Sevelamer Hydrochloride

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

• Sevelamer hydrochloride tablets are a phosphate binder indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis. ( 1 )

3. DOSAGE FORMS AND STRENGTHS 400 mg Tablets: off-white to pale yellow, oval shaped, biconvex film-coated tablets, imprinted with ‘G446’ on one side and plain on the other side. 800 mg Tablets: off-white to pale yellow, modified capsule shaped, biconvex film-coated tablets, imprinted with ‘G447’ on one side and plain on the other side.

• Tablets: 800 mg and 400 mg ( 3 )

4. CONTRAINDICATIONS Sevelamer hydrochloride is contraindicated in patients with bowel obstruction. Sevelamer hydrochloride tablets are contraindicated in patients with known hypersensitivity to sevelamer hydrochloride or to any of the excipients.

• Bowel obstruction. ( 4 )
• Known hypersensitivity to sevelamer hydrochloride or to any of the excipients. ( 4 )

5. WARNINGS AND PRECAUTIONS

• 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 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

• The most common reasons for discontinuing treatment were gastrointestinal adverse reactions. ( 6.1 )
• In a parallel design study of 12 weeks duration, treatment-emergent adverse reactions to sevelamer hydrochloride tablets in peritoneal dialysis patients included dyspepsia (12%), peritonitis (8%), diarrhea (5%), nausea (5%), constipation (4%), pruritus (4%), abdominal distension (3%), vomiting (3%), fatigue (3%), anorexia (3%), and arthralgia (3%). ( 6.1 )
• Cases of fecal impaction and, less commonly, ileus, bowel obstruction, and bowel perforation have been reported. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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. 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% to 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.

7. DRUG INTERACTIONS There are no empirical data on avoiding drug interactions between sevelamer hydrochloride 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 monitor clinical responses or blood levels of concomitant drugs that have a narrow therapeutic range. Table 4: 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 hydrochloride Dosing Recommendations Ciprofloxacin Take at least 2 hours before or 6 hours after sevelamer Mycophenolate mofetil Take at least 2 hours before sevelamer

• When clinically significant drug interactions are expected, separate the timing of administration and 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 binds ciprofloxacin and mycophenolate mofetil; dose these drugs separately from sevelamer hydrochloride. ( 7 )

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary Sevelamer hydrochloride is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. Clinical Considerations Sevelamer hydrochloride may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [ see Clinical Pharmacology ( 12.2 )] . Consider supplementing with these vitamins. 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 at 7-21 times the maximum human equivalent dose of 13 g based on 60 kg body weight. 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 occurredin the high-dose group (human equivalent dose approximately 5 times the maximum clinical trial dose based on 60 kg body weight).

8.2 Lactation Risk Summary Sevelamer hydrochloride is not absorbed systemically by the mother following oral administration and breastfeeding is not expected to result in exposure of the child to sevelamer hydrochloride. Clinical Considerations Sevelamer hydrochloride may decrease serum levels of fat soluble vitamins and folic acid in lactating women [see Clinical Pharmacology ( 12.2 )] . Consider supplementing with these vitamins.

8.4 Pediatric Use The safety and efficacy of sevelamer hydrochloride has not been established in pediatric patients.

8.5 Geriatric Use Clinical studies of sevelamer hydrochloride 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 hydrochloride tablets contain sevelamer hydrochloride, a non-absorbed binding crosslinked polymer. 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 dietary tract and decreasing absorption, sevelamer hydrochloride lowers the phosphate concentration in the serum.