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Pharmacology: Pharmacodynamics: GLUCOVANCE combines metformin hydrochloride and glibenclamide, two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Glibenclamide is a second generation sulphonylurea which appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets.
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.
Pharmacokinetics: Absorption and Bioavailability: Related to GLUCOVANCE: In bioavailability studies of GLUCOVANCE 500 mg/5 mg, the mean area under the plasma concentration versus time curve (AUC) for the glibenclamide component was 18% and 7%, respectively, greater than that of the Micronase brand of glibenclamide coadministered with metformin. The glibenclamide component of GLUCOVANCE, therefore, is not bioequivalent to Micronase. The metformin component of GLUCOVANCE is bioequivalent to metformin coadministered with glibenclamide.
Following administration of a single GLUCOVANCE 500 mg/5 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Cmax, and a relatively small effect of food on the AUC of the glibenclamide component. The Tmax for the glibenclamide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glibenclamide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate. The bioavailability of glibenclamide in the combination is unaffected by the ingestion of food, but the absorption speed of glibenclamide is increased by eating.
Bioequivalence is shown between a single 1000 mg dose of metformin and 5 mg glibenclamide administered as either one tablet of 1000/5mg metformin/glibenclamide or two tablets of 500/2.5 mg metformin/glibenclamide under fasted and fed conditions, based on AUC and Cmax.
Related to Metformin hydrochloride: The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 μg/ml. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/ml, even at maximum doses. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35 minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Related to Glibenclamide: Glibenclamide is very readily absorbed (>95%) following oral administration. The peak plasma concentration is reached in about 4 hours.
Distribution: Related to Metformin hydrochloride: The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
Related to Glibenclamide: Sulfonylurea drugs are extensively bound to serum proteins.
Metabolism and Elimination: Related to Metformin hydrochloride: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor 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 6.2 hours.
Related to Glibenclamide: The decrease of glibenclamide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glibenclamide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glibenclamide) in rabbits. Glibenclamide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.
Special Populations: Hepatic Insufficiency: No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either metformin or glibenclamide.
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 WARNINGS).
Geriatrics: There is no information on the pharmacokinetics of glibenclamide in elderly patients. Limited 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 these data, it appears that the change in metformin hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.
