Sulphonylureas.

Generic

Tablets.

Tablets, tolbutamide 500mg . Available from APS, Cox, Hillcross, Sovereign.

Diabetes mellitus.

Oral administration

1. Treatment of previously untreated diabetes: stabilisation can be achieved commencing with 2 tablets daily, and adjusting in the light of the patient's individual response. The average daily dose is 1-3 tablets as a single a divided dose. In general patients who do not respond to 4 tablets do not respond to higher doses.

2. Change over from other oral anti-diabetics can usually be carried out without a break in therapy, starting with 2 tablets daily.

3. Combination with biguanides: If adequate control is not achieved with a diet and 4 tablets of tolbutamide daily, it can often be achieved by combined administration with biguanides.

4. Change over from insulin: Some cases of non-insulin dependent diabetes previously treated with insulin can be changed to tolbutamide. Low insulin doses (less than 20 units) can be replaced immediately. With higher doses a gradual change is advisable.

Tolbutamide should not be used in patients who have or have ever had:

- diabetic ketoacidosis,

- who have insulin dependent diabetes,

- serious impairment of renal function,

- serious impairment of hepatic function,

- serious impairment of adrenocortical function

- serious impairment of thyroid function,

- hypersensitivity to tolbutamide or any of the excipients in the tablet,

- porphyria.

Tolbutamide should not be used in:

- circumstances of unusual stress,

- the first trimester of pregnancy

Debilitated aged or those patients who have difficulty metabolising tolbutamide may be more liable to hypoglycaemia.

Patients with mild to moderate renal impairment should start with lower doses and have careful monitoring of the blood glucose levels.

If fever or a sore throat occurs, a white cell count should be performed and repeated after five days as blood abnormalities may develop slowly.

The possibility of thrombocytopenia should be borne in mind and a platelet count performed if indicated.

If tolbutamide is to be used during pregnancy, treatment should be changed to insulin at least 4 days prior to delivery to lessen the risk of prolonged hypoglycaemia in the infant.

The hypoglycaemic effect of tolbutamide may be enhanced by inhibitors of CYP2C9. Significant inhibitors of CYP2C9 include fluconazole, ketoconazole and voriconazole.

The hypoglycaemic effect may also be enhanced by a wide range of medicinal products (MAOI's, beta adrenergic blocking agents, sulphonamides, chloramphenicol, cyclophosphamide, salicylates) the metabolism of some of which is potentially influenced by enzymes in the cytochrome enzyme system.

The hypoglycaemic effect of tolbutamide may be reduced by inducers of CYP2C9. A notable strong inducer of CYP2C9 is the antibiotic rifampicin.

The hypoglycaemic effect may also be diminished by a wide range of medicinal products (adrenaline, lithium, corticosteroids, oral contraceptives, thiazide diuretics and Ginkgo biloba extracts,) the metabolism of some of which is potentially influenced by enzymes in the cytochrome enzyme system.

Tolbutamide should not be co-administered with coumarins as severe hypoglycaemic reactions have occurred.

Tolbutamide may also potentiate the anti-coagulant effect of warfarin.

Alcohol should be avoided since it may cause a disulfiram-like reaction.

• Blood and lymphatic system disorders

Blood disorders are rare but may include leukopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia and aplastic anaemia.

• Immune system disorders

Hypersensitivity reactions may develop, usually within 6 to 8 weeks of starting treatment with tolbutamide. Allergic skin reactions may occur which rarely progress to erythema multiforme, exfoliative dermatitis and fever. Photosensitivity may occur.

• Metabolism and nutritional disorders

Hypoglycaemic symptoms have occasionally been reported when tolbutamide has been administered without due regard to the dietary habits of the patient.

• Nervous system disorders

Paraesthesia and headache have been reported. Patients may become intolerant to alcohol, which can cause a disulfiram-like reaction.

• Ear and labyrinth disorders

Tinnitus has been reported.

• Gastrointestinal disorders

Nausea, vomiting, diarrhoea, anorexia, increased appetite, weight gain and constipation have been reported in patients taking tolbutamide.

Patients who experience gastrointestinal disturbances may benefit from taking tolbutamide in divided doses.

• Hepatobiliary disorders

Although not common, cholestatic jaundice has been reported.

(POM)