Pharmacotherapeutic Group: Oral Antidiabetics. ATC Code: A10BA02: Gastrointestinal tract and metabolism.
Pharmacology: Pharmacodynamics: Fornidd: Metformin is a biguanide with antihyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin 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; 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 humans, independently on its action on glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin reduces total cholesterol, LDL cholesterol and triglyceride levels (GLUT).
Clinical efficacy: The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.
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/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034.
A significant reduction of the absolute risk of diabetes-related mortality: Metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 years, p=0.017.
A significant reduction of the absolute risk of overall mortality: Metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021).
A significant reduction in the absolute risk of myocardial infarction: Metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient life years (p=0.01).
For metformin used as 2nd-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 yet been formally established.
Fornidd XR: Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM) (type 2 diabetes mellitus) subjects, lowering both basal and postprandial plasma glucose. Its pharmacological mechanisms of action are different from those of sulfonylureas.
Metformin decreases hepatic glucose production and improves insulin sensitivity (increases peripheral glucose uptake and utilization). Unlike sulfonylureas, metformin does not produce hypoglycemia in either diabetic or nondiabetic subjects, and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin levels may actually decrease.
Pharmacokinetics: Fornidd: Absorption: After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a metformin 500 mg 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 absorption is saturable and incomplete. It is assumed that pharmacokinetics of metformin absorption is non-linear. At the usual metformin 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, maximum metformin plasma levels (Cmax) did not exceed 4 μg/mL, even at maximum doses. Food decreases the extent and slightly delays the absorption of metformin. Following administration of 850 mg, 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.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears 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 the plasma.
Fornidd XR: Following a single oral dose of sustained release Metformin, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. After repeated administration of a sustained-release formulation, Metformin does not accumulate in plasma. Although the extent of absorption of sustained-release Metformin increased by approximately 50% when given with food, there is no effect of food on Cmax and Tmax of Metformin.
The apparent volume of distribution (V/F) of Metformin following single oral dose of 850 mg is 654±358 L. Metformin is negligibly bound to plasma proteins. At usual clinical dosed and dosing schedules, steady state plasma concentrations of Metformin are reached within 24-48 hours and are generally <1 mg/mL.
Metformin is excreted unchanged in the urine, and does not undergo hepatic metabolism or biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of Metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 4.18 hours.
Absorption and Bioavailability: Following a single oral dose of sustained release metformin, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. After repeated administration of a sustained-release formulation, metformin does not accumulate in plasma. Although the extent of absorption of sustained-release metformin increased by approximately 50% when given with food, there is no effect of food on Cmax and Tmax of metformin.
Distribution: The apparent volume of distribution (V/F) of Metformin following single oral dose of 850 mg is 654±358 L. Metformin is negligibly bound to plasma proteins. At usual clinical doses and dosing schedules, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mg/mL.
Metabolism and Elimination: Metformin is excreted unchanged in the urine, and does not undergo hepatic metabolism or biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 4.18 hours.
Special Populations: Patients with type 2 diabetes and Gender: There are no reported differences in pharmacokinetics of Metformin Hydrochloride between patients with type 2 diabetes and normal subjects when analyzed according to gender.
Renal insufficiency: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of Metformin hydrochloride is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. This increased level may lead to condition of lactic acidosis.
Hepatic insufficiency: No pharmacokinetic studies of Metformin Hydrochloride have been conducted in patients with hepatic insufficiency.
Geriatrics: Reported data from controlled pharmacokinetic studies of Metformin Hydrochloride in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged and Cmax is increased, compared to healthy young subjects. From this data, it appears that the change in Metformin Hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatrics: No pharmacokinetic studies of Hydrochloride in pediatric patients have been conducted.
Toxicology: Fornidd: 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.
Fornidd XR: Long-term carcinogenicity studies are performed with Metformin alone in rats (dosing duration of 140 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg of Metformin. No evidence of carcinogenicity with Metformin was found in either male or female mice.
Similarly, there is no tumorigenic potential observed in male rats. There was however an increases incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/days of Metformin.
There was no evidence of mutagenic potential in the following in vitro tests Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo micronucleus test were also negative.
Fertility of male and female rats was unaffected at doses as high as 600 mg/kg/day approximately three time the maximum recommended human daily dose. Metformin was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day.