Colestipol hydrochloride granules for oral suspension contain colestipol hydrochloride, which is a lipid lowering agent for oral use. Colestipol hydrochloride is an insoluble, high molecular weight basic anion-exchange copolymer of diethylenetriamine and 1-chloro-2, 3-epoxypropane, with approximately 1 out of 5 amine nitrogens protonated (chloride form). It is a light yellow water-insoluble resin which is hygroscopic and swells when suspended in water or aqueous fluids.

Colestipol hydrochloride granules are tasteless and odorless. Inactive ingredient: silicon dioxide. One dose (1 packet or 1 level teaspoon) of colestipol hydrochloride granules contains 5 grams of colestipol hydrochloride.

Cholesterol is the major, and probably the sole precursor of bile acids. During normal digestion, bile acids are secreted via the bile from the liver and gall bladder into the intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating absorption. A major portion of the bile acids secreted is reabsorbed from the intestines and returned via the portal circulation to the liver, thus completing the enterohepatic cycle. Only very small amounts of bile acids are found in normal serum.

Colestipol hydrochloride binds bile acids in the intestine forming a complex that is excreted in the feces. This nonsystemic action results in a partial removal of the bile acids from the enterohepatic circulation, preventing their reabsorption. Since colestipol hydrochloride is an anion exchange resin, the chloride anions of the resin can be replaced by other anions, usually those with a greater affinity for the resin than chloride ion.

Colestipol hydrochloride is hydrophilic, but it is virtually water insoluble (99.75%) and it is not hydrolyzed by digestive enzymes. The high molecular weight polymer in colestipol hydrochloride apparently is not absorbed. In humans, less than 0.17% of a single 14C-labeled colestipol hydrochloride dose is excreted in the urine when given following 60 days of chronic dosing of 20 grams of colestipol hydrochloride per day.

The increased fecal loss of bile acids due to colestipol hydrochloride administration leads to an increased oxidation of cholesterol to bile acids. This results in an increase in the number of low-density lipoprotein (LDL) receptors, increased hepatic uptake of LDL and a decrease in beta lipoprotein or low density lipoprotein serum levels, and a decrease in serum cholesterol levels. Although colestipol hydrochloride produces an increase in the hepatic synthesis of cholesterol in man, serum cholesterol levels fall.

There is evidence to show that this fall in cholesterol is secondary to an increased rate of clearance of cholesterol-rich lipoproteins (beta or low density lipoproteins) from the plasma. Serum triglyceride levels may increase or remain unchanged in colestipol hydrochloride treated patients.

The decline in serum cholesterol levels with colestipol hydrochloride treatment is usually evident by one month. When colestipol hydrochloride is discontinued, serum cholesterol levels usually return to baseline levels within one month. Periodic determinations of serum cholesterol levels as outlined in the National Cholesterol Education Program (NCEP) guidelines should be done to confirm a favorable initial and long-term response1.

In a large, placebo-controlled, multiclinic study, the LRC-CPPT,2 hypercholesterolemic subjects treated with cholestyramine, a bile-acid sequestrant with a mechanism of action and an effect on serum cholesterol similar to that of colestipol hydrochloride, had reductions in total and low-density lipoprotein cholesterol (LDL-C). Over the seven-year study period the cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease death plus non-fatal myocardial infarction (cumulative incidences of 7% cholestyramine and 8.6%, placebo). The subjects included in the study were middle-aged men (age 35–59) with serum cholesterol-levels above 265 mg/dL, LDL-C above 175 mg/dL on a moderate cholesterol-lowering diet, and no history of heart disease. It is not clear to what extent these findings can be extrapolated to other segments of the hypercholesterolemic population not studied.

Treatment with colestipol hydrochloride results in a significant increase in lipoprotein LpAI. Lipoprotein LpAI is one of the two major lipoprotein particles within the high-density lipoprotein (HDL) density range3, and has been shown in cell culture to promote cholesterol efflux or removal from cells4. Although the significance of this finding has not been established in clinical studies, the elevation of the lipoprotein LpAI particle within the HDL fraction is consistent with an antiatherogenic effect of colestipol hydrochloride, even though little change is observed in HDL cholesterol.

In patients with heterozygous familial hypercholesterolemia who have not obtained an optimal response to colestipol hydrochloride alone in maximal doses, the combination of colestipol hydrochloride and nicotinic acid has been shown to further lower serum cholesterol, triglyceride, and LDL cholesterol (LDL-C) values. Simultaneously, HDL cholesterol (HDL-C) values increased significantly. In many such patients it is possible to normalize serum lipid values.5–7

Preliminary evidence suggests that the cholesterol-lowering effects of lovastatin and the bile acid sequestrant, colestipol hydrochloride, are additive.

The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low-dose resin), or with intensive combination therapy using diet and colestipol hydrochloride granules plus either nicotinic acid or lovastatin. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.8–11

Since no drug is innocuous, strict attention should be paid to the indications and contraindications, particularly when selecting drugs for chronic long-term use.

Colestipol hydrochloride granules are indicated as adjunctive therapy to diet for the reduction of elevated serum total and low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia (elevated low density lipoproteins [LDL] cholesterol) who do not respond adequately to diet. Generally, colestipol hydrochloride granules have no clinically significant effect on serum triglycerides, but with its use triglyceride levels may be raised in some patients.

Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Treatment should begin and continue with dietary therapy (see NCEP guidelines). A minimum of six months of intensive dietary therapy and counseling should be carried out prior to initiation of drug therapy. Shorter periods may be considered in patients with severe elevations of LDL-C or with definite CHD.

According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C is to be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy. The NCEP treatment guidelines are shown below.

Colestipol hydrochloride granules are contraindicated in those individuals who have shown hypersensitivity to any of its components.

TO AVOID ACCIDENTAL INHALATION OR ESOPHAGEAL DISTRESS, COLESTIPOL HYDROCHLORIDE GRANULES SHOULD NOT BE TAKEN IN ITS DRY FORM. ALWAYS MIX COLESTIPOL HYDROCHLORIDE GRANULES WITH WATER OR OTHER FLUIDS BEFORE INGESTING.

Prior to initiating therapy with colestipol hydrochloride granules, secondary causes of hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism), should be excluded, and a lipid profile performed to assess Total cholesterol, HDL-C, and triglycerides (TG). For individuals with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = Total cholesterol - [ (Triglycerides / 5)+HDL-C]

For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases colestipol hydrochloride granules may not be indicated.

Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat absorption and thus may reduce absorption of folic acid and fat soluble vitamins such as A, D, and K.

Chronic use of colestipol hydrochloride may be associated with an increased bleeding tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral administration of vitamin K1.

Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm a favorable initial and adequate long-term response.

Colestipol hydrochloride granules may produce or severely worsen pre-existing constipation. The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction. In patients with pre-existing constipation, the starting dose should be 1 packet or 1 scoop once daily for 5–7 days, increasing to twice daily with monitoring of constipation and of serum lipoproteins, at least twice, 4–6 weeks apart. Increased fluid and fiber intake should be encouraged to alleviate constipation and a stool softener may occasionally be indicated. If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. Constipation associated with colestipol hydrochloride granules may aggravate hemorrhoids.

While there have been no reports of hypothyroidism induced in individuals with normal thyroid function, the theoretical possibility exists, particularly in patients with limited thyroid reserve.

Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a possibility that prolonged use may lead to the development of hyperchloremic acidosis.

Overdosage of colestipol hydrochloride granules has not been reported. Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.

One dose (1 packet or 1 level teaspoon) of colestipol hydrochloride granules contains 5 grams of colestipol hydrochloride. The recommended daily adult dose is one to six packets or level scoopfuls given once or in divided doses. Treatment should be started with one dose once or twice daily with an increment of one dose/day at one- or two-month intervals. Appropriate use of lipid profiles as per NCEP guidelines including LDL-cholesterol and triglycerides is advised so that optimal, but not excessive doses are used to obtain the desired therapeutic effect on LDL-cholesterol level. If the desired therapeutic effect is not obtained at one to six doses/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.

To avoid accidental inhalation or esophageal distress, colestipol hydrochloride granules should not be taken in its dry form. Colestipol hydrochloride granules should always be mixed with water or other fluids before ingesting. Patients should take other drugs at least one hour before or four hours after colestipol hydrochloride granules to minimize possible interference with their absorption. (See PRECAUTIONS, Drug Interactions.)

Colestipol hydrochloride granules are available as follows:

Cartons of 30 foil packets — NDC 59762-0260-1

Cartons of 90 foil packets — NDC 59762-0260-2

Bottles of 500 grams with scoop — NDC 59762-0260-3

Each packet or level scoop supplies 5 grams of colestipol hydrochloride granules.

1.

Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 269(23):3015–3023, 1993.

2.

Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood Institute, Bethesda, MD: The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in Incidence of Coronary Heart Disease. JAMA 251:351–364, 1984.

3.

Parra HJ, et al. Differential electroimmunoassay of human LpA-I lipoprotein particles on ready-to-use plates. Clin. Chem. 36(8):1431–1435, 1990.

4.

Barbaras R, et al. Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles. Biochem. Biophys. Res. Comm. 142(1):63–69, 1987.

5.

Kane JP, et al. Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen. N Engl. J. Med. 304:251–258, 1981.

6.

Illingworth DR, et al. Colestipol plus nicotinic acid in treatment of heterozygous familial hypercholesterolemia. Lancet 1:296–298, 1981.

7.

Kuo PT, et al. Familial type II hyperlipoproteinemia with coronary heart disease: Effect of diet-colestipol-nicotinic acid treatment. Chest 79:286–291, 1981.

8.

Blankenhorn DH, et al. Beneficial Effects of Combined Colestipol-Niacin Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts. JAMA 257(23):3233–3240, 1987.

9.

Cashin-Hemphill L, et al. Beneficial Effects of Colestipol-Niacin on Coronary Atherosclerosis: A 4-Year Follow-up. JAMA 264:3013–3017, 1990.

10.

Brown G, et al. Regression of Coronary Artery Disease as a Result of Intensive Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein B. N Engl, J. Med 323:1289–1298, 1990.

11.

Kane JP, et al. Regression of Coronary Atherosclerosis During Treatment of Familial Hypercholesterolemia with Combined Drug Regimens. JAMA 264:3007–3012, 1990.

Rx only

LAB-0360-3.0

July 2014

NDC 59762-0260-1

GREENSTONE® BRAND

colestipol

hydrochloride

for oral suspension, USP

5 grams

Rx only

NDC 59762-0260-1

30 Foil Packets

GREENSTONE® BRAND

colestipol hydrochloride

for oral suspension, USP

5 grams each

Rx only

NDC 59762-0260-3

GREENSTONE® BRAND

colestipol

hydrochloride

for oral suspension, USP

500 grams

Rx only

NDC 59762-0260-3

GREENSTONE® BRAND

colestipol

hydrochloride

for oral suspension, USP

500 grams

Rx only