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Pronunciation
(tole BYOO ta mide)
Generic Available (U.S.)
Yes
Index Terms
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunct to diet for the management of type 2 diabetes mellitus (noninsulin dependent, NIDDM)
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events have been observed in animal studies; therefore, tolbutamide is classified as pregnancy category C. Tolbutamide crosses the placenta and levels can be measured in the serum of newborn infants following maternal use during pregnancy. Teratogenic effects have been noted in some case reports. Prolonged hyperinsulinemic hypoglycemia has been reported in an infant following maternal use of tolbutamide and severe hypoglycemia lasting 4-10 days has been noted in infants born to mothers taking a sulfonylurea at the time of delivery. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may in turn negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Until additional safety and efficacy data are obtained, the use of oral agents is generally not recommended as routine management of GDM or type 2 diabetes mellitus during pregnancy. The manufacturer recommends if tolbutamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
Lactation
Enters breast milk/not recommended (AAP rates "compatible"; AAP 2001 update pending)
Breast-Feeding Considerations
Tolbutamide is excreted in breast milk. Breast-feeding is not recommended by the manufacturer. Potentially, hypoglycemia may occur in a nursing infant exposed to a sulfonylurea via breast milk.
Contraindications
Hypersensitivity to tolbutamide, sulfonylureas, or any component of the formulation; treatment of type 1 diabetes; diabetic ketoacidosis
Warnings/Precautions
Concerns related to adverse reactions:
• Cardiovascular mortality: Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS) have not supported an association.
• Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function; use with caution.
• Sulfonamide allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonylurea allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.
Disease-related concerns:
• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Adverse Reactions
Frequency not defined.
Central nervous system: Headache
Dermatologic: Erythema, maculopapular rash, morbilliform rash, pruritus, urticaria, photosensitivity
Endocrine & metabolic: Disulfiram-like reactions, hypoglycemia, hyponatremia, SIADH
Gastrointestinal: Epigastric fullness, heartburn, nausea, taste alteration
Hematologic: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia
Hepatic: Cholestatic jaundice, hepatic porphyria, porphyria cutanea tarda
Miscellaneous: Hypersensitivity reaction
Metabolism/Transport Effects
Substrate of CYP2C9 (major), 2C19 (minor); Inhibits CYP2C8 (weak), 2C9 (strong)
Drug Interactions
Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Risk C: Monitor therapy
Aprepitant: May decrease the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Chloramphenicol: May decrease the metabolism of Sulfonylureas. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Fluconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Fosaprepitant: May decrease the serum concentration of TOLBUTamide. Risk C: Monitor therapy
GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with GLP-1 agonists. Risk D: Consider therapy modification
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Leflunomide: May increase the serum concentration of TOLBUTamide. Specifically, the active metabolite of leflunomide (M1) may both increase total tolbutamide concentrations and increase the free fraction (i.e., non-protein bound) of tolbutamide. TOLBUTamide may increase the serum concentration of Leflunomide. Specifically, tolbutamide may increase the proportion of non-protein-bound (i.e., free fraction) M1, which is the active metabolite of leflunomide. Risk C: Monitor therapy
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Quinolone Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. This appears to be particularly concerning early in the course of combination therapy. Quinolone Antibiotics may diminish the hypoglycemic effect of Sulfonylureas. With longer-term combination, there is a greater risk of hyperglycemia. Risk C: Monitor therapy
Ranitidine: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Rifampin: May increase the metabolism of Sulfonylureas. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Sulfonylureas. Of concern with regular, higher doses of salicylates, not sporadic, low doses. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Exceptions: Sulfacetamide. Risk C: Monitor therapy
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (possible disulfiram-like reaction).
Herb/Nutraceutical: Herbs with hypoglycemic properties may enhance the hypoglycemic effect of tolbutamide. This includes alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, stinging nettle.
Mechanism of Action
Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites, suppression of glucagon may also contribute
Pharmacodynamics/Kinetics
Onset of action: 1 hour
Duration: Oral: 6-24 hours
Absorption: Oral: Rapid
Distribution: Vd: 0.15 L/kg
Protein binding: ~95% (concentration dependent)
Metabolism: Hepatic via CYP2C9 to hydroxymethyltolbutamide (mildly active) and carboxytolbutamide (inactive); metabolism does not appear to be affected by age
Half-life elimination: 4.5-6.5 hours (range: 4-25 hours)
Time to peak, serum: 3-4 hours
Excretion: Urine (75% to 85% primarily as metabolites); feces
Dosage
Oral: Note: Divided doses may improve gastrointestinal tolerance.
Adults: Initial: 1-2 g/day as a single dose in the morning or in divided doses throughout the day. Maintenance dose: 0.25-3 g/day; however, a maintenance dose >2 g/day is seldom required.
Elderly: Initial: 250 mg 1-3 times/day; usual: 500-2000 mg; maximum: 3 g/day
Dosing adjustment in renal impairment: Adjustment is not necessary
Hemodialysis: Not dialyzable (0% to 5%)
Dosing adjustment in hepatic impairment: Reduction of dose may be necessary in patients with impaired liver function
Administration: Oral
Entire dose can be administered in AM, divided doses may improve GI tolerance.
Monitoring Parameters
Blood glucose, hemoglobin A1c; signs and symptoms of hypoglycemia
Reference Range
Recommendations for glycemic control in adults with diabetes:
Hb A1c: <7%
Preprandial capillary plasma glucose: 70-130 mg/dL
Peak postprandial capillary blood glucose: <180 mg/dL
Blood pressure: <130/80 mm Hg
Patient Education
This medication is used to control diabetes; it is not a cure. Other components of diabetic treatment plan are important; follow prescribed diet, medication, and exercise regimen. Take at the same time each day. Avoid alcohol while taking this medication; could cause severe reaction. If you experience hypoglycemic reaction, contact prescriber immediately. Maintain regular dietary intake and exercise routine and always carry quick source of sugar with you. You may be more sensitive to sunlight. You may experience side effects during first weeks of therapy (headache, nausea, diarrhea, constipation, anorexia); consult prescriber if these persist. Report extended vomiting or flu-like symptoms, skin rash, easy bruising or bleeding, or change in color of urine or stool.
Geriatric Considerations
Because of its low potency and short duration, it is a useful agent in elderly if drug interactions can be avoided. How “tightly” an elderly patient's blood glucose should be controlled is controversial; however, a fasting blood sugar <150 mg/dL is now an acceptable endpoint. Such a decision should be based on the patient's functional and cognitive status, how well they recognize hypoglycemic or hyperglycemic symptoms, and how to respond to them and their other disease states. Intensive glucose control (Hb A1c <6.5%) has been linked to increased all cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.
Cardiovascular Considerations
The possibility of higher doses of sulfonylureas eliciting an increase in cardiovascular events, because of their effects on blocking potassium sensitive ATP channels, has been raised. However, there are presently only limited data to support this premise, particularly with newer generation agents. An early study suggested poor cardiovascular outcomes in patients with diabetes treated with tolbutamide. Retrospective studies evaluating cardiovascular outcomes following angioplasty and acute myocardial infarction in patients with diabetes receiving newer sulfonylureas are inconsistent. Longer-term prospective trials of sulfonylurea therapy, such as the UKPDS, do not reveal any increased cardiovascular mortality.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Taste alteration.
Use salicylates with caution in patients taking tolazamide due to potential increased hypoglycemia; NSAIDs such as ibuprofen and naproxen may be safely used. Tolbutamide-dependent patients with diabetes (noninsulin dependent, type 2) should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Dizziness is common
Mental Health: Effects on Psychiatric Treatment
May cause agranulocytosis; use caution with clozapine and carbamazepine; concurrent use with psychotropics may produce alterations in serum glucose concentrations; monitor glucose; clinical manifestation of hypoglycemia may be blocked by beta-blockers
Nursing: Physical Assessment/Monitoring
Monitor for hypoglycemia.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 500 mg
Pricing: U.S. (www.drugstore.com)
Tablets (TOLBUTamide)
500 mg (60): $33.99
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2011,” Diabetes Care, 2011, 34(Suppl 1):11-61.
“A Study of the Effects of Hypoglycemia Agents on Vascular Complications in Patients With Adult-Onset Diabetes. VI. Supplementary Report on Nonfatal Events in Patients Treated With Tolbutamide. The University Group Diabetes Program,” Diabetes, 1976, 25(12):1129-53.
“Effect of Intensive Blood-Glucose Control With Metformin on Complications in Overweight Patients With Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group,” Lancet, 1998, 352(9131):854-65.
Garratt KN, Brady PA, Hassinger NL, et al, “Sulfonylurea Drugs Increase Early Mortality in Patients With Diabetes Mellitus After Direct Angioplasty for Acute Myocardial Infarction,” J Am Coll Cardiol, 1999, 33(1):119-24.
Huupponen R, “Adverse Cardiovascular Effects of Sulphonylurea Drugs. Clinical Significance,” Med Toxicol, 1987, 2(3):190-209.
“Intensive Blood-Glucose Control With Sulphonylureas or Insulin Compared With Conventional Treatment and Risk of Complications in Patients With Type 2 Diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group,” Lancet, 1998, 352(9131):837-53.
Klamann A, Sarfert P, Launhardt V, et al, “Myocardial Infarction in Diabetic vs Nondiabetic Subjects. Survival and Infarct Size Following Therapy With Sulfonylureas (Glibenclamide),” Eur Heart J, 2000, 21(3):220-9.
Lazner J, “Fatal Hypoglycaemia From Tolbutamide in a Nondiabetic Patient,” Med J Aust, 1970, 1:327-8.
Meinert CL, Knatterud GL, Prout TE, et al, “A Study of the Effects of Hypoglycemic Agents on Vascular Complications in Patients With Adult-Onset Diabetes. II. Mortality Results,” Diabetes, 1970, 19:789-830.
Miller AK, Adir J, and Vestal RE, “Effect of Age on the Pharmacokinetics of Tolbutamide in Man,” Pharmacologist, 1977, 19:128.
Miller AK, Adir J, and Vestal RE, “Tolbutamide Binding to Plasma Proteins of Young and Old Human Subjects,” J Pharm Sci, 1978, 67(8):1192-3.
O'Keefe JH, Blackstone EH, Sergeant P, et al, “The Optimal Mode of Coronary Revascularization for Diabetics. A Risk-Adjusted Long-Term Study Comparing Coronary Angioplasty and Coronary Bypass Surgery,” Eur Heart J, 1998, 19(11):1696-703.
Seger D, “Toxic Emergencies of Endocrine and Metabolic Therapeutic Agents,” J Emerg Med, 1988, 6(6):527-37.
Seltzer HS, “Drug-Induced Hypoglycemia: A Review Based on 473 Cases,” Diabetes, 1972, 21(9):955-66.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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