Tolbutamide

Tolbutamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolbutamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood-glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Some patients who are initially responsive to oral hypoglycemic drugs, including tolbutamide, may become unresponsive or poorly responsive over time. Alternatively, tolbutamide may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.

When administered orally, tolbutamide is readily absorbed from the gastrointestinal tract. Absorption is not impaired and glucose lowering and insulin releasing effects are not altered if the drug is taken with food. Detectable levels are present in the plasma within 20 minutes after oral ingestion of a 500 mg tolbutamide tablet, with peak levels occurring at 3 to 4 hours and only small amounts detectable at 24 hours. The half-life of tolbutamide is 4.5 to 6.5 hours. As tolbutamide has no p-amino group, it cannot be acetylated, which is one of the common modes of metabolic degradation for the antibacterial sulfonamides. However, the presence of the p-methyl group renders tolbutamide susceptible to oxidation, and this appears to be the principal manner of its metabolic degradation in man. The p-methyl group is oxidized to form a carboxyl group, converting tolbutamide into the totally inactive metabolite 1-butyl-3-p-carboxy-phenylsulfonylurea, which can be recovered in the urine within 24 hours in amounts accounting for up to 75% of the administered dose.

The major tolbutamide metabolite has been found to have no hypoglycemic or other action when administered orally and IV to both normal and diabetic subjects. This tolbutamide metabolite is highly soluble over the critical acid range of urinary pH values, and its solubility increases with increase in pH. Because of the marked solubility of the tolbutamide metabolite, crystalluria does not occur. A second metabolite, 1-butyl-3-(p-hydroxymethyl) phenyl sulfonylurea also occurs to a limited extent. It is an inactive metabolite.

The administration of 3 grams of tolbutamide to either nondiabetic or tolbutamide-responsive diabetic subjects will, in both instances, occasion a gradual lowering of blood glucose. Increasing the dose to 6 grams does not usually cause a response which is significantly different from that produced by the 3 gram dose. Following the administration of a 3 gram dose of tolbutamide solution, non-diabetic fasting adults exhibit a 30% or greater reduction in blood glucose within one hour, following which the blood glucose gradually returns to the fasting level over 6 to 12 hours. Following the administration of a 3 gram dose of tolbutamide solution, tolbutamide responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between 5 to 8 hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24^th hour has usually returned to pretest levels. The magnitude of the reduction, when expressed in terms of percent of the pretest blood glucose, tends to be similar to the response seen in the nondiabetic subject.

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.

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.

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.

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.

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.

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.

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.

Safety and effectiveness in children have not been established.

See PRECAUTIONS and OVERDOSAGE.

Cholestatic jaundice may occur rarely; tolbutamide should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.4% of patients treated during clinical trial. They tend to be dose related and may disappear when dosage is reduced.

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.1% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolbutamide; if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.

Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.

Headache and taste alterations have occasionally been reported with tolbutamide administration.

The usual starting dose is 1 to 2 grams daily. This may be increased or decreased, depending on individual patient response. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimens are more prone to exhibit unsatisfactory response to drug therapy.

Daily doses of greater than 3 grams are not recommended.

The maintenance dose is in the range of 0.25 to 3 grams daily. Maintenance doses above 2 grams are seldom required.

The total daily dose may be taken either in the morning or in divided doses through the day. While either schedule is usually effective, the divided dose system is preferred by some clinicians from the standpoint of digestive tolerance.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS).