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Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via 3 mechanisms: (1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation; (3) and delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
In clinical studies, the major non glycemic effect of metformin is either weight stability or modest weight loss.
In humans, independently of its action on glycaemia, immediate release metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: immediate release metformin reduces total cholesterol, Low-Density Lipoproteins (LDL) cholesterol and triglyceride levels. A similar action has not been demonstrated with the prolonged release formulation, possibly due to the evening administration, and an increase in triglycerides may occur.
Clinical efficacy: The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetic patients treated with immediate release metformin as first-line therapy after diet failure. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034; a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017; a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021); a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01) For metformin used as second-line therapy, in combination with a sulfonylurea, benefit regarding clinical outcome has not been shown.
In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Pharmacokinetics: Absorption: After an oral dose of the prolonged release tablet, metformin absorption is significantly delayed compared to the immediate release tablet with a Tmax at 7 hours (Tmax for the immediate release tablet is 2.5 hours). At steady state, similar to the immediate release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2 g of metformin prolonged release tablets is similar to that observed after administration of 1 g of metformin immediate release tablets two times daily.
Intrasubject variability of Cmax and AUC of metformin prolonged release is comparable to that observed with metformin immediate release tablets.
When the prolonged release tablet is administered in fasting conditions the AUC is decreased by 30% (both Cmax and Tmax are unaffected).
Mean metformin absorption from the prolonged release formulation is almost not altered by meal composition.
No accumulation is observed after repeated administration of up to 2 g of metformin as prolonged release tablets.
Following a single oral administration of 1.5 g of Metformin Extended-Release Tablets 750 mg, a mean peak plasma concentration of 1.193 mcg/mL is achieved with a median value of 5 hours and a range of 4 to 12 hours.
Metformin Extended-Release Tablets 750 mg was shown to be bioequivalent to Metformin Extended-Release Tablets 500 mg at a 1.5 g dose with respect to Cmax and AUC in healthy fed and fasted subjects.
Following a single oral administration in the fed state of one tablet of Metformin Extended-Release Tablets 1 g a mean peak plasma concentration of 1.214 mcg/mL is achieved with a median time of 5 hours (range of 4 to 10 hours).
Metformin Extended-Release Tablets 1 g was shown to be bioequivalent to Metformin Extended-Release Tablets 500 mg at a 1 g dose with respect to Cmax and AUC in healthy fed and fasted subjects.
When the 1 g prolonged release tablet is administered in fed conditions the AUC is increased by 77% (Cmax is increased by 26% and Tmax is slightly prolonged by about 1 hour).
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.
