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Pronunciation(tole BYOO ta mide)
SynonymsTolbutamide Sodium
Generic AvailableYes
Canadian Brand NamesApo-Tolbutamide®
UseAdjunct to diet for the management of mild to moderately severe, stable, type 2 diabetes mellitus (noninsulin dependent, NIDDM)
Pregnancy Risk FactorD
Pregnancy ImplicationsAbnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
LactationEnters breast milk/compatible
ContraindicationsHypersensitivity to tolbutamide, sulfonylureas, or any component of the formulation; diabetes complicated by ketoacidosis; treatment of type 1 diabetes; pregnancy
Warnings/PrecautionsFalse-positive response has been reported in patients with liver disease, idiopathic hypoglycemia of infancy, severe malnutrition, acute pancreatitis. Because of its low potency and short duration, it is a useful agent in the 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 end point. 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. 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.
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.
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Adverse ReactionsFrequency not defined. Cardiovascular: Venospasm
Central nervous system: Headache, dizziness
Dermatologic: Skin rash, urticaria, photosensitivity
Endocrine & metabolic: Hypoglycemia, SIADH
Gastrointestinal: Constipation, diarrhea, heartburn, anorexia, epigastric fullness, taste alteration
Hematologic: Aplastic anemia, hemolytic anemia, bone marrow suppression, thrombocytopenia, leukopenia, agranulocytosis
Hepatic: Cholestatic jaundice
Otic: Tinnitus
Miscellaneous: Hypersensitivity reaction, disulfiram-like reactions
Overdosage/ToxicologySymptoms of overdose include low blood sugar, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma. Treatment includes I.V. glucose (12.5-25 g), epinephrine for anaphylaxis.
Drug InteractionsSubstrate of CYP2C8/9 (major), 2C19 (minor); Inhibits CYP2C8/9 (strong) CYP2C8/9 inducers: May decrease the levels/effects of tolbutamide. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.
CYP2C8/9 inhibitors: May increase the levels/effects of tolbutamide. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.
CYP2C8/9 substrates: Tolbutamide may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.
Increased effects with salicylates, probenecid, MAO inhibitors, chloramphenicol, insulin, phenylbutazone, antidepressants, metformin, H2 antagonists, and others
Decreased effects:
Hypoglycemic effects may be decreased by beta-blockers, cholestyramine, hydantoins, thiazides, rifampin, and others
Ethanol may decrease the half-life of tolbutamide
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Ethanol/Nutrition/Herb InteractionsEthanol: Avoid ethanol (may cause hypoglycemia).
Herb/Nutraceutical: Avoid garlic, gymnema (may cause hypoglycemia).
Mechanism of ActionStimulates 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/KineticsOnset of action: Peak effect: Hypoglycemic action: Oral: 1-3 hours
Duration: Oral: 6-24 hours
Absorption: Oral: Rapid
Distribution: Vd: 6-10 L; increased with decreased albumin concentrations
Protein binding: 95% to 97%, primarily to albumin
Metabolism: Hepatic to hydroxymethyltolbutamide (mildly active) and carboxytolbutamide (inactive); metabolism does not appear to be affected by age
Half-life elimination: Plasma: 4-25 hours; Elimination: 4-9 hours
Time to peak, serum: 3-5 hours
Excretion: Urine (<2% as unchanged drug, primarily as metabolites)
DosageDivided doses may improve gastrointestinal tolerance Adults: Oral: Initial: 1-2 g/day as a single dose in the morning or in divided doses throughout the day. Total doses may be taken in the morning; however, divided doses may allow increased gastrointestinal tolerance. Maintenance dose: 0.25-3 g/day; however, a maintenance dose >2 g/day is seldom required.
Elderly: Oral: 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
AdministrationOral: Entire dose can be administered in AM, divided doses may improve GI tolerance
Monitoring ParametersFasting blood glucose, hemoglobin A1c or fructosamine
Reference RangeTarget range: Fasting blood glucose: <120 mg/dL
Adults: 80-140 mg/dL
Geriatrics: 100-150 mg/dL
Glycosylated hemoglobin: <7%
Patient EducationThis medication is used to control diabetes; it is not a cure. Inform prescriber of all other prescription or OTC medications you are taking; do not introduce new medication without consulting prescriber. Do not take other medication within 2 hours of this medication unless advised by prescriber. Other components of treatment plan are important: follow prescribed diet, medication, and exercise regimen. Take exactly as directed; at the same time each day. Do not change dose or discontinue without consulting prescriber. 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 (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). You may experience side effects during first weeks of therapy (headache, nausea, diarrhea, constipation, anorexia); consult prescriber is these persist. Report severe or persistent side effects, extended vomiting or flu-like symptoms, skin rash, easy bruising or bleeding, or change in color of urine or stool. Pregnancy precaution: Do not get pregnant; use appropriate contraceptive measures to prevent possible harm to the fetus.
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Nursing ImplicationsPatients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia
Cardiovascular ConsiderationsThe 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 diabetic patients treated with tolbutamide. Retrospective studies evaluating cardiovascular outcomes following angioplasty and acute myocardial infarction in diabetic patients 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 TreatmentUse salicylates with caution in patients taking tolazamide due to potential increased hypoglycemia; NSAIDs such as ibuprofen and naproxen may be safely used. Tolbutamide-dependent diabetics (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 PrecautionsNo information available to require special precautions
Mental Health: Effects on Mental StatusDizziness is common
Mental Health: Effects on Psychiatric TreatmentMay 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
Dosage FormsTablet: 500 mg
ReferencesAlexander RW, "Prolonged Hypoglycemia Following Acetohexamide Administration,"Diabetes, 1966, 15(5):362-4.
"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.
Cowen DL, Burtis B, and Youmans J, "Prolonged Coma After Acetohexamide Ingestion,"JAMA, 1967, 201(2):141-2.
"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.
"Standards of Medical Care for Patients With Diabetes Mellitus. American Diabetes Association,"Diabetes Care, 1994, 17(6):616-23.
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International Brand NamesApo-Tolbutamide® (CA); Arcosal® (DK); Butamide® (JP); Diaben® (JP); Diabetol® (PL); Diabetose® (JP); Diatol® (NZ); Diaval® (MX); Dirastan® (CZ); Orabet® (DE); Orsinon® (IL); Rastinon® (AU, HK, IE, LU, MX, NL); Tolbutamida L.CH.® (CL); Tolbutamid "Dak"® (DK); Tolbutamide® (GB); Tolbutamid R.A.N.® (DE); Tolbutamid® (RO); Tydadex® (ZA)
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