Diabetes mellitus, type 2: Oral:
Initial: 250 mg once daily or in divided doses if GI intolerance occurs; consider conservative doses for malnourished or debilitated patients
Titration: 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
Maintenance: 100 to 250 mg once daily or in divided doses if GI intolerance occurs; doses ≤100 mg/day may be adequate in some mildly diabetic patients; severely diabetic patients may require 500 mg/day; avoid doses >750 mg/day
Central (neurogenic) diabetes insipidus (off-label) : Note: Very limited data: Oral: 125 to 250 mg once or twice daily; higher dosages may produce additional antidiuretic effect but may also be associated with increased hypoglycemia (Cushard 1971; Wales 1971; Webster 1970)
There are no specific dosage adjustments provided in the 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.
There are no specific dosage adjustments provided in the manufacturer’s labeling; conservative initial and maintenance doses are recommended in patients with liver impairment since chlorpropamide undergoes extensive hepatic metabolism.
Avoid use (Beers Criteria [AGS 2019]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Generic: 100 mg [DSC], 250 mg [DSC]
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 100 mg, 250 mg
Oral: 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.
Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Guideline recommendations: First-generation sulfonylureas (eg, chlorpropamide) are not recommended treatment options for type 2 diabetes; later generation sulfonylureas with lower hypoglycemic risks (eg, glipizide) are preferred (ADA 2021).
Central (neurogenic) diabetes insipidus
ChlorproPAMIDE may be confused with chlorproMAZINE
Diabinese may be confused with DiaBeta
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Beers Criteria: Chlorpropamide is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) because of its prolonged half-life in older adults, which may cause prolonged hypoglycemia. In addition, chlorpropamide may cause syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Beers Criteria [AGS 2019]).
Pharmacy Quality Alliance (PQA): Chlorpropamide is identified as a high-risk medication in patients 65 years and older on the PQA's Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) Star Rating System for Medicare plans (PQA 2017).
Diabinese [Multiple international markets] may be confused with Diamox brand name for acetazolamide [Canadan, multiple international markets]
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
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%, postmarketing, and/or case reports: Proctocolitis
Hypersensitivity to chlorpropamide or any component of the formulation; type 1 diabetes mellitus; diabetic ketoacidosis (with or without coma)
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. In patients with established atherosclerotic cardiovascular disease (ASCVD), other agents are preferred (ADA 2021).
• 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:
• Bariatric surgery:
– Altered absorption: Use IR formulations after surgery to minimize the potential effects of bypassing stomach and proximal small bowel with gastric bypass or more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Apovian 2015). ER formulations may have altered release and absorption patterns after gastric bypass or sleeve gastrectomy (but not gastric band). Compared to control, Tmax in a gastric bypass cohort administered tolbutamide was significantly shorter (1.4 ± 1.8 vs 5.1±1.7 hours; P < 0.001), while Cmax and AUC0-∞ were not altered (Tandra 2013).
– Hypoglycemia: Use an antidiabetic agent without the potential for hypoglycemia if possible; hypoglycemia may occur after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period postsurgery (Mingrone 2016).
– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).
• 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.
Substrate of CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Risk C: Monitor therapy
Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Alpha-Glucosidase Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with an alpha-glucosidase inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amiodarone: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. 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. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Sulfonylureas. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Sulfonylureas. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: 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. Risk C: Monitor therapy
Chloramphenicol (Systemic): May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Clarithromycin: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of ChlorproPAMIDE. Risk C: Monitor therapy
Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Risk C: Monitor therapy
Dipeptidyl Peptidase-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. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Risk D: Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Risk X: Avoid combination
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
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 for signs or symptoms of hypoglycemia. Risk D: Consider therapy modification
Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Risk X: Avoid combination
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Probenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sodium-Glucose Cotransporter 2 (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. Risk D: Consider therapy modification
Sulfonamide Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Tetracyclines: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Thiazolidinediones: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Risk D: Consider therapy modification
Urinary Acidifying Agents: May increase the serum concentration of ChlorproPAMIDE. Risk C: Monitor therapy
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: 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. Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Possible disulfiram-like reaction may occur with concurrent ethanol use. Management: Monitor patients.
Sulfonylureas are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)
Chlorpropamide crosses the placenta.
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). The manufacturer recommends if chlorpropamide is used during pregnancy, it should be discontinued at least 1 month before the expected delivery date.
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia (ACOG 201 2018). 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 (ADA 2021; Blumer 2013).
Agents other than chlorpropamide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
Chlorpropamide is present in breast milk.
Breastfeeding is not recommended by the manufacturer.
May cause GI upset; take with food.
Blood glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors; some patients may be candidates for continuous glucose monitoring) (ADA 2021); monitor for signs and symptoms of hypoglycemia (fatigue, sweating, blurred vision).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults with diabetes (ADA 2021):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2021):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (LeRoith 2019).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Classification of hypoglycemia (ADA 2021):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites
Onset of action: 1 hour
Peak effect: 3-6 hours
Duration: 24 hours
Absorption: Rapid
Distribution: Vd: 0.13-0.23 L/kg (Arrigoni 1987)
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 (unchanged drug and as hydroxylated or hydrolyzed metabolites)
Tablets (chlorproPAMIDE Oral)
100 mg (per each): $1.20
250 mg (per each): $2.54
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