Glucovance - Warnings & Precautions - Glyburide (Glybur...

Glucovance - Warnings & Precautions

Glucovance - Warnings & Precautions

Warnings & Precautions
WARNINGS

Metformin Hydrochloride

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl 2): 747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2 ¹ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

PRECAUTIONS

General

GLUCOVANCE

Hypoglycemia

GLUCOVANCE (Glyburide and Metformin HCl Tablets) is capable of producing hypoglycemia or hypoglycemic symptoms, therefore, proper patient selection, dosing, and instruc-tions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol.



Drug Description Side Effects & Drug Interactions Warnings & Precautions
Clinical Pharmacology Overdosage & Contraindications Indications & Dosage Patient Info



Glucovance

[Glyburide/Metformin]

Renal or hepatic insufficiency may cause elevated drug levels of both glyburide and metformin hydrochlo-ride and the hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions.

Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Metformin Hydrochloride

Monitoring of renal function

Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive GLUCOVANCE.

In patients with advanced age, GLUCOVANCE should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function.

In elderly patients, particularly those 80 years of age, renal function should be monitored regularly and, generally, GLUCOVANCE should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of GLUCOVANCE therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and GLUCOVANCE discontinued if evidence of renal impairment is present.

____Use of concomitant medications that may affect renal function or metformin disposition

Concomitant medication( s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are elimi-nated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.

____ Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)

Intravascular contrast studies with iodinated materi-als can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, GLUCOVANCE should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on GLUCOVANCE therapy, the drug should be promptly discontinued.

____ Surgical procedures

GLUCOVANCE therapy should be temporarily suspended for any sur-gical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

____ Alcohol intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving GLUCOVANCE. Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of hypoglycemia.

____ Impaired hepatic function

Since impaired hepatic function has been associated with some cases of lactic acidosis, GLUCOVANCE should generally be avoided in patients with clinical or lab-oratory evidence of hepatic disease.