Sevelamer Hydrochloride (Page 2 of 4)

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% 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

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 occurred in 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.

10. OVERDOSAGE

Sevelamer hydrochloride has been given to normal healthy volunteers in doses of up to 14 g per day for eight days with no adverse effects. Sevelamer hydrochloride has been given in average doses up to 13 g per day to hemodialysis patients. There are no reports of overdosage with sevelamer hydrochloride in patients. Since sevelamer hydrochloride is not absorbed, the risk of systemic toxicity is low.

11. DESCRIPTION

The active ingredient in Sevelamer Hydrochloride Tablets is sevelamer hydrochloride, a polymeric amine that binds phosphate and is meant for oral administration. Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which 40% of the amines are protonated. It is known chemically as poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride. Sevelamer hydrochloride is hydrophilic, but insoluble in water. The structure is represented in Figure 1.

Figure 1: Chemical Structure of Sevelamer Hydrochloride

Structural Formula
(click image for full-size original)

a, b = number of primary amine groups

a + b = 9

c = number of crosslinking groups

c = 1

n = fraction of protonated amines

n = 0.4

m = large number to indicate extended polymer network

The primary amine groups shown in the structure are derived directly from poly(allylamine hydrochloride). The crosslinking groups consist of two secondary amine groups derived from poly(allylamine hydrochloride) and one molecule of epichlorohydrin.

Sevelamer Hydrochloride Tablets: Each film-coated tablet of sevelamer hydrochloride contains either 800 mg or 400 mg of sevelamer hydrochloride on an anhydrous basis. The inactive ingredients are colloidal silicon dioxide, diacetylated monoglycerides, hypromellose, lactose monohydrate, maize starch, mannitol, talc and zinc stearate. The imprinting ink for sevelamer hydrochloride tablets has the following components: black iron oxide, butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide and shellac.

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