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Tolbutamide

Class: Sulfonylureas
ATC Class: A10BB03
VA Class: HS502
CAS Number: 64-77-7

Medically reviewed by Drugs.com on Jul 22, 2020. Written by ASHP.

Introduction

Antidiabetic agent; sulfonylurea.

Uses for Tolbutamide

Diabetes Mellitus

Monotherapy as an adjunct to diet and exercise for management of type 2 (noninsulin-dependent) diabetes mellitus in patients whose hyperglycemia cannot be controlled with diet and exercise alone.

Second-line therapy in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy.

Alternative therapy in some type 2 diabetic patients being treated with insulin or other antidiabetic agent(s). Useful in combination with insulin to improve glycemic control and/or decrease insulin dosage in some type 2 diabetic patients.

Not effective as sole therapy for patients with type 1 diabetes mellitus or diabetic acidosis, ketosis, or coma; insulin is necessary. (See Contraindications under Cautions.)

Not routinely recommended in hospitalized patients with diabetes mellitus. Long duration of action precludes rapid dosage adjustments. Increased risk of hypoglycemia in hospitalized diabetic patients with irregular eating patterns.

Tolbutamide Dosage and Administration

General

  • Adjust dosage according to severity of disease, tolerance, and blood glucose determinations.

  • Monitor regularly (e.g., blood glucose concentrations) to determine minimum effective dosage and detect primary or secondary failure. (See Loss of Glycemic Control under Cautions.)

  • Monitor glycosylated hemoglobin (HbA1c) to determine patient’s continued response to therapy.

  • During transfer from insulin therapy, patients should test their blood glucose concentrations ≥3 times daily. In some patients (e.g., those requiring >40 units of insulin daily), consider hospitalization during transition period.

Administration

Oral Administration

Administer orally in divided doses after meals to avoid GI intolerance; alternatively, may administer as a single daily dose in the morning.

Dosage

Adults

Diabetes Mellitus
Initiation
Oral

Initially, 1–2 g daily.

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents
Oral

Initially, 1–2 g daily. May abruptly discontinue most other oral antidiabetic agents (except chlorpropamide). During transfer from chlorpropamide (a drug with a long elimination half-life), monitor closely for hypoglycemia during initial 2 weeks of transition period.

Initial Dosage in Patients Transferred from Insulin
Oral

Insulin requirements ≤20 units daily: Initially, 1–2 g daily. May abruptly discontinue insulin.

Insulin requirements 20–40 units daily: Initially, 1–2 g daily, reduce daily insulin dosage by 30–50%. Subsequently, adjust insulin dosage according to therapeutic response.

Insulin requirements >40 units daily: Initially, 1–2 g daily; reduce daily insulin dosage by 20%. Subsequently, adjust insulin dosage according to therapeutic response.

Titration and Maintenance Dosage
Oral

Titrate dosage according to patient’s response, using lowest possible effective dosage. Usual maintenance dosage is 250 mg–3 g daily. Patients not responding to 2 g daily are unlikely to respond to higher dosages.

Rarely, temporary increases to >2 g daily may be necessary to maintain glycemic control.

Prescribing Limits

Adults

Diabetes Mellitus
Oral

Maximum 3 g daily.

Special Populations

Hepatic Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia. (See Hepatic Impairment under Cautions.)

Renal Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia. (See Renal Impairment under Cautions.)

Geriatric Patients

Use conservative initial and maintenance dosages to avoid hypoglycemia. (See Geriatric Use under Cautions.)

Debilitated or Malnourished Patients

Use conservative initial and maintenance dosages to avoid hypoglycemia.

Adrenal or Pituitary Insufficiency

Use conservative initial and maintenance dosages to avoid hypoglycemia.

Cautions for Tolbutamide

Contraindications

  • Known hypersensitivity to tolbutamide or any ingredient in formulation.

  • Diabetic ketoacidosis, with or without coma.

  • Monotherapy for type 1 diabetes mellitus.

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased cardiovascular mortality reported. However, the American Diabetes Association (ADA) considers benefits of intensive glycemic control with insulin or sulfonylureas to outweigh risks overall.

General Precautions

Hypoglycemia

Possible severe hypoglycemia, especially in geriatric, debilitated, or malnourished patients and those with adrenal, pituitary, hepatic, or renal insufficiency. Increased risk of hypoglycemia with strenuous exercise, alcohol ingestion, insufficient caloric intake, or concurrent drug use (e.g., other antidiabetic agents, agents that enhance hypoglycemic effects).

Hypoglycemia may be difficult to recognize in geriatric patients and in those receiving β-adrenergic blocking agents.

Appropriate patient selection and careful dosing and instructions are important to avoid tolbutamide-induced hypoglycemia.

Hypoglycemia may result in coma, seizures, or other neurologic impairment.

If hypoglycemia occurs, immediately reevaluate patient and adjust insulin or tolbutamide dosage. Monitor patient for 24–48 hours; may require hospitalization and IV dextrose.

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery). May require use of insulin and/or temporary discontinuance of tolbutamide.

Efficacy of therapy may decrease over time (secondary failure); evaluate patients at regular intervals.

Assess patients for adequate adjustment of dose and adherence to diet before attributing inadequate response to secondary failure of the drug.

Manufacturer recommends discontinuance of tolbutamide if loss of satisfactory glycemic control develops. ADA and other clinicians recommend addition of other oral antidiabetic agents or insulin. (See Diabetes Mellitus under Uses.)

Specific Populations

Pregnancy

Category C.

Prolonged (4–10 days), severe hypoglycemia reported in some neonates born to women receiving a sulfonylurea at delivery; more frequent with long-acting sulfonylureas. Discontinue drug ≥2 weeks before expected delivery date to minimize the risk of neonatal hypoglycemia.

Many experts recommend the use of insulin during pregnancy.

Lactation

Distributed into milk. Manufacturer recommends discontinuing nursing or the drug. AAP classifies tolbutamide as compatible with breast-feeding.

If drug is discontinued and diet alone is inadequate for glycemic control, consider insulin.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Increased risk of hypoglycemia; hypoglycemia may be difficult to recognize. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Increased risk of hypoglycemia. (See Hepatic Impairment under Dosage and Administration.)

Evaluate liver function frequently during tolbutamide initiation.

Use with caution if history of hepatic porphyria; may exacerbate condition.

Renal Impairment

Increased risk of hypoglycemia. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, epigastric fullness, heartburn, pruritus, erythema, urticarial, morbilliform, or maculopapular eruptions.

Interactions for Tolbutamide

Metabolized mainly by CYP2C9; minor metabolism by CYP2C19.

Protein-bound Drugs

Potential pharmacokinetic interaction (increased hypoglycemic effect because of displacement of tolbutamide from binding sites on proteins). (See Specific Drugs and Laboratory Tests under Interactions.)

Close observation recommended when initiating or discontinuing concomitant therapy with a highly protein-bound drug.

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Alcohol

Disulfiram like reactions reported

Antifungals, oral azoles (i.e., fluconazole, miconazole)

Possible increased plasma concentrations of sulfonylureas and hypoglycemic effect

Not known whether interaction occurs with IV, topical, or vaginal miconazole

Anticoagulants, oral

Possible displacement of tolbutamide from plasma proteins and potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued, respectively

β-Adrenergic blocking agents

Possible potentiation of hypoglycemic effects

Signs of hypoglycemia (e.g., tachycardia) may be masked by β-adrenergic blocking agents

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued, respectively

Calcium-channel blocking agents

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Chloramphenicol

Possible potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued, respectively

Contraceptives, oral

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Corticosteroids

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Diuretics

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Estrogens

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Isoniazid

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

MAO inhibitors

Possible potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued, respectively

Niacin

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

NSAIAs

Possible displacement of tolbutamide from plasma proteins and potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued, respectively

Phenothiazines

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Phenytoin

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Probenecid

Possible potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued, respectively

Salicylates

Possible displacement of tolbutamide from plasma proteins and potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued, respectively

Sulfonamides

Possible displacement of tolbutamide from plasma proteins and potentiation of hypoglycemic effects

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued, respectively

Sympathomimetic agents

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Test for radioactive iodine reuptake

Possible decrease in radioactive iodine reuptake; may interfere with test results

Test for urinary albumin

May produce false-positive results for urine albumin using acidification-after-boiling test

No interference with sulfosalicylic acid test

Thyroid agents

Potential for decreased hypoglycemic effect

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued, respectively

Tolbutamide Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration. Peak plasma concentrations attained at ≤3–5 hours.

Onset

Following single 3-g dose (as a solution) in diabetic patients, gradual onset of hypoglycemic action; maximal effect 5–8 hours.

Duration

In diabetic patients, the hypoglycemic action may persist for up to 24 hours.

Food

Food does not affect pharmacokinetics.

Special Populations

In geriatric individuals, increased peak serum drug concentrations relative to younger adults.

Distribution

Extent

Distributed into extracellular fluids; small amounts also may be distributed into bile.

Tolbutamide crosses the placenta when administered near term and is distributed into milk.

Plasma Protein Binding

Approximately 95%.

Elimination

Metabolism

Metabolized to inactive metabolites principally via CYP2C9; minor contribution via CYP2C19.

Elimination Route

Excreted in urine (75–85%), predominantly as inactive metabolites, and in feces.

Half-life

4.5–7 hours (range: 4–25 hours).

Special Populations

Metabolism influenced by CYP2C9 polymorphism; genetic differences in drug metabolism affect drug response.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C.

Actions

  • Stimulates secretion of postprandial endogenous insulin from beta cells of the pancreas.

  • Ineffective in absence of functioning beta cells.

  • During prolonged administration, extrapancreatic effects (e.g., enhanced peripheral sensitivity to insulin, reduction of basal hepatic glucose production) contribute to hypoglycemic action.

Advice to Patients

  • Importance of informing patients of potential risks and advantages of tolbutamide therapy and of alternative forms of treatment.

  • Importance of regular testing of blood glucose concentrations and HbA1c.

  • According to manufacturer, patients should test their urine for glucose and acetone ≥3 times daily during insulin withdrawal. Report abnormal results to clinician for appropriate adjustments in therapy.

  • Importance of hygiene and avoidance of infection.

  • Advise patients about nature of diabetes mellitus, prevention and detection of complications, and importance of glycemic control.

  • Risks of hypoglycemia. Importance of patients and responsible family members understanding symptoms and treatment of hypoglycemic reactions and identifying conditions that predispose to development of such reactions.

  • Importance of understanding primary and secondary failure to therapy.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

TOLBUTamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg*

TOLBUTamide Tablets (scored)

Mylan

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 1, 2008. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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