Skip to Content

ChlorproPAMIDE

Pronunciation

(klor PROE pa mide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 100 mg, 250 mg

Pharmacologic Category

  • Antidiabetic Agent, Sulfonylurea

Pharmacology

Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites

Absorption

Rapid

Distribution

Vd: 0.13-0.23 L/kg (Arrigoni, 1987)

Metabolism

Extensively hepatic (~80%), primarily via CYP2C9; forms metabolites

Excretion

Urine (unchanged drug and as hydroxylated or hydrolyzed metabolites)

Onset of Action

1 hour; Peak effect: 3-6 hours

Time to Peak

Serum: 2-4 hours

Duration of Action

24 hours

Half-Life Elimination

~36 hours, prolonged in elderly or with renal impairment; End-stage renal disease: 50-200 hours

Protein Binding

90%

Use: Labeled Indications

Management of blood sugar in type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise to lower blood glucose

Use: Unlabeled

Central (neurogenic) diabetes insipidus

Contraindications

Hypersensitivity to chlorpropamide or any component of the formulation; type 1 diabetes mellitus (insulin dependent, IDDM); diabetic ketoacidosis (with or without coma)

Dosing: Adult

Type 2 diabetes: Oral: The dosage of chlorpropamide is variable and should be individualized based upon the patient's response

Initial dose: 250 mg daily in mild-to-moderate diabetes in middle-aged, stable diabetic patients

Titration: After 5-7 days of initiation, subsequent daily dosages may be increased or decreased by 50-125 mg at 3- to 5-day intervals

Maintenance dose: 100-250 mg daily; severe patients with diabetes may require 500 mg daily; avoid doses >750 mg daily

Dosing: Geriatric

Reduce initial dose to 100 to 125 mg/day in older patients; after 5 to 7 days of initiation, subsequent daily dosages may be increased or decreased by 50 to 125 mg at 3- to 5-day intervals (slower upward titration may be appropriate in older patients).

Dosing: Renal Impairment

No specific dosage adjustment provided in manufacturer’s labeling; conservative initial and maintenance doses are recommended.

Alternate recommendations (Aronoff, 2007):

CrCl >50 mL/minute: Reduce dose by 50%.

CrCl <50 mL/minute: Avoid use.

Hemodialysis: Avoid use.

Peritoneal dialysis: Avoid use.

Continuous renal replacement therapy (CRRT): Avoid use.

Dosing: Hepatic Impairment

No specific dosage adjustment provided in manufacturer’s labeling; conservative initial and maintenance doses are recommended in patients with liver impairment since chlorpropamide undergoes extensive hepatic metabolism.

Administration

Administer once daily with breakfast. Daily dose may be divided to reduce GI upset. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.

Dietary Considerations

May cause GI upset; take with food.

Drug Interactions

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Monitor therapy

Allopurinol: May increase the serum concentration of ChlorproPAMIDE. Monitor therapy

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antidiabetic Agents (Thiazolidinedione): May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

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. Monitor therapy

Carbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chloramphenicol: May decrease the metabolism of Sulfonylureas. Monitor therapy

Cimetidine: May increase the serum concentration of Sulfonylureas. Monitor therapy

Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Fluconazole: May increase the serum concentration of Sulfonylureas. Management: Seek alternatives when possible. If used together, monitor closely for increased effects of sulfonylureas if fluconazole is initiated/dose increased, or decreased effects if fluconazole is discontinued/dose decreased. Consider therapy modification

GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Metreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. 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. Consider therapy modification

Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Avoid combination

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Probenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RaNITIdine: May increase the serum concentration of Sulfonylureas. Monitor therapy

RifAMPin: May decrease the serum concentration of Sulfonylureas. Management: Seek alternatives to these combinations when possible. Monitor closely for diminished therapeutic effects of sulfonylureas if rifampin is initiated/dose increased, or enhanced effects if rifampin is discontinued/dose decreased. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Urinary Acidifying Agents: May increase the serum concentration of ChlorproPAMIDE. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Voriconazole: May increase the serum concentration of Sulfonylureas. Monitor therapy

Adverse Reactions

Frequency not always defined.

Central nervous system: Disulfiram-like reaction, dizziness, headache

Dermatologic: Pruritus (<3%), maculopapular rash (≤1%), urticaria (≤1%), erythema multiforme, exfoliative dermatitis, skin photosensitivity

Endocrine & metabolic: Hepatic porphyria, hypoglycemia, porphyria cutanea tarda, SIADH (syndrome of inappropriate antidiuretic hormone secretion), weight gain

Gastrointestinal: Nausea (<5%), anorexia (<2%), diarrhea (<2%), hunger (<2%), vomiting (<2%)

Hematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia

Hepatic: Cholestatic jaundice, hepatic failure, hepatitis

<1% (Limited to important or life-threatening): Proctocolitis

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, 1998) 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. Autonomic neuropathy, advanced age, and concomitant use of beta-blockers or other sympatholytic agents may impair the patient’s ability to recognize the signs and symptoms of hypoglycemia; use with caution.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

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).

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.

Monitoring Parameters

Blood glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]); monitor for signs and symptoms of hypoglycemia (fatigue, sweating, numbness of extremities)

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Chlorpropamide crosses the placenta and measurable serum concentrations can be found in infants exposed in utero. Severe hypoglycemia lasting 4 to 10 days has been noted in infants born to mothers taking a sulfonylurea (including chlorpropamide) at the time of delivery; additional adverse events have also been reported and may be influenced by maternal glycemic control (Jackson 1962; Kemball 1970; Uhrig 1983; Zucker 1968).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013). The manufacturer recommends if chlorpropamide is used during pregnancy, it should be discontinued at least 1 month before the expected delivery date.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, headache, or nausea. Have patient report immediately to prescriber dark urine, jaundice, severe loss of strength and energy, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide