Renvela

Genzyme Corporation

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese 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 RECENT MAJOR CHANGES Dosage and Administration (2) (08/2009) INDICATIONS AND USAGE Renvela® is a phosphate binder indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis. (1) DOSAGE AND ADMINISTRATION Starting dose of Renvela is 0.8 or 1.6 grams administered orally three times per day with meals. (2.1) 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) Switch gram-for-gram among sevelamer formulations. Further titration may be necessary to achieve desired phosphorus levels. (2.1) DOSAGE FORMS AND STRENGTHS Tablets: 800 mg (3) Powder: 0.8 g and 2.4 g packet (3) CONTRAINDICATIONS Bowel obstruction. (4) WARNINGS AND PRECAUTIONS Serious cases of dysphagia, bowel obstruction, and perforation have been associated with sevelamer use, some requiring hospitalization and surgery. (5.1) Side Effects 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) 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 Sevelamer decreases the bioavailability of ciprofloxacin by approximately 50%. (7.1) Sevelamer did not alter the pharmacokinetics of single doses of digoxin, warfarin, enalapril, metoprolol, or iron. (7) 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, administer the drug at least one hour before or three hours after Renvela, and monitor blood levels of the drug. (7.7)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 RENVELA INDICATIONS AND USAGE
• 2 RENVELA DOSAGE AND ADMINISTRATION
  • 2.1 General Dosing Information
  • 2.2 Sevelamer Carbonate Powder Preparation Instructions
• 3 DOSAGE FORMS AND STRENGTHS
• 4 RENVELA CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Gastrointestinal Adverse Events
  • 5.2 Monitor Serum Chemistries
  • 5.3 Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid Levels
• 6 RENVELA ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Ciprofloxacin
  • 7.2 Digoxin
  • 7.3 Warfarin
  • 7.4 Enalapril
  • 7.5 Metoprolol
  • 7.6 Iron
  • 7.7 Other Concomitant Drug Therapy
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 RENVELA DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Developmental Toxicity
• 14 CLINICAL STUDIES
  • 14.1 Cross-Over Study of Sevelamer Carbonate (Renvela) 800 mg Tablets and Sevelamer Hydrochloride (Renagel) 800 mg Tablets
  • 14.2 Cross-Over Study of Sevelamer Carbonate (Renvela) Powder and Sevelamer Hydrochloride (Renagel) Tablets
  • 14.3 Sevelamer Hydrochloride Versus Active-Control, Cross-Over Study in Hemodialysis Patients
  • 14.4 Sevelamer Hydrochloride Versus Active-Control in Hemodialysis Patients
  • 14.5 Sevelamer Hydrochloride Versus Active-Control in Peritoneal Dialysis Patients
  • 14.6 Once a Day Versus Three Times a Day Dosing
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Dosing
  • 17.2 Adverse Reactions

FULL PRESCRIBING INFORMATION

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

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.

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 2.8 grams of sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50%.

7.2 Digoxin

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.

7.3 Warfarin

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.

7.4 Enalapril

In 28 healthy subjects a single 2.4 gram dose of sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of enalapril.

7.5 Metoprolol

In 31 healthy subjects a single 2.4 gram dose of sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of metoprolol.

7.6 Iron

In 23 healthy subjects, a single 2.8 gram dose of sevelamer hydrochloride did not alter the absorption of a single oral dose of iron as 200 mg exsiccated ferrous sulfate tablet.

7.7 Other Concomitant Drug Therapy

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.

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.

8.5 Geriatric Use

Clinical studies of Renvela did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

10 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.

11 DESCRIPTION

The active ingredient in   Renvela 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- co -N,N’-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. Sevelamer carbonate is hygroscopic, but insoluble in water. The structure is represented in Figure 1.

Figure 1. Chemical Structure of Sevelamer Carbonate

a, b = number of primary amine groups     a + b = 9
c = number of crosslinking groups            c = 1
m = large number to indicate extended polymer network

Renvela^® Tablets: Each film-coated tablet of Renvela contains 800 mg of sevelamer carbonate on an anhydrous basis. The inactive ingredients are hypromellose, diacetylated monoglycerides, microcrystalline cellulose, sodium chloride and zinc stearate. The tablet imprint contains iron oxide black ink.

Renvela ^® Powder: Each packet of Renvela Powder contains 0.8 g or 2.4 g of sevelamer carbonate on an anhydrous basis. The inactive ingredients are natural and artificial citrus flavor, propylene glycol alginate, sodium chloride, sucralose, and ferric oxide (yellow).

12 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 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.

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.

12.1 Mechanism of Action

Renvela contains sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum phosphorus).

12.2 Pharmacodynamics

In addition to effects on serum phosphorus levels, sevelamer hydrochloride has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. Because sevelamer binds bile acids, it may interfere with normal fat absorption and thus may reduce absorption of fat soluble vitamins such as A, D and K. In clinical trials of sevelamer hydrochloride, both the mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks. Triglycerides, HDL cholesterol and albumin did not change.

12.3 Pharmacokinetics

A mass balance study using ¹⁴C-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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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.

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).

13.2 Developmental Toxicity

In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid- and high-dose groups (human equivalent doses approximately equal to 3-4 times the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100, 500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinical trial dose).

14 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).

14.1 Cross-Over Study of Sevelamer Carbonate (Renvela) 800 mg Tablets and Sevelamer Hydrochloride (Renagel) 800 mg Tablets

Stage 5 CKD patients on hemodialysis were entered into a five-week sevelamer hydrochloride run-in period and 79 patients received, in random order, sevelamer carbonate 800 mg tablets and sevelamer hydrochloride 800 mg tablets for eight weeks each, with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6 g/day divided among meals for both treatments. Thirty-nine of those completing the cross-over portion of the study were entered into a two-week washout period during which patients were instructed not to take any phosphate binders; this confirmed the activity of sevelamer in this study.

14.2 Cross-Over Study of Sevelamer Carbonate (Renvela) Powder and Sevelamer Hydrochloride (Renagel) Tablets

Stage 5 CKD patients on hemodialysis were entered into a four-week sevelamer hydrochloride run-in period and 31 patients received, in random order, sevelamer carbonate powder and sevelamer hydrochloride tablets for four weeks each with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6.0 g/day divided among meals for sevelamer carbonate powder and 6.4 g/day divided among meals for sevelamer hydrochloride tablets.

14.3 Sevelamer Hydrochloride Versus Active-Control, Cross-Over Study in Hemodialysis Patients

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 (Table 4).

The distribution of responses is shown in Figure 2. 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.

Figure 2. Percentage of patients (Y-axis) attaining a phosphorus reduction from baseline (mg/dL) at least as great as the value of the X-axis.

Average daily sevelamer hydrochloride dose at the end of treatment was 4.9 g (range of 0.0 to 12.6 g).

14.4 Sevelamer Hydrochloride Versus Active-Control in Hemodialysis Patients

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 (Table 5).

Sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment.

Figure 3, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment.

Figure 3. Mean Phosphorus Change from Baseline for Patients who Completed 52 Weeks of Treatment

Average daily sevelamer hydrochloride dose at the end of treatment was 6.5 g (range of 0.8 to 13 g).

14.5 Sevelamer Hydrochloride Versus Active-Control in Peritoneal Dialysis Patients

One hundred and forty-three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride (N=97) or active-control (N=46) open label for 12 weeks. Average daily sevelamer hydrochloride dose at the end of treatment was 5.9 g (range 0.8 to 14.3 g). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. There were statistically significant changes in serum phosphorus (p<0.001) for sevelamer hydrochloride (-1.6 mg/dL from baseline of 7.5 mg/dL), similar to the active-control.

14.6 Once a Day Versus Three Times a Day Dosing

Stage 5 CKD patients on hemodialysis with a serum phosphate level of > 5.5 mg/dL after washout from baseline therapies were randomized in a 2:1 ratio to receive either sevelamer carbonate powder once-daily (N=144) or sevelamer hydrochloride as a tablet with the dose divided three times per day (N=73) for 24 weeks. The initial dose for the two groups was 4.8 g/day. At the end of the study, the total daily dose was 6.2 g/day of sevelamer carbonate powder once daily and 6.7 g/day of sevelamer hydrochloride tablets three times per day. A greater percentage of subjects on the once daily dose than three times per day regimen discontinued therapy prematurely, 35% versus 15%. The reasons for discontinuation were largely driven by adverse events and withdrawal of consent in the once daily dosing regimen. Serum phosphate levels and calcium-phosphate product were better controlled on the three times per day regimen than on the once daily regimen. Mean serum phosphorus decreased 2.0 mg/dL for sevelamer carbonate powder once daily and 2.9 mg/dL for sevelamer hydrochloride tablets three times per day.

16 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)

Storage: Store at 25°C (77°F): excursions permitted to 15-30°C (59-86°F).
[See USP controlled room temperature]
Protect from moisture.

17 PATIENT COUNSELING INFORMATION

17.1 Dosing

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.

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 6 .

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.

17.2 Side Effects

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

Package Label - Principal Display Panel - 800 mg Tablets, 270 per Bottle

Renvela®

sevelamer carbonate

tablets

800 mg

270 film-coated tablets

Rx Only

USUAL DOSAGE:
SEE PACKAGE INSERT
FOR DOSAGE INFORMATION.

NDC 58468-0130-1

Manufactured by:
Genzyme Ireland Ltd.
For: Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142 USA

Package Label - Principal Display Panel - 2.4 g Packets, 90 per Carton

NDC 58468-0131-2

Renvela®

sevelamer carbonate

For oral suspension

2.4 g packets

Citrus Flavor

Package Label - Principal Display Panel - 0.8 g Packets, 90 per Carton

NDC 58468-0132-2

Renvela®

sevelamer carbonate

For oral suspension

0.8 g packets

Citrus Flavor