Colestyramine

(BAN, rINN)
Colestyramine Chemical formula
Synonyms: Cholestyramine; Cholestyramine Resin; Colestiramina; Colestyraminum; Divistyramine; Kolestiramin; Kolestiraminas; Kolestyramiini; Kolestyramin; Kolestyramina; MK-135.
Cyrillic synonym: Колестирамин.

💊 Chemical information

CAS — 11041-12-6.
ATC — C10AC01.
ATC Vet — QC10AC01.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Colestyramine). A strongly basic anion-exchange resin in the chloride form, consisting of styrene-divinylbenzene copolymer with quaternary ammonium groups. Each g exchanges not less than 1.8 g and not more than 2.2 g of sodium glycocholate, calculated with reference to the dried material. A white or almost white, fine, hygroscopic powder. Insoluble in water, in alcohol, and in dichloromethane. A 1% suspension in water has a pH of 4.0 to 6.0 after standing for 10 minutes. Store in airtight containers.

USP 31

(Cholestyramine Resin). A strongly basic anion-exchange resin containing quaternary ammonium functional groups which are attached to a styrene-divinylbenzene copolymer. Each g exchanges not less than 1.8 g and not more than 2.2 g of sodium glycocholate, calculated on the dried basis. It is used in the chloride form. A white to buff-coloured, hygroscopic, fine powder, odourless or has not more than a slight amine-like odour. It loses not more than 12% of its weight on drying. Insoluble in water, in alcohol, in chloroform, and in ether. A 1% slurry in water has a pH of 4.0 to 6.0. Store in airtight containers.

💊 Adverse Effects

The most common adverse effect of colestyramine is constipation; faecal impaction may develop and haemorrhoids may be aggravated. Other gastrointestinal adverse effects include abdominal discomfort or pain, heartburn, flatulence, nausea, vomiting, and diarrhoea. xHCl n x y x y Colestyramine in high doses may cause steatorrhoea by interfering with the absorption of fats from the gastrointestinal tract and therefore decreased absorption of fat-soluble vitamins, such as vitamins A, D, E, and K, may occur. Chronic use of colestyramine may thus result in an increased bleeding tendency due to hypoprothrombinaemia associated with vitamin K deficiency; it also has a potential to cause osteoporosis due to impaired calcium and vitamin D absorption. Colestyramine is the chloride form of an anion-exchange resin and prolonged use may produce hyperchloraemic acidosis, particularly in children. Skin rashes and pruritus of the tongue, skin, and perianal region have occasionally occurred.
1. Jacobson TA, et al. Safety considerations with gastrointestinally active lipid-lowering drugs. Am J Cardiol 2007; 99 (Issue 6 suppl 1): 47C–55C.

Incidence of adverse effects.

Results of the Lipid Research Clinics Coronary Primary Prevention Trial1 involving 3806 men given colestyramine or placebo for an average of 7.4 years showed that gastrointestinal adverse effects occurred frequently in both groups but especially in the colestyramine group. In the first year 68% of the colestyramine group had at least 1 gastrointestinal adverse effect compared with 43% of the placebo group; by the seventh year the incidence had fallen to 29% and 26% respectively. Constipation and heartburn, especially, were more frequent in the colestyramine group, which also reported more abdominal pain, belching or bloating, gas, and nausea. These adverse effects were usually not severe and could be dealt with by standard clinical means. The incidence of malignant neoplasms was similar in the 2 groups although there were differences in incidence at some sites. In particular, there were 21 cases of malignancy in the gastrointestinal tract (8 fatal) in the colestyramine group compared with 11 cases (1 fatal) in the placebo group. Rare cancers of the buccal cavity or pharynx were more common with colestyramine; during the study1 there were 6 cases in the colestyramine group and none in the placebo group, and after follow-up2 for a further 6 years and reassessment of the original diagnoses the incidences were 8 and 2, respectively. However, there was no clear dose relationship, and cigarette smoking may have been a confounder.2 Colorectal malignancies were similar in the 2 groups, although at follow-up more non-malignant colorectal neoplasms had occurred in the colestyramine group.2
1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. JAMA 1984; 251: 351–64
2. The Lipid Research Clinics Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial: results of 6 years of post-trial follow-up. Arch Intern Med 1992; 152: 1399–1410.

💊 Precautions

Colestyramine powder should be given as a suspension in water or a flavoured vehicle to minimise the risk of oesophageal obstruction. Colestyramine should not be used in patients with complete biliary obstruction as it is unlikely to be effective. Because of the risk of vitamin deficiencies, supplements of vitamins A, D, E, and K should be considered during prolonged therapy with colestyramine; if given orally they need to be in a water-miscible form. Parenteral supplementation, particularly of vitamin K for hypoprothrombinaemia, may be necessary if a deficiency becomes established. Reduced serum-folate concentrations have also been reported in children with familial hypercholesterolaemia and supplementation with folic acid should be considered in such circumstances.

💊 Interactions

Colestyramine may delay or reduce the absorption of other drugs, particularly acidic drugs. Enterohepatic circulation may be reduced. Delayed or reduced absorption of thiazide diuretics, propranolol, digoxin and related glycosides, loperamide, phenylbutazone, barbiturates, oestrogens, progestogens, thyroid hormones, warfarin, and some antibacterials, has either been reported or may be expected. It is therefore recommended that other drugs should be taken at least 1 hour before, or 4 to 6 hours after, the use of colestyramine.

💊 Uses and Administration

Colestyramine is a bile-acid binding resin and lipid regulating drug. It is used to reduce cholesterol in the treatment of hyperlipidaemias, particularly type IIa hyperlipoproteinaemia, and for the primary prevention of ischaemic heart disease in middle-aged men with primary hypercholesterolaemia. Colestyramine is also used for the relief of diarrhoea associated with ileal resection, Crohn’s disease, vagotomy, diabetic vagal neuropathy, and radiation, and to relieve the pruritus associated with the deposition in dermal tissue of excess bile acids in patients with partial biliary obstruction or primary biliary cirrhosis. Colestyramine is not absorbed from the gastrointestinal tract and binds with bile acids in the intestine to form an insoluble complex that is excreted in the faeces. The normal reabsorption of bile acids is thus prevented and this leads to an increased oxidation of cholesterol to bile acids to replace those partially removed from the enterohepatic circulation, and an increased synthesis of low-density lipoprotein (LDL)-cholesterol receptors on hepatocytes. The overall effect is a reduction of total plasma-cholesterol concentration, mainly by lowering LDL-cholesterol; this may be accompanied by moderate increases in plasma triglyceride and high-density lipoprotein (HDL)-cholesterol concentrations. Since the uses of colestyramine are based upon the removal of intestinal bile acids it is unlikely that a response will be achieved in patients with complete biliary obstruction. Colestyramine may be introduced gradually over 3 to 4 weeks to minimise gastrointestinal effects. In hyperlipidaemias and diarrhoea the usual oral dose is 12 to 24 g daily, given either as a single dose or in up to 4 divided doses. Dosage should be adjusted according to the patient’s response and may be increased to 36 g daily if necessary. Lower doses may be adequate in some forms of hyperlipidaemia. In pruritus doses of 4 to 8 g daily are usually sufficient. For the use of colestyramine in children, see below. Colestyramine should be given as a suspension in water or a flavoured vehicle.
1. Insull W. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J 2006; 99: 257–73.

Administration in children.

Colestyramine has been used in children and small studies1,2 have found that it is effective in familial hypercholesterolaemia with no adverse effects on physical growth when taken long-term;2 however, compliance may be a problem.1 For hypercholesterolaemia, the BNFC gives the usual oral dose for children aged 6 to 12 years as 4 g once daily, increased to 4 g up to 3 times daily according to response. Children aged 12 to 18 years may be given an initial dose of 4 g once daily, increased to 4 to 8 g up to 4 times daily, with a maximum daily dose of 36 g. Alternatively, licensed doses are calculated from body weight, either as a percentage of the adult (70 kg) dose, or as a dose of 240 mg/kg daily in divided doses. For pruritus or diarrhoea, the BNFC recommends the following oral doses based on age:
1 month to 1 year: initially 1 g once daily, adjusted according to response to a maximum dose of 9 g daily in 2 to 4 divided doses
1 to 6 years: initially 2 g once daily, adjusted according to response to a maximum dose of 18 g daily in 2 to 4 divided doses
6 to 12 years: initially 4 g once daily, adjusted according to response to a maximum dose of 24 g daily in 2 to 4 divided doses
12 to 18 years: initially 4 to 8 g once daily, adjusted according to response to a maximum dose of 36 g daily in 2 to 4 divided doses
1. West RJ, Lloyd JK. Long-term follow-up of children with familial hypercholesterolaemia treated with cholestyramine. Lancet 1980; ii: 873–5
2. Tonstad S, et al. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr 1996; 129: 42–9.

Antibiotic-associated colitis.

Colestyramine binds Clostridium difficile toxins and there are a few reports of use as an alternative, or as an adjunct, to vancomycin or metronidazole in patients with diarrhoea associated with C. difficile toxins after antibiotic therapy. However, evidence of benefit is limited and in general its use is not recommended.

Biliary disorders.

Colestyramine is used to relieve diarrhoea associated with bile acid malabsorption and to manage pruritus and hypercholesterolaemia in patients with primary biliary cirrhosis. It has been used for pruritus in cholestasis of pregnancy,1 although such use has been associated with severe fetal intracranial haemorrhage.2 Beneficial responses have been reported with colestyramine in the management of congenital nonobstructive nonhaemolytic hyperbilirubinaemia (CriglerNajjar disease)3,4 and in sclerosing cholangitis.5
1. Jenkins JK, Boothby LA. Treatment of itching associated with intrahepatic cholestasis of pregnancy. Ann Pharmacother 2002; 36: 1462–5
2. Sadler LC, et al. Severe fetal intracranial haemorrhage during treatment with cholestyramine for intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1995; 102: 169–70
3. Arrowsmith WA, et al. Comparison of treatments for congenital nonobstructive nonhaemolytic hyperbilirubinaemia. Arch Dis Child 1975; 50: 197–201
4. Odièvre M, et al. Case of congenital nonobstructive, nonhaemolytic jaundice: successful long-term phototherapy at home. Arch Dis Child 1978; 53: 81–2
5. Polter DE, et al. Beneficial effect of cholestyramine in sclerosing cholangitis. Gastroenterology 1980; 79: 326–33.

Diabetes mellitus.

Bile acids may have a role in modulating carbohydrate metabolism and small studies have shown that bile-acid binding resins such as colestyramine reduce blood glucose.1 Their role in type 2 diabetes mellitus is under investigation; colesevelam may be used as an adjunct to standard therapy to improve glycaemic control.
1. Staels B, Kuipers F. Bile acid sequestrants and the treatment of type 2 diabetes mellitus. Drugs 2007; 67: 1383–92.

Diarrhoea.

In addition to its use in diarrhoea associated with biliary disorders (above), colestyramine has been investigated in the management of diarrhoea and faecal incontinence from other causes.1-4 See also Antibiotic-associated Colitis, above.
1. Baert D, et al. Chronic diarrhoea in non collagenous microscopic colitis: therapeutic effect of cholestyramine. Acta Clin Belg 2004; 59: 258–62
2. Balagani R, et al. Cholestyramine improves tropical-related diarrhea. Am J Ther 2006; 13: 281–2
3. Flieger D, et al. Phase II clinical trial for prevention of delayed diarrhea with cholestyramine/levofloxacin in the second-line treatment with irinotecan biweekly in patients with metastatic colorectal carcinoma. Oncology 2007; 72: 10–16
4. Remes-Troche JM, et al. Cholestyramine—a useful adjunct for the treatment of patients with fecal incontinence. Int J Colorectal Dis 2008; 23: 189–94.

Hyperthyroidism.

Bile-acid binding resins also bind thyroid hormones and may interfere with their enterohepatic circulation. Reduced serum-thyroxine concentrations have occurred in patients given bile-acid binding resins for hyperlipidaemias and both colestyramine1,2 and colestipol3 have been tried as adjunctive treatment for hyperthyroidism. Colestyramine has also been used in thyroxine overdose.4,5
1. Mercado M, et al. Treatment of hyperthyroidism with a combination of methimazole and cholestyramine. J Clin Endocrinol Metab 1996; 81: 3191–3
2. Tsai W-C, et al. The effect of combination therapy with propylthiouracil and cholestyramine in the treatment of Graves’ hyperthyroidism. Clin Endocrinol (Oxf) 2005; 62: 521–4
3. Hagag P, et al. Role of colestipol in the treatment of hyperthyroidism. J Endocrinol Invest 1998; 21: 725–31
4. Shakir KMM, et al. The use of bile acid sequestrants to lower serum thyroid hormones in iatrogenic hyperthyroidism. Ann Intern Med 1993; 118: 112–13
5. de Luis DA, et al. Light symptoms following a high-dose intentional L-thyroxine ingestion treated with cholestyramine. Horm Res 2002; 57: 61–3.

💊 Preparations

BP 2008: Colestyramine Oral Powder; USP 31: Cholestyramine for Oral Suspension.

Proprietary Preparations

Arg.: Questran; Austral.: Questran; Austria: Quantalan; Belg.: Questran; Braz.: Questran; Canad.: Novo-Cholamine; Questran†; Cz.: Questran; Vasosan†; Denm.: Questran; Fin.: Questran; Fr.: Questran; Ger.: Colesthexal†; Colestyr; Lipocol; Quantalan; Vasosan; Gr.: Questran; Hong Kong: Questran; Indon.: Questran; Irl.: Questran; Israel: Chol-Less†; Ital.: Questran; Malaysia: Questran†; Mex.: Questran; Neth.: Questran; Norw.: Questran; NZ: Questran; Pol.: Vasosan; Port.: Quantalan; S.Afr.: Questran; Singapore: Questran; Resincolestiramina†; Spain: Efensol; Lismol†; Questran†; Resincolestiramina; Swed.: Questran; Switz.: Ipocol; Quantalan; Thai.: Questran; Resincolestiramina; Turk.: Kolestran; UK: Questran; USA: Locholest; Prevalite; Questran.
Published January 21, 2019.