The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 5 January 2011 Review of the dossier of the proprietary drugs included on the list of reimbursable medicines for a period of 5 years as from 3 September 2005 (Official Gazette of 28 April 2006) NEXEN 100 mg, tablet B/30 (CIP code: 339 285-1) NEXEN 100 mg, granules for oral solution in sachets B/30 (CIP code: 339 286-8) Applicant: THERABEL LUCIEN PHARMA nimesulide ATC code: M01AX17 List I Date of Marketing Authorisation (national): 25 July 1995 Date of latest revision of Marketing Authorisation: 23 January 2008 Reason for request: Renewal of inclusion on the list of medicines reimbursable by National Health Insurance. Joint renewal of the proprietary drug: NEXEN 100 mg, tablet B/10 (CIP: 374 140-6) Medical, Economic and Public Health Assessment Division 1/8
1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient nimesulide 1.2. Indications - Treatment of acute pain - Symptomatic treatment of painful osteoarthritis - Primary dysmenorrhoea 1.3. Dosage NEXEN 100 mg tablets should be used for the shortest possible duration, as required by the clinical situation. Adults 100 mg twice a day, i.e. one tablet or one 100-mg sachet morning and evening, after meals. Elderly In elderly patients there is no need to reduce the daily dosage. Children (below 12 years) NEXEN 100 mg tablets are contraindicated in these patients. Adolescents (from 12 to 18 years) On the basis of the pharmacokinetic profile of nimesulide in adults and its pharmacodynamic properties, no dosage adjustment in these patients is necessary. Impaired renal function On the basis of the pharmacokinetic properties of nimesulide, no dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance: 30-80 ml/min). However, NEXEN 100 mg tablets and granules are contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min). Hepatic impairment NEXEN 100 mg tablets and granules are contraindicated in patients with hepatic impairment. 2/8
1.4. Contraindications - Known hypersensitivity to nimesulide or to any other excipients of the product; - History of hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria) in response to acetylsalicylic acid or another non-steroidal anti-inflammatory drugs; - History of hepatotoxic reactions to nimesulide; - Active gastric or duodenal ulcer, a history of recurrent ulceration or gastrointestinal bleeding, cerebrovascular bleeding or other active bleeding or bleeding disorders; - Severe coagulation disorders; - Severe heart failure; - Severe renal impairment; - Hepatic impairment; - Children under 12 years; - The third trimester of pregnancy and breastfeeding. 2 REMINDER OF THE COMMITTEE S OPINIONS AND CONDITIONS OF INCLUSION Opinion of the Committee of 4 October 1995 These proprietary drugs offer no improvement in actual benefit over directly comparable medicines, i.e. NSAIDs, in the indication symptomatic treatment of disabling painful osteoarthritis'. Opinion of the Committee of 26 April 2000 Approval of retention of inclusion for the indication symptomatic treatment of disabling painful osteoarthritis in the indication and at the dosage in the Marketing Authorisation. Reimbursement rate: 65%. The Committee is awaiting a reassessment of the class to which this proprietary drug belongs. Opinion of the Committee of 10 January 2001 - Reassessment The actual benefit conferred by this proprietary drug is minor in the indication symptomatic treatment of disabling painful osteoarthritis'. Opinion of the Committee of 2 April 2003 The Transparency Committee retains the actual benefit level previously assigned to NEXEN while awaiting the conclusions of the European arbitration procedure and reassessment of the efficacy/adverse effects ratio of nimesulide. The actual benefit conferred by NEXEN 100 mg tablets and 100 mg granules for oral solution is minor. 3/8
Opinion of the Committee of 16 February 2005 The actual benefit conferred by this proprietary drug in the extensions of indication (acute pain and dysmenorrhoea) is subtantial. NEXEN does not provide any improvement in actual clinical benefit compared to the alternative treatments available for acute pain and primary dysmenorrhoea. Opinion of the Committee of 30 November 2005 NEXEN has undergone a European reassessment of its risk/benefit ratio following hepatic adverse effects. This reassessment concluded that the risk/benefit ratio was favourable for all the indications in the marketing authorisation. The efficacy/adverse effects ratio of NEXEN in the treatment of osteoarthritis, acute pain and primary dysmenorrhoea was found to be similar to that of other NSAIDs (moderate). The actual clinical benefit of NEXEN is substantial. Opinion of the Committee of 20 September 2006 Approval of inclusion of NEXEN 100 mg tablets (boxes of 10 tablets). The actual benefit of this proprietary drug is substantial. This proprietary drug is an addition to the range which offers no improvement in actual benefit. 3 SIMILAR MEDICINAL PRODUCTS 3.1. ATC Classification (2010) M: Musculoskeletal system M01: Antiinflammatory and antirheumatic products M01A: Anti-inflammatory and antirheumatic products, non-steroids M01AX: Other antiinflammatory and antirheumatic products, non-steroids M01AX17: nimesulide 3.2. Medicines in the same therapeutic category All oral NSAIDs indicated for use in the treatment of acute pain and/or dysmenorrhoea and/or painful osteoarthritis. 3.3. Medicines with a similar therapeutic aim All analgesics. 4/8
4 UPDATING OF AVAILABLE DATA SINCE THE PREVIOUS OPINION 4.1. Efficacy No new clinical data has been supplied by the company. 4.2. Tolerance Hepatic tolerance French pharmacovigilance data Analysis of reports of hepatic adverse effects in France has shown that: - 58 cases were reported between 1998 and 2006 (one case per 3,875,000 days of treatment) - 41 cases were reported between 2007 and May 2010 (one case per 3,645,000 days of treatment). See table 1 below for the details of reports of hepatic adverse effects (severity not specified) in France. Table 1. Reports of damage to hepatic function/exposure in France Number of reports Days of treatment DT 1998 6 12,104,925 1999 8 21,538,980 2000 6 27,832,980 2001 7 25,654,830 2002 8 27,494,325 2003 12 30,391,845 2004 5 33,166,905 2005 6 35,979,945 2006 12 38,159,325 2007 15 41,600,040 2008 3 47,567,070 2009 5 45,611,235 2010 (end of May) 6 14,608,135 Total 99 401,710,540 Summary of conclusions of European reassessments It should be remembered that nimesulide-based proprietary drugs underwent a European pharmacovigilance investigation in 2002 to assess their potential hepatotoxic risk. This investigation was carried out following the suspension of their marketing authorisation in Finland and later in Spain on the grounds of concerns regarding hepatotoxicity. Following this investigation it was decided that, despite the differing views put forward by Finland, Spain and Ireland, the efficacy/adverse effects ratio of nimesulide was still favourable provided that the SPC was amended. This amendment entailed harmonisation of 5/8
indications in the various European countries, a reduction of the maximum oral dose to 100 mg twice a day, the addition of a contraindication for patients with hepatic impairment and a warning regarding the risk of hepatitis, especially fulminant hepatitis, jaundice and cholestasis. These changes were taken into consideration when the Transparency Committee drew up its subsequent opinions in February and November 2005. A further European pharmacovigilance investigation was commissioned in May 2007 to reassess the potential hepatotoxicity of nimesulide following the decision by the Irish health authorities to remove nimesulide-based proprietary drugs from the market in response to reports of new cases of fulminant hepatitis. In September 2007, the conclusions of this second 1 reassessment were published by the Committee for Medicinal Products for Human Use (CHMP): assessment of all the pharmacovigilance data, clinical studies and epidemiological data has shown that the frequency of serious hepatic effects is greater for nimesulide than for other NSAIDs. However, with the exception of serious hepatic adverse effects reported in Ireland, examination of all the data submitted does not lead to any change in the tolerance profile of nimesulide as established during the first reassessment. Measures to minimise the risk were recommended, in particular amendments to the SPC 2 to emphasise that: - the decision to prescribe nimesulide must be based on an assessment of the risks; - the maximum length of treatment with nimesulide must be 15 days. Consequently, boxes containing more than 30 units must be withdrawn from the market and must not be authorised; - new contraindications must be added and the warnings must be made stronger in order to limit patient exposure, including exposure of patients with no related risk factors for hepatic effects. In addition, the retention of marketing authorisations has been made subject to the following conditions: 1. submission of PSURs (periodic safety update reports) every six months; 2. the conduct of a retrospective study, followed by a prospective study in transplant centres, to assess the relative risk of severe hepatic adverse effects leading to transplant for patients treated with nimesulide and other NSAIDs; 3. updating of the risk management plan; 4. the dispatch of a letter to inform healthcare professionals. The European Commission took the advice of the CHMP on board, imposing an additional restriction aimed at limiting the use of this medicinal product as a second-line NSAID on 16 October 2009 3,4,5. The Transparency Committee is of the opinion that serious hepatic adverse effects occurring in the short term cannot be prevented by limiting the duration of treatment to 15 days. The data available indicates that 39% of cases of hepatotoxicity have occurred within 15 days of 1 EMA. Press release European Medicines Agency recommends restricted use of nimesulide-containing medicinal products September 2007 2 currently being implemented in France by Afssaps 3 Commission decision dated 16 October 2009, taken pursuant to article 107 of European Parliament and Council Directive 2001/83/EC, regarding the marketing authorisation for medicinal products for human use containing the active substance nimesulide. 4 Appendix II. Scientific conclusions and reasons for retaining marketing authorisations and amendments to the summary of product characteristics and the patient information leaflet submitted by the EMEA. April 2010 5 Appendix V. Detailed explanation of the reasons behind the imposition of additional conditions and restrictions to the CHMP opinion. 6/8
the start of treatment, with 27% occurring during the first week of treatment. Furthermore, it would appear difficult in practice to comply with this restriction of treatment to 15 days in the indication "Symptomatic treatment of painful osteoarthritis". Moreover, the NSAID class contains several alternatives that are associated with a lower hepatotoxic risk. It should be remembered that several European countries have withdrawn nimesulide-based proprietary drugs from the market: Finland (2002), Spain (2002), Ireland (2007) and Belgium (2007), despite the EMA s conclusion that the benefit/risk ratio is favourable. The EMA is currently conducting a third reassessment (article 31 6 ) of nimesulide, based not only on hepatic tolerance but on the overall benefit/risk ratio. A case study review is being conducted to investigate the risk. The findings of this study will be presented to the CHMP in May 2011. 4.3. Conclusion Hepatotoxicity is the main risk associated with the use of nimesulide compared to other NSAIDs. Assessment of all the pharmacovigilance data, clinical studies and epidemiological studies shows that patients taking nimesulide experience severe hepatic effects more frequently than patients taking other NSAIDs. Overall, the new tolerance data available indicating that severe hepatic effects are more common in patients taking nimesulide than in patients taking other NSAIDs, must lead to a re-examination of the efficacy/adverse effects ratio, the role in treatment strategy and the actual clinical benefit of NEXEN proprietary drugs compared to the other NSAIDs which are available. 5 DRUG USAGE DATA IMS-EPPM data (November 2009) shows that 1,763,000 prescriptions for these proprietary drugs have been issued. The average dosage was 1.9 units a day, and the average length of treatment prescribed was 15.7 days. 6 This article states that, in particular cases of Community interest, the CHMP can be asked to consider a question before a decision relating to the amendment, suspension or withdrawal of a marketing authorisation is taken. 7/8
6 TRANSPARENCY COMMITTEE CONCLUSIONS 6.1. Re-evaluation of actual benefit Osteoarthritis is a chronic disabling disease. Acute pain and dysmenorrhoea are not normally serious conditions, but can reduce quality of life. NEXEN proprietary drugs are intended as symptomatic therapy. The tolerance data available has indicated that patients taking nimesulide experience severe hepatic adverse effects more frequently than patients taking other NSAIDs. Consequently, the efficacy/adverse effects ratio of nimesulide-based proprietary drugs is inferior to that of other NSAIDs which are available. As a result, these proprietary drugs have no role in treatment strategy. There are numerous alternative treatments. In the light of this, the Transparency Committee considers that the actual benefit of these propriety drugs, in comparison with other treatments that are already available, is not sufficient to allow it to be refundable by National Health Insurance. 6.2. Transparency Committee recommendations The Transparency Committee does not recommend maintaining inclusion on the list of medicines refundable by National Health Insurance or on the list of medicines approved for hospital use and various public services in the indications and at the dosages in the Marketing Authorisation. The Transparency Committee recommends removal from the list of medicines refundable by National Health Insurance and from the list of medicines approved for hospital use and various public services in the indications and at the dosages in the Marketing Authorisation. 8/8