Variation Assessment Report Relifex 1 g Film-Coated ...

1 MHRA PAR- erythromycin 250mg gastro - resistant tablets 1 Relifex 1 G Film-Coated tablets (Nabumetone) PL 15142/0105 UK PAR TABLE OF CONTENTS Lay summary Page 2 Scientific discussion Page 3 Steps taken for Assessment Labelling Page 11 Page 12 Steps taken after Assessment Page 16 Annex 1 Clinical Variation Assessment Report Page 17 Summary of Product Characteristics Page 21 Patient Information leaflet Page 22 MHRA PAR- Relifex 1g Film-Coated tablets 2 Relifex 1 G Film-Coated tablets PL 15142/0105 LAY SUMMARY The MHRA granted Valeant Pharmaceuticals Limited a Marketing Authorisation (licence) for the medicinal product Relifex 1 g Film-Coated tablets on 09 November 2010. This product is a prescription-only medicine (POM).

2 Relifex 1 g Film-Coated tablets contain the active ingredient nabumetone and are used to treat the pain, stiffness and swelling of joints which are affected by osteoarthritis or rheumatoid arthritis. Nabumetone belongs to a group of medicines called non-steroidal anti-inflammatory drugs (known as NSAIDs). It works by reducing the production of some natural chemicals found in the body. These chemicals (prostaglandins) cause the symptoms of inflammation such as pain and swelling. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Relifex 1 g Film-Coated tablets outweigh the risks; hence a Marketing Authorisation has been granted. MHRA PAR- Relifex 1g Film-Coated tablets 3 Relifex 1 G Film-Coated tablets PL 15142/0105 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical Assessment Page 5 Non-clinical Assessment Page 7 Clinical Assessment Page 8 Overall conclusions and risk benefit Assessment Page 10 MHRA PAR- Relifex 1g Film-Coated tablets 4 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted a Marketing Authorisation for the medicinal product Relifex 1 g Film-Coated tablets (PL 15142/0105) to Valeant Pharmaceuticals Limited on 09 November 2010.

3 This product is a prescription-only medicine (POM) indicated for the treatment of osteoarthritis and rheumatoid arthritis requiring anti-inflammatory and analgesic treatment. The application was submitted as a complete and independent application of a known active substance according to Article of Directive 2001/83/EC as amended. This application is a line extension for a new pharmaceutical strength of nabumetone ( Relifex 1 g Film-Coated tablets ) with Relifex 500 mg Film-Coated tablets (PL 15142/0106) authorised to Meda Pharmaceuticals Limited (following a change of ownership from Valeant Pharmaceuticals Limited -PL 19166/0060) as the reference product. Nabumetone is a non-acidic non-steroidal anti-inflammatory agent which is a relatively weak inhibitor of prostaglandin synthesis.

4 However, following absorption from the gastrointestinal tract it is rapidly metabolised in the liver to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), a potent inhibitor of prostaglandin synthesis. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Relifex 1 g Film-Coated tablets outweigh the risks; hence a Marketing Authorisation has been granted. MHRA PAR- Relifex 1g Film-Coated tablets 5 PHARMACEUTICAL Assessment ACTIVE SUBSTANCE INN: Nabumetone Chemical Name: 4-(6'-Methoxy-2'-naphthyl)butan-2-one Molecular Formula: C15H16O2 Structure: Molecular weight: Appearance: A white to off-white crystalline powder.

5 Nabumetone is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance nabumetone are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability Certificates of analysis have been provided for all packaging used. The primary packaging has been shown to comply with current regulations concerning plastic containers and closures for pharmaceutical use, and with legislation relating to contact with foodstuff. A suitable retest period has been set, based on appropriate stability data submitted for the active substance when stored in the proposed packaging. MEDICINAL PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients hypromellose (E464), macrogol 6000, sodium laurilsulfate, sodium starch glycollate, type A, microcrystalline cellulose (E460) and titanium dioxide (E171).

6 All excipients comply with their respective European Pharmacopoeia monograph. Suitable batch analysis data have been provided for each excipient, showing compliance with their respective monograph/specification. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to produce a safe, efficacious product containing 1 g nabumetone. The formulation for Relifex 1 g Film-Coated tablets is a direct up-scaling of the Relifex 500 mg Film-Coated tablets . A satisfactory account of the pharmaceutical development has been provided. MHRA PAR- Relifex 1g Film-Coated tablets 6 Manufacturing Process A description and flow-chart of the manufacturing method have been provided.

7 In-process controls are satisfactory based on process validation data and controls on the finished product. Finished Product Specification The finished product specifications are satisfactory. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for all working standards used. Container Closure System The finished product is packaged in: High density polyethylene (HDPE) bottles containing 100 or 200 tablets Polyvinylchloride/aluminium foil blisters containing 20 or 100 tablets . Not all pack sizes may be marketed. Satisfactory specifications and certificates of analysis have been provided for all packaging components.

8 All primary packaging complies with the current European regulations concerning materials suitable for contact with food. Stability of the Product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 3 years, with the special storage conditions Store the tablets in the original bottle in order to protect from light (HDPE bottle only). The blister packs do not require any special storage conditions. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are pharmaceutically satisfactory. 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, as amended.

9 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. MAA Form The MAA form is satisfactory. Expert Report The pharmaceutical expert Report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended. MHRA PAR- Relifex 1g Film-Coated tablets 7 NON-CLINICAL Assessment The application was submitted as a complete application of a known active substance according to Article of Directive 2001/83/EC as amended.

10 This application is a line extension for a new pharmaceutical strength of nabumetone ( Relifex 1 g Film-Coated tablets ) with Relifex 500 mg Film-Coated tablets as the reference product. The pharmacodynamic, pharmacokinetic and toxicological properties of nabumetone are well-known. Thus, no new data have been provided and none are required. A non-clinical expert Report has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. A suitable justification has been provided for non-submission of an environmental risk Assessment . MHRA PAR- Relifex 1g Film-Coated tablets 8 CLINICAL Assessment BACKGROUND Nabumetone (ATC Code: M01AX01, group: non-steroidal anti-inflammatory/anti-rheumatic) is a pro-drug which undergoes extensive first pass metabolism in the liver.