COLESEVELAM HYDROCHLORIDE (Page 3 of 6)

7.2 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication

Table 5 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication
Metformin Extended-Release (ER)
Clinical Impact: In vivo drug interactions studies showed an increase in metformin extended release (ER) when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients’ glycemic control.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Colesevelam hydrochloride is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. Limited available data on the use of colesevelam hydrochloride are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of either maternal or fetal toxicity was found in rats or rabbits exposed to colesevelam hydrochloride during the period of fetal organogenesis at 8 and 5 times, respectively, the maximum recommended human dose (MRHD) of 3.75 g/day, based on body surface area (mg/m 2). No adverse effects on offspring survival and development were observed in rats administered 5 times the MRHD (see Data). Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. There are no data available on the effect of colesevelam hydrochloride on the absorption of fat-soluble vitamins in pregnant women. If the patient becomes pregnant while taking colesevelam hydrochloride, the patient should be advised of the lack of known clinical benefit with continued use during pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

There are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and a causal association with congenital anomalies has not been established.

Animal Data

In pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days 7 through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were 8 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2).

In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days 6 through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2).

In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day 6 through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2).

8.2 Lactation

Risk Summary

Colesevelam hydrochloride is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to colesevelam hydrochloride.

8.3 Females and Males of Reproductive Potential

Contraception

Use of colesevelam hydrochloride may reduce the efficacy of oral contraceptives. Advise patients to take oral contraceptives at least 4 hours prior to taking colesevelam hydrochloride [see Drug Interactions (7)].

8.4 Pediatric Use

The safety and effectiveness of colesevelam hydrochloride as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age, with HeFH [see Clinical Studies (14.1)] . The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [see Adverse Reactions (6.1)] .

Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. Dose adjustments are not required when colesevelam hydrochloride is administered to children 10 to 17 years of age.

Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in pre-menarchal girls.

8.5 Geriatric Use

Primary Hyperlipidemia

Of the 1,350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥ 65 years old, and 58 (4%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 OVERDOSAGE

Colesevelam hydrochloride is not absorbed and the risk of systemic toxicity is low. Excessive doses of colesevelam hydrochloride may cause more severe local gastrointestinal effects (e.g., constipation).

11 DESCRIPTION

Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering agent for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule.

Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6‑(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:

Chemical Structure
(click image for full-size original)

wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1‑bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone cross-linking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥ 100 to indicate an extended polymer network. A small amount of the amines are dialkylated and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.

Colesevelam hydrochloride tablets are white to off-white, oval-shaped, film-coated tablets, printed with “COL” on one side with black ink containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide. The tablets are imprinted using a water-soluble black ink (ferrosoferric oxide, hypromellose, and propylene glycol). The coating material contains polyethylene glycol, polysorbate 80 and talc (approximately 5 calories per 6 tablets).

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