Tolbutamide Tablets BP 500mg

Each tablet contains 500 mg tolbutamide BP

For the full list of excipients, see section 6.1.

Round, biconvex white tablets, marked on one side with “T” above a scoreline and “500” below it.

The scoreline is not intended for breaking the tablet.

For the treatment of non - insulin dependent diabetes in patients who respond inadequately to dietary treatment. It should not be used to replace dietetic therapy in the obese diabetic patient.

Posology

The tablets may be taken as a single dose with, or immediately after, the first main meal of the day, or as a divided dose for optimum control of blood sugar.

Treatment of previously untreated diabetes: stabilisation can be achieved commencing with 2 tablets (1 g) daily, and adjusting in the light of the patient's individual response. The average daily dose is 1-3 tablets (0.5 – 1.5 g) which can be taken as a single or divided dose. In general, patients who do not respond to 4 tablets (2 g) do not respond to higher doses.

Change over from other oral hypoglycaemics: It is possible to freely inter- change hypoglycaemic agents (including chlorpropamide) without a break in treatment, starting with 2 tablets (1 g) daily, followed by a maintenance dose depending on response.

Combination with biguanides: If adequate control is not achieved with diet and 4 tablets (2 g) of tolbutamide daily, it can often be achieved by combined administration with a biguanide derivative.

Change over from insulin: Some patients with non - insulin dependent diabetes and who are already taking insulin may be changed to tolbutamide. Low insulin doses (less than 20 units) can be replaced immediately. With higher doses a gradual change is advisable by giving insulin and tolbutamide concurrently and gradually reducing the dose of insulin.

Paediatric population: There is insufficient data on the efficacy and safety of tolbutamide in children and adolescents and therefore its use in this age group is not recommended

ELDERLY: Tolbutamide is particularly suitable for elderly patients as the risk of hypoglycaemia is lower with tolbutamide than other sulfonylureas.

However, treatment should be initiated at a lower dose.

Method of administration

Oral administration

• Hypersensitivity to tolbutamide or any of the excipients in the tablet.

• Patients who have, or have ever had, diabetic ketoacidosis.

• Patients with insulin-dependent diabetes mellitus.

• Patients with serious impairment of renal, hepatic, adrenocorticoid or thyroid function.

• Patients in circumstances of unusual stress (eg surgical operations or during pregnancy) when dietary treatment and insulin are essential.

• Patients with porphyria.

• Women who are breast feeding.

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

Elderly patients are especially sensitive to sulfonylurea-induced hypoglycaemia and the onset may be insidious and the impaired performance prolonged.

Tolbutamide should not be used as a substitute for dietary treatment in obese patients.

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.

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

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since tolbutamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

The hypoglycaemic effect of tolbutamide may be enhanced by dicoumarol, MAOI's, beta-adrenergic blocking agents, sulphonamides, phenylbutazone, chloramphenicol, cyclophosphamide and salicylates or diminished by adrenaline, lithium, rifampicin, corticosteroids, oral contraceptives or thiazide diuretics.

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

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

Pregnancy

Oral hypoglycaemics are not indicated for use by the pregnant diabetic as they will not provide good control of plasma glucose levels in patients that cannot be controlled by diet alone. Insulin should be used to control gestational diabetes if dietary control is not sufficient.

Tolbutamide should not be used during the first trimester of pregnancy. There is some evidence of harmful effects in pregnancy in animals and isolated reports which suggest a hazard in human pregnancy. Placental transfer of tolbutamide may result in prolonged hypoglycaemia in the neonate.

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

Breast-feeding

Tolbutamide has been detected in breast milk in small quantities. The effect on the neonate is unknown but there is a theoretical risk of hypoglycaemia. Breast-feeding is best avoided in mothers taking tolbutamide.

While tolbutamide does not cause any adverse effects that may affect a patient's ability to drive or operate machinery, the patient should ensure that their blood glucose levels are adequately controlled before driving or operating machinery.

• 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

Hypoglycaemia and 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, (see section 4.5).

• 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.

• Hepatobiliary disorders

Disturbances in liver function and cholestatic jaundice have been reported.

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; website: www.mhra.gov.uk/yellowcard.

Symptoms

The features are those of hypoglycaemia and include nausea, vomiting, sweating, hyperventilation, tachycardia, hypotension, bizarre behaviour and drowsiness leading to coma with increased muscle tone, hyperreflexia and extensor plantar responses. Convulsions and cerebral oedema may occur.

The duration of the risk of hypoglycaemia varies according to the plasma half- life of the drug. As the half-life of tolbutamide is generally 4-8 hours, a minimum observation period of 24 hours is recommended.

Treatment

1. If the patient is conscious give activated charcoal (50 g) or consider gastric lavage in adults within 1 hour of the overdose, provided the airway can be protected.

2. Correct hypoglycaemia as quickly as possible.

3. If the patient is awake give oral glucose followed by a carbohydrate meal.

4. If the patient is drowsy or unconscious give up to 500 ml 5% or 250 ml 10% dextrose IV. 50ml 50% dextrose IV may be given but is irritant to veins and can cause skin necrosis in cases of extravasation.

5. Glucagon 1-2 mg IM may also be used if IV access is difficult or the patient is combative but its effects are dependent on available glycogen stores.

6. Maintenance treatment with 10% dextrose infusion will be required to prevent persistent hypoglycaemia.

7. Check blood sugar hourly and adjust rate of infusion accordingly.

8. Check urea and electrolytes regularly. Potassium supplements may be necessary.

9. If the patient is persistently hypoglycaemic despite receiving 10% dextrose infusion increase the concentration to 20% dextrose. This is irritant to veins and ideally should be given through a central venous line. Additional potassium may also be required.

10. In cases of severe refractory hypoglycaemia contact NPIS.

ATC CODE A10B B03

Tolbutamide is an oral sulfonylurea hypoglycaemic agent from the sulphonamide, urea derivative group.

Tolbutamide is used to treat type II diabetes when diet modification is not effective on its own.

Tolbutamide has several mechanisms of action which appear to be mediated by the inhibition of ATP sensitive potassium channels. Initially secretion of insulin by functioning islet beta cells is increased. However, when the insulin secretion falls again the hypoglycaemic effect persists possibly due to the inhibition of hepatic glucose production and increased sensitivity to any available glucose.

Absorption

Tolbutamide is readily absorbed from the gastrointestinal tract. Peak plasma levels are reached within 3-4 hours.

Distribution

The half-life is generally within the range of 4-8 hours but may be considerably longer. Tolbutamide is 97% bound to plasma proteins.

Metabolism

It is metabolised in the liver and involves the cytochrome P450 isoenzyme CYP2C9.

Elimination

Excretion in the urine, chiefly as metabolites with little hypoglycaemic activity. Tolbutamide has been detected in breast milk.

None stated

Starch

Povidone

Sodium Starch Glycollate

Magnesium Stearate

Stearic acid

None known.

36 months.

Do not store above 25°C.

Keep in the original container or package in which they were packed in order to protect from light and moisture.

Securitainer of 28, 50 and 500 tablets and PVC/alu blister packs of 28 tablets.

No special requirements.

Waymade PLC

T/A Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex SS14 3FR

PL 06464/0212

11/03/2009

26/01/2017