Sevelamer Carbonate

SEVELAMER CARBONATE- sevelamer carbonate tablet, film coated
Unit Dose Services

1 INDICATIONS AND USAGE

Sevelamer carbonate is 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. However, due to Genzyme Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

Starting Dose for Adult Patients Not Taking a Phosphate Binder. The recommended starting dose of sevelamer carbonate is 0.8 to 1.6 g taken orally with meals based on serum phosphorus level. Table 1 provides recommended starting doses of sevelamer carbonate 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 800 mg Tablet
> 5.5 and < 7.5 mg/dL 0.8 g three times daily with meals
≥ 7.5 mg/dL 1.6 g three times daily with meals

Dose Titration for Adult Patients Taking Sevelamer Carbonate Tablets. Titrate the sevelamer carbonate dose by 0.8 g 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 g 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 based on a patient’s current calcium acetate dose.

Table 3. Starting Dose for Dialysis Patients Switching From Calcium Acetate to Sevelamer carbonate
Calcium Acetate 667 mg (Tablets per meal) Sevelamer Carbonate Tablet
1 tablet 0.8 g
2 tablets 1.6 g
3 tablets 2.4 g

Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets. However, due to Genzyme Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 0.8 g off-white, film coated, modified capsule shaped, biconvex tablets de-bossed with ‘I 8’ on one side.

4 CONTRAINDICATIONS

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.

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 sevelamer carbonate clinical studies.

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 to 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.

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 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.

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
DigoxinEnalapril Iron Metoprolol Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer carbonate
Dosing Recommendations
CiprofloxacinMycophenolate mofetil Take at least 2 hours before or 6 hours after sevelamerTake at least 2 hours before sevelamer
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