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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

1 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


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). 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.



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


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. 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 8.3 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. 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.


PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Nabumetone

Chemical Name: 4-(6'-Methoxy-2'-naphthyl)butan-2-one

Molecular Formula: C15H16O2 Structure:

Molecular weight: 228.3 Appearance: A white to off-white crystalline powder. 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). 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.


Manufacturing Process 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. 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. 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. 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.


NON-CLINICAL ASSESSMENT The application was submitted as a complete application of a known active substance according to Article 8.3 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 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.


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. Nabumetone exerts its pharmacological effect via the metabolite 6-MNA (6-methoxy-2-naphthylacetic acid). 6-MNA is highly bound to serum-proteins (>99%) and is hydroxylated and conjugated before being excreted in the urine. Nabumetone is intended for use in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The anti-inflammatory effect of 6-MNA is exerted through the inhibition of prostaglandin synthesis. Nabumetone has a weak effect on platelet aggregation and has no effect on the bleeding-time. Lower incidence of peptic ulcers, bleeding and perforations has been reported for nabumetone compared to other NSAIDs. INDICATIONS Relifex 1 g Film-coated Tablets are indicated for the treatment of osteoarthritis and rheumatoid arthritis requiring anti-inflammatory and analgesic treatment. The therapeutic indications are in keeping with the reference product. PHARMACOKINETICS In support of this application, the Marketing Authorisation holder has submitted the following bioequivalence study: A randomised, open-label, single-dose, two-period, non-placebo crossover study comparing the bioequivalence of 1000mg nabumetone given as a single oral dose of 1 x 1000mg film-coated tablet of the test product (Relifex 1 g Film-coated Tablets) versus 2 x 500mg film-coated tablet of the reference product (Relifex 500 mg Film-coated tablets) in healthy subjects under fasting conditions. Subjects were dosed with either treatment after at least a 10-hour fast. Blood sampling was performed pre- and up to 96 hours post dose in each treatment period. The washout period between the two treatment arms was at least 8 days. The pharmacokinetic results for 6-MNA the active metabolite of nebumetone (presented as arithmetic mean ± SD, tmax median, 90% confidence intervals) are presented below: Table 1.Pharmacokinetic parameters for 6-MNA, the active metabolite of nebumetone Test

(100mg nabumetone) Reference (2 x 500mg

nabumetone)

90% CI (confidence

Interval) AUC0-t (ng/ml h) 1023.3 ±341.2

1106.4 ±371.9

84.3-100.3

Cmax (ng/ml) 21.1 ±6.7

23.2 ±8.7

86.0-100.2

Tmax (h) 12.5 ±7.8

12.3 ±7.1

-

T1/2 (h) 21.7 ±5.7

22.0 ±3.3

-

AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration

Tmax time for maximum concentration T1/2 half-life


The 90% confidence interval of the test/reference ratio of geometric means for AUC0-t, and Cmax for the active metabolite 6-MNA lie within the acceptable limits. Thus, the data support the claim that the test product is bioequivalent to the reference product. EFFICACY No new data on the efficacy have been submitted and none are required for this type of application. SAFETY Four subjects (21 %) experienced 5 adverse events after treatment with the test product and 6 (30 %) experienced 11 adverse events after treatment with the reference product. None of these events were serious. All events were of mild to moderate intensity and resolved by the end of the study. Headache was the only event which was considered to be drug related and it was the most frequently reported adverse event. Headache is a described side effect of nabumetone. There were no deaths or serious adverse events. Mean values for laboratory parameters, vital signs and ECG remained unchanged during the study. No new or unexpected safety issues were raised by the bioequivalence data. PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN The pharmacovigilance system, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for not submitting a risk management plan for this product. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELS The SmPC, PIL and labels are medically acceptable. The SmPC is consistent with that for the Relifex 500 mg strength product. CLINICAL EXPERT REPORT The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. CONCLUSION The grant of a Marketing Authorisation is recommended.


OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Relifex 1 g Film-coated Tablets, are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. EFFICACY Bioequivalence has been demonstrated between the applicant’s Relifex 1 g Film-coated Tablets (given as a single-tablet dose) and Relifex 500 mg Film-coated Tablets (given as a two-tablet dose). SAFETY No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product, where appropriate. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study demonstrates that the applicant’s Relifex 1 g Film-coated Tablets (given as a single-tablet dose) and Relifex 500 mg Film-coated Tablets (given as a two-tablet dose) are equivalent. Extensive clinical experience with nabumetone is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.



(Nabumetone)

PL 15142/0105

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the Marketing Authorisation application on 29/03/2007.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 09/05/2007.

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 11/06/2007 and 29/06/2010 and the clinical dossier on 29/06/2007.

4 The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 26/10/2009 and 21/10/2010 and the clinical dossier on 08/04/2010.

5 The application was determined on 09/11/2010


LABELLING Carton:


Bottle label:


Carton:


Blister:


Module 6


PL 15142/0105

STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Description Outcome

14/05/2013 VAR Medical Type II

To update sections 4.8 (undesirable effects), 5.1 (pharmacodynamics) and 5.2 (pharamacokinetics) of the SPC and the leaflet in line with the Company Core Data Sheet.

Variation granted 14/05/2013


ANNEX 1 – CLINICAL VARIATION ASSESSMENT REPORT

Reason: To update sections 4.8 (undesirable effects), 5.1 (pharmacodynamics) and 5.2 (pharmacokinetics) of the SmPC and the leaflet in line with the Company Core Data Sheet. Linked / Related Variation(s) or Case(s): The Assessment Report refers to the Collection ID 139309 and covers the following submissions PL 15142/0106 – 0012 Relifex 500 mg tablets. Supporting Evidence A clinical expert report is written by an appropriately qualified physician and has been submitted to support the proposed changes in line with the Company Core Data Sheet dated on 9th May 2012. Literature references have been provided to support the changes. Evaluation


The changes proposed above are acceptable. However:

1 There is repetition of information in SmPC Section 5.2 and the following text should be deleted:

Although nabumetone is absorbed essentially intact through the small intestine, extensive metabolism occurs during the first pass through the liver. As a result, concentrations in plasma of nabumetone are barely detectable after oral dosage. Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character. The active metabolite, 6-MNA, binds strongly to plasma proteins; it is distributed into inflamed tissue and crosses the placenta into foetal tissue. It is found in the milk of lactating females. 6-MNA is eliminated by metabolism, principally conjugation with glucuronic acid, and o-demethylation followed by conjugation, the main route of excretion being the urine. The plasma elimination half-life is about 1 day in man.

2 PIL mock up- clean version Insert a comma before anxiety.

Conclusion This variation is approvable pending resolution of minor outstanding points. Decision - Request for Further Information (RFI) OUTSTANDING POINTS

1 Section 5.2 of SmPC delete the following:

Although nabumetone is absorbed essentially intact through the small intestine, extensive metabolism occurs during the first pass through the liver. As a result, concentrations in plasma of nabumetone are barely detectable after oral dosage. Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character. The active metabolite, 6-MNA, binds strongly to plasma proteins; it is distributed into inflamed tissue and crosses the placenta into foetal tissue. It is


found in the milk of lactating females. 6-MNA is eliminated by metabolism, principally conjugation with glucuronic acid, and o-demethylation followed by conjugation, the main route of excretion being the urine. The plasma elimination half-life is about 1 day in man.

2 PIL mock up- clean version Insert a comma before anxiety.

------------------------------------------------------------------------------------------------------------------------ ASSESSMENT OF APPLICANT’S RESPONSE DATED 3 MAY 2013 (received 8/5/2013) The applicant has submitted amended section 5.2 of SmPC and PIL as requested in the RFI. There are no outstanding points. Decision-Approvable


SUMMARY OF PRODUCT CHARACTERISTICS Following approval of the variation on 14th May 2013 the SmPC was updated. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) for products that have been granted Marketing Authorisations at a national level are available on the MHRA website.


PATIENT INFORMATION LEAFLET Following approval of the variation on 14th May 2013 the Patient Information Leaflet was updated. In accordance with Directive 2010/84/EU the Patient Information Leaflets for products that are granted Marketing Authorisations at a national level are available on the MHRA website.

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