Colesevelam - Drug Monograph

Introduction

Colesevelam hydrochloride is a second-generation bile acid sequestrant used primarily for the management of hyperlipidemia and type 2 diabetes mellitus. As a non-systemic polymer, it offers a unique mechanism of action distinct from other lipid-lowering and glucose-controlling agents. First approved by the FDA in 2000, colesevelam represents an important therapeutic option for patients who require additional lipid or glucose control with a favorable safety profile.

Mechanism of Action

Colesevelam is a non-absorbed, polymeric bile acid sequestrant that binds bile acids in the intestinal lumen, forming an insoluble complex that is excreted in feces. This binding prevents the reabsorption of bile acids through the enterohepatic circulation. The resulting depletion of bile acid pools stimulates hepatic conversion of cholesterol into bile acids through upregulation of cholesterol 7-alpha-hydroxylase, the rate-limiting enzyme in bile acid synthesis. This increased cholesterol utilization leads to enhanced hepatic LDL receptor expression and increased clearance of LDL cholesterol from the bloodstream.

In diabetes management, colesevelam's mechanism appears to involve activation of the nuclear bile acid receptor FXR (farnesoid X receptor) in the intestine, which enhances glucagon-like peptide-1 (GLP-1) secretion and improves glycemic control through incretin-mediated pathways.

Indications

1. Primary Hyperlipidemia: As adjunctive therapy to diet and exercise for reduction of elevated LDL-C in adults with primary hyperlipidemia (Fredrickson Type IIa) 2. Type 2 Diabetes Mellitus: To improve glycemic control in adults with type 2 diabetes mellitus, as an adjunct to diet and exercise 3. Heterozygous Familial Hypercholesterolemia: As monotherapy or in combination with statins in pediatric patients aged 10-17 years

Dosage and Administration

• Tablets: 3.75 g daily administered as 6 tablets once daily or 3 tablets twice daily
• Oral suspension: 3.75 g daily administered as one packet once daily or 1.875 g twice daily

• Take with meals and liquid
• Tablets should be swallowed whole; do not cut, crush, or chew
• For oral suspension: mix powder with 4-8 ounces of water, fruit juice, or diet soft drink

• Renal impairment: No dosage adjustment required
• Hepatic impairment: No specific recommendations; use with caution
• Geriatric patients: No dosage adjustment required
• Pediatric patients (10-17 years): 3.75 g daily

Pharmacokinetics

Contraindications

1. History of bowel obstruction 2. Serum triglyceride levels >500 mg/dL 3. History of pancreatitis secondary to hypertriglyceridemia 4. Hypersensitivity to colesevelam or any component of the formulation

Warnings and Precautions

Drug Interactions

• Other Oral Medications: May bind to and decrease absorption of concurrently administered drugs

- Administer other medications at least 4 hours before colesevelam - Particularly affects: warfarin, verapamil, metoprolol, quinidine, levothyroxine, oral contraceptives, phenytoin, and glyburide

• Cyclosporine: May reduce cyclosporine absorption
• Fat-Soluble Vitamins: May impair absorption of vitamins A, D, E, and K

Adverse Effects

• Constipation (11%)
• Dyspepsia (8%)
• Nausea (4%)
• Abdominal pain (3%)
• Pharyngitis (3%)
• Influenza (3%)
• Rhinitis (3%)
• Accidental injury (2%)

• Bowel obstruction (rare)
• Severe hypertriglyceridemia
• Pancreatitis (in patients with pre-existing hypertriglyceridemia)

Monitoring Parameters

• Lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides)
• HbA1c and fasting glucose (for diabetic patients)
• Nutritional assessment (especially fat-soluble vitamins)
• Gastrointestinal history

• Lipid profile: Within 4-6 weeks of initiation and periodically thereafter
• HbA1c: Every 3 months in diabetic patients
• Triglyceride levels: Periodically, especially if elevated at baseline
• Signs of vitamin deficiency: Particularly vitamins A, D, E, and K
• Gastrointestinal symptoms: Constipation, abdominal discomfort

Patient Education

• Take with meals and plenty of fluid to reduce gastrointestinal side effects
• Swallow tablets whole; do not cut, crush, or chew
• If taking other medications, take them at least 4 hours before colesevelam
• Report severe constipation, abdominal pain, or difficulty swallowing
• Maintain recommended diet and exercise program
• Be aware that colesevelam may affect absorption of other medications and vitamins
• For diabetic patients: Continue regular blood glucose monitoring
• Notify all healthcare providers about colesevelam use before starting new medications

References

1. FDA Prescribing Information: Welchol (colesevelam hydrochloride) 2. Bays HE, Davidson M, Jones MR, et al. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol. 2006;97(8):1198-1205. 3. Goldberg RB, Fonseca VA, Truitt KE, et al. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med. 2008;168(14):1531-1540. 4. Handelsman Y, Goldberg RB, Garvey WT, et al. Colesevelam HCl to treat hypercholesterolemia and improve glycemic control in patients with type 2 diabetes. Expert Rev Endocrinol Metab. 2009;4(2):119-129. 5. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S1-S291. 6. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082-e1143.