Brands, Medical Use, Clinical Data
- Tablets (off-white, film-coated, solid tablets containing 625 mg colesevelam)
Brands / Synonyms
CholestaGel; Colesevelam hydrochloride; Welchol; Welchol
For use, alone or in combination with an HMG-CoA reductase inhibitor, as adjunctive therapy to diet and exercise for the reduction of elevated LDL cholesterol in patients with primary hypercholesterolemia (Fredrickson Type IIa).
Colesevelam is a high capacity bile-acid binding molecule. Colesevelam binds to bile acids in the intestine which reduces the amount of bile acids that are returned to the liver via enterohepatic circulation. Clinical studies have demonstrated that elevated levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (Apo B, a protein associated with LDL-C) are associated with an increased risk of atherosclerosis in humans. Similarly, decreased levels of high-density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the levels of total-C and LDL-C, and inversely with the level of HDL-C. The combination of colesevelam and an HMG-CoA reductase inhibitor is effective in further lowering serum total-C and LDL-C levels beyond that achieved by either agent alone.
Mechanism of Action
Colesevelam 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-(alpha)-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, hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, and increasing the number of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects result in increased clearance of LDL cholesterol (LDL-C) from the blood, resulting in decreased serum LDL-C levels. Serum triglyceride levels may increase or remain unchanged. The end result is increased clearance of LDL-cholesterol from the blood with decreased serum LDL-cholesterol.
Not hydrolyzed by digestive enzymes and is not absorbed.
Symptoms of overdose may include eye irritation, constipation, abdominal cramps, nausea, vomiting, diarrhea, and hypersensitivity. However, as colesevelam is not absorbed, the risk of systemic toxicity is low. Doses in excess of 4.5 g per day have not been tested.
Biotrnasformation / Drug Metabolism
Not applicable (not hydrolyzed by digestive enzymes and not absorbed).
WelChol® is contraindicated in individuals with bowel obstruction and in individuals who have shown
hypersensitivity to any of the components of WelChol®.
WelChol® has been studied in several human drug interaction studies in which it was administered with a meal
and the test drug. WelChol® was found to have no significant effect on the bioavailability of digoxin,
lovastatin, metoprolol, quinidine, valproic acid, and warfarin. WelChol® decreased the Cmax and AUC of
sustained-release verapamil (Calan SR®) by approximately 31% and 11%, respectively. Since there is a high degree
of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear. In clinical
studies, coadministration of WelChol® with atorvastatin, lovastatin, or simvastatin did not interfere with the
lipid-lowering activity of the HMG-CoA reductase inhibitor. Other drugs have not been studied. When administering
other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy,
physicians should consider monitoring drug levels or effects.