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ChlorproPAMIDE

Medically reviewed by Drugs.com. Last updated on Aug 29, 2020.

Pronunciation

(klor PROE pa mide)

Dosage Forms

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]

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

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 2020).

Off Label Uses

Central (neurogenic) diabetes insipidus

Data from a number of case reports and noncontrolled trials in patients with various forms of diabetes insipidus (including neurogenic diabetes insipidus) suggest that chlorpropamide may be beneficial for the treatment of central (neurogenic) diabetes insipidus [Cushard 1971], [Rado 1974], [Wales 1971], [Webster 1970].

Contraindications

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

Dosing: Adult

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)

Dosing: Geriatric

Avoid use (Beers Criteria [AGS 2019]).

Administration

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.

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

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). 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. Consider therapy modification

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

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

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

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

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

Chloramphenicol (Systemic): May increase the serum concentration 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 Inhibitors (Moderate): May increase the serum concentration of Sulfonylureas. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of ChlorproPAMIDE. Monitor therapy

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

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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 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). Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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

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

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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. Monitor therapy

RaNITIdine (Withdrawn from US Market): May increase the serum concentration of Sulfonylureas. Monitor therapy

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

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

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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. Consider therapy modification

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

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

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

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%, postmarketing, and/or case reports: 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. In patients with established atherosclerotic cardiovascular disease (ASCVD), other agents are preferred (ADA 2020).

• 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 2013). 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.

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 2020]); monitor for signs and symptoms of hypoglycemia (fatigue, sweating, blurred vision)

Pregnancy Considerations

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 birth defects, 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 2020; Blumer 2013).

Agents other than chlorpropamide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness

• Headache

• Upset stomach

• Feeling full

• Heartburn

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Dark urine

• Yellow skin or eyes

• Severe loss of strength and energy

• Chills

• Sore throat

• Bruising

• Bleeding

• Low blood sugar like dizziness, headache, feeling tired, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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