Tolbutamide

Tolbutamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Tolbutamide FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tolbutamide in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolbutamide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Tolbutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tolbutamide in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolbutamide in pediatric patients.

Contraindications

Tolbutamide tablets are contraindicated in patients with:

• Known hypersensitivity or allergy to the drug.
• Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
• Type I diabetes, as sole therapy.

Warnings

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-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.

• 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 2½ 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 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.

Adverse Reactions

Clinical Trials Experience

Hypoglycemia

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.

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.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.

Endocrine Reactions

Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.

Miscellaneous Reactions

• Headache and taste alterations have occasionally been reported with tolbutamide administration.

Postmarketing Experience

There is limited information regarding Tolbutamide Postmarketing Experience in the drug label.

Drug Interactions

• 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, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving 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, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Tolbutamide in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolbutamide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Tolbutamide during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Tolbutamide in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Tolbutamide in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Tolbutamide in geriatric settings.

Gender

There is no FDA guidance on the use of Tolbutamide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tolbutamide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Tolbutamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Tolbutamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tolbutamide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tolbutamide in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Tolbutamide Administration in the drug label.

Monitoring

There is limited information regarding Tolbutamide Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Tolbutamide and IV administrations.

Overdosage

Overdosage of sulfonylureas including 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.

Pharmacology

Mechanism of Action

• 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.

Structure

• 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 benzenesulfonamide, N-[(butylamino)-carbonyl]-4-methyl-. Its structure can be represented as follows:

This image is provided by the National Library of Medicine.

M.W. 270.35      C12H18N2O3S

• 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.

Pharmacodynamics

There is limited information regarding Tolbutamide Pharmacodynamics in the drug label.

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 20 minutes after oral ingestion of a 500 mg tolbutamide tablet, with peak levels occurring at 3 to 4 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 6 to 12 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 5 to 8 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.

Nonclinical Toxicology

Carcinogenicity and Mutagenicity

• Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of tolbutamide for 78 weeks. No evidence of carcinogenicity was found.

• Tolbutamide has also been demonstrated to be non mutagenic in the Ames salmonella/mammalian microsome mutagenicity test.

Clinical Studies

There is limited information regarding Tolbutamide Clinical Studies in the drug label.

How Supplied

• Tolbutamide Tablets, USP are available containing 500 mg of tolbutamide, USP. The tablets are white to off-white round, scored tablets debossed with M to the left of the score and 13 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:

• NDC 0378-0215-01

 bottles of 100 tablets

• NDC 0378-0215-05

 bottles of 500 tablets

Storage

Store at 20° to 25°C (68° to 77°F).

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Tolbutamide Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Tolbutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Tolbutamide Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Tolbutamide Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Tolbutamide

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Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	US FDA: Tolbutamide
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral (tablet)
ATC code	A10BB03 (WHO) V04CA01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	96%
Metabolism	Hepatic (CYP2C19-mediated)
Elimination half-life	4.5 to 6.5 hours
Excretion	Renal
Identifiers
IUPAC name 3-butyl-1-(4-methylphenyl)sulfonyl-urea
CAS Number	64-77-7
PubChem CID	5505
DrugBank	APRD00267
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C12H18N2O3S
Molar mass	270.349 g/mol

WikiDoc Resources for Tolbutamide
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Evidence Based Medicine
Cochrane Collaboration on Tolbutamide Bandolier on Tolbutamide TRIP on Tolbutamide
Clinical Trials
Ongoing Trials on Tolbutamide at Clinical Trials.gov Trial results on Tolbutamide Clinical Trials on Tolbutamide at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Tolbutamide NICE Guidance on Tolbutamide NHS PRODIGY Guidance FDA on Tolbutamide CDC on Tolbutamide
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For patient information, click here

Tolbutamide is a first generation potassium channel blocker, sulfonylurea oral hypoglycemic drug sold under the brand name Orinase. This drug may be used in the management of type II diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas. Since the pancreas must synthesize insulin in order for this drug to work, it is not effective in the management of type I diabetes. It is not routinely used due to a higher incidence of adverse effects compared to newer second generation sulfonylureas, such as glyburide.

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