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Pronunciation
(klor PROE pa mide)
Generic Available (U.S.)
Yes
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of blood sugar in type 2 diabetes mellitus (noninsulin dependent, NIDDM)
Use: Unlabeled
Neurogenic diabetes insipidus
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal reproduction studies have not been conducted; therefore, the manufacturer classifies chlorpropamide as pregnancy category C. Chlorpropamide crosses the placenta and measurable serum concentrations can be found in infants exposed in utero. Teratogenic effects have been associated with chlorpropamide use in some studies; however, it is unknown if this is related to the medication or uncontrolled diabetes. Nonteratogenic adverse effects (eg, severe neonatal hypoglycemia, increased perianatal mortality) have also been associated with maternal chlorpropamide use. 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 chlorpropamide is used during pregnancy, it should be discontinued at least 1 month 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
Breast-Feeding Considerations
Chlorpropamide is found 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 chlorpropamide, sulfonylureas, sulfonamides, or any component of the formulation; type 1 diabetes mellitus (insulin dependent, IDDM); diabetic ketoacidosis
Warnings/Precautions
Concerns related to adverse effects:
• 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 or sulfonamide 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 issues:
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.
• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Special populations:
• Elderly: Avoid use in this age group due to prolonged half-life/hypoglycemia and risk of causing SIADH (Beers Criteria).
Other warnings/precautions:
• Long half-life: Patients should be properly instructed in the early detection and treatment of hypoglycemia; long half-life may complicate recovery from excess effects.
• Secondary failure: Loss of efficacy may be observed following prolonged use as a result of the progression of type 2 diabetes mellitus which results in continued beta cell destruction. In patients who were previously responding to sulfonylurea therapy, consider additional factors which may be contributing to decreased efficacy (eg, inappropriate dose, nonadherence to diet and exercise regimen). If no contributing factors can be identified, consider discontinuing use of the sulfonylurea due to secondary failure of treatment. Additional antidiabetic therapy (eg, insulin) will be required.
Adverse Reactions
Frequency not defined.
Central nervous system: Dizziness, headache
Dermatologic: Erythema multiforme, exfoliative dermatitis, maculopapular eruptions, photosensitivity, pruritus, urticaria
Endocrine & metabolic: Disulfiram-like reactions, hypoglycemia, SIADH
Gastrointestinal: Anorexia, diarrhea, hunger, nausea, proctocolitis, vomiting
Hematologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, leukopenia, pancytopenia, porphyria cutanea tarda, thrombocytopenia
Hepatic: Cholestatic jaundice, hepatic porphyria, hepatitis, liver failure
Metabolism/Transport Effects
Substrate of CYP2C9 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Risk C: Monitor therapy
Allopurinol: May increase the serum concentration of ChlorproPAMIDE. 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 (Strong): May increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. 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
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
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Mifepristone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. 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 chlorpropamide. 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
Pharmacodynamics/Kinetics
Onset of action: 1 hour
Peak effect: 3-6 hours
Duration: 24 hours
Absorption: Rapid
Distribution: Vd: 0.13-0.23 L/kg
Protein binding: 90%
Metabolism: Extensively hepatic (~80%), primarily via CYP2C9; forms metabolites
Half-life elimination: ~36 hours; prolonged in elderly or with renal impairment
End-stage renal disease: 50-200 hours
Time to peak, serum: 2-4 hours
Excretion: Urine
Dosage
Oral: The dosage of chlorpropamide is variable and should be individualized based upon the patient's response
Initial dose:
Adults: 250 mg/day in mild-to-moderate diabetes in middle-aged, stable diabetic
Elderly: 100-125 mg/day in older patients
Subsequent dosages may be increased or decreased by 50-125 mg/day at 3- to 5-day intervals
Maintenance dose: 100-250 mg/day; severe diabetics may require 500 mg/day; avoid doses >750 mg/day
Dosing adjustment/comments in renal impairment: Clcr <50 mL/minute: Avoid use
Hemodialysis: Removed with hemoperfusion
Peritoneal dialysis: Supplemental dose is not necessary
Dosing adjustment in hepatic impairment: Dosage reduction is recommended. Conservative initial and maintenance doses are recommended in patients with liver impairment because chlorpropamide undergoes extensive hepatic metabolism.
Administration: Oral
May be administered with food to reduce GI upset. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.
Monitoring Parameters
Blood glucose, Hgb A1c; monitor for signs and symptoms of hypoglycemia (fatigue, sweating, numbness of extremities)
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
Dietary Considerations
May cause GI upset; take with food.
Geriatric Considerations
Because of chlorpropamide's long half-life, duration of action, drug interactions, and the increased risk for hypoglycemia, it is not considered a hypoglycemic agent of choice in the elderly. Intensive glucose control (HbA1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. Patients who are unable to accurately draw up their dose will need assistance, such as prefilled syringes. Initial doses may require considerations for renal function in the elderly with dosing adjusted subsequently based on blood glucose monitoring. 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.
This medication is considered to be potentially inappropriate in this patient population (Beers Criteria: Quality of evidence - high; Strength of recommendation - strong).
Anesthesia and Critical Care Concerns/Other Considerations
Long half-life may complicate recovery from excess effects. Patients previously maintained on insulin at <40 units/day may be directly changed to chlorpropamide. Patients previously receiving larger insulin doses should have their insulin doses decreased by 50% daily for the first few days, then gradually reduced further as necessary.
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
Chlorpropamide-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
Rare reports of agranulocytosis; use caution with clozapine and carbamazepine
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 100 mg, 250 mg
Pricing: U.S. (www.drugstore.com)
Tablets (ChlorproPAMIDE)
100 mg (60): $17.24
250 mg (60): $20.99
References
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2012,” Diabetes Care, 2012, 35(Suppl ):11-63.
"American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults," J Am Geriatr Soc, 2012 [epub ahead of print].
Arrigoni L, Fundak G, Horn J, et al, “Chlorpropamide Pharmacokinetics in Young Healthy Adults and Older Diabetic Patients,” Clin Pharm, 1987, 6(2):162-4.
“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.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, "Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada," Can J Diabetes, 20078, 32(suppl 1):1-201.
“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.
Erickson T, Arora A, Lebby TI, et al, “Acute Oral Hypoglycemic Ingestions,” Vet Hum Toxicol, 1991, 33(3):256-8.
Forrest JAH, “Chlorpropamide Overdosage: Delayed and Prolonged Hypoglycemia,” Clin Toxicol, 1974, 7(1):19-24.
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.
Gordon MR, Flockhart D, Zawadzki JK, et al, “Hypoglycemia Due to Inadvertent Dispensing of Chlorpropamide,” Am J Med, 1988, 85(2):271-2.
Graw RG and Clarke RR, “Chlorpropamide Intoxication - Treatment With Peritoneal Dialysis,” Pediatrics, 1970, 45(1):106-8.
“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.
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.
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.
Seltzer HS, “Drug-Induced Hypoglycemia. A Review of 1418 Cases,” Endocrinol Metab Clin North Am, 1989, 18(1):163-83.
Verbalis JG, “Diabetes Insipidus,” Rev Endocr Metab Disord, 2003, 4(2):177-85.
International Brand Names
Lexi-Comp.com
Last full review/revision April 2012
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