Gliclazide Tablets 80mg BP

Each tablet contains Gliclazide 80mg

For a full list of excipients see section 6.1

Tablet

Gliclazide Tablets 80mg BP are white, circular tablets with GZ80 and a breakline on one face and blank on the reverse

Non insulin-dependent diabetes mellitus.

For oral administration

Adults

The total daily dose may vary from 40 to 320mg taken orally. The dose should be adjusted according to the individual patient's response, commencing with 40-80mg daily (¹/₂ - 1 tablet) and increasing until adequate control is achieved. A single dose should not exceed 160mg (two tablets). When higher doses are required, gliclazide tablets should be taken twice daily 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 in 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 show that gliclazide is effective and well tolerated. However, care should be exercised when prescribing sulphonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.

Renal and hepatic impairment.

The starting dose should be 40mg daily (¹/₂ tablet) increasing until adequate control is achieved.

Children

As with other sulphonylureas, gliclazide is not indicated for the treatment of juvenile onset diabetes mellitus.

Hypersensitivity to the active substance or to any of the excipients, other sulphonylureas and related drugs.

Juvenile onset diabetes

Ketoacidosis.

Severe infection, stress, trauma, surgical procedures or other severe conditions where the drug is unlikely to control the hyperglycaemia.

Severe impairment of renal or hepatic function.

Diabetic coma and pre-coma.

Pregnancy and lactation

Treatment with Miconazole (see section 4.5)

Gliclazide should, where possible, be avoided in porphyria.

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

Hypoglycaemia: 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.

Factors which increase the risk of hypoglycaemia:

• In patients controlled by diet alone. 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

• certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency

• concomitant administration of alcohol or certain other medicines (see section 4.5).

• In cases of accidental overdose.

• When calorie or glucose intake is insufficient

• In patients with hepatic and/or renal impairment. However, in long-term clinical trials patients with renal insufficiency have been treated satisfactorily using gliclazide at reduced doses with careful patient monitoring.

In order to reduce the risk of hypoglycaemia it is therefore recommended:

• To initiate treatment for non-insulin dependent diabetics by diet alone, if this is possible. 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.

• To take into account the age of the patient: blood sugar levels not strictly controlled by diet alone might be acceptable in the elderly.

• To adjust the dose of gliclazide according to the blood glucose response and to the 24 hour urinary glucose during the first days of treatment

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

Dosage adjustment may be necessary:

• On the occurrence of mild symptoms of hypoglycaemia (sweating, pallor, hunger pangs, tachycardia, sensation of malaise). Such findings should be treated with oral glucose and adjustment made in drug dosage and/or meal patterns.

• On the occurrence of severe hypoglycaemic reactions (coma or neurological impairment, (see overdose).

• On loss of control of blood glucose (hyperglycaemia). When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such time, it may be necessary to increase progressively the dosage of gliclazide and if this is insufficient, to discontinue treatment with gliclazide and to administer insulin. As with other sulphonylureas, hypoglycaemia will occur if the patients' dietary intake is reduced or if they are receiving a larger dose of gliclazide than required

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), ACE inhibitors, testosterone, anabolic steroids, beta-blockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H₂-receptor antagonists, MAOIs, trimethoprim, sulfonamides, and nonsteroidal anti-inflammatory agents.

The warning signs of hypoglycaemia (such as tremor) may also be masked by beta-blockers.

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.

Clofibrate group drugs may improve glucose tolerance and have an additive effect. Octreotide possibly reduces antidiabetic drug requirements in diabetes mellitus. Fluconazole and miconazole increase plasma concentrations of sulphonylureas. Rifamycins, phenothiazines, corticosteroids, loop and thiazide diuretics, diazoxide, oestrogens, progesterones, oral contraceptives, aminoglutethimide, thyroid hormones and abuse of laxatives may reduce the effect of sulphonylureas.

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.

Gliclazide is contraindicated in pregnancy.

Lactation

It has not been established whether gliclazide is transferred to human milk. However, some sulphonylureas are excreted in breast milk. Given the risk of neonatal hypoglycaemia, the product is contra-indicated in breast-feeding mothers.

Gliclazide has influence on the ability to drive and use machines.

Patients should be informed that their concentration might be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment. (See Special Warnings and Special Precautions for use.)

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, but this type of adverse reaction can be avoided if gliclazide is taken with a meal.

Hypersensitivity reactions can occur, usually in the first 6-8 weeks of therapy, and they consist mainly of allergic skin reactions including pruritis, erythema and bullous eruption.

The following undesirable effects have been more rarely reported:

- Blood and lymphatic system disorders: anaemia, leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia and aplastic anaemia and granulocytopenia have been observed during treatment with gliclazide but are not known to be directly attributable to the drug.

- 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), hepatic failure, 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.

Pharmacotherapeutic group: Sulfonamides, urea derivatives

ATC code: A10BB09

Gliclazide is an oral hypoglycaemic sulphonylurea which stimulates the release of insulin from pancreatic ß-cells, probably by facilitating Ca^{2 +} transport across the ß-cell membranes. The effect of gliclazide on increasing the secretion of insulin is most marked in the early phases of the response to a rise in plasma glucose. Nevertheless, hypoglycaemic effects can be shown even without any increase in the plasma levels of insulin. Like other sulphonylureas, it exerts an important hypoglycaemic effect on the cell surface at one or more post-binding sites, although there is 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. This would help to explain the extrapancreatic action of the sulphonylureas of inhibiting hepatic gluconeogenesis through phosphofructokinase and fructose diphosphatase activities and also the reduction of insulin resistance in non-insulin dependent diabetes.

In man, apart from having similar hypoglycaemic effect to other sulphonylureas, gliclazide has been shown to reduce platelet adhesiveness and increase fibrinolytic activity. Those factors are thought to be implicated in the pathogenesis of long term complications of diabetes mellitus.

The speed of absorption from the gastrointestinal tract varies considerably, and individuals can be classified as slow or fast absorbers, although the apparent difference may depend more on first-pass metabolism than absorption rate. For an 80mg dose in normal volunteers the average time to maximum is four hours and maximum concentration 3.9mg.1^-1. Presystemic metabolism has not been properly studied, but the low plasma clearance (13 ml.min^-1) suggests it is not significant. The mean plasma half-life is ten hours and the volume of distribution is about 25L. About 95% (85-97%) of gliclazide is bound to protein in plasma, mostly to albumin. Ethyl alcohol has been shown to reduce the binding to albumin, possibly explaining an enhanced hypoglycaemic effect. It may also be important that non-enzymatic glycolization of human serum albumin induced by chronic hyperglycaemia markedly decreases its binding to sulphonylureas, thus increasing the proportion of free and active drug.

Gliclazide is extensively metabolised in the liver to metabolites without significant hypoglycaemic activity. Both unchanged drug and metabolites are excreted in the urine.

No studies have reported the presence of gliclazide in human breast milk.

There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.

Lactose monohydrate

colloidal anhydrous silica

Pregelatinised maize starch

purified talc

Magnesium Stearate

Not applicable

36 months

Do not store above 25°C.

Blister composed of Opaque White PVC 250 micron with Aluminium foil 20 microns containing 28, 30, 56 or 60 tablets in cartons.

Not all pack sizes may be marketed.

No special requirements

Accord Healthcare Limited

Sage House

319 Pinner Road

Harrow

Middlesex

HA1 4HG

PL 20075/0114

12/04/2006

11/08/2011

IF APPLICABLE

IF APPLICABLE