Sevelamer

149.62

149.0607417

DTXSID80872282

V03AE02|V - Various

0.559

Insoluble

Store at 25 °C (77 °F): excursions permitted to 15-30 °C (59-86 °F).

Insoluble in water. Hydrophilic /Hydrochloride/

Store at -20°C

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sevelamer carbonate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sevelamer carbonate/|The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sevelamer hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sevelamer hydrochloride/

Sevelamer has been given to normal healthy volunteers in doses of up to 14 grams per day for eight days with no adverse effects. Sevelamer has been given in average doses up to 13 grams per day to hemodialysis patients. There are no reported overdosages of sevelamer in patients. Since sevelamer is not absorbed, the risk of systemic toxicity is low.

... The acute effects ... of three medications on thyroxine absorption in seven normal volunteers /was studied/. On each study day, the subjects ingested 1 mg levothyroxine sodium, either taken separately or co-administered with sevelamer hydrochloride, a phosphate-binding medication used in the treatment of hyperphosphatemia), chromium picolinate (an over-the-counter nutritional supplement), or ezetimibe, a drug used in the treatment of hypercholesterolemia). Serum thyroxine was measured at intervals over a 6-hour period following drug ingestion. Sevelamer hydrochloride and chromium picolinate each significantly (p < 0.05) decreased the area under the serum thyroxine concentration curve, while ezetimibe had no effect. Hypothyroid patients taking sevelamer hydrochloride or chromium picolinate should be advised to separate the time of ingestion of these drugs from their thyroid hormone preparation by several hours.|A 30-year-old dialysis patient affected by secondary hyperparathyroidism started sevelamer treatment, 4.8 g/day, with a basal serum phosphate of 6.9 mg/dL. The patient was also treated with omeprazole (20 mg/day) because of chronic gastritis. Phosphate levels normalized (4.2 mg/dL), but after four months of follow-up serum phosphate unexpectedly increased to 7.2 mg/dL. ... In the same period /the patient/ had autonomously increased the dosage of omeprazole to 80 mg/day, due to worsening of dyspepsia. Gastric pH measurement showed a median level of 4.1, rather than the normal values of 1 - 2, indicating excessive pharmacological alkalinization. When omeprazole was reduced to the correct dose of 20 mg/day, ... a rapid decrease of phosphate levels /occurred/. This case report highlights the influence of gastric pH on sevelamer phosphate binding capacity. The high dose of omeprazole and the consequent excessive increase in gastric pH was probably responsible for a decreased phosphate binding capacity of sevelamer. When patients taking appropriate doses of sevelamer do not respond to treatment, a potential interaction with drugs determining an increase of gastric pH should be considered.|Pharmacokinetic interaction (decrease in ciprofloxacin bioavailability of about 50%) when sevelamer is used concomitantly with ciprofloxacin.|After renal transplantation, patients with insufficient graft function may require phosphate binders. It is still unknown if sevelamer, a new calcium-free phosphate binder, interferes with the uptake of immunosuppressants. Its effects on the pharmacokinetics of cyclosporin A (CsA) and mycophenolate mofetil /were studied/. Ten adults and eight children with stable renal graft function and stable CsA trough levels /were examined/. A 12 hr pharmacokinetic profile (10 observation points) was conducted without sevelamer, after a single dose and after 4 days of treatment with it. CsA levels were measured with both a monoclonal antibody assay (CEDIA) and a polyclonal antibody assay (FPIA), mycophenolic acid (MPA) levels by EMIT assay and CsA metabolites AM1, AM9 and AM4N by a modified HPLC method. Sevelamer had no significant effect on CsA kinetics [area under the curve (AUC), peak concentration (C(max)), time of C(max)]. The AUC of AM1 was decreased by 30% and C(max) by 25% after 4 days of sevelamer intake. MPA levels were significantly reduced by a mean of 25% of the AUC (P<0.05) and by 30% of the C(max) after a single dose of sevelamer. A single sevelamer dose reduces the C(max) and the AUC of MPA. Its intake for several days does not significantly influence CsA kinetics.

Renagel is contraindicated in patients with hypophosphatemia or bowel obstruction.|The safety and efficacy of Renagel in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including severe constipation, or major GI tract surgery have not been established. Consequently, caution should be exercised when Renagel is used in patients with these GI disorders.

While data specific to sevelamer were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

For the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis.|FDA Label|Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis.Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy vitamin D3 or one of its analogues to control the development of renal bone disease.

Vascular calcification and endothelial dysfunction contribute to the development of cardiovascular disease in patients with chronic kidney disease (CKD). Sevelamer, a non-calcium-based phosphate binder, has been shown to attenuate cardiovascular calcification in CKD patients, although the exact mechanism has not been clarified. This study was designed to investigate the effect of short-term sevelamer treatment on both serum fetuin-A concentrations and endothelial dysfunction seen in CKD patients. Fifty nondiabetic stage 4 CKD patients whose phosphate levels were > or =5.5 mg/dL were enrolled in this 8-wk randomized prospective study. Thirty-six healthy volunteers served as matched controls. Patients were treated with either sevelamer (n = 25, 12 males) or calcium acetate (n = 25, 13 males). Fetuin-A, high-sensitivity C-reactive protein, Ca x PO4 product, flow-mediated dilation (FMD), insulin, and homeostasis model assessment (HOMA) were obtained at baseline and after the treatment period. As expected, CKD patients had significantly lower levels of fetuin-A and FMD, and significantly higher levels of intact parathyroid hormone, Ca x PO4 product, and high-sensitivity C-reactive protein than controls (P < 0.001 for all). The use of sevelamer led to a significant increase in the fetuin-A concentration with improvement in FMD, whereas no significant difference was observed in the calcium acetate group. In a multiple regression analysis, FMD levels were independently related to fetuin-A both before (beta = 0.63, P < 0.001) and after (beta = 0.38, P = 0.004) treatment. This small, randomized, prospective study shows that short-term sevelamer treatment significantly increases fetuin-A levels and improves FMD in nondiabetic stage 4 CKD patients.|Sevelamer hydrochloride is used to reduce serum phosphorus in patients with chronic kidney disease (CKD) who are undergoing hemodialysis. Safety and efficacy of sevelamer in patients with CKD who are not undergoing hemodialysis have not been studied. The risk of developing hypercalcemia appears to be less with sevelamer hydrochloride than with calcium (e.g., calcium acetate) salts.|/EXP THER/ Sevelamer, a non-calcium-containing, non-aluminum-containing phosphate binder, is frequently prescribed for treatment in adults with hyperphosphatemia secondary to end-stage renal disease (ESRD). However, published information regarding sevelamer use in children younger than 11 years is lacking. ...the use of sevelamer as a phosphate binder in a 19-month-old girl with ESRD who was receiving calcium carbonate ... for hyperphosphatemia /is described/. ... The patient's initial serum phosphorus concentration was 8.6 mg/dL, and the calcium-phosphorus product was 75 mg(2)/dL(2). This was well above the level that places patients at risk for complications such as joint, vessel, and soft-tissue calcification.... During sevelamer therapy, her serum phosphorus concentration dropped as low as 5.2 mg/dL; at discharge it was 6.5 mg/dL, with a corresponding calcium-phosphorus product in the upper 50s. No adverse effects associated with sevelamer were observed. In the dosages we used, sevelamer resulted in an acceptable calcium-phosphorus product and returned the patient's serum phosphorus concentration to near normal.|/EXP THER/ This pilot study was designed to evaluate the efficacy and acceptability of sevelamer hydrochloride as a phosphate binder in pediatric patients treated with dialysis. A 6-month open-label trial of sevelamer hydrochloride (Renagel) was initiated in 17 patients, aged 11.8+/-3.7 years, undergoing hemodialysis ( n=3) or peritoneal dialysis ( n=14). Following a 2-week washout period of the phosphate binders, serum phosphorus increased from 5.2+/-1.3 mg/dL to 7.5+/-2.2 mg/dL ( P<0.0002). After initiation of therapy with sevelamer hydrochloride, serum phosphorus levels decreased to 6.2+/-1.2 mg/dl ( P<0.01) during the first 8 weeks and final values were 6.3+/-1.5 mg/dL. Serum calcium concentration decreased during the washout period from 9.4+/-0.9 mg/dL to 8.9+/-1.5 mg/dL ( P<0.01); values remained unchanged thereafter. The serum calcium-phosphorus ion product decreased during the first 8 weeks and values did not change subsequently. Serum bicarbonate, parathyroid hormone, total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, and triglyceride levels did not change. ... Sevelamer hydrochloride was well tolerated and without adverse effects related to the drug. /Sevelamer hydrochloride/

Safety and efficacy not established in children younger than 18 years of age.|Adverse effects occurring in 2% or more of patients include diarrhea, constipation, dyspepsia, flatulence, nausea, vomiting, hypertension, hypotension, thrombosis, infection (nasopharyngitis, bronchitis, upper respiratory infection), cough, dyspnea, pain (e.g., limb pain, back pain), headache, arthralgia, pyrexia, and pruritus.|The safety and efficacy of Renagel in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including severe constipation, or major GI tract surgery have not been established. Consequently, caution should be exercised when Renagel is used in patients with these GI disorders.|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|For more Drug Warnings (Complete) data for SEVELAMER (9 total), please visit the HSDB record page.

Patients with end-stage renal disease (ESRD) retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum calcium resulting in ectopic calcification. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 55 mg²/dL², there is an increased risk that ectopic calcification will occur. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. An increase in parathyroid hormone (PTH) levels is characteristic of patients with chronic renal failure. Increased levels of PTH can lead to osteitis fibrosa, a bone disease. A decrease in serum phosphorus may decrease serum PTH levels. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer taken with meals has been shown to decrease serum phosphorus concentrations in patients with ESRD who are on hemodialysis. In vitro studies have shown that the capsule and tablet formulations bind phosphate to a similar extent. Sevelamer treatment also results in a lowering of low-density lipoprotein (LDL) and total serum cholesterol levels.

Chemicals that bind to and remove ions from solutions. Many chelating agents function through the formation of COORDINATION COMPLEXES with METALS. (See all compounds classified as Chelating Agents.)

Not absorbed following oral administration, however no absorption studies have been performed in patients with renal disease. Sevelamer may bind to dietary phosphates and prevent its gastrointestinal absorption when sevelamer is administered in combination with food.|Six rats received a single oral dose of ((3)H)sevelamer and six rats were pretreated with unlabelled sevelamer in the diet for 28 days followed by a single dose of ((3)H)sevelamer on day 29. Total urine and feces were collected at intervals up to 72 hours post dose, and tissues were obtained at the time of sacrifice. In the clinical trial, subjects received a single oral dose of (14)C sevelamer following 28 days of pretreatment with unlabelled sevelamer. Blood, urine and feces samples were collected at intervals up to 96 hours. In the rat study, no significant urinary excretion of radioactivity was observed. The average recovery of radioactivity in the feces was 98% in the single-dose group and greater than 100% in the group pretreated with unlabelled sevelamer for 28 days. A total of less than 0.1% of the dose was found in the tissues. In the human study, no detectable amount of (14)C was found in the blood of any subject at any time. The majority of subjects had no detectable amounts of (14)C recovered in the urine. In subjects where (14)C was recovered in the urine, less than 0.02% was detected, a level equivalent to the free (14)C detected in the [(14)C]sevelamer preparation. On average, greater than 99% of the administered dose was recovered in the feces of the subjects. These studies demonstrate that sevelamer is a non-absorbed compound.|A mass balance study using (14)C-sevelamer hydrochloride in 16 healthy male and female volunteers showed that sevelamer hydrochloride is not systemically absorbed. No absorption studies have been performed in patients with renal disease.

Sevelamer prevents hyperphosphatemia by binding to dietary phosphate in the gut, preventing its absorption and thus decreasing serum parathyroid hormone levels.

/HUMAN EXPOSURE STUDIES/ Sevelamer hydrochloride, a major phosphate binder for patients on maintenance hemodialysis (MHD) is associated with reduced serum bicarbonate concentration due to hydrochloric acid release in the gut and to the binding of short chain fatty acids in the large intestine. Since metabolic acidosis can be deleterious, a study was devised to compare the time course of serum bicarbonate concentration during treatment with sevelamer hydrochloride or calcium carbonate. Sixteen well nourished patients on MHD who were in excellent clinical conditions and achieving target levels for blood pressure (BP) and hemoglobin (Hb), while on a protein intake of 1.1g/kg body weight (bw), were enrolled in the study. After a 2-week washout period, the patients were divided into two groups, each consisting of eight patients, and randomized either to 24 weeks of sevelamer followed by 24 weeks of calcium carbonate (group A) or to 24 weeks of calcium carbonate followed by 24 weeks of sevelamer (group B). Protein intake, n-protein catabolic rate (nPCR), serum concentrations of calcium, phosphate, calcium x phosphate (Ca x P) product, bicarbonate, intact parathyroid hormone (iPTH) and albumin were monitored. Time course changes in serum bicarbonate concentrations in relation to short and long dialytic intervals (48 vs. 72 hr) were also investigated. Both sevelamer and calcium carbonate effectively controlled serum phosphate and the Ca x P product. During calcium carbonate treatment plasma phosphate concentrations were significantly below those of patients on sevelamer. Plasma bicarbonate concentration fell within target DOQI values during calcium carbonate administration both in group A and in group B, a goal which was not achieved under sevelamer administration. After a long dialytic interval in patients on sevelamer, serum bicarbonate concentration averaged 17.3 +/- 1.1 mEq/L, whereas it averaged 21.1 +/- 0.7 mEq/L in patients on calcium carbonate (p<0.01). Finally, a 24-week sevelamer administration caused a statistically significant (p<0.05) reduction (0.8 g/dL) in serum albumin concentration, without affecting iPTH. Taken together, these results indicate that sevelamer worsens metabolic acidosis, which needs to be corrected. /Sevelamer hydrocholoride/|/CASE REPORTS/ Stercoral ulceration results from impaction of hard fecal mass on the colonic wall and is a relatively unknown cause of lower gastrointestinal bleeding. In this report, we describe a case of lower gastrointestinal bleeding due to stercoral ulceration resulting from Sevelamer, a drug which is commonly associated with constipation.|/EPIDEMIOLOGY STUDIES/ ... A randomized comparison of sevelamer and calcium-based phosphate binders was performed in hemodialysis patients treated up to 45 months. The primary endpoint was mortality. Secondary endpoints included cause-specific mortality and hospitalization; 2103 patients were randomized, 2040 received treatment, and 1065 completed treatment. Overall mortality was not significantly reduced by sevelamer (adjusted relative risk = 0.92; 95% confidence interval, 0.78 to 1.09; log-rank P = .40). Among patients > or = 65 years of age, sevelamer reduced the risk of death (adjusted relative risk = 0.77; 95% confidence interval, 0.62 to 0.97; log-rank P = .02). Sevelamer patients had a trend toward fewer hospitalizations (P = .06) and fewer hospital days (P = .09). A statistically significant reduction in mortality in the overall study population was not observed. Sevelamer was associated with a survival benefit among patients > or = 65 years of age.

Carbonate, Sevelamer

Oral: Tablets, film-coated: 400 mg Renagel, (Genzyme), 800 mg Renagel, (Genzyme)

Follows the general formula of (C3H7N.C3H5ClO)n

Human drugs -> Renagel -> EMA Drug Category|All other therapeutic products -> Human pharmacotherapeutic group