European Medicines Agency Evaluation of Medicines for Human Use Doc.Ref.: EMEA/350097/2008 CHMP ASSESSMENT REPORT FOR Trevaclyn International Nonproprietary Name: nicotinic acid / laropiprant Procedure No. EMEA/H/C/897 authorised Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. longer no product Medicinal 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 85 45 E-mail: [email protected] http://www.emea.europa.eu © European Medicines Agency, 2008. Reproduction is authorised provided the source is acknowledged. TABLE OF CONTENTS 1 BACKGROUND INFORMATION ON THE PROCEDURE........................................... 3 1.1 Submission of the dossier ........................................................................................................ 3 1.2 Steps taken for the assessment of the product.......................................................................... 3 2 SCIENTIFIC DISCUSSION................................................................................................. 4 2.1 Introduction.............................................................................................................................. 4 2.2 Quality aspects......................................................................................................................... 5 2.3 Non-clinical aspects................................................................................................................. 9 2.4 Clinical aspects ...................................................................................................................... 17 2.5 Pharmacovigilance................................................................................................................. 47 2.6 Overall conclusions, risk/benefit assessment and recommendation ...................................... 54 authorised longer no product Medicinal 2/57 EMEA 2008 1 BACKGROUND INFORMATION ON THE PROCEDURE 1.1 Submission of the dossier The applicant Merck Sharp & Dohme Ltd. submitted on 25 July 2007 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for Trevaclyn, through the centralised procedure under Article 3(2)a of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMEA/CHMP on 24 January 2007. The legal basis for this application refers to Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application The application submitted is a complete dossier composed of administrative information, complete quality data, non-clinical and clinical data based on applicants’ own tests and studies and/or bibliographic literature substituting/supporting certain tests or studies The applicant applied for the following indication: Trevaclyn is indicated as adjunctive therapy to diet for use in patients with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia: • who are treated with a statin and could benefit from having Trevaclyn added to their regimen, • in whom a statin is considered inappropriate or not tolerated Scientific Advice: The applicant received Scientific Advice from the CHMP on 24 Februaryauthorised 2006. The Scientific Advice pertained to clinical aspects of the dossier. Licensing status: The product was not licensed in any country at the time oflonger submission of the application. The Rapporteur and Co-Rapporteur appointed by theno CHMP and the evaluation teams were: Rapporteur: Harald Enzmann, Co-Rapporteur: Pieter de Graeff 1.2 Steps taken for the assessment of the product • The application was received productby the EMEA on 25 July 2007. • The procedure started on 15 August 2007. The agreed time table was in alignment with the Tredaptive procedure. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 4 October 2007. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 5 October 2007. • During the meeting on 12-15 November 2007, the CHMP agreed on the consolidated List of Questions Medicinalto be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 15 November 2007. • The applicant submitted the responses to the CHMP consolidated List of Questions on 17 December 2007. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 1 February 2008. • During the CHMP meeting on 18-21 February 2008, the CHMP agreed on a List of Outstanding Issues to be addressed in writing by the applicant. • The applicant submitted the responses to the CHMP List of Outstanding Issues on 19 March 2008. • The Rapporteurs circulated the Joint Assessment Report on the responses to the List of Outstanding Issues on 4 April 2008. • During the meeting on 21-24 April 2008, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a 3/57 EMEA 2008 Marketing Authorisation to Trevaclyn on 24 April 2008. The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on 21 April 2008. • The CHMP opinions were forwarded in all official languages of the European Union, to the European Commission, which adopted the corresponding Decision on 3 July 2008. 2 SCIENTIFIC DISCUSSION 2.1 Introduction Hypercholesterolaemia or mixed dyslipidemia should be treated as other known factors to reduce the risk for cardiovascular disease. Treatment is based on diet and lifestyle adjustment to reduce low density lipoprotein cholesterol (LDL-C), raise high density lipoprotein cholesterol (HDL-C) and if needed, reduce triglycerides (TG) and other lipids. If adjunctive medication is needed, statins are the medications of the first choice. Reduction in cardiovascular morbidity and mortality has been demonstrated in the past with nicotinic acid (also known as niacin) at a time when statins were not available yet. Adverse events (AEs) are its main limitation, in particular flushing, gastrointestinal symptoms and elevation of liver enzymes. For these reasons, its use in patients with dyslipidemia is mainly second or third line therapy in those patients who do not respond to statins or fibrates. The use of nicotinic acid however has been limited by its tolerability. The most common adverse effect occurring during the treatment with nicotinic acid is flushing. Although the mechanism by which nicotinic acid induces flushing is not completely understood, observationsauthorised suggest that blockade of the prostaglandin D2 (PGD2) receptor, specifically the subtype 1 (DP1), may suppress the flushing symptoms associated with nicotinic acid in the human. Importantly, although these flushing effects are mediated by the nicotinic acid receptor, they appear to be independent of the beneficial lipid-altering effects of nicotinic acid. longer Treatment with nicotinic acid has been shown to reduce the risk of overall and cardiovascular morbidity and mortality, as well as to slow progrnoession or promote regression of atherosclerotic lesions. The Coronary Drug Project, completed in 1975, assessed the safety and efficacy of nicotinic acid and other lipid-altering drugs in men 30 to 64 years old with a history of MI (Coronary Drug Project Research Group, 1975). Nicotinic acid showed a statistically significant benefit in decreasing nonfatal, recurrent MIs. The incidence of definite, non fatal MI was 8.9% for the 1,119 patients randomized to nicotinic acid versusproduct 12.2% for the 2,789 patients who received placebo (p<0.004). Though total mortality was similar in the two groups at five years (24.4% with nicotinic acid versus 25.4% with placebo; p=N.S.), in a fifteen-year cumulative follow-up there were 11% (69) fewer deaths in the nicotinic acid group compared to the placebo cohort (52.0% versus 58.2%; p=0.0004) (Canner et al., 1986). Based on the established nicotinic acid efficacy and risk-benefit profile the key objective of the prolonged releaseMedicinal nicotinic acid and laropiprant programme was to demonstrate improved tolerability of nicotinic acid when laropiprant is added. A fixed dose combination tablet of prolonged release nicotinic acid with laropiprant, a selective antagonist of the PGD2 receptor subtype 1 (DP1), is intended to reduce these PGD2 mediated flushes and improve the tolerability profile, while the lipid lowering properties are maintained. Trevaclyn is indicated for the treatment of dyslipidaemia, particularly in patients with combined mixed dyslipidaemia (characterised by elevated levels of LDL-C and TGs and low HDL-cholesterol) and in patients with primary hypercholesterolaemia (heterozygous familial and non-familial). Trevaclyn should be used in patients in combination with hydroxy-methyl-glutaryl-Co-enzyme-A (HMG-CoA) reductase inhibitors (statins), when the cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. It can be used as monotherapy only in patients in whom HMG-CoA reductase inhibitors are considered inappropriate or not tolerated. Diet and other non-pharmacological treatments (e.g. exercise, weight reduction) should be continued during therapy with Trevaclyn. 4/57 EMEA 2008 2.2 Quality aspects Introduction Trevaclyn is presented as modified-release tablets containing two active substances. Each tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant. Tablets are bilayer and the lower