VA Class:CV350
Cholestyramine resin is a bile acid sequestrant antilipemic agent.
Cholestyramine resin is used as an adjunct to dietary therapy to decrease elevated serum total and low-density lipoprotein (LDL) cholesterol concentrations in the management of primary hypercholesterolemia (type IIa hyperlipoproteinemia).100, 187, 188
The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline emphasizes lifestyle modification as the foundation of atherosclerotic cardiovascular disease (ASCVD) risk reduction.400 If pharmacologic therapy is needed, hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL cholesterol, the lipoprotein fraction found to be a major cause of ASCVD.400 The addition of a nonstatin drug (e.g., ezetimibe, bile acid sequestrants, PCSK9 inhibitor) may be considered in certain circumstances such as in patients with very severe elevations of LDL-cholesterol concentrations who are not achieving adequate LDL lowering with maximally tolerated statin therapy.400 For additional details on prevention of ASCVD, see the HMG-CoA Reductase Inhibitors General Statement 24:06.08.
Dietary management often is relatively effective in young children (2-5 years of age) with heterozygous familial hypercholesterolemia; however, older children with this disorder usually require the addition of drug therapy.126 Bile acid sequestrants (e.g., cholestyramine) or statins generally are considered the initial drugs of choice for the management of dyslipidemia or primary prevention of coronary heart disease (CHD) in selected children and adolescents (i.e., those 10 years of age and older with higher risk of developing CHD) in whom initial nonpharmacologic therapy (i.e., a 6- to 12-month trial of therapeutic lifestyle changes) does not provide an adequate response. A bile acid sequestrant combined with a statin may be useful in hypercholesterolemic patients in whom initial drug therapy does not provide an adequate response or is not tolerated.357 Children with homozygous familial hypercholesterolemia usually respond poorly to combined dietary management and drug (e.g., combined bile acid sequestrant and niacin) therapy.136, 160, 161, 162, 163, 164, 165, 166, 167 More radical forms of therapy (e.g., plasma exchange,118, 130, 131, 133, 148, 165, 169, 170, 171, 172, 181 portacaval shunt,129, 132, 134, 148, 168, 181 liver transplantation)136, 148, 166, 181 combined with adjuvant drug therapy (e.g., bile acid sequestrants and niacin) and dietary management may be necessary in homozygous patients, but specialists should be consulted.118, 126, 127, 129, 130, 131, 132, 133, 134, 135, 136, 137, 148, 158, 165, 166, 168, 169, 170, 171, 172, 181
Cholestyramine and colestipol hydrochloride are equally effective in lowering serum cholesterol concentrations. The choice of bile acid sequestrant generally is individualized based on patient tolerance, including palatability and taste preference, and cost.148, 181 Cholestyramine is generally more effective in heterozygous familial hypercholesterolemia than in homozygous familial hypercholesterolemia; however, it has been reported that even among heterozygotes, response to the drug is variable. In patients with type IIb hyperlipoproteinemia, the effect of cholestyramine on very low-density lipoprotein (VLDL) and triglyceride concentrations must be carefully monitored; calorie control or adjunctive therapy may be required. In patients with primary type IIa hyperlipoproteinemia in whom a regimen of diet and cholestyramine or colestipol hydrochloride therapy has not resulted in normal serum cholesterol concentrations, niacin may be a useful addition to therapy.
In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT; a large, multicenter, placebo-controlled study), long-term (up to 7 years) administration of cholestyramine resin to asymptomatic men with primary hypercholesterolemia (type II hyperlipoproteinemia) who received dietary management was shown to reduce the risk of CHD.100, 101, 102, 103, 104, 105, 109, 110, 157, 173, 185 Average plasma concentrations of total cholesterol and LDL were reduced by 13.4 and 20.3%, respectively, in patients in this study and were associated with a 19% reduction in the combined incidence of CHD death and nonfatal myocardial infarction; however, the difference in overall mortality was similar in the cholestyramine-treated and placebo groups.100, 101, 102, 103, 105, 109, 110, 187, 188 These findings indicate that reducing plasma total cholesterol concentrations by reducing plasma LDL concentrations may decrease the incidence of morbidity and mortality associated with CHD in males at high risk of developing CHD secondary to increased plasma LDL concentrations.100, 101, 102, 103, 157, 173
Additional findings of the LRC-CPPT suggest that plasma high-density lipoprotein (HDL) cholesterol concentrations are inversely related to the risk of morbidity and mortality associated with CHD in males with hypercholesterolemia.138, 183 In cholestyramine-treated patients, each 1-mg/dL pretreatment increment above the overall mean pretreatment plasma HDL-cholesterol concentration (44.3 mg/dL) was associated with a 5.5% reduction in risk of death attributable to CHD or nonfatal myocardial infarction over a 7- to 10-year period, and each 1-mg/dL increase in plasma HDL-cholesterol during therapy from the patient's pretreatment level was associated with a 4.4% risk reduction during this period.138 Although mean HDL-cholesterol concentrations in cholestyramine-treated patients exceeded those of patients receiving placebo during each year of the trial, differences in CHD between the groups could not be explained by differences in HDL-cholesterol alone.138 Cholestyramine therapy appeared to reduce the risk of CHD to a greater extent in those patients who maintained the highest HDL-cholesterol concentrations, and it was suggested that relatively high HDL-cholesterol prior to and during therapy may have enhanced the beneficial effect of cholestyramine-induced reductions in plasma LDL concentrations on CHD risk.138
There is also some evidence that cholestyramine therapy combined with dietary management may have a beneficial effect in modifying the rate of progression of CHD in hypercholesterolemic patients with CHD (e.g., by slowing progression and/or inducing regression of atherosclerosis in coronary arteries).100, 104, 107, 111, 112, 187, 188
For further information on the role of antilipemic therapy in the treatment of lipoprotein disorders, the prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.
Pruritus Associated with Partial Cholestasis
Cholestyramine resin is used for the relief of pruritus associated with partial cholestasis. The resin provides symptomatic relief of pruritus associated with partial obstructive jaundice including primary biliary cirrhosis and other incomplete biliary obstructions; the effect of the drug on serum cholesterol in these patients is variable. Cholestyramine resin usually has no effect on pruritus or serum bile acid concentrations in patients with relatively complete biliary obstruction, and the resin is ineffective in complete atresia in which no bile products reach the intestine. Relief of pruritus usually occurs within 1-3 weeks after initiation of therapy. Withdrawal of the drug usually results in an increase in serum concentrations of bile acids and return of pruritus within 1-2 weeks.
Cholestyramine resin has been used as an adjunct in the treatment of cardiac glycoside toxicity† in a limited number of patients. When administered soon after ingestion of a cardiac glycoside, cholestyramine may reduce initial absorption of the glycoside. When administered after onset of toxicity due to digitoxin (no longer commercially available in the US), the resin also may reduce the duration of toxicity by binding digitoxin in the GI tract during enterohepatic circulation of the glycoside. However, most clinicians believe that cholestyramine is not useful when cardiac glycoside toxicity is life-threatening.
Cholestyramine has been used with some success in the management of diarrhea associated with excess fecal bile acids†, pseudomembranous colitis†, erythroprotoporphyria†, and acquired hyperoxaluria†. Cholestyramine has been used to decrease the biological half-life of chlordecone†. The resin has also been used as an adjunct in the management of chlordane toxicity to enhance the fecal elimination of heptachlor†.114
Cholestyramine resin is administered orally as a suspension prepared from the powder.100, 173 Cholestyramine suspension should be administered at mealtime.100, 187, 188 Patients should be instructed to take other drugs at least 1 hour before or 4-6 hours (or as long an interval as possible) after taking cholestyramine suspension to minimize possible interference with absorption.100, 187, 188 Although the recommended dosing schedule is twice daily, cholestyramine may be administered in 1-6 doses per day.100, 187, 188
Cholestyramine powder should not be taken in its dry form; the resin should always be mixed with water or other fluids before ingesting .100, 187, 188 Just prior to administration, each packet or level scoop of cholestyramine powder (containing 4 g of dried cholestyramine resin) should be mixed with 60-180 mL of water or another noncarbonated beverage (e.g., fruit juice).100, 186, 187, 188 Some clinicians suggest that palatability and compliance may be increased if the entire next-day's dose is mixed in one of these liquids in the evening and then refrigerated.127 Use of a heavy or pulpy fruit juice may minimize complaints about consistency of suspensions of the drug.148 To minimize excessive swallowing of air, patients should be advised to avoid rapid ingestion of suspensions of the drug.148 If a carbonated beverage is used, excessive foaming can be minimized by mixing the powder slowly in a large glass. Alternatively, cholestyramine resin may be mixed with a highly fluid soup or a pulpy fruit with a high moisture content such as applesauce or crushed pineapple.100, 157, 173
Dosage of cholestyramine is expressed in terms of the anhydrous (i.e., dried) resin. Each 9 g of Questran®100 or generic (nonproprietary) cholestyramine,188 5.5 g of Prevalite®,187 or 5 g of Questran Light®100 or generic cholestyramine light188 powder contains about 4 g of anhydrous cholestyramine resin.100, 187, 188 In calculating pediatric dosages, each 100 mg of Questran®, generic cholestyramine, Prevalite®, Questran® Light, or generic cholestyramine light powder contains 44.4,100 44.4,188 72.7,187 80,100 or 80 mg,188 respectively, of anhydrous cholestyramine resin. Dosage must be carefully adjusted according to the condition being treated and the patient's response and tolerance.
For the management of primary hypercholesterolemia, the usual adult dosage of anhydrous cholestyramine resin is 4-24 g (1-6 packets or level scoops) daily taken once or in divided doses.100, 187, 188 To optimize antilipemic effects while minimizing the risk of adverse GI effects (e.g., fecal impaction), dosage should be adjusted carefully and titrated slowly.100, 187, 188 Cholestyramine therapy generally is initiated in adults with 4 g (1 packet or level scoop) once or twice daily; if the initial dosage is well tolerated, the dosage may be titrated upward as necessary at intervals of no less than 4 weeks.100, 187, 188 In patients with preexisting constipation, the initial dosage of anhydrous cholestyramine resin should be 4 g (1 packet or level scoop) daily for 5-7 days, increasing to 4 g twice daily with monitoring of constipation and of serum lipoprotein values, at least twice, 4-6 weeks apart; if the initial dosage is well tolerated, the dosage may be increased as needed by one dose (i.e., 4 g) per day at monthly intervals.100, 187, 188 Serum lipoprotein concentrations should be determined periodically and dosage adjusted accordingly to achieve the desired effect while avoiding excessive dosage.100, 187, 188 The usual maintenance dosage recommended by the manufacturers is 8-16 g (2-4 packets or level scoops) daily, given in 2 divided doses;100, 187, 188 the usual dosage range suggested by the Third Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel [ATP] III) is 4-16 g daily.186 The maximum recommended dosage is 24 g (6 packets or level scoops) daily.100, 186, 187, 188 If constipation worsens or the desired effect is not achieved with acceptable adverse effects within the usual dosage range of 1-6 doses (i.e., 4-24 g) per day, substitution or addition of another antilipemic agent should be considered.100, 187, 188
The manufacturers state that the optimal dosage of cholestyramine resin for pediatric patients has not been established.100, 157, 173, 187, 188 Pediatric dosages of anhydrous cholestyramine resin generally have ranged from 8-16 g daily in 2 or 3 divided doses before meals.116, 117, 118, 119, 120, 124, 125 The usual pediatric dosage suggested by the manufacturers and some clinicians is 240 mg/kg daily, given in 2 or 3 divided doses, not to exceed 8 g daily.100, 187, 188 Some clinicians suggest that children older than 6 years of age be given 80 mg/kg or 2.35 g/m2 3 times daily. Alternatively, some clinicians suggest initiating cholestyramine at a pediatric dosage of 2 or 4 g twice daily before meals, and then gradually increasing the dosage until a serum total cholesterol concentration of 250 mg/dL or less is achieved or intolerable adverse effects occur.116
The most common adverse effects of cholestyramine involve the GI tract, especially after high doses (more than 24 g daily) and in patients older than 60 years of age. The most frequent adverse effect of cholestyramine resin is constipation,100, 185, 187, 188 which occurs in about 20% of patients receiving the drug; cholestyramine resin may also increase the severity of preexisting constipation. Fecal impaction and/or hemorrhoids with or without bleeding have been reported rarely in association with constipation, most often when high doses of cholestyramine have been used in children and in the elderly. One seriously ill, dehydrated 10-month-old baby with biliary atresia died subsequent to impaction and sepsis following administration of 3 g of cholestyramine 3 times daily for 3 days. Although constipation is usually mild, transient, and controllable with standard treatment, it may occasionally be severe and may aggravate hemorrhoids.100, 187, 188 In patients with preexisting constipation or in those who develop constipation during cholestyramine therapy, dosage should be decreased or the drug discontinued temporarily; in addition, increased fluid and fiber intake should be encouraged, and a stool softener or laxative may be administered occasionally to overcome the constipating effect.100, 185, 187, 188 Complete withdrawal of the drug is occasionally necessary. Particular effort should be made to avoid constipation in patients with symptomatic coronary heart disease.
Other less common adverse GI effects of cholestyramine are abdominal discomfort and/or pain, abdominal distention, bloating, flatulence, nausea, vomiting, diarrhea, eructation, anorexia, dyspepsia, heartburn, biliary colic, steatorrhea, and indigestion.100, 187, 188 Bloating and flatulence often disappear with continued therapy. Intestinal obstruction, including 2 deaths, has been reported rarely in pediatric patients.100, 187, 188 Other reported adverse GI effects include dysphagia, hiccups, ulcer attack, rectal bleeding, black stools, sour taste, pancreatitis, bleeding from known duodenal ulcer, rectal pain, and diverticulitis; however, a direct relationship of these effects to drug therapy has not been established.
Metabolic and Electrolyte Effects
Large quantities of chloride, which are liberated from cholestyramine resin, may be absorbed in place of intestinal bicarbonate and can lead to hyperchloremic acidosis and increased urinary calcium excretion. This effect is prevalent mainly with high doses or usual doses in small patients or children and may be partially offset by decreasing chloride intake. Acidosis occurred in a 10-year-old child with renal impairment who received prolonged cholestyramine therapy; therefore, prolonged therapy with the drug should be used with caution in patients with renal impairment or volume depletion and in patients receiving concomitant spironolactone.100, 187, 188 Fecal excretion of calcium has been reported to be decreased or unchanged. Increased urinary excretion of calcium may potentially lead to osteoporosis. Serum alkaline phosphatase may increase in patients receiving large doses of cholestyramine. Calcification of the biliary tree including the gallbladder has been observed in patients with biliary cirrhosis who were receiving cholestyramine resin, but this has not been attributed directly to the drug. Slight increases in urinary magnesium excretion have also been reported. Altered absorption of phosphorus and nitrogen has also been observed following administration of cholestyramine resin. Serum electrolytes should be determined periodically during cholestyramine therapy.
Adverse dermatologic effects of cholestyramine have included rash and irritation of the skin, tongue, and perianal area.
The following adverse reactions have been reported in patients receiving cholestyramine; however, a direct relationship to the drug has not been established. Urticaria, asthma, wheezing, and shortness of breath have been reported. Adverse hematologic effects include increased prothrombin time, ecchymosis, and anemia. Periodic hematologic studies should be performed during cholestyramine therapy. Claudication, xanthomata of the hands and fingers, angina pectoris and chest pain, arteritis, thrombophlebitis, myocardial infarction, and myocardial ischemia have occurred. Adverse musculoskeletal effects including backache, muscle and joint pains, and arthritis have occurred during cholestyramine therapy as have neurologic effects such as headache, anxiety, vertigo, dizziness, fatigue, tinnitus, syncope, drowsiness, femoral nerve pain, and paresthesia. Arcus juvenilis, uveitis, liver function abnormalities, hematuria, dysuria, burnt odor of the urine, diuresis, weight loss or gain, increased libido, swollen glands, edema, dental bleeding, dental caries, erosion of tooth enamel, and tooth discoloration have also been reported.100, 187, 188
Precautions and Contraindications
Prior to institution of antilipemic therapy with cholestyramine, a vigorous attempt should be made to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of the lipid abnormality. Serum cholesterol concentrations usually decrease within the first week following initiation of cholestyramine therapy, and most patients respond maximally within 1-3 weeks. Treatment may be continued as long as serum cholesterol remains below baseline concentrations. When cholestyramine is discontinued, serum cholesterol usually returns to pretreatment concentrations within 2-4 weeks. In some patients, dose-related increases in serum triglyceride concentrations may occur during cholestyramine therapy. Findings of the LRC-CPPT suggest that serum triglycerides may increase from pretreatment baseline values by 5% after 1 year of cholestyramine therapy and by 4.3% after 7 years of therapy.
Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each 5-g dose of Questran Light®, 5-g dose of generic cholestyramine light, or 5.5-g dose of Prevalite® contains aspartame (NutraSweet®), which is metabolized in the GI tract to provide about 14, 14, or 14.1 mg, respectively, of phenylalanine following oral administration.100, 173, 174, 175, 176, 177, 178, 187, 188
Cholestyramine should be used with caution in patients with GI dysfunction such as constipation. (See Cautions: GI Effects.)
Prolonged use of cholestyramine may be associated with an increased bleeding tendency as a result of hypoprothrombinemia secondary to vitamin K deficiency. (See Drug Interactions: Vitamins.) Because cholestyramine is a chloride-containing anion-exchange resin, the possibility that prolonged use of the drug may produce hyperchloremic acidosis should be considered, particularly in children and small patients. (See Cautions: Metabolic and Electrolyte Effects.)
Sipping or holding the cholestyramine suspension in the mouth for prolonged periods may lead to changes in the surface of the teeth, resulting in discoloration, erosion of enamel, or decay.100, 187, 188 Patients should be advised to maintain good oral hygiene.100, 187, 188
Cholestyramine resin is ineffective and, therefore, is contraindicated in patients with complete biliary obstruction in which no bile products reach the intestine. Cholestyramine resin is also contraindicated in patients who are hypersensitive to the drug or any ingredient in its formulation.
The manufacturers indicate that safety and efficacy of long-term administration of cholestyramine resin in children have not been established. Cholestyramine, combined with dietary management, has been used in a limited number of children for the management of hypercholesterolemia (see Uses: Dyslipidemias), but the potential effect of the resin on vitamin absorption and on electrolytes should be considered.100, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 157, 173, 181 (See Drug Interactions: Vitamins and also see Cautions: Metabolic and Electrolyte Effects.) The manufacturers also state that because of limited experience with cholestyramine resin in infants and children, an optimal dosage schedule has not been established.100, 157, 173, 187, 188
Mutagenicity and Carcinogenicity
In studies in rats in which cholestyramine resin was used as a tool to investigate the role of various GI factors (e.g., fat, bile salts, GI flora) in the development of alimentary tumors induced by potent carcinogens, the incidence of these tumors was greater in cholestyramine-treated rats than in the control group.100 The relevance of these findings to clinical use of the resin in humans is not known.100, 157, 173 In the LRC-CPPT study (see Uses: Dyslipidemias), the overall incidence of fatal and nonfatal neoplasms was similar in the cholestyramine-treated and placebo groups.100, 187, 188 When the many different categories of tumors were examined, the incidence of alimentary tract tumors was somewhat higher in the cholestyramine-treated group;100, 101, 103, 157, 173, 187, 188 however, no firm conclusions could be drawn about the importance of these findings because of the relatively small number of patients with neoplasms and the multiple categories of neoplasms examined.100, 187, 188 In view of the fact that cholestyramine resin is confined to the GI tract and not absorbed and in light of the evidence of carcinogenic potential in animals, a six-year follow-up of the LRC-CPPT study patient population was completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no substantial difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine- and placebo-treated patients.100, 187, 188
Since cholestyramine resin is not absorbed systemically, the drug is not expected to cause fetal harm when administered in usual dosages to pregnant women. However, there are no adequate and controlled studies to date using cholestyramine resin in pregnant women, and the known interference with absorption of fat-soluble vitamins may cause fetal harm even in the presence of supplementation. Currently, most experts recommend that dyslipidemias in pregnant women be managed with dietary measures;106, 148 consultation with a lipid specialist may be indicated for pregnant women with severe forms of dyslipidemia.148
Cholestyramine resin should be used with caution in nursing women, and the potential effect on the nursing infant of cholestyramine-induced interference with maternal absorption of fat-soluble vitamins should be considered.100, 157, 173
Effects on GI Absorption of Drugs
Since cholestyramine is an anion-exchange resin, it is capable of binding to a number of drugs in the GI tract and may delay or reduce their absorption. Acidic drugs are strongly adsorbed to cholestyramine, and neutral and basic drugs may be nonspecifically bound. Patients should be instructed to allow as long a time interval as possible between ingestion of other drugs and cholestyramine; however, separation of doses may not prevent interactions with drugs that undergo enterohepatic circulation. The manufacturers recommend that other drugs be administered at least 1 hour before or 4-6 hours (or as long an interval as possible) after cholestyramine.100, 157, 173
Cholestyramine resin binds to thyroid hormones in the GI tract and substantially impairs their absorption. The resin also has been shown to bind to digoxin in the GI tract and interfere with its initial absorption.
Orally administered warfarin sodium and probably other coumarin-derivative anticoagulants are bound by cholestyramine, and their absorption may be decreased. In addition, by interfering with enterohepatic circulation of warfarin, the half-life of this anticoagulant may be decreased. However, because vitamin K absorption may also be decreased by cholestyramine, the net effect of concurrent oral anticoagulant and cholestyramine therapy is difficult to predict. The possibility that discontinuance of cholestyramine in patients stabilized on an oral anticoagulant may lead to increased absorption of the anticoagulant and bleeding tendencies should be considered. Caution should be used when cholestyramine and oral anticoagulants are used concurrently, and it is probably preferable not to use cholestyramine in patients who require oral anticoagulant therapy.
Cholestyramine may decrease GI absorption of thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide).100, 140, 141, 142, 143 Single doses of cholestyramine administered concurrently with hydrochlorothiazide have resulted in approximately an 85% decrease in hydrochlorothiazide absorption.140, 141, 142, 143 Administration of cholestyramine prior to hydrochlorothiazide appears to have a greater effect on absorption than administration after the diuretic.140 Following oral administration of a single 8-g dose of cholestyramine 2 hours before or after oral administration of a single 75-mg dose of hydrochlorothiazide in healthy individuals, urinary excretion of unchanged hydrochlorothiazide over 24 hours was decreased by 65 or 26%, respectively.140 Administration of multiple doses of cholestyramine in individuals receiving hydrochlorothiazide reduced area under the concentration-time curve, peak plasma concentration, and urinary excretion of hydrochlorothiazide.140 Cholestyramine and thiazide diuretics should be administered at different times, separated by as long a time interval as possible;142 however, regardless of the interval between administration of the drugs, increased dosage of the diuretic may be necessary.140, 141, 142, 143 Some clinicians suggest that cholestyramine optimally should be administered 4 hours after administration of hydrochlorothiazide; however, at least a 30-35% reduction in hydrochlorothiazide absorption can occur with this dosing interval.140
Limited data indicate that administration of cholestyramine resin following a single oral dose of amiodarone may decrease the elimination half-life and plasma concentrations of amiodarone, possibly by interfering with enterohepatic circulation of the antiarrhythmic agent.139, 147 Further evaluation of this potential interaction is needed.139, 147
Conflicting data have been reported,144, 145 but concomitant administration of cholestyramine and propranolol may decrease GI absorption of the β-adrenergic blocking agent.100, 144, 157, 173, 180 Further studies are needed to evaluate the interaction and determine its clinical importance, if any.144, 145, 146 When cholestyramine therapy is initiated or discontinued in patients receiving oral propranolol, dosage adjustment of the β-adrenergic blocking agent may be necessary.144, 146 The effect of separating administration of the drugs remains to be evaluated.144, 146
Cholestyramine may decrease absorption of chenodiol (no longer commercially available in the US) and interfere with its action. Other drugs whose absorption may be decreased by binding to cholestyramine include iron salts, phenylbutazone, phenobarbital, tetracycline, penicillin G, loperamide, and estrogens and progestins.100, 187, 188 Concomitant administration of cholestyramine with clofibrate slightly decreases the rate of absorption of clofibrate.
Bile acid binding resins may interfere with the absorption of oral phosphate supplements.
The possibility that discontinuance of cholestyramine in patients stabilized on potentially toxic drugs that bind to the resin may lead to toxicity and that administration of cholestyramine to patients stabilized on other drugs may reduce the effect of these drugs should be considered.
Because cholestyramine binds bile acids, the drug may interfere with normal fat digestion and absorption and, therefore, may prevent absorption of fat-soluble vitamins (i.e., vitamins A, D, E, K).100, 187, 188 Vitamin deficiencies (vitamin D deficiency, hypoprothrombinemia secondary to vitamin K deficiency, and night blindness secondary to vitamin A deficiency) have been reported only rarely, however. Supplemental administration of water-miscible (or parenteral) forms of fat-soluble vitamins should be considered if cholestyramine is given for a prolonged period.100, 187, 188 Vitamin K deficiency and hypoprothrombinemia can be treated or prevented with phytonadione. If bleeding occurs in patients receiving cholestyramine, parenteral administration of phytonadione is usually valuable in promptly restoring normal clotting time, and oral administration of phytonadione can be used for the prevention of recurrent bleeding. Routine supplementation of fat-soluble vitamins in children receiving cholestyramine generally is not necessary, but serum concentrations of the vitamins and prothrombin time should be monitored periodically and the diet supplemented as necessary.100, 116, 117, 118, 119, 120, 121, 122, 124, 125, 157, 173
Reduced absorption of folic acid has been reported in patients, including children, receiving cholestyramine. Patients should be monitored for folic acid deficiency, and some clinicians recommend supplementation with 5 mg of folic acid daily, especially in children.
Overdosage of cholestyramine has been reported in at least one patient receiving 150% of the maximum recommended daily dosage for a period of several weeks; no adverse effects were reported.100, 187, 188 The principal risk of acute overdosage of the drug is expected to be GI obstruction.100, 157, 173 Specific measures for management would depend on the degree and location of obstruction and GI motility,100, 157, 173 and experts should be consulted for specific recommendations.
Cholestyramine and colestipol hydrochloride are bile acid sequestrants that have similar pharmacologic actions.
Following oral administration, cholestyramine resin releases chloride ions and adsorbs bile acids in the intestine, forming a nonabsorbable complex that is excreted along with unchanged resin in the feces. This results in partial removal of bile acids from the enterohepatic circulation. A compensatory increase in the oxidation of cholesterol to bile acids and in hepatic cholesterol production accompanies the 2- to 15-fold increase in fecal excretion of bile acids. In spite of increased production of cholesterol, plasma cholesterol and low-density lipoprotein (LDL) concentrations fall in patients with primary type II hyperlipoproteinemia, possibly secondary to an increased rate of clearance of LDL from the plasma. In very high doses, malabsorption of fats may also be a contributing factor. In patients with type II hyperlipoproteinemia receiving 12-32 g of cholestyramine resin daily, serum cholesterol decreased 20-50%. Some investigators have reported regression or disappearance of xanthomata with long-term therapy. Long-term cholestyramine therapy has been reported to cause a modest increase (less than 10%) in the high-density lipoprotein (HDL)-cholesterol fraction in patients with type II hyperlipoproteinemia,101, 102, 107, 108, 110, 111, 112 an effect that may be beneficial in slowing the progression of atherosclerosis and decreasing the risk of coronary heart disease (CHD).102, 104, 106, 107, 108, 110, 112, 115, 138 Fecal neutral sterols may be unchanged or slightly increased after administration of cholestyramine. Plasma triglyceride concentrations may increase during cholestyramine therapy, due to increases in very low-density lipoprotein (VLDL) concentrations. In patients with type II hyperlipoproteinemia receiving cholestyramine resin, mean plasma triglyceride concentrations increased approximately 5 and 4.3% over pretreatment values after 1 and 7 years of therapy with the drug, respectively, when compared with placebo. Increases in VLDL triglyceride concentrations are especially evident in patients with type III, IV, or V hyperlipoproteinemia receiving the drug; these patients may also experience increased serum cholesterol concentrations.
Assuming that pruritus in patients with cholestasis is caused by bile acid retention, cholestyramine resin may relieve pruritus by increasing fecal excretion of bile acids, thereby mobilizing bile acids deposited in the skin. Relief of pruritus is usually associated with a concomitant decrease in serum and tissue bile acid concentrations but, in some studies, concentration of serum and tissue bile acids had no consistent relationship to the intensity of pruritus.
Since cholestyramine is an anion-exchange resin, it may bind other negatively charged substances, usually those with a greater affinity for the resin than the chloride ion. (See Drug Interactions.)
Cholestyramine resin is a bile acid sequestrant antilipemic agent. The drug is the chloride form of a basic quaternary ammonium anion-exchange resin in which the basic groups are attached to a styrene-divinylbenzene copolymer. In vitro, each gram of the dried resin binds about 1100 µmol of taurocholate and 825 µmol of glycocholate. Cholestyramine resin occurs as a white to buff-colored, fine, hygroscopic powder which may have a slight, amine-like odor and is insoluble in water and in alcohol. Cholestyramine resin is commercially available as powders for oral suspension.100, 173 The commercially available powders for oral suspension are mixtures of the resin and citric acid, propylene glycol alginate, and flavors; the powders also may contain sucrose (i.e., Questran®, generic cholestyramine) or aspartame (i.e., Questran Light®, Prevalite®, generic cholestyramine light) as sweeteners, and other excipients.100, 173, 187, 188
Commercially available cholestyramine resin powder should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.100, 187, 188 The color of the commercially available products may vary between batches, but this does not affect the potency of the drug.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | For suspension | 4 g (of dried cholestyramine resin) per 9 g* | Cholestyramine | |
4 g (of dried cholestyramine resin) per 5.5 g | ||||
4 g (of dried cholestyramine resin) per 5 g* | ||||
Questran® Light | Par |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
100. Par Pharmaceutical Companies, Inc. Questran® Powder (cholestyramine for oral suspension) and Questran® Light (cholestyramine for oral suspension) prescribing information. Spring Valley, NY; 2005 Feb.
101. National Heart, Lung and Blood Institute Lipid Metabolism-Atherogenesis Branch. The Lipid Research Clinics Coronary Primary Prevention Trial results. Part I: reduction in incidence of coronary heart disease. JAMA . 1984; 251:351-64. [PubMed 6361299]
102. National Heart, Lung and Blood Institute Lipid Metabolism-Atherogenesis Branch. The Lipid Research Clinics Coronary Primary Prevention Trial results. Part II: relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA . 1984; 251:365-74. [PubMed 6361300]
103. Anon. Addition to labeling of cholestyramine. FDA Drug Bull . 1985; 15:7-8. [PubMed 3858190]
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