Action And Clinical Pharmacology: Chlorpropamide is an orally active hypoglycemic agent which reduces blood sugar concentration without affecting glucose tolerance. It probably acts by stimulating insulin secretion in the presence of functioning pancreatic islet tissue.
Chlorpropamide is absorbed readily from the gastrointestinal tract and is bound to plasma proteins. Within 1 hour after a single oral dose, it is detectable in the blood, and the level reaches a maximum within 2 to 4 hours. It is slowly excreted by the kidneys as unchanged chlorpropamide, 2-hydroxy-chlorpropamide, p-chlorbenzene- sulfonylurea, and other metabolites. The biological half-life of a single dose of chlorpropamide averages about 36 hours. Within 96 hours, 80 to 90% of a single oral dose is excreted in the urine. When the drug is administered daily in the appropriate therapeutic dose, it accumulates in the body until a steady state equilibrium develops between the amount administered (daily) and the amount eliminated (daily) through metabolism and excretion. This equilibrium is usually reached in about 5 to 7 days and no further accumulation occurs thereafter unless the dosage is excessive.
Chlorpropamide exerts a hypoglycemic effect in normal humans within 1 hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours.
Indications And Clinical Uses: In mild, stable diabetes mellitus of the maturity-onset (or adult) variety to control hyperglycemia responsive to the drug. It should not be used in those patients who are prone to ketosis or who can be controlled by dietary management and exercise alone or for whom insulin therapy is more appropriate.
Contra-Indications: Known hypersensitivity or allergy to chlorpropamide. Unstable and/or insulin dependent diabetes mellitus; ketoacidosis; coma; during stress conditions such as severe infections, trauma or surgery. Pregnancy. In patients with serious impairment of hepatic, renal or thyroid function.
Manufacturers’ Warnings In Clinical States: Chlorpropamide will not prevent the development of complications peculiar to diabetes mellitus.
Chlorpropamide administration must be considered as treatment in addition to a proper dietary regimen and not as a substitute for diet.
Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic agents because of deterioration of their diabetic state. If a loss of adequate blood glucose lowering response to chlorpropamide is detected, discontinue the drug.
Precautions: Patient Selection and Follow-up: Careful selection of patients is important. It is imperative that there be rigid attention to diet, careful adjustment of dosage, instruction of the patient on hypoglycemic reactions and their control as well as regular thorough follow-up examinations.
Since the effects of oral hypoglycemic agents on the vascular changes and other long-term sequelae of diabetes mellitus are not fully known, patients receiving such drugs must be closely observed for both short- and long-term complications. Periodic assessment of cardiovascular, ophthalmic, renal and hepatic status is advisable.
Although chlorpropamide given alone has controlled some patients with mild maturity-onset diabetes of the stable type during the stress of mild infection or minor surgery, insulin therapy is generally essential during intercurrent complications (for example, ketoacidosis, severe trauma, major surgical procedures, severe infections, severe diarrhea, nausea and vomiting). The severity of the diabetes, the nature of the complications, and availability of laboratory facilities determine whether therapy can be continued or should be withdrawn while insulin is being used.
Hypoglycemic Reactions: Severe hypoglycemia can be induced by all sulfonylurea drugs. Particularly susceptible are elderly subjects, patients with impaired hepatic or renal function, those who are debilitated or malnourished and patients with primary or secondary adrenal insufficiency. Hypoglycemia is more likely to occur when the caloric intake is inadequate or after strenuous or prolonged exercise.
Because of the long biological half-life of chlorpropamide, if the patient becomes hypoglycemic during therapy, withdraw the drug and keep the patient under close supervision for 5 to 6 days. Subsequent reinstitution of chlorpropamide at lower dose levels may be considered.
Drug Interactions: As a result of drug interaction, hypoglycemia may be potentiated when a sulfonylurea is used concurrently with agents such as: long-acting sulfonamides, tuberculostatics, phenylbutazone, clofibrate, MAO inhibitors, coumarin derivatives, salicylates, probenecid, or beta-adrenergic blocking agents such as propranolol.
Certain drugs tend to produce hyperglycemia and may lead to loss of blood sugar control; these include diuretics (thiazides, furosemide), corticosteroids, oral contraceptives (estrogen plus progestogen) and nicotinic acid in pharmacologic doses.
Barbiturates should be used cautiously in patients receiving an oral hypoglycemic agent, since their action may be prolonged.
Intolerance to alcohol (disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia) may occur in patients treated with a sulfonylurea. This reaction can be prevented by avoiding alcohol.
Adverse Reactions: The majority of the side effects have been dose-related, transient, and have responded to dose reduction or withdrawal of the medication. However, clinical experience thus far has shown that, as with other sulfonylureas, some side effects associated with hypersensitivity may be severe and deaths have been reported in some instances.
Certain untoward reactions associated with idiosyncrasy or hypersensitivity have occurred, including jaundice, skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis, and probably depression of formed elements of the blood; these reactions show no direct relationship to the size of the dose.
They occur characteristically during the first 6 weeks of therapy. With a few exceptions, these manifestations have been mild and readily reversible on the withdrawal of the drug.
Hypoglycemia (see Precautions): Severe hypoglycemia which mimics acute CNS disorders may occur. Hepatic and/or renal disease, malnutrition, debility, advanced age, alcoholism, adrenal or pituitary insufficiency may be predisposing factors.
Gastrointestinal: Nausea, epigastric fullness and heartburn are common reactions, tend to be dose related and may disappear when dosage is reduced. Cholangiolytic jaundice due to intracanalicular biliary stasis with elevation of serum alkaline phosphatase has been reported rarely. In patients with progressive elevation of serum alkaline phosphatase, chlorpropamide should be discontinued.
Dermatologic: Allergic skin reactions such as pruritus, erythema, urticaria, morbilliform or maculopapular eruptions have been observed. These may subside on continued use of chlorpropamide, but if they persist, discontinue the drug. Porphyria cutanea tarda and photosensitivity reactions have been reported.
Hematologic: leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia.
Metabolic: hepatic porphyria, disulfiram-like reactions.
Endocrine: Reduced RAI uptake by the thyroid gland has been reported.
Chlorpropamide on some occasions has caused a reaction similar to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. This is characterized by excessive water retention and hyponatremia, low serum osmolality and high urine osmolality.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage with sulfonylureas may result in hypoglycemia, but it should be noted that the dosage which causes hypoglycemia varies widely, and may be within the accepted therapeutic range in sensitive individuals.
The manifestations of hypoglycemia include sweating, flushing or pallor, numbness, chilliness, hunger, trembling, headache, dizziness, increased pulse rate, palpitations, increase in blood pressure and apprehensiveness in the mild cases. In more severe cases, coma appears. However, symptoms of hypoglycemia are not necessarily as typical as described above and sulfonylureas may cause insidious development of symptoms mimicking cerebrovascular insufficiency.
Treatment: Discontinue medication and treat hypoglycemia by giving dextrose promptly and in sufficient quantity. Some sulfonylurea-induced hypoglycemias may be refractory to treatment and susceptible to relapse, especially in elderly or malnourished patients. Continuous dextrose infusions for hours to days have been necessary.
Dosage And Administration: In diabetic subjects there is no fixed dosage regimen for management of blood glucose levels. Individual determination of the minimum dose that will lower the blood glucose adequately should be made.
If the maximal recommended dose fails to lower blood glucose adequately in patients on initial trial, discontinue chlorpropamide. During the course of therapy a loss of effectiveness may occur. It is advisable to ascertain chlorpropamide’s contribution in the control of blood glucose by discontinuing the medication semi-annually or at least annually with careful patient monitoring. If the need for chlorpropamide is not evident, the drug should not be resumed. In some diabetic subjects, short-term chlorpropamide administration may be sufficient during periods of transient loss of blood sugar control.
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.
Usual Starting Dose: The stable, mild, nonketosis-prone maturity-onset or adult type diabetic should be started on 250 mg daily. Because the geriatric diabetic patient appears to be more sensitive to the hypoglycemic effect of sulfonylurea drugs, older patients should be started on smaller amounts of chlorpropamide in the range of 100 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 appropriate dosage.
Changeover From Insulin: If a change from insulin to chlorpropamide is desirable in a patient with stable, mild, maturity-onset diabetes, treatment with insulin should be discontinued abruptly or gradually as appropriate. After an insulin-free period of 2 or 3 days it is possible to determine whether any therapy other than dietary regulation and exercise is needed. During this withdrawal and insulin-free interval, the patient’s urine should be tested at least 3 times daily for glucose and ketone bodies, and the results monitored carefully. The appearance of significant ketonuria accompanied by glucosuria within 12 to 24 hours after withdrawal of insulin strongly suggests that the patient is ketosis prone and precludes the change from insulin to chlorpropamide.
Five to seven 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 to 125 mg at intervals of 3 to 5 days to obtain optimal control. More frequent adjustments are usually undesirable.
In most patients the response to chlorpropamide will be evident within an initial trial period of 7 days. Others may require up to 1 month for maximum control. Provided severe loss of control does not intervene, a patient should not be classified as a primary failure unless 4 weeks of therapy have failed to produce a satisfactory response.
Usual Maintenance Dose: Most diabetic patients responsive to chlorpropamide are controlled by approximately 250 mg daily. Many investigators have found that some of these diabetics do well on daily doses of 100 mg or less, but others may require as much as 500 mg daily for adequate control. Patients who do not respond completely to 500 mg daily will usually not respond to higher doses.
Maximal Dose: Maintenance doses above 500 mg daily should be avoided.
Availability And Storage: 100 mg: Each oval, pale yellow, scored tablet with Pfizer impressed on one side, contains: chlorpropamide 100 mg. Nonmedicinal ingredients: alginic acid, aluminum hydroxide, calcium carbonate, cornstarch, D&C Yellow No. 10, FD&C Yellow No. 6, hydroxypropyl cellulose and magnesium stearate/sodium lauryl sulfate. Tartrazine-free. Bottles of 100.
250 mg: Each oval, white, scored tablet with Pfizer impressed on one side, contains: chlorpropamide 250 mg. Nonmedicinal ingredients: alginic acid, calcium carbonate, cornstarch, hydroxypropyl cellulose and magnesium stearate/sodium lauryl sulfate. Tartrazine-free. Bottles of 100 and 500.
Store between 15 and 30°C. (Shown in Product Recognition Section)
DIABINESE Pfizer Chlorpropamide Oral Hypoglycemic