Gliclazide, metformin hydrochloride.
Each uncoated tablet contains Gliclazide BP 80 mg, Metformin Hydrochloride BP 500 mg.
Glizid-M contains Gliclazide and Metformin Hydrochloride. Gliclazide, chemically is 1-(3-azabicyclo [3.3.0.]Oct-3-yl)-3-p-tolylsulphonylurea. Metformin Hydrochloride is 1,1-dimethyl biguanide hydrochloride.
PHARMACOLOGY: Gliclazide reduces blood glucose levels by correcting both defective insulin secretion and peripheral insulin resistance. This occurs by closure of K+ channels in b-cells of pancreas. Subsequently, Ca2+ channel open leading to increase in intracellular calcium and induction of insulin release. Gliclazide also increases the sensitivity of b-cells to glucose. Gliclazide restores peripheral insulin sensitivity such as decreasing hepatic glucose production and increasing glucose clearance. It has anti-platelet adhesive activity and reduces level of free radicles, thereby preventing vascular complications.
Metformin acts as an antihyperglycaemic agent by improving hepatic and peripheral tissue sensitivity to insulin. It also appears to have beneficial effect on serum lipid levels and so on fibrinolytic activity.
Metformin therapy is not associated with increase in body weight.
RATIONALITY: Sulfonylureas & biguanides act complementary to each other. Both compounds have an additive antihyperglycaemic effect without increasing the adverse effects of either pharmacological class.
Gliclazide acts via stimulating b cells of pancreas to release insulin & also increases peripheral sensitivity of insulin. Metformin acts via enhanced peripheral glucose uptake & utilization. It also reduces hepatic glucose production, thereby metformin diminishes insulin resistance.
There are reports in which combination treatment of sulfonylurea with metformin has been reported to achieve satisfactory glycaemic control for several years. Such combination has been reported to be quite useful in comparative studies where secondary sulfonylurea failure had occurred. The combination may therefore provide additional glycaemic control (blood glucose lowering effect by 20%) & thus obviate the need for insulin in some patients.
Since metformin is reported to have predominant peripheral mechanism of action, therefore it lacks the anabolic effects of sulfonylureas and does not cause weight gain.
Gliclazide appears to be useful in both macro-vascular & micro-vascular complications. Metformin is associated with a decrease in fasting & postprandial blood sugar & triglyceride levels, increase in HDL cholesterol, increase of tissue plasminogen activator, decrease in platelet aggregation.
Pharmacokinetically the two drugs appear to be compatible, as metformin is not plasma protein bound & does not get metabolized in liver. So interaction with gliclazide (having 80-90% plasma protein binding & metabolized via liver) does not appear to be possible. Hence the combination of Gliclazide & metformin would help in treatment of Type II diabetes mellitus and probably prevention of its associated macrovascular and microvascular complications.
PHARMACOKINETICS: Single oral dose of gliclazide, 40 to 120 mg, 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 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 faeces. Metformin has absolute oral bioavailability of 50-60%. GIT absorption is complete within 6 hrs of ingestion. Metformin is rapidly distributed in body after absorption. The renal elimination of metformin is biphasic. 95% of the absorbed metformin is eliminated during primary elimination phase having half-life of 6 hours. Rest of the 5% is eliminated during slow terminal elimination phase with mean half-life of 20 hours. Metformin is not bound to plasma proteins, 40-60% of the dose is recovered as unchanged drug in urine with a further 30% recovered as unchanged drug in faces.
Type II diabetes mellitus; diabetes with or without obesity in adults.
1-2 tablets once or twice daily with meals to a maximum of 4 tablets/day.
Adjust dose of combination according to blood and urinary glucose levels during the first few months.
Hypoglycaemia may occur in case of an overdosage. In the event of an overdosage, gastric lavage should be performed and correction of hypoglycaemia should be attempted by intravenous administration of hypertonic glucose (10 or 30%) with continued monitoring of the patient's blood glucose levels.
Renal or hepatic failure, alcoholism, Type II diabetes mellitus complicated by severe ketosis and acidosis, diabetic precoma and coma, patients undergoing surgery, after severe trauma or during infections, chronic obstructive pulmonary disease, coronary heart disease, cardiac failure, peripheral vascular disease, known hypersensitivity to any of the ingredients.
1. To be prescribed by the physician only. If dizziness and syncope occur, please immediately consult with the physician.
2. Should not be used in a patient with known hypersensitivity to sulfonylurea.
3. Should not be used in a patient with type I diabetes mellitus, diabetic ketoacidosis, severe infection and severe accident.
4. Should not be used concomitantly with alcohol.
5. Use with caution, it may result in hypoglycemia (excessive hunger, fainting, fatigue, palpitation, excess sweating, light-headedness etc).
6. If any combination of red itchy rash with blisters and peeling of the skin and/or of the lips, eyes, mouth, throat, nose or genitals (signs of Stevens-Johnson syndrome) occurs, please stop using this product immediately and consult with the physician.
7. Use with caution in patient with renal or hepatic impairment.
8. Hypoglycaemia may occur if the patient's dietary intake is reduced or after accidental or deliberate overdose or after severe exercise, trauma and stress. Hypoglycaemic symptoms can be reduced by prescribing a diabetic meal plan. Immediate intervention should be done if signs and symptoms of hypoglycaemia occur.
Use in Pregnancy & Lactation: Should not be used in pregnant women and in breastfeeding mother.
Lactic acidosis may occur in patients with renal or hepatic impairment.
Use in pregnancy: Contraindicated.
Use in Children: Safety and effectiveness in children have not been established.
Usage in pregnancy: Contraindicated.
Should not be used in pregnant women and in breastfeeding mother.
Gastrointestinal disturbances: Nausea, diarrhoea, gastric pain, constipation, vomiting, metallic taste in mouth.
Dermatological effects: Rash, pruritus, urticaria, erythema and flushing.
Miscellaneous: Headache and dizziness.
Gliclazide appears to be associated with a low incidence of hypoglycaemia.
Gliclazide has been an established agent for the treatment of Type II diabetes mellitus for a number of years without adverse cardiovascular effects. Impaired gastrointestinal absorption of vitamin B12 and folic acid has been associated with long term metformin therapy.
Diuretics, barbiturates, phenytoin, rifampicin, corticosteroids, estrogens, estroprogestogens and pure progestogens may reduce the glycaemic control. Its hypoglycaemic action may be potentiated by salicylates, phenylbutazone, sulphonamides, beta-blockers, clofibric acid, vitamin k antagonist, allopurinol, theophylline, caffeine and monoamine oxidase inhibitors. Concomitant administration of micronazole, perhexiline or cimetidine with gliclazide may result in hypoglycaemia. Concomitant administration of gliclazide with agents that increase blood glucose levels should not be considered without careful monitoring of blood glucose levels to avoid hyperglycaemia. Acarbose and guar gum has been shown to decrease the oral bioavailability of metformin significantly.
Store at a temperature below 25°C, protect from light and moisture.
A10BD02 - metformin and sulfonylureas ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
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