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Drug Welchol for Hypercholesterolemia

Brand Name Drug: Welchol
Active Ingredient Drug: colesevelam hydrochloride
Indication: For the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia, as an adjunct to diet and exercise
Company Name: GelTex Pharmaceuticals, Inc.
Availability: Approved by FDA on May 26, 2000

Introduction

An estimated 52 million people in the US have at least mild hypercholesterolemia and would benefit from lipid-lowering therapy. Bile acid sequestrants are a class of lipid-lowering agents that work nonsystemically and therefore are an attractive treatment option for certain patients with elevated LDL cholesterol levels, particularly young adults with familial hypercholesterolemia. Bile acid sequestrants work without entering the bloodstream and are generally regarded as safer than absorbed agents such as statins, which require frequent liver function tests. In fact, the National Cholesterol Education Program recommends that physicians prescribe bile acid sequestrants as first-line cholesterol-lowering therapy. They may be used as monotherapy or in combination with other drugs such as the HMG-CoA reductase inhibitors (statins).

The biggest drawback to bile acid sequestrants, however, has been gastrointestinal side effects, including a high incidence of constipation as well as bloating, flatulence, and cramping. Welchol (colesevelam hydrochloride) is a new bile acid sequestrant manufactured by GelTex Pharmaceuticals, Inc. Welchol (formerly known as Cholestagel) is a nonabsorbed polymer (water-absorbing hydrogel) that has been specifically engineered to bind to bile acids. On May 26, 2000, the FDA approved Welchol for the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia.

Each Welchol tablet contains 625 mg of colesevelam. The recommended starting dose of Welchol as monotherapy is 3 tablets taken twice per day with meals or 6 tablets taken once a day with a meal. The Welchol dose can be increased up to 7 tablets, if necessary. When administered with an HMG-CoA reductase inhibitor, Welchol at doses of 4-6 tablets per day has been shown to be safe and effective when taken at the same time as the HMG-CoA reductase inhibitor or when the two drugs are taken at different times. The recommended dose of Welchol in combination with an HMG-CoA reductase inhibitor is 3 tablets twice daily or 6 tablets once daily, taken with a meal.

How It Works

Bile acids are synthesized by the liver from cholesterol and secreted into the intestines to aid digestion of fats. Bile acid sequestrants such as Welchol bind to bile acids in the intestinal tract and increase their excretion from the body. To replenish the bile acid pool, the liver draws cholesterol from the bloodstream, resulting in a reduction in blood cholesterol levels.

Welchol (colesevelam hydrochloride) has been found to have a high affinity for both trihydroxy and dihydroxy bile acids in the intestine, leading to increased fecal bile acid excretion. Preliminary in vivo and in vitro studies suggest that Welchol has superior bile acid binding efficacy compared with cholestyramine. Furthermore, since Welchol is not absorbed in the gastrointestinal tract, there is minimal potential for toxic effects. Its water-retaining ability creates a soft, gelatinous-like material that minimizes the potential for gastrointestinal irritation.

Welchol (colesevelam hydrochloride): Clinical Study Results

The efficacy of Welchol for lowering LDL cholesterol was demonstrated in eight clinical trials involving approximately 1,400 patients who were treated for 4-50 weeks. Welchol was found to be effective as initial monotherapy for patients with mild-to-moderate hypercholesterolemia.

One clinical study compared various doses of Welchol (1.5, 2.25, 3.0, or 3.75 g/d) to placebo in 137 patients with hypercholesterolemia (LDL cholesterol level greater than 160 mg/dL) who took Welchol or placebo with their morning and evening meals for 6 weeks. LDL cholesterol concentrations decreased in a dose-dependent manner by 4.2 mg/dL (1.8%) in the 1.5-g/d Welchol treatment group and up to 39 mg/dL (19.1%) in the 3.75-g/d Welchol treatment group. LDL cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0-g/d and 3.75-g/d Welchol treatment groups.

Total cholesterol levels demonstrated a similar response to Welchol treatment, with an 8.1% decrease from baseline in the 3.75-g/d treatment group. High-density lipoprotein cholesterol levels rose significantly in the 3.0-g/d and 3.75-g/d Welchol treatment groups, by 11.2% and 8.1%, respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups.

In a study in patients with LDL cholesterol of 130-220 mg/dL, Welchol was given for 24 weeks in divided doses with the morning and evening meals. Mean LDL cholesterol reductions were 15% and 18% for the 3.8 g and 4.5 g doses, respectively, with respective mean total cholesterol reductions of 7% and 10%. HDL cholesterol increased by 3% with both doses of Welchol.

Co-administration of Welchol with an HMG-CoA reductase inhibitor (atorvastatin, lovastatin, or simvastatin) demonstrated additive reduction of LDL cholesterol in three clinical trials. Welchol at doses of 2.3 g/d and 3.8 g/d resulted in additional 8% and 16% reductions in LDL cholesterol, respectively, above that seen with the HMG-CoA reductase inhibitor alone.

What the Patient Should Know

The most common side effects reported by patients in clinical trials of Welchol were flatulence (12% for Welchol vs. 14% for placebo) and constipation (11% for Welchol vs. 7% for placebo). The incidence of gastrointestinal side effects was less than that associated with other drugs in its class; constipation, for example, occurs in up to 39% of patients taking conventional bile acid sequestrants.

Welchol (colesevelam hydrochloride) should not be taken by patients with bowel obstruction and those who have shown a hypersensitivity to any of its components.

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