Tolbutamide Tablets Bp 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tolbutamide Tablets BP 500mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Tolbutamide BP 500mg
3. PHARMACEUTICAL FORM
Tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Non - insulin dependent diabetes in patients who respond inadequately to
dietary treatment.
4.2 Posology and Method of Administration
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 or 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 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.
CHILDREN: Not recommended
ELDERLY: Initiate treatment at a lower dose.
4.3. Contraindications
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 (see section 4.6).
4.4. Special Warnings and Precautions for Use
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 (see section 4.6 Pregnancy and Lactation).
4.5. Interactions with other Medicaments and other forms of Interaction
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.
4.6. Pregnancy and Lactation
Pregnancy
Oral hypoglycaemics are not indicated for use in 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.
Lactation
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.
4.7. Effects on Ability to Drive and Use Machines
Tolbutamide 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.
4.8. Undesirable Effects
• 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.
4.9 Overdose
Hypoglycaemia may be treated in the conscious patient by the administration of glucose or 3-4 lumps of sugar with water. Repeat as necessary. If the patient is comatose, up to 50 ml of 50% glucose solution should be given as a rapid i/v injection. This may be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose level at about 5.6 mmol/l. The patient should be monitored closely for 24- 48 hrs.
5 PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
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.
5.2. Pharmacokinetic Properties
Orally administered, tolbutamide is rapidly absorbed. It is extensively metabolised in the liver via the cytochrome P450 isoenzyme CYP2C9, prior to excretion in the urine.
5.3 Pre-clinical Safety Data
None stated
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Starch
Povidone
Sodium Starch Glycollate Magnesium Stearate Stearic acid
6.2 Incompatibilities
None known.
6.3 Shelf-Life
36 months.
6.4 Special precautions for storage
Do not store above 25 °C.
Keep in the original container in which they were packed.
6.5 Nature and contents of container
Securitainer of 28, 50 and 500 tablets and PVC/alu blister packs of 28 tablets.
6.6 Instruction for use, handling and disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Waymade PLC
T/A Sovereign Medical
Sovereign House
Miles Gray Road
Basildon
Essex SS14 3FR
8. MARKETING AUTHORISATION NUMBER(S)
PL 06464/0212
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/03/2009
10 DATE OF REVISION OF THE TEXT
27/04/2009