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Tolbutamide (Tolbutamide) - Warnings and Precautions

 
 



WARNINGS

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 (supp.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 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 advantages of tolbutamide 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.

PRECAUTIONS

General

Hypoglycemia

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of tolbutamide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary 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 prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

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 tolbutamide and administer insulin.

The effectiveness of any oral hypoglycemic drug, including tolbutamide, 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 the diabetes or to diminished responsiveness to the drug. This phenomenon is known as a secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because tolbutamide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post-marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Information for Patients

Patients should be informed of the potential risks and advantages of tolbutamide and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Laboratory Tests

Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful.

A metabolite of tolbutamide in urine may give a false positive reaction for albumin if measured by the acidification-after-boiling test, which causes the metabolite to precipitate. There is no interference with the sulfosalicylic acid test.

Drug Interactions

The hypoglycemia action of sulfonylurea may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving tolbutamide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving tolbutamide, the patient should be observed closely for loss of control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving tolbutamide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving tolbutamide, the patient should be observed closely for hypoglycemia.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

Carcinogenicity and Mutagenicity

Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of tolbutamide for 78 weeks. No evidence of carcinogenicity was found.

Tolbutamide has also been demonstrated to be nonmutagenic in the Ames salmonella/mammalian microsome mutagenicity test.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Tolbutamide has been shown to be teratogenic in rats when given in doses 25 to 100 times the human dose. In some studies, pregnant rats given high doses of tolbutamide have shown ocular and bony abnormalities and increased mortality in offspring. Repeat studies in other species (rabbits) have not demonstrated a teratogenic effect. There are no adequate and well controlled studies in pregnant women. Tolbutamide is not recommended for the treatment of pregnant diabetic patients.

Serious consideration should also be given to the possible hazards of the use of tolbutamide in women of childbearing age and in those who might become pregnant while using the drug.

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

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If tolbutamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether tolbutamide 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 discontinue 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 inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness in children have not been established.

Page last updated: 2009-02-01

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