4.1. Therapeutic indications

This medicine is used for:

1. Primary prevention of coronary heart disease in men between 35 and 59 years of age and with primary hypercholesterolaemia who have not responded to diet and other appropriate measures.

2. Reduction of plasma cholesterol in hypercholesterolaemia, particularly in those patients who have been diagnosed as Fredrickson's Type II (high plasma cholesterol with normal or slightly elevated triglycerides).

3. Relief of pruritus associated with partial biliary obstruction and primary biliary cirrhosis.

4. Relief of diarrhoea associated with ileal resection, Crohn's disease, vagotomyand diabetic vagal neuropathy.

5. Management of radiation-induced diarrhoea.

4.2. Posology and method of administration

Posology

Adults:

1. Monotherapy: For primary prevention of coronary heart disease and to reduce cholesterol: After initial introduction over a three to four week period, 3 to 6 sachets per day, administered either as a single daily dose or in divided doses up to four times daily, according to dosage requirements and patient acceptability. Dosage may be modified according to response and can be increased to 9 sachets per day if necessary.

Occasional slight gastrointestinal upsets, e.g. constipation, may occur when starting Colestyramine. These usually pass with continued usage of Colestyramine and are minimised by starting therapy gradually.

Final dose required

Week 1

Week 2

Week 3

Week 4

Sachets per day

3

1

2

3

3

4

1

2

3

4

6

1

2

3

6

Combination therapy

The cholesterol-lowering effect of colestyramine on total and LDL-cholesterol is enhanced when it is combined with an HMG-CoA reductase inhibitor (e.g. pravastatin, simvastatin, lovastatin). Enhanced lowering of LDL-cholesterol is also seen with combined nicotinic acid/colestyramine therapy. There is also evidence to support the addition of colestyramine to gemfibrozil therapy in order to further lower LDL-cholesterol in patients with high LDL- cholesterol and triglycerides and low HDL-cholesterol.

2. To relieve pruritus: One or two sachets daily are usually sufficient.

3. To relieve diarrhoea: As for reduction of cholesterol but it may be possible to reduce this dosage. In all patients presenting with diarrhoea induced by bile acid malabsorption, if a response is not seen within 3 days, then alternative therapy should be initiated.

Doses of more than 24 g a day of colestyramine resin may interfere with normal fat absorption.

Paediatric population

Children 6 - 12 years:

The initial dose is determined by the following formula:

Subsequent dosage adjustment may be necessary where clinically indicated.

To minimise potential gastrointestinal side effects, it is desirable to begin all therapy in children with one dose of this medicine daily. The dosage is then increased gradually, every five to seven days to the desired level for effective control.

Children under 6 years:

Colestyramine should not be used in children under 6 years. There are no data to support its use.

Colestyramine should not be used in patients with exudative or bloody diarrhoea.

Elderly:

No dosage adjustment is necessary.

Method of administration

As a precautionary measure, where concurrent drug therapy exists then such drugs should be administered at least one hour before or 4-6 hours after taking this medicine.

Colestyramine should not be taken in its dry form.

Colestyramine should be administered mixed with water or a suitable liquid, such as fruit juice, and stirred to a uniform consistency.

Colestyramine may also be mixed with skimmed milk, thin soups, pulpy fruits with high moisture content, e.g. apple sauce, etc.

The suggested time of administration is mealtime, but this may be modified to avoid interference with absorption of other medications.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In patients with complete biliary obstruction, since this medicine cannot be effective where bile is not secreted into the intestine.

4.4. Special warnings and precautions for use

Before instituting therapy with Colestyramine, diseases contributing to increased blood cholesterol such as hypothyroidism, diabetes mellitus, nephrotic syndrome, dysproteinaemias and obstructive liver disease should be investigated and specifically treated. In addition, prior to instituting therapy with Colestyramine, an attempt should be made to control serum cholesterol by appropriate dietary regimen, weight reduction, and the treatment of any underlying disorder which might be the cause of the hypercholesterolaemia. Serum cholesterol levels should be determined frequently during the first few months of therapy and periodically thereafter. A favourable trend in cholesterol reduction should occur during the first month of Colestyramine therapy. The therapy should be continued to sustain cholesterol reduction. Serum triglyceride levels should be measured periodically to detect whether significant changes have occurred.

Reduction of serum folate concentrations has been reported in children with familial hypercholesterolaemia. Supplementation with folic acid should be considered in these cases.

Since Colestyramine may interfere with the absorption of fat-soluble vitamins, the diet may require supplementation with Vitamins A, D and K during prolonged high dose administration.

Chronic use of this medicine may be associated with increased bleeding tendency due to hypoprothrombinaemia associated with Vitamin K deficiency. This will usually respond promptly to parenteral Vitamin K administration. Recurrences can be prevented by oral administration of Vitamin K.

Since colestyramine may bind other drugs given concurrently, the interval between the administration of colestyramine and other medication should be as great as is feasible. Patients should take other drugs at least one hour before or four to six hours after colestyramine to avoid impeding their absorption.

There is a possibility that prolonged use of colestyramine resin in high doses may produce hyperchloremic acidosis, since it is the chloride form of an anion exchange resin. This is especially true in younger and smaller patients where the relative dosage may be higher as well as in patients with renal impairment.

Colestyramine may produce or aggravate pre-existing constipation or related conditions, such as haemorrhoids. In patients with constipation, the dosage of colestyramine should be decreased, since it may produce impaction. In patients presenting with clinically symptomatic coronary artery disease, where straining of the stool is to be avoided, the dosage of this medicine should be titrated to avert constipation.

This medicine contains 3.79 g sucrose in each sachet. This should be taken into account in patients with diabetes mellitus.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicine contains 97.5 mg propylene glycol (as alginate) in each sachet.

If the patient is less than 5 years old, co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects. For propylene glycol doses exceeding 50 mg/kg/day, medical monitoring is required in patients with impaired renal or hepatic function.

4.5. Interaction with other medicinal products and other forms of interaction

Colestyramine may delay or reduce the absorption of certain drugs (such as digitalis, tetracycline, chlorothiazide, warfarin and thyroxine). The discontinuation of Colestyramine could pose a hazard to health if a potentially toxic drug such as digitalis has been titrated to a maintenance level while the patient was taking this medicine. The response to concomitant medication should be closely monitored and appropriate adjustments made if necessary.

Colestyramine may interfere with the pharmacokinetics of drugs that undergo enterohepatic recirculation. Colestyramine in combination with spironolactone may increase the potential for the development of hyperchloraemic acidosis.

Patients should take other drugs at least one hour before or 4-6 hours after taking this medicine to minimise possible interference with their absorption.

Tabulated list of Colestyramine drug-drug interactions:

Drug Class

Drug(s)

Anti-arrhythmics

Amiodarone

Anti-convulsants

Valproate

Anti-infectives

Vancomycin, tetracycline

Antimetabolites

Methotrexate

Bile acids

Ursodeoxycholic acid

Cholesterol lowering drugs

Ezetimibe

Combined hormonal contraceptive

Ethinylestradiol

Coumarins

Phenprocoumon, warfarin

Digitalis glycosides

Digitoxin, digoxin

Disease-modifying antirheumatics

Leflunomide

Immunosuppressants

Mycophenolate

Loop Diuretics

Furosemide

Nonsteroidal anti-inflammatory drugs

Diclofenac, meloxicam, piroxicam, sulindac, tenoxicam

Potassium sparing diuretics

Spironolactone

Thiazide diuretics

Chlorothiazide, hydrochlorothiazide

Thyroid hormones

Levothyroxine, liothyronine, thyroid extract

4.6. Fertility, pregnancy and lactation

The safety of colestyramine in pregnancy and lactation has not been established and the possibility of interference with absorption of fat-soluble vitamins should be considered.

4.7. Effects on ability to drive and use machines

This medicine has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

The most common adverse reaction is constipation. Predisposing factors for most of these complaints when this medicine is used as a cholesterol lowering agent are: high dose and increased age (more than 60 years old). Most instances of constipation are mild, transient and controlled with conventional therapy. Some patients require a temporary decrease in dosage or discontinuation of therapy.

Tabulated list of adverse reactions:

System Organ Class

Frequency

Adverse Reaction(s)

Blood and lymphatic system disorders

Uncommon

Bleeding tendencies due to hypoprothrombinaemia (Vitamin K deficiency) as well as Vitamin A (night blindness has been reported rarely) and D deficiencies

Not known

Anaemia

Metabolism and nutrition disorders

Uncommon

Anorexia, hyperchloremic acidosis in children and patients with renal impairment

Not known

Oedema

Gastrointestinal disorders

Very common

Constipation

Uncommon

Abdominal discomfort, flatulence, nausea, vomiting, diarrhoea, heartburn, dyspepsia and steatorrhea

Rare

Reports of intestinal obstruction have been received post marketing, including deaths in paediatric patients

Not known

Acute abdominal symptom complex ("pasty mass" in the transverse colon on X-ray), eructation

Skin and subcutaneous tissue disorders

Uncommon

Rash and irritation of skin, tongue and perianal area

Musculoskeletal and connective tissue disorders

Uncommon

Osteoporosis

Not known

Arthritis, backache

Renal and urinary disorders

Not known

Calcified material has occasionally been observed in the biliary tree (including calcification of the gall bladder), burnt odour to urine

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

One case of medication error experienced heartburn and nausea after taking colestyramine 27 g three times a day for a week. The potential problem in overdosage 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.