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Tolazamide

Class: Sulfonylureas
ATC Class: A10BB05
VA Class: HS502
Chemical Name: 1-(Hexahydro-1-H-azepin-1-yl)-3-(p)-tolylsulfonyl) urea
CAS Number: 1156-19-0

Medically reviewed by Drugs.com on Apr 21, 2021. Written by ASHP.

Introduction

Antidiabetic agent; sulfonylurea.

Uses for Tolazamide

Diabetes Mellitus

Monotherapy as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus in patients whose hyperglycemia cannot be controlled by 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) or unresponsive to other sulfonylureas. 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.

Tolazamide 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 to detect primary or secondary failure.

  • 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.

Administration

Oral Administration

Administer orally as a single dose with breakfast or first main meal; for dosages >500 mg daily, administer in 2 divided doses.

Dosage

Adults

Type 2 Diabetes Mellitus
Initial Dosage
Oral

Initially, 100–250 mg daily.

Manufacturer suggests that, if the fasting blood glucose is <200 mg/dL, initially, 100 mg daily; if fasting blood glucose >200 mg/dL, initially, 250 mg daily.

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents

May discontinue most other oral antidiabetic agents abruptly.

Oral

Acetohexamide: Initially, 100 mg daily for each 250 mg daily of acetohexamide.

Chlorpropamide: Administer the nearest equivalent total daily dosage; however, an exaggerated hypoglycemic response may occur in some patients during the transition because of the prolonged elimination half-life of chlorpropamide. Monitor closely for hypoglycemia during the initial 1- to 2-week transition period.

Tolbutamide: Tolbutamide dosages ≤1 g daily, initially 100 mg daily. Tolbutamide dosage >1 g daily, initially, 250 mg daily.

Initial Dosage in Patients Transferred from Insulin
Oral

Insulin requirements <20 units daily: Initially, 100 mg daily. May abruptly discontinue insulin.

Insulin requirements 20–40 units of insulin daily: Initially, 250 mg daily. May abruptly discontinue insulin.

Insulin requirements >40 units daily: Initially, 250 mg daily; reduce daily insulin dosage by 50%. 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. Adjust dosage in increments or decrements of 100–250 mg daily at weekly intervals.

Usual maintenance dosage is 100 mg to 1 g daily (average 250–500 mg daily). Patients not responding to 1 g daily are unlikely to respond to higher dosages.

Prescribing Limits

Adults

Type 2 Diabetes Mellitus
Oral

Maximum 1 g daily.

Special Populations

Hepatic Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia.

Renal Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia.

Geriatric Patients

Initially, 100 mg daily. May increase dosage by 50–125 mg daily at weekly intervals. Use conservative initial and maintenance dosages to avoid hypoglycemia.

Debilitated or Malnourished Patients

Initially, 100 mg daily. May increase dosage by 50–125 mg daily at weekly intervals. Use conservative initial and maintenance dosages to avoid hypoglycemia.

Cautions for Tolazamide

Contraindications

  • Known hypersensitivity to tolazamide.

  • Monotherapy for type 1 diabetes mellitus.

  • Diabetic ketoacidosis, with or without coma.

  • Acute complications (e.g., major surgery, severe infection, or severe trauma).

  • Uremia.

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased cardiovascular mortality reported with certain other antidiabetic agents (i.e., tolbutamide, phenformin). However, the American Diabetes Association (ADA) considers the benefits of intensive glycemic control with insulin or sulfonylureas to outweigh the risks overall.

Sensitivity Reactions

Dermatologic Reactions

Possible allergic skin reaction (e.g., pruritus, erythema, urticaria, rash, morbilliform or maculopapular eruptions). May be transient; discontinue the drug if reaction persists.

Photosensitivity Reactions

Rarely, photosensitivity reactions reported.

General Precautions

Hypoglycemia

Possibly severe hypoglycemia reported, especially in debilitated, malnourished, or geriatric patients and patients with adrenal, pituitary, hepatic, or renal insufficiency. Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.

Hypoglycemia may be difficult to recognize in geriatric patients and in those receiving β-adrenergic blocking agents. (See Specific Drugs under Interactions.)

Increased risk of hypoglycemia in patients with irregular eating patterns.

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

If hypoglycemia occurs, immediately reevaluate patient and adjust insulin or tolazamide 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 tolazamide.

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.

Manufacturer recommends discontinuance of tolazamide if satisfactory glycemic control no longer is achieved. ADA and other clinicians recommend addition of other oral antidiabetic agents or insulin. (See Diabetes Mellitus under Uses.)

Hepatic Effects

Cholestatic jaundice and alterations in liver function test results (e.g., bilirubin, cholesterol, AST, ALT) reported. If cholestatic jaundice occurs, discontinue the drug.

Use with caution in patients with a history of hepatic porphyria; sulfonylureas may exacerbate this condition.

Specific Populations

Pregnancy

Category C.

Many experts recommend the use of insulin during pregnancy.

Not recommended for use during pregnancy by manufacturer. Prolonged (4–10 days), severe hypoglycemia reported in some neonates born to women receiving a sulfonylurea at delivery; more frequent with long-acting sulfonylureas. If used during pregnancy, discontinue ≥2 weeks before the expected delivery date to minimize the risk of neonatal hypoglycemia.

Lactation

Not known whether tolazamide is distributed into human milk. Some sulfonylurea drugs are distributed into human milk. Discontinue nursing or the drug.

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.

Possible increased risk of hypoglycemia due to age-related decreases in renal function. Renal function monitoring recommended; select dosage with caution.

Hepatic Impairment

Increased risk of hypoglycemia; conservative dosing recommended.

Renal Impairment

Increased risk of hypoglycemia; conservative dosing recommended. (See Renal Impairment under Special Populations in Dosage and Administration.)

Common Adverse Effects

Nausea, epigastric fullness, heartburn, vomiting, anorexia, intestinal gas, diarrhea, constipation, cramps.

Interactions for Tolazamide

Protein-bound Drugs

Potential pharmacokinetic interaction (increased hypoglycemic effect). (See Specific Drugs under Interactions.)

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

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible disulfiram-like reactions

May predispose patients to the development of hypoglycemia

Anticoagulants, oral

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

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

Increased plasma concentrations of the oral antidiabetic agent and/or possible hypoglycemia

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

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

β-Adrenergic blocking agents

Possible potentiation of hypoglycemic effects

Signs of hypoglycemia may be masked by β-adrenergic blocking agents

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Calcium-channel blocking agents

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Chloramphenicol

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Contraceptives, oral

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Corticosteroids

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Diuretics

Potential for decreased hypoglycemic effect

May cause temporary loss of diabetic control or secondary failure

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Estrogens

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Insulin

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Isoniazid

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

MAO inhibitors

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Niacin

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control or when concurrent therapy is initiated or discontinued

NSAIAs

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Phenothiazines

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Phenytoin

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Probenecid

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Salicylates

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Sulfonamides

Possible potentiation of hypoglycemic effects

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Sympathomimetic agents

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Thyroid agents

Potential for decreased hypoglycemic effect

Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued

Tolazamide Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed following oral administration. Peak serum concentrations attained at 3–4 hours.

Onset

Following a single 500 mg dose in nondiabetic, fasting adults, hypoglycemic effect occurs within 20 minutes; peak hypoglycemic effect occurs at 1–4 hours.

Following a single 500 mg dose in fasting diabetics, peak hypoglycemic effect occurs at 4–6 hours.

In nonfasting diabetics, onset of hypoglycemic effect occurs within 4–6 hours.

Duration

In nondiabetic, fasting adults, pharmacologic effects persist for at least 20 hours.

In nonfasting diabetics, hypoglycemic activity persists for about 10 hours; blood glucose concentrations begin to increase at 14–16 hours following a single dose.

Distribution

Extent

Distributed into extracellular fluids; distribution not fully characterized.

Not known whether tolazamide is distributed into milk.

Elimination

Metabolism

Metabolized to active and inactive metabolites, probably in the liver.

Elimination Route

Excreted principally in urine (85%) principally as metabolites and in feces (7%); small amounts excreted in urine unchanged.

Half-life

Approximately 7 hours.

Stability

Storage

Oral

Tablets

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

Actions

  • Mechanism of long-term hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established. Appears to lower blood glucose concentration principally by stimulating the secretion of endogenous insulin from the beta cells of the pancreas.

  • Ineffective in the absence of functioning beta cells.

  • Lowers blood glucose concentration in diabetic and nondiabetic individuals.

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

  • A gradual decline in the insulin secretory response to drug may occur; however, blood glucose lowering effect persists.

  • May produce a mild diuresis by enhancement of renal free water clearance.

Advice to Patients

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

  • Importance of regular monitoring of blood glucose (preferable self-monitoring) and of 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 adherence to diet and exercise regimen.

  • Risk of photosensitivity reactions.

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

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Inform patients that tolazamide is not recommended during pregnancy.

  • 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

TOLAZamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

250 mg*

TOLAZamide Tablets (scored)

500 mg*

TOLAZamide Tablets (scored)

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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