tolazamide
Tolinase

Available forms
Available by prescription only
Tablets: 100 mg, 250 mg, 500 mg

Indications and dosages
 Adjunct to diet to lower blood glucose levels in patients with non-insulin-dependent diabetes mellitus (type 2). Adults: Initially, 100 mg P.O. daily with breakfast if fasting blood glucose level is below 200 mg/dl. Or, 250 mg P.O. daily if fasting blood glucose level is above 200 mg/dl. May adjust dose at weekly intervals in increments of 100 to 250 mg based on blood glucose response. Maximum dosage is 500 mg P.O. b.i.d. before meals.
Elderly patients: Initially, 100 mg P.O. daily.
≡ Dosage adjustment. Initially, malnourished or underweight patients may be given 100 mg P.O. daily.

Pharmacodynamics
Antidiabetic action: Tolazamide lowers blood glucose levels by stimulating insulin release from functioning beta cells of the pancreas. After prolonged administration, the hypoglycemic effects of drug appear to reflect extrapancreatic effects, possibly including reduction of basal hepatic glucose production and enhanced peripheral sensitivity to insulin.

Pharmacokinetics
Absorption: Absorbed well from the GI tract.
Distribution: Probably distributed into the extracellular fluid.
Metabolism: Metabolized probably by the liver to several mildly active metabolites.
Excretion: Excreted in urine primarily as metabolites, with small amounts excreted as unchanged drug. Half-life is 7 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or other sulfonylureas; in patients with type 1 diabetes or diabetes that can be adequately controlled by diet; in patients with type 2 diabetes complicated by ketosis, acidosis, coma, or other acute complications such as major surgery, severe infection, or severe trauma; in patients with uremia; and in pregnant or breast-feeding women.
  Use cautiously in geriatric, debilitated, or malnourished patients and in those with impaired renal or hepatic function or those with adrenal or pituitary insufficiency.

Interactions
Drug-drug. Beta blockers, including ophthalmics: Increases risk of hypoglycemia, masking its symptoms (increasing pulse rate and blood pressure) and prolonging it by blocking gluconeogenesis. Use together cautiously.
Calcium channel blockers, corticosteroids, estrogens, hormonal contraceptives, isoniazid, phenothiazines, phenytoin, sympathomimetics, thiazide diuretics, thyroid hormones, triamterene: Decreases hypoglycemic effect. Monitor blood glucose level and adjust dose accordingly.
Chloramphenicol, insulin, MAO inhibitors, NSAIDs, probenecid, salicylates, sulfonamides: Increases hypoglycemic effect. Monitor blood glucose level closely.
Oral anticoagulants: May increase hypoglycemic activity or enhance anticoagulant effect. Monitor blood glucose level and PT and INR.
Drug-herb. Aloe, bitter melon, bilberry leaf, burdock, dandelion, fenugreek, garlic, ginseng: May improve blood glucose control. A reduction in antidiabetic dosage may be needed.
Drug-lifestyle. Alcohol use: Causes disulfiram-like reaction (nausea, vomiting, abdominal cramps, headaches). Discourage alcohol use.

Adverse reactions
CNS: weakness, fatigue, dizziness, vertigo, malaise, headache.
GI: nausea, vomiting, epigastric distress, heartburn.
Hematologic: leukopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, agranulocytosis, pancytopenia.
Metabolic: hyponatremia, hypoglycemia.
Skin: photosensitivity reactions.

Effects on lab test results
• May decrease glucose and sodium levels.
• May decrease hemoglobin and WBC, RBC, platelet, and granulocyte counts.

Overdose and treatment
Signs and symptoms of overdose include low blood glucose levels, tingling of lips and tongue, hunger, nausea, decreased cerebral function (lethargy, yawning, confusion, agitation, nervousness), increased sympathetic activity (tachycardia, sweating, tremor), and ultimately seizures, stupor, and coma.
 Mild hypoglycemia, without loss of consciousness or neurologic findings, responds to treatment with oral glucose and adjustments in drug doses and meal patterns. If patient loses consciousness or has neurologic findings, give rapid injection of D₅₀W followed by continuous infusion of D₁₀W at a rate to maintain blood glucose levels above 100 mg/dl. Monitor patient for 24 to 48 hours.

Special considerations
• Over time, patients may become unresponsive (uncontrolled blood glucose level) to therapy with this agent as well as other sulfonylureas; monitor patient appropriately.
• To avoid GI intolerance for those patients receiving doses of 500 mg or more daily and to improve control of hyperglycemia, divided doses are recommended; these are given before the morning and evening meals.
• Tablets may be crushed to ease administration.
• Use cautiously in women of childbearing age. Tolazamide isn’t recommended for treatment of diabetes related to pregnancy.
• Oral antidiabetics have been linked to an increased risk of CV mortality compared with diet or diet and insulin therapy.
• To change from insulin to oral therapy with tolazamide, if insulin dose is less than 20 units daily, insulin may be stopped and oral therapy started at 100 mg P.O. daily in the morning. If insulin dose is 20 to 40 units daily, insulin may be stopped and oral therapy started at 250 mg P.O. daily in the morning. If insulin dose is more than 40 units daily, decrease insulin dose by 50% and start oral therapy at 250 mg P.O. daily with breakfast. Increase doses as appropriate based on blood glucose response.
• When substituting tolazamide for chlorpropamide therapy, monitor patient closely for 1 to 2 weeks because of prolonged retention of chlorpropamide in the body, which may result in hypoglycemia.
Pregnant patients
• Contraindicated in pregnant women.
Breast-feeding patients
• Because of the risk of hypoglycemia in the breast-fed infant, a decision should be made to discontinue either drug or breast-feeding.
Pediatric patients
• Tolazamide is ineffective in type 1 diabetes. Safety and efficacy in children haven’t been established.
Geriatric patients
• These patients may be more sensitive to the effects of drug because of reduced metabolism and elimination. Hypoglycemia causes more neurologic symptoms in these patients. Geriatric patients usually require a lower initial dose.

Patient education
• Advise patient to take drug at the same time each day. If patient misses a dose, tell him to take the missed dose immediately, unless it’s almost time to take the next dose. Caution him not to double the doses.
• Warn patient to avoid alcohol when taking tolazamide.
• Recommend that patient take drug with food to minimize GI upset.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use