GLICLAZIDE TABLETS BP 80mg

Each tablet contains 80mg gliclazide.

Tablet.

White, circular, flat, bevelled-edge uncoated tablets plain with a central division line on one face and the identifying letters “G” and “Z” on either side of a central division line on the reverse.

1) Indicated for the treatment of maturity onset diabetes mellitus.

Adults: The total daily dose may vary from 40-320mg. The dose should be adjusted according to the individual's response, commencing with 40-80mg daily and increasing until adequate control is achieved. A single dose should not exceed 160mg. When higher doses are required, gliclazide should be taken twice daily and according to the main meals of the day.

In obese patients or those not showing adequate response to gliclazide alone, additional therapy may be required.

Elderly: Plasma clearance of gliclazide is not altered in the elderly and steady state plasma levels can therefore be expected to be similar to those in adults under 65 years. Clinical experience in the elderly to date shows that gliclazide is effective and well tolerated. Care should be exercised however, when prescribing sulphonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.

Children: Gliclazide, as with other sulphonylureas, is not indicated for the treatment of juvenile onset diabetes mellitus.

For oral use.

Known hypersensitivity to gliclazide or to any of the excipients, other sulfonylureas or sulfonamides

Type I diabetes

Diabetes complicated by ketosis or acidosis

Diabetics undergoing surgery, after severe trauma or during infections

Diabetic pre-coma and coma

Severe renal or hepatic insufficiency

Treatment with miconazole (see section 4.5)

Lactation (see section 4.6).

Gliclazide should, where possible, be avoided in porphyria.

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, if 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.

Hypoglycaemia may occur following administration of sulfonylureas (see section 4.8). Some cases may be severe and prolonged. Hospitalisation may be necessary and glucose administration may need to be continued for several days.

Careful selection of patients, of the dose used, and clear patient directions are necessary to reduce the risk of hypoglycaemic episodes.

Factors which increase the risk of hypoglycaemia:

• patient refuses or (particularly in elderly subjects) 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 (see section 4.5).

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, together 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 antidiabetic 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 antidiabetic 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. Adequate dose adjustment and dietary compliance should be considered before classifying the patient as secondary failure.

Laboratory tests

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 G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

The following products are likely to increase the risk of hypoglycaemia

Contraindicated combination

- Miconazole (systemic route, oromucosal gel): increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.

Combinations which are not recommended

- Phenylbutazone (systemic route): increases the hypoglycaemic effect of sulfonylureas (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. Avoid alcohol or medicines containing alcohol.

Combinations requiring precautions 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, for example:

Other antidiabetic agents (insulins, acarbose, biguanides), beta-blockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H₂-receptor antagonists, MAOIs, sulfonamides, and nonsteroidal anti-inflammatory agents.

The following products may cause an increase in blood glucose levels

Combination which is not recommended

- Danazol: diabetogenic effect of danazol.

If the use of this active substance cannot be avoided, warn the patient and emphasise the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic agent during and after treatment with danazol.

Combinations requiring precautions during use

- Chlorpromazine (neuroleptic agent): high doses (> 100 mg per day of chlorpromazine) increase blood glucose levels (reduced insulin release).

Warn the patient and emphasise the importance of blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with the neuroleptic agent.

- Glucocorticoids (systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactrin: increase in blood glucose levels with possible ketosis (reduced tolerance to carbohydrates due to glucocorticoids).

Warn the patient and emphasise the importance of blood glucose monitoring, particularly at the start of treatment. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with glucocorticoids.

- Ritodrine, salbutamol, terbutaline: I.V.

Increased blood glucose levels due to beta-2 agonist effects.

Emphasise the importance of monitoring blood glucose levels. If necessary, switch to insulin.

Combination which must be taken into account

- Anticoagulant therapy (e.g. warfarin):

Sulfonylureas may lead to potentiation of anticoagulation during concurrent treatment.

Adjustment of the anticoagulant may be necessary.

The hypoglycaemic effect of gliclazide may be potentiated by salicylates, sulphonamides, octreotide, azapropazone, sulfinpyrazone, metabolism of gliclazide may be accelerated by aminoglutethimide, testosterone, tetracycline compounds, chloramphenicol, clofibrate, disopyramide, cimetidine. Co-trimoxazole rarely enhances the effect of gliclazide.

Gliclazide may be diminished by rifamycins, oral contraceptives, thiazide diuretics, diazoxide, phenothiazine derivatives, thyroid hormones, loop diuretics, and abuse of laxatives.

Calcium channel blockers (nifedipine) may occasionally impair glucose tolerance as well as Lithium may occasionally impair glucose tolerance.

Pregnancy

There is no experience with the use of gliclazide during pregnancy in humans, even though there are few data with other sulfonylureas.

In animal studies, gliclazide is not teratogenic.

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. Other sulfonylureas have been found in milk. Given the risk of neonatal hypoglycaemia, the product is contra-indicated in breast-feeding mothers.

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.

Based on the experience with gliclazide and with other sulfonylureas, the following undesirable effects have to be mentioned.

Hypoglycaemia

As for other sulfonylureas, treatment with Gliclazide can cause hypoglycaemia, if mealtimes 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 sulfonylureas 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 are required.

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:

- Blood and lymphatic system disorders: Changes in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon discontinuation of gliclazide.

- Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, erythema, maculopapular rashes, bullous reactions, photosensitivity skin reactions.

- Hepatobiliary disorders: Raised hepatic enzyme levels (ASAT, ALAT, alkaline phosphatase), hepatitis (isolated reports). Discontinue treatment if cholestatic jaundice appears.

These symptoms usually disappear after discontinuation of treatment.

- Eye disorders: Transient visual disturbances may occur, especially on initiation of treatment, due to changes in blood glucose levels.

Class attribution effects

Cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia and allergic vasculitis have been described for other sulfonylureas.

With sulfonylureas cases were also observed of elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening liver failure in isolated cases.

An overdose of sulfonylureas 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.

If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 ml of concentrated glucose solution (20 to 30%). This should be followed by continuous infusion of a more dilute glucose solution (10%) at a rate that will maintain blood glucose levels above 1 g/l. Patients should be monitored closely and, depending on the patient's condition after this time, the doctor will decide if further monitoring is necessary.

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

Gliclazide is a sulphonylurea hypoglycaemic agent.

Gliclazide stimulates the release of insulin from pancreatic β-cells, probably by facilitating Ca²⁺ transport across the β-cell membranes. Like other sulphonylureas, it exerts an important hypoglycaemic effect on the cell surface at one or more postbinding sites, although there is some evidence that there may sometimes be an increase in insulin receptors. The sulphonylureas also have an important hypoglycaemic action by decreasing hepatic glucose output, and it has recently been shown that the sulphonylureas, including gliclazide, stimulate the most potent activator of liver phosphofructokinase at concentrations which are found in the blood of treated diabetic patients.

Gliclazide is readily absorbed from the gastrointestinal tract. It is extensively bound to plasma proteins. The half-life is about 10-12 hours. Gliclazide is extensively metabolised in the liver to metabolites without significant hypoglycaemic activity. Both unchanged drug and metabolites are excreted in the urine.

Not applicable.

Also contains: magnesium stearate, maize starch, stearic acid, E460.

None.

Shelf-life

Two years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

Store below 25°C in a dry place.

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s.

Not applicable.

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

Barnstaple

N Devon EX32 8NS

PL 0142/0400

Not applicable.

23.03.11

IF APPLICABLE

IF APPLICABLE