Vademecum

Description: RenaGel� is a nonabsorbable, calcium- and aluminum- free, polyallylamine-epichlorhydrin polymer that is approved for use as an oral agent for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The safety and efficacy in patients with ESRD who are not on hemodialysis have not been studied. Sevelamer lowers serum phosphate in end-stage renal disease patients without the risk of increasing serum calcium levels. The phosphate lowering effects of sevelamer were comparable to calcium acetate or aluminum phosphate binders.[2112] [2113] Thus, sevelamer is an alternative to calcium salts in hyperphosphatemic patients who also have a high calcium-phosphorus product (e.g. Ca X P product > 66). Since it does not contain aluminum or calcium, sevelamer does not cause aluminum intoxication or hypercalcemia. In addition, sevelamer has beneficial cholesterol-lowering effects which may be useful in patients with renal disease and coexisting diabetes or atherosclerotic disease. Sevelamer was first approved by the FDA on October 30, 1998. Mechanism of Action: Sevelamer binds dietary phosphate within the gastrointestinal tract. Amine groups in the sevelamer molecule cross-link with phosphate in the gut, thereby preventing phosphate absorption. When taken with meals, sevelamer lowers both serum phosphate and parathyroid hormone, but does not increase serum calcium. Sevelamer also lowers serum total and LDL cholesterol levels with no effect on HDL cholesterol or triglyceride levels in healthy volunteers and end-stage renal disease patients.[2114] Pharmacokinetics: Sevelamer is administered orally. A mass balance study using 14C-sevelamer hydrochloride in healthy volunteers showed that sevelamer is not absorbed systemically. No absorption studies have been conducted in patients with renal disease.

Indications...Dosage For the management of hyperphosphatemia in patients with end stage renal disease: Oral dosage (Renagel� Capsules or Renagel� 400 mg Tablets, which contain 400 mg of sevelamer per dosage unit): Adults not receiving phosphate binders: Initially, the dosage range is 2�4 capsules or tablets (800�1600 mg) PO three times daily with meals, based on the severity of the hyperphosphatemia. If the serum phosphate level is 6.1�7.4 mg/dl, the initial dose is 2 capsules or tablets (800 mg) three times per day; if the serum phosphate value is 7.5�8.9 mg/dl, the initial dose should be 3 capsules or tablets (1200 mg) three times per day; if the serum phosphate value is >= 9.0 mg/dl, the initial dose should be 4 capsules or tablets (1600 mg) three times per day. The dosage should be gradually adjusted based on serum phosphate concentrations with a target goal of <= 6.0 mg/dl. The dose may be increased or decreased gradually by one capsule or tablet per meal. Maximum dosage studied is 10 Renagel� capsules per meal or 30 Renagel� capsules/day (equivalent to 12,090 mg/day). The recommended monitoring parameters include serum phosphate, calcium, chloride and bicarbonate concentrations. Adults being switched from calcium acetate to sevelamer: Calcium acetate may be converted to sevelamer based on the dosage conversion used in pre-marketing clinical trials. One tablet of 667 mg calcium acetate per meal may be switched to 2 capsules or tablets of sevelamer (800 mg) per meal; two tablets of 667 mg calcium acetate per meal may be switched to 3 capsules or tablets of sevelamer (1200 mg) per meal; and 3 tablets of 667 calcium acetate per meal may be switched to 5 capsules or tablets of sevelamer (2000 mg) per meal. Elderly: See adult dosage. Children, infants, and neonates: Safe and effective use has not been established. Oral dosage (Renagel� 800 mg Tablets, which contain 800 mg sevelamer per tablet): Adults not receiving phosphate binders: Initially, 1�2 tablets (800�1600 mg) PO three times daily with meals, based on the severity of the hyperphosphatemia. If the serum phosphate level is 6.1�7.4 mg/dl, the initial dose is 1 tablet (800 mg) three times per day; if the serum phosphate value is 7.5�8.9 mg/dl, the initial dose should be 2 tablets (1600 mg) three times per day; if the serum phosphate value is >= 9.0 mg/dl, the initial dose should be 2 tablets (1600 mg) three times per day. The dosage should be gradually adjusted based on serum phosphate concentrations with a target goal of <= 6.0 mg/dl. The dose may be increased or decreased gradually by one tablet per meal. Maximum dosage of sevelamer that has been studied is 12,090 mg/day, which is approximately equivalent to five Renagel� 800 mg tablets per meal (15 tablets per day). The recommended monitoring parameters include serum phosphate, calcium, chloride and bicarbonate concentrations. Adults being switched from calcium acetate to sevelamer: Calcium acetate may be converted to sevelamer based on the dosage conversion used in pre-marketing clinical trials. One tablet of 667 mg calcium acetate per meal may be switched to 1 tablet of sevelamer (800 mg) per meal; two tablets of 667 mg calcium acetate per meal may be switched to 2 tablets of sevelamer (1600 mg) per meal; and 3 tablets of 667 calcium acetate per meal may be switched to 3 tablets of sevelamer (2400 mg) per meal. Elderly: See adult dosage. Children, infants, and neonates: Safe and effective use has not been established. Maximum Dosage Limits: �Adults: 12,090 mg/day PO. �Elderly: 12,090 mg/day PO. �Adolescents: Safe and effective use has not been established. �Children: Safe and effective use has not been established. Patients with hepatic impairment: No dosage adjustment is needed; the drug is not systemically absorbed. Patients with renal impairment: No dosage adjustment is needed. Sevelamer is indicated in patients with renal impairment. Intermittent hemodialysis: No dosage adjustment is needed; the drug is not systemically absorbed.

Administration Oral Administration �Sevelamer capsules or tablets are administered orally with meals. Instruct patient to swallow capsules or tablets intact with water. Capsules or tablets should not be taken apart, divided, crushed, or chewed. �If a potential drug interaction is to be avoided (see Drug Interactions), administer the other drug at least 1 hour before or 3 hours after the dose of sevelamer.

Contraindications Sevelamer is absolutely contraindicated in patients with hypophosphatemia, ileus, fecal impaction, and GI obstruction. Sevelamer is relatively contraindicated in appendicitis, dysphagia, GI bleeding, and major GI surgery. It has not been studied in patients with gastrointestinal disorders. Sevelamer is rated by the FDA as a pregnancy risk category C drug. There are no adequate and well-controlled studies in pregnant women. The effect of sevelamer on the absorption of vitamins and other nutrients has also not been studied in pregnant women. There is no data regarding the use of sevelamer in breast-feeding women. The safety and efficacy of sevelamer have not been evaluated in children.

Interactions Sevelamer is not systemically absorbed. Drug interaction studies which have been conducted to date which have included small numbers (e.g., 14�31) of patients. These studies have demonstrated no effect of sevelamer on the single-dose pharmacokinetics of digoxin, warfarin, enalapril, or metoprolol. The effect of sevelamer on the pharmacodynamics (e.g., prothrombin time) of warfarin has not been evaluated; therefore, separation of drug administration is prudent. Despite the lack of documented interactions with sevelamer, the potential for reduced drug absorption could result in clinical significance for oral drugs with a narrow therapeutic range, with the potential for loss of efficacy. These drugs could include antiarrhythmics and anticonvulsants which were excluded from sevelamer pre-marketing trials, and quinolones, tetracyclines, levothyroxine, liothyronine, and theophylline. Potential for drug interactions with oral concomitant medications can be minimized by administering other drugs at least 1 hour before or 3 hours after administration of sevelamer doses. Phosphate salts counteract the pharmacological benefits of sevelamer. It would be illogical to administer phosphate salts or phosphorus salts to patients who require sevelamer.

Adverse Reactions Adverse reactions possibly related to sevelamer, which were not dose-related included nausea/vomiting (7%), dyspepsia (5%), diarrhea (4%), flatulence (4%), and constipation (2%). Diarrhea (16% vs. 10%), dyspepsia (11% vs. 4%), infection (15% vs. 11%), thrombosis (10% vs. 6%), and vomiting (12% vs. 5%) appeared to occur more frequently with sevelamer than with calcium acetate in a comparative cross-over trial; however both the sample size (n=82) and the absolute count of each of these adverse events were very low. Significant electrolyte imbalances did not occur in pre-marketing clinical trials with sevelamer. In animal studies, sevelamer reduces vitamin D, E, K, and folic acid levels at doses of 6�100 times the recommended human dose. However, in clinical trials there was no evidence of reduced serum levels of vitamins. Most (about 75%) patients in the sevelamer clinical trials received vitamin supplements, which is typical for patients receiving hemodialysis. Sevelamer have been given to normal healthy volunteers in doses of up to 14 grams, the equivalent of thirty-five 403 mg capsules, per day for eight days with no adverse effects. There are no reported overdosages of sevelamer in patients. Since sevelamer is not absorbed, the risk of systemic toxicity is low.

 

Sevelamer RenaGel�

2112. Chertow GM, Burke SK, Lazarus JM et al. Poly

2113. Goldberg DI, Dillon MA, Slatopolsky EA et al. Effect of RenaGel, a non-absorbed, calcium- and aluminum-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients. Nephrol Dial Transplant 1998;13:2303�10.

2114. Wilkes BM, Reiner D, Kern M et al. Simultaneous lowering of serum phosphate and LDL-cholesterol by sevelamer hydrochloride (Renagel) in dialysis patients. Clin Nephrol 1998;50:381�6.