Public Assessment Report UKPAR Atorvastatin 10mg … Atorvastatin 10mg, 20mg and 40mg Film-coated...

PAR Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets PL 24668/0184-0186

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Public Assessment Report

UKPAR

Atorvastatin 10mg Film-coated Tablets Atorvastatin 20mg Film-coated Tablets Atorvastatin 40mg Film-coated Tablets

(Atorvastatin calcium trihydrate).

UK Licence No: PL 24668/0184, 0185 and 0186.

Caduceus Pharma Limited


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LAY SUMMARY

Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets

(atorvastatin calcium trihydrate, film-coated tablets, 10mg, 20mg and 40mg)

This is a summary of the Public Assessment Report (PAR) for Atorvastatin 10mg Film-coated Tablets (PL 24668/0184), Atorvastatin 20mg Film-coated Tablets (PL 24668/0185) and Atorvastain 40mg Film-coated Tablets (PL 24668/0186). It explains how Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets For practical information about using Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets patients should read the package leaflet or contact their doctor or pharmacist. What are Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets and what are they used for? Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets contain the active ingredient atorvastatin which is used to lower lipids known as cholesterol and triglycerides in the blood when a low fat diet and life style changes on their own have failed. If a patient is at an increased risk of heart disease, Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets can also be used to reduce such risk even if the patient’s cholesterol levels are normal. The patient should maintain a standard cholesterol lowering diet during treatment. This medicine is identical to Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375) which were first granted Marketing Authorisations on 26 June 2009. How are Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets used? The patient must always take this medicine exactly as their doctor has told them. The patient should check with their doctor or pharmacist if they are not sure. Before starting treatment, the patient’s doctor will place the patient on a low-cholesterol diet, which they should maintain also during therapy with this medicine. The usual starting dose is 10mg of atorvastatin once a day in adults and children aged 10 years or older. This may be increased if necessary by the patient’s doctor until the patient is taking the amount they need. The patient’s doctor will adapt the dose at intervals of 4 weeks or more. The maximum dose of atorvastatin is 80mg once daily for adults and 20mg once daily for children. The tablets should be swallowed whole with a drink of water and can be taken at any time of day, with or without food. Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets can be obtained only with a prescription. For further information on how Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets are used, refer to the package leaflet and Summary of Product Characteristics available on the Medicines and Healthcare products Regulatory Agency (MHRA) website. How do Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets work? Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets belong to a group of medicines called statins, which are lipid (fat) regulating medicines. Statins lower blood cholesterol (and triglycerides).


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What benefits of Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets have been shown in studies? The applications for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets are considered to be identical to the previously authorised applications for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375), with the same benefits and risks. So, no new studies have been provided for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets. However, reference is made to the studies for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375). The company (Caduceus Pharma Limited) referred to data provided by Actavis group PTC ehf Ltd for the grant of the licences for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375) as a basis for the grant of identical licences for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 24668/0184-0186). What are the possible side effects from Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets? Like all medicines, this medicine can cause side effects, although not everybody gets them. Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 24668/0184-0186) are considered to be identical to the previously authorised applications for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375) with the same benefits and risks. For a full list of all the side effects reported with Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets see section 4 of the package leaflet, available on the Medicines and Healthcare products Regulatory Agency (MHRA) website.

Why are Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets approved? No new or unexpected safety concerns arose from these applications. The MHRA, therefore, considered that the benefits of Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets outweigh their risks; and the grant of Marketing Authorisations (licences) was recommended. What measures are being taken to ensure the safe and effective use of Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets? A Risk Management Plan has been developed to ensure that Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets are used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics and the package leaflets for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets Marketing Authorisations were granted in the UK on 02 March 2015. The full PAR for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets follows this summary. For more information about treatment with Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in March 2015.


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TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 7 III Non-clinical aspects Page 9 IV Clinical aspects Page 9 V User consultation Page 11 VI Overall conclusion, benefit/risk assessment and

recommendation Page 11


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I INTRODUCTION The Medicines and Healthcare products Regulatory Agency (MHRA) granted Caduceus Pharma Limited Marketing Authorisations for the medicinal products Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 24668/0184-0186) on 02 March 2015. The products are prescription-only medicines (POM) indicated for:

• Atorvastatin 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 children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.

Hypercholesterolaemia

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

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Prevention of cardiovascular events in patients estimated to have a high risk for a first cardiovascular event (see section 5.1 of the summary of product characteristics), as an adjunct to correction of other risk factors.

Prevention of cardiovascular disease

These applications were submitted as abridged applications according to Article 10c of Directive 2001/83/EC, as amended. The applications cross-refer to Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0054-56) which were originally authorised to Actavis Group PTC ehf on 26 June 2009 via the Decentralised Procedure (DCP) with Denmark as reference Member State (RMS). The licences subsequently underwent change of ownership procedures on 27 November 2009 to Ratiopharm GMBH (PL 15773/0858-0860) and on 09 July 2011 to the current licence holder, Actavis Group PTC ehf (PL 30306/0373-375). 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, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor). Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL. Atorvastatin 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


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HDL-C and apolipoprotein A1 in a dose response study. 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. No new data were submitted nor were necessary to be submitted for these applications, as the data are identical to that of the previously granted cross-reference product. .


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II QUALITY ASPECTS II.1 Introduction These are abridged applications for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 24668/0184-0186) submitted under Article 10c of Directive 2001/83/EC, as amended. The applications cross-refer to Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375) which were first authorised to Actavis Group PTC ehf on 26 June 2009. The applications are considered valid. II.2. Drug Substance Drug substance specification The proposed drug substance specifications are consistent with the details registered for the cross-reference product.

II.3. Medicinal Product Name The proposed product names for these applications are Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets. The product has been named in line with current requirements. Strength, pharmaceutical form, route of administration, container and pack sizes Each film-coated tablet contains 10mg, 20mg or 40mg atorvastatin as atorvastatin calcium trihydrate. All strengths of the finished product are packed into:

• Aluminium/aluminium blister packs in pack sizes of 10, 20, 28, 30, 50, 90, 98 and 100 tablets. • High-density polyethylene (HDPE) containers closed with a low-density polyethylene (LDPE)

snap-on-cap with a tamper evident ring and a desiccant (silica gel) in pack sizes of 30, 100, 250 and 500 tablets.

Not all pack sizes may be marketed. The proposed shelf life for both presentations (blister pack and container) of the unopened product is 2 years. After opening the tablet container, the in-use shelf life is 100 days. This medicinal product does not require any special storage conditions. The proposed packaging, shelf-life and storage conditions are consistent with the details registered for the cross-reference product. Legal status On approval, the products will be available as prescription-only medicines (POM). Marketing Authorisation Holder/Contact Persons/Company Caduceus Pharma Ltd, 6th floor, 94 Wigmore Street, London, W1U 3RF, UK. The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory CV has been provided.


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Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference product and evidence of Good Manufacturing Practice (GMP) compliance has been provided. Qualitative and quantitative composition The proposed compositions are consistent with the details registered for the cross-reference product. Manufacturing process The proposed manufacturing process is consistent with the details registered for the cross-reference product and the maximum batch sizes are stated. Finished product/shelf-life specification The proposed finished product specifications are in line with the details registered for the cross-reference product. TSE Compliance None of the excipients contain materials of animal or human origin. This is consistent with the cross-reference product. Bioequivalence No bioequivalence data are required to support these simple abridged applications because the proposed products are manufactured to the same formula utilising the same processes as the cross-reference products, Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375). Expert Report The applicant cross-refers to the data for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375) to which these applications are claimed to be identical. This is acceptable. Product Name and Appearance See Section II.3 ‘Medicinal Product; Name’ for details of the proposed product name. The appearance of each product is identical to that of the cross-reference product. II.4 Discussion on chemical, pharmaceutical and biological aspects The data submitted with the applications are acceptable. The grant of Marketing Authorisations is recommended.


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III NON-CLINICAL ASPECTS Introduction As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no new non-clinical data have been supplied and none are required. Ecotoxicity/environmental risk assessment (ERA) Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As the applications are identical versions of an already authorised product, it is not expected that environmental exposure will increase following approval of the Marketing Authorisations for the proposed products. Discussion on the non-clinical aspects The grant of Marketing Authorisations is recommended. IV CLINICAL ASPECTS Introduction As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no new clinical data have been supplied and none are required. Risk Management Plan (RMP) The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), 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 Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: Summary table of safety concerns:


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Summary table of Risk Minimisation Measures:


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In line with the cross-referred product, the proposed risk minimisation measures are sufficient to minimise the risks of the product in the proposed indications. The RMP is acceptable. No new risks have been identified for these products, which are not already recognised for the reference product. Discussion on the clinical aspects The grant of Marketing Authorisations is recommended. V User consultation User-testing of the PILs for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets has been accepted based on the bridging report provided by the applicant making reference to the successful user-testing of the PIL for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets (PL 30306/0373-0375) as the ‘parent PIL’. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The applicant’s products are identical to the cross-reference products. Extensive clinical experience with atorvastatin is considered to have demonstrated the therapeutic value of the compound. The benefit/risk balance is, therefore, considered to be positive.


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Summaries of Product Characteristics (SmPC), Patient Information Leaflets (PIL) and Labels The Summaries of Product Characteristics and Patient Information Leaflets (PILs) are consistent with the details registered for the cross-reference products. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for Atorvastatin 10mg, 20mg and 40mg Film-coated Tablets is presented below:


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Public Assessment Report UKPAR Atorvastatin 10mg … Atorvastatin 10mg, 20mg and 40mg Film-coated...

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