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SEVELAMER CARBONATE for oral suspension

The active ingredient in sevelamer carbonate for oral suspension 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.

Sevelamer Carbonate Powder: Each pouch of Sevelamer Carbonate Powder contains 0.8 g or 2.4 g of sevelamer carbonate on an anhydrous basis. The inactive ingredients are ferric oxide (yellow), orange flavor, sucralose and xanthan gum.

INDICATIONS AND USAGE

Sevelamer carbonate for oral suspension 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 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.

Mechanism of Action

Sevelamer carbonate for oral suspension 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).

DOSAGE AND ADMINISTRATION

Starting Dose for Adult Patients Not Taking a Phosphate Binder.

The recommended starting dose of sevelamer carbonate for oral suspension 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 oral suspension 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 for Oral Suspension
> 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 for Oral Suspension.

Titrate the sevelamer carbonate for oral suspension 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 for oral suspension based on a patient’s current calcium acetate dose.

Table 3. Starting Dose for Dialysis Patients Switching From Calcium Acetate to Sevelamer Carbonate for Oral Suspension

Calcium Acetate 667 mg (Tablets per meal)	Sevelamer Carbonate for Oral Suspension
1 Tablet	0.8 g
2 Tablet	1.6g
3 Tablet	2.4g

Sevelamer Carbonate Powder Preparation Instructions

Sevelamer carbonate powder is available in 0.8 or 2.4 g pouches. Place the sevelamer carbonate powder in a cup and suspend in the amount of water described in Table 4.

Table 4. Sevelamer Carbonate Powder Preparation Instructions

Amount of Sevelamer Carbonate Powder	Minimum amount of water for dose preparation (either ounces, mL or Tablespoon)
	ounces	mL	Tablespoons
0.8 g	1	30	2
2.4 g	2	60	4

Instruct patients to stir the mixture vigorously (it does not dissolve), resuspend, if necessary, right before administration, and drink the entire preparation within 30 minutes.

As an alternative to water, the entire contents of the pouch may be pre-mixed with a small amount of food or beverage and consumed immediately (within 30 minutes) as part of the meal.

Do not heat Sevelamer Carbonate Powder (e.g., microwave) or add to heated foods or liquids.

CONTRAINDICATIONS

Sevelamer carbonate for oral suspension is contraindicated in patients with bowel obstruction.

Sevelamer carbonate for oral suspension is contraindicated in patients with known hypersensitivity to sevelamer carbonate, sevelamer hydrochloride, or to any of the excipients.

WARNINGS AND PRECAUTIONS

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.

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.

ADVERSE REACTIONS

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug.

Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women. Consider supplementation.

Lactation: 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.

Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women. Consider supplementation.

Pediatric Use: Sevelamer carbonate has 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.

Geriatric Use: Clinical studies of sevelamer carbonate did not include sufficient numbers of subjects aged65 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.

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.

SEVELAMER CARBONATE for oral suspension

SEVELAMER CARBONATE for oral suspension