DIABREZIDE Tablet Ref.[50283] Active ingredients: Gliclazide

Use of sulphonylureas must be limited to the treatment of maturity onset diabetes mellitus, not ketogenic, unable to be controlled by diet, and for which insulin therapy is not appropriate. Warnings and precautions of use concern:

Hypoglycaemia

All sulphonylureas, taken in too high doses in relation to the requirement, are capable of producing hypoglycaemia, even of severe degree, which may lead to neurological damage and may have a fatal outcome.

Diabrezide can provoke a moderate or severe hypoglycaemia particularly in the following circumstances:

• Insufficient glucose or caloric intake.
• Too high posology or accidental overdoses.
• Prolonged physical activity.
• Patients with uncompensated thyroid function disorders.

In order to lower the risk of hypoglycaemia it is recommended to start the treatment with a low dose of Diabrezide.

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

Renal or hepatic insufficiency may cause elevated drug levels and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycaemic reactions.

Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycaemic action of glucose-lowering drugs. Hypoglycaemia may be difficult to recognise in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycaemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Hypoglycaemia can be promptly controlled by immediate intake of carbohydrates (glucose or sugar, e.g. in the form of sugar lumps, sugar-sweetened fruit juice or tea, see under 4.9).

So that initial corrective action can be taken immediately, patients should carry a minimum of 1-2 lumps of sugar with them at all times.

To reduce the risk of hypoglycaemia a number of precautions should be taken when Diabrezide is first prescribed, including adjusting the dose according to blood glucose levels during the first few months, and beginning treatment with low doses especially in the elderly and in patients with renal and/or hepatic impairment.

Loss of control of blood glucose

When a patient stabilised on any diabetic regimen is exposed to stress such a fever, trauma infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue gliclazide and administer insulin.

Concomitant administration of Diabrezide with agents that increase blood glucose levels (see under 4.5) should not be considered without careful monitoring of blood glucose levels to avoid hyperglycaemia.

Hepatic disease

Definite hepatic disease should contraindicate the use of Diabrezide, since gliclazide is almost completely metabolised in the liver; in moderate hepatic disease a dosage reduction is advisable.

Renal disease

Although renal disease does not appear significantly to alter the pharmacokinetics of gliclazide, it may be wise to limit the maximum dose when the serum creatinine starts to rise.

Elderly

Some elderly patients may be more sensitive to the drug; although the plasma clearance is not altered so that increased plasma levels are unlikely, it is wise to start the therapy at the lowest dosage. The physician gives the patient guidance on the frequency of blood glucose measurements, as well as on whether, how often and when urine test for glucose must be performed. In addition, it is recommended that the quality of metabolic control be checked by regular determinations of glycated haemoglobin.

Diabrezide contains lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Concomitant administration of certain drugs may lead to an increase in the blood glucose lowering effect and susceptibility to hypoglycaemia, and may necessitate dose adjustment.

These drugs include:

• medicinal products used for the same indication, such as insulin, acarbose, other sulphonylureas (not recommended association), biguanides;
• sulphonamides, phenylbutazone, non steroidal anti-inflammatory drugs (NSAID’s), aspirin and salicylates, coumarins, allopurinol, miconazole, ketoconazole;
• fibrates (patients stabilised on Diabrezide should be very closely monitored when starting or ending a therapy with fibrates);
• theophylline, caffeine, monoamine oxidase inhibitors;
• beta-adrenoceptor antagonists (they alter recovery from hypoglycaemia and suppress hypoglycaemic symptoms);
• ACE inhibitor;
• anabolic steroids and male sex hormones;
• chloramphenicol;
• cyclophosphamide and derivatives.

Other drugs may reduce the blood glucose lowering effect and increase the tendency to hyperglycaemia. Adjustment of the gliclazide dose may become necessary also in such cases.

These drugs include:

• barbiturates, phenytoin, and rifampicin;
• corticosteroids, corticotropin, estrogens, progestogens, oral contraceptives, diazoxide and sympathomimetic drugs, thyroid hormones.
• thiazide diuretics (hyponatremia have been reported when used concomitantly)

Alcohol may cause an increase in blood glucose levels. Large amounts of alcohol may, in addition, impair gluconeogenesis and thus increase the risk of hypoglycaemia. The carbohydrate content of alcoholic beverages must also be taken into consideration.

H₂-receptor antagonists (as cimetidine, ranitidine) may either increase or reduce the blood glucose lowering effect of sulphonylureas.

Patients treated with drugs other than gliclazide should discuss possible interactions with their prescribing physician.

There is no experience with the use during pregnancy in humans. Oral hypoglycaemic agents are not suitable for the treatment of diabetes during pregnancy, because the blood glucose level can be controlled more tightly by insulin. Insulin is the drug of first choice for treatment of diabetes during pregnancy. It is recommended that oral hypoglycaemic therapy is changed to insulin before a pregnancy is attempted.

It is not known whether gliclazide or its metabolites are excreted in breast milk. Diabrezide is not indicated in nursing mothers.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of a special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

At dosages used in the treatment of maturity onset diabetes mellitus, the most frequently reported side effect is hypoglycaemia, which in most cases is the result of overdose or inadequate diet rather than an adverse effect of the drug and therefore can be corrected by dosage reduction.

The following frequencies are used for the description of the occurrence of adverse reactions: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Rare (≥1/10,000 to <1/1,000): Leucopoenia, agranulocytosis, thrombocytopoenia, haemolytic anaemia, aplastic anaemia.

Nervous system disorders

Rare (≥1/10,000 to <1/1,000): Dizzines.

Gastrointestinal disorders

Common (≥1/100 to <1/10): Gastrointestinal upset (such as abdominal pain, nausea or vomiting, dyspepsia, diarrhoea, constipation). It can be avoided or minimised if gliclazide is taken with breakfast.

Skin and subcutaneous tissue disorders

Rare (≥1/10,000 to <1/1,000): Skin reactions (erythema, pruritus).

Metabolism and nutrition disorders

Common (≥1/100 to <1/10): Hypoglycemia* (see additional information below).

Rare (≥1/10,000 to <1/1,000): Slight disulfiram-like reactions after taking alcohol.

Hepatobiliary disorders

Rare (≥1/10,000 to <1/1,000): Sulphonylureas can occasionally cause disturbances of liver functions, which rarely may lead to hepatitis.

As per other sulphonylureas, the following skin and subcutaneous tissue disorders have been reported: rash, pruritus, urticaria, angioedema, erythema, rash maculo-papular, dermatitis bullous (as Stevens-Johnson syndrome and Toxic epidermal necrolysis).

^* Hypoglycaemia

All sulphonylureas can produce hypoglycaemia. This can be prolonged by gliclazide and may lead to severe hypoglycaemia with life-threatening coma. In cases of very slow progression of nervous lesion (autonomous neuropathy) or sympatholytic concomitant therapy (see “Special warning and precautions for use” and “Interactions”), typical premonitory symptoms of hypoglycaemia may be weaker or absent. Hypoglycaemia is characterised by decrease in blood sugar to less than approx. 50 to 40 mg/dl.

The following premonitory simptoms can alert the patient or her/his surroundings of a too great blood sugar decrease: sudden sweating, palpitation, tremor, sensation of hunger, restlessness, tingling sensation in the mouth area, paleness, headache, somnolence, sleep disorder, anxiety, depression, touchiness, altered behaviour, unsteady movements, transient neurological symptoms (e.g. speech and visual disorders, paralytic symptoms or sensitivity disorders). In severe hypoglycaemia the patient may loose self-control and consciousness. In this case the patient’s skin is often cool and she/he tends to have cramps. For treatment of hypoglycaemia see “Overdose”.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Not applicable.