PRECAUTIONS
General: The safety and efficacy of Renagel in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, or major GI tract surgery have not been established. Consequently, caution should be exercised when Renagel is used in patients with these GI disorders.
Renagel does not contain calcium or alkali supplementation; serum calcium, bicarbonate, and chloride levels should be monitored.
In preclinical studies in rats and dogs, sevelamer hydrochloride reduced vitamin D, E, K, and folic acid levels at doses of 6-100 times the recommended human dose. In clinical trials, there was no evidence of reduction in serum levels of vitamins with the exception of a one year clinical trial in which Renagel treatment was associated with reduction of 25-hydroxyvitamin D (normal range 10 to 55 mcg/mL) from 39 ± 22 mcg/mL to 34 ± 22 mcg/mL (p<0.01). Most (approximately 75%) patients in Renagel clinical trials received vitamin supplements, which is typical of patients on hemodialysis.
Information for the patient: The prescriber should inform patients to take Renagel with meals and adhere to their prescribed diets. Instructions should be given on concomitant medications that should be dosed apart from Renagel. Because the contents of Renagel expand in water, tablets should be swallowed intact and should not be crushed, chewed, broken into pieces, or taken apart prior to administration. Drug interactions: Renagel Capsules were studied in human drug-drug interaction studies with digoxin, warfarin, enalapril metoprolol and iron.
Digoxin: In 19 healthy subjects receiving 6 Renagel capsules three times a day with meals for 2 days, Renagel did not alter the pharmacokinetics of a single dose of digoxin.
Warfarin: In 14 healthy subjects receiving 6 Renagel capsules three times a day with meals for 2 days, Renagel did not alter the pharmacokinetics of a single dose of warfarin. Enalapril: In 28 healthy subjects a single dose of 6 Renagel capsules did not alter the pharmacokinetics of a single dose of enalapril. Metoprolol: In 31 healthy subjects a single dose of 6 Renagel capsules did not alter the pharmacokinetics of a single dose of metoprolol. Iron: In 23 healthy subjects, a single dose of 7 Renagel capsules did not alter the absorption of a single oral dose of iron as 200 mg exsiccated ferrous sulfate tablet.
However, when administering any other oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on safety or efficacy, the drug should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels of the drug. Patients taking anti-arrhythmic and anti-seizure medications were excluded from the clinical trials. Special precautions should be taken when prescribing Renagel to patients also taking these medications. Carcinogenesis, mutagenesis, and impairment of fertility: Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given sevelamer hydrochloride by diet at 0.3, 1, 3 g/kg/day. There was an increased incidence of urinary bladder transitional cell papilloma in male rats (3 g/kg/day) at exposures 2 times the maximum human oral dose of 13 g, based on a comparison of relative body surface area. Mice received mean dietary doses of 0.8, 3, 9 g/kg/day. Increased incidence of tumors was not observed in mice at exposures up to 3 times the maximum human oral dose of 13g, based on a comparison of relative body surface area.
In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay.
In a study designed to assess potential impairment of fertility, female rats were given dietary doses of 0.5, 1.5, 4.5 g/kg/day beginning 14 days prior to mating and continuing through gestation. Male rats were given the same doses and treated for 28 days before mating. Sevelamer hydrochloride did not impair fertility in male or female rats at exposures 3 times the maximum human oral dose of 13 g, based on a comparison of relative body surface area.
PREGNANCY:
PREGNANCY CATEGORY C
In pregnant rats given dietary doses of 0.5, 1.5, 4.5 g/kg/day during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D occurred in the mid and high dose groups (exposures less than the maximum human dose of 13g, based on a comparison of relative body surface area). In pregnant rabbits given oral doses of 100, 500, 1000 mg/kg/day by gavage during organogenesis an increased incidence of early resorptions occurred at exposures 2 times the maximum human dose of 13 g, based on a comparison of relative body surface area. Requirements for vitamins and other nutrients are increased in pregnancy. The effect of Renagel on the absorption of vitamins and other nutrients has not been studied in pregnant women. Geriatric use: There is no evidence for special considerations when Renagel is administered to elderly patients. Pediatric use: The safety and efficacy of Renagel has not been established in pediatric patients.
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