GLYZERIC Metformin Hydrochloride / Gliclazide 500mg / 80mg Film-Coated Tablet 1's

As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who are already treated with Gliclazide and Metformin or whose diabetes is not adequately controlled with Metformin alone, or for those patients who have initially responded to Gliclazide alone and require additional glycemic control.

The recommended dose is one tablet twice daily. Or as prescribed by the physician.

Severe hypoglycemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as medical emergency, requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 mL of concentrated glucose solution (20-30%). This must be followed by the infusion of more dilute glucose solution (10%) at a rate that will maintain blood glucose levels above 1g/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 not beneficial to patient due to strong binding of Gliclazide to plasma protein.
Overdosage of sulfonylureas, including Gliclazide, can produce hypoglycemia. Mild hypoglycemia symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger.
Lactic acidosis is a rare, but serious, metabolic complication that can occur if Metformin accumulates during treatment due to overdosing. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.

Should be taken with food.

Contraindicated in patients with: known hypersensitivity to Gliclazide, Metformin or any components of the product; renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 1.5mg/dL [males], 1.4mg/dL [females] or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicemia; congestive heart failure requiring pharmacologic treatment; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; patients undergoing radiological studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Cardiac Effects: The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. In view of close similarities between the oral hypoglycemic drugs, this warning also applies for Gliclazide.
Lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to Metformin accumulation during treatment with Gliclazide and Metformin combination therapy; when it occurs, it is fatal approximately 50% of cases. When Metformin is implicated as the cause of lactic acidosis, Metformin plasma levels >5 ug/mL are generally found. The reported incidence of lactic acidosis in patients receiving Metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency and congestive heart failure.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage and instructions are important to avoid hypoglycemic episodes.
Loss of control of blood glucose: When a patient stabilized in any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold the diabetic regime and temporarily administer insulin. The oral antidiabetic therapy may be reinstituted after the acute episode is resolved.
Surgical procedures: Oral antidiabetic therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake: Alcohol is known to potentiate the effect of Metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin.
Effects on ability to drive and use machine: There is no pattern of reported adverse events suggesting that patients taking Gliclazide and Metformin combination will have any impairment of ability to drive and use hazardous machinery.
Renal impairment: The use of Gliclazide and Metformin is contraindicated in patients with renal impairment.
Hepatic impairment: The use of Gliclazide and Metformin is not recommended in patients with hepatic impairment.
Use in Children: Safety and effectiveness of Gliclazide and Metformin combination in pediatric patients have not been established.
Use in Elderly: Metformin is known to be excreted by the kidneys and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, hence Gliclazide and Metformin should be used only in patients with normal renal function.
Because aging is associated with reduced renal function the use of Gliclazide and Metformin combination should be with caution as age increases. Care should be taken with the dose selection and regular renal function be monitored.

Pregnancy: Recent information suggested that abnormal blood glucose levels during pregnancy are associated with higher incidence of congenital abnormalities. Most experts suggest insulin be used to maintain the blood glucose levels as close to normal as possible. The use of Gliclazide and Metformin combination is not recommended for use in pregnancy.
Lactation: Studies in lactating rats show that Metformin is excreted in to milk and reaches levels comparable to those in plasma. Similar studies have not been conducted on nursing mothers. It is not known whether Gliclazide or its metabolites are excreted in breast milk. Hence, the use of Gliclazide and Metformin combination is not recommended for use in lactating mothers, and if the diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Gastrointestinal disturbances: Nausea, diarrhea, gastric pain, constipation, vomiting, metallic taste in mouth. These reactions are generally dose related and disappear when the dose is reduced.
Dermatological effects: Rash, pruritus, urticaria, erythema and flushing.
Miscellaneous: Headache and dizziness.
Hypoglycemia: Gliclazide appears to be associated with a low incidence of hypoglycemia. Gliclazide may have the potential to produce adverse cardiovascular effects; however Gliclazide has been established agent for the treatment of type-2 diabetes mellitus for a number of years without adverse cardiovascular effects.

Cationic drugs: Certain medications used concomitantly with Metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretions (e.g.: amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, ranitidine, or vancomycin) may decrease Metformin elimination by competing for common renal tubular transport systems. Hence, careful patient monitoring and dose adjustment of Metformin and/or interfering cationic drug is recommended.
Miconazole (systemic route, oromucosal gel) and Phenylbutazone (systemic route): Increases hypoglycemic effect of Gliclazide.
Furosemide: A single-dose, Metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the Metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in Metformin renal clearance. When administered with Metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of Metformin and furosemide when co-administered chronically.
Vitamin B₁₂: Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium dependent binding of the intrinsic factor vitamin B12 complex to its receptor. The reaction very rarely results in pernicious anemia that is reversible with discontinuation of Metformin or with vitamin B12 supplementation.
Nifedipine: Nifedipine appears to enhance the absorption of Metformin, it increases plasma Metformin Cmax and AUC by 20% and 9% respectively and increases the amount of Metformin excreted in the urine. Metformin has minimal effects on nifedipine.
Salicylates: If salicylates are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control.
Thiazide: Interactions between thiazide diuretics and oral antidiabetic agents decreases insulin sensitivity thereby leading to glucose intolerance and hyperglycemia, thus leading to a loss of diabetic control. Hence diabetic patients should be monitored closely. Concomitant administration of angiotensin enzyme inhibitors (captopril, enalapril), other antidiabetic drugs (insulin, acarbose) beta-blockers, fluconazole, histamine (H2) receptor antagonist, monoamine oxidase inhibitors (MAOIs), sulphonamides and non-steroidal anti-inflammatory agents increases sensitivity to insulin and potentiation of blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Dosage of the oral antidiabetic agent may need to be reduced. Patients receiving estrogens or oral contraceptives, phenytoin, quinolones should be closely monitored for loss of diabetic control when therapy is instituted or discontinued.

Store at temperatures not exceeding 30°C. Protect from light.

Pharmacology: Pharmacodynamics: Gliclazide is a second generation sulfonylurea which acts by stimulating beta cells of the islet of Langerhans of pancreas to release insulin. Gliclazide also enhances peripheral insulin sensitivity. Metformin enhances peripheral glucose uptake by the tissues and its utilization. It also reduces hepatic glucose production. Metformin diminishes insulin resistance.
There are reports in which combination treatment of sulfonylurea with Metformin has shown to achieve satisfactory control of blood sugar level for several years, than either agent used alone. Such combination has been reported to be quite useful in comparative studies where secondary failure to sulfonylureas has occurred. The combination provides an additional glycemic control (shown to lower blood glucose by 20%) and thus obviates the need for insulin in some patients.
Gliclazide has less propensities to cause hypoglycemia and weight increase unlike other sulfonylureas. Gliclazide promptly induces the first phase of insulin release as is not commonly observed with Glibenclamide; the second phase of insulin release is as well maintained. Thus, the necessary insulin is released to meal intake. Further, Gliclazide has significantly shown to reduce the micro- and macro-vascular combinations. This can be attributed to its action in improving peripheral utilization of glucose, reducing insulin resistance and thus hyperinsulinemia which contributes to positive influence on the lipid metabolism. This ultimately results in reduction of oxidative stress on LDL, free fatty acids and deposition of cholesterol in the small or larger blood vessels.
Unlike other sulfonylureas, Gliclazide has beneficial effect in reducing platelet aggregation as well as mild increase in levels of tissue plasminogen activator (in patients with diabetes mellitus, levels of TPA are found to be suppressed). By improving TPA levels, Gliclazide improves microcirculation since the tendency of clot formation is hampered and there is clot lysis.
Metformin also reduces hepatic glucose production. Metformin in certain studies has also shown to reduce intestinal absorption of carbohydrates which at the moment appears to be insignificant in contributing to its antidiabetic action. It is less likely to cause lactic acidosis, unlike its counter part i.e. Phenformin. Metformin has favorable effect on the lipid metabolism. It has also shown to reduce blood fibrinogen levels, thus minimizing intravascular coagulation. It produces cholesterol uptake by the arteries and also reduces platelet adhesiveness, which contributes to the protection from intravascular coagulation. In obese diabetics it promotes weight loss. Thus besides being antidiabetic, it also exerts cardio-protective effects.
Pharmacokinetics: Single oral dose of Gliclazide, 40 to 120mg results in a Cmax of 2.2 to 8 mg/L within 2 to 8 hours. Steady state concentrations are achieved after 2 days of administration of 40-120 mg of Gliclazide. Administration of Gliclazide with food reduces Cmax and delays Tmax. The volume of distribution is low due to extensive protein binding (85-97%). The half life of Gliclazide varies from 8.1-20.5 hours after single dose administration. Gliclazide is extensively is metabolized to 7 metabolites predominantly excreted in the urine, the most abundant being the carboxylic acid derivative: 60-70% of the dose is excreted in the urine and 10-20% in the feces.
Metformin has absolute oral bioavailability of 50-60%. GIT absorption is complete within 6 hours of ingestion.

Antidiabetic Agents