Pharmacology: Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM/type-2 diabetes mellitus) subjects, lowering both basal and postprandial plasma glucose.
Mechanism of Action: Metformin has a different mechanism of action from those of sulfonylureas. It decreases hepatic glucose production and improves insulin sensitivity (increases peripheral glucose uptake and utilization). Unlike sulfonylureas, metformin does not produce hypoglycemia in either diabetic or nondiabetic subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin levels may actually decrease.
Pharmacokinetics: Absorption and Bioavailability: Following a single oral dose of sustained-release metformin, Cmax is achieved with a median value of 7 hrs and a range of 4-8 hrs. After repeated administration of a sustained-release (SR) formulation, metformin does not accumulate in plasma. Although the extent of absorption of metformin SR increases by approximately 50% when given with food, there is no effect of food on Cmax and Tmax of metformin.
Distribution: The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg is 654±375 L. Metformin is negligibly bound to plasma proteins. At usual clinical doses and dosing schedules, steady-state plasma concentrations of metformin are reached within 24-48 hrs and are generally <1 mg/mL.
Metabolism and Elimination: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism or biliary excretion. Renal clearance is approximately >3.5 times creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hrs, with a plasma elimination half-life of approximately 17.6 hrs.
Special Populations: Patients with Type-2 Diabetes and Gender: There are no reported differences in pharmacokinetics of metformin HCl between patients with type-2 diabetes and normal subjects when analyzed according to gender.
Renal Insufficiency: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin HCl is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. This increased level may lead to condition of lactic acidosis.
Hepatic Insufficiency: No pharmacokinetic studies of metformin HCl have been conducted in patients with hepatic insufficiency.
Geriatrics: Reported data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged and Cmax is increased, compared to healthy young subjects. From this data, it appears that the change in metformin HCl pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatrics: No pharmacokinetic studies of metformin HCl in pediatric patients have been conducted.
In maturity onset (non-insulin-dependent) obese diabetics and juvenile diabetics in whom diet alone has failed as monotherapy or in combination with insulin, glitazones or sulfonylureas. Also as an adjunct to diet and exercise to improve glycemic control in patients with type-2 diabetes.
Glitazones are used in combination with metformin HCl when glycemic control is poor on metformin HCl monotherapy and maximum tolerated dose (preferable) of metformin HCl has been tried. The combination of glitazone plus metformin HCl is preferred to glitazone plus sulfonylurea, particularly for obese patients.
Dosage of Panfor SR must be individualized on the basis of both effectiveness and tolerance in patients. The maximum recommended daily dose of 2000 mg should not be exceeded.
Metformin HCl should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to the drug and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose.
Short-term administration of metformin HCl may be sufficient during periods of transient loss of blood glucose control in patients usually well-controlled on diet alone.
Usual Starting Dose: 500 mg once daily with the evening meal. Dosage increase should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on 2000 mg once daily, trial of 1000 mg twice daily should be considered.
The tablet should be swallowed whole and not to be chewed. The tablet should be taken after meals.
Hemodialysis may be useful for removal of accumulating drug from patients in whom metformin HCl overdosage is suspected.
Renal or hepatic failure, alcoholism, NIDDM 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, pregnancy, hypoglycemia and known hypersensitivity to metformin.
Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin HCl accumulation. The reported incidence of lactic acidosis during metformin HCl treatment is <0.1 case/1000 patient-years and the mortality risk is even lower.
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis, metformin HCl should be discontinued immediately and general supportive measures promptly instituted.
Adjust dose according to blood glucose levels during the first few months.
Use in pregnancy & lactation: Use during pregnancy is contraindicated (see Contraindications).
Studies have not been conducted in nursing mothers but caution should be exercised in such patients and a decision should be made to discontinue nursing or to discontinue Panfor SR, taking into account the importance of metformin HCl to the mother.
Use in children: Safety and effectiveness in children has not been established.
Use in the elderly: As aging is associated with reduced renal function, care should be taken in dose selection and should be based on careful and regular monitoring of renal functions.
Use during pregnancy is contraindicated (see Contraindications).
Studies have not been conducted in nursing mothers but caution should be exercised in such patients and a decision should be made to discontinue nursing or to discontinue Panfor SR, taking into account the importance of metformin HCl to the mother.
Gastrointestinal Disturbances: Nausea, diarrhoea, gastric pain, constipation, vomiting and metallic taste in mouth.
Dermatological Effects: Rash, pruritus, urticaria, erythema and flushing.
Miscellaneous: Headache and dizziness. Impaired GI absorption of vitamin B12 and folic acid has been associated with long-term metformin HCl therapy. However, if such symptoms occur, consult with a physician.
Drug interactions of metformin HCl is seen with phenprocoumon, hyperglycemic agents (eg, thiazides, corticosteroids), alcohol, furosemide, nifedipine and cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, cimetidine and vancomycin). Acarbose and guar gum may reduce the absorption of metformin HCl.
Store at temperatures below 25°C. Protect from light and moisture.
Shelf-Life: 36 months.
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.
Tab 500 mg (uncoated, sustained-release) x 5 x 20's. 750 mg x 10 x 10's. 1000 mg x 5 x 20's.
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