Welchol (Page 3 of 6)

8.2 Lactation

Risk Summary

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

8.3 Females and Males of Reproductive Potential

Contraception

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

8.4 Pediatric Use

Primary Hyperlipidemia

The safety and effectiveness of WELCHOL to reduce LDL-C levels in boys and postmenarchal girls 10 to 17 years of age with HeFH who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification have been established. Use of WELCHOL for this indication is supported by a study in 129 WELCHOL-treated pediatric patients aged 10 to 17 years with HeFH [see Clinical Studies (14.1)]. Adverse reactions commonly observed in pediatric patients compared to placebo, but not in adults, included headache (3.9%), creatine phosphokinase increase (2.3%), and vomiting (2.3%) [see Adverse Reactions (6.1)]. There were no significant effects on fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo.

Due to WELCHOL tablet size, WELCHOL for oral suspension is recommended for use in the pediatric population [see Dosage and Administration (2.2, 2.4)]. The safety and effectiveness of WELCHOL in pediatric patients with HeFH less than 10 years of age or in premenarchal females have not been established.

Type 2 Diabetes Mellitus

The safety and effectiveness of WELCHOL to improve glycemic control in pediatric patients with type 2 diabetes mellitus have not been established. Effectiveness was not demonstrated in a 6-month, adequate and well-controlled study conducted in 141 WELCHOL-treated pediatric patients aged 10 to 17 years with type 2 diabetes mellitus.

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.

Type 2 Diabetes Mellitus

Of the 2048 patients enrolled in the six diabetes studies, 397 (19%) were ≥65 years old, and 36 (2%) were ≥75 years old. In these trials, WELCHOL 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Type 2 Diabetes Mellitus

Of the 2048 patients enrolled in the six diabetes studies, 807 (39%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 61 (3%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl ≥50 mL/min (n=1075) in the add-on to metformin, sulfonylureas, and insulin diabetes studies. In the monotherapy study and add-on to pioglitazone study, only 3 and 5 patients, respectively, had moderate renal insufficiency.

10 OVERDOSAGE

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

11 DESCRIPTION

WELCHOL (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:

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.

WELCHOL tablets are off-white, oval, film-coated, solid tablets each containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink (<5 calories per 6 tablets).

WELCHOL for oral suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in a packet containing 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate (<5 calories per 3.75 gram single-dose packet). PHENYLKETONURICS: WELCHOL for oral suspension contains 27 mg phenylalanine per 3.75 gram dose.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in WELCHOL, 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.

Type 2 Diabetes Mellitus: The mechanism by which WELCHOL improves glycemic control is unknown.

12.2 Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of WELCHOL was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to WELCHOL, as reflected by a reduction in HbA1c, was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 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 Studies

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 WELCHOL with these drugs is unlikely. WELCHOL 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 WELCHOL are presented in Table 6.

Table 6 Mean Change in Drug Exposure (AUC0-∞ and Cmax ) when Administered with WELCHOL (3.75 g)*
Drug Dose Co-administered 1 hr prior to WELCHOL 4 hrs prior to WELCHOL
AUC0-∞ Cmax AUC0-∞ Cmax AUC0-∞ Cmax
N/A − not available
*
With verapamil, the dose of WELCHOL was 4.5 g.
Oral contraceptive containing norethindrone and ethinyl estradiol
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

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