VA Class:HS502
ATC Class:A10BB03
Tolbutamide is a sulfonylurea antidiabetic agent.
Tolbutamide is used for the management of mild to moderately severe, stable, type 2 diabetes mellitus. Sulfonylureas, including tolbutamide, also may be used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. 135 145 146 147 148 149 167 168 170 171 172 173 174 175 176 177, 187, 188, 698, 704
Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A1c; HbA1c], weight, and cardiovascular mortality).698, 704, 705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698, 704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA1c exceeding 7.5% or at least 1.5% above the target level.698, 704 In metformin-intolerant patients with high initial HbA1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action.698, 704
Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698, 704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704
Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698, 699, 704, 705, 706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.698, 704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698, 704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.
Tolbutamide is used as monotherapy as an adjunct to diet for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet.187
Secondary failure to sulfonylurea drugs is characterized by progressively decreasing diabetic control106 following 1 month to several years of good control.160 Interim data from a substudy (UKPD 26) of the UKPD study in newly diagnosed type 2 diabetic patients receiving intensive antidiabetic therapy (maintenance of fasting plasma glucose below 108 mg/dL by increasing doses of either a sulfonylurea [i.e., glyburide] or chlorpropamide [no longer commercially available in the US] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL or symptoms of hyperglycemia despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide) occurred overall at about 7% per year.112, 113 The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide.113 In the UKPD studies, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control.111, 113, 114, 120, 127, 130, 131 In another substudy (UKPD 49), progressive deterioration in diabetes control was such that monotherapy was effective in only about 50% of patients after 3 years and in only about 25% of patients after 9 years; thus, most patients require multiple-drug antidiabetic therapy over time to maintain such target levels of disease control.131 At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.113, 131
Combination Therapy with Metformin or Other Oral Antidiabetic Agents
Sulfonylureas may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, thiazolidinedione derivatives) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. 167 170 171 172 173 174 175 176 178 179, 188, 698, 704 For information on the stepwise approach to drug therapy in patients with type 2 diabetes mellitus, see Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.
Combination Therapy with Insulin
Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of the oral agent and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested.135, 145, 146, 147, 148, 149, 188 Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times) 145, 146, 150, 153, 154, 156, 159 and one or more oral antidiabetic agents appears to improve glycemic control with lower dosages of insulin than would be required with insulin alone and may decrease the potential for body weight gain associated with insulin therapy.135, 145, 146, 150, 151, 153, 154, 155, 156, 157, 158 Oral antidiabetic therapy combined with insulin therapy may delay progression to either intensive insulin monotherapy or to a second daytime injection of insulin combined with oral antidiabetic therapy.188, 153 However, such combined therapy may increase the risk of hypoglycemic reactions.146, 147, 152, 153, 154
Tolbutamide is administered orally.187 The drug may be administered as a single daily dose in the morning, but is preferably administered in divided doses after meals.187 Although either dosage regimen may be effective, the divided-dose regimen is preferred since it is associated with a decreased frequency of GI disturbances, particularly in patients receiving large doses of the drug.187
Dosage of tolbutamide is variable and should be individualized according to the severity of the disease and the patient's therapeutic response; adult dosage ranges from 250 mg to 3 g daily.187 Patients who do not respond to 2 g daily usually will not respond to a higher dosa however, dosage adjustment may occasionally be necessary during maintenance therapy with the drug, and temporary increases to more than 2 g daily may be required to maintain control in some patients. The manufacturer states that maintenance dosages greater than 2 g daily are seldom required.187
For the management of type 2 diabetes mellitus, the usual initial adult dosage of tolbutamide is 1-2 g daily.187 Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage.
In general, patients who were previously maintained on insulin dosages of 20 units or less daily may be transferred directly to tolbutamide, and administration of insulin may be abruptly discontinued.187 In patients requiring 20-40 units daily or more than 40 units daily, insulin dosage should be reduced initially by 30-50% or reduced by 20% on the first day of the transition period, respectively; subsequently, insulin dosage should be reduced daily according to the patient's therapeutic response to tolbutamide.187 During the period of insulin withdrawal, patients should test their urine at least 3 times daily for glucose and acetone, and should be instructed to report the results to their clinician so that appropriate adjustments in therapy may be made, if necessary; whenever feasible, patient or laboratory monitoring of blood glucose concentration is preferable.187 In some patients, hospitalization may be necessary during the transition from insulin to tolbutamide.187
Many patients who initially respond to tolbutamide therapy later develop unsatisfactory control.187 Loss of adequate control may be attributed to dietary indiscretion, emotional stress, secondary failure, or other factors (e.g., fever, trauma, infection, surgery).187 Secondary failure to sulfonylurea antidiabetic agents is characterized by progressively decreasing diabetic control over a period of time.187
Nausea, epigastric fullness, heartburn, and headache have occurred in patients receiving tolbutamide. These adverse effects appear to be dose related and frequently subside following a reduction in dosage to maintenance levels or by administering the total daily dosage of the drug in divided doses after meals.
Allergic skin reactions including pruritus, erythema, and urticarial, morbilliform, or maculopapular eruptions have also been reported. These adverse dermatologic effects are usually transient and frequently subside during continued administration of the drug; however, if adverse dermatologic effects persist or are severe, tolbutamide should be discontinued.
Tolbutamide therapy has rarely been associated with hepatic dysfunction and jaundice; tolbutamide-induced jaundice usually subsides following discontinuance of the drug. If jaundice persists following discontinuance of the drug, the possibility of pancreatic carcinoma or another cause of extrahepatic biliary obstruction should be excluded.
Like other sulfonylureas, tolbutamide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia.
Hypoglycemia, which may be severe, has occurred in patients receiving tolbutamide and may resemble acute neurologic disorders such as cerebral thrombosis. Hypoglycemia may result from excessive dosa however, since the development of hypoglycemia is a function of many factors including diet, this effect may occur in some patients receiving usual dosages of the drug. Hypoglycemia is readily controlled by administration of glucose. If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of tolbutamide dosage are necessary.
Therapy with sulfonylureas, including tolbutamide, may be associated with weight gain.142, 143, 144 Although the exact mechanisms associated with such alterations in weight have not been established, suggested mechanisms include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or an increase in blood leptin concentrations.142, 143, 144 Data from the United Kingdom Prospective Diabetes (UKPD) study in patients receiving long-term therapy (over 10 years) with glyburide and other antidiabetic agents indicate that weight gain was greatest in those receiving intensive therapy (stepwise introduction of a sulfonylurea then insulin or an oral sulfonylurea and insulin, or insulin alone to achieve fasting glucose concentrations of 108 mg/dL) than conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations less than 270 mg/dL without symptoms of hyperglycemia), and weight gain was greatest in those initially receiving insulin or chlorpropamide (no longer commercially available in the US) compared with those receiving glyburide.111
Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving tolbutamide.
Photosensitivity reactions, hepatic porphyria, and porphyria cutanea tarda have also been reported in patients receiving tolbutamide. Although tolbutamide is mildly goitrogenic in animals receiving large doses and has caused decreased radioactive iodine uptake in humans, clinical hypothyroidism or thyroid enlargement has not been reported in humans.
Precautions and Contraindications
Tolbutamide shares the toxic potentials of other sulfonylurea antidiabetic agents, and the usual precautions associated with their use should be observed. The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin are generally necessary with tolbutamide. Tolbutamide should only be prescribed for carefully selected patients by clinicians who are familiar with the indications, limitations, and patient-selection criteria for therapy with oral sulfonylurea antidiabetic agents.
The manufacturer states that patients should communicate daily with their physician during the first week of tolbutamide therapy. During the first month of therapy, the patient should be evaluated weekly (including physical examination) for definitive evaluation of efficacy of the drug. During the withdrawal period in patients in whom tolbutamide is replacing insulin, patients should be instructed to test their urine for glucose and acetone at least 3 times daily, and to report the results to their physician daily; when feasible, patient or laboratory monitoring of blood glucose concentration is preferable. Care should be taken to avoid ketosis, acidosis, and coma during the withdrawal period in patients being switched from insulin to tolbutamide. Frequent evaluation of liver function is recommended during the initial use of tolbutamide. Because of the spontaneous tendency of diabetes to fluctuate in severity, and because secondary failures may occur, patients receiving tolbutamide should continue to be evaluated at regular intervals following the initial month of therapy with the drug; the exact frequency of regular evaluations is variable, and depends on the physician's judgment and the patient's response to therapy.
Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents.106, 107, 108, 109, 111, 112, 115, 128 For information on these studies and associated recommendations, see Cautions: Precautions and Contraindications, in Glyburide 68:20.20. The American Diabetes Association (ADA) considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks in most patients.112, 122, 128, 192
Patients should be fully and completely advised about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition. Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes, and that tolbutamide therapy is only used as an adjunct to, and not a substitute for, proper dietary regulation. Patients should also be advised that they should not neglect dietary restrictions, develop a careless attitude about their condition, or disregard instructions about body-weight control, exercise, hygiene, and avoidance of infection. Patients should be instructed to contact their physician immediately if they do not feel as well as usual or if any feeling of illness develops during therapy with the drug.
Patients should be properly instructed in the early detection and treatment of hypoglycemia, since hypoglycemic reactions may occasionally occur during therapy with tolbutamide. Debilitated, malnourished, or geriatric patients and patients with impaired hepatic and/or renal function should be carefully monitored and dosage of tolbutamide carefully adjusted, since these patients may be predisposed to developing hypoglycemia (sometimes severe). Alcohol ingestion and adrenal or pituitary insufficiency may also predispose patients to the development of hypoglycemia. Intensive treatment (e.g., IV dextrose) and close medical supervision may be required in some patients who develop severe hypoglycemia during tolbutamide therapy.
To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary use of insulin, either alone or in combination with tolbutamide, may be required.
Tolbutamide should be used with caution in patients with a history of hepatic porphyria since, like sulfonamides and barbiturates, sulfonylurea antidiabetic agents may exacerbate this condition.
Tolbutamide is contraindicated as sole therapy in patients with type 1 diabetes mellitus and in those with diabetic ketoacidosis, with or without coma.187 Tolbutamide also is contraindicated in patients with known hypersensitivity or allergy to the drug.187
Although there are no adequate and controlled studies to date in humans, tolbutamide has been shown to be teratogenic in rats when given at dosages of 25-100 times the human dosage.187 There are no adequate and well-controlled studies in pregnant women.187 The manufacturer recommends that tolbutamide not be used for the management of diabetes mellitus in pregnancy; the drug should be used with caution in women of childbearing age who may become pregnant.187 Experts recommend the use of insulin when glycemic control is needed during pregnancy.707, 708
The hypoglycemic action of sulfonylureas could be potentiated by concomitant therapy with other drugs that are highly protein bound; such drugs include nonsteroidal anti-inflammatory agents (NSAIAs), salicylates, sulfonamides, chloramphenicol, probenecid, coumarin anticoagulants, monoamine oxidase inhibitors, and β-adrenergic blocking agents.187 Patients receiving tolbutamide with any of these drugs should be observed closely for hypoglycemia.187 When such drugs are initiated or withdrawn in patients receiving tolbutamide, the patient should be observed for evidence of hypoglycemia or loss of glycemic control, respectively.187
Thiazide and other diuretics may cause hyperglycemia and may exacerbate glycemic control in patients with diabetes mellitus.187 Patients receiving tolbutamide with diuretics should be observed closely for loss of glycemic control (hyperglycemia).187 When such drugs are initiated or withdrawn in patients receiving tolbutamide, the patient should be observed for evidence of hypoglycemia.187
Disulfiram-like reactions187 have occurred in some patients following the concomitant use of alcohol and tolbutamide.208, 209
Concomitant use of certain azole antifungal agents (i.e., miconazole, fluconazole) and oral antidiabetic agents has resulted in increased plasma concentrations of the oral antidiabetic agent and/or hypoglycemia.168, 187 Clinically important hypoglycemia may be precipitated by concomitant use of oral hypoglycemic agents and fluconazole, and at least one fatality has been reported from hypoglycemia in a patient receiving glyburide and fluconazole concomitantly.169 Severe hypoglycemia has been reported with concomitant use of oral hypoglycemic agents and oral miconazole.187 Whether this interaction occurs with other routes of administration of miconazole (i.e., IV, topical, intravaginal) is not known.187 (See Drug Interactions: Sulfonylurea Antidiabetic Agents, in Fluconazole 8:14.08.)
Beta-Adrenergic Blocking Agents
Although propranolol has decreased the hypoglycemic effect of tolbutamide (presumably by decreasing insulin secretion) in one study in healthy individuals, it is likely that, in diabetic patients treated with sulfonylurea antidiabetic agents, concomitant use of propranolol would blunt the rebound increase in blood glucose concentration following drug-induced hypoglycemia. In addition, β-adrenergic blocking agents block hypoglycemia-induced tachycardia but do not inhibit hypoglycemic sweating. When tolbutamide and a β-adrenergic blocking agent are used concomitantly, the patient should be monitored closely for altered antidiabetic response and advised that tachycardia, a warning sign of hypoglycemia, usually will not occur.
Drugs that cause hyperglycemia and may lead to loss of glycemic control in patients with diabetes mellitus include thiazides and other diuretics, corticosteroids, niacin, thyroid preparations, estrogens, oral contraceptives, phenytoin, sympathomimetics, phenothiazines, calcium-channel blocking agents, and isoniazid.187
Tolbutamide reportedly decreases the uptake of radioactive iodine and may interfere with test results of radioactive iodine uptake.
The carboxyl metabolite of tolbutamide may interfere with tests for urinary albumin that use heat and acetic acid or sulfosalicylic acid, resulting in pseudoalbuminuria. False-positive reactions result from precipitation of the tolbutamide metabolite as flocculent particles. False-positive reactions do not appear to occur when bromphenol reagent strips are used to test for urinary albumin.
Sulfonylurea antidiabetic agents lower blood glucose concentration in diabetic and nondiabetic individuals. Although the hypoglycemic action of the various sulfonylureas is generally similar, the drugs may differ quantitatively and/or possibly qualitatively in the extent to which they produce specific effects, and the effects may vary as a function of duration of treatment. The hypoglycemic response that occurs following oral administration of a single 50-mg/kg tolbutamide dose to healthy, nondiabetic adults, is approximately the same as that produced following IV injection of a single 0.1-unit/kg dose of insulin.
The precise mechanism of hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established, but the drugs initially appear to lower blood glucose concentration principally by stimulating the secretion of endogenous insulin from the beta cells of the pancreas. Like other sulfonylureas, tolbutamide alone is ineffective in the absence of functioning beta cells. During prolonged administration of sulfonylureas, extrapancreatic effects appear to substantially contribute to the hypoglycemic effect of the drugs. Many extrapancreatic effects of the drugs have been proposed and/or studied, but the principal effects appear to include enhanced peripheral sensitivity to insulin and reduction of basal hepatic glucose production; however, the nature of the long-term hypoglycemic effect and the mechanism(s) involved remain to be fully elucidated.
Tolbutamide is readily absorbed from the GI tract following oral administration. Following oral administration of a single dose, the drug is detectable in plasma within 30-60 minutes and peak plasma tolbutamide concentrations occur within 3-5 hours. Of currently available sulfonylurea antidiabetic agents, tolbutamide has the shortest duration of action. Following oral administration of a single 3-g tolbutamide dose (as a solution) in healthy, fasting adults, a 30% or greater decrease in blood glucose concentration usually occurs within 1 hour, and blood glucose concentration gradually returns to fasting levels within 6-12 hours. Following oral administration of a single 6-g tolbutamide dose (as a solution) to healthy, fasting adults, the maximum decrease in blood glucose concentration is not substantially different from that produced by a 3-g dose of the drug.
Following oral administration of a single 3-g tolbutamide dose to responsive diabetic patients, the onset of hypoglycemic action is gradual and peak hypoglycemic activity usually occurs within 5-8 hours; blood glucose concentrations then begin to increase gradually and return to pretreatment levels within 24 hours.
Although the time of peak hypoglycemic activity differs in the nondiabetic and diabetic individual, the magnitude of the reduction in blood glucose concentration, when expressed as a percent of pretreatment blood glucose concentrations, appears to be similar. In one study comparing the hypoglycemic effect of a single 50-mg/kg oral dose of tolbutamide in healthy adults and responsive diabetic patients, the maximum decrease in blood glucose concentration averaged 45.9% and 46.3% in nondiabetic and diabetic individuals, respectively; the average mean decrease in blood glucose concentration during the 5-hour observation period in this study was 31.7% and 31.8% for nondiabetic and diabetic patients, respectively.
Distribution of tolbutamide into human body tissues and fluids has not been fully characterized, but sulfonylureas are distributed into extracellular fluids. Small amounts of tolbutamide may also be distributed into bile. Tolbutamide is reported to be approximately 95% bound to plasma proteins.
Tolbutamide has a half-life (t½) of approximately 7 hours; however, there may be considerable interindividual variation in the t½ of the drug, and a range of 4-25 hours has been reported. Although the exact metabolic fate of tolbutamide has not been clearly established, the drug appears to be principally metabolized in the liver via oxidation of the p -methyl group resulting in a carboxyl metabolite (1-butyl-3- p -carboxyphenylsulfonylurea). The drug may also be metabolized to hydroxytolbutamide. Unlike antibacterial sulfonamides, tolbutamide is not acetylated in the body since it does not have a p -amino group. Tolbutamide and its metabolites are excreted in urine and feces. Approximately 75-85% of a single oral dose of tolbutamide is excreted in urine, principally as 1-butyl-3- p -carboxyphenylsulfonylurea, within 24 hours; this metabolite is readily soluble in urine at pHs of 5 or more (280 mg/dL at pH 5, 2 g/dL at pH 5.5, and 30 g/dL at pH 6).
Tolbutamide is a sulfonylurea antidiabetic agent. The drug is structurally similar to acetohexamide, chlorpropamide, and tolazamide. Although chemically related to sulfonamides, tolbutamide has no antibacterial activity.
Tolbutamide occurs as a white or practically white, practically odorless, crystalline powder with a slightly bitter taste and is practically insoluble in water and soluble in alcohol.
Commercially available tolbutamide tablets should be stored in well-closed containers between 15-30°C.187
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 500 mg* | Tolbutamide Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions June 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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