ATC Class:A10BB05
VA Class:HS502
Tolazamide is a sulfonylurea antidiabetic agent.
Tolazamide is used for the management of mild to moderately severe, stable, type 2 (noninsulin-dependent) diabetes mellitus. Sulfonylureas 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. 136, 146, 147, 148, 149, 150, 166, 167, 169, 170, 171, 172, 173, 174, 175, 176
The American Diabetes Association (ADA) currently classifies diabetes mellitus into several subclasses including type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes).105 Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth.105 Type 2 diabetes mellitus was previously described as adult-onset (AODM) diabetes mellitus.105 However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on clinical presentation rather than on the age of onset.105 Many patients' diabetes mellitus does not easily fit into a single classification.105 Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.134
Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency.105 Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. 133, 134, 136, 138, 139, 140, 186 Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk.105, 200 While children with immune-mediated type 1 diabetes mellitus generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population.134 Distinguishing between type 1 and type 2 diabetes in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).134, 202
Oral antidiabetic agents are not effective as sole therapy for patients with type 1 diabetes mellitus;101, 103, 106, 132 insulin is necessary in these patients.101, 102, 106 Sulfonylurea antidiabetic agents are not routinely recommended in hospitalized patients with diabetes mellitus.119 Because of their long duration of action (7 hours with tolazamide), sulfonylureas do not allow rapid dosage adjustments to meet changing needs of hospitalized patients.119, 132 In addition, the risk of hypoglycemia during sulfonylurea therapy is increased in such patients with irregular eating patterns.119
Patients with type 2 diabetes mellitus are not dependent on insulin nor prone to ketosis;105, 106 however, insulin may occasionally be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis may occasionally develop during periods of severe stress (e.g., acute infections, trauma, surgery).101, 102, 105, 106 Type 2 diabetes mellitus is a heterogeneous subclass of the disease, and subclassification criteria (e.g., basal and stimulated plasma insulin concentrations, insulin resistance) remain to be clearly established.104, 105, 106, 107 Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal.104, 105, 106 In type 2 diabetic patients, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.104
Glycemic Control and Microvascular Complications
Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus,114, 115, 116 and results of randomized, controlled studies in patients with type 1 or 2 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., retinopathy, nephropathy, neuropathy) complications associated with the disease.108, 109, 115, 117, 119, 120 HbA1c concentration reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for development of diabetic microvascular complications.121, 189, 190 Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.203, 204
In the Diabetes Control and Complications Trial (DCCT), the reduction in risk of microvascular complications in patients with type 1 diabetes mellitus correlated continuously with the reduction in HbA1c concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in HbA1c).120 These data imply that any decrease in HbA1c levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic complications.116, 119, 120 Data from the largest United Kingdom Prospective Diabetes Study (UKPDS) and other smaller studies in patients with type 2 diabetes mellitus generally are consistent with the same benefits on microvascular complications as those observed with type 1 diabetes mellitus in the DCCT study.108, 109, 117, 120, 123, 124, 125, 164
Data from long-term follow-up (over 10 years) of UKPDS patients with type 2 diabetes mellitus who received initial therapy with conventional (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia) antidiabetic treatment or intensive (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) antidiabetic regimens indicate that intensive treatment with monotherapy generally is not capable of maintaining strict glycemic control (i.e., maintenance of blood glucose concentrations of 108 mg/dL or normal values) over time and that combination therapy eventually becomes necessary in most patients to attain target glycemic levels in the long term; in UKPDS, intensive treatment that eventually required combination therapy in most patients resulted in median HbA1c concentrations of 7%.108, 110, 111, 117, 124, 126, 127 Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time.109, 112, 125, 186 For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or 2 diabetes mellitus, see Glycemic Control and Microvascular Complications under Uses: Diabetes Mellitus, in Metformin 68:20.04.
Glycemic Control and Macrovascular Complications
Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials.108, 109, 112, 120, 125, 191, 195, 197, 198, 199, 202 Reduction in blood pressure to a mean of 144/82 mm Hg (“tight blood pressure control”) in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points.126, 130, 138, 141, 142 While intensive antidiabetic therapy titrated with the goal of reducing HbA1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes,108, 120, 195, 197, 198, 199, 202 results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus.195, 196, 198, 202, 205, 206, 207 For additional details regarding the effects of intensive antidiabetic therapy on macrovascular outcomes, see Glycemic Control and Macrovascular Complications, under Uses: Diabetes Mellitus, in Metformin 68:20.04.
The ADA currently states that it is reasonable to attempt to achieve in patients with type 2 diabetes mellitus the same blood glucose and HbA1c goals recommended for patients with type 1 diabetes mellitus.119 Based on target values for blood glucose and HbA1c used in clinical trials (e.g., DCCT) for type 1 diabetic patients, modified somewhat to reduce the risk of severe hypoglycemia, ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 70-130 and less than 180 mg/dL, respectively, and HbA1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in patients with type 1 or type 2 diabetes mellitus who are not pregnant.119 HbA1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA1c concentrations of less than 7%.110, 115 HbA1c values of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA1c concentrations of less than 7%.186 Patients with diabetes mellitus who have elevated HbA1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal.119 Treatment with agents (e.g., α-glucosidase inhibitors, exenatide, pramlintide) that principally lower postprandial glucose concentrations to within target ranges also should reduce HbA1c.185, 186
More stringent treatment goals (i.e., an HbA1c less than 6%) may be considered in selected patients.119, 186, 187 An individualized HbA1c goal that is closer to normal without risking substantial hypoglycemia is recommended in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy.119, 186, 195, 202 Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin.119, 195, 196, 202 Achievement of HbA1c values of less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy.119, 186 For additional details on individualizing treatment in patients with diabetes mellitus, see Treatment Goals under Uses: Diabetes Mellitus, in Metformin 68:20.04.
Considerations in Initiating and Maintaining Antidiabetic Therapy
When initiating therapy for patients with type 2 diabetes mellitus who do not have severe symptoms, most clinicians recommend that diet be emphasized as the primary form of treatment;101, 102, 107, 129, 186 caloric restriction and weight reduction are essential in obese patients.101, 102, 107 Although appropriate dietary management and weight reduction alone may be effective in controlling blood glucose concentration and symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and maintain adequate glycemic control with dietary modification alone.116, 153, 161, 162, 163, 147, 164, 165
Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, ADA currently suggests initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus.186 Other experts suggest concurrent initiation of lifestyle interventions and antidiabetic agents only when HbA1c levels of 9% or greater are present at the time of diagnosis of type 2 diabetes mellitus.188 ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated.186 The manufacturer states that patients and clinicians should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that antidiabetic therapy is used only as an adjunct to, and not as a substitute for or a convenient means to avoid, proper dietary management.101, 102, 132 In addition, loss of blood glucose control on diet alone may be temporary in some patients, requiring only short-term management with drug therapy.101, 102, 132 The importance of regular physical activity also should be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible.101, 102, 129 If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentration, initiation of monotherapy with an oral antidiabetic agent (e.g., sulfonylurea, metformin, acarbose) or insulin should be considered.101, 102, 106, 188
If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentrations within 2-3 months of diagnosis, initiation of monotherapy with metformin or another oral antidiabetic agent (e.g., a sulfonylurea, acarbose) or insulin should be considered.188 For more information on the stepwise approach to the management of type 2 diabetes mellitus, See Uses: Diabetes Mellitus, in Metformin 68:20.04.
Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents. For information on these studies and associated recommendations, see Cautions: Precautions and Contraindications, in Glyburide 68:20.20. The ADA currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall.
Tolazamide occasionally may be useful in some patients with type 2 diabetes mellitus who are unresponsive to other sulfonylurea antidiabetic agents. The manufacturer states that approximately one-third of patients with diabetes who are reported as primary or secondary failures to other sulfonylurea antidiabetic agents have reportedly responded to tolazamide. Some patients who have developed clinically important adverse effects or intolerance to other sulfonylureas may subsequently be successfully maintained on tolazamide. A therapeutic trial of at least 7 days should be used to determine if a patient will respond to tolazamide. If the patient is receiving other sulfonylurea antidiabetic agents, these drugs may be discontinued during the trial period; if the patient is receiving insulin, insulin should be slowly withdrawn as a therapeutic response to tolazamide is obtained. The prognosis for tolazamide therapy is favorable if a decrease in blood glucose concentration occurs, if glycosuria and ketonuria are diminished, and if symptoms such as pruritus, polyuria, polydipsia, and polyphagia subside during the trial period. The patient is considered nonresponsive to tolazamide therapy if ketonuria, increasing glycosuria, unsatisfactory lowering or persistent elevation of blood glucose concentrations occur; if severe adverse effects develop; or if the patient fails to show objective or subjective evidence of clinical improvement.
ADA generally recommends metformin as initial oral antidiabetic therapy because of the absence of weight gain or hypoglycemia, relatively low expense, and generally low adverse effect profile compared with other oral antidiabetic agents.186 (See Uses: Diabetes Mellitus, in Metformin 68:20.04.)
Although tolazamide initially may be effective in some patients with secondary failure to another sulfonylurea, response to tolazamide may not be sustained and secondary failure to tolazamide will eventually occur in some patients transferred to the drug. Secondary failure to sulfonylurea drugs is characterized by progressively decreasing diabetic control106 following 1 month to several years of good control.110, 160 Interim data from a substudy (UKPDS 26) of UKPDS in newly diagnosed type 2 diabetic patients receiving intensive therapy (maintenance of fasting plasma glucose below 108 mg/dL by increasing doses of either a sulfonylurea [i.e., glyburide or chlorpropamide] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide or symptoms of hyperglycemia) occurred overall at about 7% per year.109, 110 The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide.110 In UKPDS, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control.108, 110, 111, 117, 124, 127, 128 In another substudy (UKPDS 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.127 At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.110, 128
Tolazamide is not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.
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, thiazolidinedione derivatives, α-glucosidase inhibitors) 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. 166, 169, 170, 171, 172, 173, 174, 175, 177, 178 Combined therapy with oral antidiabetic agents generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy. 124, 147, 179, 180, 181, 182, 183, 186
For additional information on combination therapy with sulfonylureas and other oral antidiabetic agents, see the sections on combination therapy in Uses in the individual monographs in 68:20.
When lifestyle interventions, metformin, and a second oral antidiabetic agent are not effective in maintaining the target glycemic goal in patients with type 2 diabetes mellitus, ADA and other clinicians generally recommend the addition of insulin therapy.186, 188 In patients whose HbA1c is close to the target level (less than 8%) on metformin and a second oral antidiabetic agent, addition of a third oral antidiabetic agent instead of insulin may be considered.186 However, ADA states that triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy.186
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.136, 146, 147, 148, 149, 150, 159 In patients with a HbA1c exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times) 146, 147, 151, 154, 155, 157 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.136, 146, 147, 151, 152, 154, 155, 156, 157, 158, 159 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.154 However, combined therapy may increase the risk of hypoglycemic reactions.147, 148, 153, 154, 155
ADA and other clinicians state that combined therapy with insulin and metformin with or without other oral antidiabetic agents is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy with metformin, the preferred initial oral antidiabetic therapy.186 When patients are not controlled with metformin with or without other oral antidiabetic agents (i.e., sulfonylurea, thiazolidinedione) and basal insulin (e.g., given as intermediate- or long-acting insulin at bedtime or in the morning), therapy with insulin should be intensified by adding additional short-acting or rapid-acting insulin injections at mealtimes.186 Therapy with insulin secretagogues (i.e., sulfonylureas, meglitinides) should be tapered and discontinued when intensive insulin therapy is initiated, as insulin secretagogues do not appear to be synergistic with such insulin therapy.186, 188
Tolazamide is administered orally.
In patients receiving tolazamide dosages of 500 mg or less daily, the drug may usually be given as a single daily dose; however, in patients who require more than 500 mg daily, the drug usually should be administered as 2 divided doses daily.
Dosage of tolazamide is variable and should be individualized according to the severity of the disease; adult dosage ranges from 100 mg to 1 g daily. Patients who do not respond to 1 g daily usually will not respond to a higher dosage.
Dosage in Previously Untreated Patients
For the management of type 2 diabetes mellitus in patients not previously receiving insulin or sulfonylurea antidiabetic agents, the usual initial adult dosage of tolazamide is 100-250 mg daily given with breakfast; the manufacturer suggests that the initial dosage of tolazamide should be 100 mg daily in patients with fasting blood glucose concentrations less than 200 mg/dL, and 250 mg daily in patients with fasting blood glucose concentrations greater than 200 mg/dL. Because geriatric, underweight, or undernourished patients may be more sensitive to the hypoglycemic effect of tolazamide, the usual initial dosage in these patients should be 100 mg daily. Subsequent dosage adjustment should be made according to the patient's urinary glucose test results, weekly blood glucose determinations, and evaluations by the clinician; dosage may be increased or decreased, as necessary, by 100-250 mg daily at weekly intervals. To avoid hypoglycemic reactions, dosage should be increased by only 50-125 mg daily at weekly intervals in underweight, undernourished, or geriatric patients. Most patients require 250-500 mg daily. Maintenance dosage of tolazamide should be conservative in debilitated, malnourished, or geriatric patients or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients.
Dosage in Patients Transferred from Other Antidiabetic Agents
A transition period generally is not required when transferring from other sulfonylurea antidiabetic agents to tolazamide. For the management of type 2 diabetes mellitus in patients previously receiving daily tolbutamide dosages of 1 g or less, the usual initial adult dosage of tolazamide is 100 mg daily; in patients previously receiving more than 1 g of tolbutamide daily, the usual initial dosage of tolazamide is 250 mg daily.
In patients previously receiving chlorpropamide, the usual initial adult dosage of tolazamide is the same as the chlorpropamide dosa however, because of the prolonged elimination half-life of chlorpropamide, an exaggerated hypoglycemic response may occur in some patients during the transition to tolazamide and patients being transferred from chlorpropamide should be closely monitored for the occurrence of hypoglycemia during the initial 1- to 2-week transition period.
In patients previously receiving acetohexamide, the usual initial adult dosage of tolazamide is 100 mg daily for each 250 mg of acetohexamide daily.
In general, patients who were previously maintained on insulin dosages less than 40 units daily may be transferred directly to tolazamide and administration of insulin may be abruptly discontinued. In patients requiring insulin dosages greater than 40 units daily, insulin dosage should be reduced initially by 50% daily; subsequent adjustments of insulin dosage should be made according to the patient's therapeutic response to tolazamide. In patients previously receiving less than 20 units of insulin daily, the usual initial adult dosage of tolazamide is 100 mg daily; in patients previously receiving greater than 20 units of insulin daily, the usual initial adult dosage of tolazamide is 250 mg daily. Subsequent tolazamide dosage should be adjusted on a weekly basis (or more frequently in patients previously requiring more than 40 units of insulin daily) according to the patient's therapeutic response. During the period of insulin withdrawal, patients should test their urine at least 3 times a day for glucose and acetone, and should be instructed to report the results frequently to their physician so that appropriate adjustments in therapy may be made, if necessary; when feasible, patient or laboratory monitoring of blood glucose concentration is preferable. If substantial acetonuria occurs, or if the patient can not be completely transferred to tolazamide, tolazamide should be discontinued and insulin therapy reinstituted.
Nausea, vomiting, anorexia, intestinal gas, diarrhea, constipation, and cramps have occurred in patients receiving tolazamide. Various adverse nervous system effects including weakness, fatigue, lethargy, dizziness, vertigo, malaise, and headache have also been reported.
Hypersensitivity reactions including urticaria and rash have occurred in some patients receiving tolazamide. Tolazamide therapy has occasionally been associated with cholestatic jaundice and alterations in liver function test results (e.g., bilirubin, cholesterol, AST [SGOT], ALT [SGPT]). Transient increases in serum concentrations of alkaline phosphatase commonly occur following initiation of sulfonylurea therapy, but are usually not clinically important and may frequently occur in patients with diabetes.
Like other sulfonylurea drugs, tolazamide may rarely cause leukopenia, thrombocytopenia, agranulocytosis, and anemia; these adverse hematologic effects may be associated with urticaria and rash.
Hypoglycemia, which may be severe, has occurred in patients receiving tolazamide 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 tolazamide dosage are necessary; reduction of tolazamide dosage generally results in alleviation of most mild to moderately severe hypoglycemic symptoms.
Therapy with sulfonylureas, including tolazamide, may be associated with weight gain.143, 144, 145 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.143, 144, 145 Data from the United Kingdom Prospective Diabetes Study (UKPDS) 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 compared with those receiving glyburide.108
Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving tolazamide. Hyponatremia appears to occur more often in patients who concurrently are receiving other medications or have medical conditions known to cause hyponatremia or an increased release of vasopressin.
Photosensitivity reactions occur occasionally in patients receiving tolazamide.
Precautions and Contraindications
Tolazamide 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 generally are necessary with tolazamide. Tolazamide 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.
During the first 6 weeks of tolazamide 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 tolazamide 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; 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 tolazamide. Because of the spontaneous tendency of diabetes to fluctuate in severity, and because secondary failures may occur, patients receiving tolazamide should continue to be evaluated at regular intervals following the initial 6 weeks 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, 108, 109, 112, 125, 129, 130, 131 For information on these studies and associated recommendations, see Cautions: Precautions and Contraindications, in Glyburide 68:20.20. The American Diabetes Association (ADA) currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall.109, 119, 125
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 tolazamide 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 properly instructed in the early detection and treatment of hypoglycemia, since hypoglycemic reactions may occasionally occur during therapy with tolazamide. Debilitated, malnourished, or geriatric patients and patients with impaired hepatic and/or renal function should be carefully monitored and dosage of tolazamide 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.
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 tolazamide, may be required.
Tolazamide 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.
Tolazamide is contraindicated as sole therapy in patients with type 1 diabetes mellitus and in those with diabetes complicated by ketosis, acidosis, diabetic coma, or other acute complications such as major surgery, severe infection, or severe trauma. Tolazamide is not recommended in patients with concurrent liver, renal, or endocrine disease since the drug has not been studied extensively in these patients; tolazamide is contraindicated in patients with uremia.
Safety of tolazamide during pregnancy has not been established, and the manufacturer states that the drug is contraindicated during pregnancy. Tolazamide should be used with caution in women of childbearing age who may become pregnant.
Thiazide diuretics may exacerbate diabetes mellitus, resulting in increased requirements of sulfonylurea antidiabetic agents, temporary loss of diabetic control, or secondary failure to the antidiabetic agent. When thiazide diuretics are administered concomitantly with sulfonylurea antidiabetic agents, caution should be used.
Disulfiram-like reactions have occurred in some patients following the concomitant use of alcohol and tolazamide.
Concomitant use of certain antifungal antibiotics (i.e., miconazole, fluconazole) and oral antidiabetic agents has resulted in increased plasma concentrations of the oral antidiabetic agent and/or hypoglycemia.167 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.168 (See Drug Interactions: Sulfonylurea Antidiabetic Agents, in Fluconazole 8:14.08.)
The manufacturer cautions that insulin, sulfonamides, phenylbutazone, oxyphenbutazone, salicylates, probenecid, and monoamine oxidase inhibitors may enhance the hypoglycemic effect of tolazamide.
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. On a weight basis, tolazamide is approximately 5 times as potent as tolbutamide in patients with diabetes; in healthy, nondiabetic patients, tolazamide is 6.7 times as potent as tolbutamide.
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, tolazamide 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.
Tolazamide does not appear to have antidiuretic activity, but has reportedly caused a mild diuresis in some individuals.
Tolazamide is slowly but well absorbed from the GI tract following oral administration. Studies using radiolabeled tolazamide show only minimal interpatient variation in the absorption characteristics of the drug.
Following oral administration of therapeutic doses, peak blood tolazamide concentrations occur within 4-8 hours. Following oral administration of a single 500-mg tolazamide dose in healthy, fasting adults, peak hypoglycemic activity usually occurs within 1 hour and pharmacologic effects persist for 20 hours. Following oral administration of a single dose of tolazamide to fasting, diabetic patients, peak hypoglycemic activity occurs within 4-6 hours. In nonfasting patients with diabetes, the onset of hypoglycemic action of tolazamide occurs within 4-6 hours and the duration of maximum hypoglycemic activity is about 10 hours; blood glucose concentration begins to increase in these patients within 14-16 hours following oral administration of a single dose of the drug.
Following long-term administration of therapeutic doses of tolazamide, the drug does not accumulate in blood in most patients after 4-6 doses.
Distribution of tolazamide into human body tissues and fluids has not been fully characterized, but sulfonylurea drugs are distributed into extracellular fluids.
Tolazamide has a half-life of approximately 7 hours. Although the exact metabolic fate of tolazamide has not been clearly established, the drug is metabolized, probably in the liver, to two hydroxymetabolites, p -toluenesulfonamide, p -carboxytolazamide, and an unidentified metabolite; several of these metabolites are pharmacologically active. Tolazamide is excreted in urine principally as metabolites; small amounts are excreted in urine unchanged. Approximately 85% of a single oral dose of tolazamide is excreted in urine.
Tolazamide is a sulfonylurea antidiabetic agent. The drug is structurally similar to acetohexamide, chlorpropamide, and tolbutamide. Although chemically related to sulfonamides, tolazamide has no antibacterial activity.
Tolazamide occurs as a white to off-white, crystalline powder, is odorless or has a slight odor, and is very slightly soluble in water and slightly soluble in alcohol.
Commercially available tolazamide tablets should be stored at a controlled room temperature of 20-25°C.
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 | 250 mg* | Tolazamide Tablets | |
500 mg* | Tolazamide Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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