Chlorpropamide

Class: Sulfonylureas
ATC Class: A10BB02
VA Class: HS502
CAS Number: 94-20-2
Brands: Diabinese

Introduction

Antidiabetic agent; sulfonylurea.

Uses for Chlorpropamide

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for management of type 2 (noninsulin-dependent) diabetes mellitus in patients whose hyperglycemia cannot be controlled with diet and exercise alone.

Used as second-line therapy in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus in whom adequate glycemic control cannot be achieved with oral antidiabetic agent monotherapy.

Alternative therapy in some type 2 diabetic patients being treated with insulin or other antidiabetic agent(s). Useful in combination with insulin to improve glycemic control and/or decrease insulin dosage in some type 2 diabetic patients.

Not effective as sole therapy in patients with type 1 diabetes mellitus or diabetic acidosis, ketosis, or coma; insulin is necessary. (See Contraindications under Cautions.)

Not routinely recommended in hospitalized patients with diabetes mellitus. Long duration of action precludes rapid dosage adjustments. Increased risk of hypoglycemia in hospitalized diabetic patients with irregular eating patterns.

Chlorpropamide Dosage and Administration

General

Adjust dosage according to severity of disease, tolerance, and blood glucose determinations.
Monitor regularly (e.g., blood glucose concentrations) to determine minimum effective dosage and to detect primary failure or secondary failure. (See Loss of Glycemic Control under Cautions.)
Monitor glycosylated hemoglobin (HbA_1c) to determine patient’s continued response to therapy.
Administration of loading dose is not recommended.
During transfer from insulin therapy, patients should test their blood glucose concentrations ≥3 times daily. (See Advice to Patients.) Early hypoglycemia (≤24 hours) following transfer from intermediate or long-acting insulins usually results from insulin carry-over rather than from chlorpropamide. In some patients, consider hospitalization during transition period.

Administration

Oral Administration

Administer orally as a single daily dose each morning with breakfast. May administer in 2 divided doses if GI intolerance occurs.

Dosage

Adults

Diabetes Mellitus

Initiation

Oral

Initially, 250 mg daily.

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents

Oral

Initially, 250 mg daily. May abruptly discontinue the other oral antidiabetic agent.

Initial Dosage in Patients Transferred from Insulin

Oral

Insulin requirements ≤40 units daily: Initially, 250 mg daily. Abruptly discontinue insulin.

Insulin requirements >40 units daily: Initially, 250 mg daily; reduce daily insulin dosage by 50% for first few days. Subsequently, adjust insulin dosage according to therapeutic response.

Titration and Maintenance Dosage

Oral

5–7 days after initiating therapy, titrate dosage in increments or decrements of ≤50–125 mg daily at 3- to 5-day intervals to achieve adequate glycemic control; more frequent dosage adjustments usually undesirable.

Usual maintenance dosage is 100–500 mg daily. Patients not responding to 500 mg daily are unlikely to respond to higher dosages.

Prescribing Limits

Adults

Diabetes Mellitus

Oral

Maximum 750 mg daily.

Special Populations

Hepatic Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia. (See Hepatic Impairment under Cautions.)

Renal Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia. (See Renal Impairment under Cautions.)

Geriatric Patients

Initially, 100–125 mg daily. Use conservative initial and maintenance dosages to avoid hypoglycemia. (See Geriatric Use under Cautions.)

Debilitated or Malnourished Patients

Use conservative initial and maintenance dosages to avoid hypoglycemia.

Pituitary or Adrenal Insufficiency

Use conservative initial and maintenance dosages to avoid hypoglycemia.

Cautions for Chlorpropamide

Contraindications

Known hypersensitivity to chlorpropamide or any ingredient in formulation.
Diabetic ketoacidosis with or without coma.
Monotherapy for type 1 diabetes mellitus.

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased cardiovascular mortality reported with certain other antidiabetic agents (i.e., tolbutamide, phenformin). However, ADA considers benefits of intensive glycemic control with insulin or sulfonylureas to outweigh the risks overall.

General Precautions

Hypoglycemia

Possible severe hypoglycemia, especially in geriatric, debilitated, or malnourished patients and those with adrenal, pituitary, hepatic, or renal insufficiency. Increased risk of hypoglycemia with strenuous exercise, alcohol ingestion, insufficient caloric intake, or concurrent drug use (e.g., other antidiabetic agents, agents that enhance hypoglycemic effects). (See Specific Drugs under Interactions.)

Higher incidence of hypoglycemia at therapeutic dosages with chlorpropamide than other sulfonylureas; may result from prolonged duration of action. (See Duration under Pharmacokinetics.)

Hypoglycemia may be difficult to recognize in geriatric patients and those receiving β-adrenergic blocking agents.

Appropriate patient selection and careful dosing and instructions are important to avoid chlorpropamide-induced hypoglycemia.

Hypoglycemia may result in coma, seizures, or other neurologic impairment.

If hypoglycemia occurs, immediately reevaluate patient and adjust insulin or chlorpropamide dosage. Monitor patient for 24–48 hours; may require hospitalization and IV glucose. Carefully supervise dose and give frequent feedings for ≥3–5 days.

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery). May require use of insulin and/or temporary discontinuance of chlorpropamide.

Efficacy of therapy may decrease over time (secondary failure); evaluate patients at regular intervals.

Assess patient for adequate adjustment of dose and adherence to diet before attributing inadequate response to secondary failure of the drug.

Manufacturer recommends discontinuance of chlorpropamide if loss of satisfactory glycemic control develops. ADA and other clinicians recommend addition of other oral antidiabetic agents or insulin. (See Diabetes Mellitus under Uses.)

Specific Populations

Pregnancy

Category C.

Prolonged (4–10 days), severe hypoglycemia reported in some neonates born to women receiving a sulfonylurea at delivery; more frequent with long-acting sulfonylureas (e.g., chlorpropamide). Discontinue drug ≥1 month before expected delivery date to minimize the risk of neonatal hypoglycemia.

Many experts recommend the use of insulin during pregnancy.

Lactation

Distributed into milk. Use not recommended.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Safety and efficacy not established. Increased risk of hypoglycemia and/or hyponatremia; hypoglycemia may be difficult to recognize. Cautious dosing recommended. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Diminished gluconeogenic capacity and increased risk of hypoglycemia; conservative dosing recommended. (See Hepatic Impairment under Dosage and Administration.)

Monitor liver function frequently during chlorpropamide initiation.

Renal Impairment

Increased risk of hypoglycemia; conservative dosing recommended. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Hypoglycemia, nausea, weight gain.

Interactions for Chlorpropamide

Metabolized mainly by CYP2C9. (See Elimination under Pharmacokinetics.)

Protein-bound Drugs

Potential pharmacokinetic interaction (increased hypoglycemic effect because of displacement of chlorpropamide from binding sites on proteins). (See Specific Drugs under Interactions.)

Close observation recommended when initiating or discontinuing concomitant therapy with a highly protein-bound drug.

Specific Drugs

Drug	Interaction	Comments
Alcohol	Disulfiram-like reactions reported Moderate-to-large amounts of alcohol may increase the risk of hypoglycemia	If intolerant, attempt therapy with another sulfonylurea agent
Antifungals, oral azoles (i.e., fluconazole, miconazole)	Increased plasma concentrations of sulfonylureas and hypoglycemic effect	Not known whether interaction occurs with IV, topical, or vaginal miconazole
Anticoagulants, oral	Possible potentiation of hypoglycemic effects	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued
Barbiturates	May prolong action of barbiturates	Use concurrently with caution
β-Adrenergic blocking agents	Possible potentiation of hypoglycemic effects Signs of hypoglycemia may be masked by β-adrenergic blocking agents	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued
Calcium-channel blocking agents	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Chloramphenicol	Possible potentiation of hypoglycemic effects	Observe closely for hypoglycemia when concurrent therapy is initiated or discontinued
Contraceptives, oral	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Corticosteroids	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Diuretics	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Estrogens	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Isoniazid	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
MAO inhibitors	Possible potentiation of hypoglycemic effects	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued
Niacin	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
NSAIAs	Possible displacement of chlorpropamide from plasma proteins and potentiation of hypoglycemic effects	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued
Phenothiazines	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Phenytoin	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Probenecid	Possible potentiation of hypoglycemic effects	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued
Salicylates	Possible displacement of chlorpropamide from plasma proteins and potentiation of hypoglycemic effects	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued
Sulfonamides	Possible displacement of chlorpropamide from plasma proteins and potentiation of hypoglycemic effects	Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued
Sympathomimetic agents	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued
Thyroid agents	Potential for decreased hypoglycemic effect	Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued

Chlorpropamide Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained within 2–4 hours.

Onset

In healthy individuals, hypoglycemic action begins ≤1 hour; maximal at 3–6 hours.

Duration

In healthy individuals, hypoglycemic action persists for ≥24 hours; longest duration of action of the sulfonylureas.

Food

Food does not appear to affect absorption or bioavailability; decreases peak serum concentrations of drug.

Special Populations

Following administration of a single dose in healthy elderly and young adult individuals, age did not affect pharmacokinetics of chlorpropamide.

Distribution

Extent

Sulfonylureas are distributed into extracellular fluids.

Chlorpropamide crosses the placenta and is distributed into milk. (See Pregnancy under Cautions.)

Plasma Protein Binding

Highly bound to plasma proteins.

Elimination

Metabolism

Extensively metabolized, mainly by CYP2C9.

Elimination Route

Excreted in urine (80–90%) mainly as metabolites.

Increased or decreased rate of elimination in alkaline or acidic urine, respectively.

Half-life

36 hours (range: 25–60 hours).

Special Populations

Renal or hepatic insufficiency may affect pharmacokinetics and increase the risk of serious hypoglycemic reactions.

Metabolism influenced by CYP2C9 polymorphism; genetic differences in drug metabolism affect drug response.

Stability

Storage

Oral

Tablets

<30°C.

Actions

Stimulates secretion of postprandial endogenous insulin from beta cells of pancreas.
Ineffective in absence of functioning beta cells.
During prolonged administration, extrapancreatic effects (e.g., enhanced peripheral sensitivity to insulin, reduction of basal hepatic glucose production) contribute to hypoglycemic action.

Advice to Patients

Inform patients of potential risks and advantages of chlorpropamide therapy and alternative forms of treatment.
Importance of regular testing of blood glucose concentrations and HbA_1c values.
During insulin withdrawal, importance of testing blood glucose concentrations ≥3 times daily. Importance of patients immediately informing clinicians of abnormal results for appropriate adjustments in therapy, if necessary.
Importance of adhering to diet and exercise regimen.
Importance of hygiene and avoidance of infection.
Advise patients about nature of diabetes mellitus, prevention and detection of complications, and importance of glycemic control.
Importance of understanding primary and secondary failure to therapy.
Risks of hypoglycemia. Importance of patients and responsible family members understanding symptoms and treatment of hypoglycemic reactions and identifying conditions that predispose to development of such reactions.
Risk of alcohol intolerance (e.g., facial flushing).
Advise patients to use caution while driving and operating machinery.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name