Prescription Drugs

CLINICAL PHARMACOLOGYActions 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 TOLINASE (tolazamide) Tablets, may become unresponsive or poorly responsive over time. Alternatively, TOLINASE (tolazamide) Tablets 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. 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 doses. Tolazamide is metabolized to five major metab-olites 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 post administration. When normal fasting nondiabetic 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 tolbu-tamide on a milligram basis. Clinical experience in diabetic patients has demonstrated tolazamide to be approximately five times more potent than tolbu-tamide on a milligram basis, and approximately equivalent in milligram potency to chlorpropamide.

Tolinase® (tolazamide) Tablets, USPDESCRIPTION TOLINASE Tablets contain tolazamide, an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide is a white or creamy-white powder with a melting point of 165° to 173° C. The sol-ubility of tolazamide at pH 6.0 (mean urinary pH) is 27.8 mg per 100 mL. The chemical names for tolazamide are (1) Ben-zenesulfonamide, N-[[(hexahydro-1H-azepin-1-yl) amino] carbonyl]-4-methyl-; (2) 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea and its molecular weight is 311.40. TOLINASE (tolazamide) Tablets for oral administration are available as scored, white tablets containing 100 mg, 250 mg or 500 mg tolazamide. Inactive ingredients: calcium sulfate, docusate sodium, magnesium stearate, methylcellulose, sodium alginate.

INDICATIONS TOLINASE (tolazamide) Tablets are 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 satisfactorily controlled by diet alone. In initiating treatment for noninsulin-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 sul-fonylurea or insulin should be considered. Use of TOLINASE (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 diet alone may be transient thus requiring only short-term administration of TOLINASE (tolazamide) . During maintenance programs, TOLINASE (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 TOLINASE (tolazamide) in asymp-tomatic patients, it should be recognized that controlling the blood glucose in noninsulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes. DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of diabetes mellitus with TOLINASE (tolazamide) Tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patientγ¢††s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of adequate blood glucose response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patientγ¢††s response to therapy. Short-term administration of TOLINASE (tolazamide) may be sufficient during periods of transient loss of control in patients usually controlled well on diet. Usual Starting Dose The usual starting dose of TOLINASE (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. Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapyγ¢††Transfer of patients from other oral antidiabetes regimens to TOLINASE (tolazamide) should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlor-propamide to TOLINASE (tolazamide) , no transition period or initial or priming dose is necessary. When transferring from chlorpropamide, particular care should be exercised to avoid hypoglycemia. Tolbutamide: If receiving less than 1 gm/day, begin at 100 mg of tolazamide per day. If receiving 1 gm or more per day, initiate at 250 mg of tolaza-mide per day as a single dose. Chlorpropamide: 250 mg of chlorpropamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of tolazamide. The patient should be observed carefully for hypoglycemia during the transition period from chlorpropamide to TOLINASE (tolazamide) (one to two weeks) due to the prolonged retention of chlor-propamide in the body and the possibility of a subsequent overlapping drug effect. Acetohexamide: 100 mg of tolazamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of ace-tohexamide. Patients Receiving Insulinγ¢††Some Type II diabetic patients who have been treated only with insulin may respond satisfactorily to therapy with TOLINASE (tolazamide) . If the patientγ¢††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 TOLINASE (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 TOLINASE (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 glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy. Maximum Dose Daily doses of greater than 1000 mg are not recommended. Patients will generally have no further response to doses larger than this. 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 patientγ¢††s blood glucose response. 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 hep-atic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). HOW SUPPLIED TOLINASE (tolazamide) Tablets are available in the following strengths and package sizes: 100 mg (white, round, scored, imprinted TOLINASE (tolazamide) 100) Unit-of-Use Bottles of 100 NDC 0009-0070-02 250 mg (white, round, scored, imprinted TOLINASE (tolazamide) 250) Bottles of 200 NDC 0009-0114-04 Bottles of 1000 NDC 0009-0114-02 Unit-of-Use Bottles of 100 NDC 0009-0114-05 500 mg (white, round, scored, imprinted TOLINASE (tolazamide) 500) Unit-of-Use Bottles of 100 NDC 0009-0477-06 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Pharmacia & Upjohn Company, Kalamazoo, Michigan 49001, USA, Revised January 2000

PATIENT INFORMATION Patients should be informed of the potential risks and advantages of TOLINASE (tolazamide) and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained. Laboratory Tests Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful in some patients. Please also refer to the WARNINGS and PREACAUTIONS sections.

WARNINGS SPECIAL WARNINGS ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with noninsulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (DIABETES, 19 (supp. 2):747-830, 1970.) UGDP reported that patients treated for five to eight years with diet plus a fixed dose of tolbu-tamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 21/2 times that of patients with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of TOLINASE (tolazamide) and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. PRECAUTIONSGeneral Hypoglycemia--All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of tolazamide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Loss of Control of Blood Glucoseγ¢††When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, loss of control of blood glucose may occur. At such times it may be necessary to discontinue TOLINASE (tolazamide) Tablets and administer insulin. The effectiveness of any hypoglycemic drug, including TOLINASE (tolazamide) , in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.