Sevelamer Carbonate For Oral Suspension: Package Insert and Label Information

SEVELAMER CARBONATE FOR ORAL SUSPENSION- sevelamer carbonate for suspension
Hangzhou Anprime Biopharm Co., Ltd.

1 INDICATIONS AND USAGE

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.

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
>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. 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.

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 g to 1.6 g 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 g	Titrate by 0.4 g
≥1.2	1.6 g	Titrate by 0.8 g

Dose Titration for Pediatric Patients Taking Sevelamer Carbonate. Titrate the sevelamer carbonate 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 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
1 tablet	0.8 g
2 tablets	1.6 g
3 tablets	2.4 g

2.2 Sevelamer Carbonate Preparation Instructions

Sevelamer carbonate is available in 0.8 or 2.4 g packets. For dose increments of 0.4 g, use one half of a 0.8 g packet. Place the sevelamer carbonate in a cup and suspend in the amount of water described in Table 4.

Table 4: Sevelamer Carbonate Preparation Instructions

Amount of Sevelamer Carbonate	Minimum Amount of Water for Dose Preparation (either ounces, mL, or tablespoon)
	Ounces	mL	Tablespoons
0.4 g	1	30	2
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 packet 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 (e.g., microwave) or add to heated foods or liquids.

3 DOSAGE FORMS AND STRENGTHS

Powder: 0.8 g and 2.4 g pale-yellow powder packaged in an opaque, foil-lined, heat-sealed packets

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

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.

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 8-52 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.

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

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 3–4 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.