Colesevelam HCL (Page 3 of 5)

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 premenarchal girls.

8.5 Geriatric Use

Primary Hyperlipidemia Of the 1350 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 and glucose-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:

Colesevelam-Struct
(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 an off-white to light yellow colored, oval, film coated tablets imprinted “C625” on one side. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, and sodium stearyl fumarate. The coating material contains hypromellose and propylene glycol. Colesevelam Hydrochloride Tablets are imprinted with edible ink which contains shellac, iron oxide black and propylene glycol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in colesevelam hydrochloride, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

12.2 Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4 to 6 weeks of treatment and reached maximal or near-maximal effect after 12 to 18 weeks of treatment.

12.3 Pharmacokinetics

Absorption:
Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution:
Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.


Elimination
Metabolism
Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450.


Excretion
In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14 C-labeled colesevelam hydrochloride dose was excreted in the urine.
Drug Interaction StudiesDrug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of colesevelam hydrochloride with these drugs is unlikely. Colesevelam hydrochloride was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol, phenytoin, pioglitazone, quinidine, rosiglitazone, sitagliptin, valproic acid, and warfarin. The results of additional in vivo drug interactions of colesevelam hydrochloride are presented in Table 6.

Table 6

Mean Change in Drug Exposure (AUC0-∞ and Cmax ) when Administered with Colesevelam Hydrochloride (3.75 g)*

Drug Dose Co-administered 1 hr prior to colesevelam hydrochloride 4 hr prior to colesevelam hydrochloride
AUC0 to ∞ Cmax AUC0 to ∞ Cmax AUC0 to ∞ Cmax
Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A
Ethinyl Estradiol 0.035 mg -24% -24% -18% -1% -12% 0%
Glimepiride 4 mg -18% -8% N/A N/A -6% 3%
Glipizide 20 mg -12% -13% N/A N/A -4% 0%
Glyburide 3 mg -32% -47% -20% -15% -7% 4%
Levothyroxine 600 μg -22% -33% 6% -2% 1% 8%
Metformin ER 1500 mg 44% 8% N/A N/A N/A N/A
Norethindrone 1 mg -1% -20% 5% -3% 6% 7%
Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4%
Repaglinide 2 mg -7% -19% -6% -1% N/A N/A
Verapamil sustained-release 240 mg -31% -11% N/A N/A N/A N/A

* With verapamil, the dose of colesevelam hydrochloride was 4.5 g

Oral contraceptive containing norethindrone and ethinyl estradiol.

N/A – not available

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