Gluclazide SR

Gliclazide.

White to almost white, oval, biconvex tablets.
Each prolonged-release tablet contains: Gliclazide 60 mg.

Pharmacotherapeutic group: Sulfonamides, urea derivatives.
Pharmacology: Pharmacodynamics: Mechanism of action: Gliclazide is a hypoglycemic sulfonylurea 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. Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.
In addition to these metabolic properties, gliclazide has hemovascular properties.
Pharmacodynamic effects: 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.
Hemovascular 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.
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 liters.
A single daily intake of gliclazide prolonged-release tablets maintains effective gliclazide plasma concentrations over 24 hours.
Biotransformation: Gliclazide is mainly metabolized 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 between 12 and 20 hours.
Linearity/Non-Linearity: The relationship between the dose administered ranging up to 120mg and the area under the concentration-time carve is linear.
Special populations: Elderly: No clinically relevant changes in the pharmacokinetic parameters have been observed in elderly patients.

For non-insulin-dependent diabetes (type 2) in adults, in association with dietary measures and with exercise, when these measures alone are not sufficient.

The daily dose of gliclazide may vary from one half to 2 tablets per day i.e. 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 hypoglycemic agent, the dose should be adjusted according to the individual patient's metabolic response (blood glucose, HbA_1C).
The recommended initial dose is 30 mg daily (half a tablet of Gliclazide 60 mg prolonged-release tablet). 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.
One gliclazide 60 mg prolonged-release tablet corresponds to two gliclazide 30 mg prolonged-release tablets. The breakability of the Gliclazide 60 mg prolonged-release tablets enables flexibility of dosing to be achieved.
Switching from gliclazide (80 mg) tablets (immediate-release formulation) to gliclazide 60 mg tablets with modified release: One tablet of gliclazide (80 mg) is comparable to one prolonged-release tablet 30 mg i.e. half a Gliclazide 60 mg prolonged-release tablet. Consequently, the switch can be performed with careful blood monitoring.
Switchover from another oral antidiabetic medicinal product to Gliclazide 60mg: Gliclazide prolonged-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 gliclazide 60 mg prolonged-release tablet.
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 previously.
When switching from a hypoglycemic sulfonylurea 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 hypoglycemia. The procedure described for initiating treatment should also be used when switching to treatment with gliclazide prolonged-release tablets, i.e., a starting dose of 30 mg/day, followed by a stepwise increase in dose, depending on the metabolic response. Or as prescribed by the physician.
Combination with other antidiabetic medicines: Gliclazide prolonged-release tablets can be given in combination with biguanides, alpha-glucosidase inhibitors or insulin. In patients not adequately controlled with gliclazide 60 mg prolonged-release tablets, concomitant insulin therapy can be initiated under dose medical supervision.
Special populations: Elderly: Gliclazide prolonged-release tablets should be prescribed using the same dosing regimen recommended for patients under 65 years of age.
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 hypoglycemia: 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 30mg is used.
Pediatric population: The safety and efficacy of gliclazide in children and adolescents have not been established.
No data are available in children.
Method of administration: Gliclazide is to be taken as a single intake at breakfast time.
It is recommended to swallow the half tablet or tablet(s) without crushing or chewing.

Symptoms: An overdose of sulfonylureas may cause hypoglycemia. Moderate symptoms of hypoglycemia 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 hypoglycemic reactions with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalization.
Management: If a hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid IV. 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 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.

Hypersensitivity to gliclazide or to any of the excipients, other sulfonylureas or sulfonamides; Insulin-dependent diabetes (type 1); Diabetic pre-coma and coma, diabetic ketoacidosis; Severe renal or hepatic insufficiency (in these cases the use of insulin is recommended); Treatment with miconazole; Lactation.

Hypoglycemia 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 hypoglycemia if a meal is taken late, if an inadequate amount of food is consumed or if the food is low in carbohydrate.
Hypoglycemia is more likely to occur during low caloric diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycemic agents is being used.
Hypoglycemia may occur following administration of sulfonylureas. Some cases may be severe and prolonged. Hospitalization 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 hypoglycemic episodes.
Factors which increase the risk of hypoglycemia: 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 gliclazide prolonged-release tablet; certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency; concomitant administration with certain other medicines.
Patient information: The risk of hypoglycemia, 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 sugar controls: The blood glucose control in a patient receiving antidiabetic treatment may be affected by any of the following: St John's Wort (Hypericum perforatum) preparations, fever, trauma, infection or surgical intervention. In some cases it may be necessary to administer insulin.
The hypoglycemic 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.
Dysglycemia: Disturbances in blood glucose, including hypoglycemia and hyperglycemia have been reported, in diabetic patients receiving concomitant treatment with fluoroquinolones, especially in elderly patients. Indeed, careful monitoring of blood glucose is recommended in all patients receiving at the same time gliclazide and a fluoroquinolone.
Laboratory tests: Measurement of glycated hemoglobin 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-deflciency with sulfonylurea agents can lead to hemolytic anemia.
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: Gliclazide prolonged-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.
Renal and hepatic insufficiency: The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic insufficiency or severe renal failure. A hypoglycemic episode occurring in these patients may be prolonged; so appropriate management should be initiated.
Effects on ability to drive and use machines: Gliclazide 60 mg prolonged-release tablet has no or negligible influence on the ability to drive and use machines. However, patients must be made aware of the symptoms of hypoglycemia and should be careful if driving or operating machinery, especially at the beginning of treatment.

Pregnancy: There is no or limited amount of data (less than 300 pregnancy outcomes) from the use of gliclazide in pregnant women, even though there are few data with other sulfonylureas.
In animal studies, gliclazide is not teratogenic.
As a precautionary measure, it is preferable to avoid the use of gliclazide during pregnancy.
Control of diabetes should be obtained before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes. Oral hypoglycemic agents are not suitable, insulin is the drug of first choice for treatment of diabetes during pregnancy. It is recommended that oral hypoglycemic therapy is changed to insulin before a pregnancy is attempted, or as soon as pregnancy is discovered.
Breastfeeding: It is unknown whether gliclazide or its metabolites is excreted in human milk. Given the risk of neonatal hypoglycemia the product is contraindicated in breastfeeding mother.
A risk to the newborns/infants cannot be excluded.
Fertility: No effect on fertility or reproductive performance was noted in male and female rats.

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 <1/1 00); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Description of selected adverse reactions: Hypoglycemia: The most frequent adverse reaction with Gliclazide is hypoglycemia.
As with other sulfonylureas, treatment with Gliclazide prolonged-release tablets can commonly cause hypoglycemia if meals are taken irregularly, and, in particular, if they are skipped. Possible symptoms of hypoglycemia 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 sulfonylureas shows that hypoglycemia can recur even when measures prove effective initially.
If a hypoglycemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalization are required.
Other undesirable effects: Gastrointestinal disorders: Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea and constipation am uncommon; if these should occur, they can be avoided or minimized 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) and exceptionally, drug rash with eosinophilia and systemic symptoms (DRESS).
Blood and lymphatic system disorders: Changes in hematology are rare. They may include anemia, leucopenia, thrombocytopenia and granulocytopenia. These are generally reversible upon discontinuation of the medication.
Hepatobiliaty 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 sulfonylureas, the following undesirable effects have been observed: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, 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 sulfonylurea or led to life-threatening liver failure in isolated cases.

The following medicines can increase the risk of hypoglycemia: Contraindicated combination: Miconazole (systemic route, oromucosal gel): Increases the hypoglycemic effect with possible onset of hypoglycemic symptoms, or even coma.
Combinations which are not recommended: Phenylbutazone (systemic route): Increases the hypoglycemic 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 emphasize 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 hypoglycemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycemic coma. 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 hypoglycemia 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), beta blockers, fluconazole, ACE inhibitors (captopril, enalapril), H2-receptor antagonists, MAO inhibitors, sulfonamides, clarithromycin and non-steroidal anti-inflammatory agents.
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: 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.
Saint John's Wort (Hypericum perforatum) preparations: Gliclazide exposure is decreased by Saint John's Wort. Emphasize the importance of blood glucose levels monitoring.
The following products may cause dysglycemia: Combinations requiring precautions during use: Fluoroquinolones: In case of a concomitant use of gliclazide and a fluoroquinolone, the patient should be warned of the risk of dysglycemia, and the importance of blood glucose monitoring should be emphasized.
Combination which has to be taken into account: Anticoagulant therapy (e.g., warfarin, etc.): Sulfonylureas 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.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

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

Rx