Simvastatin 80 mg, film coated tablets PL …

1 Simvastatin 80 mg , film coated tablets PL 08215/0090 UKPAR TABLE OF CONTENTS Lay summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 16 Summary of product characteristics Page 17 Patient information leaflet Page 36 Labelling Page 39 MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 1 Simvastatin 80 mg , FILM coated tablets PL 08215/0090 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation (licence) for the medicinal product Simvastatin 80 mg , film coated tablets (Product Licence number: PL 08215/0090) on 26 August 2011. Simvastatin belongs to a group of medicines known as the HMG-CoA reductase inhibitors.

2 These are used to reduce the level of cholesterol and fats (triglycerides) in the blood. Simvastatin 80 mg , film coated tablets are used to treat: Coronary heart disease Higher than normal levels of fats in the blood (hyperlipidaemia) An inherited condition causing high levels of cholesterol in the blood (homozygous familial hypercholesterolaemia) Simvastatin 80 mg , film coated tablets raised no clinically significant safety concerns and it was, therefore, judged that the benefits of using this product outweigh the risks; hence a Marketing Authorisation has been granted. MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 2 Simvastatin 80 mg , FILM coated tablets PL 08215/0090 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Preclinical assessment Page 8 Clinical assessment Page 9 Overall conclusions and benefit-risk assessment Page 15 MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 3 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing Authorisation for the medicinal product Simvastatin 80 mg , film coated tablets to Kent Pharmaceuticals Limited on 26 August 2011.

3 This medicine is only available on prescription. Simvastatin 80 mg , film coated tablets are used for the following indications: Hypercholesterolaemia Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments ( exercise, weight reduction) is inadequate. Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments ( LDL apheresis) or if such treatments are not appropriate. Cardiovascular prevention Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section ). This application is submitted under Article of Directive 2001/83/EC, as amended.

4 The applicant claims that Simvastatin 80 mg , film coated tablets is a generic version of Zocor 80 mg (PL 00025/0366), which has been licensed to Merck Sharp & Dohme Limited since 17 March 2000. Since Zocor 80 mg has been authorised in the EEA for over 10 years, the legal basis of this application is acceptable and the ten year rule is complied with. Assurance has been provided that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture, assembly and batch release of this product. No new preclinical studies were conducted, which is acceptable given that the application is for a generic version of an originator product that has been licensed for over 10 years. No new clinical studies other than the bioequivalence studies were conducted, which is acceptable given that the application is for a generic version of an originator product that has been licensed for over 10 years.

5 The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 4 PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE: Simvastatin General information INN: Simvastatin Chemical names: [1 S-[1 ,3 ,7 ,8 (2S*,4S*),8 ]]-1,2,3,7,8,8 Hexahydro-3,7-dimethyl-8[2 tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl )ethyl-]-1-naphthalenyl 2,2 dimethylbutanonate Butanoic acid,2,2-dimethyl-1,2,3,7,8,8 , [2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran- 2-yl)ethyl]-1-naphthalenylester,[1S-[1 ,3 ,7 ,8 (2S*4S*),8a ]]. (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydrox y-6-oxotetrahydro-2-H-pyran-2-yl]ethyl]3 ,7dimethyl 1,2,3,7,8,8 -hexahydronaphthalen-1-yl 2,2-dimethylbutonate CAS number: 79902-63-9 Structure: Molecular formula: C25H38O5 Molecular mass: General properties Polymorphism: According to the literature no polymorphs other than that represented by the X-ray pattern have been observed Morphology: Crystalline Hygroscopicity: Simvastatin is a slightly hygroscopic solid.

6 Solubility: Simvastatin is insoluble in water, but is soluble in polar organic solvents. Specific optical rotation: Simvastatin has seven chiral centres and has optical activity. The specific optical rotation [ ]25D is +292 for a solution in acetonitrile. MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 5 Manufacture and control All aspects of the manufacture and control of the drug substance are supported by an EDQM Certificate of Suitability. This certificate is accepted as confirmation of the suitability of this drug substance for inclusion in this medicinal product. Stability studies have been performed with the drug substance and no significant changes of the parameters were observed. On the basis of the results, a suitable re-test period was approved. DRUG PRODUCT: Simvastatin 80 mg , FILM coated tablets Composition Simvastatin 80 mg , film coated tablets contain the pharmaceutical excipients lactose monohydrate, microcrystalline cellulose, pregelatinised starch 1500, butylated hydroxyanisole (E320), ascorbic acid, citric acid, colloidal anhydrous silica, talc and magnesium stearate (which make up the tablet core) and hypromellose, Red iron oxide (E172), triethyl citrate, titanium dioxide (E171), talc and povidone K-30 (which make up the tablet coating).

7 All excipients comply with their respective Ph Eur monographs, with the exception of Red iron oxide (E172), which is controlled according to USP specifications. In the absence of a Ph Eur monograph for this excipient, this is acceptable. Satisfactory certificates of analysis have been provided for all excipients. Pharmaceutical development The objective of the pharmaceutical development programme was to formulate a robust, stable, solid oral dosage form equivalent to the reference product, Zocor 80 mg and exhibiting the same bioavailability in order to comply with the regulations pertaining to generic medicinal product applications. Suitable pharmaceutical development data have been provided for this application. The physico-chemical properties of the drug product have been compared with those of the originator product. These data demonstrate that the proposed product can be considered a generic version of Zocor 80 mg .

8 Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory, based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results are satisfactory. Finished product specification The finished product specifications are satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for any working standards used. MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 6 Container closure system The tablets are sealed in blister packs of PVC/PDVC/aluminium containing 28 tablets . Specifications and certificates of analysis for all packaging materials have been provided. These are satisfactory. All primary packaging complies with EU legislation regarding contact with food.

9 Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 36 months has been set for the product, which is satisfactory when the storage precautions Do not store above 25 C and Store in the original container are applied. Expert report A satisfactory expert report is provided from an appropriately qualified author. Product literature The SmPC, PIL and labels are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.

10 Pharmaceutical conclusion It is recommended that a Marketing Authorisation is granted for this application. MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 7 PRECLINICAL ASSESSMENT As the pharmacodynamic, pharmacokinetic and toxicological properties of Simvastatin are well-known, no preclinical studies are required and none have been provided. The applicant s preclinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the product s pharmacology and toxicology. There are no objections to the approval of this product from a preclinical viewpoint. MHRA PAR; Simvastatin 80 mg , FILM coated tablets , PL 08215/0090 8 CLINICAL ASSESSMENT INTRODUCTION Simvastatin is a lipid-lowering agent that reduces cholesterol, low-density lipoprotein, very low-density lipoprotein and plasma triglycerides, while increasing high-density lipoprotein concentrations.