Sevelamer Hydrochloride

SEVELAMER HYDROCHLORIDE- sevelamer hydrochloride tablet, film coated
Winthrop U.S.

1 INDICATIONS AND USAGE

Sevelamer hydrochloride is indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. The safety and efficacy of sevelamer hydrochloride in CKD patients who are not on dialysis have not been studied.

2 DOSAGE AND ADMINISTRATION

Patients Not Taking a Phosphate Binder. The recommended starting dose of sevelamer hydrochloride is 800 to 1600 mg, which can be administered as one or two 800 mg sevelamer hydrochloride tablets with meals based on serum phosphorus level. Table 1 provides recommended starting doses of sevelamer hydrochloride for patients not taking a phosphate binder.

Table 1: Starting Dose for Dialysis Patients Not Taking a Phosphate Binder
Serum Phosphorus Sevelamer Hydrochloride 800 mg
>5.5 and <7.5 mg/dL 1 tablet three times daily with meals
≥7.5 and <9.0 mg/dL 2 tablets three times daily with meals
≥9.0 mg/dL 2 tablets three times daily with meals

Patients Switching from Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride and calcium acetate. Table 2 gives recommended starting doses of sevelamer hydrochloride based on a patient’s current calcium acetate dose.

Table 2: Starting Dose for Dialysis Patients Switching from Calcium Acetate to Sevelamer Hydrochloride
Calcium Acetate 667 mg(Tablets per meal) Sevelamer Hydrochloride 800 mg(Tablets per meal)
1 tablet 1 tablet
2 tablets 2 tablets
3 tablets 3 tablets

Dose Titration for All Patients Taking Sevelamer Hydrochloride. Adjust dosage based on the serum phosphorus concentration with a goal of lowering serum phosphorus to 5.5 mg/dL or less. Increase or decrease by one tablet per meal at two-week intervals as necessary. Table 3 gives a dose titration guideline. The average dose in a Phase 3 trial designed to lower serum phosphorus to 5.0 mg/dL or less was approximately three sevelamer hydrochloride 800 mg tablets per meal. The maximum average daily sevelamer hydrochloride dose studied was 13 g.

Table 3: Dose Titration Guideline
Serum Phosphorus Sevelamer Hydrochloride Dose
>5.5 mg/dL Increase 1 tablet per meal at 2-week intervals
3.5-5.5 mg/dL Maintain current dose
<3.5 mg/dL Decrease 1 tablet per meal

3 DOSAGE FORMS AND STRENGTHS

Tablets: 800 mg white, oval, film-coated, compressed tablets imprinted with RENAGEL 800.

4 CONTRAINDICATIONS

Sevelamer hydrochloride is contraindicated in patients with bowel obstruction.

Sevelamer hydrochloride is contraindicated in patients with known hypersensitivity to 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 hydrochloride clinical studies.

Dysphagia and esophageal tablet retention have been reported in association with use of sevelamer tablets, 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 hydrochloride discontinuation. Treatment with sevelamer hydrochloride should be re-evaluated in patients who develop severe gastrointestinal symptoms.

5.2 Monitor Serum Chemistries

Bicarbonate and chloride levels should be monitored.

5.3 Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid Levels

In preclinical studies in rats and dogs, sevelamer hydrochloride 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 received vitamin supplements, which is typical of patients on dialysis.

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.

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-control 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%-16%).

In 143 peritoneal dialysis patients studied for 12 weeks, most 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. Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of sevelamer hydrochloride: 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.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

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