Renvela Information
Renvela () Indications And Usage
Renvela () (sevelamer carbonate) is indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis.
Renvela () Dosage And Administration
Because of the rapid reaction with the hydrochloric acid in the stomach, the dosing of Renvela () powder or tablet is anticipated to be similar to that of the sevelamer hydrochloride salt or tablet.
Renvela () should be given three times a day with meals.
Table 1
Table 2
The entire contents of each 0.8 or 2.4 g packet should be placed in a cup and mixed thoroughly with the amount of water described in .
Multiple packets may be mixed together with the appropriate amount of water. Patients should be instructed to stir the mixture vigorously (it does not dissolve) and drink the entire preparation within 30 minutes and resuspend the preparation right before drinking.
Based on clinical studies, the average prescribed daily dose of sevelamer carbonate is approximately 7.2 g per day.
Renvela () Dosage Forms And Strengths
Tablets: 800 mg white oval, film-coated, compressed tablets imprinted with “Renvela () 800”
Powder: 0.8 g and 2.4 g pale yellow powder packaged in an opaque, foil lined, heat sealed packet
Renvela () Contraindications
Renvela () is contraindicated in patients with bowel obstruction.
Renvela () Adverse Reactions
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.
There are limited data on the safety of Renvela () . However, based on the fact that it contains the same active ingredient as the hydrochloride salt, the adverse event profiles of the two salts should be similar. In a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout the adverse reactions on sevelamer carbonate tablets were similar to those reported for sevelamer hydrochloride. In another cross-over study in hemodialysis patients, with treatment durations of four weeks each and no washout between treatment periods, the adverse reactions on sevelamer carbonate powder were similar to those reported for sevelamer hydrochloride.
In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-comparator group (n=101). Overall adverse reactions 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 sevelamer hydrochloride was gastrointestinal adverse reactions (3-16%).
In one hundred and forty-three peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, 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 peritoneal dialysis 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.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.
The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride, which has the same active moiety as sevelamer carbonate: pruritus, 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.
Renvela () Drug Interactions
Sevelamer carbonate has been studied in human drug-drug interaction studies with warfarin and digoxin. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been studied in human drug-drug interaction studies with ciprofloxacin, digoxin, warfarin, enalapril, metoprolol and iron.
In 19 healthy subjects receiving 2.4 grams of sevelamer hydrochloride three times a day with meals for 2 days, sevelamer did not alter the pharmacokinetics of a single dose of digoxin.
In 18 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of digoxin.
In 14 healthy subjects receiving 2.4 g of sevelamer hydrochloride three times a day with meals for two days sevelamer did not alter the pharmacokinetics of a single dose of warfarin.
In 14 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of warfarin.
There are no empirical data on avoiding drug interactions between Renvela () and most concomitant drugs. During postmarketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Monitor TSH levels and signs of hypothyroidism in patients receiving both medications.
When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, there is no information that suggests a dosing regimen that would be universally appropriate for all drugs. One may, however, administer the drug one hour before or three hours after Renvela () , and monitor blood levels of the drug. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials.
Renvela () Use In Specific Populations
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Sevelamer products should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The effect of sevelamer hydrochloride on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. In pregnant rats given doses of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred at a dose approximately equal to the maximum clinical trial dose of 13 g on a body surface area basis. In pregnant rabbits given oral doses of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred at dose approximately twice the maximum clinical trial dose on a body surface area basis .
Renvela () Overdosage
Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been given to normal healthy volunteers in doses of up to 14 grams per day for eight days with no adverse effects. In CKD patients on dialysis, the maximum dose studied was 14 grams of sevelamer carbonate and 13 grams of sevelamer hydrochloride. There are no reports of overdosage with sevelamer carbonate or sevelamer hydrochloride in patients. Since sevelamer is not absorbed, the risk of systemic toxicity is low.
Renvela () Description
The active ingredient inRenvela () is sevelamer carbonate, a polymeric amine that binds phosphate and is meant for oral administration. It was developed as a pharmaceutical alternative to sevelamer hydrochloride (Renagel). Sevelamer carbonate is an anion exchange resin, with the same polymeric structure as sevelamer hydrochloride, in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer itself, the active moiety involved in phosphate binding, is the same.
Renvela () (sevelamer carbonate) is known chemically as poly(allylamine--N,N’-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. Sevelamer carbonate is hygroscopic, but insoluble in water. The structure is represented in .
a, b = number of primary amine groups a + b = 9c = number of crosslinking groups c = 1m = large number to indicate extended polymer network
Renvela () Clinical Pharmacology
Patients with chronic kidney disease (CKD) retain phosphorus and can develop hyperphosphatemia. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 55 mg/dL, there is an increased risk that ectopic calcification will occur. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency.
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 carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis.
Renvela () Nonclinical Toxicology
Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There was an increased incidence of urinary bladder transitional cell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trial dose of 13 g). Mice received dietary administration of sevelamer hydrochloride at doses of up to 9 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose). There was no increased incidence of tumors observed in mice.
In an 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.
Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration study in which the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating. The highest dose in this study was 4.5 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 g).
Renvela () Clinical Studies
The ability of sevelamer to control serum phosphorus in CKD patients on dialysis was predominantly determined from the effects of the hydrochloride salt to bind phosphate. Six clinical trials used sevelamer hydrochloride and three clinical trials used sevelamer carbonate. The sevelamer hydrochloride studies include one double-blind, placebo-controlled 2-week study (sevelamer N=24); two open-label, uncontrolled, 8-week studies (sevelamer N=220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (sevelamer N=256). The sevelamer carbonate studies include one double-blind, active-controlled, cross-over study with two 8-week treatment periods using sevelamer carbonate tablets (N=79), one open-label, active-controlled, cross-over study with two 4-week treatment periods using sevelamer carbonate powder (N=31) and one randomized, parallel, open-label study using sevelamer carbonate powder (N=144) dosed once daily or sevelamer hydrochloride tablets (N=73) dosed three times daily for 24 weeks. Six of the active-controlled studies are described here (three sevelamer carbonate and three sevelamer hydrochloride studies).
Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6.0 mg/dL) following a two-week phosphate binder washout period were randomized in a cross-over design to receive in random order sevelamer hydrochloride and active-control for eight weeks each. Treatment periods were separated by a two-week phosphate binder washout period. Patients started on treatment three times per day with meals. Over each eight-week treatment period, at three separate time points the dose of sevelamer hydrochloride could be titrated up to control serum phosphorus, the dose of active-control could also be altered to attain phosphorus control. Both treatments significantly decreased mean serum phosphorus by about 2 mg/dL ().
The distribution of responses is shown in . The distributions are similar for sevelamer hydrochloride and active control. The median response is a reduction of about 2 mg/dL in both groups. About 50% of subjects have reductions between 1 and 3 mg/dL.
Average daily sevelamer hydrochloride dose at the end of treatment was 4.9 g (range of 0.0 to 12.6 g).
Two hundred CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride 800 mg tablets (N=99) or an active-control (N=101). At week 52, using last-observation-carried-forward, sevelamer and active-control both significantly decreased mean serum phosphorus ().
Sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment.
Figure 3
Average daily sevelamer hydrochloride dose at the end of treatment was 6.5 g (range of 0.8 to 13 g).
Renvela () How Supplied/storage And Handling
Tablets: Renvela () 800 mg Tablets are supplied as white oval, film-coated, compressed tablets, imprinted with “Renvela () 800”, containing 800 mg of sevelamer carbonate on an anhydrous basis, microcrystalline cellulose, hypromellose, diacetylated monoglycerides, sodium chloride, and zinc stearate.
1 Bottle of 30 ct 800 mg Tablets (NDC 58468-0130-2)
1 Bottle of 270 ct 800 mg Tablets (NDC 58468-0130-1)
Powder: Renvela () for Oral Suspension is supplied as opaque, foil lined, heat sealed, packets containing 0.8 g or 2.4 g of sevelamer carbonate on an anhydrous basis, natural and artificial citrus flavor, propylene glycol alginate, sodium chloride, sucralose, and ferric oxide (yellow).
1 Box (NDC 58468-0131-2) of 90 ct 2.4 g packets (NDC 58468-0131-1)
1 Box (NDC 58468-0132-2) of 90 ct 0.8 g packets (NDC 58468-0132-1)
1 Sample Box (NDC 58468-0131-4) of 90 ct 2.4 g packets (NDC 58468-0131-3)
1 Sample Box (NDC 58468-0131-5) of 15 ct 2.4 g packets (NDC 58468-0131-3)
Renvela () Patient Counseling Information
Inform patients to take Renvela () as directed with meals and adhere to their prescribed diets.
For patients using an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, advise the patient to take the oral medication at least one hour before or three hours after Renvela () . Blood levels of the oral medication should be monitored, if applicable, to determine if there is a significant interaction between the oral medication and Renvela () .
For Renvela () powder, brief the patient on preparation of the powder in water.
The entire contents of each 0.8 or 2.4 g packet should be placed in a cup and mixed thoroughly with the amount of water described in .
Multiple packets may be mixed together with the appropriate amount of water. Patients should be instructed that the powder does not dissolve and therefore it should be stirred vigorously just before drinking. The entire preparation should be consumed within 30 minutes.
Renvela () may cause constipation that if left untreated, may lead to severe complications. Patients should be cautioned to report new onset or worsening of existing constipation promptly to their physician.
Distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142 USA
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