GLITISOL Tablet Ref.[28295] Active ingredients: Glibenclamide

Epidemiological studies suggest that the administration of glibenclamide is associated with an increased risk of cardiovascular mortality, when compared to treatment with metformin or gliclazide. This risk was especially observed in patients with diagnosed coronary diseases.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

Persons allergic to other sulphonamide derivatives may develop an allergic reaction to glibenclamide as well.

During treatment with glibenclamide, glucose levels in blood and urine must be measured regularly.

Adjustment of the dosage of hypoglycaemic agents may be required in patients suffering from intercurrent infections, trauma, shock or anaesthesia.

For major surgery, insulin therapy should be substituted for oral hypoglycaemics.

Hepatic or renal dysfunction may require reduction in dosage.

Patients for whom sulphonylurea therapy is intended should be carefully selected, and limited to those who cannot be controlled on dietary measures alone, do not require insulin, and do not suffer from those disorders, the course of which might be affected by this therapy.

Elderly, debilitated patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycaemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly. The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. In exceptional stress situations (e.g. trauma, surgery, febrile infections), blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.

As is necessary during treatment with any blood-glucose-lowering drug, the patient and the doctor must be aware of the risk of hypoglycaemia.

Factors favoring hypoglycaemia include:

• unwillingness or incapacity of the patient to co-operate
• undernourishment, irregular mealtimes or missed meals
• imbalance between physical exertion and carbohydrate intake
• alterations of diet
• impaired renal function
• elderly patients
• serious liver dysfunction
• overdosage with glibenclamide
• uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency)
• concurrent administration of certain other medicines.

If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of glibenclamide or the entire therapy. This also applies whenever illness occurs during therapy or the patient’s lifestyle changes.

Those symptoms of hypoglycaemia, which reflect the body’s adrenergic counter-regulation may be milder or absent where hypoglycaemia develops gradually, where there is autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine, or other sympatholytic drugs.

Hypoglycaemia can, almost always, be promptly controlled by immediate intake of carbohydrates.

Despite initially successful counter-measures, hypoglycaemia may recur. Patients must, therefore, remain under close observation.

Severe hypoglycaemia, or a protracted episode, which can only be temporarily controlled by usual amounts of sugar, further requires immediate treatment and follow-up by a doctor and, in some circumstances, in-patient hospital care.

Treatment of patients with G-6-phosphate-dehydrogenase deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since Glitisol 5 mg Tablets belongs to the class of sulfonylurea agents, caution should be used in patients with G-6-phosphate-dehydrogenase deficiency and a non-sulfonylurea alternative should be considered.

Glitisol is mainly metabolised by CYP 2C9 and to a lesser extent by CYP 3A4. This should be taken into account when glibenclamide is co-administered with inducers or inhibitors of CYP 2C9.

Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when taking other drugs, including:

Insulin and other, oral antidiabetics, ACE inhibitors, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, ifosfamide, MAO inhibitors, miconazole, para-aminosalicyclic acid, pentoxifylline, phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, sulfonamides, sympatholytic agents such as beta-blockers and guanethidine, clarithromycin, tetracyclines, tritoqualine, trosfosfamide.

Weakening of the blood-glucose-lowering effect and, thus, raised blood glucose levels may occur when taking other drugs, including:

Acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine and other sympathomimetic agents, glucagon, laxatives, nicotinic acid, oestrogens and progestogens, phenothiazines, phenytoin, thyroid hormones, rifampicin.

H₂-receptor antagonists, clonadine, and resperine may lead to either potentiation or weakening of the blood-glucose lowering effect.

Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and resperine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.

Glitisol may increase cyclosporine plasma concentration and potentially lead to its increased toxicity.

Both acute and chronic alcohol intake may potentiate or weaken the blood glucose lowering action of glibenclamide in an unpredicted fashion.

Glitisol may either potentiate or weaken the effect of coumarin derivatives.

Bosentan: An increased incidence of elevated liver enzymes was observed in patients receiving glibenclamide concomitantly with bosentan.

Both glibenclamide and bosentan inhibit the bile salt export pump, leading to intracellular accumulation of cytotoxic bile salts. Therefore, this combination should not be used.

Pregnancy

Glitisol must not be taken during pregnancy. The patient must change over to insulin during pregnancy. Animal studies showed some teratogenic effects.

Fertility

Patients planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin.

Breast-feeding

Glitisol must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.

Alertness and reactions may be impaired by hypo- or hyperglycaemic episodes, especially when beginning or after altering treatment, or when Glitisol is not taken regularly. This may affect the ability to drive or operate machinery.

Hypoglycaemia:

Hypoglycaemia, sometimes prolonged and even life-threatening, may occur as a result of the blood glucose lowering action of glitisol tablets.

Possible symptoms of hypoglycaemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, alertness, and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to an including coma, shallow respiration and bradycardia.

Signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias. The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke. The symptoms of hypoglycaemia nearly always subside when hypoglycaemia is corrected.

Eyes:

Temporary visual impairment.

Digestive tract:

Gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fullness in the epigastrium, abdominal pain and diarrhea may occur. In isolated cases, there may be elevation of liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice and hepatitis which can regress after withdrawal of glitisol tablets, although they may lead to life-threatening liver failure). Treatment with sulphonylureas has been associated with occasional disturbances of liver function and cholestatic jaundice.

Blood:

Potentially life-threatening changes in the blood picture may occur. They may include – rarely – mild to severe thrombopenia (e.g. presenting as purpura) - isolated cases – haemolytic anaemia, erythrocytopenia, leucopenia, granulocytopenia, agranulocytosis and (e.g. due to myelosuppression) pancytopenia.

General disorder:

Occasionally, allergic or pseudoallergic reactions may occur, e.g. in the form itching or rashes. In isolated cases, mild reactions in the form of urticaria may develop into serious and even life-threatening reactions with dyspnoea and fall in blood pressure, sometimes progressing to shock. In the event of urticaria, a physician must therefore be notified immediately.

A hypersensitivity reaction may be directed against glibenclamide itself, but may alternatively be triggered by excipients. Allergy to sulphonamide derivatives may also be responsible for an allergic reaction to glibenclamide.

In isolated cases, allergic vasculitis may arise and, in some circumstances, may be life-threatening. In isolated cases, hypersensitivity of the skin to light may occur, and sodium concentration in the serum may decrease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 national reporting system.

Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Fax: +357 22608649, Website: www.moh.gov.cy/phs.

Not applicable.