Sevelamer Carbonate

1 INDICATIONS AND USAGE Sevelamer carbonate tablets are indicated for the control of serum phosphorus in adults and children 6 years of age and older with chronic kidney disease (CKD) on dialysis. Sevelamer carbonate tablet is a phosphate binder indicated for the control of serum phosphorus in adults and children 6 years of age and older with chronic kidney disease on dialysis. (1 )

2 DOSAGE AND ADMINISTRATION 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 and based on body surface area (BSA) category for pediatric patients ( 2.1 ) Titrate by 0.8 grams per meal in two week intervals for adult patients as needed to obtain serum phosphorus target. ( 2.1 ) Titrate based on BSA category for pediatric patients in two week intervals for 6 weeks and then every 4 weeks 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 > 5.5 and < 7.5 mg/dL 0.8 grams three times daily with meals ≥ 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. Starting Dose for Pediatric Patients Not Taking a Phosphate Binder. The recommended starting dose for pediatric patients 6 years of age and older is 0.8 to 1.6 grams taken three times per day with meals based on the patient’s body surface area (BSA) category; see Table 2. Table 2: Recommended Starting Dosage and Titration Increment Based on Pediatric Patient’s Body Surface Area (m 2 ) BSA (m 2 ) Starting Dose Per Meal/Snack Titration Increases/ Decreases Per Dose ≥0.75 to <1.2 0.8 grams Titrate by 0.4 grams ≥1.2 1.6 grams Titrate by 0.8 grams Dose Titration for Pediatric Patients Taking Sevelamer Carbonate Tablets . Titrate the sevelamer caronate dose as needed to achieve target levels at two-week intervals based on BSA category, as shown in Table 2. 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

6 ADVERSE REACTIONS Most of the safety experience is with sevelamer carbonate 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 postapproval use of sevelamer hydrochloride or sevelamer carbonate: hypersensitivity, pruritus, rash, abdominal pain, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, 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.

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. Coadministered 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 coadministered. During postmarketing experience, cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients coadministered sevelamer hydrochloride and levothyroxine. Reduction in concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (for example, graft rejection). The possibility of an interaction cannot be excluded with these drugs.