SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Colestyramine Powder for Oral Suspension.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient    Grams per sachet

Colestyramine resin USP    4.00

3 PHARMACEUTICAL FORM

Powder for oral suspension

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Colestyramine is indicated for:

1.    The primary prevention of coronary heart disease in middle aged men (35 -59 years of age) with primary hypercholesterolaemia who have not responded to diet and other appropriate measures.

2.    Reduction of plasma cholesterol in patients with hypercholesterolaemia, either alone or as an adjunct to diet, exercise and HMG-CoA reductase inhibitors.

3.    Symptomatic relief of pruritus in patients with primary biliary cirrhosis and partial biliary obstruction.

4.    Relief of diarrhoea associated with ileal resection, Crohn’s disease, vagotomy and diabetic vagal neuropathy.

5.    Control of radiation-induced diarrhoea.

4.2 Posology and method of administration

Dosage and administration

Colestyramine is administered orally. To minimise possible interactions, other concomitantly administered drugs should be given at least one hour before or, four to six hours following, colestyramine administration.

To avoid oesophageal irritation or blockage or intestinal blockage, the drug should not be taken in its dry form. Colestyramine should always be mixed with an appropriate fluid prior to ingestion.

To minimise gastro-intestinal side effects and to familiarise the patient with colestyramine, it is desirable to begin with one dose daily. After one to two days the dosage can be increased to meet the patient’s needs.

Dosage schedules

Adults

For primary prevention of coronary heart disease and to reduce cholesterol:-After an introduction period of three to four weeks, the dose is 12 to 24 grams of colestyramine resin (i.e. three to six sachets) to be taken in single or divided doses up to four times daily, according to dosage requirements and patient acceptability. Dosage may be modified according to response up to 36 grams (nine sachets) a day in resistant cases.

For the relief of diarrhoea:-

As in prevention of coronary heart disease and reduction of cholesterol above, but it may be possible to reduce this dose. 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.

For the relief ofpruritus:-

Four to eight grams (one to two sachets) a day should be sufficient.

Children aged 6 to 12 years

The initial dose is determined by the following formula:

Child’s weight in Kg x adult dose 70

Subsequent dosage adjustment may be required where clinically indicated.

Children under 6 years of age

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

Elderly

There is no specific dosage schedule for the elderly but doses may need to be reduced to prevent adverse reactions.

Preparation

The contents of one sachet of colestyramine are placed on the surface of 120 - 180ml of water or non-carbonated beverage such as skimmed milk or fruit juice and stirred for one to two minutes to produce a uniform dispersion.

Colestyramine may also be mixed in thin soups or pulpy fruits with a high moisture content.

-    Hypersensitivity to colestyramine or any of the excipients.

-    Patients with complete biliary obstruction, since colestyramine cannot be effective where bile is not secreted into the intestine.

4.4 Special warnings and precautions for use

Prolonged use of colestyramine resin may be associated with an increased bleeding tendency as a result of hypoprothrombinaemia secondary to vitamin K deficiency. If bleeding occurs in patients receiving colestyramine, parenteral administration of vitamin K₁ is usually valuable in restoring normal clotting time and oral administration of vitamin K₁ can be used to prevent recurrent bleeding.

Because colestyramine is a chloride-containing anion exchange resin, the possibility that prolonged use of the drug may produce hyperchloraemic acidosis should be considered, particularly in children and smaller patients where the relative dosage may be higher.

Serum or red cell folate deficiency has been reported with long term administration of colestyramine resin. Supplementation with folic acid should be considered in these cases.

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

Colestyramine contains aspartame, a source of phenylalanine.

4.5 Interaction with other medicinal products and other forms of interaction

Colestyramine, being a basic anion exchange resin, has the potential to interfere with the absorption of a number of drugs including digoxin, chlorothiazide, levothyroxine, tetracycline, vancomycin, warfarin, phenylbutazone, paracetamol and the thiazide diuretics. It is possible that it may interfere with the absorption or elimination of other drugs and so patients receiving concomitant therapies should be advised to report any perceived change in efficacy of their medication. The response should be closely monitored and appropriate adjustments made if necessary.

Patients should take other drugs at least one hour before or 4-6 hours after Colestyramine to minimise possible interference with their absorption. However, separation of doses may not prevent interaction with drugs that undergo enterohepatic circulation.

The possibility that discontinuation of colestyramine in patients stabilised on potentially toxic drugs that bind to the resin may lead to toxicity, and, that

administration of colestyramine to patients stabilised on other drugs may reduce the effect of these drugs should be kept in mind.

In patients receiving long-term high dose colestyramine therapy, absorption of fat-soluble vitamins from the intestine may be impaired. Vitamin D deficiencies, bleeding deficiencies due to hypoprothrombinaemia secondary to vitamin K deficiency and night blindness secondary to vitamin A deficiency have been reported only rarely. Daily administration of vitamin A and D should be considered in patients receiving prolonged high dose colestyramine therapy or when malabsorption is suspected. Vitamin K deficiency and hypoprothrombinaemia can be treated or prevented with phytomenadione or menadiol sodium phosphate.

Several cases of hyperchloraemic metabolic acidosis have been reported following colestyramine administration. In such an event, the colestyramine therapy should be discontinued. Patients who have concomitant renal insufficiency or volume depletion or who are taking spironolactone are at particular risk and should be monitored carefully.

4.6 Pregnancy and lactation

Colestyramine is almost totally unabsorbed after oral administration, so it is not expected to cause foetal harm when administered in recommended doses during pregnancy and lactation. However, there are no adequate and well-controlled studies in pregnant women and the known interference with fat-soluble vitamin absorption may be detrimental to the foetus and nursing infant even with supplementation. In the circumstances, it should not be given to pregnant or lactating women unless considered essential.

4.7 Effects on ability to drive and use machines

None reported.

4.8 Undesirable effects

Gastrointestinal effects

Gastrointestinal effects are those most frequently reported. The principal complaint is constipation which may be controlled with the usual remedies and frequently disappears on continued usage of colestyramine. Large doses of Colestyramine can cause diarrhoea.

Rare reports of intestinal obstruction have been received.

Metabolic and electrolyte effects

Hyperchloraemic acidosis and increased urinary calcium excretion have been seen with high doses or usual doses in small patients or children. Increased urinary excretion of calcium may lead to osteoporosis.

Chronic use of Colestyramine may be associated with increased bleeding tendency due to hypoprothrombinaemia associated with vitamin K deficiency. This will usually respond promptly to vitamin K administration; recurrences can be prevented by oral administration of vitamin K.

Skin effects

Skin irritation/rashes, following the use of products containing colestyramine, have been reported rarely.

Taste disturbances have been reported rarely but causal relationship to colestyramine remains undetermined.

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.

4.9 Overdose

One case of medication error experienced heartburn and nausea after taking colestyramine 27 g t.i.d. for a week. Should overdosage occur however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction and the presence or absence of normal gut motility would determine treatment.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Colestyramine resin is the chloride form of a basic quaternary ammonium anion exchange resin in which the basic groups are attached to a styrene-divinylbenzene co-polymer.

Following oral administration, colestyramine resin releases chloride ions and absorbs bile acids in the intestine forming a non-absorbable complex which is excreted together with unchanged resin in the faeces. This results in a continuous, though partial, removal of bile acids from the enterohepatic circulation by preventing their reabsorption. Colestyramine is hydrophilic but it is not soluble in water, nor is it hydrolysed by digestive enzymes.

Cholesterol is 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 small intestine. Bile acids emulsify the fat and lipid materials present in foods, thus facilitating absorption. A major portion of the bile acids secreted are reabsorbed from the ileum and returned via the portal vein to the liver, thus completing the enterohepatic cycle. The increased faecal loss of bile acids following colestyramine resin administration leads to an increased oxidation of cholesterol to bile acids, a decrease in beta lipoprotein or low density lipoprotein plasma levels and a decrease in serum cholesterol levels. Only very small amounts of bile acids are found in normal serum. Although, colestyramine resin produces an increase in hepatic synthesis of cholesterol in man, plasma cholesterol levels fall.

In patients with partial biliary obstruction, the reduction of bile acid levels following colestyramine resin administration reduces bile acids deposited in the dermal tissue with resultant decrease in pruritus.

5.2 Pharmacokinetic properties

Not applicable because colestyramine resin is not absorbed from the gastrointestinal tract.

5.3 Preclinical safety data

Colestyramine resin has been in use for a long time with a well established clinical profile.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Aspartame powder Propylene glycol alginate Colloidal silicon dioxide Citric acid anhydrous Sunset Yellow (E110) Orange flavour WL16739

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store in a dry place, below 30^oC

6.5 Nature and contents of container

The individual sachets consist of a layer of polyethylene, then a layer of aluminium, another layer of polyethylene and finally a layer of paper printed with the product details. The sachets contain 5g of powder.

Sachets are packed in cartons of 30, 50, 60 or 180 (The 180 pack comprises six cartons of 30 in a fully labelled outer box).

6.6 Special precautions for disposal

The contents of one sachet of colestyramine are placed on the surface of 120 -180ml of water or non-carbonated beverage such as skimmed milk or fruit juice and stirred for one to two minutes to produce a uniform dispersion.

Colestyramine may also be mixed with thin soups or pulpy fruits with a high moisture content.

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1488

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24 April 1997

DATE OF REVISION OF THE TEXT

11/06/2015