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Pharmacotherapeutic group: Biguanides and sulphonamide(s) in combination. ATC code: A10BD02.
Pharmacology: Pharmacodynamics: Metformin 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 may act via 3 mechanisms: (1) by reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation; (3) and 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 studies: 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 second 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.
Paediatric patients: In a 26-week, active controlled, double-blind, clinical study performed in 167 paediatric patients aged 9 to 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 one tablet of metformin and one 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 approximately 2.5 hours (tmax). Absolute bioavailability of a 500 mg 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 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.
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 to 276 l.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Biotransformation: 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 plasma.
Related to glibenclamide: Absorption: Glibenclamide is very readily absorbed (> 95%) following oral administration. The peak plasma concentration is reached in about 4 hours.
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 two metabolites. Hepatocellular failure decreases glibenclamide metabolism and appreciably slows down its excretion.
Elimination: Glibenclamide is excreted in the form of metabolites via biliary route (60%) and urine (40%), elimination being complete within 45 to 72 hours. Its terminal elimination half-life is 4 to 11 hours.
Biliary excretion of the metabolites increases in cases of renal insufficiency, according to the severity of renal impairment until a creatinine clearance at 30 ml/min. Thus, glibenclamide elimination is unaffected by renal insufficiency as long as the creatinine clearance remains above 30 ml/min.
Paediatric patients: There were no differences in pharmacokinetics of glibenclamide and metformin between paediatric patients and weight- and gender-matched healthy adults.
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 Use in Pregnancy & Lactation).
