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Genzymeclinicalresearch.com

Renagel® Tablets
(sevelamer hydrochloride)

------------------------------ADVERSE REACTIONS-------------------------------
The most common reasons for discontinuing treatment weregastrointestinal adverse reactions. (6.1) In a parallel design study, of 12 weeks duration, treatment emergentadverse reactions to Renagel Tablets in peritoneal dialysis patients HIGHLIGHTS OF PRESCRIBING INFORMATION
included dyspepsia (12%), peritonitis (8%), diarrhea (5%), nausea (5%),constipation (4%), pruritus (4%), abdominal distension (3%), vomiting These highlights do not include all the information needed to use Renagel
(3%), fatigue (3%), anorexia (3%), and arthralgia (3%). (6.1) safely and effectively.
Similar reactions at similar rates occurred in hemodialysis and peritoneal See full prescribing information for Renagel.
Renagel (sevelamer hydrochloride) Tablet for Oral use
Cases of fecal impaction and, less commonly, ileus, bowel obstruction, Initial U.S. Approval: 2000
and bowel perforation have been reported. (6.2) ----------------------------INDICATIONS AND USAGE---------------------------
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation
at 1-800-847-0069 and or FDA at 1-800-FDA-1088 or

Renagel® is a phosphate binder indicated for the control of serum www.fda.gov/medwatch
phosphorus in patients with chronic kidney disease on dialysis. (1) ------------------------------DRUG INTERACTIONS-------------------------------
----------------------DOSAGE AND ADMINISTRATION-----------------------
Decreases the bioavailability of ciprofloxacin by approximately 50%. (7.1) Starting dose is one or two 800 mg or two to four 400 mg tablets threetimes per day with meals. (2) In normal volunteer studies, sevelamer hydrochloride did not alter thepharmacokinetics of a single dose of digoxin, warfarin, enalapril, Adjust by one tablet per meal in two week intervals as needed to obtain serum phosphorus target (3.5 to 5.5 mg/dL). (2) During postmarketing experience, very rare cases of increased TSH levels ---------------------DOSAGE FORMS AND STRENGTHS----------------------
have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is thereforerecommended in patients receiving both medications. (7.7) ---------------------------CONTRAINDICATIONS----------------------------------
When administering an oral medication where a reduction in the In patients with hypophosphatemia or bowel obstruction. (4) bioavailability of that medication would have a clinically significant effect -----------------------WARNINGS AND PRECAUTIONS------------------------
on its safety or efficacy, the drug should be administered at least one hourbefore or three hours after Renagel, or the physician should consider The safety and efficacy of Renagel in patients with dysphagia, swallowing monitoring blood levels of the drug. (7.7) disorders, severe GI motility disorders including severe constipation, ormajor GI tract surgery have not been established. Caution should be See 17 for PATIENT COUNSELING INFORMATION
exercised when Renagel is used in patients with these GI disorders. (5.1) Revised: 11/2007
FULL PRESCRIBING INFORMATION: CONTENTS*
10 OVERDOSAGE
11 DESCRIPTION

1 INDICATIONS AND USAGE
12 CLINICAL PHARMACOLOGY
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
13 NONCLINICAL TOXICOLOGY
5.1 Use Caution in Patients with Gastrointestinal Disorders 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES
5.3 Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic 14.1 Active-Control, Cross-Over Study in Hemodialysis Patients 14.2 Active-Control, Parallel Study in Hemodialysis Patients 6 ADVERSE REACTIONS
14.3 Active-Control, Parallel Study in Peritoneal Dialysis Patients 16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
7 DRUG INTERACTIONS
*Sections or subsections omitted from the full prescribing information 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
Renagel® Tablets
Renagel® Tablets
(sevelamer hydrochloride)
(sevelamer hydrochloride)
1. INDICATIONS AND USAGE
5.3 Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid
Levels

RENAGEL®1 (sevelamer hydrochloride) is indicated for the control of serumphosphorus in patients with chronic kidney disease (CKD) on dialysis. The In preclinical studies in rats and dogs, sevelamer hydrochloride reduced vita- safety and efficacy of Renagel in CKD patients who are not on dialysis have not mins 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 noevidence of reduction in serum levels of vitamins. However, in a one-year clin- 2. DOSAGE AND ADMINISTRATION
ical trial, 25-hydroxyvitamin D (normal range 10 to 55 ng/mL) fell from 39 ± 22 Patients Not Taking a Phosphate Binder. The recommended starting dose of ng/mL to 34 ± 22 ng/mL (p<0.01) with sevelamer hydrochloride treatment.
Renagel is 800 to 1600 mg, which can be administered as one or two 800 mg Most (approximately 75%) patients in sevelamer hydrochloride clinical trials Renagel® Tablets or two to four 400 mg Renagel® Tablets, with meals based on received vitamin supplements, which is typical of patients on dialysis.
serum phosphorus level. Table 1 provides recommended starting doses of 6. ADVERSE REACTIONS
Renagel for patients not taking a phosphate binder.
6.1 Clinical Trials Experience
Table 1. Starting Dose for Dialysis Patients Not Taking a Phosphate Binder
Because clinical trials are conducted under widely varying conditions, adverse Serum Phosphorus
Renagel® 800 mg
Renagel® 400 mg
reaction rates observed in the clinical trials of a drug can not be directly 1 tablet three times daily 2 tablets three times daily 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 2 tablets three times daily 3 tablets three times daily with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-controlgroup (n=101). Overall adverse reactions among those treated with sevelamer 2 tablets three times daily 4 tablets three times daily 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 Switching From Calcium Acetate. In a study in 84 CKD patients on patients treated with comparator withdrew from the study due to adverse reac- hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of Renagel and calcium acetate.
Table 2 gives recommended starting doses of Renagel based on a patient’s Based on studies of 8-52 weeks, the most common reason for withdrawal from Renagel was gastrointestinal adverse reactions (3-16%).
Table 2. Starting Dose for Dialysis Patients Switching From Calcium Acetate
In one hundred and forty-three peritoneal dialysis patients studied for 12 weeks to Renagel
most adverse reactions were similar to adverse reactions observed in hemodial-ysis patients. The most frequently occurring treatment emergent serious Calcium Acetate 667 mg
Renagel® 800 mg
Renagel® 400 mg
adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer (Tablets per meal)
(Tablets per meal)
(Tablets per meal)
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 peri- toneal dialysis should be closely monitored to ensure the reliable use of appro-priate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis.
6.2 Postmarketing Experience
Dose Titration for All Patients Taking Renagel. Dosage should be adjusted The following adverse reactions have been identified during post-approval use based on the serum phosphorus concentration with a goal of lowering serum of sevelamer hydrochloride (Renagel®): pruritus, rash, abdominal pain, fecal phosphorus to 5.5 mg/dL or less. The dose may be increased or decreased by impaction and uncommon cases of ileus, intestinal obstruction, and intestinal one tablet per meal at two week intervals as necessary. Table 3 gives a dose perforation. Appropriate medical management should be given to patients who titration guideline. The average dose in a Phase 3 trial designed to lower serum develop constipation or have worsening of existing constipation to avoid severe phosphorus to 5.0 mg/dL or less was approximately three Renagel 800 mg tablets per meal. The maximum average daily Renagel dose studied was 13grams.
Because these reactions are reported voluntarily from a population of uncertainsize, it is not always possible to estimate their frequency or to establish a causal Table 3. Dose Titration Guideline
7. DRUG INTERACTIONS
Serum Phosphorus
Renagel® Dose
Renagel has been studied in human drug-drug interaction studies with Increase 1 tablet per meal at 2 week intervals ciprofloxacin, digoxin, warfarin, enalapril, metoprolol and iron.
7.1 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 byapproximately 50%.
3. DOSAGE FORMS AND STRENGTHS
7.2 Digoxin
In 19 healthy subjects receiving 6 Renagel capsules three times a day with 4. CONTRAINDICATIONS
meals for 2 days, Renagel did not alter the pharmacokinetics of a single dose ofdigoxin.
Renagel is contraindicated in patients with hypophosphatemia or bowelobstruction.
7.3 Warfarin
5. WARNINGS AND PRECAUTIONS
In 14 healthy subjects receiving 6 Renagel capsules three times a day withmeals for 2 days, Renagel did not alter the pharmacokinetics of a single dose of 5.1 Use Caution in Patients with Gastrointestinal Disorders
The safety of Renagel has not been established in patients with dysphagia, 7.4 Enalapril
swallowing disorders, severe gastrointestinal (GI) motility disorders includingsevere constipation, or major GI tract surgery. Use caution in patients with In 28 healthy subjects a single dose of 6 Renagel capsules did not alter the pharmacokinetics of a single dose of enalapril.
5.2 Monitor Serum Chemistries
7.5 Metoprolol
Bicarbonate and chloride levels should be monitored.
In 31 healthy subjects a single dose of 6 Renagel capsules did not alter thepharmacokinetics of a single dose of metoprolol.
Renagel® Tablets
Renagel® Tablets
(sevelamer hydrochloride)
(sevelamer hydrochloride)
The primary amine groups shown in the structure are derived directly frompoly(allylamine hydrochloride). The crosslinking groups consist of two In 23 healthy subjects, a single dose of 7 Renagel capsules did not alter the secondary amine groups derived from poly(allylamine hydrochloride) and one absorption of a single oral dose of iron as 200 mg exsiccated ferrous sulfate Renagel® Tablets: Each film-coated tablet of Renagel contains either 800 mg
7.7 Other Concomitant Drug Therapy
or 400 mg of sevelamer hydrochloride on an anhydrous basis. The inactive There are no empirical data on avoiding drug interactions between Renagel® ingredients are hypromellose, diacetylated monoglyceride, colloidal silicon and most concomitant drugs. During postmarketing experience, very rare dioxide, and stearic acid. The tablet imprint contains iron oxide black ink.
cases of increased thyroid stimulating hormone (TSH) levels have been 12. CLINICAL PHARMACOLOGY
reported in patients co-administered sevelamer hydrochloride and levothy-roxine. Closer monitoring of TSH levels is therefore recommended in patients Patients with chronic kidney disease (CKD) on dialysis retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitateserum calcium resulting in ectopic calcification. When the product of serum When administering an oral medication where a reduction in the bioavailability calcium and phosphorus concentrations (Ca x P) exceeds 55 mg2/dL2, there is of that medication would have a clinically significant effect on its safety or effi- an increased risk that ectopic calcification will occur. Hyperphosphatemia plays cacy, the drug should be administered at least one hour before or three hours a role in the development of secondary hyperparathyroidism in renal insuffi- after Renagel, or the physician should consider monitoring blood levels of the drug. Patients taking anti- arrhythmic medications for the control of arrhyth-mias and anti-seizure medications for the control of seizure disorders were Treatment of hyperphosphatemia includes reduction in dietary intake of phos- excluded from the clinical trials. Special precautions should be taken when phate, inhibition of intestinal phosphate absorption with phosphate binders, and prescribing Renagel to patients also taking these medications.
removal of phosphate with dialysis. Renagel taken with meals has been shownto decrease serum phosphorus concentrations in patients with CKD who are on 8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
12.1 Mechanism of Action
Pregnancy Category C: The effect of Renagel on the absorption of vitamins and Renagel contains sevelamer hydrochloride, a non-absorbed binding crosslinked other nutrients has not been studied in pregnant women. Requirements for polymer. It contains multiple amines separated by one carbon from the vitamins and other nutrients are increased in pregnancy. In pregnant rats given polymer backbone. These amines exist in a protonated form in the intestine doses of Renagel during organogenesis, reduced or irregular ossification of and interact with phosphate molecules through ionic and hydrogen bonding.
fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, By binding phosphate in the dietary tract and decreasing absorption, sevelamer occurred. In pregnant rabbits given oral doses of Renagel by gavage during hydrochloride lowers the phosphate concentration in the serum.
organogenesis, an increase of early resorptions occurred. [See NONCLINICALTOXICOLOGY (13.1)] 12.2 Pharmacodynamics
8.2 Labor and Delivery
In addition to effects on serum phosphate levels, sevelamer hydrochloride hasbeen shown to bind bile acids in vitro and in vivo in experimental animal No Renagel treatment-related effects on labor and delivery were seen in animal models. Bile acid binding by ion exchange resins is a well-established method studies. The effects of Renagel on labor and delivery in humans are not known.
of lowering blood cholesterol. Because sevelamer binds bile acids, it may inter- [See NONCLINICAL TOXICOLOGY (13.1)] fere with normal fat absorption and thus may reduce absorption of fat-soluble 8.4 Pediatric Use
vitamins such as A, D and K. In clinical trials of sevelamer hydrochloride, boththe mean total and LDL cholesterol declined by 15-31%. This effect is The safety and efficacy of Renagel has not been established in pediatric observed after 2 weeks. Triglycerides, HDL cholesterol and albumin did not 8.5 Geriatric Use
12.3 Pharmacokinetics
Clinical studies of Renagel did not include sufficient numbers of subjects aged A mass balance study using 14C-sevelamer hydrochloride in 16 healthy male 65 and over to determine whether they respond differently from younger and female volunteers showed that sevelamer hydrochloride is not systemically subjects. Other reported clinical experience has not identified differences in absorbed. No absorption studies have been performed in patients with renal 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 thedosing range.
13. NONCLINICAL TOXICOLOGY
10. OVERDOSAGE
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Renagel has been given to normal healthy volunteers in doses of up to 14 Standard lifetime carcinogenicity bioassays were conducted in mice and rats.
grams per day for eight days with no adverse effects. Renagel has been given Rats were given sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There in average doses up to 13 grams per day to hemodialysis patients. There are was an increased incidence of urinary bladder transitional cell papilloma in male no reports of overdosage with Renagel in patients. Since Renagel is not rats of the high dose group (human equivalent dose twice the maximum clin- absorbed, the risk of systemic toxicity is low.
ical trial dose of 13 g). Mice received dietary administration of sevelamerhydrochloride at doses of up to 9 g/kg/day (human equivalent dose 3 times the 11. DESCRIPTION
maximum clinical trial dose). There was no increased incidence of tumors The active ingredient in Renagel Tablets is sevelamer hydrochloride, a polymeric amine that binds phosphate and is meant for oral administration. Sevelamer In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohy- hydrochloride caused a statistically significant increase in the number of struc- drin in which forty percent of the amines are protonated. It is known chemically tural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in as poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) hydrochlo- ride. Sevelamer hydrochloride is hydrophilic, but insoluble in water. The struc-ture is represented in Figure 1.
Sevelamer hydrochloride did not impair the fertility of male or female rats in adietary administration study in which the females were treated from 14 days Figure 1. Chemical Structure of Sevelamer Hydrochloride
prior to mating through gestation and the males were treated for 28 days priorto mating. The highest dose in this study was 4.5 g/kg/day (human equivalentdose 3 times the maximum clinical trial dose of 13 g).
a, b = number of primary amine groupsa + b = 9 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 m = large number to indicate extended polymernetwork Renagel® Tablets
Renagel® Tablets
(sevelamer hydrochloride)
(sevelamer hydrochloride)
bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred Sixty-one percent of Renagel patients and 73% of the control patients in mid- and high-dose groups (human equivalent doses less than the completed the full 52 weeks of treatment.
maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of100, 500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during Figure 3, a plot of the phosphorus change from baseline for the completers, organogenesis, an increase of early resorptions occurred in the high-dose illustrates the durability of response for patients who are able to remain on group (human equivalent dose twice the maximum clinical trial dose).
14. CLINICAL STUDIES
Figure 3. Mean Phosphorus Change from Baseline for Patients who
Completed 52 Weeks of Treatment

The ability of Renagel to lower serum phosphorus in CKD patients on dialysiswas demonstrated in six clinical trials: one double-blind placebo controlled 2- week study (Renagel N=24); two open-label uncontrolled 8-week studies (Renagel N=220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (Renagel N=256). Three of the active-controlled studies are described here. One is a crossover study with two 8-week periods comparing Renagel to an active-control. The second is a 52-week parallel study comparing Renagel with active-control. The third is a 12-week parallel study comparing Renagel and active-control in peritoneal dialysis patients.
Sevelamer Hydrochloride
Active Control

14.1 Active-Control, Cross-Over Study in Hemodialysis Patients
Eighty-four CKD patients on hemodialysis who were hyperphosphatemic Study Week
(serum phosphorus > 6.0 mg/dL) following a two-week phosphate binderwashout period received Renagel and active-control for eight weeks each in Average daily Renagel dose at the end of treatment was 6.5 g (range of 0.8 to 13 g).
random order. Treatment periods were separated by a two-week phosphate 14.3 Active-Control, Parallel Study in Peritoneal Dialysis Patients
binder washout period. Patients started on treatment three times per day withmeals. Over each eight-week treatment period, at three separate time points the One hundred and forty-three patients on peritoneal dialysis who were hyper- dose of Renagel could be titrated up 1 capsule or tablet per meal (3 per day) to phosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phos- control serum phosphorus, the dose of active-control could also be altered to phate binder washout period were randomized to receive Renagel® (N=97) or attain phosphate control. Both treatments significantly decreased mean serum active-control (N=46) open label for 12 weeks. Average daily Renagel dose at phosphorus by about 2 mg/dL (Table 4).
the end of treatment was 5.9 g (range 0.8 to 14.3 g).There were statisticallysignificant changes in serum phosphorus (p<0.001) for Renagel (-1.6 mg/dL from baseline of 7.5 mg/dL), similar to the active-control.
Mean Serum Phosphorus (mg/dL) at Baseline and Endpoint
16. HOW SUPPLIED/STORAGE AND HANDLING
Renagel® 800 mg Tablets are supplied as oval, film-coated, compressed tablets,imprinted with “RENAGEL 800” containing 800 mg of sevelamer hydrochloride on an anhydrous basis, hypromellose, diacetylated monoglyceride, colloidal silicon dioxide, and stearic acid. Renagel® 800 mg Tablets are packaged in Renagel® 400 mg Tablets are supplied as oval, film-coated, compressed tablets, *p<0.0001, within treatment group comparison imprinted with “RENAGEL 400” containing 400 mg of sevelamer hydrochloride Figure 2 shows that the proportion of patients achieving a given level of serum on an anhydrous basis, hypromellose, diacetylated monoglyceride, colloidal phosphorus lowering is similar in the two treatment groups. Median decrease silicon dioxide, and stearic acid. Renagel® 400 mg Tablets are packaged in in phosphorus was 2 mg/dL on each treatment.
Figure 2. Cumulative percent of patients (Y-axis) attaining a phosphorus
1 Bottle of 30 ct 800 mg Tablets (NDC 58468-0021-3) change from baseline at least as great as the value of the X-axis. A shift to
1 Bottle of 180 ct 800 mg Tablets (NDC 58468-0021-1) the left of a curve indicates a better response.
1 Bottle of 360 ct 400 mg Tablets (NDC 58468-0020-1) Storage Store at 25°C (77°F): excursions permitted to 15-30°C (59-86°F).
Do not use Renagel® after the expiration date on the bottle.
Cumulative
17 PATIENT COUNSELING INFORMATION
17.1 Dosing Recommendations
Phosphorus Change from Baseline (mg/dL)
The prescriber should inform patients to take Renagel with meals and adhere to Average daily Renagel dose at the end of treatment was 4.9 g (range of 0.0 to their prescribed diets. Instructions should be given on concomitant medica- tions that should be dosed apart from Renagel.
14.2 Active-Control, Parallel Study in Hemodialysis Patients
17.2 Adverse Reactions
Two hundred CKD patients on hemodialysis who were hyperphosphatemic Renagel may cause constipation that if left untreated, may lead to severe (serum phosphorus >5.5 mg/dL) following a two-week phosphate binder complications. Patients should be cautioned to report new onset or worsening washout period were randomized to receive Renagel 800 mg tablets (N=99) or of existing constipation promptly to their physician.
an active-control (N=101). The two treatments produced similar decreases in serum phosphorus. At week 52, using last-observation-carried-forward,Renagel and active-control both significantly decreased mean serum phos-phorus (Table 5).
Mean Serum Phosphorus (mg/dL) and Ion Product at Baseline and Change
from Baseline to End of Treatment
1 Renagel is a Registered Trademark of Genzyme Corporation.

Source: http://www.genzymeclinicalresearch.com/pdf/renagel_pi.pdf

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