Composition:

Each tablet contains 30 mg Gliclazide.

Pharmacodynamic properties:

Gliclazide is a sulphonylurea, oral anti-diabetic agent.

Gliclazide reduces blood glucose levels by stimulating insulin secretion from the β-cells of the islets of Langerhans. In addition to these metabolic properties, gliclazide has haemovascular properties.

Effects on insulin release: In type 2 diabetics, gliclazide restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion.

Haemovascular properties: Gliclazide decreases microthrombosis which may be involved in complications of diabetes.

Pharmacokinetic properties:

Absorption: Gliclazide is completely absorbed. Food intake does not affect the rate or degree of absorption.

Distribution: Plasma protein binding is approximately 95%.

Elimination: Gliclazide is mainly metabolised in the liver and excreted in the urine, the elimination half-life of gliclazide varies between 12 and 20 hours.

Indications:

Non insulin-dependent diabetes (type 2) in adults when dietary measures, physical exercise and weight loss alone are not sufficient to control blood glucose.

Contraindications:

• Hypersensitivity to the active substance or to any of the excipients.
• Hypersensitivity to other sulphonylureas or sulphonamides
• Type 1 diabetes
• Diabetic pre-coma and coma, diabetic keto-acidosis
• Severe renal or hepatic insufficiency. In these cases the use of insulin is recommended
• Treatment with miconazole
• Lactation

Posology and method of administration:

The daily dose may vary from 30 to 120 mg per day taken orally in a single intake at breakfast time.

If a dose is forgotten, there must be no increase in the dose taken the next day.

As with any hypoglycaemic agent, the dose should be adjusted according to the individual patient's metabolic response (blood glucose, HbAlc).

Initial dose: The recommended starting dose is 30 mg daily.

If blood glucose is effectively controlled, this dose may be used for maintenance treatment. If blood glucose is not adequately controlled, the dose may be increased to 60, 90 or 120 mg daily, in successive steps. The interval between each dose increment should be at least 1 month except in patients whose blood glucose has not reduced after two weeks of treatment. In such cases, the dose may be increased at the end of the second week of treatment.

The maximum recommended daily dose is 120 mg.

Switching from gliclazide 80 mg tablets to gliclazide 30mg, 60 mgsustained release tablets:1 tablet of gliclazide 80 mg is comparable to 1 tablet of Gliclazide 30 mg sustained -release. Consequently, the switch can be performed provided careful blood monitoring is undertaken.

Switching from another oral anti-diabetic agent to Gliclazide: Gliclazide can be used to replace other oral anti-diabetic agents. The dosage and the half-life of the previous anti-diabetic agent should be taken into account when switching to Gliclazide.

A transitional period is not generally necessary. A starting dose of 30 mg should be used and this should be adjusted to suit the patient's blood glucose response, as described above. When switching from a hypoglycaemic sulphonylurea with aprolonged half-life, a treatment free period of a few days may be necessary to avoid an additive effect of the two products, which might cause hypoglycaemia.

The procedure described for initiating treatment should also be used when switching to treatment with Gliclazide, i.e. a starting dose of 30 mg/day, followed by a stepwise increase in dose, depending on the metabolic response.

Combination treatment with other anti-diabetic agents: Gliclazide can be given in combination with biguanides, alpha glucosidase inhibitors or insulin. In patients not adequately controlled with Gliclazide, concomitant insulin therapy can be initiated under close medical supervision.

Older people (over 65 years of age): Gliclazide should be prescribed using the same dosing regimen recommended for patients under 65 years of age.

Patients with mild to moderate renal insufficiency: The same dosing regimen can be used as in patients with normal renal function with careful patient monitoring.

Patients at risk of hypoglycaemia: There is an increased risk of hypoglycaemia in the following circumstances:

• Undernourished or malnourished patients
• Patients with severe or poorly compensated endocrine disorders (hypopituitarism, hypothyroidism, adrenocorticotrophic insufficiency)
• Following withdrawal of prolonged and/or high dose corticosteroid therapy
• Patients with severe vascular disease (severe coronary heart disease, severe carotid impairment or diffuse vascular disease)

It is recommended that the minimum daily starting dose of 30 mg is used.

Paediatric population: The safety and efficacy of Gliclazide in children and adolescents has not been established.

Warnings and precautions:

• Hypoglycaemia: This treatment should be prescribed only if the patient is likely to have a regular food intake (including breakfast). It is important to have a regular carbohydrate intake due to the increased risk of hypoglycaemia if a meal is taken late, an inadequate amount of food is consumed or if the food is low in carbohydrate. Hypoglycaemia is more likely to occur during low-calorie diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycaemic agents is being used.

Some cases of Hypoglycaemia may be severe and prolonged. Hospitalisation may be necessary and glucose administration may need to be continued for several days.

Factors which increase the risk of hypoglycaemia:

• Patient refuses or is unable to co-operate
• Malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes
• Imbalance between physical exercise and carbohydrate intake
• Renal insufficiency
• Severe hepatic insufficiency
• Overdose of Gliclazide
• Certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency
• Concomitant administration of alcohol or certain other medicines.
• Renal and hepatic insufficiency: The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic insufficiency or severe renal failure. A hypoglycaemic episode occurring in these patients may be prolonged, so appropriate management should be initiated.
• Patient information: The risks of hypoglycaemia, with its symptoms, treatment and conditions that predispose to its development, should be explained to the patient and to family members. The patient should be informed of the importance of following dietary advice, of taking regular exercise, and of regular monitoring of blood glucose levels.
• Poor blood glucose control: Blood glucose control in a patient receiving anti-diabetic treatment may be affected by any of the following: Fever, trauma, infection or surgical intervention. In some cases, it may be necessary to administer insulin. The hypoglycaemic efficacy of any oral anti-diabetic agent, including gliclazide, is attenuated over time in many patients. This may be due to progression in the severity of the diabetes, or to a reduced response to treatment. This phenomenon is known as secondary failure, which is distinct from primary failure, when an active substance is ineffective as first-line treatment.
• Measurement of glycated haemoglobin levels or fasting venous plasma glucose is recommended in assessing blood glucose control. Blood glucose self-monitoring may also be useful.
• Treatment of patients with glucose-6-phosphate (G6PD)-deficiency with sulphonylurea agents can lead to haemolytic anaemia. Since gliclazide belongs to the class of sulphonylurea drugs, caution should be used in patients with G6PD-deficiency and a non-sulphonylurea alternative should be considered.
• This drug should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Drug Interaction:

1. The following products are likely to increase the risk of hypoglycaemia

1. Contraindicated combination:
   • Miconazole (systemic route, oromucosal gel): increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.
2. Combinations which are not recommended:
   • Phenylbutazone :increases the hypoglycaemic effect of sulphonylureas (displaces their binding to plasma proteins and/or reduces their elimination). It is preferable to use a different anti-inflammatory agent, or else to warn the patient and emphasise the importance of self-monitoring. Where necessary, adjust the dose during and after treatment with the anti-inflammatory agent.
   • Alcohol: increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Alcohol or medicines containing alcohol should be avoided.
3. Combinations requiring precaution for use:

Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur when one of the following drugs is taken: Other anti-diabetic agents, beta-blockers; fluconazole; angiotensin converting enzyme inhibitors ,H2-receptor antagonists; monoamine oxidase inhibitors (MAOIs); sulphonamides; clarithromycin; and non-steroidal anti-inflammatory agents.

2. The following products may cause an increase in blood glucose levels

1. Combination which is not recommended:
   • Danazol:has a diabetogenic effect. If the use of this active substance cannot be avoided, the patient should be warned and emphasised about the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the anti- diabetic agent during and after treatment with danazol.
2. Combinations requiring precaution during use
   • Chlorpromazine: High doses increase blood glucose levels (reduced insulin release). the patient should be warned and emphasised about the importance of blood glucose monitoring. It may be necessary to adjust the dose of the anti-diabetic during and after treatment with the neuroleptic agent.
   • Glucocorticoids(systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactrin: increase blood glucose levels with possible ketosis. The patient should be warned and emphasised about the importance of blood glucose monitoring, particularly at the start of treatment. It may be necessary to adjust the dose of the anti-diabetic agent during and after treatment with glucocorticoids.

Ritodrine, salbutamol and terbutaline (I.V. administration): increased blood glucose levels due to beta-2 agonist effects. The importance of monitoring blood glucose levels should be emphasised. If necessary, switch to insulin.

3. Combination which must be taken into account:

Anticoagulant therapy (e.g. warfarin): Sulphonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.

Pregnancy:

There is no experience with the use of gliclazide during pregnancy in humans. Control of diabetes should be obtained before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes.

Oral hypoglycaemic agents are not suitable. 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, or as soon as pregnancy is discovered.

Lactation:

It is not known whether gliclazide or its metabolites are excreted in breast milk. Given the risk of neonatal hypoglycaemia, gliclazide is contra-indicated in breast-feeding mothers.

Effects on ability to drive and use machines:

gliclazide has no known influence on the ability to drive and use machines. However, patients should be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machinery, especially at the beginning of treatment.

Undesirable effects:

Hypoglycaemia: As for other sulphonylureas, treatment with gliclazide can cause hypoglycaemia, if meal times are irregular and, in particular, if meals are skipped. Possible symptoms of hypoglycaemia are: headache, intense hunger, nausea, vomiting, lassitude, sleep disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disorders, dizziness, feeling of powerlessness, loss of self-control, delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and lethal outcome.

In addition, signs of adrenergic counter-regulation may be observed: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.

Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners have no effect. Experience with other sulphonylureas shows that hypoglycaemia can recur even when measures prove effective initially.

If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalisation is required.

Other undesirable effects: Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation have been reported. These can be avoided or minimised if gliclazide is taken with a meal.

The following undesirable effects have been more rarely reported:

1. Rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, and bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis),
2. Changes in haematology (They may include anaemia, leucopenia, thrombocytopenia, granulocytopenia) these are in general reversible upon discontinuation of gliclazide.
3. Raised hepatic enzyme levels (AST, ALT, alkaline phosphatase) and hepatitis (isolated reports),treatment should discontinued if cholestatic jaundice appears, these symptoms usually disappear after discontinuation of treatment.
4. Transient visual disturbances may occur, especially on initiation of treatment, due to changes in blood glucose levels.

The following adverse events have been described for other sulphonylureas: Erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatraemia, elevated liver enzyme levels and even impairment of liver function and hepatitis, which regressed after withdrawal of the sulphonylurea or led to life-threatening liver failure in isolated cases.

Overdose:

An overdose of sulphonylureas may cause hypoglycaemia. Moderate symptoms of hypoglycaemia, without any loss of consciousness or neurological signs, must be corrected by carbohydrate intake, dose adjustment and/or change of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalisation.

Dialysis is of no benefit to patients due to the strong binding of gliclazide to proteins.