Sevelamer Carbonate

6 ADVERSE REACTIONS 2. Most of the safety experience is with sevelamer tablets and sevelamer hydrochloride. 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. There are limited clinical trial data on the safety of sevelamer carbonate. However, because it contains the same active ingredient as the hydrochloride salt, the adverse event profiles of the two salts are expected to be similar. In a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout, and 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 to 52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3 to 16%). In 143 peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, most common 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. 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 or sevelamer carbonate: hypersensitivity, 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.

4 CONTRAINDICATIONS Sevelamer carbonate tablets are contraindicated in patients with bowel obstruction. Sevelamer carbonate tablets are contraindicated in patients with known hypersensitivity to sevelamer carbonate, sevelamer hydrochloride, or to any of the excipients. 3. Bowel obstruction. ( 4 ) 4. Known hypersensitivity to sevelamer carbonate,sevelamer hydrochloride, or to any of the excipients. ( 4 )

11 DESCRIPTION The active ingredient in sevelamer carbonate tablet 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. 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. 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 Sevelamer carbonate Tablets: Each film-coated tablet of sevelamer carbonate contains 800 mg of sevelamer carbonate on an anhydrous basis. The inactive ingredients are ammonium hydroxide, colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, lecithin, mannitol, polyvinyl alcohol, propylene glycol, shellac, talc, xanthan gum and zinc stearate. The tablet imprint contains iron oxide black ink. figure1

2 DOSAGE AND ADMINISTRATION 3. Starting dose of sevelamer carbonate tablet is 0.8 or 1.6 grams administered orally three times per day with meals based on serum phosphorus levels for adult patients. ( 2.1 ) 4. Titrate by 0.8 grams per meal in two week intervals for adult patients as needed to obtain serum phosphorus target. ( 2.1 ) 2.1 General Dosing Information Starting Dose for Adult Patients Not Taking a Phosphate Binder . The recommended starting dose of sevelamer carbonate tablets are 0.8 to 1.6 grams taken orally with meals based on serum phosphorus level. Table 1 provides recommended starting doses of sevelamer carbonate tablets for adult patients not taking a phosphate binder. Table 1. Starting Dose for Adult Dialysis Patients Not Taking a Phosphate Binder Serum Phosphorus Sevelamer Carbonate greater than 5.5 and less than 7.5 mg/dL 0.8 grams three times daily with meals greater than or equal to 7.5 mg/dL 1.6 grams three times daily with meals Dose Titration for Adult Patients Taking Sevelamer Carbonate Tablets . Titrate the sevelamer carbonate tablets dose by 0.8 grams three times per day with meals at two-week intervals as necessary to achieve target serum phosphorus levels. Based on clinical studies, the average prescribed adult daily dose of sevelamer carbonate is approximately 7.2 grams per day. The highest daily adult dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis. Switching from Sevelamer Hydrochloride Tablets . For adult patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Switching between Sevelamer Carbonate Tablets and Powder . Use the same dose in grams. Switching from Calcium Acetate . Table 3 gives recommended starting doses of sevelamer carbonate tablets based on a patient’s current calcium acetate dose. Table 3. Starting Dose for Dialysis Patients Switching From Calcium Acetate to Sevelamer carbonate Tablets Calcium Acetate 667 mg (Tablets per meal) Sevelamer Carbonate 1 tablet 0.8 grams 2 tablets 1.6 grams 3 tablets 2.4 grams Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing exclusivity rights, these drug products are not labeled with that pediatric information.

1 INDICATIONS AND USAGE Sevelamer carbonate tablets are indicated for the control of serum phosphorus in adults with chronic kidney disease (CKD) on dialysis. Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing exclusivity rights, these drug products are not labeled with that pediatric information. 2. Sevelamer carbonate tablet is a phosphate binder indicated for the control of serum phosphorus in adults with chronic kidney disease on dialysis. ( 1 )

10 OVERDOSAGE 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.

7 DRUG INTERACTIONS There are no empirical data on avoiding drug interactions between sevelamer carbonate 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. Table 5. Sevelamer Drug Interactions Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly Digoxin Enalapril Iron Metoprolol Warfarin Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer carbonate Ciprofloxacin Mycophenolate mofetil Dosing Recommendations Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer • For oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy consider separation of the timing of administration and/or monitor clinical responses or blood levels of the concomitant medication. ( 7 ) • Sevelamer did not alter the pharmacokinetics of digoxin, enalapril, iron, metoprolol and warfarin. ( 7 ) • Sevelamer has demonstrated interaction with ciprofloxacin, mycophenolate mofetil, and therefore these drugs should be dosed separately from sevelamer carbonate. ( 7 ) Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing exclusivity rights, these drug products are not labeled with that pediatric information.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sevelamer carbonate tablet 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. 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 to 31% the clinical significance of this finding, which was observed after 2 weeks, is unclear. Triglycerides, HDL cholesterol and albumin did not change. 12.3 Pharmacokinetics A mass balance study using 14 C-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. Drug Interactions In vivo Sevelamer carbonate has been studied in human drug-drug interaction studies (9.6 grams once daily with a meal) with warfarin and digoxin. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been studied in human drug-drug interaction studies (2.4 to 2.8 grams single dose or three times daily with meals or two times daily without meals) with ciprofloxacin, digoxin, enalapril, iron, metoprolol, mycophenolate mofetil and warfarin. Co-administered single dose of 2.8 grams of sevelamer hydrochloride in fasted state decreased the bioavailability of ciprofloxacin by approximately 50% in healthy subjects. Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA C max and AUC 0-12h by 36% and 26% respectively. Sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of enalapril, digoxin, iron, metoprolol and warfarin when co-administered. During postmarketing experience, cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Reduction in concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in transplant patients when co-administered with sevelamer hydrochloride without any clinical consequences (for example, graft rejection). The possibility of an interaction cannot be excluded with these drugs.

12.1 Mechanism of Action Sevelamer carbonate tablet 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. 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 to 31% the clinical significance of this finding, which was observed after 2 weeks, is unclear. Triglycerides, HDL cholesterol and albumin did not change.

12.3 Pharmacokinetics A mass balance study using 14 C-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. Drug Interactions In vivo Sevelamer carbonate has been studied in human drug-drug interaction studies (9.6 grams once daily with a meal) with warfarin and digoxin. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been studied in human drug-drug interaction studies (2.4 to 2.8 grams single dose or three times daily with meals or two times daily without meals) with ciprofloxacin, digoxin, enalapril, iron, metoprolol, mycophenolate mofetil and warfarin. Co-administered single dose of 2.8 grams of sevelamer hydrochloride in fasted state decreased the bioavailability of ciprofloxacin by approximately 50% in healthy subjects. Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA C max and AUC 0-12h by 36% and 26% respectively. Sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of enalapril, digoxin, iron, metoprolol and warfarin when co-administered. During postmarketing experience, cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Reduction in concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in transplant patients when co-administered with sevelamer hydrochloride without any clinical consequences (for example, graft rejection). The possibility of an interaction cannot be excluded with these drugs.

20211215

2

3 DOSAGE FORMS AND STRENGTHS Tablets: 0.8 grams white to off-white, oval, film-coated tablets plain on one side and imprinted ‘R789’ on other side. 2. Tablets: 0.8 grams ( 3 )

Sevelamer Carbonate Sevelamer Carbonate Sevelamer Carbonate Sevelamer Ammonia Silicon Dioxide CROSPOVIDONE (15 MPA.S AT 5%) HYDROXYPROPYL CELLULOSE (110000 WAMW) Lecithin, Soybean Mannitol POLYVINYL ALCOHOL, UNSPECIFIED Propylene Glycol Shellac Talc Xanthan Gum Zinc Stearate Ferrosoferric Oxide white to off-white R789

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 grams/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 grams). Mice received dietary administration of sevelamer hydrochloride at doses of up to 9 grams/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 grams/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 grams).

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 grams/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 grams). Mice received dietary administration of sevelamer hydrochloride at doses of up to 9 grams/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 grams/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 grams).

ANDA206094

Sevelamer Carbonate

Sevelamer Carbonate

0904-6707

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel Sevelamer Carbonate Tablets 800 mg 50 Tablets carton label

Indications and Usage ( 1 ) 11/2016 Dosage and Administration ( 2 ) 11/2016 Contraindications ( 4 ) 03/2016

17 PATIENT COUNSELING INFORMATION Inform patients to take sevelamer carbonate tablets 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 sevelamer carbonate. Advise patients to report new onset or worsening of existing constipation promptly to their physician. R X only Distributor: Dr. Reddy’s Laboratories Inc., Princeton NJ 08540, USA Made in India Distributed By: MAJOR® PHARMACEUTICALS 17177 N Laurel Park Dr., Suite 233 Livonia, MI 48152 Revised: 0718

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 Tablets 800 mg and Sevelamer Hydrochloride Tablets 800 mg 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 grams/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. 14.4 Sevelamer Hydrochloride Versus Active-Control, Cross-Over Study in Hemodialysis Patients Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6 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 6). Table 6. Mean Serum Phosphorus (mg/dL) at Baseline and Endpoint Sevelamer Hydrochloride(N=81) Active Control(N=83) Baseline at End of Washout 8.4 8 Endpoint 6.4 5.9 Change from Baseline at Endpoint (95% Confidence Interval) -2* (-2.5, -1.5) -2.1* (-2.6, -1.7) *p<0.0001, within treatment group comparison The distribution of responses is shown in Figure 3. 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 3. 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 grams (range of 0 to 12.6 grams). figure2 14.5 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 7). Table 7. Mean Serum Phosphorus (mg/dL) and Ion Product at Baseline and Change from Baseline to End of Treatment Sevelamer HCl (N=94) Active-Control (N=98) Phosphorus Baseline Change from Baseline at Endpoint 7.5 -2.1 7.3 -1.8 Ca x Phosphorus Ion Product Baseline Change from Baseline at Endpoint 70.5 -19.4 68.4 -14.2 Sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment. Figure 4, 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 4. 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 grams (range of 0.8 to 13 grams). figure3 14.6 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 grams (range 0.8 to 14.3 grams). 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. 14.7 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 grams/day. At the end of the study, the total daily dose was 6.2 grams/day of sevelamer carbonate powder once daily and 6.7 grams/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 mg/dL for sevelamer carbonate powder once daily and 2.9 mg/dL for sevelamer hydrochloride tablets three times per day.

8.5 Geriatric Use Clinical studies of sevelamer carbonate 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.

8.2 Lactation Risk Summary Sevelamer carbonate is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to sevelamer carbonate. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology ( 12.2 ) ]. Consider supplementation.

8.4 Pediatric Use Sevelamer carbonate tablets have not been studied in pediatric patients below 6 years of age. Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing exclusivity rights, these drug products are not labeled with that pediatric information.

8.1 Pregnancy Risk Summary Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology ( 12.2 ) ]. Consider supplementation. Data Animal Data 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 to 4 times the maximum clinical trial dose of 13 grams). 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).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology ( 12.2 ) ]. Consider supplementation. Data Animal Data 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 to 4 times the maximum clinical trial dose of 13 grams). 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). 8.2 Lactation Risk Summary Sevelamer carbonate is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to sevelamer carbonate. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology ( 12.2 ) ]. Consider supplementation. 8.4 Pediatric Use Sevelamer carbonate tablets have not been studied in pediatric patients below 6 years of age. Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing exclusivity rights, these drug products are not labeled with that pediatric information. 8.5 Geriatric Use Clinical studies of sevelamer carbonate 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets: Sevelamer carbonate Tablets 800 mg are supplied as white to off-white, oval, film-coated tablets plain on one side and imprinted ‘R789’ on one side, containing 800 mg of sevelamer carbonate on an anhydrous basis, ammonium hydroxide, colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, lecithin, mannitol, polyvinyl alcohol, propylene glycol, shellac, talc, xanthan gum and zinc stearate. The tablet imprint contains iron oxide black ink. Cartons of 50 tablets (10 tablets per blister card x 5), NDC 0904-6707-06 Cartons of 100 tablets (4 tablets per blister card x 25) NDC 0904-6707-82 Storage: Store at 20°-25°C (68°-77°F); [See USP Controlled Room Temperature] Protect from moisture.