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Cholestyramine (Oral-Local)


VA CLASSIFICATION
Primary: CV359
Secondary: AD400; DE890; GA208; GU900

Commonly used brand name(s): Questran; Questran Light.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihyperlipidemic—

antipruritic (cholestasis)—

antidiarrheal (postoperative colonic bile acids)—

antidote (anion-exchange resin)—

antihyperoxaluric—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hyperlipidemia (treatment)—Cholestyramine is indicated for use in patients with primary hypercholesterolemia (type IIa hyperlipidemia) and a significant risk of coronary artery disease who have not responded to diet or other measures alone. {28} {29} Cholestyramine reduces plasma total cholesterol and low density lipoprotein (LDL) concentrations, {28} {29} but causes no change or a slight increase in serum triglyceride concentrations, and so is not useful in patients with elevated triglyceride concentrations alone. Its use is limited in other types of hyperlipidemia (including type IIb) because it may cause further elevation of triglycerides.
—Studies have suggested that control of elevated cholesterol and triglycerides may not lessen the danger of cardiovascular disease and mortality, although incidence of nonfatal myocardial infarctions may be decreased.
—For additional information on initial therapeutic guidelines related to the treatment of hyperlipidemia, see Appendix III.
—Cholestyramine is indicated to reduce the risks of atherosclerotic heart disease and myocardial infarctions.

Pruritus, associated with partial biliary obstruction (treatment)—Cholestyramine is indicated for the relief of pruritus associated with partial biliary obstruction (including primary biliary cirrhosis and various other forms of bile stasis). It is not useful in patients with complete biliary obstruction or with pruritus due to other causes. {01} {08} {28} {29}

[Diarrhea, due to bile acids (treatment)]—Cholestyramine has also been used to treat diarrhea caused by increased bile acids in the colon after surgery, although the risk of steatorrhea is increased. {06} {09}

[Hyperoxaluria (treatment)]1—Cholestyramine is also being used in the treatment of hyperoxaluria. {10} {11}

—[Cholestyramine has been used in the treatment of digitalis glycoside overdose; however, it generally has been replaced by other agents such as digoxin immune fab.{03}{12}]

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Cholestyramine is an anion-exchange resin

Mechanism of action/Effect:

Cholestyramine binds with bile acids in the intestine, preventing their reabsorption and producing an insoluble complex, which is excreted in the feces.


Antihyperlipidemic:

Cholestyramine binds with bile acids in the intestine, causing an increase in hepatic synthesis of bile acids from cholesterol. This depletion of hepatic cholesterol increases hepatic low-density lipoprotein (LDL) receptor activity, which removes LDL cholesterol from the plasma. Cholestyramine may also increase hepatic very low–density lipoprotein (VLDL) production, thereby increasing the plasma concentration of triglycerides, especially in patients with hypertriglyceridemia. {01} {02} {04} {08}



Antipruritic (cholestasis):

Reduction of serum bile acids and subsequent reduction of excess bile acids, which are deposited in dermal tissue, may lead to reduced pruritus. {01}



Antidiarrheal (postoperative colonic bile acids):

Cholestyramine binds with and removes bile acids.



Antidote (anion-exchange resin):

Because it is an anion-exchange resin, cholestyramine is capable of binding negatively charged medications as well as some others, causing a decreased effect or shortened half-life.


Absorption:

Not absorbed from the gastrointestinal tract.

Onset of action:

Reduction of plasma cholesterol concentrations—Generally reduced within 1 to 2 weeks {34} after initiation of cholestyramine therapy, but may continue to fall for up to 1 year. In some patients, after the initial decrease, serum cholesterol concentrations return to or exceed baseline levels with continued therapy.

Relief of pruritus associated with biliary stasis—Usually occurs within 1 to 3 weeks after initiation of therapy.

Relief of diarrhea associated with bile acids—Within 24 hours.

Duration of action:

Reduction of plasma cholesterol concentrations—After withdrawal of cholestyramine, cholesterol concentrations return to baseline in about 2 to 4 weeks.

Relief of pruritus associated with biliary stasis—Pruritus returns within 1 to 2 weeks when the medication is withdrawn.


Precautions to Consider

Tumorigenicity

Cholestyramine was found to increase the incidence of intestinal tumors in rats receiving potent carcinogens. {28}

Pregnancy/Reproduction

Pregnancy—
Problems in humans have not been documented. Cholestyramine is almost totally unabsorbed after oral administration; however, adverse effects on the fetus may potentially occur because of impaired maternal absorption of vitamins and nutrients. {28}

Breast-feeding

Problems in humans have not been documented. Cholestyramine is almost totally unabsorbed after oral administration. However, the possible impaired maternal vitamin and nutrient absorption may have an effect on nursing infants. {06} {28}

Pediatrics

Several studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of cholestyramine in children. {30} {31} {32} {33} {35} {36} However, experience with cholestyramine in children younger than 10 years of age is limited. Therefore, caution is recommended since cholesterol is required for normal development.


Geriatrics


Appropriate studies on the relationship of age to the effects of cholestyramine 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.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants, coumarin- or indandione-derivative    (concurrent use may significantly increase the anticoagulant effect as a result of depletion of vitamin K, but cholestyramine may also bind with oral anticoagulants in the gastrointestinal tract and reduce their effects; administration at least 6 hours before cholestyramine and adjustment of anticoagulant dosage based on frequent prothrombin-time determinations are recommended {01} {13} {28})


Chenodiol or{14}
Ursodiol{22}    (effect may be decreased when chenodiol or ursodiol is used concurrently with cholestyramine, which binds these medications and decreases their absorption and also tends to increase cholesterol saturation of bile)


» Digitalis glycosides, especially digitoxin    (cholestyramine may reduce the half-life of these medications by decreasing intestinal reabsorption and enterohepatic circulation; caution is recommended, especially when cholestyramine is withdrawn from a patient who was stabilized on the digitalis glycoside while receiving cholestyramine, because of the potential for serious toxicity; some clinicians recommend administration of cholestyramine approximately 8 hours after the digitalis glycoside {01} {13} {28})


» Diuretics, thiazide, oral or{01}{13}{15}{17}{18}
» Penicillin G, oral or{01}{25}{28}
» Phenylbutazone or{01}{13}{25}{28}
» Propranolol, oral or{01}{15}{19}{28}
» Tetracyclines, oral{01}{25}{28}    (concurrent use with cholestyramine may result in binding of these medications, thus decreasing their absorption; an interval of several hours between administration of cholestyramine and any of these medications is recommended)


Folic acid    (concurrent use with cholestyramine may interfere with absorption of folic acid; folic acid supplementation recommended in patients receiving cholestyramine for prolonged periods {01} {02})


» Thyroid hormones, including dextrothyroxine    (concurrent use with cholestyramine may decrease the effects of thyroid hormones by binding and delaying or preventing absorption; an interval of 4 to 5 hours between administration of the two medications and regular monitoring of thyroid function tests are recommended {01} {13} {28})


» Vancomycin, oral    (cholestyramine has been shown to bind oral vancomycin significantly when used concurrently, resulting in decreased stool concentrations and marked reduction in antibacterial activity of vancomycin; concurrent use is not recommended; patients should be advised to take oral vancomycin and cholestyramine several hours apart {23} {24} {25})


Vitamins, fat-soluble    (cholestyramine may interfere with absorption of fat-soluble vitamins as a result of its interference with fat absorption; supplemental vitamins A and D in water-miscible or parenteral form are recommended in patients receiving cholestyramine for prolonged periods; supplemental vitamin K may be required in some patients who develop bleeding tendencies {01} {16})


Medications, other    (cholestyramine may delay or reduce absorption of other medications administered concurrently because of its anion-binding activity; administration of other medications 1 to 2 hours before or 4 to 6 hours after cholestyramine is recommended, although absorption of some medications is impaired even then; caution is recommended when cholestyramine is withdrawn because of the risk of toxicity when suddenly increased absorption of the other medication leads to higher serum concentrations {01} {28})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase values and
Aspartate aminotransferase (AST [SGOT]) values and
Chloride concentrations, serum and
Phosphorus concentrations, serum    (may be increased)


Calcium    (serum concentrations may be decreased due to impaired absorption; may lead to osteoporosis, especially in patients with biliary cirrhosis who already have impaired calcium absorption)


Potassium and
Sodium    (serum concentrations may be decreased)


Prothrombin time (PT)    (may be prolonged {07})


Schilling test for absorption of vitamin B 1 2    (test may be falsely abnormal due to drug binding with intrinsic factor, which prevents the formation of an intrinsic factor-vitamin B 1 2 complex needed for absorption {20} {21})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Bleeding disorders{01} or
Gallstones or
Gastrointestinal function impairment or
Hypothyroidism or
Malabsorption states, especially steatorrhea or
Peptic ulcer    (these conditions may be exacerbated)


» Complete biliary obstruction or complete atresia    (no bile acids in gastrointestinal tract for cholestyramine to bind {01} {28})


» Constipation    (risk of fecal impaction {01} {28})


Coronary artery disease and
Hemorrhoids    (exacerbation of these conditions may occur because of the risks associated with severe constipation {01} {28})


» Phenylketonuria{26}    (sensitivity to phenylalanine in aspartame, which is included in sugar-free preparation)


Renal function impairment    (increased risk of development of hyperchloremic acidosis)


Sensitivity to cholestyramine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Calcium concentrations, serum    (recommended periodically because of decreased absorption of calcium associated with chronic use of cholestyramine)


Cholesterol concentrations, serum and
Triglyceride concentrations, serum    (determinations recommended prior to initiation of therapy of hyperlipidemia and at periodic intervals during therapy to confirm efficacy and determine that a positive response is maintained {01})


Prothrombin-time (PT) determinations    (recommended periodically because vitamin K deficiency associated with chronic use of cholestyramine may increase bleeding tendency {01} {28})




Side/Adverse Effects

Note: Side effects are more likely to occur with high doses and in patients over 60 years of age. {28}
Less frequently, osteoporosis has been reported as a result of chronic long-term cholestyramine use. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Constipation —usually mild and transient, but may be severe and lead to fecal impaction{01}

Incidence rare
    
Gallstones or pancreatitis (severe stomach pain with nausea and vomiting)
    
gastrointestinal bleeding or peptic ulcer{01} (black, tarry stools)
    
steatorrhea or malabsorption syndrome (sudden loss of weight)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Heartburn or indigestion{01}
    
nausea or vomiting{01}
    
stomach pain{01}

Incidence less frequent
    
Belching{01}
    
bloating{01}
    
diarrhea{01}
    
dizziness{01}
    
headache{01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cholestyramine (Oral) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cholestyramine





Use in children—Caution with use in children less than 10 years of age since cholesterol is required for normal development






Use in the elderly—Increased incidence of gastrointestinal side effects and potentially adverse nutritional effects in patients over 60 years of age

Other oral medications, especially anticoagulants, digitalis glycosides, thiazide diuretics, penicillin G, phenylbutazone, propranolol, tetracyclines, thyroid hormones, or vancomycin
Other medical problems, especially complete biliary obstruction or complete atresia, constipation, or phenylketonuria

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage
» Importance of mixing with fluids before taking; instructions for measuring and mixing—Placing in 2 ounces of any beverage and stirring vigorously, then adding 2 to 4 ounces of beverage and shaking vigorously (does not dissolve); rinsing glass and drinking to make sure all medication is taken; may also be mixed with milk in cereals, thin soups, or pulpy fruits

For use as an antihyperlipidemic
» Diet as preferred therapy; importance of following prescribed diet

This medication does not cure the condition but rather helps control it

Precautions while using this medication
» Importance of close monitoring by the physician

» Not taking any other medication unless discussed with physician

For use as an antihyperlipidemic
» Checking with physician before discontinuing medication; blood lipid concentrations may increase significantly


Side/adverse effects
Signs of potential side effects, especially constipation, gallstones, pancreatitis, gastrointestinal bleeding, peptic ulcer, and steatorrhea or malabsorption syndrome


General Dosing Information
To prevent accidental inhalation or esophageal distress with the dry form, it is recommended that cholestyramine for suspension be mixed with at least 120 to 180 mL of water or other fluids before being ingested. It may also be taken in soups or with cereals or pulpy fruits.

Reduction in cholestyramine dosage or withdrawal of the medication may be necessary in some patients if constipation occurs or worsens, to prevent impaction. Administration of a laxative or stool softener or increased fluid intake may be helpful.

For use as an antihyperlipidemic
If a paradoxical increase in plasma cholesterol concentrations occurs, it is recommended that cholestyramine therapy be withdrawn.

If response is inadequate after 1 to 3 months of treatment, cholestyramine therapy should be withdrawn, except in the case of xanthoma tuberosum, which may require up to 1 year of treatment as long as reduction in size and/or number of xanthomata occurs.

For use as an antipruritic
Dosage may be reduced when relief of pruritus occurs.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CHOLESTYRAMINE FOR ORAL SUSPENSION USP

Usual adult and adolescent dose
Antihyperlipidemic; or
Antipruritic (cholestasis); or
[Antidiarrheal, postoperative colonic bile acids]
Initial: Oral, 4 grams (anhydrous cholestyramine) one or two times a day before meals, adjusted according to response.

Maintenance: Oral, 8 to 24 grams (anhydrous cholestyramine) a day, in two to six divided doses. {28}


Note: A single daily dose or two divided daily doses are equally effective, but up to six divided daily doses may be administered and may be more convenient for the patient, especially with the larger doses. {28}


Usual adult prescribing limits
Antihyperlipidemic—24 grams (anhydrous cholestyramine) a day. {28}

Antipruritic (cholestasis)—Up to 16 grams (anhydrous cholestyramine) a day.

Usual pediatric dose
Antihyperlipidemic
Initial: Oral, 4 grams (anhydrous cholestyramine) a day, in two divided doses. {33}

Maintenance: Oral, 8 to 24 grams (anhydrous cholestyramine) a day, in two or more divided doses. {32} {33}


Size(s) usually available:
U.S.—


5 grams (4 grams of anhydrous cholestyramine) per packet or level scoop (Rx) [Questran Light (aspartame) (phenylalanine 16.8 mg per 5-gram dose)]


9 grams (4 grams of anhydrous cholestyramine) per packet or level scoop (Rx) [Questran (sucrose)]

Canada—


5 grams (4 grams of anhydrous cholestyramine) per packet or level scoop (Rx) [Questran Light (aspartame) (phenylalanine 16.8 mg per 5-gram dose)]


9 grams (4 grams of anhydrous cholestyramine) per packet or level scoop (Rx) [Questran]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Preparation of dosage form:
Cholestyramine is prepared for administration by placing the measured powder in 2 ounces of any beverage and stirring vigorously. An additional 2 to 4 ounces of beverage should then be added, again shaking vigorously (does not dissolve). After the patient drinks the suspension, the glass should be rinsed with more liquid to make sure all the medication is taken. Cholestyramine may also be mixed with milk in hot or regular breakfast cereals, in thin soups (tomato or chicken noodle), or in pulpy fruits such as pineapple, pears, peaches, or fruit cocktail. {01}

Stability:
Variations in color do not reflect changes in potency of the product. {01}

Auxiliary labeling:
   • Take mixed in cold water or juice.



Revised: 08/13/1998



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Questran product information (Bristol—US), Rec 6/89, Rev 6/88.
  1. Panel Report. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36-69.
  1. Kelley RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol 1992; 69: 108G-119G.
  1. Shepherd J. Mechanism of action of bile acid sequestrants and other lipid-lowering drugs. Cardiology 1989; 76(Suppl 1): 65-74.
  1. Crouse J. Hypertriglyceridemia: A contraindication to the use of bile acids. Am J Med 1987; 83: 243-8.
  1. Questran product monograph. In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 27th ed. Ottawa: Canadian Pharmaceutical Association, 1992: 953.
  1. Handbook of clinical drug data. 6th ed. 1988: 153.
  1. Garden J, et al. Pruritus in hepatic cholestasis. Arch Dermatol 1985; 121: 1415-20.
  1. Thompson W. A strategy for management of the irritable bowel. Am J Gastroenterol 1986; 81(2): 95-100.
  1. Williams H, Smith L. Primary hyperoxaluria, Chapter 9.
  1. Hofmann A. Acquired hyperoxaluria and intestinal disease. Mayo Clin Proc 1973; 48: 35-42.
  1. Panelist comment, 1991 revision cycle.
  1. Hansten's drug interactions, 1990.
  1. Chenix product information (U.S.), Rec 10/88.
  1. National education programs working group report on the management of patients with hypertension and high blood cholesterol. Ann Intern Med 1991; 114(3): 224-37.
  1. Roe D. Diet and drug interactions, 1989: 93.
  1. Hunninghake D, Hibbard D. Influence of time intervals for cholestyramine dosing on the absorption of hydrochlorothiazide. Clin Pharmacol Ther 1986; 39(3): 329-34.
  1. Hunninghake D, King S, LaCroix K. The effect of cholestyramine and colestipol on the absorption of hydrochlorothiazide. Int J Clin Pharmacol Ther Toxicol 1982; 20(4): 151-4.
  1. Hibbard D, Peters J, Hunninghake D. Effects of cholestyramine and colestipol on the plasma concentrations of propranolol. Br J Clin Pharmacol 1984; 18: 337-42.
  1. Panelist comment, 1990 revision cycle.
  1. Hldik W, Saha G, Study K. Essentials of nuclear medicine science. Baltimore: Williams and Wilkins, 1987: 209-10.
  1. Actigall product information (Ciba—US), Rec 1/89, Rev 6/88.
  1. King CY, Barriere SL. Analysis of the in vitro interaction between vancomycin and cholestyramine. Antimicrob Agents Chemother 1981; 19(2): 326-7.
  1. Taylor NS, Bartlett JG. Binding of Clostridium difficile cytotoxin and vancomycin by anion-exchange resins. J Infect Dis 1980; 141(1): 92-7.
  1. Manufacturer comments, 1991 revision cycle.
  1. Questran Light product information (Bristol—US), Rec 3/89, Rev 2/89.
  1. Cholybar product information (Parke-Davis—US), Rec 8/88, Rev 4/88.
  1. Questran package insert (Bristol—US), Rev 8/92, Rec 7/93.
  1. Questran Light package insert (Bristol—US), Rev 8/92, Rec 7/93.
  1. West RJ, Lloyd JK. Long-term follow-up of children with familial hypercholesterolemia treated with cholestyramine. Lancet 1980; 2: 873-5.
  1. Glueck CJ, Mellies MJ, Dine M, Perry T, Laskarzewski P. Safety and efficacy of long-term diet and diet plus bile acid binding resin cholesterol-lowering therapy in 73 children heterozygous for familial hypercholesterolemia. Pediatrics 1986; 78: 338-48.
  1. Cortner JA, Coates PM, Liacouras CA, Jarvik GP. Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management. J Pediatr 1993; 123: 177-84.
  1. Liacouras CA, Coates PM, Gallagher PR, Cortner JA. Use of cholestryramine in the treatment of children with familial combined hyperlipidemia. J Pediatr 1993; 122: 477-82.
  1. Reviewer comment, 5/94.
  1. Glueck CJ, Lewis B. Summary and recommendations of the conference on blood lipids in children: optimal levels for early prevention of coronary artery disease. Preventive Med 1983; 12(6): 728-40.
  1. Glueck CJ. Therapy of familial and acquired hyperlipoproteinemia in children and adolescents. Preventive Med 1983; 12(6): 835-47.
  1. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36-69.
  1. NIH Consensus Conference. Lowering blood cholesterol to prevent heart disease. JAMA 1985; 253: 2080-6.
  1. Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987; 2: 10-32.
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