Colestid (Colestipol HCl)

COLESTID®

Pharmacia & Upjohn

Colestipol HCl

Oral Antihypercholesterolemic

Action And Clinical Pharmacology: Colestipol is hygroscopic, water insoluble, and it is neither hydrolyzed by digestive enzymes nor is it absorbed. Colestipol binds with bile acids in the intestine forming a complex that is excreted in the feces. This non-systemic action results in a continuous, partial removal of bile acids from the enterohepatic circulation preventing their reabsorption. This increased fecal loss of bile acids due to colestipol administration leads to an increased oxidation of cholesterol to bile acids. This results in an increase in the number of hepatic low density lipoprotein (LDL) receptors, and consequently an increased uptake of LDL and a decrease in serum/plasma beta lipoprotein or total and LDL cholesterol levels. Although colestipol produces an increase in the hepatic synthesis of cholesterol in man, serum cholesterol levels fall.

Pharmacokinetics: Following oral ingestion of 4-labelled colestipol by humans, at a dosage level of 0.07 g/kg body weight, 0.0214% of the radioactive drug was excreted in urine over a 7-day period. Eighty percent of the material excreted in urine was voided during the first day. Recovery of radioactivity in the feces accounted for an additional 93.4% of the administered dose. No drug-related radioactivity was found in plasma samples taken at intervals during the 4-day period following drug administration. In this case, the sensitivity of the plasma level measurements was such that 0.01% of the administered dose, distributed in total body plasma, would have been detected.

Indications And Clinical Uses: As adjunctive therapy to diet and exercise for the reduction of elevated serum cholesterol in patients with primary hypercholesterolemia (elevated low density lipoproteins). Such a reduction of serum cholesterol may reduce the risks of atherosclerotic coronary artery disease and myocardial infarction. In patients with combined hypercholesterolemia and hypertriglyceridemia, colestipol may be useful in lowering elevated cholesterol but is not indicated where hypertriglyceridemia is the abnormality of most concern.

Patients should be placed on a standard cholesterol-lowering diet at least equivalent to the American Heart Association (AHA) Step 1 Diet, which should be continued during treatment. If appropriate, a programme of weight control and physical exercise should be implemented.

Contra-Indications: In patients with complete biliary obstruction where bile is not secreted into the intestine.

In individuals who have shown hypersensitivity to any of the components of the products.

In addition, the orange granules are contraindicated in phenylketonurics as each 7.5 g contains 18.2 mg phenylalanine.

Manufacturers’ Warnings In Clinical States: The granules and orange granules should never be taken in its dry form. Esophageal spasm or respiratory distress can result from attempting to swallow the granules dry. The granules and orange granules should always be mixed with water, beverages, cereals, soups or other foods with sufficient fluid for mixing.

Precautions: Studies have suggested that control of elevated cholesterol and triglycerides may not lessen the danger of cardiovascular related mortality, although the incidence of nonfatal myocardial infarctions is decreased.

Before instituting therapy with colestipol, diseases contributing to increased serum cholesterol such as hypothyroidism, diabetes mellitus, nephrotic syndrome, dysproteinemias and obstructive liver disease should be ruled out or specifically treated. In addition, the current medications of the patient should be reviewed for their potential to increase serum LDL-C or total cholesterol.

It should be verified that an elevated LDL-C is responsible for the high total cholesterol level, especially in those patients with marked elevations of HDL-C and elevations of triglyceride over 4.5 mmol/L (400 mg/100 mL). An LDL-C level may be estimated using the following formula:

LDL-C = total cholesterol-HDL-C-triglyceride 2.19

All units are in mmol/L. The accuracy of this approximation falls when triglycerides are greater than 4.5 mmol/L. Patients with triglyceride levels above 4.5 mmol/L should not be considered for initial therapy with colestipol alone. Instead, the use of colestipol given in combination with another lipid lowering agent like a fibrate or niacin would be more beneficial.

When used as the sole therapy, colestipol does not improve hypertriglyceridemia and in fact may elevate serum triglycerides. This elevation is generally transient, but may sometimes persist. If a significant rise in triglyceride level occurs consideration should be given to dose reduction, drug discontinuation or combination therapy with another lipid lowering agent.

Appropriate use of serum lipid profiles (with LDL-C and triglyceride levels) at regular intervals is advised so that therapeutic effect can be determined.

Colestipol may produce or worsen pre-existing constipation. In patients with pre-existing constipation, the starting dose should be 5 g colestipol granules, or 2 g colestipol tablets, given once or twice daily. Increased fluid and fiber intake is encouraged to alleviate the constipation. A stool softener may be added if needed. If the initial dose is well tolerated, the dosage may be increased (by daily increments of 5 g colestipol granules or 2 to 4 g colestipol tablets) at monthly intervals. If the constipation worsens or the desired therapeutic response is not achieved at the maximum recommended dose, then combination lipid-lowering therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. Constipation may aggravate hemorrhoids.

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

Carcinogenesis and Mutagenesis: In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent similar to colestipol) was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin treated rats than in control rats. The relevance of this laboratory observation from studies in rats with cholestyramine resin to the clinical use of colestipol is not known. When colestipol was administered in the diet to rats for 18 months, there was no evidence of any drug related intestinal tumor formation. In the Ames assay, colestipol was not mutagenic.

Pregnancy and Lactation: The use of colestipol in pregnancy or lactation or by women of childbearing potential requires that the benefits of drug therapy be weighed against the possible hazards to the mother and the child. Safety for use in pregnant women has not been established.

Children: The use of colestipol in children is limited. Clinical trials conducted in children with the granules have usually employed doses of 5 to 20 g/day. The National Cholesterol Education Program (NCEP) Expert Panel recommends drug therapy be considered in children 10 years or older, who have previously undergone an adequate trial of diet therapy but still have unacceptably high serum cholesterol levels. In certain situations where a young child has extremely high serum cholesterol levels, drug treatment may even be initiated before 10 years of age. If the child is started on drug therapy, a carefully assessed diet therapy should also be continued in order to obtain optimal results.

However, the safety of using the tablets in patients under the age of 18 years has not been established.

Because bile acid sequestrants may interfere with the absorption of fat-soluble vitamins, appropriate monitoring of growth and development is essential if colestipol is used in children.

Geriatrics: Appropriate studies on the relationship of age to the effects of colestipol have not been performed in the geriatric population. However, patients over 60 years of age may be more likely to experience gastrointestinal side effects, as well as adverse nutritional effects.

Effect on Vitamin Absorption: Due to the action of colestipol in sequestering bile acids, colestipol may theoretically interfere with normal fat absorption and thus may reduce the absorption of folic acid and fat soluble vitamins A, D and K. In general, supplementation of vitamins A, D and K is not needed unless a deficiency is shown to exist.

Chronic use of colestipol has been rarely associated with an increased bleeding tendency due to hypoprothrombinemia resulting from vitamin K deficiency. This deficiency can be corrected with oral vitamin K.

Drug Interactions: Since colestipol is an anion-exchange resin, it may have a strong affinity for anions other than the bile acids. Colestipol does not bind in vivo with an affinity and to an extent that results in clinically significant drug-drug interactions with all anionic compounds or weak acids. Clinically relevant reductions in bioavailability have been found for several weakly acid drugs (summarized below). However, other weakly acid (anionic) drugs have been studied and found not to be affected by colestipol co-administration. The drugs that are affected by co-administration of colestipol vary widely in pharmacologic effect and mechanisms, in magnitude of doses, and in physicochemical characteristics. Therefore, it is not possible to predict a priori whether or not co-administration with colestipol will interfere with absorption. Unless a particular drug has been studied, it should be assumed that concomitantly administered drugs have the potential for interacting with colestipol. Since colestipol may bind other drugs given concurrently, patients should take other drugs at least 1 hour before or 4 hours after colestipol (or at as great an interval as possible) to avoid impeding their absorption.

Drug Interactions with Other Lipid-Lowering Drugs: Fibric acid derivatives: Based upon the definitions above, colestipol reduced the bioavailability of gemfibrozil (Cmax reduced 27%, AUC reduced 30%) when both drugs were administered together; this interaction was avoided by dosing gemfibrozil either 2 hours before or after colestipol. Colestipol had little or no effect on the bioavailability of clofibrate and fenofibrate.

Niacin (nicotinic acid): Niacin plasma concentrations were highly variable among subjects due in part to rapid absorption and elimination of niacin. The median Cmax and AUC were 35 and 48% lower when niacin was given with colestipol, but were not statistically significantly different from a niacin alone treatment. Concomitant multiple dosing of colestipol and niacin had minimal effect on niacin absorption. The interaction between colestipol and niacin does not appear to be clinically significant as evidenced by the additive efficacy of combination colestipol and niacin.

Other classes of lipid-lowering drugs: Colestipol drug interaction studies have not been conducted with HMG-CoA reductase inhibitors (i.e. lovastatin, simvastatin, etc.) or with probucol. However, clinical studies indicate that the cholesterol-lowering effects of colestipol and HMG-CoA reductase inhibitors are additive; therefore a clinically significant drug interaction is unlikely. Other drug interaction studies have been conducted with cholestyramine (another bile acid sequestrant) and various HMG-CoA reductase inhibitors. Cholestyramine significantly reduced the bioavailability of fluvastatin and pravastatin when the HMG-CoA reductase inhibitor was given 1 hour before and up to 4 hours after the cholestyramine dose. However, in clinical studies cholestyramine and HMG-CoA reductase inhibitors had additive cholesterol-lowering effects. The relevance of these cholestyramine drug interaction findings to colestipol is unknown.

Drug Interactions with Other Drugs: Antibiotics: When co-administered, colestipol significantly reduced the bioavailability of penicillin G (Cmax reduced 79%, AUC reduced 84%) and tetracycline (Cmax reduced 52% and AUC reduced 59%). Colestipol had little effect on clindamycin bioavailability.

Anticoagulants: Colestipol had little effect on the bioavailability of warfarin sodium or phenprocoumon.

Anticonvulsants: Colestipol had little or no effect on the bioavailability of phenytoin or carbamazepine.

Antihypertensives: Repeated doses of colestipol given prior to a single dose of propranolol have been reported to decrease propranolol absorption. However, in a follow-up study involving healthy volunteers, single dose administration of colestipol and propranolol, twice-a-day administration for 5 doses of both agents, did not affect the extent of propranolol absorption, but had a small yet statistically significant effect on its rate of absorption. The time to reach maximum concentration was delayed approximately 30 minutes. Therefore, patients on propranolol should be observed when colestipol is either added or deleted from a therapeutic regimen. The effects on the absorption of other beta-blockers have not been determined. Colestipol had little effect on the bioavailability of methyldopa.

Anti-inflammatory Agents: Colestipol had little effect on the bioavailability of ASA.

Cardiac Glycosides: Particular caution should be exercised with digitalis preparations because there are conflicting results about the effects of colestipol on the bioavailability of digoxin and digitoxin in clinical and animal studies. In a single-dose, crossover study in healthy volunteers, the Cmax and AUC of digoxin did not differ when digoxin was co-administered with colestipol vs. when digoxin was given alone (Cmax was 118% and AUC was 97% of the values determined with digoxin alone). Since the potential for binding of digoxin and digitoxin to colestipol may exist, the serum digoxin and digitoxin levels should be monitored during periods of administration or discontinuation of colestipol products.

Diuretics: Colestipol significantly lowered the bioavailability of hydrochlorothiazide (Cmax reduced 14%, 24-hour urinary excretion reduced 31%), chlorothiazide (urinary excretion reduced 58%) and furosemide (Cmax reduced 86%, AUC reduced 79%).

Hypoglycemic Agents: Colestipol had little effect on the bioavailability of tolbutamide.

Nonmedicinal Ingredients: 1) Silicon Dioxide: The granules and the tablets contain silicon dioxide that can adversely influence patients with irritable bowel syndrome, diverticulosis and diverticulitis. 2) Aspartame: The orange granules contain aspartame. Phenylketonurics are sensitive to the phenylalanine in aspartame.

Adverse Reactions: The most frequently encountered adverse effects in clinical trials with colestipol products are gastrointestinal. Constipation is the major single complaint and at times is severe and occasionally accompanied by fecal impaction. Hemorrhoids may be aggravated. Most instances of constipation are mild, transient and controlled with standard treatment. See Precautions for recommendation on how to minimize constipation side effect. Predisposing factors for most complaints of constipation are high dose and increasing age (more than 60 years of age).

Less frequent gastrointestinal complaints are abdominal discomfort (abdominal pain and cramping), bloating, flatulence, indigestion, heartburn, nausea, vomiting, diarrhea and loose stools.

Peptic ulceration, gastrointestinal irritation and bleeding, cholecystitis and cholelithiasis have been rarely reported and are not necessarily drug related. Bleeding hemorrhoids and blood in the stool have been infrequently reported.

Other rarely reported adverse reactions include rash, urticaria, dermatitis, muscle and joint pains, arthritis, headache, dizziness, anxiety, vertigo, drowsiness, anorexia, fatigue, weakness, and shortness of breath.

Transient and modest elevations of AST, ALT and serum alkaline phosphatase were infrequently observed in patients treated with colestipol.

During initial registration studies for the granules, adverse reactions occurring at a frequency of 0.1% or more are listed by body system as follows:

Gastrointestinal: (10%): constipation; (1 to 5%): abdominal pain and distension, belching, flatulence, nausea, vomiting, diarrhea; (0.1 to 1%): peptic ulceration, gastrointestinal irritation and bleeding, cholecystitis, cholelithiasis.

Hypersensitivity: (0.1 to 1%): urticaria, dermatitis.

Musculoskeletal: (0.1 to 1%): muscle and joint pains, arthritis.

Neurologic: (0.1 to 1%): headache, dizziness, anxiety, vertigo, drowsiness.

Miscellaneous: (0.1 to 1%): anorexia, fatigue, weakness, shortness of breath.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with colestipol has not been reported. Should overdosage occur, 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.

Dosage And Administration: Treatment for elevated serum cholesterol levels should begin with dietary therapy. Patients should be placed on a standard cholesterol-lowering diet at least equivalent to the American Heart Association (AHA) Step 1 Diet, which should be continued during treatment. If appropriate, a programme of weight control and physical exercise should be implemented. A minimum of 6 months of dietary therapy and counselling should usually be undertaken before initiating drug therapy. Shorter periods can be considered in patients with severe elevations of LDL-C (greater than 225 mg/100 mL or 5.85 mmol/L) or with definite coronary heart disease. Drug therapy should be added to dietary therapy and not substituted for it.

Granules and Orange Granules: Adults: Recommended in doses of 5 to 30 g/day of colestipol given once or in divided doses. Initiation of therapy is recommended at 5 g either once or twice a day, with daily increments of 5 g no more frequently than at 1 month intervals.

Tablets: Adults: Recommended in doses of 2 to 16 g/day given once or in divided doses. Initiation of therapy is recommended at 2 g either once or twice a day. Dosage increments of 2 g once or twice daily may be instituted no more frequently than at 1 month intervals.

Serum cholesterol (total, fractionated and triglyceride levels) should be monitored periodically. Consideration should be given to reducing the dosage of colestipol if serum cholesterol levels fall below the targeted range, such as that recommended by the Second Report of the U.S. National Cholesterol Education Program (NCEP). If the desired serum cholesterol levels are not obtained at maximal colestipol doses with good compliance and acceptable side effects, combination lipid lowering therapy or alternate treatment should be considered.

According to the U.S. NCEP Expert Panel, children 10 years and older can be considered for drug therapy after an adequate trial of diet therapy alone is unsuccessful. If drug therapy is initiated, diet therapy should be continued in order to make the entire treatment regimen as effective as possible. The dose of colestipol used is not related to the body weight of the child but to the levels of total and LDL cholesterol after an adequate trial of diet therapy. Initially start the child on the lowest dose of the granules or orange granules. If needed, this dose is increased gradually over time in order to achieve the required total and LDL cholesterol levels. Breakfast and dinner are preferred times for the administration of this medication to children (see Precautions, Children).

Preparation: The granules and orange granules should always be taken mixed in a liquid such as water or a beverage; or in foods such as cereals, soups, yogurt, pudding, cottage cheese or pulpy fruits.

To avoid accidental inhalation or esophageal distress, the granules and orange granules should not be taken in their dry form.

With beverages: 1. Add the prescribed amount of granules or orange granules to a glass (100 mL or more) of water, milk, flavored drink, juice (orange, tomato, pineapple, etc.), or carbonated beverage. A heavy or pulpy juice may minimize complaints relative to consistency. An unsweetened juice may improve palatability. 2. Stir the mixture until the medication is completely suspended. The granules and orange granules will not dissolve in the liquid. 3. After drinking the mixture, rinse the glass with a small amount of additional beverage to make sure all the medication is taken.

With cereals, soups and fruits: The granules or orange granules may be taken with milk in hot or regular breakfast cereals, or in soups with a high fluid content. It may also be added to fruits that are pulpy such as crushed pineapple, pears, peaches, or fruit cocktail.

The tablets should be swallowed whole. Do not cut, chew or crush the tablets. The prescribed amount of tablets can be taken with water or any other appropriate fluid based on patient preference. The tablets should be taken with meals.

Availability And Storage: Granules: Each packet contains: colestipol HCl 5 g. Nonmedicinal ingredients: silicon dioxide. Cartons of 30 foil packets.

Orange Granules: Each level scoop or packet contains: 7.5 g orange granules equivalent to 5 g colestipol HCl. Nonmedicinal ingredients: aspartame (phenylalanine 18.2 mg/7.5 g granules), artificial flavor, beta carotene, citric acid, glycerin, maltol, mannitol, methylcellulose, natural flavor. Bottles of 450 g (equivalent to approximately 60 doses) with a scoop. Cartons of 30 foil packets.

Tablets: Each light yellow, film-coated tablet contains: colestipol HCl 1 g. Nonmedicinal ingredients: carnauba wax, cellulose acetate phthalate, colloidal silicon dioxide, magnesium stearate, methylhydroxypropylcellulose, povidone and triacetin. The tablets contain no calories. Bottles of 120.

Store at controlled room temperature (15 to 30°C). Protect from moisture and humidity.

COLESTID® Pharmacia & Upjohn Colestipol HCl Oral Antihypercholesterolemic

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