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Author: Admin | 2025-04-28
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 sulphonylurea 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 sulphonylurea 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 sulphonylurea, 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. 5.2 Pharmacokinetic properties 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 2000 mg of metformin prolonged-release tablets is similar to that observed after administration of 1000 mg of metformin immediate release tablets b.i.d. 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 2000 mg of metformin as prolonged-release tablets. Following a single oral administration of 1500 mg of metformin 750 mg prolonged-release tablets, a mean peak plasma concentration of 1193 ng/ml is achieved with a median value of 5 hours and a range of 4 to 12 hours. Metformin 750 mg prolonged-release tablets were shown to be bioequivalent to metformin 500 mg prolonged-release tablets at a 1500 mg 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 1000 mg prolonged-release tablets, a mean peak plasma concentration of 1214 ng/ml is achieved with a median time of 5 hours (range of 4 to 10 hours). Metformin 1000 mg prolonged-release tablets were shown to be bioequivalent to metformin 500 mg prolonged-release tablets at a 1000 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects. When the 1000 mg prolonged-release tablet is administered in fed conditions the AUC is increased by 77% (Cmax is increased by
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