Chlorpropamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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Overview
Chlorpropamide is a 1st generation sulfonylurea and hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, diarrhea, hunger, loss of appetite, nausea and vomiting.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
There is no fixed dosage regimen for the management of type 2 diabetes with chlorpropamide or any other hypoglycemic agent. The patient’s blood glucose must be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy.
Short-term administration of chlorpropamide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.
The total daily dosage is generally taken at a single time each morning with breakfast. Occasionally cases of gastrointestinal intolerance may be relieved by dividing the daily dosage. A loading or priming dose is not necessary and should not be used.
Initial Therapy
- The mild to moderately severe, middle-aged, stable type 2 diabetes patient should be started on 250 mg daily. In elderly patients, debilitated or malnourished patients, and patients with impaired renal function or impaired hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. Older patients should be started on smaller amounts of chlorpropamide, in the range of 100 mg to 125 mg daily.
- No transition period is necessary when transferring patients from other oral hypoglycemic agents to chlorpropamide. The other agent may be discontinued abruptly and chlorpropamide started at once. In prescribing chlorpropamide, due consideration must be given to its greater potency.
Many mild to moderately severe, middle-aged, stable type 2 diabetes patients receiving insulin can be placed directly on the oral drug and their insulin abruptly discontinued. For patients requiring more than 40 units of insulin daily, therapy with chlorpropamide may be initiated with a 50% reduction in insulin for the first few days, with subsequent further reductions dependent upon the response.
During the initial period of therapy with chlorpropamide, hypoglycemic reactions may occasionally occur, particularly during the transition from insulin to the oral drug. Hypoglycemia within 24 hours after withdrawal of the intermediate or long-acting types of insulin will usually prove to be the result of insulin carry-over and not primarily due to the effect of chlorpropamide.
During the insulin withdrawal period, the patient should self-monitor glucose levels at least 3 times daily. If they are abnormal, the physician should be notified immediately. In some cases, it may be advisable to consider hospitalization during the transition period.
Five to 7 days after the initial therapy, the blood level of chlorpropamide reaches a plateau. Dosage may subsequently be adjusted upward or downward by increments of not more than 50 mg to 125 mg at intervals of 3 to 5 days to obtain optimal control. More frequent adjustments are usually undesirable.
Maintenance Therapy
Most moderately severe, middle-aged, stable type 2 diabetes patients are controlled by approximately 250 mg daily. Many investigators have found that some milder diabetics do well on daily doses of 100 mg or less. Many of the more severe diabetics may require 500 mg daily for adequate control. Patients who do not respond completely to 500 mg daily will usually not respond to higher doses. Maintenance doses above 750 mg daily should be avoided.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Chlorpropamide in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Chlorpropamide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Chlorpropamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Chlorpropamide in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Chlorpropamide in pediatric patients.
Contraindications
Chlorpropamide tablets are contraindicated in patients with:
- Known hypersensitivity to any component of this medicine.
- Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
Warnings
Special Warning on Increased Risk of Cardiovascular Mortality
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 [supp 2]:747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of chlorpropamide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Adverse Reactions
Clinical Trials Experience
- Body as a Whole: Disulfiram-like reactions have rarely been reported with chlorpropamide
- Central and Peripheral Nervous System: Dizziness and headache.
- Hypoglycemia
Gastrointestinal: Gastrointestinal disturbances are the most common reactions; nausea has been reported in less than 5% of patients, and diarrhea, vomiting, anorexia, and hunger in less than 2%. Other gastrointestinal disturbances have occurred in less than 1% of patients including proctocolitis. They tend to be dose related and may disappear when dosage is reduced.
- Liver/Biliary: Cholestatic jaundice may occur rarely; chlorpropamide should be discontinued if this occurs. Hepatic porphyria and disulfiram-like reactions have been reported with chlorpropamide.
- Skin/Appendages: Pruritus has been reported in less than 3% of patients. Other allergic skin reactions, e.g., urticaria and maculopapular eruptions have been reported in approximately 1% or less of patients. These may be transient and may disappear despite continued use of chlorpropamide; if skin reactions persist the drug should be discontinued.
- As with other sulfonylureas, porphyria cutanea tarda and photosensitivity reactions have been reported. Skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis have also been reported.
- Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas.
- Metabolic/Nutritional Reactions: Hypoglycemia. Hepatic porphyria and disulfiram-like reactions have been reported with chlorpropamide.
- Endocrine Reactions: On rare occasions, chlorpropamide has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This reaction has also been reported for other sulfonylureas.
Postmarketing Experience
There is limited information regarding Chlorpropamide Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Chlorpropamide Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Chlorpropamide in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chlorpropamide in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Chlorpropamide during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Chlorpropamide in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Chlorpropamide in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Chlorpropamide in geriatric settings.
Gender
There is no FDA guidance on the use of Chlorpropamide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Chlorpropamide with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Chlorpropamide in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Chlorpropamide in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Chlorpropamide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Chlorpropamide in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Chlorpropamide Administration in the drug label.
Monitoring
There is limited information regarding Chlorpropamide Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Chlorpropamide and IV administrations.
Overdosage
Overdosage of sulfonylureas including chlorpropamide can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.
Pharmacology
Mechanism of Action
Chlorpropamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which chlorpropamide lowers blood glucose during long-term administration has not been clearly established. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. While chlorpropamide is a sulfonamide derivative, it is devoid of antibacterial activity.
Structure
There is limited information regarding Chlorpropamide Structure in the drug label.
Pharmacodynamics
Chlorpropamide exerts a hypoglycemic effect in healthy subjects within one hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The potency of chlorpropamide is approximately 6 times that of tolbutamide. Some experimental results suggest that its increased duration of action may be the result of slower excretion and absence of significant deactivation.
Pharmacokinetics
Chlorpropamide is absorbed rapidly from the gastrointestinal tract. Within one hour after a single oral dose, it is readily detectable in the blood, and the level reaches a maximum within 2 to 4 hours. It undergoes metabolism in humans and it is excreted in the urine as unchanged drug and as hydroxylated or hydrolyzed metabolites. The biological half-life of chlorpropamide averages about 36 hours. Within 96 hours, 80% to 90% of a single oral dose is excreted in the urine. However, long-term administration of therapeutic doses does not result in undue accumulation in the blood, since absorption and excretion rates become stabilized in about 5 to 7 days after the initiation of therapy.
Nonclinical Toxicology
There is limited information regarding Chlorpropamide Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Chlorpropamide Clinical Studies in the drug label.
How Supplied
There is limited information regarding Chlorpropamide How Supplied in the drug label.
Storage
There is limited information regarding Chlorpropamide Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Chlorpropamide Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Chlorpropamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Chlorpropamide Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Chlorpropamide Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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| Elimination half-life | 36 hours |
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| Formula | C10H13ClN2O3S |
| Molar mass | 276.741 g/mol |
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Chlorpropamide is an example of a drug class called sulphonylureas used to treat type 2 diabetes mellitus.
Mechanism of action
The sulphonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present; during long-term administration they also have an extrapancreatic action. All may cause hypoglycaemia but this is uncommon and usually indicates excessive dosage. Sulphonylurea-induced hypoglycemia may persist for many hours and must always be treated in hospital.
Sulphonylureas are considered for patients who are not overweight, or in whom metformin is contra-indicated or not tolerated. Several sulphonylureas are available and choice is determined by side-effects and the duration of action as well as the patient’s age and renal function. The long-acting sulphonylureas chlorpropamide and glibenclamide are associated with a greater risk of hypoglycaemia; for this reason they should be avoided in the elderly and shorter-acting alternatives, such as gliclazide or tolbutamide, should be used instead. Chlorpropamide also has more side-effects than the other sulphonylureas and therefore it is no longer recommended.
When the combination of strict diet and sulphonylurea treatment fails other options include:
combining with metformin(reports of increased hazard with this combination remain unconfirmed);
combining with acarbose, which may have a small beneficial effect, but flatulence can be a problem;
combining with pioglitazone or rosiglitazone
combining with bedtime isophane insulin but weight gain and hypoglycaemia can occur.
Insulin therapy should be instituted temporarily during intercurrent illness (such as myocardial infarction, coma, infection, and trauma). Sulphonylureas should be omitted on the morning of surgery; insulin is required because of the ensuing hyperglycaemia in these circumstances.
Cautions Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite adequate attempts at dieting; metformin is considered the drug of choice in obese patients. Caution is needed in the elderly and in those with mild to moderate hepatic and renal impairment because of the hazard of hypoglycaemia. The short-acting tolbutamide may be used in renal impairment, as may gliquidone and gliclazide which are principally metabolised in the liver, but careful monitoring of blood-glucose concentration is essential; care is required to choose the smallest possible dose that produces adequate control of blood glucose.
Contra-indications Sulphonylureas should be avoided where possible in severe hepatic and renal impairment and in porphyria. They should not be used while breast-feeding and insulin therapy should be substituted during pregnancy. Sulphonylureas are contra-indicated in the presence of ketoacidosis.
Side-effects Side-effects of sulphonylureas are generally mild and infrequent and include gastro-intestinal disturbances such as nausea, vomiting, diarrhoea and constipation.
Chlorpropamide has appreciably more side-effects, mainly because of its very prolonged duration of action and the consequent hazard of hypoglycemia and it should no longer be used. It may also cause facial flushing after drinking alcohol; this effect does not normally occur with other sulphonylureas. Chlorpropamide may also enhance antidiuretic hormone secretion and very rarely cause hyponatraemia (hyponatraemia is also reported with glimepiride and glipizide).
Sulphonylureas can occasionally cause a disturbance in liver function, which may rarely lead to cholestatic jaundice, hepatitis and hepatic failure. Hypersensitivity reactions can occur, usually in the first 6–8 weeks of therapy, they consist mainly of allergic skin reactions which progress rarely to erythema multiforme and exfoliative dermatitis, fever and jaundice; photosensitivity has rarely been reported with chlorpropamide and glipizide. Blood disorders are also rare but may include leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia, and aplastic anaemia.
Indications type 2 diabetes mellitus
Cautions see notes above. Also causes disulfiram-like reaction with alcohol
Contra-indications see notes above
Side-effects see notes above. Dose
Initially 250 mg daily with breakfast (elderly 100–125 mg but avoid—see notes above), adjusted according to response; max. 750 mg daily
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