WARNINGS
Metformin Hydrochloride
Lactic acidosis
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with glyburide and metformin hydrochloride; 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 mcg/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). 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. Glyburide and metformin hydrochloride 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, glyburide and metformin hydrochloride 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, glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, glyburide and metformin hydrochloride 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). Glyburide and metformin hydrochloride tablets 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 glyburide and metformin hydrochloride, 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 glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride, 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).
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SUMMARY
GLYBURIDE AND METFORMIN HYDROCHLORIDE TABLETS, 1.25 mg/250 mg, 2.5 mg/500 mg and 5 mg/500 mg
Glyburide and metformin hydrochloride tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide and metformin hydrochloride. Glyburide is an oral antihyperglycemic drug of the sulfonylurea class.
Glyburide and metformin hydrochloride tablets are indicated as initial therapy, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone.
Glyburide and metformin hydrochloride tablets are indicated as second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes. For patients requiring additional therapy, a thiazolidinedione may be added to glyburide and metformin hydrochloride tablets to achieve additional glycemic control.
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NEWS HIGHLIGHTS RELATED TO GLYBURIDE AND METFORMIN
Published Studies Related to Glyburide and Metformin (Glyburide / Metformin)
Comparison of extended-release metformin in combination with a sulfonylurea (glyburide) to sulfonylurea monotherapy in adult patients with type 2 diabetes: a multicenter, double-blind, randomized, controlled, phase III study. [2007.05]
BACKGROUND: Metformin is widely used in the management of type 2 diabetes, either as monotherapy or in combination with other oral antihyperglycemic agents such as sulfonylureas and thiazolidinediones. Combination treatment with metformin and sulfonylurea in patients who failed monotherapy has been reported to be effective in maintaining glycemic control. OBJECTIVE: The purpose for this study was to compare the efficacy and tolerability of extended-release metformin (MER) administered with a sulfonylurea (glyburide) to sulfonylurea monotherapy in patients with type 2 diabetes... CONCLUSIONS: The combination of QD or BID treatment with MER+S was significantly more effective in lowering HbA(1c) and glucose levels than sulfonylurea monotherapy in these adult patients with type 2 diabetes. However, a significant increase in the prevalence of hypoglycemia was observed in the MER+S treatment groups compared with the sulfonylurea monotherapy group.
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. [2006.12.07]
BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known... CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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.
Cardiovascular, metabolic and hormonal responses to the progressive exercise performed to exhaustion in patients with type 2 diabetes treated with metformin or glyburide. [2008.03]
OBJECTIVES: To evaluate the effects of Metformin and Glyburide on cardiovascular, metabolic and hormonal parameters during progressive exercise performed to exhaustion in the post-prandial state in women with type 2 diabetes (T2DM)... CONCLUSION: Progressive exercise performed to exhaustion, in the post-prandial state did not worsen glucose control during and after exercise. The administration of the usual dose of Glyburide or Metformin to T2DM patients did not influence the cardiovascular, metabolic and hormonal response to exercise.
Clinical Trials Related to Glyburide and Metformin (Glyburide / Metformin)
AVANDIA With Glyburide In African American And Hispanic Patients With Type 2 Diabetes Not Controlled by Glyburide Alone [Completed]
This study was designed to evaluate the safety and efficacy of AVANDIA (rosiglitazone) (8mg
once daily) in African American and Hispanic patients with type 2 diabetes mellitus. As
microvascular and macrovascular disease are significant contributors to diabetes morbidity
and mortality and previous studies suggest that the thiazolidinedione compounds could have
potentially beneficial vascular effects, the effects of rosiglitazone therapy on serum
parameters associated with endothelial dysfunction, vascular inflammation and impaired
fibrinolysis were examined in this study. Improvement in these parameters suggests that
rosiglitazone may provide an additional beneficial vascular effect, apart from its ability to
improve glycemic control.
A Drug-Drug Interaction Study of GK Activator (2) and Glyburide in Patients With Type 2 Diabetes. [Completed]
This study will assess the potential pharmacodynamic and potential pharmacokinetic
interaction between GK Activator (2) and glyburide, in type 2 diabetes patients not
adequately controlled with glyburide as standard prescribed therapy. Patients will enter the
study taking a dose of glyburide (10-20mg po daily) as prescribed prior to study start. GK
Activator (2) 100mg bid will be added for 5 days. From days 6-12 patients will receive GK
Activator (2) monotherapy, and from day 13 GK Activator (2) will be discontinued and
glyburide treatment re-started. The anticipated time on study treatment is <3 months, and the
target sample size is <100 individuals.
Effect of GlucoNorm vs Glyburide on Post-Prandial Hyperglycemia in Elderly Subjects With Type 2 Diabetes [Recruiting]
The results from the DECODE Study have shown that postprandial (1 - 2 hours after a meal)
hyperglycemia (elevated blood sugar) is more common in elderly people with diabetes than
younger people with diabetes and is the best predictor of the development of complications.
The DECODE Study involved 6941 people who already had diabetes and 702 who did not have
diabetes. Diabetes is diagnosed when the blood sugar 1st thing in the morning is over 7. 0
mmol/L. The DECODE Study showed that people at risk for diabetes can have a normal blood
sugar 1st thing in the morning but have a high blood sugar 2 hours after a meal and that
these people are at risk for developing heart disease and other complications of diabetes.
These people would not be identified as at risk if only a fasting blood sugar is done.
Studies in younger people with diabetes have shown that after a meal, insulin levels are more
like a person without diabetes and glucose (blood sugar) levels are lower with GlucoNorm than
with Glyburide. There is no data available that demonstrates this in elderly people with type
2 diabetes.
You have been invited to participate in this study because you have type 2 diabetes
controlled by diet and/or exercise or metformin only and are over 65 years of age.
The purpose of this study is to determine whether GlucoNorm has a greater effect than
Glyburide on insulin levels and glucose (blood sugar) levels after a meal in elderly people
with type 2 diabetes who control their diabetes with diet and exercise.
Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients [Completed]
The purpose of this study is to compare the vascular effects of two commonly used diabetes
medications, rosiglitazone and glyburide in type 2 diabetic patients.
Glyburide Compared to Insulin in the Management of White's Classification A2 Gestational Diabetes [Recruiting]
The purpose of this study is to determine whether the oral administration of glyburide is as
effective as insulin in the treatment of gestational diabetes.
1. SYNOPSIS: Infants born to mothers with gestational diabetes(GDM) are at risk for a
variety of adverse perinatal outcomes including macrosomia with subsequent birth trauma
and cesarean delivery, neonatal hypoglycemia, polycythemia, jaundice, hypocalcemia,
respiratory depression and newborn intensive care unit admission. These adverse
outcomes are thought to be related to the degree of maternal hyperglycemia during
pregnancy. Women with GDM are typically treated with insulin to lower blood glucose
levels to as near-normal as possible. A single randomized trial has suggested that the
oral sulfonylurea, glyburide is a clinically effective and safe alternative to insulin
therapy.
2. Many obstetric care providers have adopted the use of glyburide in the routine
management of gestational diabetes. The American College of Obstetrics and Gynecology
and the American Diabetic Association both state that further studies are needed in a
larger patient population before the use of newer oral hypoglycemic agents can be
supported for use in pregnancy.
3. STATUS: Previous studies have demonstrated that there is no maternal-fetal transfer of
glyburide and when compared to insulin is an effective alternative to insulin.
Additionally, a published cost analysis concluded that glyburide is significantly less
costly than insulin for the treatment of GDM. The benefits of an oral agent for the
management of gestational diabetes include less discomfort for the patient in drug
administration, lower requirement for patient education in the administration of
injectable medications and less chance of error in dosing. Our study population is more
ethnically diverse and our incidence of large for gestational age infants is lower than
in the largely Hispanic population studied by Langer et al. Many obstetricians,
including ourselves, apply different criteria than Langer for diagnosing gestational
diabetes , and for deciding when to institute insulin therapy. It is our goal to
confirm the prior single study concerning the safety and efficacy of glyburide in
reducing the complications of GDM utilizing a more ethnically diverse population with
more realistic goals in glycemic control. To this end we will add to the medical
literature supporting this alternative therapy to insulin.
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Page last updated: 2008-08-10
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