Pharmacology Update
Colesevel Hydrochloride Tablets (Welchol—Sankyo Parke Davis)
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
In june, the fda approved the first new bile sequestrant in many years. Colesevelam hydrochloride is a nonabsorbable polymer that has a high affinity for both trihydroxy and dihydroxy bile acids in the intestine. The drug prevents the reabsorption of bile acids, thus lowering LDL cholesterol. Colesevelam is distinguished from previous bile sequestrants such as cholestyramine and colestipol by having a lower incidence of gastrointestinal (GI) side effects. These side effects, along with the popularity and ease of use of statins, have limited their use in recent years. Sankyo Parke Davis, the company marketing the new sequestrant, is hoping to reverse that trend. Colesevelam is licensed from GelTex Pharmaceuticals, Inc., and will be marketed under the trade name Welchol.
Indications
Colesevelam is approved 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).1
Dosage
The recommended starting dose of colesevelam for monotherapy is three tablets taken twice daily with meals or six tablets once daily with a meal. The dose can be increased to seven tablets, depending upon the desired therapeutic effects.
In combination therapy (with a HMG-CoA reductase inhibitor), the recommended dose of colesevelam is three tablets taken twice daily with meals or six tablets taken once daily with a meal. Colesevelam should be taken with liquid.
It is supplied as 625 mg tablets.
Potential Advantages
Colesevelam appears to be well tolerated. GI side effects were generally not different among placebo groups and those taking doses ranging from 1.5 g to 3.75 g per day.1,2 In contrast to other bile sequestrants, colesevelam binds to bile acids to produce a soft gelatinous-like material compared to the insoluble complexes that form from use of cholestyramine or colestipol. This physiochemical property of colesevelam is believed to significantly reduce the potential for GI side effects. Drug interactions with colesevelam are generally not problematic. No interactions have been reported with coadministration with digoxin, lovastatin, metoprolol, quinidine, valproic acid, or warfarin.1
Potential Disadvantages
The lipid-lowering effects of colesevelam are modest. LDL-cholesterol is reduced 15-19% from baseline, total cholesterol from 7-10%, and HDL-cholesterol level increased from 3% to 11%.1,2 There is a modest tablet burden, 6-7 tablets need to be taken daily.
Comments
Colesevelam is a nonabsorbed, water-absorbing polymer made of a polyallylamine cross-linked with epichlorohydrin and alkylated with 1-bromodecane and 5-bromohexyltrimethylammonium bromide.2
As with other bile sequestrants, these drugs interrupt the enterohepatic circulation of bile acids. Depletion of bile acids results in the increased conversion of cholesterol to bile acids by upregulation of cholesterol 7-alpha hydroxylase as well as increased numbers of LDL-receptors. This results in the decrease in serum cholesterol. Clinical studies indicate that the efficacy of colesevelam is similar to that of other bile sequestrants although there have been no published comparative studies. LDL-cholesterol reduction of up to 30% have been reported with high doses of cholestyramine (24 g/d) or colestipol (30 g/d); however compliance with these doses was generally poor.4,5 A 16-21% reduction is a more realistic reduction with these agents.5,6 The major advantages of colesevelam appear to be a lower potential for GI side effects and no apparent drug interactions. It is expected to be launched in the fall. Cost is not available at this time.
Clinical Implications
Bile sequestrants are useful as monotherapy in patients with moderately elevated LDL-cholesterol, particularly young adult men and premenopausal women as well as in combination therapy in more severe forms of hypercholesterolemia.3 They have been shown to reduce cardiovascular mortality and morbidity.4,7-9 GI side effects and drug interactions have limited their use. Colesevelam provides an alternative to other bile sequestrants as monotherapy or combination therapy with reduced potential for side effects and drug interactions.
References
1. Welchol Product Information. Sankyo Parke Davis. June 2000.
2. Davidson MH, et al. Arch Intern Med 1999;159:
1893-1900.
3. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel II). 1993.
4. Farmer A, Gotto AM Jr. Drugs 1996;52(5):682-695.
5. Lipid Research Clinics Program. JAMA 1984;251:
365-374.
6. Schectman G, Hiatt J. Am J Med 1996;100:197-204.
7. Brown G, et al. N Engl J Med 1990;323:1289-1298.
8. Blackenhorn DH, et al. JAMA 1987;257:3233-3240.
9. Cashin-Hemphill, et al. JAMA 1990;264:3013-3017.
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