MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

1

Simvastatin 10 mg film-coated tablets Simvastatin 20 mg film-coated tablets Simvastatin 40 mg film-coated tablets Simvastatin 80 mg film-coated tablets

PL 11311/0501 PL 11311/0502 PL 11311/0503 PL 11311/0504

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 9

Summary of Product Characteristics

Page 10

Patient Information Leaflet

Page 11

Labelling Page 12

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

2

SIMVASTATIN 10 MG FILM-COATED TABLETS SIMVASTATIN 20 MG FILM-COATED TABLETS SIMVASTATIN 40 MG FILM-COATED TABLETS SIMVASTATIN 80 MG FILM-COATED TABLETS

PL 11311/0501 PL 11311/0502 PL 11311/0503 PL 11311/0504

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Marketing Authorisations (licences) for the medicinal products Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets (product licence numbers: PL 11311/0501-0504) to Tillomed Laboratories Ltd on 25 October 2012. These medicines are only available by prescription. Simvastatin is an HMG-CoA reductase inhibitor and lipid-lowering agent used to lower elevated cholesterol levels in blood. Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets are used: (1) To treat elevated blood lipid levels that are not caused by another disease in combination with a controlled diet when response to diet and other non-pharmacological measures is not sufficient. Simvastatin is also used to treat hereditary elevated blood lipid values. Simvastatin is used alongside a controlled diet and other lipid-lowering measures or if such measures are not appropriate. (2) To reduce the frequency of cardiovascular induced deaths and events in patients with atherosclerotic heart disease or diabetes mellitus whose cholesterol values are normal or elevated. It is used in combination with other treatments to correct other risk factors and as cardioprotective therapy. Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets raised no clinically significant safety concerns and it was, therefore, judged that the benefits of using these products outweigh the risks; hence Marketing Authorisations have been granted.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

3

SIMVASTATIN 10 MG FILM-COATED TABLETS SIMVASTATIN 20 MG FILM-COATED TABLETS SIMVASTATIN 40 MG FILM-COATED TABLETS SIMVASTATIN 80 MG FILM-COATED TABLETS

PL 11311/0501 PL 11311/0502 PL 11311/0503 PL 11311/0504

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 6

Clinical assessment

Page 7

Overall conclusions and risk benefit assessment Page 8

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

4

INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted Marketing Authorisations for the medicinal products Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets (PL 11311/0501-0504) to Tillomed Laboratories Ltd on 25 October 2012. These are abridged applications submitted under Article 10(c) of EC Directive 2001/83, last paragraph. The applicant claims that the products are identical to the reference products Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets (PL 11311/0398-0401) which were licensed in the UK to Tillomed Laboratories Ltd on 1 December 2009. The applications for these reference products were, in turn, submitted under Article 10(c) of EC Directive 2001/83, last paragraph, as the products are identical to Simvastatin 10 mg, 20 mg and 40 film-coated tablets (PL 04012/0059-0061), which were licensed in the UK to HEXAL A/S on 16 January 2002, and Simvastatin 80 mg film-coated tablets (PL 04012/0062), which was licensed in the UK to HEXAL A/S on 31 March 2005. Product licenses PL 04012/0059-61 were cancelled on 29 Jun 2010. No new data were submitted, nor was it necessary for these simple applications, as the data are identical to those for the previously granted cross-reference products.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

5

PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE: SIMVASTATIN The simvastatin used in these products is identical to that used in the reference products and is, therefore, satisfactory. DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT Each tablet contains 10 mg, 20 mg, 40 mg or 80 mg simvastatin and the excipients pregelatinized starch, lactose monohydrate, cellulose, microcrystalline, butylhydroxyanisole (E320), ascorbic acid, citric acid monohydrate and magnesium stearate (which make up the tablet core) and the film-coating ingredients hypromellose, talc and titanium dioxide (E171). The 10 mg and 20 mg tablets also contain iron oxide yellow (E172) and the 10 mg, 20 mg and 40 mg tablets contain iron oxide red (E172). The 80 mg tablets contain indigotine lake (E132) and quinoline yellow lake (E104).There are no differences between the compositions of the proposed products and those of the already licensed cross reference products. ADDITIONAL DATA REQUIREMENTS The manufacturing process, active ingredient specifications and finished product specifications are in line with those for the reference products and are satisfactory. EXPERT REPORTS Satisfactory expert reports in the form of quality, non-clinical and clinical overall summaries are provided, with signed declarations from each expert confirming that the applicant’s products are identical to the reference products in all particulars. Expert CVs are also submitted and are acceptable. PRODUCT LITERATURE All product literature is essentially identical to that for the reference product and is satisfactory. A Patient Information Leaflet (PIL) 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 PIL text 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 PIL information. ASSESSOR’S OVERALL CONCLUSIONS Marketing Authorisations may be granted for these products.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

6

PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with these applications and none is required for applications of this type.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

7

CLINICAL ASSESSMENT

OVERVIEW A statement has been provided confirming that the clinical particulars for Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets (PL 11311/0501-0504) are identical to those for the already licensed products; Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets (PL 11311/0398-0401). This is satisfactory.

BIOAVAILABILITY AND BIOEQUIVALENCE No bioequivalence study has been performed to support these applications and none is needed. PRODUCT LITERATURE All product literature is medically satisfactory. ASSESSOR’S OVERALL CONCLUSIONS It is recommended that Marketing Authorisations can be granted.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

8

OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

QUALITY Simvastatin 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets are identical to the already licensed reference products. The products are, therefore, pharmaceutically satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY The efficacy of simvastatin is well established. The product literature is satisfactory and consistent with that for the reference product. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable, no significant preclinical or clinical safety concerns were identified, and benefit has been shown to be associated with simvastatin. The benefit/risk balance is therefore considered to be acceptable and Marketing Authorisations may be granted.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

9

SIMVASTATIN 10 MG FILM-COATED TABLETS SIMVASTATIN 20 MG FILM-COATED TABLETS SIMVASTATIN 40 MG FILM-COATED TABLETS SIMVASTATIN 80 MG FILM-COATED TABLETS

PL 11311/0501 PL 11311/0502 PL 11311/0503 PL 11311/0504

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation applications on 16 March

2012 2 Following standard checks and communication with the applicant the MHRA

considered the applications valid on 10 May 2012 3 Following assessment of the applications the MHRA requested further

information relating to the dossier on 2 July 2012 4 The applicant responded to the MHRA’s request, providing further information

on the dossier on 24 July 2012 5 The application was determined on 25 October 2012

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

10

SUMMARY OF PRODUCT CHARACTERISTICS In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) for products granted Marketing Authorisations at a national level are available on the MHRA website.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

11

PATIENT INFORMATION LEAFLET

In accordance with Directive 2010/84/EU the Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website.

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

12

LABELLING

Simvastatin 10 mg film-coated tablets Blister:

Label:

Label with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

13

Carton:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

14

Carton with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

15

Simvastatin 20 mg film-coated tablets Blister:

Label:

Label with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

16

Carton:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

17

Carton with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

18

Simvastatin 40 mg film-coated tablets Blister:

Label:

Label with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

19

Carton:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

20

Carton with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

21

Simvastatin 80 mg film-coated tablets Blister:

Label:

Label with Braille:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

22

Carton:

MHRA PAR; SIMVASTATIN 10 MG, 20 MG, 40 MG AND 80 MG FILM-COATED TABLETS, PL 11311/0501-0504

23

Carton with Braille: