This information is intended for use by health professionals

1. Name of the medicinal product

Tolbutamide 500mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 500mg Tolbutamide

3. Pharmaceutical form

Tablet

White biconvex tablets, 13mm in diameter with a breakline; “T” above breakline and “500" below

4. Clinical particulars
4.1 Therapeutic indications

Tolbutamide is indicated for the oral treatment of patients with non-insulin dependent diabetes (maturity-onset or type II diabetes) who respond inadequately to dietary treatment alone.

4.2 Posology and method of administration

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.

1. Treatment of previously untreated diabetes. Stabilisation can be achieved by 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 or divided dose. In general, patients who do not respond to 4 tablets daily do not respond to higher doses.

2. Change over from other oral antidiabetics can usually be carried out without a break in therapy, starting with 2 tablets daily, followed by a maintenance doe depending on response

3. Combination with biguanides: If adequate control is not achieved with diet and 4 tolbutamide 500mg tablets 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.

Children:

Elderly:

Not recommended

treatment at a lower dose.

Method of administration

For oral use

4.3 Contraindications

Hypersensitivity to the active ingredient or any of the excipients

Should not be used in patients who have or have ever had diabetic ketoacidosis, who have insulin-dependent diabetes, serious impairment of renal, hepatic, adrenocortical or thyroid function, porphyria or in circumstances of unusual stress (e.g. surgical operations or during pregnancy) when dietary treatment and insulin are essential.

Should not be used while breast-feeding

4.4 Special warnings and precautions for use

Caution is required in patients with impaired liver function.

Debilitated aged or those patients who have difficulty in metabolising the drugare more likely to become hypoglycaemic .

Elderly patients are more prone to sulfonylurea-induced hypoglycaemia and symptoms may be insidious or prolonged.

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

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

Perform a full blood count if the patient develops a persistent fever or sore throat or if there is clinical suspicion of low platelet count. Repeat the blood count 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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Many interactions are reported with sulfonylureas, either pharmacokinetic interactions (due to displacement of tolbutamide from plasma proteins, or alterations in its metabolism or excretion), or pharmacological interactions with other drugs having independent effects on blood glucose.

Increased hypoglycaemic effects have occurred or might be expected with:

• ACE inhibitors

• alcohol (may also cause disulfiram like reaction)

• allopurinol

• some analgesics (azapropazone, phenylbutazone and salicylates)

• azole antifungals (fluconazole, ketoconazole and miconazole)

• chloramphenicol

• cyclophosphamide

• cimetidine

• clofibrate and related compounds

• coumarin anticoagulants

• dicoumarol

• fluoroquinolones

• heparin

• MAOIs

• octreotide (may also cause hyperglycaemia)

• ranitidine

• sulfinpyrazone

• sulphonamides (including co-trimoxazole and sulfafurazole)

• St John's Wort

• tetracyclines

• tricyclic antidepressants

• beta-blocker

Beta-blockers have been reported to increase hypoglycaemia and to mask the typical sympathetic warning signs.

Decreased hypoglycaemic effect may occur with:

• adrenaline

• lithium

• rifampicin

• corticosteroids

• oral contraceptives

• thiazide diuretics

Extracts of ginkgo biloba may decrease absorption of tolbutamide and thereby decrease its efficacy.

There are conflicting reports of interactions with calcium channel blockers.

4.6 Fertility, pregnancy and lactation

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 in the first trimester of pregnancy. There is some evidence of harmful effects in animal pregnancy and suggestions of a hazard in human pregnancy. Placental transfer of tolbutamide may result in prolonged hypoglycaemia in the neonate. Insulin is normally substituted for oral hypoglycaemics during pregnancy.

If Tolbutamide is given, 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 human milk in small quantities - effects on the neonate are unknown but there is a theoretical risk of hypoglycaemia. Use should be avoided whilst breast-feeding.

4.7 Effects on ability to drive and use machines

At the start of treatment, vision may be affected (i.e. blurred) if this happens, do not drive or operate machinery. The patient should ensure their blood glucose levels are adequately controlled before driving or operating machinery.

4.8 Undesirable effects

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)

• Blood and lymphatic system disorders:

Rare: Blood disorders including leukopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia and aplastic anaemia.

• Immune system disorders:

Not known: Hypersensitivity reactions may develop, usually within 6 – 8 weeks of starting therapy. Allergic skin reactions may occur, which progress rarely to erythema multiforme, exfoliative dermatitis and fever. Photosensitivity can occur.

• Metabolism and Nutrition disorders:

Not known: Hypoglycaemia has been reported when tolbutamide has been administered without due regard to the patient's dietary habits.

• Nervous system disorders:

Not known:

Paraesthesia and headaches have been reported. Patients may become intolerant to alcohol.

• Ear and labyrinth disorders:

Not known: Tinnitus

• Gastrointestinal disorders:

Not known: Nausea, vomiting, diarrhoea, anorexia, increased appetite; weight gain and constipation have been reported.

• Hepatobiliary disorders:

Not known: Disturbances in liver function and cholestatic jaundice.

Elderly or debilitated patients may be more prone to hypoglycaemia.

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

4.9 Overdose

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 (50g) 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 500ml 5% or 250ml 10% dextrose IV. 50ml 50% dextrose IV may be given but is an irritant to veins and can cause skin necrosis in cases of extravasation.

5. Glucagon 1-2mg 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 an 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC CODE A10B B03

Tolbutamide is an oral sulfonylurea hypoglycaemic agent from the sulfonamide, 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 inhibition of hepatic glucose production and increased sensitivity to any available insulin.

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

No relevant information additional to that already contained elsewhere in the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Maize Starch

Povidone (K90)

Sodium Starch Glycolate (Type A)

Magnesium Stearate

Stearic Acid

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original container or package.

6.5 Nature and contents of container

Polypropylene tablet containers with Polyethylene (HDPE/LDPE) cap.

Pack sizes 28, 50, 100 and 500 tablets. Also available in a PVC/ PVDC blister, with aluminium lidding foil, containing 28 tablets.

6.6 Special precautions for disposal and other handling

None stated

7. Marketing authorisation holder

Kent Pharmaceuticals Ltd

Unit 200, Westminster 42,

Westminster Industrial Estate,

Repton Road, Measham,

Swadlincote, DE12 7DT, U.K.

8. Marketing authorisation number(s)

PL 08215/0007

9. Date of first authorisation/renewal of the authorisation

Date of Renewal: 01/09/2006

10. Date of revision of the text

10/02/2017