Tolbutamide Information
Tolbutamide (Tolbutamide) Description
Tolbutamide (Tolbutamide) is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolbutamide (Tolbutamide) is a pure, white, crystalline compound which is practically insoluble in water. The chemical name is benzenesulfonamide, N-[(butylamino)-carbonyl]-4-methyl-. Its structure can be represented as follows:
Tolbutamide (Tolbutamide) is supplied as compressed tablets containing 500 mg of Tolbutamide (Tolbutamide) , USP.
Each tablet for oral administration contains 500 mg of Tolbutamide (Tolbutamide) and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.
Tolbutamide (Tolbutamide) Clinical Pharmacology
Tolbutamide (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 (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 (Tolbutamide) , may become unresponsive or poorly responsive over time. Alternatively, Tolbutamide (Tolbutamide) may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.
When administered orally, Tolbutamide (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 20 minutes after oral ingestion of a 500 mg Tolbutamide (Tolbutamide) tablet, with peak levels occurring at 3 to 4 hours and only small amounts detectable at 24 hours. The half-life of Tolbutamide (Tolbutamide) is 4.5 to 6.5 hours. As Tolbutamide (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 (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 (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 (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 (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 (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 (Tolbutamide) to either nondiabetic or Tolbutamide (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 (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 6 to 12 hours. Following the administration of a 3 gram dose of Tolbutamide (Tolbutamide) solution, Tolbutamide (Tolbutamide) responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between 5 to 8 hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24 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.
Tolbutamide (Tolbutamide) Indications And Usage
Tolbutamide (Tolbutamide) 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 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 (Tolbutamide) tablets 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 (Tolbutamide) tablets.
During maintenance programs, Tolbutamide (Tolbutamide) tablets 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 (Tolbutamide) tablets 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.
Tolbutamide (Tolbutamide) Contraindications
Tolbutamide (Tolbutamide) tablets are contraindicated in patients with:
Tolbutamide (Tolbutamide) Precautions
Patients should be informed of the potential risks and advantages of Tolbutamide (Tolbutamide) 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.
Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful.
A metabolite of Tolbutamide (Tolbutamide) in urine may give a false positive reaction for albumin if measured by the acidification-after-boiling test, which causes the metabolite to precipitate. There is no interference with the sulfosalicylic acid test.
The hypoglycemia action of sulfonylurea may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving Tolbutamide (Tolbutamide) , the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Tolbutamide (Tolbutamide) , the patient should be observed closely for loss of control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Tolbutamide (Tolbutamide) , the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Tolbutamide (Tolbutamide) , the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.
Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of Tolbutamide (Tolbutamide) for 78 weeks. No evidence of carcinogenicity was found.
Tolbutamide (Tolbutamide) has also been demonstrated to be nonmutagenic in the Ames salmonella/mammalian microsome mutagenicity test.
Tolbutamide (Tolbutamide) Adverse 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 (Tolbutamide) ; if skin reactions persist, the drug should be discontinued.
Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Tolbutamide (Tolbutamide) Overdosage
Overdosage of sulfonylureas including Tolbutamide (Tolbutamide) can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) dextrose injection. This should be followed by a continuous infusion of a more dilute (10%) dextrose injection at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.
Tolbutamide (Tolbutamide) Dosage And Administration
There is no fixed dosage regimen for the management of diabetes mellitus with Tolbutamide (Tolbutamide) tablets 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 (Tolbutamide) tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet.
Tolbutamide (Tolbutamide) How Supplied
Tolbutamide (Tolbutamide) Tablets, USP are available containing 500 mg of Tolbutamide (Tolbutamide) , USP. The tablets are white to off-white round, scored tablets debossed with to the left of the score andto the right of the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0215-01bottles of 100 tablets
NDC 0378-0215-05bottles of 500 tablets
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mylan Pharmaceuticals Inc.Morgantown, WV 26505
REVISED FEBRUARY 2009TOLB:R14
Tolbutamide (Tolbutamide)
100 Tablets
Each tablet containsTolbutamide (Tolbutamide) , USP 500 mg
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication outof the reach of children.
