There is no fixed dosage regimen for the management of diabetes mellitus with tolazamide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy. Short-term administration of tolazamide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.<br/>Usual Starting Dose: The usual starting dose of tolazamide tablets for the mild to moderately severe type II diabetic patient is 100���250 mg daily administered with breakfast or the first main meal. Generally, if the fasting blood glucose is less than 200 mg/dL the starting dose is 100 mg/day as a single daily dose. If the fasting blood glucose value is greater than 200 mg/dL, the starting dose is 250 mg/day as a single dose. If the patient is malnourished, underweight, elderly, or not eating properly, the initial therapy should be 100 mg once a day. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimen are more prone to exhibit unsatisfactory response to drug therapy.<br/>Transfer from other Hypoglycemic Therapy:<br/>Patients Receiving Other Oral Antidiabetic Therapy-Transfer: Transfer of patients from other oral antidiabetes regimens to tolazamide should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to tolazamide, no transition period or initial or priming dose is necessary. When transferring from chlorpropamide, particular care should be exercised to avoid hypoglycemia.<br/>Patients Receiving Insulin: Some type II diabetic patients who have been treated only with insulin may respond satisfactorily to therapy with tolazamide. If the patient's previous insulin dosage has been less than 20 units, substitution of 100 mg of tolazamide per day as a single daily dose may be tried. If the previous insulin dosage was less than 40 units, but more than 20 units, the patient should be placed directly on 250 mg of tolazamide per day as a single dose. If the previous insulin dosage was greater than 40 units, the insulin dosage should be decreased by 50% and 250 mg of tolazamide per day started. The dosage of tolazamide should be adjusted weekly (or more often in the group previously requiring more than 40 units of insulin). During this conversion period when both insulin and tolazamide are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glucosuria indicates that the patient is a type I diabetic who requires insulin therapy.<br/>Maximum Dose: Daily doses of greater than 1000 mg are not recommended. Patients will generally have no further response to doses larger than this.<br/>Usual Maintenance Dose: The usual maintenance dose is in the range of 100���1000 mg/day with the average maintenance dose being 250���500 mg/day. Following initiation of therapy, dosage adjustment is made in increments of 100 mg to 250 mg at weekly intervals based on the patient's blood glucose response.<br/>Dosage Interval: Once a day therapy is usually satisfactory. Doses up to 500 mg/day should be given as a single dose in the morning. 500 mg once daily is as effective as 250 mg twice daily. When a dose of more than 500 mg/day is required, the dose may be divided and given twice daily. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions .
Tolazamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolazamide is a white or creamy-white powder very slightly soluble in water and slightly soluble in alcohol. The chemical name is 1-(Hexahydro-1-H-azepin-1-yl)-3-(p)-tolylsulfonyl) urea. Tolazamide has the following structural formula: Each tablet for oral administration contains 250 mg or 500 mg of tolazamide, USP and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium (Type A), magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
Actions: Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance.<br/>Pharmacokinetics: Tolazamide is rapidly and well absorbed from the gastrointestinal tract. Peak serum concentrations occur at three to four hours following a single oral dose of the drug. The average biological half-life of the drug is seven hours. The drug does not continue to accumulate in the blood after the first four to six doses are administered. A steady or equilibrium state is reached during which the peak and nadir values do not change from day to day after the fourth to sixth dose. Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0���70%. They are excreted principally in the urine. Following a single oral dose of tritiated tolazamide, 85% of the dose was excreted in the urine and 7% in the feces over a five day period. Most of the urinary excretion of the drug occurred within the first 24 hours postadministration. When normal fasting non-diabetic subjects are given a single 500 mg dose of tolazamide orally, a hypoglycemic effect can be noted within 20 minutes after ingestion with a peak hypoglycemic effect occurring in two to four hours. Following a single oral dose of 500 mg tolazamide, a statistically significant hypoglycemic effect was demonstrated in fasted nondiabetic subjects 20 hours after administration. With fasting diabetic patients, the peak hypoglycemic effect occurs at four to six hours. The duration of maximal hypoglycemic effect in fed diabetic patients is about ten hours, with the onset occurring at four to six hours and with the blood glucose levels beginning to rise at 14 to 16 hours. Single dose potency of tolazamide in normal subjects has been shown to be 6.7 times that of tolbutamide on a milligram basis. Clinical experience in diabetic patients has demonstrated tolazamide to be approximately five times more potent than tolbutamide on a milligram basis, and approximately equivalent in milligram potency to chlorpropamide.
Tolazamide is contraindicated in patients with:
Tolazamide tablets are available containing either 250 mg or 500 mg of tolazamide, USP. The 250 mg tablets are white to off-white, round, biconvex, scored tablets debossed with MYLAN above the score and 217 below the score on one side of the tablet and 250 on the other side. They are available as follows: NDC 0378-0217-01bottles of 100 tablets The 500 mg tablets are white to off-white, round, biconvex, scored tablets debossed with MYLAN above the score and 551 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-0551-01bottles of 100 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature]. Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Tolazamide tablets have generally been well tolerated. In clinical studies in which more than 1,784 diabetic patients were specifically evaluated for incidence of side effects only 2.1% were discontinued from therapy because of side effects.<br/>Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.<br/>Gastrointestinal Reactions: Cholestatic jaundice may occur rarely; tolazamide tablets should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occurred in 1% of patients treated during clinical trials. They tend to be dose-related and may disappear when dosage is reduced.<br/>Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, morbilliform or maculopapular eruptions, occurred in 0.4% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolazamide; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.<br/>Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.<br/>Metabolic Reactions: Hepatic porphyria and disulfiram-like reactions with tolazamide have been reported very rarely. Cases of hyponatremia have been reported with tolazamide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.<br/>Miscellaneous: Weakness, fatigue, dizziness, vertigo, malaise and headache were reported infrequently in patients treated during clinical trials. The relationship to therapy with tolazamide is difficult to assess.
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY:
Tolazamide is indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone. In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of tolazamide must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on a diet alone may be transient, thus requiring only short-term administration of tolazamide. During maintenance programs, tolazamide should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations. In considering the use of tolazamide in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.