Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4249
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Tolbutamide (Tablet)
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There is no fixed dosage regimen for the management of diabetes mellitus with tolbutamide 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 tolbutamide 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 is 1 to 2 grams daily. This may be increased or decreased, depending on individual patient response. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimens are more prone to exhibit unsatisfactory response to drug therapy.<br/>Transfer From Other Hypoglycemic Therapy:<br/>Patients Receiving Other Antidiabetic Therapy: Transfer of patients from other oral antidiabetes regimens to tolbutamide should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to tolbutamide, no transition period and no initial or priming doses are necessary. When transferring patients from chlorpropamide, however, particular care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide, in the body and the possibility that subsequent overlapping drug effects might provoke hypoglycemia.<br/>Patients Receiving Insulin: Patients requiring 20 units or less of insulin daily may be placed directly on tolbutamide and insulin abruptly discontinued. Patients whose insulin requirement is between 20 and 40 units daily may be started on therapy with tolbutamide with a concurrent 30 to 50% reduction in insulin dose, with further daily reduction of the insulin when response to tolbutamide is observed. In patients requiring more than 40 units of insulin daily, therapy with tolbutamide may be initiated in conjunction with a 20% reduction in insulin dose the first day, with further careful reduction of insulin as response is observed. Occasionally, conversion to tolbutamide in the hospital may be advisable in candidates who require more than 40 units of insulin daily. During this conversion period when bothinsulin and tolbutamide 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 type I diabetic who requires insulin therapy.<br/>Maximum Dose: Daily doses of greater than 3 grams are not recommended.<br/>Usual Maintenance Dose: The maintenance dose is in the range of 0.25���3 grams daily. Maintenance doses above 2 grams are seldom required.<br/>Dosage Interval: The total daily dose may be taken either in the morning or in divided doses through the day. While either schedule is usually effective, the divided dose system is preferred by some clinicians from the standpoint of digestive tolerance. 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 .
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Tolbutamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolbutamide is a pure, white, crystalline compound which is practically insoluble in water. The chemical name is benzene-sulfonamide, N-[(butylamino)-carbonyl]-4-methyl-. Its structure can be represented as follows: M.W. 270.35 CHNOS Tolbutamide is supplied as compressed tablets containing 500 mg of tolbutamide, USP. Each tablet for oral administration contains 500 mg of tolbutamide and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.
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Actions: Tolbutamide 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 tolbutamide 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 tolbutamide, may become unresponsive or poorly responsive over time. Alternatively, tolbutamide may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.<br/>Pharmacokinetics: When administered orally, tolbutamide is readily absorbed from the gastrointestinal tract. Absorption is not impaired and glucose lowering and insulin releasing effects are not altered if the drug is taken with food. Detectable levels are present in the plasma within twenty minutes after oral ingestion of a 500 mg tolbutamide tablet, with peak levels occurring at three to four hours and only small amounts detectable at 24 hours. The half-life of tolbutamide is 4.5 to 6.5 hours. As tolbutamide has no p-amino group, it cannot be acetylated, which is one of the common modes of metabolic degradation for the antibacterial sulfonamides. However, the presence of the p-methyl group renders tolbutamide susceptible to oxidation, and this appears to be the principal manner of its metabolic degradation in man. The p-methyl group is oxidized to form a carboxyl group, converting tolbutamide into the totally inactive metabolite 1-butyl-3-p-carboxy-phenylsulfonylurea, which can be recovered in the urine within 24 hours in amounts accounting for up to 75% of the administered dose. The major tolbutamide metabolite has been found to have no hypoglycemic or other action when administered orally and IV to both normal and diabetic subjects. This tolbutamide metabolite is highly soluble over the critical acid range of urinary pH values, and its solubility increases with increase in pH. Because of the marked solubility of the tolbutamide metabolite, crystalluria does not occur. A second metabolite, 1-butyl-3-(p-hydroxymethyl) phenyl sulfonylurea also occurs to a limited extent. It is an inactive metabolite. The administration of 3 grams of tolbutamide to either nondiabetic or tolbutamide-responsive diabetic subjects will, in both instances, occasion a gradual lowering of blood glucose. Increasing the dose to 6 grams does not usually cause a response which is significantly different from that produced by the 3 gram dose. Following the administration of a 3 gram dose of tolbutamide solution, non-diabetic fasting adults exhibit a 30% or greater reduction in blood glucose within one hour, following which the blood glucose gradually returns to the fasting level over six to twelve hours. Following the administration of a 3 gram dose of tolbutamide solution, tolbutamide responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between five to eight hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24th hour has usually returned to pretest levels. The magnitude of the reduction, when expressed in terms of percent of the pretest blood glucose, tends to be similar to the response seen in the nondiabetic subject.
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Tolbutamide is contraindicated in patients with:
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Tolbutamide tablets, USP are available containing 500 mg of tolbutamide. The tablets are white to off-white, scored, round tablets marked with M13. They are available as follows: NDC 0378-0215-01bottles of 100 tablets NDC 0378-0215-05bottles of 500 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.
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Tolbutamide
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Tolbutamide (Tablet)
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Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.<br/>Gastrointestinal Reactions: Cholestatic jaundice may occur rarely; tolbutamide should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.4% of patients treated during clinical trial. They tend to be dose-related and may disappear when dosage is reduced.<br/>Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.1% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolbutamide; 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 have been reported with sulfonylureas.<br/>Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.<br/>Miscellaneous Reactions: Headache and taste alterations have occasionally been reported with tolbutamide administration.
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SPECIAL WARNING 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 non-insulin-dependentdiabetes. 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 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 1/2 times that of patients treated 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 tolbutamide 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 standpointto 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.
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Tolbutamide 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 tolbutamide 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 tolbutamide. During maintenance programs, tolbutamide 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 tolbutamide 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.
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Tolbutamide
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