Glubitor/Glubitor-OD

Glubitor: Each tablet contains 80 mg gliclazide.
Glubitor-OD: MR tab: Each modified-release tablet contains: Gliclazide 30 mg.
Gliclazide (Glubitor-OD) 30 mg is a modified-release, white, plain, elliptical tablet intended for once-daily dosing to improve patient compliance and glycemic control in patients with type 2 diabetes.
PR tab: Each prolonged-release tablet contains: Gliclazide 60 mg.

Pharmacotherapeutic group: Glubitor: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, sulfonylureas. Glubitor-OD: PR tab: Sulfonamides, urea derivatives. ATC code: Glubitor: A10BB09.
Pharmacology: Pharmacodynamics: Glubitor/Glubitor-OD (PR tab): Mechanism of action: Gliclazide is a hypoglycemic sulfonylurea oral antidiabetic active substance 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.
Glubitor-OD (MR tab): Gliclazide is a sulfonylurea oral antidiabetic agent whose primary action is to increase the sensitivity of the β-cells from the pancreas. It potentiates glucose-stimulated insulin secretion from functioning pancreatic islet β-cells inhibiting ATP-sensitive potassium (K⁺-ATP) channels resulting in depolarization which opens voltage-sensitive calcium channels and brings about influx of calcium that triggers insulin release.
As with other sulfonylureas, gliclazide has actions on peripheral tissues. Gliclazide enhances glycogen synthesis and inhibits glycogenolysis and gluconeogenesis in the liver. Gliclazide may also improve peripheral glucose uptake in muscles.
Pharmacokinetics: Glubitor/Glubitor-OD (PR tab): 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 (L). A single daily intake 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 varies/is between 12 and 20 hours.
Linearity/Non-Linearity: The relationship between the dose administered ranging up to 120 mg and the area under the concentration-time curve is linear.
Special populations: Elderly people: No clinically significant/relevant changes in the pharmacokinetic parameters have been observed in elderly patients.
Glubitor-OD (MR tab): Gliclazide is readily absorbed from the gastrointestinal tract although systemic bioavailability of an oral dose may vary considerably depending more on first-pass metabolism than absorption.
After an 80 mg dose of the immediate release preparation in normal volunteers, the average time to reach peak plasma concentration is about 4-6 hours. Gliclazide is about 95% bound to plasma proteins, mostly to albumin. Its volume of distribution is low. It has a mean plasma half-life of about 10-12 hours.
Gliclazide modified-release (Gliclazide OD) is a once-daily gliclazide formulation. The progressive release of gliclazide in this formulation parallels the 24-hour glycemic profile in untreated patients with type 2 diabetes. Gliclazide OD is highly bioavailable and its absorption is unaffected by food intake.
The following are important pharmacokinetic parameters of Gliclazide OD in adult volunteers who received 60 mg (2 tablets) single oral dose: See Table 1.

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Gliclazide OD's apparent clearance in type 2 diabetic patients is 0.9 L/h and its apparent volume of distribution is 19 L; the effective half-life is approximately 16 hours.
Gliclazide is distributed to the extracellular fluid, with high concentrations found in the liver, kidneys, skin, lungs, skeletal muscle, intestinal and cardiac tissue in animals. Gliclazide has been also shown to cross the placental barrier and penetrate the fetus.
Gliclazide is extensively metabolized with about <1% excreted in the urine unchanged. Approximately 60-70% of the administered dose appears to be excreted in the urine and 10-20% excreted in the feces.
The metabolism and excretion of sulfonylureas such as gliclazide may be slowed in patients with impaired renal and hepatic function.
Toxicology: Glubitor: 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 fetal body weight was observed in animals receiving doses 25 fold higher than the maximum recommended dose in humans.

Glubitor: Non insulin-dependent diabetes (type 2) in adults when dietary measures, physical exercise and weight loss alone are not sufficient to control blood glucose.
Glubitor-OD: MR tab: Type 2 diabetes mellitus uncontrolled by diet and exercise.
PR tab: For non-insulin-dependent diabetes (type 2) in adults, in association with dietary measures and with exercise, when these measures alone are not sufficient.

Glubitor: Dosage: The daily adult dose may vary from 1 to 4 tablets per day, i.e. from 30 to 120 mg taken orally in a single intake at breakfast time.
It is recommended that the tablet(s) be swallowed whole.
If a dose is forgotten, there must be no increase in the dose taken the next day.
As with any hypoglycemic agent, the dose should be adjusted according to the individual patient's metabolic response (blood glucose, HbA_1c).
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 tablets containing 80 mg of gliclazide to gliclazide modified-release tablet: 1 tablet containing 80 mg of gliclazide is comparable to 1 modified-release tablet of gliclazide. Consequently, the switch can be performed provided a careful blood monitoring.
Switching from another oral antidiabetic agent to gliclazide: Gliclazide can be used to replace other oral antidiabetic agents. The dosage and the half-life of the previous antidiabetic 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 previously.
When switching from a hypoglycemic sulfonylurea with 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, 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 agents: Gliclazide can be given in combination with biguanides, alpha glucosidase inhibitors and insulin. In patients not adequately controlled with gliclazide, concomitant insulin therapy can be initiated under close medical supervision.
Special population: Elderly people: Gliclazide 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 insufficiency, 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: Undernourished or malnourished; Severe or poorly compensated endocrine disorders (hypopituitarism, hypothyroidism, adrenocorticotropic insufficiency); Withdrawal of prolonged and/or high dose corticosteroid therapy; Severe vascular disease (severe coronary heart disease, severe carotid impairment, diffuse vascular disease).
It is recommended that the minimum daily starting dose of 30 mg is used.
Pediatric population: The safety and efficacy of gliclazide in children and adolescents have not been established. No data are available.
Glubitor-OD: MR tab: General Dosing Recommendations: There is usually no fixed dosage regimen with any hypoglycemic agent for the management of diabetes mellitus. Adjust dose according to patient's response.
Monitor glycemic control through frequent measurements of fasting blood glucose and periodic testing of glycosylated hemoglobin (HbA_1c). These measurements are important in determining the minimum effective dose for the patient, detecting primary failure (i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication), and detecting secondary failure (i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness).
Fever, trauma, infection, or surgical intervention may affect blood glucose control in patients receiving anti-diabetic treatment. These patients should be closely monitored and administration of insulin may be required.
Hepatic function should be assessed prior to initiation and periodically thereafter in patients with impaired hepatic function.
Periodic monitoring and special care is required in the elderly especially those who are malnourished, and those with impaired hepatic, renal, or adrenal function. (See Table 2.)

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PR tab: 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 tablet 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 60 mg: 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 30 mg 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.

Glubitor/Glubitor-OD (PR tab): 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 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 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.
Glubitor-OD (MR tab): Overdosage with gliclazide and other sulfonylureas will likely result in hypoglycemia which may need to be treated with intravenous infusion of 5% glucose for 12 to 14 hours with frequent monitoring of blood glucose level. Potassium levels should also be monitored. Cerebral edema may also need to be treated in unusually severe cases.
In comatose patients, glucagon injection may be administered before intravenous glucose therapy although this may induce vomiting. Efficacy of this treatment will also be dependent on hepatic glycogen status.
In severe sulfonylurea overdose, diazoxide and octreotide may reduce insulin secretion and hypoglycemia.
Continue frequent oral feeding and blood glucose and potassium monitoring until recovery.

Hypersensitivity to gliclazide or to any of the excipients/ingredient in these products, other sulfonylureas, sulfonamides.
Type 1 diabetes/diabetes mellitus/Insulin-dependent diabetes (type 1).
Diabetic pre-coma and coma, diabetic keto-acidosis/Diabetes complicated by ketosis and acidosis.
Severe renal or hepatic insufficiency. In these cases the use of insulin is recommended.
Treatment with miconazole via systemic route or oromucosal gel drugs (see INTERACTIONS).
Glubitor/Glubitor-OD (PR tab): This medicinal product is contraindicated in case of: Lactation (see USE IN PREGNANCY & LACTATION).
Glubitor-OD (MR tab): Unstable or brittle diabetes.
Use in pregnant and breastfeeding women is contraindicated.
During stress conditions, e.g., serious infection, trauma or surgery.

Glubitor/Glubitor-OD (PR tab): 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-calorie 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 (see ADVERSE REACTIONS). 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 carbohydrate intake; Renal impairment/insufficiency; Severe hepatic impairment/insufficiency; Overdose of gliclazide/gliclazide prolonged-release tablet; Certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency; Concomitant administration of/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 hypoglycemic episode occurring in these patients may be prolonged, so appropriate management should be initiated.
Patient information: The risks of hypoglycemia, 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 glucose/sugar control(s): 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 (see INTERACTIONS), 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-deficiency 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.
Effects on ability to drive and use machines: Gliclazide has no or negligible influence on the ability to drive and use machines. However, patients should be informed that their concentration may be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment.
Glubitor-OD (MR tab): Development of complications peculiar to diabetes mellitus (e.g., heart disease, blindness, kidney disease, hypertension, nerve damage, etc.) will not be prevented by the use of gliclazide.
Gliclazide should not be used as a substitute for diet. It must be considered only as an additional treatment to proper dietary regimen.
Administration of gliclazide over a long period of time decreases its efficacy in many patients. This may be due to continuing depletion of β-cell reserve. Discontinue the use of gliclazide if a loss of adequate blood glucose-lowering response is detected. Insulin therapy may be required in these patients.
Hypoglycemia: All sulfonylureas, including gliclazide, may cause severe hypoglycemia. Debilitated or malnourished patients, those with adrenal, pituitary, renal or hepatic insufficiency and patients controlled with diet alone are particularly susceptible to the hypoglycemic action of gliclazide. Use of gliclazide in combination with other oral hypoglycemic agents may increase the potential for hypoglycemia.
Inadequate caloric intake, severe or prolonged exercise, and alcohol ingestion may also increase the risk of hypoglycemia.
Gliclazide overdose, certain endocrine disorders (i.e., thyroid disorders, hypopituitarism and adrenal insufficiency) as well as withdrawal of prolonged and/or high dose corticosteroid therapy, severe vascular disease (severe coronary heart disease, severe carotid impairment, diffuse vascular disease) and concomitant administration of certain drugs (see INTERACTIONS) may also increase the risk of hypoglycemia.
The following measures are recommended to reduce the risk of hypoglycemia: initiate treatment of type 2 diabetes mellitus by diet alone, if possible; take into account the patient's age: blood sugar levels not strictly controlled by diet alone might be acceptable in the elderly; adjust gliclazide dose according to the blood glucose response and to the 24-hour urinary glucose during the first days of treatment.
Patients with mild symptoms of hypoglycemia such as sweating, pallor, hunger pangs, tachycardia, sensation of malaise may require treatment with oral glucose and adjustments in gliclazide dose and/or meal patterns.
Loss of Control of Blood Glucose: Exposure to stress such as fever, trauma, infection, or surgery may lead to loss of glycemic control. Temporary discontinuation of oral hypoglycemic therapy and administration of insulin may be necessary in such cases.
Progression of the severity of diabetes may lead to secondary failure or decreased effectiveness of any hypoglycemic drug (including gliclazide). Adequate assessment of dosage adjustment and diet adherence is necessary before classifying secondary failure in a patient. Insulin therapy should be initiated in patients who experience secondary failure after therapy with gliclazide.
Increased Risk of Cardiovascular Mortality: Based on a long term prospective study conducted by the University Group Diabetes Program (UGDP), it has been reported that diabetic patients treated for 5-8 years with diet plus a fixed dose of tolbutamide (1.5 g/day), a sulfonylurea, had a risk of cardiovascular mortality approximately 2 ½ times that of patients treated with diet alone.
In the United Kingdom Prospective Diabetes Study (UKPDS), however, intensive glycemic control with either sulfonylureas or insulin did not have an adverse effect on cardiovascular outcomes. Despite questions regarding the design of these studies and interpretation of the results, these studies provide a basis for caution especially in high risk patients with cardiovascular disease.
Hemolytic Anemia: Sulfonylureas may cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Use sulfonylureas with caution and consider a non-sulfonylurea alternative in these patients.
Transferring to Gliclazide: Patients who have been previously treated with sulfonylureas or biguanides alone or in combination may be transferred to gliclazide alone or in combination with other oral antidiabetics. Careful observation is essential during the transitional phase.
Generally, it is not recommended that insulin treated patients be transferred to gliclazide.
Renal and Hepatic Insufficiency: Treatment with gliclazide (i.e., initial dosing, dose increments, and maintenance dose) in patients with renal and hepatic insufficiency should start in small doses to avoid hypoglycemic reactions. Careful patient monitoring is also recommended since the metabolism and excretion of sulfonylureas such as gliclazide may be slowed in patients with impaired renal and hepatic function.
Effects on Ability to Drive or Use Machines: Patients who need to perform activities requiring mental alertness or physical coordination should avoid gliclazide since it may affect concentration if diabetes is not satisfactorily controlled (usually at the beginning of treatment).
Use in Children: The safety and efficacy of gliclazide in children have not been established. Gliclazide is not recommended for use in infants and children.
Use in the Elderly: Elderly patients are particularly susceptible to hypoglycemia. Moreover, hypoglycemia may be difficult to recognize in the elderly. Carefully determine the appropriate initial dose, dose increments and maintenance dose to avoid hypoglycemic episodes.
Glubitor-OD (PR tab): 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.
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: Glubitor/Glubitor-OD (PR tab): 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.
Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
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.
Glubitor-OD (MR tab): Category C. Oral hypoglycemic agents (including gliclazide) are not recommended during pregnancy. Maintaining blood glucose levels as close to normal as possible is necessary during pregnancy since abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is recommended during pregnancy.
Breastfeeding/Lactation: Glubitor/Glubitor-OD (PR tab): It is unknown whether gliclazide or its metabolites are excreted in human milk. Given the risk of neonatal hypoglycemia, the product is therefore contraindicated in breastfeeding mothers. A risk to the newborn infant/children cannot be excluded.
Glubitor-OD (MR tab): It is not known whether breastfeeding will lead to exposure of the human infant to gliclazide. However, gliclazide should not be used by breastfeeding mothers since other sulfonylureas have been found in human milk. Discontinue use in breastfeeding mothers because of potential hypoglycemia in breastfeeding infants. Consider insulin therapy for adequate glycemic control if gliclazide is discontinued.
Fertility: Glubitor/Glubitor-OD (PR tab): No effect on fertility or reproductive performance was noted in male and female rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).

Glubitor: Based on the experience with gliclazide, the following undesirable effects have been reported.
The most frequent adverse reaction with gliclazide is hypoglycemia.
As for other sulfonylureas, treatment with gliclazide can cause hypoglycemia, if mealtimes are irregular and, in particular, if meals are skipped. Possible symptoms of hypoglycemia are: headache, intense hunger, nausea, vomiting, fatigue, sleep disorders, agitation, aggression, impaired 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 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 is required.
Gastrointestinal disorders: Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation have been reported. 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: Blood and lymphatic system disorders: Changes in hematology are rare. They may include anemia, leucopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon discontinuation of medication.
Hepatobiliary disorders: Raised hepatic enzyme levels (AST, ALT, alkaline phosphatase), hepatitis (isolated reports). Discontinue treatment if cholestatic jaundice appears.
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).
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: As for other sulfonylureas, the following adverse events 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.
Glubitor-OD: MR tab: Metabolic-Nutritional: Hypoglycemia characterized by weakness, nervousness, shakiness, paresthesia, and coma. Severe hypoglycemia which mimics acute CNS disorders may also occur. Predisposing factors may include hepatic and/or renal disease, malnutrition, debility, advanced age, alcoholism, adrenal or pituitary insufficiency.
Hyperglycemia, lipid metabolism disorder, gout, glycosuria, hypercholesterolemia, hypertriglyceridemia, hyperlipemia, and thirst have also been reported.
Gastrointestinal: Nausea, vomiting, heartburn, gastroesophageal reflux, anorexia, diarrhea, constipation, abdominal pain, dyspepsia, gastric irritation, gastritis, gastroenteritis, anal fissure, colitis, duodenal ulcer, epigastric fullness, fecal incontinence, flatulence and metallic taste; other adverse effects include GI neoplasm benign, hemorrhoids, melena, dry mouth, saliva increased, toothache, and tooth disorder.
Hepatobiliary: Cholestasis, jaundice, abnormal liver function, hepatitis which may lead to liver failure or hepatic dysfunction, hepatic porphyria reactions, hepatomegaly, and increased liver enzyme levels (AST, ALT, alkaline phosphatase). Discontinue treatment if cholestatic jaundice appears.
Dermatological: Allergic reactions (e.g., pruritus, rash, erythema, urticaria, morbilliform or maculopapular rash, bullous reactions), porphyria cutanea tarda, photosensitivity reactions, fungal dermatitis, dermatitis, skin disorder, eczema, hyperkeratosis, nail disorder, onychomycosis, dry skin, and skin ulceration have been reported.
Hematologic: Hemolytic anemia, leukopenia, agranulocytosis, thrombocytopenia, pancytopenia, erythrocytopenia, and allergic vasculitis.
Cardiovascular: Arteritis, cardiac failure, cerebrovascular disorder, coronary artery disorder, epistaxis, hypotension, hypertension, angina pectoris, myocardial infarction, edema legs, palpitations, tachycardia, thrombophlebitis, and vein disorder.
Endocrine Reactions: Hypothyroidism - a report of decreased uptake of radioactive iodine by the thyroid gland has been reported with sulfonylurea drugs. This has not been shown with the use of gliclazide 80 mg in a small study involving 15 patients.
Respiratory: Rhinitis, bronchitis, pharyngitis, upper respiratory infection, coughing, pneumonia, dyspnea, asthma, tracheitis, and sinusitis.
CNS: Disulfiram-like reactions, anxiety, confusion, nervousness, dizziness, depression, insomnia, and neuralgia.
Urinary: Urinary tract infections, increased urinary frequency, albuminuria, cystitis, nocturia, polyuria, renal calculus, and renal cyst.
Musculoskeletal: Back pain, arthralgia, arthrosis, arthropathy, bursitis, hernia congenital, skeletal pain, spine malformation, arthritis, tendinitis, and myalgia.
Reproductive: Balanoposthitis, benign female breast neoplasm, impotence, mastitis, menstrual disorder, prostatic disorder, and vaginitis.
EENT: Conjunctivitis, visual disturbance/abnormal vision, cataract, conjunctival hemorrhage, diplopia, glaucoma, abnormal lacrimation, retinal disorder, vitreous disorder, xerophthalmia, otitis media, hearing decreased, tinnitus, and impaired speech disorder.
Body as a Whole: Headache, asthenia, allergy, carpal tunnel syndrome, chest pain, sweating, viral infection, infection, fungal infection, leg pain, malaise, pain.
Miscellaneous: Inflicted injury.
PR tab: 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).
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 are 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.
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 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.

Glubitor/Glubitor-OD (PR tab): The following products/medicines are/can likely to 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. Where necessary, adjust the dose of the antidiabetic active substance during and after treatment with the anti-inflammatory agent.
Alcohol: Increases the hypoglycemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycemic coma. Alcohol or/and medicines containing alcohol/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 drugs/medicinal products is taken: other antidiabetic agents (insulins, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists), beta-blockers, fluconazole, angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril), H₂-receptor antagonists, MAOIs (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, warn the patient and emphasize/inform 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 (reduction of/reduced insulin release). Warn the patient and emphasize/inform 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). Warn the patient and emphasize/inform 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/sugar levels due to beta-2 agonist effects. Emphasize/inform the importance of monitoring blood glucose levels. If necessary, switch to insulin.
St. John's Wort (Hypericum perforatum) preparations: Gliclazide exposure is decreased by St. John's Wort (Hypericum perforatum). 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/must 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.
Glubitor-OD (MR tab): Hepatic enzyme inhibitors such as sulfonamides, tuberculostatics, clarithromycin, phenylbutazone, clofibrate, coumarin derivatives, salicylates, nonsteroidal anti-inflammatory agents (NSAIDs), probenecid, beta-blockers (e.g., propranolol), tetracycline compounds, chloramphenicol, azole antifungal agents (e.g., miconazole, ketoconazole, itraconazole), H2-receptor antagonists (e.g., cimetidine), disopyramide and angiotensin-converting enzymes (ACE) inhibitors (e.g., captopril and enalapril), and monoamine oxidase (MAO) inhibitors may increase gliclazide's hypoglycemic effect.
Inducers of hepatic enzymes such as rifampicin, barbiturates, thyroid hormones and phenytoin may lower gliclazide's plasma concentration.
Concomitant administration with anticoagulants (warfarin and other anticoagulants) may lead to potentiation of anticoagulation. Adjustment of anticoagulant dosage may be necessary.
Drugs that induce hyperglycemia leading to a loss of control of blood sugar: diuretics (thiazides, furosemide), corticosteroids and tetracosactrin, danazol, chlorpromazine, ritodrine/salbutamol/terbutaline (IV), oral contraceptives (estrogens plus progestogens, and nicotinic acid in pharmacologic doses.
Acute or chronic alcohol intake may unpredictably potentiate or reduce the activity of gliclazide.

Glubitor: Incompatibilities: Not applicable.
Glubitor-OD: PR tab: 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.

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