CHLORPROPAMIDE
DESCRIPTION:
DIABINESE(R) (chlorpropamide) is an oral blood- glucose-lowering drug of the
sulfonylurea class. Chlorpropamide is 1-((p-Chlorophenyl) sulfonyl)-3-
propylurea, C10H13ClN2O3S.
Chlorpropamide is a white crystalline powder, that has a slight odor. It is
practically insoluble in water at pH 7.3 (solubility at pH 6 is 2.2 mg/ml). It
is soluble in alcohol and moderately soluble in chloroform. The molecular weight
of chlorpropamide is 276.74. DIABINESE is available as 100 mg and 250 mg
tablets.
ACTIONS/CLINICAL PHARMACOLOGY:
DIABINESE 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 DIABINESE lowers blood glucose
during long-term administration has not been clearly established. Extra-
pancreatic 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.
DIABINESE may also prove effective in controlling certain patients who have
experienced primary or secondary failure to other sulfonylurea agents.
A method developed which permits easy measurement of the drug in blood is
available on request.
Chlorpropamide does not interfere with the usual tests to detect albumin in the
urine.
DIABINESE 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 two to four 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, 80-90% 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.
DIABINESE exerts a hypoglycemic effect in normal humans within one hour,
becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The
potency of chlorpropamide is approximately six 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.
INDICATIONS AND USAGE:
DIABINESE is indicated as an adjunct to diet to lower the blood glucose in
patients with non- insulin-dependent diabetes mellitus (type II) whose
hyperglycemia cannot be controlled by diet alone.
In initiating treatment for non-insulin-dependent diabetes, diet should be
emphasized as the primary form of treatment. Caloric restriction and weight loss
are essential in the obese diabetic patient. Proper dietary management alone may
be effective in controlling the blood glucose and symptoms of hyperglycemia. The
importance of regular physical activity should also be stressed, and
cardiovascular risk factors should be identified and corrective measures taken
where possible.
If this treatment program fails to reduce symptoms and/or blood glucose, the use
of an oral sulfonylurea or insulin should be considered. Use of DIABINESE must
be viewed by both the physician and patient as a treatment in addition to diet,
and not as a substitute for diet or as a convenient mechanism for avoiding
dietary restraint. Furthermore, loss of blood glucose control on diet alone may
be transient, thus requiring only short-term administration of DIABINESE.
During maintenance programs, DIABINESE should be discontinued if satisfactory
lowering of blood glucose is no longer achieved. Judgments should be based on
regular clinical and laboratory evaluations.
In considering the use of DIABINESE in asymptomatic patients, it should be
recognized that controlling the blood glucose in non- insulin-dependent
diabetes, has not been definitely established to be effective in preventing the
long-term cardiovascular or neural complications of diabetes.
CONTRAINDICATIONS:
DIABINESE is contraindicated in patients with:
1. Known hypersensitivity to the drug.
2. 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 2 1/2 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 OVER-ALL
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 DIABINESE
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.
PRECAUTIONS:
GENERAL
Hypoglycemia: All sulfonylurea drugs are capable of producing severe
hypoglycemia. Proper patient selection, dosage, and instructions are important
to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause
elevated blood levels of DIABINESE and the latter may also diminish
gluconeogenic capacity, both of which increase the risk of serious hypoglycemic
reactions. Elderly, debilitated or malnourished patients, and those with adrenal
or pituitary insufficiency are particularly susceptible to the hypoglycemic
action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in
the elderly, and in people who are taking beta-adrenergic blocking drugs.
Hypoglycemia is more likely to occur when caloric intake is deficient, after
severe or prolonged exercise, when alcohol is ingested, or when more than one
glucose-lowering drug is used.
Because of the long half-life of chlorpropamide, patients who become
hypoglycemic during therapy require careful supervision of the dose and frequent
feedings for at least 3 to 5 days. Hospitalization and intravenous glucose may
be necessary.
Loss Of Control Of Blood Glucose: When a patient stabilized on any diabetic
regimen is exposed to stress such as fever, trauma, infection, or surgery, a
loss of control may occur. At such times, it may be necessary to discontinue
DIABINESE and administer insulin.
The effectiveness of any oral hypoglycemic drug, including DIABINESE, in
lowering blood glucose to a desired level decreases in many patients over a
period of time, which may be due to progression of the severity of the diabetes
or to diminished responsiveness to the drug. The phenomenon is known as
secondary failure, to distinguish it from primary failure in which the drug is
ineffective in an individual patient when first given.
INFORMATION FOR PATIENTS
Patients should be informed of the potential risks and advantages of DIABINESE
and of alternative modes of therapy. They should also be informed about the
importance of adherence to dietary instructions, of a regular exercise program,
and of regular testing of urine and/or blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development should be explained to patients and responsible
family members. Primary and secondary failure should also be explained.
Patients should be instructed to contact their physician promptly if they
experience symptoms of hypoglycemia or other adverse reactions.
LABORATORY TESTS
Blood and urine glucose should be monitored periodically. Measurement of
glycosylated hemoglobin may be useful.
DRUG INTERACTIONS
The hypoglycemic action of sulfonylurea may be potentiated by certain drugs
including nonsteroidal anti-inflammatory agents and other drugs that are highly
protein bound, salicylates, sulfonamides, chloramphenicol, probenecid,
coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents.
When such drugs are administered to a patient receiving DIABINESE, the patient
should be observed closely for hypoglycemia. When such drugs are withdrawn from
a patient receiving DIABINESE, the patient should be observed closely for loss
of control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
When such drugs are administered to a patient receiving DIABINESE, the patient
should be closely observed for loss of control. When such drugs are withdrawn
from a patient receiving DIABINESE, the patient should be observed closely for
hypoglycemia.
Since animal studies suggest that the action of barbiturates may be prolonged by
therapy with chlorpropamide, barbiturates should be employed with caution. In
some patients, a disulfiram-like reaction may be produced by the ingestion of
alcohol.
A potential interaction between oral miconazole and oral hypoglycemic agents
leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is
not known.
Carcinogenesis, Mutagenesis, Impairment Of Fertility: Chronic toxicity studies
have been carried out in dogs and rats. Dogs treated for 6, 13, or 20 months
with doses of DIABINESE greater than 20 times the human dose, have not shown any
gross histological or pathological abnormalities. After treatment with 100 mg/kg
of DIABINESE for 20 months, a dog showed no histopathological liver changes.
Rats treated with continuous DIABINESE therapy for 6 to 12 months showed varying
degrees of suppression of spermatogenesis at higher dosage levels (up to 125
mg/kg). The extent of suppression seemed to follow that of growth retardation
associated with chronic administration of high-dose DIABINESE in rats.
PREGNANCY
Teratogenic Effects:
Pregnancy Category C. Animal reproductive studies have not been conducted with
DIABINESE. It is also not known whether DIABINESE can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. DIABINESE
should be given to a pregnant woman only if clearly needed.
Because recent information suggests that abnormal blood glucose levels during
pregnancy are associated with a higher incidence of congenital abnormalities,
many experts recommend that insulin be used during pregnancy to maintain blood
glucose levels as close to normal as possible.
Nonteratogenic Effects:
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born
to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-
lives. If DIABINESE is used during pregnancy, it should be discontinued at least
one month before the expected delivery date.
Nursing Mothers: An analysis of a composite of two samples of human breast milk,
each taken five hours after ingestion of 500 mg of chlorpropamide by a patient,
revealed a concentration of 5 mcg/ml. For reference, the normal peak blood level
of chlorpropamide after a single 250 mg dose is 30 mcg/ml. Therefore, it is not
recommended that a woman breast feed while taking this medication.
Use In Children: Safety and effectiveness in children have not been established.
DRUG INTERACTIONS:
The hypoglycemic action of sulfonylurea may be potentiated by certain drugs
including nonsteroidal anti-inflammatory agents and other drugs that are highly
protein bound, salicylates, sulfonamides, chloramphenicol, probenecid,
coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents.
When such drugs are administered to a patient receiving DIABINESE, the patient
should be observed closely for hypoglycemia. When such drugs are withdrawn from
a patient receiving DIABINESE, the patient should be observed closely for loss
of control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
When such drugs are administered to a patient receiving DIABINESE, the patient
should be closely observed for loss of control. When such drugs are withdrawn
from a patient receiving DIABINESE, the patient should be observed closely for
hypoglycemia.
Since animal studies suggest that the action of barbiturates may be prolonged by
therapy with chlorpropamide, barbiturates should be employed with caution. In
some patients, a disulfiram-like reaction may be produced by the ingestion of
alcohol.
A potential interaction between oral miconazole and oral hypoglycemic agents
leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is
not known.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
Gastrointestinal Reactions: Cholestatic jaundice may occur rarely; DIABINESE
should be discontinued if this occurs. 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.
Dermatologic Reactions: 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 DIABINESE; if skin reactions persist
the drug should be discontinued.
Porphyria cutanea tarda and photosensitivity reactions have been reported with
sulfonylureas.
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 Reactions: Hepatic porphyria and disulfiram-like reactions have been
reported with DIABINESE. See DRUG INTERACTIONS section.
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.
OVERDOSAGE:
Overdosage of sulfonylureas including DIABINESE 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.
DOSAGE AND ADMINISTRATION:
There is no fixed dosage regimen for the management of diabetes mellitus with
DIABINESE or any other hypoglycemic agent. In addition to the usual monitoring
of urinary glucose, the patient's blood glucose must also 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 DIABINESE 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: 1. The mild to moderately severe, middle-aged, stable, non-
insulin- dependent diabetic patient should be started on 250 mg daily. In
elderly patients, debilitated or malnourished patients, and patients with
impaired renal or hepatic function, the initial and maintenance dosing should be
conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Older
patients should be started on smaller amounts of DIABINESE, in the range of 100
to 125 mg daily.
2. No transition period is necessary when transferring patients from other oral
hypoglycemic agents to DIABINESE. 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, non-insulin-dependent
diabetic 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 DIABINESE may be initiated with a 50 per cent
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 test his urine for
sugar and ketone bodies at least three times daily and report the results
frequently to his physician. 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 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 l25mg at intervals of three to five days to
obtain optimal control. More frequent adjustments are usually undesirable.
MAINTENANCE THERAPY: Most moderately severe, middle-aged, stable, non-insulin-
dependent diabetic 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.
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