Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR
MORTALITY
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose- lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (supp.
2): 747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of GLUBEN and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

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

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

During treatment with GLUBEN, 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.

Severe renal or hepatic insufficiency may cause elevated blood levels of GLUBEN and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious, prolonged hypoglycemic reactions. Hepatic or renal dysfunction may require reduction in dosage.

Patients for whom sulfonylurea 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, malnourished 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 patients with autonomic neuropathy, the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes.

Factors favouring 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

- alcohol ingestion
- more than one glucose-lowering drug is used

- overdosage with GLUBEN

- 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 patients 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.

The effectiveness of any oral hypoglycemic drug, including GLUBEN, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given.

Treatment of patients with G-6-phosphate-dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since GLUBEN 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. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glibenclamide or any other anti-diabetic drug.

Laboratory Tests
Periodic fasting blood glucose measurements should be performed to monitor therapeutic response. A glycosylated hemoglobin determination should also be performed periodically.

Effects on Driving

4.7 Effects on ability to drive and use machines
Alertness and reactions may be impaired by hypo or hyperglycaemic episodes, especially when beginning or after altering treatment, or when GLUBEN is not taken regularly. This may affect the ability to drive or operate machinery.