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Pharmacology: Pharmacodynamics: Mode of Action: Metformin hydrochloride 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 hydrochloride may act via 3 mechanisms: Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization; delay of intestinal glucose absorption.
Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.
In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin hydrochloride reduces total-cholesterol, low-density lipoprotein (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.
Effect on Body Weight: In the clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
Clinical Efficacy: The prospective randomized study (UKPDS) has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.
Analysis of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed a significant reduction of the absolute risk of any diabetes-related complication in the metformin hydrochloride 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 hydrochloride (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 hydrochloride (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 hydrochloride (11 events/1000 patient-years), diet alone (18 events/1000 patient-years), p=0.01].
Benefit regarding clinical outcome has not been shown for metformin hydrochloride used as 2nd-line therapy, in combination with a sulfonylurea.
In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Controlled clinical studies in a limited pediatric population 10-16 years treated for 1 year demonstrated a similar response in glycemic control to that seen in adults.
Pharmacokinetics: Absorption: After an oral dose of metformin hydrochloride, Tmax is reached in 2.5 hrs. Absolute bioavailability of metformin hydrochloride 500- or 850-mg tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.
After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption is nonlinear.
At the recommended metformin hydrochloride doses and dosing schedules, steady-state plasma concentrations are reached within 24-48 hrs and are generally <1 mcg/mL. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 4 mcg/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a 850 mg dose, a 40% lower plasma peak concentration, a 25% decrease in area under the curve (AUC) and a 35 min prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.
Distribution: Plasma protein-binding is negligible. Metformin hydrochloride 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 volume of distribution (Vd) ranged between 63-276 L.
Metabolism: Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin hydrochloride is >400 mL/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hrs.
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 hydrochloride in plasma.
Children and Adolescents: Single-Dose Study: After single doses of metformin hydrochloride 500 mg, pediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.
Multiple-Dose Study: Data are restricted to 1 study. After repeated doses of 500 mg twice daily for 7 days in pediatric patients, the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.
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 and reproductive toxicity.
