm 80 mg film-coated tablets, and the reference product, Lipitor 80 mg film-coated tablets, following a single dose, three way cross-over design under fasting conditions for atorvastatin and for 2-hydroxy-atorvastatin. The results of the bioequivalence study performed with the 80 mg tablets apply to the other strengths. The RMS has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.2 Risk management plan & Pharmacovigilance system Atorvastatin was first approved in 1996, and there is now more than 10 years post-authorisation experience with the active substance. The safety profile of atorvastatin can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. The Pharmacovigilance system described fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the identification and notification of any potential risks occurring either in the Community or in a third country. V. PRODUCT INFORMATION SmPC and Package leaflet 6/8

7 The content of the SmPC and package leaflet approved during the decentralised procedure is in accordance with that accepted for the reference product Zarator marketed by Pfizer ApS. In addition, the wordings from PhVWP for statins agreed in November 2009 have been incorporated. Readability test A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Atorvastatin Apotex 10 mg, 20 mg, 40 mg and 80 mg tablets, NL/H/1557/ /DC. The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Atorvastatin Orifarm 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets has a proven chemicalpharmaceutical quality and is a generic form of Zarator film-coated tablets. Zarator is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with other atorvastatin containing products. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Atorvastatin Orifarm with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 22 September Atorvastatin Orifarm was authorised in Denmark on 5 November A European harmonised birth date (EUHBD) for atorvastatin has been allocated ( ). The MAH wishes to follow the EUHBD and the related data lock point (DLP) for atorvastatin. The first PSUR will be submitted with a DLP of 31 October 2011, after which the PSUR submission cycle is 3 years. The date for the first renewal will be: 22 September The following post-approval commitments have been made during the procedure: Drug substance One production scale batch of the active substance will be put on long-term stability each year (if available) and tested initially, at 12 months and yearly thereafter. Test parameters include: Appearance, ID (by IR) assay, chromatographic purity, specific rotation, water content. The results will be reported in subsequent updates. In case of significant changes to the manufacturing process, stability studies at accelerated will be initiated as well to evaluate the impact of the change on the stability profile. Commitment is also made to withdraw any lot(s) not meeting the specifications from the market. 7/8

8 The manufacturer commits to continue on-going stability studies of the active substance throughout the proposed re-test period and to provide notification to the regulatory authority of any out of specification result or near result that has an impact on the established re-test period. Any proposed action plan relating to the OOS or near results will also be communicated to the regulatory authority. Drug product Process validation will be carried out on three commercial batches per strength. The enclosed stability studies will be continued. The manufacturer has committed to test batches of calcium acetate to the specification which meets criteria of the current calcium acetate EP monograph. A Pharm Europa monograph exists (Vol. 21, No. 1) for Calcium Acetate. When these changes are published in the EP, the manufacturer will commit to follow it for release of future calcium acetate batches. The first three commercial production batches of the largest and smallest marketed sizes of each container closure system will be placed on accelerated and long-term stability programs. Every year thereafter, one production batch will be added to the long-term stability program. In-use stability studies will be performed on batches close to the end of shelf-life. Product Information The MAH commits to update the SPC in regard of the results of the ongoing Article 30(2) and Article PAD-29 referral procedures for atorvastatin (EMEA/H/A-30/1154 and EMEA/H/A-PAD- 29/1253, 1254, 1255). 8/8