Pharmacokinetic and Pharmacodynamic Atorvastatin

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    Public Assessment Report

    Decentralised Procedure

    ATORVASTATIN 10 MG FILM-COATED TABLETSATORVASTATIN 20 MG FILM-COATED TABLETSATORVASTATIN 40 MG FILM-COATED TABLETSATORVASTATIN 80 MG FILM-COATED TABLETS

    (Atorvastatin calcium trihydrate)

    Procedure No: UK/H/3637/001-4/DC

    UK Licence No: PL 34088/0008-11

    ALKALOID-INT D.O.O.

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    LAY SUMMARY

    On 30 August 2012, Bulgaria, Czech Republic, Hungary, Poland, Romania, Slovenia,Slovakia and the UK agreed to grant Marketing Authorisations to Alkaloid INT.d.o.o forthe medicinal products Atorvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets(PL 34088/0008-11; UK/H/3637/001-4/DC). The licences were granted via theDecentralised Procedure (DCP), with the UK as Reference Member State (RMS). After asubsequent national phase, Marketing Authorisations were granted in the UK on 25 October2012. These are Prescription-Only Medicines (POM).

    Atorvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets contain atorvastatin as theactive ingredient. Atorvastatin belongs to a group of medicines known as statins, which arelipid (fat) regulating medicines.

    Atorvastatin is used to lower lipids known as cholesterol and triglycerides in the bloodwhen a low fat diet and life style changes on their own have failed. If you are at anincreased risk of heart disease, atorvastatin can also be used to reduce such risk even if yourcholesterol levels are normal. You should maintain a standard cholesterol lowering dietduring treatment.

    No new or unexpected safety concerns arose from these applications and it was judged thatthe benefits of taking Atorvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tabletsoutweigh the risks and therefore Marketing Authorisations were granted.

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    TABLE OF CONTENTS

    Module 1: Information about initial procedure Page 4

    Module 2: Summary of Product Characteristics Page 5

    Module 3: Patient Information Leaflet Page 6

    Module 4: Labelling Page 7

    Module 5: Scientific discussion during initial procedure Page 14

    I IntroductionII About the productIII Scientific Overview and discussionIII.1 Quality aspectsIII.2 Non-clinical aspectsIII.3 Clinical aspectsIV Overall Conclusions and benefit-risk assessment

    Module 6 Steps taken after initial procedure Page 23

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    Module 1

    Product Name Atorvastatin 10 mg film-coated tabletsAtorvastatin 20 mg film-coated tabletsAtorvastatin 40 mg film-coated tablets.Atorvastatin 80 mg film-coated tablets.

    Type of Application Generic, Article 10.1

    Active Substances Atorvastatin calcium trihydrate

    Form Film-coated tablets

    Strength 10 mg, 20 mg, 40 mg and 80 mg.

    MA Holder ALKALOID-INT d.o.o.landrova ulica 41231 Ljubljana -rnue

    SloveniaReference Member State (RMS) UK

    Concerned Member States (CMS) Bulgaria, Czech Republic, Hungary, Poland, Romania,Slovenia and Slovakia

    Procedure Number UK/H/3637/001-4/DC

    Timetable Day 210 30 August 2012.

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    Module 2Summary of Product Characteristics

    In accordance with Directive 2010/84/EU the Summaries of Product Characteristics(SmPC) and Patient Information Leaflets (PIL) for products granted Marketing

    Authorisations at a national level are available on the MHRA website.

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    Module 4Labelling

    Carton:

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    Blister:

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    Carton:

    Blister:

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    Carton:

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    Blister:

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    Carton:

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    Module 5Scientific discussion during initial procedure

    I INTRODUCTIONBased on the review of the data on quality, safety and efficacy, the Member Statesconsidered that the applications for Atorvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets (PL 34088/0008-11; UK/H/3637/001-4/DC) could be approved. Theseapplications were submitted via the decentralised procedure, with the UK as ReferenceMember State (RMS) and Bulgaria, Czech Republic, Hungary, Poland, Romania, Sloveniaand Slovakia as Concerned Member States (CMS). These products are prescription-onlymedicines (POM).

    Atorvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets are indicated for: Hypercholesterolaemia

    Atorvastatin is indicated as an adjunct to diet for reduction of elevated totalcholesterol (total-C), low-density lipoprotein (LDL)-cholesterol (LDL-C),apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 yearsor older with primary hypercholesterolaemia including familialhypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia(Corresponding to Types IIa and IIb of the Fredrickson classification) whenresponse to diet and other non-pharmacological measures is inadequate.

    Atorvastatin is also indicated to reduce total-C and LDL-C in adults withhomozygous familial hypercholesterolaemia as an adjunct to other lipid-loweringtreatments (e.g. LDL apheresis) or if such treatments are unavailable.

    Prevention of cardiovascular diseasePrevention of cardiovascular events in adult patients estimated to have a high riskfor a first cardiovascular event (see section 5.1 of SmPC), as an adjunct to correctionof other risk factors.

    These are abridged applications submitted under Article 10(1) of Directive 2001/83/EC asamended, cross-referring to Lipitor 10mg, 20mg, 40mg and 80mg Tablets (Pfizer IrelandPharmaceuticals, UK), which were first authorised on 07 November 1996 (10 mg, 20 mgand 40 mg strength) and 15 August 2000 (80 mg strength). The reference products have been registered in the EEA for more than 10 years, hence the period of data exclusivity hasexpired. The reference product used in the bioequivalence study was Sortis 80 mg film-coated tablets (Parke-Davis GmbH/Pfizer Pharma GmbH) taken from the German market. Ithas been confirmed that this product is identical to the equivalent product in the UK (Lipitor80mg Tablets).

    Atorvastatin is a selective, competitive HMG- CoA reductase inhibitor. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterolsynthesis in the liver, and by increasing the number of hepatic low-density lipoprotein(LDL) receptors on the cell-surface to enhance uptake and catabolism of LDL. Atorvastatinalso reduces LDL production and the number of LDL particles.

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    No new non-clinical studies were conducted, which is acceptable given that the products areintended to be generic versions of the originator products that have been licensed for over10 years.

    One bioequivalence study (single dose) was submitted to support these applications,comparing the test product Atorvastatin 80 mg film-coated tablets (Alkaloid INT.d.o.o)with the reference product Sortis 80 mg film-coated tablets (Parke-Davis GmbH/PfizerPharma GmbH).

    With the exception of the bioequivalence study, no new clinical studies were conducted,which is acceptable given that the applications were for products that are intended to begeneric versions of the originator products that have been licensed for over 10 years. The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP).

    The RMS has been assured that acceptable standards of Good Manufacturing Practice(GMP) are in place for these product types at all sites responsible for the manufacture,assembly and batch release of these products.

    The RMS and CMS considered that the applications could be approved with the end of procedure (Day 210) on 30 August 2012. After the subsequent national phase, the licenceswer