Colestid®

colestipol hydrochloride tablets

DESCRIPTION
The active ingredient in COLESTID Tablets is micronized colestipol hydrochloride,
which is a lipid lowering agent for oral use. Colestipol 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.

Each COLESTID Tablet contains one gram of micronized colestipol hydrochloride.

COLESTID Tablets are light yellow in color and are tasteless and odorless. Inactive
ingredients: cellulose acetate phthalate, glyceryl triacetate, carnauba wax, hypromellose,
magnesium stearate, povidone, silicon dioxide. COLESTID Tablets contain no calories.

CLINICAL PHARMACOLOGY
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 the 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 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 LDL 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

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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
response.1

In a large, placebo-controlled, multiclinic study, the LRC-CPPT2, 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 LDL-C. Over the 7-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 (CHD) death plus nonfatal myocardial infarction
(cumulative incidences of 7% cholestyramine and 8.6% placebo). The subjects included
in the study were middle-aged men (aged 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 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 (HDL-C).

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-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 COLESTID Granules plus either nicotinic acid or lovastatin. When
compared to conventional measures, intensive lipid-lowering combination therapy

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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

INDICATIONS AND USAGE

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

COLESTID Tablets are indicated as adjunctive therapy to diet for the reduction of
elevated serum total and LDL-C in patients with primary hypercholesterolemia (elevated
LDL-C) who do not respond adequately to diet. Generally, COLESTID Tablets have no
clinically significant effect on serum triglycerides, but with their 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.

LDL-Cholesterol
mg/dL (mmol/L)
Definite Two or More Initiation Goal
Atherosclerotic Other Risk Level
Disease* Factors**
No No ≥190 <160
(≥4.9) (<4.1)
No Yes ≥160 <130
(≥4.1) (<3.4)
Yes Yes or No ≥130 ≤100
(≥3.4) (≤2.6)
* Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
** Other risk factors for coronary heart disease (CHD) include: age (males: ≥45 years; female: ≥55 years
or premature menopause without estrogen replacement therapy); family history of premature CHD;
current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (0.91 mmol/L); and diabetes
mellitus. Subtract one risk factor if HDL-C is ≥60 mg/dL (1.6 mmol/L).

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CONTRAINDICATIONS
COLESTID Tablets are contraindicated in those individuals who have shown
hypersensitivity to any of their components.

PRECAUTIONS
Prior to initiating therapy with COLESTID Tablets, 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 COLESTID Tablets 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.

COLESTID Tablets 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 2 grams
once or twice a day. 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 a further 2 to 4 grams/day (at monthly
intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the
desired therapeutic response is not achieved at 2 to 16 grams/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 COLESTID Tablets 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.

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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 hyperchloremia acidosis.

Carcinogenesis, Mutagenesis and Impairment of Fertility

In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent
similar to colestipol hydrochloride) 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 COLESTID Tablets is not known. In the LRC-CPPT study
referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both
treatment groups. When the many different categories of tumors are examined, various
alimentary system cancers were somewhat more prevalent in the cholestyramine group.
The small numbers and the multiple categories prevent conclusions from being drawn.
Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned
for cause-specific mortality and cancer morbidity. When colestipol hydrochloride 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 hydrochloride was not
mutagenic.

Use in Pregnancy
Since colestipol hydrochloride is essentially not absorbed systemically (less than 0.17%
of the dose), it is not expected to cause fetal harm when administered during pregnancy in
recommended dosages. There are no adequate and well-controlled studies in pregnant
women, and the known interference with absorption of fat-soluble vitamins may be
detrimental even in the presence of supplementation. The use of COLESTID tablets in
pregnancy or by women of childbearing potential requires that the potential benefits of
drug therapy be weighed against possible hazards to the mother or child.

Nursing Mothers
Caution should be exercised when COLESTID Tablets are administered to a nursing
mother. The possible lack of proper vitamin absorption described in the “Pregnancy”
section may have an effect on nursing infants.

Pediatric Use
Safety and effectiveness in the pediatric population have not been established.

Information for Patients

COLESTID Tablets may be larger than pills you have taken before. If you have had
swallowing problems or choking with food, liquids or other tablets or capsules in the
past, you should discuss this with your doctor before taking COLESTID Tablets.

It is important that you take COLESTID Tablets correctly:

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 1. Always take one tablet at a time and swallow promptly.
2. Swallow each tablet whole. Do not cut, crush, or chew the tablets.
3. COLESTID Tablets must be taken with water or another liquid that you prefer.
Swallowing the tablets will be easier if you drink plenty of liquid as you swallow
each tablet.

Difficulty swallowing and temporary obstruction of the esophagus (the tube between
your mouth and stomach) have been rarely reported in patients taking COLESTID
Tablets. If a tablet does get stuck after you swallow it, you may notice pressure or
discomfort. If this happens to you, you should contact your doctor. Do not take
COLESTID Tablets again without your doctor’s advice.

If you are taking other medications, you should take them at least one hour before or four
hours after taking COLESTID Tablets.

DRUG INTERACTIONS
Since colestipol hydrochloride is an anion exchange resin, it may have a strong affinity
for anions other than the bile acids. In vitro studies have indicated that colestipol
hydrochloride binds a number of drugs. Therefore, COLESTID Tablets may delay or
reduce the absorption of concomitant oral medication. The interval between the
administration of COLESTID Tablets and any other medication should be as long as
possible. Patients should take other drugs at least one hour before or four hours after
COLESTID Tablets to avoid impeding their absorption.

Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in

human trials have been reported to decrease propranolol absorption. However, in a
follow-up study in normal subjects, single-dose administration of colestipol
hydrochloride and propranolol and twice-a-day administration for 5 days 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. Effects on the absorption of other beta-blockers have
not been determined. Therefore, patients on propranolol should be observed when
COLESTID Tablets are either added or deleted from a therapeutic regimen.

Studies in humans show that the absorption of chlorothiazide as reflected in urinary

excretion is markedly decreased even when administered one hour before colestipol
hydrochloride. The absorption of tetracycline, furosemide, penicillin G,
hydrochlorothiazide, and gemfibrozil was significantly decreased when given
simultaneously with colestipol hydrochloride; these drugs were not tested to determine
the effect of administration one hour before colestipol hydrochloride.

No depressant effect on blood levels in humans was noted when colestipol hydrochloride
was administered with any of the following drugs: aspirin, clindamycin, clofibrate,
methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin or warfarin. Particular
caution should be observed with digitalis preparations since there are conflicting results
for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin. The

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potential for binding of these drugs if given concomitantly is present. Discontinuing
colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is
significantly bound to the resin has been titrated to a maintenance level while the patient
was taking colestipol hydrochloride.

Bile acid binding resins may also interfere with the absorption of oral phosphate
supplements and hydrocortisone.

A study has shown that cholestyramine binds bile acids and reduces mycophenolic acid
exposure. As colestipol also binds bile acids, colestipol may reduce mycophenolic acid
exposure and potentially reduce efficacy of mycophenolate mofetil.

ADVERSE REACTIONS
Gastrointestinal
The most common adverse reactions are confined to the gastrointestinal tract. To achieve
minimal GI disturbance with an optimal LDL-C lowering effect, a gradual increase of
dosage starting with 2 grams, once or twice daily is recommended. Constipation is the
major single complaint and at times is severe. Most instances of constipation are mild,
transient, and controlled with standard treatment. Increased fluid intake and inclusion of
additional dietary fiber should be the first step; a stool softener may be added if needed.
Some patients require decreased dosage or discontinuation of therapy. Hemorrhoids may
be aggravated.

Other, less frequent gastrointestinal complaints consist of abdominal discomfort

(abdominal pain and cramping), intestinal gas (bloating and flatulence), indigestion and
heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and
blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and
cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride
granules, and are not necessarily drug related.

Difficulty swallowing and transient esophageal obstruction have been rarely reported in
patients taking COLESTID Tablets.

Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine

aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more
occasions in various patients treated with colestipol hydrochloride.

The following nongastrointestinal adverse reactions have been reported with generally
equal frequency in patients receiving COLESTID Tablets, colestipol granules, or placebo
in clinical studies:

Cardiovascular
Chest pain, angina, and tachycardia have been infrequently reported.

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Hypersensitivity
Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in
patients receiving colestipol hydrochloride granules.

Musculoskeletal
Musculoskeletal pain, aches and pains in the extremities, joint pain and arthritis, and
backache have been reported.

Neurologic
Headache, migraine headache, and sinus headache have been reported. Other infrequently
reported complaints include dizziness, light-headedness, and insomnia.

Miscellaneous
Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have
been infrequently reported.

OVERDOSAGE
Overdosage of COLESTID Tablets 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.

DOSAGE AND ADMINISTRATION

For adults, COLESTID Tablets are recommended in doses of 2 to 16 grams/day given
once or in divided doses. The starting dose should be 2 grams once or twice daily.
Dosage increases of 2 grams, once or twice daily should occur at 1- or 2-month intervals.
Appropriate use of lipid profiles as per NCEP guidelines including LDL-C and
triglycerides, is advised so that optimal but not excessive doses are used to obtain the
desired therapeutic effect on LDL-C level. If the desired therapeutic effect is not obtained
at a dose of 2 to 16 grams/day with good compliance and acceptable side effects,
combined therapy or alternate treatment should be considered.

COLESTID Tablets must be taken one at a time and be promptly swallowed whole, using
plenty of water or other appropriate liquid. Do not cut, crush, or chew the tablets. Patients
should take other drugs at least one hour before or four hours after COLESTID Tablets to
minimize possible interference with their absorption. (See DRUG INTERACTIONS.)

Before Administration of COLESTID Tablets

1. Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
2. Institute a trial of diet and weight reduction.
3. Establish baseline serum total and LDL-C and triglyceride levels.

During Administration of COLESTID Tablets

1. The patient should be carefully monitored clinically, including serum cholesterol
and triglyceride levels. Periodic determinations of serum cholesterol levels as

8
 outlined in the NCEP guidelines should be done to confirm a favorable initial and
long-term response.
2. Failure of total or LDL-C to fall within the desired range should lead one to first
examine dietary and drug compliance. If these are deemed acceptable, combined
therapy or alternate treatment should be considered.
3. Significant rise in triglyceride level should be considered as indication for dose
reduction, drug discontinuation, or combined or alternate therapy.

HOW SUPPLIED
COLESTID Tablets are yellow, elliptical, imprinted U, and are supplied as follows:
Bottles of 120 NDC 0009-0450-03

Each tablet contains 1 gram of micronized colestipol hydrochloride.

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

REFERENCES
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 1993; 269(23):3015–
3023.
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 1984; 251:351–364.
3. Parra HJ, et al. Differential electroimmunoassay of human LpA-I lipoprotein
particles on ready-to-use plates. Clin. Chem. 1990; 36(8):1431–1435.
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.
1987; 142(1):63–69.
5. Kane JP, et al. Normalization of low-density-lipoprotein levels in heterozygous
familial hypercholesterolemia with a combined drug regimen. N Engl. J. Med.
1981; 304:251–258.
6. Illingworth DR, et al. Colestipol plus nicotinic acid in treatment of heterozygous
familial hypercholesterolemia. Lancet 1981; 1:296–298.
7. Kuo PT, et al. Familial type II hyperlipoproteinemia with coronary heart disease:
Effect of diet-colestipol-nicotinic acid treatment. Chest 1981; 79:286–291.
8. Blankenhorn DH, et al. Beneficial Effects of Combined Colestipol-Niacin
Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts. JAMA
1987; 257(23):3233–3240.
9. Cashin-Hemphill L, et al. Beneficial Effects of Colestipol-Niacin on Coronary
Atherosclerosis: A 4-Year Follow-up. JAMA 1990; 264:3013–3017.
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. 1990; 323:1289–1298.

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

Rx only

LAB-0053-5.0
Revised May 2017

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