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 bioequivalence study where Orivast 80 mg film-coated tablets is compared with the reference product, Lipitor. For the remaining strengths 10 mg, 20 mg and 40 mg, a biowaiver was applied for. In addition, a clinical overview based on literature review was submitted.

Biowaiver

The Applicant requested biowaiver for strengths 10 mg, 20 mg and 40 mg. Biowaiver is justified according to Guideline on the Investigation of Bioequivalence (CHMP/EWP/QWP/1401/98 Rev 1 /Corr).

• All strength have similar qualitative form and are of proportional in the composition. The proposed tablets are all film-coated tablets. • All strengths of the product are manufactured at the same site utilizing the same manufacturing process. • Pharmacokinetic data has demonstrated to be linear across the complete dosage range from 10 mg to 80 mg. • In vitro dissolution profiling to demonstrate immediate drug release. Comparative dissolution profiles have demonstrated.

The Applicant provided comparative dissolution data for the applied strengths and the corresponding reference product for which biowaiver is applied for (namely 10 mg, 20 mg PAR Scientific discussion 5/10 and 40 mg) during the marketing authorisation procedure, as per the authority’s request. The dissolution data for 20 mg and 40 mg in three pH environments indicate that the products are similar. The data provided for 10 mg suggest that the dissolution profiles are similar also for 10 mg strength. Consequently, the biowaiver is considered acceptable for all the lower strengths.

Bioequivalence studies

The Applicant conducted an open-label, randomized, two-treatment, two-sequence, four- period, full replicate, single-dose, oral bioequivalence study in 48 healthy male subjects to compare Atorvastatin calcium tablets 80 mg (test product) with Lipitor (atorvastatin) film- coated tablets 80 mg (reference product) from Pfizer. A wash-out period of at least 12 days was maintained between each treatment periods.

The subjects received either Atorvastatin calcium 80 mg tablet or Lipitor 80 mg tablet (reference) after an overnight fast of at least 10 hours with approximately 240 ml of drinking water as per randomization schedule in four periods. Lunch was served 4 hours post dose, snack 8 hour and dinner 13 hours post dose in each period. Breakfast was served 24 hours after the dose as well as lunch (28 hr), snack (32 hr) and dinner (36 hr) post dose on the second day of treatment period. Drinking water restriction was maintained one hour before dosing and until one hour post dose and all the subjects were refrained from taking water during this period.

Blood samples (4 ml) were collected in precooled K2EDTA vacutainers prior drug administration and at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 18.00, 24,00, 36.00, 48.00 and 72.00 hours post dose in each period of the study. Plasma concentrations of atorvastatin, ortho-hydroxy atorvastatin and para-hydroxy atorvastatin were analysed by validated LC-MS/MS method. Pharmacokinetic variables were calculated by non-compartmental model and standard statistical methods were used.

The study was conducted in two groups. Group-I included 36 subjects and group-II 12 subjects. 12 subjects were dropped out/withdrawn from the study so 36 subjects completed the study. 41 subjects were included in the bioanalysis, pharmacokinetic and statistical analysis as per protocol.

The bioequivalence results for atorvastatin are presented in Table 1. PAR Scientific discussion 6/10

The extrapolated AUC of atorvastatin was under 10 % in all subjects both after the test and reference product indicating that the sampling schedule was long enough. Also the wash-out period was long enough as there were no measurable concentrations of atorvastatin in the pre- dose samples in any of the treatment periods.

90% confidence intervals for the ratio of the test and reference product are within the acceptance range 80.00-125.00 for AUC. Atorvastatin Cmax is within the widened 90 % confidence intervals 75.12-133.01. The use of the widened confidence intervals for Cmax was pre-specified in the study protocol and is therefore acceptable.

Bioequivalence between the test and reference product has also been demonstrated for the metabolites ortho-hydroxylated atorvastatin and para-hydroxylated atorvastatin. The 90 % confidence intervals for AUC were within 80.00-125.00 and for Cmax within pre-specified limit 79.52-125.76 for ortho-hydroxylated atorvastatin and 77.92-128.33 for para-hydroxy atorvastatin (see Tables 2 and 3).

PAR Scientific discussion 7/10

Conclusion on bioequivalence studies:

Based on the submitted bioequivalence study Orivast 80 mg film-coated tablets is considered bioequivalent with Lipitor 80 mg film-coated tablets.

The results of with 80 mg formulation can be extrapolated to other strengths 10 mg, 20 mg and 40 mg, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.

PAR Scientific discussion 8/10

The justification for BCS (Biopharmaceutics Classification System) - based biowaiver can be accepted.

IV.3 Pharmacodynamics

No clinical pharmacodynamic studies have been performed or required. The pharmacodynamic properties of atorvastatin are well known.

IV.4 Clinical efficacy

No new studies on clinical efficacy have been performed or required.

IV.5 Clinical safety

Total seventeen (17) adverse events were reported in thirteen (13) subjects during the BE study. All the reported adverse events were mild in intensity except one which was moderate in intensity. The adverse events were similar between the treatments. In-house adverse events resolved completely on follow-up. The safety profile of studied products seems to be comparable.

IV.6 Risk Management Plan

The Applicant has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Orivast.

Summary of safety concerns:

Important identified risks - Rhabdomyolysis and potential rhabdomyolysis-related events - Skeletal muscle effects - Hyperglycaemia, which may require diabetes care in patients with diabetes risk factors - Stevens-Johnson syndrome and toxic epidermal necrolysis - Concomitant use of coumarin anticoagulants/warfarin (acenocoumarol, clorindione, dicoumarol, diphenadione, ethyl biscoumasetate, fluindione, phenindione, phenprocoumon, tioclomarol, warfarin) - Immune-mediated necrotizing myopathy - Interstitial lung disease Important potential risks - Haemorrhagic stroke - Other autoimmune events Missing information - Use in paediatric patients <10 years old

Pharmacovigilance Plan No additional pharmacovigilance activities were proposed by the Applicant. The suggested routine pharmacovigilance activities are sufficient to identify and characterize the risks of the product.

Risk minimisation measures

PAR Scientific discussion 9/10

No additional risk minimisation activities were proposed by the Applicant. The routine risk minimisation measures including SPC and PL are sufficient to minimise the risks of the product in the proposed indications.

IV.7 Discussion on the clinical aspects

The marketing authorisation application contains an adequate review of published clinical data and the bioequivalence to the reference product has been shown. As Orivast is a generic medicine, there is no need to repeat all the clinical studies already conducted with the originator product, Lipitor. Approval of Orivast 10 mg, 20 mg, 40 mg and 80 mg is recommended from the clinical point of view.

V. USER CONSULTATION

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 Burana gel (DE/H/5281/01/DC, design/layout) and Atorvastatin (UK/H/2900/001-4/DC, key safety messages). The bridging report submitted by the Applicant has been found acceptable.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Orivast is a generic lipid-lowering medicinal product, which contains atorvastatin as active substance. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase that efficiently lowers plasma cholesterol and lipoprotein serum concentrations. The pharmacodynamic, pharmacokinetic and toxicological properties of atorvastatin are well known and it has recognized clinical efficacy and established safety profile. Atorvastatin has been marketed in EU for several years e.g. under the trade name Lipitor.

The marketing authorisation application of Orivast is made on the basis of article 10(1) of Directive 2001/83/EC as amended, and thus, no additional clinical pharmacodynamic, safety or efficacy studies have been conducted or submitted as part of the application. The application is based on demonstration of essential similarity with the reference product, Lipitor. The submitted chemical-pharmaceutical documentation in relation to Orivast is of sufficient high quality in view of the present European regulatory requirements. In addition, the application contains an adequate review of published non-clinical and clinical data and bioequivalence between the test and reference product has been shown. Moreover, the product information has been harmonised with the reference product PI as the proposed indications and posology are identical with those of Lipitor.

Based on review of the quality, nonclinical and clinical data submitted, it can be concluded that the benefit/risk ratio of Orivast is comparable to the reference product. The generic application for Orivast 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets in the treatment of hypercholesterolaemia and prevention of cardiovascular disease is considered approvable and marketing authorisation is recommended.

PAR Scientific discussion 10/10