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

Introduction

Antidiabetic agent; sulfonylurea.^{a b}

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.^{a b}

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. ^{136 146 147 148 149 150 166 167 169 170 171 172 173 174 175 176}

Alternative therapy in some type 2 diabetic patients being treated with insulin or other antidiabetic agent(s) or unresponsive to other sulfonylureas.^a Useful in combination with insulin to improve glycemic control and/or decrease insulin dosage in some type 2 diabetic patients.^{136 146 147 151 152 154 155 156 157 158 159}

Not effective as sole therapy for patients with type 1 diabetes mellitus^{101 103 106 132 b} or diabetic acidosis, ketosis, or coma; insulin is necessary.^{101 102 106 a b} (See Contraindications under Cautions.)

Not routinely recommended in hospitalized patients with diabetes mellitus.¹¹⁹ Long duration of action precludes rapid dosage adjustments.^{119 132} Increased risk of hypoglycemia in hospitalized diabetic patients with irregular eating patterns.¹¹⁹

Tolazamide Dosage and Administration

General

• 
  

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

  
  


• 
  

  Monitor regularly (e.g., blood glucose concentrations) to determine minimum effective dosage and to detect primary or secondary failure.^{119 a b}

  
  


• 
  

  Monitor glycosylated hemoglobin (HbA_1c) to determine patient’s continued response to therapy.¹¹⁹

  
  


• 
  

  During transfer from insulin therapy, patients should test their blood glucose concentrations ≥3 times daily.^{a b}

  
  

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.^{a b}

Dosage

Adults

Type 2 Diabetes Mellitus

Initial Dosage

Oral

Initially, 100–250 mg daily.^{a b}

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.^{a b}

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents

May discontinue most other oral antidiabetic agents abruptly.^{a b}

Oral

Acetohexamide: Initially, 100 mg daily for each 250 mg daily of acetohexamide.^{a b}

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.^{a b} Monitor closely for hypoglycemia during the initial 1- to 2-week transition period.^{a b}

Tolbutamide: Tolbutamide dosages ≤1 g daily, initially 100 mg daily.^b Tolbutamide dosage >1 g daily, initially, 250 mg daily.^{a b}

Initial Dosage in Patients Transferred from Insulin

Oral

Insulin requirements <20 units daily: Initially, 100 mg daily.^{a b} May abruptly discontinue insulin.^a

Insulin requirements 20–40 units of insulin daily: Initially, 250 mg daily.^{a b} May abruptly discontinue insulin.^a

Insulin requirements >40 units daily: Initially, 250 mg daily; reduce daily insulin dosage by 50%.^{a b} Subsequently, adjust insulin dosage according to therapeutic response.^{a b}

Titration and Maintenance Dosage

Oral

Titrate dosage according to patient's response, using lowest possible effective dosage.^{a b} Adjust dosage in increments or decrements of 100–250 mg daily at weekly intervals.^{a b}

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

Prescribing Limits

Adults

Type 2 Diabetes Mellitus

Oral

Maximum 1 g daily.^{a b}

Special Populations

Hepatic Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia.^{a b}

Renal Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia.^{a b}

Geriatric Patients

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

Debilitated or Malnourished Patients

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

Cautions for Tolazamide

Contraindications

• 
  

  Known hypersensitivity to tolazamide.^b

  
  


• 
  

  Monotherapy for type 1 diabetes mellitus.^{a b}

  
  


• 
  

  Diabetic ketoacidosis, with or without coma.^{a b}

  
  


• 
  

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

  
  


• 
  

  Uremia.^a

  
  

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased cardiovascular mortality reported with certain other antidiabetic agents (i.e., tolbutamide, phenformin).^{106 108 109 112 125 129 130 131 b} However, the American Diabetes Association (ADA) considers the benefits of intensive glycemic control with insulin or sulfonylureas to outweigh the risks overall.^{109 119 125}

Sensitivity Reactions

Dermatologic Reactions

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

Photosensitivity Reactions

Rarely, photosensitivity reactions reported.^{a b}

General Precautions

Hypoglycemia

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

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

Increased risk of hypoglycemia in patients with irregular eating patterns.¹¹⁹

Appropriate patient selection and careful dosing and instructions are important to avoid tolazamide-induced hypoglycemia.^{a b}

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

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).^{a b} May require use of insulin and/or temporary discontinuance of tolazamide.^{a b}

Efficacy of therapy may decrease over time (secondary failure); evaluate patients at regular intervals.^{a b}

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

Manufacturer recommends discontinuance of tolazamide if satisfactory glycemic control no longer is achieved.^b ADA and other clinicians recommend addition of other oral antidiabetic agents or insulin.^{124 147 179 180 181 182 183 186 188} (See Diabetes Mellitus under Uses.)

Hepatic Effects

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

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

Specific Populations

Pregnancy

Category C.^b

Many experts recommend the use of insulin during pregnancy.^b

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

Lactation

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

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

Pediatric Use

Safety and efficacy not established.^b

Geriatric Use

Increased risk of hypoglycemia;^{a b} hypoglycemia may be difficult to recognize.^b

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

Hepatic Impairment

Increased risk of hypoglycemia; conservative dosing recommended.^{a b}

Renal Impairment

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

Common Adverse Effects

Nausea,^{a b} epigastric fullness,^b heartburn,^b vomiting,^a anorexia,^a intestinal gas,^a diarrhea,^a constipation,^a cramps.^a

Interactions for Tolazamide

Protein-bound Drugs

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

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

Specific Drugs

Drug	Interaction	Comments
Alcohol	Possible disulfiram-like reactionsa May predispose patients to the development of hypoglycemiab
Anticoagulants, oral	Possible potentiation of hypoglycemic effectsb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Antifungals, oral (i.e., fluconazole, miconazole)	Increased plasma concentrations of the oral antidiabetic agent and/or possible hypoglycemia167 b	Not known whether interaction occurs with IV, topical, or vaginal miconazoleb Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
β-Adrenergic blocking agents	Possible potentiation of hypoglycemic effectsb Signs of hypoglycemia may be masked by β-adrenergic blocking agentsb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Calcium-channel blocking agents	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Chloramphenicol	Possible potentiation of hypoglycemic effectsb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Contraceptives, oral	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Corticosteroids	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Diuretics	Potential for decreased hypoglycemic effecta b May cause temporary loss of diabetic control or secondary failurea	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinueda b
Estrogens	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Insulin	Possible potentiation of hypoglycemic effectsa	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Isoniazid	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
MAO inhibitors	Possible potentiation of hypoglycemic effectsa b	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Niacin	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control or when concurrent therapy is initiated or discontinuedb
NSAIAs	Possible potentiation of hypoglycemic effectsb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Phenothiazines	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Phenytoin	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Probenecid	Possible potentiation of hypoglycemic effectsa b	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Salicylates	Possible potentiation of hypoglycemic effectsa b	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Sulfonamides	Possible potentiation of hypoglycemic effectsa b	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Sympathomimetic agents	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb
Thyroid agents	Potential for decreased hypoglycemic effectb	Observe carefully for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinuedb

Tolazamide Pharmacokinetics

Absorption

Bioavailability

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

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.^{a b}

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

In nonfasting diabetics, onset of hypoglycemic effect occurs within 4–6 hours.^{a b}

Duration

In nondiabetic, fasting adults, pharmacologic effects persist for at least 20 hours.^{a b}

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

Distribution

Extent

Distributed into extracellular fluids; distribution not fully characterized.^a

Not known whether tolazamide is distributed into milk.^b

Elimination

Metabolism

Metabolized to active and inactive metabolites, probably in the liver.^{a b}

Elimination Route

Excreted principally in urine (85%) principally as metabolites and in feces (7%); small amounts excreted in urine unchanged.^{a b}

Half-life

Approximately 7 hours.^{a b}

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C.^{a b} Protect from light.^b

ActionsActions

• 
  

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

  
  


• 
  

  Ineffective in the absence of functioning beta cells.^a

  
  


• 
  

  Lowers blood glucose concentration in diabetic and nondiabetic individuals.^{a b}

  
  


• 
  

  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 b}

  
  


• 
  

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

  
  


• 
  

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

  
  

Advice to Patients

• 
  

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

  
  


• 
  

  Importance of regular monitoring of blood glucose (preferable self-monitoring) and of HbA_1c.^b

  
  


• 
  

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

  
  


• 
  

  Importance of hygiene and avoidance of infection.^a

  
  


• 
  

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

  
  


• 
  

  Risks of hypoglycemia.^{a b} Importance of patients and responsible family members understanding symptoms and treatment of hypoglycemic reactions and identifying conditions that predispose to development of such reactions.^{a b}

  
  


• 
  

  Importance of understanding primary and secondary failure to therapy.^b

  
  


• 
  

  Importance of adherence to diet and exercise regimen.^{a b}

  
  


• 
  

  Risk of photosensitivity reactions.^{a b}

  
  


• 
  

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

  
  


• 
  

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

  
  


• 
  

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

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* 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)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

TOLAZamide 100MG Tablets (IVAX PHARMACEUTICALS INC.): 60/$26.99 or 180/$68.97

TOLAZamide 250MG Tablets (MYLAN): 60/$35.99 or 180/$96.97

TOLAZamide 500MG Tablets (MYLAN): 30/$45.99 or 90/$109.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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