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Chlorpropamide

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

Introduction

Antidiabetic agent; sulfonylurea.189 a

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.189 a

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.135 145 146 147 148 149 169 170 171 172 173 174 175 176 177 178 179 180

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Alternative therapy in some type 2 diabetic patients being treated with insulin or other antidiabetic agent(s).189 a Useful in combination with insulin to improve glycemic control and/or decrease insulin dosage in some type 2 diabetic patients.135 145 146 150 151 153 154 155 156 157 158

Not effective as sole therapy in patients with type 1 diabetes mellitus or diabetic acidosis, ketosis, or coma; 101 103 106 insulin is necessary.101 102 106 (See Contraindications under Cautions.)

Not routinely recommended in hospitalized patients with diabetes mellitus.122 Long duration of action precludes rapid dosage adjustments.122 Increased risk of hypoglycemia in hospitalized diabetic patients with irregular eating patterns.122

Chlorpropamide Dosage and Administration

General

  • Adjust dosage according to severity of disease, tolerance, and blood glucose determinations.189 a

  • Monitor regularly (e.g., blood glucose concentrations) to determine minimum effective dosage and to detect primary failure or secondary failure.189 a (See Loss of Glycemic Control under Cautions.)

  • Monitor glycosylated hemoglobin (HbA1c) to determine patient’s continued response to therapy.189

  • Administration of loading dose is not recommended.189 a

  • During transfer from insulin therapy, patients should test their blood glucose concentrations ≥3 times daily.189 (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.189 a In some patients, consider hospitalization during transition period.189 a

Administration

Oral Administration

Administer orally as a single daily dose each morning with breakfast.189 a May administer in 2 divided doses if GI intolerance occurs.189 a

Dosage

Adults

Diabetes Mellitus
Initiation
Oral

Initially, 250 mg daily.189 a

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents
Oral

Initially, 250 mg daily.189 a May abruptly discontinue the other oral antidiabetic agent.189 a

Initial Dosage in Patients Transferred from Insulin
Oral

Insulin requirements ≤40 units daily: Initially, 250 mg daily.189 a Abruptly discontinue insulin.189 a

Insulin requirements >40 units daily: Initially, 250 mg daily; reduce daily insulin dosage by 50% for first few days.189 a Subsequently, adjust insulin dosage according to therapeutic response.189 a

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.189

Usual maintenance dosage is 100–500 mg daily.189 a Patients not responding to 500 mg daily are unlikely to respond to higher dosages.189 a

Prescribing Limits

Adults

Diabetes Mellitus
Oral

Maximum 750 mg daily.189 a

Special Populations

Hepatic Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia.189 (See Hepatic Impairment under Cautions.)

Renal Impairment

Use conservative initial and maintenance dosages to avoid hypoglycemia.189 (See Renal Impairment under Cautions.)

Geriatric Patients

Initially, 100–125 mg daily.189 Use conservative initial and maintenance dosages to avoid hypoglycemia.189 (See Geriatric Use under Cautions.)

Debilitated or Malnourished Patients

Use conservative initial and maintenance dosages to avoid hypoglycemia.189

Pituitary or Adrenal Insufficiency

Use conservative initial and maintenance dosages to avoid hypoglycemia.189

Cautions for Chlorpropamide

Contraindications

  • Known hypersensitivity to chlorpropamide or any ingredient in formulation.189

  • Diabetic ketoacidosis with or without coma.189 a

  • Monotherapy for type 1 diabetes mellitus.189 a

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased cardiovascular mortality reported with certain other antidiabetic agents (i.e., tolbutamide, phenformin).111 189 d However, ADA considers benefits of intensive glycemic control with insulin or sulfonylureas to outweigh the risks overall.112 115 128

General Precautions

Hypoglycemia

Possible severe hypoglycemia, especially in geriatric, debilitated, or malnourished patients and those with adrenal, pituitary, hepatic, or renal insufficiency.189 a d 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).189 d (See Specific Drugs under Interactions.)

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

Hypoglycemia may be difficult to recognize in geriatric patients and those receiving β-adrenergic blocking agents.189

Appropriate patient selection and careful dosing and instructions are important to avoid chlorpropamide-induced hypoglycemia.189

Hypoglycemia may result in coma, seizures, or other neurologic impairment.189 a d

If hypoglycemia occurs, immediately reevaluate patient and adjust insulin or chlorpropamide dosage.a Monitor patient for 24–48 hours;189 may require hospitalization and IV glucose.189 a Carefully supervise dose and give frequent feedings for ≥3–5 days.189

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).101 102 105 106 189 May require use of insulin and/or temporary discontinuance of chlorpropamide.189 a

Efficacy of therapy may decrease over time (secondary failure); evaluate patients at regular intervals.189 a

Assess patient for adequate adjustment of dose and adherence to diet before attributing inadequate response to secondary failure of the drug.189

Manufacturer recommends discontinuance of chlorpropamide if loss of satisfactory glycemic control develops.189 ADA and other clinicians recommend addition of other oral antidiabetic agents or insulin.127 146 173 175 184 185 186 191 192 (See Diabetes Mellitus under Uses.)

Specific Populations

Pregnancy

Category C.189

Prolonged (4–10 days), severe hypoglycemia reported in some neonates born to women receiving a sulfonylurea at delivery;189 more frequent with long-acting sulfonylureas (e.g., chlorpropamide).189 Discontinue drug ≥1 month before expected delivery date to minimize the risk of neonatal hypoglycemia.189

Many experts recommend the use of insulin during pregnancy.189

Lactation

Distributed into milk.189 Use not recommended.189

Pediatric Use

Safety and efficacy not established.189

Geriatric Use

Safety and efficacy not established.189 Increased risk of hypoglycemia and/or hyponatremia; hypoglycemia may be difficult to recognize.189 d Cautious dosing recommended.189 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Diminished gluconeogenic capacity and increased risk of hypoglycemia; conservative dosing recommended.189 a (See Hepatic Impairment under Dosage and Administration.)

Monitor liver function frequently during chlorpropamide initiation.a

Renal Impairment

Increased risk of hypoglycemia; conservative dosing recommended.189 a (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Hypoglycemia,111 189 a nausea,189 a weight gain.111 142 143 144

Interactions for Chlorpropamide

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

Protein-bound Drugs

Potential pharmacokinetic interaction (increased hypoglycemic effect because of displacement of chlorpropamide from binding sites on proteins).189 a (See Specific Drugs under Interactions.)

Close observation recommended when initiating or discontinuing concomitant therapy with a highly protein-bound drug.189 a

Specific Drugs

Drug

Interaction

Comments

Alcohol

Disulfiram-like reactions reported189 a

Moderate-to-large amounts of alcohol may increase the risk of hypoglycemia189

If intolerant, attempt therapy with another sulfonylurea agenta

Antifungals, oral azoles (i.e., fluconazole, miconazole)

Increased plasma concentrations of sulfonylureas and hypoglycemic effect182 183 189

Not known whether interaction occurs with IV, topical, or vaginal miconazole189

Anticoagulants, oral

Possible potentiation of hypoglycemic effects189 a

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued189

Barbiturates

May prolong action of barbiturates189 a

Use concurrently with caution189 a

β-Adrenergic blocking agents

Possible potentiation of hypoglycemic effects189

Signs of hypoglycemia may be masked by β-adrenergic blocking agents189

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued189

Calcium-channel blocking agents

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Chloramphenicol

Possible potentiation of hypoglycemic effects189

Observe closely for hypoglycemia when concurrent therapy is initiated or discontinued189

Contraceptives, oral

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Corticosteroids

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Diuretics

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Estrogens

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Isoniazid

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

MAO inhibitors

Possible potentiation of hypoglycemic effects189

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy is initiated or discontinued189

Niacin

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

NSAIAs

Possible displacement of chlorpropamide from plasma proteins and potentiation of hypoglycemic effects189

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued189

Phenothiazines

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Phenytoin

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Probenecid

Possible potentiation of hypoglycemic effects189

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued189

Salicylates

Possible displacement of chlorpropamide from plasma proteins and potentiation of hypoglycemic effects189

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued189

Sulfonamides

Possible displacement of chlorpropamide from plasma proteins and potentiation of hypoglycemic effects189

Observe closely for hypoglycemia or loss of glycemic control when concurrent therapy initiated or discontinued189

Sympathomimetic agents

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Thyroid agents

Potential for decreased hypoglycemic effect189

Observe closely for loss of glycemic control or hypoglycemia when concurrent therapy is initiated or discontinued189

Chlorpropamide Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained within 2–4 hours.189 a b

Onset

In healthy individuals, hypoglycemic action begins ≤1 hour; maximal at 3–6 hours.189

Duration

In healthy individuals, hypoglycemic action persists for ≥24 hours;189 longest duration of action of the sulfonylureas.a d

Food

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

Special Populations

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

Distribution

Extent

Sulfonylureas are distributed into extracellular fluids.a

Chlorpropamide crosses the placenta and is distributed into milk.189 (See Pregnancy under Cautions.)

Plasma Protein Binding

Highly bound to plasma proteins.a

Elimination

Metabolism

Extensively metabolized, mainly by CYP2C9.c

Elimination Route

Excreted in urine (80–90%) mainly as metabolites.189 a c

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

Half-life

36 hours (range: 25–60 hours).189 a b c d

Special Populations

Renal or hepatic insufficiency may affect pharmacokinetics and increase the risk of serious hypoglycemic reactions.189

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

Stability

Storage

Oral

Tablets

<30°C.189

Actions

  • Stimulates secretion of postprandial endogenous insulin from beta cells of pancreas.189 a d

  • Ineffective in absence of functioning beta cells.189 a

  • During prolonged administration, extrapancreatic effects (e.g., enhanced peripheral sensitivity to insulin, reduction of basal hepatic glucose production) contribute to hypoglycemic action.189 a

Advice to Patients

  • Inform patients of potential risks and advantages of chlorpropamide therapy and alternative forms of treatment.189

  • Importance of regular testing of blood glucose concentrations and HbA1c values.189

  • During insulin withdrawal, importance of testing blood glucose concentrations ≥3 times daily.189 Importance of patients immediately informing clinicians of abnormal results for appropriate adjustments in therapy, if necessary.189

  • Importance of adhering to diet and exercise regimen.101 102 107 110 189

  • Importance of hygiene and avoidance of infection.a

  • Advise patients about nature of diabetes mellitus, prevention and detection of complications, and importance of glycemic control.a

  • Importance of understanding primary and secondary failure to therapy.189

  • Risks of hypoglycemia.189 Importance of patients and responsible family members understanding symptoms and treatment of hypoglycemic reactions and identifying conditions that predispose to development of such reactions.189

  • Risk of alcohol intolerance (e.g., facial flushing).a

  • Advise patients to use caution while driving and operating machinery.189

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.189

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.189

  • Importance of informing patients of other important precautionary information.189 (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

Chlorpropamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg*

Diabinese (scored)

Pfizer

250 mg*

Diabinese (scored)

Pfizer

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

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