Colesevelam Hydrochloride (Page 3 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed.

In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

8.3 Nursing Mothers

Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.

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 of 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 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.

8.6 Hepatic Impairment

No special considerations or dosage adjustments are recommended when colesevelam hydrochloride is administered to patients with hepatic impairment.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

10 OVERDOSAGE

Doses of colesevelam hydrochloride in excess of 4.5 g/day have not been tested. Because colesevelam hydrochloride is not absorbed, the risk of systemic toxicity is low. However, excessive doses of colesevelam hydrochloride may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.

11 DESCRIPTION

Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended 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:

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 off-white to pale yellow film-coated oval tablets, debossed with “L61” on one side and plain on the other side, containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, copovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and talc.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in colesevelam hydrochloride tablets, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their re-absorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is up-regulated, 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.

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.

Metabolism: Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

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 Interactions: Drug 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 5.

Table 5 Mean Change in Drug Exposure (AUC _{0 to ∞} and C _max ) when Administered with Colesevelam Hydrochloride (3.75 g) *

Drug	Dose	Co-administered		1 hr prior to Colesevelam Hydrochloride		4 hr prior to Colesevelam Hydrochloride
		AUC 0 to ∞	C max	AUC 0 to ∞	C max	AUC 0 to ∞	C max
N/A — Not Available
* With verapamil, the dose of colesevelam hydrochloride was 4.5 g. † Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7)] . ‡ Oral contraceptive containing norethindrone and ethinyl estradiol. § Should be administered at least 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7)] . ¶ Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs [see Drug Interactions (7)] .
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 mcg	-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