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 compli- cations 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 grams per day) had a rate of cardiovascular mortality approximately 2½ 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 regard- ing the interpretation of these results, the find- ings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of MICRONASE 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 oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

General

Hypoglycemia: All sulfonylureas are capable of pro- ducing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insuffi- ciency may cause elevated drug levels of glyburide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or mal- nourished patients, and those with adrenal or pitu- itary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or pro- longed exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combina- tion therapy.

Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times it may be necessary to discontinue MICRONASE and administer insulin.

The effectiveness of any hypoglycemic drug, including MICRONASE, in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsive- ness to the drug. This phenomenon is known as sec- ondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when MICRONASE is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Laboratory Tests

Therapeutic response to MICRONASE Tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/ alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, how- ever, no adequate and well controlled studies in pregnant women. Because animal reproduction stud- ies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associ- ated with a higher incidence of congenital abnormali- ties, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible.

Nonteratogenic Effects: Prolonged severe hypo- glycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sul- fonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If MICRONASE is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discon- tinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued, and if diet alone is inade- quate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and mainte- nance dosing should be conservative to avoid hypo- glycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insuffi- ciency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.

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