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Glucovance (Glyburide / Metformin Hydrochloride) - Summary



Lactic acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOVANCE (Glyburide and Metformin HCl) Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOVANCE treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, GLUCOVANCE should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, GLUCOVANCE should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUCOVANCE, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOVANCE should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). GLUCOVANCE should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUCOVANCE, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUCOVANCE do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking GLUCOVANCE, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)



GLUCOVANCE® (Glyburide and Metformin HCl) Tablets contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide and metformin hydrochloride.

GLUCOVANCE (Glyburide and Metformin HCl) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Published Studies Related to Glucovance (Glyburide / Metformin)

Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes. [2006.07]
This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance) vs... Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.

Investigation of the pharmacokinetic and pharmacodynamic interactions between memantine and glyburide/metformin in healthy young subjects: a single-center, multiple-dose, open-label study. [2005.10]
BACKGROUND: The high prevalence rates of both Alzheimer's disease (AD) and type 2 diabetes mellitus in the elderly population suggest that concomitant pharmacotherapy is likely. Given the renal tubular transport and extensive urinary excretion of memantine and metformin, it was of interest to assess the pharmacokinetic and pharmacodynamic interaction with glyburide/metformin. OBJECTIVE: The primary goal of this study was to determine whether an in vivo pharmacokinetic or pharmacodynamic interaction exists between memantine (an uncompetitive, moderate-affinity, N-methyl-D-aspartate receptor antagonist with fast blocking/unblocking kinetics that is available in the United States for moderate to severe AD) and glyburide/metformin (a combination pharmacotherapy formulation approved for glycemic control in patients with type 2 diabetes mellitus)... CONCLUSIONS: No pharmacokinetic interactions between memantine and glyburide/metformin were detected in this study of healthy young volunteers. Memantine had no effect on the pharmacodynamic activities of glyburide and metformin, and the drug combination was well tolerated in this population.

PRESERVE-beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin. [2005.09]
CONCLUSIONS: Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy.

Durable efficacy of metformin/glibenclamide combination tablets (Glucovance) during 52 weeks of open-label treatment in type 2 diabetic patients with hyperglycaemia despite previous sulphonylurea monotherapy. [2004.09]
Oral anti-diabetic combinations that address insulin resistance and beta-cell dysfunction (e.g... Metformin-glibenclamide combination tablets are an effective and well-tolerated therapeutic option for intensifying oral anti-diabetic therapy.

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. [2004.02.15]
PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%)... CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.

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Clinical Trials Related to Glucovance (Glyburide / Metformin)

Glyburide/Metformin 5 mg/500 mg Film-Coated Tablets, Fed [Completed]

Glyburide/Metformin 5 mg/500 mg Film-Coated Tablets, Fasting [Completed]

Comparison of Glucovance to Insulin for Diabetes During Pregnancy [Recruiting]
Pregnant women with gestational or Type 2 diabetes who require medication are placed in one of two groups: Insulin injections or Glucovance (oral administration). Blood glucose is checked 5 times per day, and medication adjusted by perinatologist according to glucose levels. The hypothesis is that patients will have similar or improved blood glucose control on an oral agent as compared to control on insulin.

A Research Study to Determine the Safety and Efficacy of Glucovance Compared to Metformin and Glyburide in Children and Adolescents With Type 2 Diabetes. [Completed]
The purpose of this clinical research study is to see if Glucovance, a medication currently approved for use in adults with type 2 diabetes, can control type 2 diabetes safely and effectively in children 9 to 16 years of age.

A Research Study to Assess the Mechanism By Which Glucovance, Metformin, and Glyburide Work To Control Glucose Levels In Patients With Type 2 Diabetes [Completed]
The purpose of this clinical research study is to support earlier observations that Glucovance controls glucose levels after a mean, and improves overall glucose control better than metformin or glyburide therapy alone in adults with type 2 diabetes.

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Reports of Suspected Glucovance (Glyburide / Metformin) Side Effects

Hepatic Cirrhosis (5)Lactic Acidosis (3)Myalgia (3)Blood Glucose Increased (3)Disseminated Intravascular Coagulation (2)Coma (2)Multi-Organ Failure (2)Pyelonephritis (2)Renal Failure Acute (2)Hepatic Fibrosis (2)more >>

Page last updated: 2007-05-02

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