Gliclada

Gliclazide.

Each modified-release tablet contains 60 mg gliclazide.
Excipients/Inactive Ingredients: Excipient(s) with known effect: Each modified-release tablet contains 88.7 mg lactose.
Hypromellose; Lactose monohydrate; Silica, colloidal anhydrous; Magnesium stearate.

Pharmacotherapeutic Group: Sulfonamides, urea derivatives. ATC Code: A10BB09.
Pharmacology: Pharmacodynamics: Gliclazide is a hypoglycaemic sulphonylurea oral antidiabetic differing from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.
Gliclazide reduces blood glucose levels by stimulating insulin secretion from the β-cells of the islets of Langerhans. Gliclazide shows high affinity, strong selectivity and reversible binding to the β-cell KATP channels with a low affinity for cardiac and vascular KATP channels. Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.
In addition to these metabolic properties, gliclazide has extra-pancreatic effects and 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. A significant increase in insulin response is seen in response to stimulation induced by a meal or glucose.
Extra-pancreatic effects: Gliclazide has been shown to increase peripheral insulin sensitivity: In muscle, euglycaemic hyperinsulinaemic clamp studies with gliclazide have demonstrated significantly increased (35%) insulin mediated glucose uptake which may improve diabetes control.
Gliclazide potentiates insulin action on muscle glycogen synthase. These effects are consistent with a post-transcriptional action of gliclazide on GLUT4 glucose transporters.
Studies on glucose turnover have further shown that gliclazide decreases hepatic glucose production, leading to an improvement in fasting blood glucose levels.
Haemovascular properties: Gliclazide decreases microthrombosis by two mechanisms which may be involved in complications of diabetes: a partial inhibition of platelet aggregation and adhesion with a decrease in the markers of platelet activation (beta thromboglobulin, thromboxane B₂); an action on the vascular endothelium fibrinolytic activity with an increase in tPA activity.
Other properties: Gliclazide has been shown in some studies to have actions independent of that on glucose levels.
Anti-oxidant properties, notably a reduction in plasma lipid peroxides and increased erythrocytesuperoxide dismutase activity.
Inhibition of the increased adhesiveness of type II diabetic patient's monocytes to endothelial cells in vitro.
The anti-oxidant, platelet inhibiting and fibrinolytic actions of gliclazide involve processes which have been implicated in the pathogenesis of vascular complications of type II diabetes. There is no clinical evidence that the haemovascular effects of gliclazide are of therapeutic benefit in type II diabetes patients.
Pharmacokinetics: Absorption: Plasma levels increase progressively during the first 6 hours, reaching a plateau which is maintained from the sixth to the twelfth hour after administration.
Intra-individual variability is low.
Gliclazide is completely absorbed. Food intake does not affect the rate or degree of absorption.
Distribution: Plasma protein binding is approximately 95%. The volume of distribution is around 30 litres. A single daily intake of gliclazide modified-release tablets maintains effective gliclazide plasma concentrations over 24 hours.
Biotransformation: Gliclazide is mainly metabolised in the liver and excreted in the urine; less than 1% of the unchanged form is found in the urine. No active metabolites have been detected in plasma.
Elimination: The elimination half-life of gliclazide is approximately 16 hours.
Linearity/non-linearity: The relationship between the dose administered ranging up to 90 mg/day and the area under the concentration-time curve is linear. At the highest evaluated dose (135mg/day), the AUC increases slightly more than proportionally to the dose.
Special populations: Elderly: No clinically relevant changes in the pharmacokinetic parameters have been observed in elderly patients.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazards for humans based on conventional studies of repeated dose toxicity and genotoxicity. Long term carcinogenicity studies have not been done. No teratogenic changes have been shown in animal studies, but lower foetal body weight was observed in animals receiving doses 25 fold higher than the maximum recommended dose in humans.

Gliclazide is indicated for the treatment of type II diabetes in association with dietary measures and with physical exercise when these measures alone are inadequate to control blood glucose.
During controlled clinical trials in patients with type II diabetes, a modified release formulation of gliclazide (30 mg- 120 mg), taken as a single daily dose, was shown to be effective long term in controlling blood glucose levels, based on monitoring of HbA1c.

Posology: The daily dose of gliclazide may vary from 30 to 120 mg taken orally in a single intake at breakfast time.
If a dose is forgotten, there must be no increase in the dose taken next day.
As with any hypoglycaemic agent, the dose should be adjusted according to the individual patient's metabolic response (blood glucose, HbA1c).
Initial dose: The recommended initial 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 (immediate release formulation) to Gliclada 60 mg tablets with modified release: Two immediate release tablets of gliclazide (160 mg) are comparable to one gliclazide modified-release tablet 60 mg. Consequently, the switch can be performed with careful blood monitoring.
Switchover from another oral antidiabetic medicinal product to Gliclada 60 mg: Gliclada modified-release tablets can be used to replace another oral antidiabetic medicinal product. The dosage and the half-life of the previous antidiabetic agent should be taken into account when switching to Gliclada 60 mg modified release tablets.
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 previously described.
When switching from a hypoglycaemic sulphonylurea with a prolonged 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 Gliclada modified release tablets, i.e. a starting dose of 30 mg/day, followed by a stepwise increase in dose, depending on the metabolic response.
Combination with other antidiabetic medicines: Gliclada modified-release tablets can be given in combination with biguanides, alpha-glucosidase inhibitors or insulin. In patients not adequately controlled with Gliclada 60 mg modified-release tablets, concomitant insulin therapy can be initiated under close medical supervision.
Special populations: Elderly: Gliclazide modified-release tablets should be prescribed using the same dosing regimen recommended for patients under 65 years of age.
Patients with renal impairment: In patients with mild to moderate renal impairment, the same dosing regimen can be used as in patients with normal renal function with careful patient monitoring. These data have been confirmed in clinical trials.
Patients at risk of hypoglycaemia: undernourishment or malnourishment, severe or poorly compensated endocrine disorders (hypopituitarism, hypothyroidism, adrenocorticotrophic insufficiency), withdrawal of a prolonged and/or high-dose corticoid therapy, severe vascular disease (serious coronary heart disease, severe carotid impairment, diffuse vascular disease).
It is recommended that the minimum daily dose of 30 mg is used.
Paediatric population: The safety and efficacy of gliclazide in children and adolescents have not been established.
No data are available in children.
Method of administration: Gliclada is to be taken as a single dose at breakfast time.
It is recommended that the tablet(s) is swallowed whole. The tablet should not be divided into equal halves in order to obtain a 30 mg dose. The tablet should not be chewed or crushed.

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.
If a 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 a 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 closely monitored for at least 48 hours and depending on the patient's condition after this time the doctor will decide if further monitoring is necessary.
Plasma clearance of gliclazide may be prolonged in patients with hepatic disease. Dialysis is of no benefit to patients due to the strong binding of gliclazide to proteins.

Hypersensitivity to gliclazide or to any of the excipients listed in Description, other sulphonylureas or sulphonamides; Insulin-dependent diabetes (Type I); Diabetic pre-coma and coma, diabetic ketoacidosis; Severe renal or hepatic insufficiency (in these cases the use of insulin is recommended); Treatment with miconazole (see Interactions); Pregnancy and lactation (see Use in Pregnancy & Lactation).

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 caloric diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycaemic agents is being used.
Hypoglycaemia may occur following administration of sulphonylureas (see Adverse Reactions). 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 cooperate; malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes; imbalance between physical exercise and of carbohydrates intake; renal insufficiency; severe hepatic insufficiency; overdose of Gliclada modified-release tablet; certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency; concomitant administration with certain other medicines (see Interactions).
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 risk of hypoglycaemia, together with its symptoms (see Adverse Reactions), 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 sugar controls: The 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 discontinue treatment and 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 reinforcement of 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. Since gliclazide belongs to the chemical class of sulfonylurea drugs, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.
Other ingredients: Gliclada modified release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Gliclazide has no known influence on the ability to drive and use machines. However, patients must be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machinery, especially at the beginning of treatment.

Pregnancy: There is no experience with the use of gliclazide during pregnancy in humans, even though there are few data with other sulphonylureas. The sulfonylureas may enter the fetal circulation and cause neonatal hypoglycaemia.
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.
Breast-feeding: It is not known whether gliclazide or its metabolites is excreted into breast milk. Given the risk of neonatal hypoglycaemia the product is contraindicated in breast-feeding mother.

Based on the experience with gliclazide, the following undesirable effects have been reported. Frequencies are defined as follows: 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 (cannot be estimated from the available data).
Hypoglycaemia: As with other sulphonylureas, treatment with gliclazide modified-release tablets can commonly cause hypoglycaemia if meals are taken irregularly, and, in particular, if they 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 the 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 are required.
In long-term comparative studies, the percentage of patients experiencing hypoglycaemic episodes was similar between patients treated with the modified release formulation of gliclazide (11.6%) and those treated with the immediate release formulation of gliclazide (11.1%). However, the number of hypoglycaemic episodes per 100 patient months was lower in the modified release group (3.5) than in the immediate release group (4.8).
Analysis of elderly patients (over 65 years old) showed less hypoglycaemia than in the general population, with a prevalence of hypoglycaemic episodes lower in the modified release group (2.6 hypoglycaemic episodes for 100 patient months) than in the immediate release group (4.1).
The percentage of patients experiencing hypoglycaemic episodes in the sub-population with renal failure, was similar to that observed in the general population.
Other undesirable effects: Adverse events reported during controlled clinical trials with the modified release formulation of gliclazide were those expected in an ageing population with diabetes.
Adverse events that were reported in at least 2.0% of patients, in long-term controlled clinical studies, are presented in the following table. The most frequent adverse events were not specifically related to the disease (such as respiratory infections or back pain). (See table.)

Click on icon to see table/diagram/image

Analysis of adverse events in sub-populations showed a similar pattern to that seen in the general population. Gender, age and renal insufficiency had no significant influence on the safety profile of the modified release formulation of gliclazide.
Gastrointestinal disorders: Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation are uncommon; if these should occur, they can be avoided or minimised if gliclazide is taken with breakfast.
The following undesirable effects have been more rarely reported: Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis).
Blood and lymphatic system disorders: Changes in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia and granulocytopenia. These are generally reversible upon discontinuation of the medication.
Hepatobiliary disorders: Raised hepatic enzyme levels (AST, ALT, alkaline phosphatase), hepatitis (isolated reports); Discontinuation of therapy if cholestatic jaundice appears.
These undesirable effects normally 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: As for other sulphonylureas, the following undesirable effects have been observed: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulphonylurea or led to life-threatening liver failure in isolated cases.

The following medicines can 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 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. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with the anti-inflammatory agent.
Alcohol: increases in the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Ingestion of alcohol may also cause a disulfiram-like reaction with characteristic flushing of the face, throbbing headache, giddiness, tachypnoea, tachycardia or angina pectoris. Chronic alcohol abuse may, as a result of liver enzyme induction, increase the metabolism of sulfonylurea drugs, shortening the plasma half life and duration of action. Alcohol and alcoholic medicinal products should be avoided.
Combinations requiring precautions for use: Potentiation of the blood glucose lowering effect and thus in some instances hypoglycaemia may also occur when one of the following medicinal products is taken: other antidiabetics (insulins, acarbose, metformin, thiazolidinediones, dipeptidylpeptidase-4 inhibitors, GLP-1 receptor agonists), clofibrate, salicylates (high doses), chloramphenicol, beta blockers, fluconazole, ACE inhibitors (captopril, enalapril), H₂-receptor antagonists, MAO inhibitors, sulphonamides, clarithromycin and non-steroidal anti-inflammatory agents.
The patient must be warned and informed of the importance of self-monitoring of blood glucose levels. It may be necessary to adjust the dose of the antidiabetic agent during treatment with these substances.
The following medicinal 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, the patient must be warned and informed of the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with danazol.
Combinations requiring precautions during use: As with all hypoglycaemics, caution should be observed in administering thiazide diuretics, since these diuretics have been reported to aggravate the diabetic state.
Chlorpromazine (neuroleptic agent): High doses (>100 mg per day of chlorpromazine) increase in blood glucose levels (reduction of insulin release).
The patient must be warned and informed of 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 the glucocorticoids). The patient must be warned and informed of 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 sugar level due to beta-2-agonist effects. The patient must be informed of the importance of blood glucose monitoring. A switch to insulin treatment may be necessary.
Combination which has to be taken into account: Anticoagulant therapy (e.g. warfarin, etc.): Sulphonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the dose of the anticoagulant may be necessary.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Do not store above 30°C.
Store in the original package in order to protect from moisture.
Shelf-Life: 2 years.

Antidiabetic Agents

A10BB09 - gliclazide ; Belongs to the class of sulfonylureas. Used in the treatment of diabetes.

POM