Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: Laboratori Guidotti S.p.A, Via Livornese 897, La Vettola 56122, PISA, Italy Local Representative, Menarini Hellas S.A., An. Damvergi 7, Athens, Greece, Τel.: 210-8316111
Pharmacotherapeutic group: hypoglycaemising agents, excluding insulins, biguanides
ATC code: A10BA02
Metformin may act through 3 mechanisms:
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all currently known types of membrane glucose transporters (GLUT).
Metformin is a biguanide with anti-hyperglycaemic effects that lowers both basal and postprandial blood glucose levels. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Irrespective of its action on glycaemia in humans, metformin has beneficial effects on the lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term and long-term clinical trials: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
A prospective randomised (UKPDS) study demonstrated the long-term benefit of intensive blood glucose control in Type 2 diabetic adult patients.
Analyses of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed:
Benefits regarding the clinical outcome have not been demonstrated for metformin hydrochloride used as second-line therapy in combination with a sulphonylurea.
In Type 1 diabetes, the combination of metformin and insulin has been used in selected patients, however the clinical benefit of this combination has not been officially established.
Controlled clinical trials conducted in the paediatric population limited to children aged 10 to 16 treated for one year showed a blood glucose control response similar to that observed in adults.
After an oral dose of metformin hydrochloride, Tmax is reached in 2.5 hours. The absolute bioavailability of a 500 mg or 850 mg tablet of metformin hydrochloride is approximately 50–60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20–30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the usual metformin hydrochloride doses and dosing schedules, steady-state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 µg/ml. In controlled clinical trials, the maximum metformin plasma levels (Cmax) did not exceed 4 µg/ml, even at maximum doses.
Food decreases and slightly delays the absorption of metformin. Following administration of a 850-mg dose of metformin hydrochloride, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35‑minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Plasma protein binding is negligible. Metformin hydrochloride is distributed in the red blood cells. 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 distribution volume (Vd) ranges between 63–276 l.
Metformin is excreted unaltered in the urine. No metabolites have been identified in humans.
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 the plasma.
After the administration of single 500-mg doses of metformin hydrochloride, paediatric patients showed a similar pharmacokinetic profile to that observed in healthy adults.
After the administration of repeated 500-mg doses of metformin hydrochloride twice daily for 7 days in paediatric patients, the plasma peak concentration (Cmax) and systemic exposure (AUC0-t) decreased by approximately 33% and 40%, respectively compared to adult diabetic patients who received repeated 500-mg doses of metformin hydrochloride twice daily for 14 days. Since the dose is individually titrated depending on the blood glucose control, this aspect is of limited clinical relevance.
Preclinical data reveal no specific hazards for humans based on conventional trials regarding pharmacological safety, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproduction toxicity.
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