VERDICT & SUMMARY Sevelamer (Renagel®)

For the control of hyperphosphataemia

Committee’s Verdict: CATEGORY B (Q1) BNF: 9.5.2.2 Sevelamer is suitable for prescribing in primary care with the guidance of an ESCA, once it has been initiated and the dose stabilised in secondary care. However, because many patients on dialysis are seen and monitored frequently in secondary care, it may be more practical for all their related prescribing needs to be met in secondary care. Category B: suitable for restricted prescribing under defined conditions Q1 rating: The evidence for the efficacy of sevelamer was considered to be relatively strong. One double-blind and four open-label RCTs Q2 Q1 evaluated sevelamer in patients receiving haemo- or peritoneal dialysis higher place higher place and found that it was more effective than placebo and as effective as other weaker evidence stronger evidence phosphate binders in reducing serum phosphorus levels. A second double-blind RCT found that was more effective than sevelamer. As a that does not contain calcium, the Q4 Q3 place in therapy for sevelamer was considered to be relatively high. lower place lower place weaker evidence stronger evidence The Q rating relates to the drug’s position on the effectiveness indicator

grid. The strength of the evidence is determined by the quality and quantity of in primary care Place therapy in studies that show significant efficacy of the drug compared with placebo or Strength of evidence for efficacy alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input. MTRAC updated the review on this drug to include an extension to the licensed indications. Licensed indications hyperphosphataemia in patients on haemodialysis include control of dietary phosphate intake (mainly Sevelamer is indicated for the control of protein) and the concomitant use of oral phosphate hyperphosphataemia in adult patients receiving binders such as calcium , calcium acetate, haemodialysis or peritoneal dialysis. It should be , sevelamer and lanthanum used within the context of a multiple therapeutic carbonate. approach, which could include calcium supplements, Sevelamer is a poly(allylamine hydrochloride) polymer 1,25 – dihydroxy vitamin D3 or one of its analogues to control the development of renal bone disease.1 that acts by binding phosphate molecules in the gut and thus lowering serum phosphate levels. Background information Clinical efficacy Chronic renal failure is usually the result either of primary renal disease (e.g. glomerulosclerosis) or of Haemodialysis renal damage in a multi-system disorder (e.g. 2 Two double-blind randomised controlled trials (DB diabetes mellitus and ). End-stage renal RCTs) (n = 134; 2 or 8 weeks’ treatment)4,5 and two disease is defined as an irreversible decline in kidney 3 open-label RCTs (n = 284; 8 or 40 weeks’ function that is fatal in the absence of dialysis. The treatment)6,7 evaluated sevelamer as a phosphate reduced kidney function leads to protein energy binder compared with placebo, calcium acetate or malnutrition, fluid retention (contributing to in patients receiving haemodialysis hypertension and cardiovascular events), anaemia, who had hyperphosphataemia. The clinical outcomes dyslipidaemia, and disturbances in bone and mineral included serum levels of phosphorus and calcium. metabolism (such as hyperphosphataemia, hypo- or Two further open-label RCTs (n = 315; 12 or 18 hypercalcaemia). Hyperphosphataemia, together with months’ treatment)8,9 used cardiovascular calcification reduced production of vitamin D3, leads to the as the main study outcome. Comparators in all the development of secondary hyperparathyroidism. open-label RCTs were calcium-containing phosphate In 2001, the number of patients receiving renal binders (calcium salts). replacement therapy (dialysis or transplantation) in In the placebo-controlled DB RCT,4 there were England was 547 patients per million population.2 significantly greater decreases in the serum levels of About half of these were on dialysis. phosphorus (p = 0.037), total cholesterol (p = 0.013) and LDL cholesterol (p = 0.003) in sevelamer-treated Current treatment options for controlling

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patients compared with placebo. appropriate dose of sevelamer is determined In the second DB RCT,5 compared with calcium individually based on serum phosphate concentrations (see the Summary of Product Characteristics for acetate, sevelamer-treated patients had significantly 1 higher levels of serum phosphorus (p < 0.05). Serum further details). Patients should take sevelamer with calcium levels were significantly lower with sevelamer meals and adhere to their dietary advice. treatment compared with calcium acetate treatment Sevelamer is contraindicated in patients with (p < 0.01). hypophosphataemia and patients with bowel In the two open-label RCTs,6,7 there was no difference obstruction. between patients treated with sevelamer or a calcium At current prices a year’s treatment with sevelamer (9 salt for reductions in serum phosphorus levels from tablets of 800 mg daily) costs £2,240. baseline. In both studies, there were significantly References greater increases in serum calcium levels for patients treated with calcium salts compared with sevelamer- 1. Genzyme Therapeutics. Renagel 800 mg film-coated treated patients (p ≤ 0.002). tablets. Summary of Product Characteristics 2006. 2. National Service Framework for Renal Services: Part The open-label RCTs that measured cardiovascular 8,9 One - Dialysis and transplantation. Department of calcification found that sevelamer-treated patients Health. 2004. showed significantly less progression of calcification http://www.dh.gov.uk/en/Publicationsandstatistics/Public than patients treated with calcium salts (p ≤ 0.05). ations/PublicationsPolicyAndGuidance/DH_4070359 Significantly more sevelamer-treated patients showed 3. Hall Y, Chertow G. End stage renal disease. Clinical some regression of calcification (p ≤ 0.05). In one Evidence. 15th ed. BMJ Publishing Group Ltd, 2006. pp. study, the incidence of mortality (a secondary 1171-1181. endpoint) was reported to be higher in patients treated 4. Chertow G, Burke S, Lazarus J et al. Poly[allylamine with calcium salts than in those treated with hydrochloride] (Renagel): A noncalcaemic phosphate 10 binder for the treatment of hyperphosphataemia in sevelamer. chronic renal failure. Am J Kidney Dis 1997;29:66-71. 5. Qunibi WY, Hootkins RE, McDowell LL et al. Treatment Peritoneal dialysis of in hemodialysis patients: The A small, open-label crossover study11 and a larger, Calcium Acetate Renagel Evaluation (CARE Study). unpublished, open-label RCT12 evaluated sevelamer Kidney Int 2004;65:1914-1926. as a phosphate binder in patients receiving peritoneal 6. Bleyer A, Burke S, Dillon M et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride dialysis. with calcium acetate in the treatment of In the crossover study (n = 30; 8 weeks’ treatment),11 hyperphosphataemia in haemodialysis patients. Am J there was no significant difference in the reduction in Kidney Dis 1999;33:694-701. serum phosphorus levels from baseline between 7. Chertow G, Burke S, Raggi P. Sevelamer attenuates sevelamer- and aluminium hydroxide-treated patients. the progression of coronary and aortic calcification in Sevelamer treatment showed significant reductions in haemodialysis patients. Kidney Int 2002;62:245-252. 8. Raggi P, Bommer J, Chertow GM. Valvular calcification total cholesterol and LDL cholesterol, unlike in hemodialysis patients randomized to calcium-based aluminium hydroxide. phosphorus binders or sevelamer. J Heart Valve Dis The larger, unpublished, open-label RCT (n = 143; 12 2004;13:134-141. weeks)12 found that both sevelamer and calcium 9. Block GA, Spiegel DM, Ehrlich J et al. Effects of acetate significantly reduced serum phosphorus from sevelamer and calcium on coronary artery calcification in baseline and that sevelamer was not inferior to patients new to haemodialysis. Kidney Int 2005;68:1815- 1824. calcium acetate. 10. Block GA, Raggi P, Bellasi A et al. Mortality effect of Adverse effects coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007;71:438- The main adverse events attributed to treatment in 441. trials were gastrointestinal complaints (e.g. 11. Katopodis KP, Andrikos EK, Gouva CD et al. Sevelamer , flatulence, vomiting), which occurred in hydrochloride versus aluminum hydroxide: effect on one study in 34% of sevelamer-treated patients and serum phosphorus and lipids in CAPD patients. Perit 28% of calcium acetate-treated patients.6 Dial Int 2006;26:320-327. 12. EMEA. Renagel EMEA/H/C/000254/II/56 2007. Additional information http://www.emea.europa.eu/humandocs/PDFs/EPAR/Re nagel/Renagel-H-C-254-II-56%20-AR.pdf For patients who are not on phosphate binders the

Launch date: April 2000 Manufacturer: Genzyme Therapeutics EU/1/99/123/008 - 012 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 RELEVANT NICE GUIDANCE WAS NOT AVAILABLE AT THE TIME OF ISSUE OF THIS VERDICT Date: July 2007 ©Midlands Therapeutics Review & Advisory Committee VS07/17 (THIS VERDICT AND SUMMARY SHEET REPLACES VS04/10 & SS04/10)