Welchol (colesevelam hydrochloride) - 3 Indications

Scroll down for more information on each indication:

• to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia; approved in 2000
• to reduce LDL-C in pediatrics 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH); approved in 2000
• for the treatment of glycemic control in type 2 diabetes mellitus; approved January 2008

General Information

Welchol contains colesevelam hydrochloride, a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent. 

Welchol is specifically indicated for the following:

• reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia
• reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH)
• improve glycemic control in adults with type 2 diabetes mellitus

Welchol is supplied as tablets and as an oral suspension. Obtain lipid parameters, including serum triglyceride (TG) levels, before starting Welchol.

• The recommended dosage for adults and children 10 to 17 years old with primary hyperlipidemia is 3.75 grams daily.
• The recommended dosage for adults with type 2 diabetes mellitus is 3.75 grams daily.

Welchol should be taken as follows:

Tablets: Take 6 tablets once daily or 3 tablets twice daily with a meal and liquid.

For Oral Suspension: Take one packet once daily with a meal. To prepare, empty the entire contents of one packet into a glass or cup. Add 1 cup of water, fruit juice, or diet soft drinks. Stir well and drink.

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.

Side Effects

Adverse events associated with the use of Welchol may include, but are not limited to, the following:

• Constipation
• Nasopharyngitis
• Dyspepsia
• Hypoglycemia
• Nausea
• Hypertension

Indication 1 - to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia

approved in 2000

Clinical Trial Results

Welchol reduces total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia. Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to Welchol was achieved within 2 weeks and was maintained during long-term therapy.

Indication 2- to reduce LDL-C in pediatrics 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH)

approved in 2000

Clinical Trial Results

The safety and efficacy of Welchol in pediatric patients were evaluated in an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with HeFH, taking a stable dose of an FDA-approved statin (with LDL-C > 130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C > 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL. During the double-blind treatment period, patients were assigned randomly to treatment: Welchol  3.8 g/day (n=64), Welchol  1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, Welchol  3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo.

Indication 3 - for the treatment of glycemic control in type 2 diabetes mellitus

approved January 2008

Clinical Trial Results

The FDA approval of Welchol for this indication was based on the results of three clinical trials. These double-blind, placebo-controlled add-on therapy trials enrolled a total of 1,018 subjects with baseline A1C 7.5-9.5%. The subjects received Welchol, in combination with metformin, sulfonylureas or insulin or placebo administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

Add-on Combination Therapy with Metformin:
Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 subjects already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). The combination of Welchol plus metformin resulted in statistically significant placebo-corrected reductions in A1C with a -0.6 treatment difference (p<0.001) and FPG with a -14 treatment difference (p=0.10). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with Welchol compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for Welchol and -0.3 kg for placebo.

Add-on Combination Therapy with Sulfonylurea:
Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). In combination with a sulfonylurea, Welchol resulted in statistically significant placebo corrected reductions in A1C and FPG. Welchol also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 11). The mean percent change in serum LDLC levels with Welchol compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with Welchol compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for Welchol and -0.4 kg for placebo.

Add-on Combination Therapy with Insulin:
Welchol 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the Welchol group and 65 units in the placebo group. In combination with insulin, Welchol resulted in a statistically significant placebo-corrected reduction in A1C (Table 12). Welchol also reduced LDL-C and Apo B, but increased serum TG (Table 13). The mean percent change in serum LDL-C levels with Welchol compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with Welchol compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for Welchol and 0.2 kg for placebo.