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Metformin may act via 3 mechanisms, by reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation; by delaying 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 of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical dtudies. Metformin reduces total cholesterol, LDL-cholesterol and triglyceride levels. In clinical trials conducted so far with combination therapy with metformin and glibenclamide, these favourable effects on lipid metabolism have not been shown.
Glibenclamide is a 2nd-generation sulphonylurea with a medium half-life it causes acute lowering of blood glucose by stimulating the release of insulin by the pancreas, this effect being dependent on the presence of functioning beta cells in the islets of Langerhans.
The stimulation of insulin secretion by glibenclamide in response to a meal is of major importance.
The administration of glibenclamide to diabetics induces an increase in the postprandial insulin-stimulating response. The increased postprandial responses in insulin and C-peptide secretion persist after at least 6 months of treatment. Metformin and glibenclamide have different mechanisms and sites of action, but their action is complementary. Glibenclamide stimulates the pancreas to secrete insulin, while metformin reduces cell resistance to insulin by acting on peripheral (skeletal muscle) and hepatic sensitivity to insulin.
Results from controlled, double blind clinical trials versus reference products in the treatment of type 2 diabetes inadequately controlled by monotherapy with metformin or glibenclamide combined with diet and exercise, have demonstrated that the combination had an additive effect on glucose regulation.
Pediatric Patients: In a 26-week, active controlled, double-blind, clinical study performed in 167 paediatric patients 9-16 years with type 2 diabetes not adequately controlled with diet and exercise, with or without an oral antidiabetic treatment, a fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg was not shown more effective to either metformin hydrochloride or glibenclamide in reducing HbA1c from baseline. Therefore, Glucovance should not be used in paediatric patients.
Pharmacokinetics: Related to the Combination: The bioavailability of metformin and glibenclamide in the combination is similar to that noted when 1 tablet of metformin and 1 tablet of glibenclamide are taken simultaneously. The bioavailability of metformin in the combination is unaffected by the ingestion of food. The bioavailability of glibenclamide in the combination is unaffected by the ingestion of food, but the absorption speed of glibenclamide is increased by eating.
Related to Metformin: Absorption: After an oral dose of metformin, maximum plasma concentration (Cmax) is reached in 2.5 hrs (Tmax). Absolute bioavailability of a 500- or 850-mg metformin tablet 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 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 plasma levels (Cmax) did not exceed 4 mcg/mL, even at maximum doses.
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 volume of distribution Vd ranged from 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Related to Glibenclamide: Absorption: Glibenclamide is very readily absorbed (>95%) following oral administration. The peak plasma concentration is reached in about 4 hrs.
Distribution: Glibenclamide is extensively bound to plasma albumin (99%), which may account for certain drug interactions.
Metabolism: Glibenclamide is completely metabolised in the liver to 2 metabolites. Hepatocellular failure decreases glibenclamide metabolism and appreciably slows down its excretion.
Excretion: Glibenclamide is excreted in the form of metabolites via biliary route (60%) and urine (40%), elimination being complete within 45-72 hrs. Its terminal elimination half-life is 4-11 hrs.
Biliary excretion of the metabolites increases in cases of renal insufficiency, according to the severity of renal impairment until a creatinine clearance (CrCl) at 30 mL/min. Thus, glibenclamide elimination is unaffected by renal insufficiency as long as the creatinine clearance remains >30 mL/min.
Toxicology: Preclinical Safety Data: No preclinical studies have been performed on the combination product. Preclinical evaluation of the constituents metformin and glibenclamide revealed no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential.
Animal studies on metformin and glibenclamide do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Precautions).
Special Populations Patients with Type 2 Diabetes: Multiple-dose studies with glibenclamide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.
In the presence of normal renal function, there are no differences between single-or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.
Hepatic Insufficiency: No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glibenclamide or metformin.
Renal Insufficiency: No information is available on the pharmacokinetics of glibenclamide in patients with renal insufficiency. In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see Precautions).
Geriatrics: There is no information on the pharmacokinetics of glibenclamide in elderly patients.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young max subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients >80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
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 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 in plasma.
Click on icon to see table/diagram/imagePediatrics: There were no differences in pharmacokinetics of glibenclamide and metformin between paediatric patients and weight-and gender-matched healthy adults.
Gender: There is no information on the effect of gender on the pharmacokinetics of glibenclamide.
Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Race: No information is available on race differences in the pharmacokinetics of glibenclamide.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).
