Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse events reported for sevelamer hydrochloride (n=99) were similar to those reported for the active comparator group (n=101). Overall adverse events among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions.

Based on studies of 8-52 weeks, the most common reason for withdrawal from Renagel was gastrointestinal adverse reactions (3-16%).

In one hundred and forty-three peritoneal dialysis patients studied for 8 weeks most adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active control. Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active control group discontinued, mostly for gastrointestinal adverse reactions. Patients on PD should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride (Renagel®): pruritis, rash, abdominal pain, fecal impaction and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

Renagel has been studied in human drug-drug interaction studies with ciprofloxacin, digoxin, warfarin, enalapril, metoprolol and iron.

Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 7 Renagel Capsules (approximately 2.8 g) decreased the bioavailability of ciprofloxacin by approximately 50%.

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.

Other Concomitant Drug Therapy

There are no empirical data on avoiding drug interactions between Renagel® and most concomitant drugs. However, when administering an oral medication where a reduction in bioavailability of the medication would have a clinically significant effect on its 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.

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