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Public Assessment Report Scientific Discussion Orivast 10 Mg, 20 Mg, 40 Mg, 80 Mg Film-Coated Tablets

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Public Assessment Report Scientific Discussion Orivast 10 Mg, 20 Mg, 40 Mg, 80 Mg Film-Coated Tablets Public Assessment Report Scientific discussion Orivast 10 mg, 20 mg, 40 mg, 80 mg film-coated tablets (atorvastatin calcium trihydrate) FI/H/1018/01-04/DC Date: 27.04.2020 This module reflects the scientific discussion for the approval of Orivast. The procedure was finalised at 17.2.2020 (day 210). For information on changes after this date please refer to the module ‘Update’. I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Orivast 10 mg / 20 mg / 40 mg / 80 mg film-coated tablets, from Orion Corporation. The product is indicated for the treatment of hypercholesterolaemia and prevention of cardiovascular disease. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. The generic application was submitted via the decentralised procedure FI/H/1018/01-04/DC with Finland as the reference member state. The marketing authorisation procedure was finalised on 17.2.2020. The reference medicinal products are Lipitor 10 mg / 20 mg / 40 mg film-coated tablets (Marketing Authorisation Holder: Pfizer Oy), authorised in Finland on 21.4.1997 in procedure DE/H/0109/01-03 and Lipitor 80 mg film-coated tablets (Marketing Authorisation Holder: Pfizer Oy), authorised in Finland on 21.01.2002 in procedure DE/H/0109/04. II. QUALITY ASPECTS II.1 Introduction The finished product is an immediate release film-coated tablet containing four strengths with following descriptions of the tablets: 10 mg: White coloured, oval shaped, biconvex, film-coated tablets debossed with "MA" on one side and "1" on other side. Tablet size is 9 x 5 mm. 20 mg: White coloured, oval shaped, biconvex, film-coated tablets debossed with "MA" on one side and "2" on other side. Tablet size is 12 x 7 mm. 40 mg: White coloured, oval shaped, biconvex, film-coated tablets debossed with "MA" on one side and "3" on other side. Tablet size is 15 x 8 mm. 80 mg: White coloured, oval shaped, biconvex, film-coated tablets debossed with "MA" on one side and "4" on other side. Tablet size is 19 x 10 mm. The excipients are: Tablet core – lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, polysorbate 80, magnesium aluminometasilicate, calcium carbonate, hydroxypropylcelloulose and magnesium stearate. Tablet coat - polyvinyl alcohol (partially hydrolysed), titanium dioxide, talc, macrogol and soya lecithin (E322). The product is packed both in blister and in bottle. PAR Scientific discussion 2/10 II.2 Drug Substance The active substance is atorvastatin calcium trihydrate, described in the European Pharmacopoeia (Ph.Eur.). It is a white or almost white powder, which is very slightly soluble in water, slightly soluble in ethanol and practically insoluble in methylene chloride. Polymorphic form I is used. Atorvastatin calcium exhibits isomerism and the manufactured structure is R-isomer. The specification is set in line with the Ph.Eur. monograph, with additional requirements for residual solvents. Batch analysis data showing compliance with the drug substance specification are provided for three batches. II.3 Medicinal Product The development of the product has been adequately performed, the choice of excipients is justified and their functions are explained. The drug product is a conventional tablet manufactured with standard methods. The composition of the drug product is simple with mainly widely used pharmaceutical excipients. The product is essentially similar to the originator product, showing comparable dissolution results with the reference product. The reference product to which BE study has been demonstrated is Lipitor 80 mg and the biowaiver is considered acceptable for 10 mg, 20 mg and 40 mg strengths. The product specifications cover the usual appropriate parameters for this dosage form and includes tests for description, identification, (also for colorant), average mass, uniformity of dosage units (content uniformity), dissolution, assay, related substance and microbiological quality. These specifications are considered acceptable. The analytical methods have been adequately described and validated. Batch analysis results for three batches of all strengths showed compliance to the specification. The conditions used in the stability studies are according to the ICH stability guideline. Shelf- life requirements are set according to the different stability study results between the different strenghts and are also accepted: Atorvastatin 10 mg film-coated tablets: a shelf-life of 12 months with a storage condition requirement “store below 25°C”. Atorvastatin 20 mg film-coated tablets: a shelf-life of 18 months with a storage condition requirement “store below 25°C”. Atorvastatin 40 mg & 80 mg film-coated tablets: a shelf-life of 24 months with “no special storage recommendations”. Additionally for 80 mg 90 tablets bottle pack: Shelf life after first opening 90 days. II.4 Discussion on chemical, pharmaceutical and biological aspects PAR Scientific discussion 3/10 Based on the submitted dossier, the member states consider that Orivast has a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. III. NON-CLINICAL ASPECTS III.1 Introduction Orivast 10 mg / 20 mg / 40 mg / 80 mg film-coated tablets contain atorvastatin as active substance. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate- limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols. Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver. It also increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL. III.2 Pharmacology, pharmacokinetics and toxicology The pharmacodynamic, pharmacokinetic and toxicological properties of atorvastatin are well known. The originator product has been authorized in EU for more than 20 years ago. As atorvastatin is a widely used, well-known active substance, the Applicant has not conducted new nonclinical PK, PD or toxicity studies. Instead, a nonclinical overview based on literature review was submitted to support the marketing authorization application. III.3 Ecotoxicity/environmental risk assessment (ERA) Since Orivast is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.4 Discussion on the non-clinical aspects Since the pharmacodynamic, pharmacokinetic and toxicological properties of the active substance, atorvastatin, are well known, the omission of nonclinical studies is considered acceptable. Generally, in case of abridged applications, there is no need to repeat the same in vitro and animal studies already conducted with the originator product. The submitted non- clinical overview is considered adequate. The nonclinical sections of the Summary of Product Characteristics (SmPC) are identical to those of the reference product. There are no objections to approval of Orivast 10 mg / 20 mg / 40 mg / 80 mg film-coated tablets from a nonclinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction Orivast is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and PAR Scientific discussion 4/10 children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia when response to diet and other nonpharmacological measures is inadequate. Orivast is also indicated in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable and for prevention of cardiovascular disease. The active substance of Orivast, atorvastatin, is a lipid-lowering agent, which reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products. Atorvastatin has been shown to reduce concentrations of total-C (30 % - 46 %), LDL-C (41 % - 61 %), apolipoprotein B (34 % - 50 %), and triglycerides (14 % - 33 %) while producing variable increases in HDL-C and apolipoprotein A1. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia and mixed hyperlipidaemia, including patients with noninsulin- dependent diabetes mellitus. Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality. The dose of Orivast should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response. The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day. IV.2 Pharmacokinetics To support the MA application of Orivast, the Applicant submitted a report of one clinical
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