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Pharmacology: Pharmacodynamics: Metformin is a biguanide antidiabetic agent that reduces both basal and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus by improving both peripheral and hepatic sensitivity to insulin. It does not stimulate insulin secretion and therefore does not produce hypoglycemia when used alone. Fasting insulin levels and day-long insulin response remain the same or may even decrease with metformin therapy.
Metformin may act via three mechanisms: It reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increases insulin sensitivity in the skeletal muscles and adipocytes, improving peripheral glucose uptake and utilization; and delays intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also increases the transport capacity of all types of membrane glucose transporters.
Metformin has demonstrated modest favorable effects on lipid metabolism in patients with type 2 diabetes. It lowers total cholesterol, mean fasting serum triglycerides and low-density lipoprotein cholesterol levels; it has no adverse effects on other lipid levels.
Pharmacokinetics:
Metformin distributes rapidly to peripheral body tissues and fluids. It also appears to distribute slowly into erythrocytes and a deep tissue compartment. Metformin is negligibly bound to plasma proteins. Steady-state plasma concentrations of metformin are generally <1 mcg/mL and are reached within 24 to 48 hours at usual clinical doses and dosing schedules.
Renal elimination of metformin is via glomerular filtration and secretion by the proximal convoluted tubules as an unchanged drug. The principal plasma elimination half-life of metformin is about 6.2 hours with 90% of the total dose being cleared within 24 hours in patients with normal renal function. In blood, the elimination half-life is about 17.6 hours.
Special Populations: Renal Insufficiency: The plasma and blood half-life of metformin is prolonged and the renal clearance decreased in proportion to the decrease in creatinine clearance in patients with decreased renal function (based on measured creatinine levels).
Geriatrics: The limited pharmacokinetic data of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, half-life is prolonged, and Cmax is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily related to a change in renal function.
Tab & FC tab: Immediate-release Tablet: Metformin HCl is slowly and incompletely absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of metformin tablet under fasting conditions is approximately 50 to 60% with metformin doses of 500 mg to 1,500 mg. Single doses of metformin 500 mg to 1,500 mg show a lack of dose proportionality with increasing doses which is due to decreased absorption rather than altered elimination.
Pediatrics: After oral administration of a single metformin 500 mg tablet with food, Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years old) compared with healthy adults (20 to 45 years old), all with normal renal function.
SR tab: Metformin HCl sustained-release tablet is intended for once a day dosing. Once a day dosing is possible through control of metformin release rate and prolonging absorption in the upper gastrointestinal tract.
At steady-state, after administration of sustained-release metformin tablet, the AUC and peak plasma concentrations are not dose proportional within the range of 500 mg to 2,000 mg. Time to reach maximum plasma concentrations (Tmax) is approximately 7 hours (range from 4 to 8 hours). The extent of metformin absorption (based on AUC) for metformin sustained-release tablet at 2,000 mg once a day dose is similar as that for metformin immediate-release tablet at 1,000 mg twice a day dose.
Pediatrics: The safety and efficacy of metformin HCl sustained-release tablet has not been established in pediatric patients. Pharmacokinetic studies have not been conducted in these patients.
