Sevelamer Carbonate

Sevelamer carbonate is 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 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 )

Tablets: 800 mg white oval, film-coated, compressed tablets, engraved with RV800 on one side Powder: 0.8 g and 2.4 g pale-yellow powder packaged in an opaque, foil-lined, heat-sealed packets Tablets: 800 mg ( 3 ) Powder: 0.8 g and 2.4 g packets ( 3 )

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

Serious cases of dysphagia, bowel obstruction, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, and perforation have been associated with sevelamer use, some requiring hospitalization and surgery. ( 5.1 )

5.1 Gastrointestinal Adverse Events Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, including severe constipation, or major GI tract surgery were not included in the sevelamer carbonate clinical studies. 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, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, and perforation have also been reported with sevelamer use [see Adverse Reactions (6.2) ] . Inflammatory disorders may resolve upon sevelamer carbonate discontinuation. Treatment with sevelamer carbonate should be re-evaluated in patients who develop severe gastrointestinal symptoms.

5.2 Reductions in 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 were receiving vitamin supplements.

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 Genzyme Corporation at 1-800-847-0069 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 8–52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3%–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.

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 Dosing Recommendations Ciprofloxacin Take at least 2 hours before or 6 hours after sevelamer Mycophenolate mofetil 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 )

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 3–4 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).

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 The safety and efficacy of sevelamer carbonate in lowering serum phosphorus levels was studied in patients 6 years of age and older with CKD. In this study, sevelamer carbonate was apparently less effective in children with a low baseline serum phosphorus, which described children <13 years of age and children not on dialysis. Given its mechanism of action, sevelamer carbonate is expected to be effective in lowering serum phosphorus levels in pediatric patients with CKD. Most adverse events that were reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. No new risks or safety signals were identified with the use of sevelamer carbonate in the trial. Sevelamer carbonate has not been studied in pediatric patients below 6 years of age.

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.

Sevelamer carbonate is a non-absorbed phosphate-binding cross-linked 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).