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Colesevelam (Cholestagel®▼)

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Colesevelam (Cholestagel®▼) VERDICT & SUMMARY Colesevelam (Cholestagel®▼) For the treatment of primary hypercholesterolaemia Committee’s Verdict: Category D BNF: 2.12 Colesevelam cannot be recommended for prescribing. Its place in therapy is uncertain because of the availability of a number of alternative effective lipid-lowering agents and the absence of trials comparing colesevelam with such agents. No long-term studies (> 24 weeks) of colesevelam, or trials studying its effect on patient-oriented outcomes, have been published. There is concern about its potential to bind other drugs in the gut. Category D: cannot be recommended for prescribing because of inadequate evidence for efficacy and/or safety MTRAC reviewed this drug because it is a new product with potential for prescribing in primary care. Licensed indication The current options for lipid-lowering therapy are statins, fibrates, anion-exchange resins, nicotinic acid Colesevelam co-administered with a statin is indicated and ezetimibe. Omega-3 fatty acids are also as adjunctive therapy to diet to provide an additive indicated as lipid-lowering agents. Lipid-lowering reduction in low-density lipoprotein cholesterol therapy must be combined with advice on diet and (LDL-C) levels in patients with primary lifestyle measures to reduce overall cardiovascular hypercholesterolaemia who are not adequately risk. controlled with a statin alone.1 Like the anion-exchange resins (cholestyramine and Colesevelam as monotherapy is indicated as colestipol), colesevelam is a bile acid sequestrant. adjunctive therapy to diet for reduction in elevated These drugs are lipid-lowering agents for the total and LDL-C in patients with isolated primary treatment of primary hypercholesterolaemia. hypercholesterolaemia, in whom a statin is considered inappropriate or is not well tolerated.1 Clinical efficacy Background information Eight RCTs evaluated colesevelam as monotherapy, or as additional therapy to statins, fenofibrate, or Hypercholesterolaemia is defined as the presence of ezetimibe. No trials were found that compared high concentrations of cholesterol in the blood. colesevelam with other active therapy. Patients Primary hypercholesterolaemia is associated with an enrolled in the trials had elevated levels of plasma underlying genetic cause, and has familial and non- 2 LDL-C, and most had a diagnosis of primary familial forms. Elevated serum concentrations of total hypercholesterolaemia. Eligible patients were cholesterol, LDL-C, and total triglycerides resulting randomised to treatment after starting a cholesterol- from hypercholesterolaemia are associated with 2 lowering diet. The primary outcome measure in the increased coronary heart disease (CHD) risk. The studies was the mean change in LDL-C levels from prevalence of familial hypercholesterolaemia in the baseline to the end of treatment. UK population is estimated to be about 0.2%,3 which means that approximately 110,000 people are Two dose-ranging RCTs (n = 149, 494; treatment affected. The population prevalence of primary non- duration 6, 24 weeks)7,8 evaluated colesevelam at familial hypercholesterolaemia is about 4% (about 1.5 doses of 1.5 to 4.5 g/day. Both studies found that million people affected).3 colesevelam treatment decreased LDL-C levels in a dose-dependent manner, and that the decreases were It is well established in clinical trials that reducing total significantly greater with colesevelam at doses ≥ 2.25 cholesterol and LDL-C levels with statins reduces the g/day than with placebo (-0.3 to -1.01 mmol/L [5 to incidence of myocardial infarction (MI), coronary 19%] vs. 0 to -0.02 mmol/L; p < 0.001).8 deaths and overall mortality,4,5 in both secondary and primary prevention. A meta-analysis6 of data from Three RCTs compared colesevelam as additional trials on statins found that there was a 12% therapy to a statin, with colesevelam, statin, or proportional reduction in all-cause mortality per placebo alone.9-11 The statins were lovastatin (n = mmol/L reduction in LDL-C (RR 0.88, 95% CI 0.84 to 135; treatment duration 4 weeks),9 atorvastatin (n = 0.91; p < 0.0001). This reduction in all-cause 94; 4 weeks),10 and simvastatin (n = 251; 7 weeks).11 mortality was attributable mainly to the 19% The studies found that the addition of colesevelam to proportional reduction in deaths from CHD (RR 0.81, statin therapy decreased LDL-C significantly more 95% CI 0.76 to 0.85; p < 0.0001) per mmol/L than either component alone (e.g. colesevelam 3.8 reduction in LDL-C. g/day -16%, simvastatin 10 mg/day -26%, combined April 2008 Page 1 of 2 treatment: -42%; p < 0.0001).11 The atorvastatin References study found that the addition of colesevelam 3.8 g/day 1. Genzyme Therapeutics. Cholestagel 625 mg film-coated to atorvastatin 10 mg therapy decreased LDL-C more tablets. Summary of Product Characteristics. 2007. than monotherapy (p < 0.05), but not more than high- 10 http://www.emc.medicines.org.uk/ dose atorvastatin alone (80 mg/day; p < 0.07). 2. National Institute for Clinical Excellence. Technology One RCT evaluated colesevelam in addition to Appraisal: Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) fenofibrate therapy (unlicensed use), in patients with hypercholesterolaemia. TA132. NICE. 2007. mixed hyperlipidaemia (n = 129; treatment duration 6 12 http://www.nice.org.uk/guidance/index.jsp?action=byID& weeks). The study found that the addition of o=11886 colesevelam to fenofibrate decreased LDL-C levels by 3. National Institute for Clinical Excellence. Costing 12% more than the decrease achieved using statement: Ezetimibe for the treatment of primary fenofibrate alone (p < 0.0001).12 (heterozygous-familial and non-familial) hypercholesterolaemia. NICE. 2007. Two RCTs evaluated colesevelam in addition to http://www.nice.org.uk/guidance/index.jsp?action=downl ezetimibe (n = 20, 85; treatment duration 12, 6 weeks; oad&o=38347 unlicensed use).13,14 The smaller study found no 4. LaRosa JC, et al. Effect of statins on risk of coronary significant difference in the size of the LDL-C disease. JAMA 1999;282:2340-6. decrease between ezetimibe monotherapy and 5. Ross SD, Allen IE, Connelly JE et al. Clinical outcomes ezetimibe plus colesevelam.13 In the larger study, the in statin treatment trials. Arch Intern Med 1999;159:1793-1802. addition of colesevelam to ezetimibe therapy reduced 6. Cholesterol Treatment Trialists' Collaborators. Efficacy LDL-C by 11% more than ezetimibe treatment alone 14 and safety of cholesterol-lowering treatment: prospective (p < 0.001). meta-analysis of data from 90,056 participants in 14 Adverse effects randomised trials of statins. Lancet 2005;366:1267-78. 7. Davidson MH, Dillon MA, Gordon B et al. Colesevelam In the trials in this review, about 800 patients were hydrochloride (Cholestagel). Arch Intern Med exposed to treatment with colesevelam. The studies 1999;159:1893-1900. reported that about 35 to 68% of patients experienced 8. Insull W, Toth P, Mullican W et al. Effectiveness of an adverse event,7,9,10,12,14 of which 39 to 45% were colesevelam hydrochloride in decreasing LDL 7,8,12 cholesterol in patients with primary considered to be drug-related. hypercholesterolaemia: a 24-week randomised In two studies, the most frequently reported adverse controlled trial. Mayo Clin Proc 2001;76:971-982. events were infections (10 to 24% for colesevelam 9. Davidson MH, Toth P, Weiss S et al. Low-dose combination therapy with colesevelam hydrochloride and treatment vs. 4 to 5% for placebo; type of infection not 9,10 lovastatin effectively decreases low-density lipoprotein specified). Gastrointestinal adverse events cholesterol in patients with primary (abdominal distention, constipation, dyspepsia, hypercholesterolaemia. Clin Cardiol 2001;24:467-474. 8 flatulence) were classed as mild in severity, and 10. Hunninghake D, Insull W, Toth P et al. Coadministration occurred in 13 to 37% of colesevelam-treated patients of colesevelam hydrochloride with atorvastatin lowers compared with about 10 to 30% of placebo-treated LDL cholesterol additively. Atherosclerosis patients.7,9-11,14 2001;158:407-416. 11. Knapp HH, Schrott H, Ma P et al. Efficacy and safety of For additional information on adverse events, refer to combination simvastatin and colesevelam in patients the Summary of Product Characteristics (SPC).1 with primary hypercholesterolaemia. Am J Med 2001;110:352-360. Additional information 12. McKenney J, Jones M, Abby S. Safety and efficacy of • The recommended daily dose of colesevelam is 4 colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidaemia. to 6 tablets (total dose 2.25 to 3.75 g/day) as Curr Med Res Opin 2005;21:1403-1412. adjunctive therapy and up to 7 tablets (4.38 g/day) 13. Knopp RH, Tsunehara C, Retzlaff BM et al. Lipoprotein as monotherapy. effects of combined ezetimibe and colesevelam • Colesevelam treatment increases triglyceride hydrochloride versus ezetimibe alone in levels. Caution should be exercised when treating hypercholesterolaemic subjects: a pilot study. Metab Clin patients with triglyceride levels greater than 3.4 Exp 2006;55:1697-1703. 1 14. Bays H, Rhyne J, Abby S et al. Lipid-lowering effects of mmol/L. colesevelam HCl in combination with ezetimibe. Curr • At current prices, a year’s treatment with Med Res Opin 2006;22:2191-2200. colesevelam (4 to 6 tablets per day) costs £752 to £1,127. Launch date: November 2007 Manufacturer: Genzyme Therapeutics Ltd EU/1/03/268/001-003 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk NO GUIDANCE FROM NICE FOR COLESEVELAM WAS AVAILABLE AT THE TIME OF ISSUE OF THIS VERDICT Date: April 2008 ©Midlands Therapeutics Review & Advisory Committee VS08/09 .
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