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Renvela (sevelamer carbonate) For Oral Suspension
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Renvela safely and effectively. See full prescribing information for Renvela.
Renvela (sevelamer carbonate) Tablet, Film Coated for Oral use
Renvela (sevelamer carbonate) For Oral Suspension
Initial U.S. Approval: 2000
INDICATIONS AND USAGE
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Renvela® is a phosphate binder indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis. (1)
DOSAGE AND ADMINISTRATION
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Starting dose of Renvela is 0.8 or 1.6 grams administered orally three times per day with meals. (2.1)
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Titrate by 0.8 g per meal in two week intervals as needed to obtain serum phosphorus target (3.5 to 5.5 mg/dL). (2.1)
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Switch gram-for-gram among sevelamer formulations. Further titration may be necessary to achieve desired phosphorus levels. (2.1)
DOSAGE FORMS AND STRENGTHS
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Tablets: 800 mg (3)
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Powder: 0.8 g and 2.4 g packet (3)
WARNINGS AND PRECAUTIONS
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Serious cases of dysphagia, bowel obstruction, and perforation have been associated with sevelamer use, some requiring hospitalization and surgery. (5.1)
ADVERSE REACTIONS
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Most of the safety experience is with sevelamer tablets. The most frequently occurring adverse reactions in a short term study with sevelamer carbonate tablets (8-week cross-over) study were: nausea (3%) and vomiting (3%). In a short term study of sevelamer carbonate powder, adverse events were similar to those reported for sevelamer carbonate tablets. In long-term studies with sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, the most common adverse events included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). (6.1)
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Cases of fecal impaction and, less commonly, ileus, bowel obstruction and bowel perforation have been reported. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-847-0069 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
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When clinically significant drug interactions are expected, consider separation of the timing of administration and/or monitor clinical responses or blood levels of the concomitant medication. (7)
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Sevelamer did not alter the pharmacokinetics of digoxin, enalapril, iron, metoprolol and warfarin. (7)
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Sevelamer has demonstrated interaction with ciprofloxacin, mycophenolate mofetil, and therefore these drugs should be dosed separately from Renvela. (7)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
Renvela® (sevelamer carbonate) is indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis.
2 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.
2.1 General Dosing Information
Renvela should be given three times a day with meals.
Patients Not Taking a Phosphate Binder. The recommended starting dose of Renvela is 0.8 to 1.6 g with meals based on serum phosphorus level. Table 1 provides recommended starting doses of Renvela for patients not taking a phosphate binder.
Switching from Sevelamer Hydrochloride Tablets. For patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. The highest daily dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis.
Switching between Sevelamer Carbonate Tablets and Powder. Use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels.
Switching from Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride and calcium acetate. Table 2 gives recommended starting doses of Renvela based on a patient's current calcium acetate dose.
Dose Titration for All Patients Taking Renvela. Titrate the Renvela dose by 0.8 g three times per day with meals at two-week intervals as necessary with the goal of controlling serum phosphorus within the target range.
2.2 Sevelamer Carbonate Powder Preparation Instructions
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 Table 3.
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.
3 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
4 CONTRAINDICATIONS
Renvela is contraindicated in patients with bowel obstruction.
5 WARNINGS AND PRECAUTIONS
5.1 Gastrointestinal Adverse Events
Cases of dysphagia and esophageal tablet retention have been reported in association with use of the tablet formulation of sevelamer, some requiring hospitalization and intervention. Consider using sevelamer suspension in patients with a history of swallowing disorders.
Cases of bowel obstruction and perforation have also been reported with sevelamer use.
Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including severe constipation, or major GI tract surgery were not included in the Renvela clinical studies.
5.2 Monitor Serum Chemistries
Bicarbonate and chloride levels should be monitored.
5.3 Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid Levels
In preclinical studies in rats and dogs, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, reduced vitamins D, E, and K (coagulation parameters) and folic acid levels at doses of 6–10 times the recommended human dose. In short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. However, in a one-year clinical trial, 25-hydroxyvitamin D (normal range 10 to 55 ng/mL) fell from 39 ± 22 ng/mL to 34 ± 22 ng/mL (p<0.01) with sevelamer hydrochloride treatment. Most (approximately 75%) patients in sevelamer hydrochloride clinical trials received vitamin supplements, which is typical of patients on dialysis.
6 ADVERSE REACTIONS
6.1 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.
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.
6.2 Postmarketing Experience
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.
7 DRUG INTERACTIONS
There are no empirical data on avoiding drug interactions between Renvela and most concomitant oral drugs. For oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy (e.g., cyclosporine, tacrolimus, levothyroxine), consider separation of the timing of the administration of the two drugs [see Clinical Pharmacology (12.3)]. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Where possible consider monitoring clinical responses and/or blood levels of concomitant drugs that have a narrow therapeutic range.
During postmarketing experience, cases of increased phosphate levels have been reported in patients taking proton pump inhibitors co-administered with sevelamer carbonate.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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 [see Nonclinical Toxicology (13.2)].
8.2 Labor and Delivery
No sevelamer hydrochloride treatment-related effects on labor and delivery were seen in animal studies [see Nonclinical Toxicology (13)]. The effects of sevelamer carbonate on labor and delivery in humans is unknown.
8.4 Pediatric Use
The safety and efficacy of Renvela has not been established in pediatric patients.
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