Acetohexamide (0092)
[ a-seat-oh-hex'-a-mide ]
| Ingredients: |
Acetohexamide |
| Indications: |
Diabetes mellitus |
| Pregnancy Category: |
C |
| FDA Approved: |
1964- 02- 01 |
| Classes: |
Antidiabetic agents; Sulfonylureas, first generation |
| Brand Names: |
Dimelin
-
Japan
;
Dimelor
-
South-africa, Taiwan
;
Toyobexin
-
Japan
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$38.25
(
Diabetes ;
Generic Tablets (Barr) ;
500 mg ;
1 tablet/day ;
30 day supply
)
|
DESCRIPTION
|
| |
Acetohexamide is an oral blood- glucose lowering drug of the sulfonylurea class. Acetohexamide is a white to off- white, crystalline,
practically odorless powder. It is practically insoluble in water and ether, soluble in pyridine and dilute solutions of alkali
hydroxides, and slightly soluble in alcohol and chloroform. Chemically, it is benzenesulfonamide, 4- acetyl- N - [[cyclohexylamino]carbonyl]- or 1- [( p - acetylphenyl)sulfonyl]- 3- cyclohexylurea. The empirical formula for acetohexamide is C15 H2 ON2 O4 S. Its molecular weight is 324.39.
Acetohexamide is supplied in 250 mg (770 μmol) and 500 mg (1, 540 μmol) tablets. The tablets contain corn starch, magnesium
stearate, polacrillin potassium, and talc. The 500 mg tablet also contains D&C yellow no. 10 and FD&C yellow no. 6.
|
CLINICAL PHARMACOLOGY
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| |
Acetohexamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect
that is dependent on functioning β cells in the pancreatic islets. The mechanism by which acetohexamide lowers blood glucose
during long- term administration has not been clearly established.
Acetohexamide is rapidly absorbed from the gastrointestinal tract, and maximum hypoglycemic activity is observed about 3 hours
after ingestion. The total duration of action is 12 to 24 hours. Much of the activity is ascribable to a metabolite, hydroxyhexamide,
which has a plasma half- life of approximately 6 hours; the parent compound, acetohexamide, has a plasma half- life of 1.3
hours. In persons with normal renal and hepatic function, more than 80% is excreted, largely as metabolites, in 24 hours.
|
INDICATIONS AND USAGE
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Acetohexamide is indicated as an adjunct to diet for lowering the blood glucose in patients with non- insulin- dependent diabetes
mellitus (Type 2) whose hyperglycemia cannot be controlled by diet alone.
In initiating treatment for Type 2 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 when possible.
If this treatment program fails to reduce symptoms and/ or blood glucose, the use of an oral sulfonylurea or insulin should
be considered. The use of acetohexamide 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 with diet alone may be transient, thus requiring only short- term administration of acetohexamide.
During maintenance programs, acetohexamide should be discontinued if satisfactory lowering of blood glucose is no longer achieved.
Judgements should be based on regular clinical and laboratory evaluations.
In considering the use of acetohexamide in asymptomatic patients, it should be recognized that controlling the blood glucose
in Type 2 diabetes has not been definitely established as being effective in preventing the long- term cardiovascular or neural
complications of diabetes.
|
CONTRAINDICATIONS
|
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Acetohexamide is contraindicated in patients with:
- 1. Known hypersensitivity to the drug.
- 2. Diabetic ketoacidoses, with or without coma. This condition should be treated with insulin.
- 3. Insulin- dependent (Type 1) diabetes mellitus, as sole therapy.
- 4. Diabetes when complicated by pregnancy (see PRECAUTIONS, Pregnancy ).
|
WARNINGS
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Special Warning on Increased Risk of Cardiovascular Mortality
|
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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 Type 2 diabetes. The study involved 823 patients
who were randomly assigned to 1 of 4 treatment groups ( Diabetes 1970;19 [suppl 2]:747- 830).
UGDP reported that patients treated for 5- 8 years with diet plus a fixed dose of tolbutamide (1.5 g/ day) had a rate of cardiovascular
mortality approximately 2 ½ 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 acetohexamide and of alternative modes of therapy.
Although only 1 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
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General
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Hypoglycemia
|
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All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are
important for avoiding hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of acetohexamide,
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 β- 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 1 glucose- lowering drug is used.
|
Loss of Control of Blood Glucose
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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 acetohexamide and administer insulin.
The effectiveness of any oral hypoglycemic drug, including acetohexamide, in lowering blood glucose to a desired level decreases
in many patients over a period of time; this decrease in effectiveness may be due to progression of the severity of the diabetes
or to diminished responsiveness to the drug. This 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.
|
|
Laboratory Tests
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Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful.
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
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Long- term studies in rats and mice revealed no evidence of carcinogenicity of acetohexamide. A sister chromatid exchange
study performed with acetohexamide showed no evidence of mutagenicity. No animal studies have been conducted to determine
whether acetohexamide has the potential to impair fertility.
|
Pregnancy Category C
|
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Teratogenic Effects
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Acetohexamide has been shown to be teratogenic in animals. However, teratogenesis in animals has been observed following administration
of high doses of the sulfonylurea agents. There are no adequate and well- controlled studies in pregnant women. Therefore,
acetohexamide is not recommended for the management of diabetes when complicated by pregnancy.
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
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Prolonged severe hypoglycemia (4- 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. The
use of acetohexamide is not recommended for the management of diabetes when complicated by pregnancy.
|
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Nursing Mothers
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It is not known whether this drug is excreted in human milk. Because some sulfonylurea drugs are excreted in human milk and
because of the potential for serious adverse reactions in nursing infants from acetohexamide, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
|
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DRUG INTERACTIONS
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The hypoglycemic action of sulfonylurea agents 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 β- adrenergic blocking agents. When such drugs are administered to a patient receiving acetohexamide,
the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving acetohexamide,
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 acetohexamide, the
patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving acetohexamide,
the patient should be observed closely for hypoglycemia.
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.
|
ADVERSE REACTIONS
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Gastrointestinal Reactions
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Cholestatic jaundice may occur rarely; acetohexamide should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1- 40 patients. These reactions tend
to be dose related and may disappear when dosage is reduced.
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Dermatologic Reactions
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Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1 in 100 patients. These may
be transient and may disappear despite continued use of acetohexamide; if skin reactions persist, the drug should be discontinued.
Porphyria cutanea tarda and photosensitivity reactions have been reported with this and other sulfonylurea agents.
|
Endocrine Reactions
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Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this
and other sulfonylurea agents.
|
Hematologic Reactions
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Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with
sulfonylurea agents.
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Metabolic Reactions
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Hepatic porphyria and disulfiram- like reactions have been reported with sulfonylurea agents.
|
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OVERDOSAGE
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Signs and Symptoms
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Hypoglycemia is the predominant finding in cases of sulfonylurea overdose (including overdose with acetohexamide), but this
condition may be preceded by nausea, vomiting, and mild epigastric pain. Symptoms of hypoglycemia may include headache, weakness,
confusion, dizziness, lethargy, convulsions, coma and death. Patients may be especially susceptible hypoglycemia if they are
elderly, if they have had restricted carbohydrate intake (especially during periods of exercise), or if they have kidney or
liver dysfunction.
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Treatment
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To obtain up- to- date information about the treatment of overdose, a good resource is your certified regional poison control
center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual
drug kinetics in your patient.
Overdosage of sulfonylureas, including acetohexamide, 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 neurologic 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 of about 100 mg/ dl. Patients should be closely
monitored for a minimum of 24- 48 hours, since hypoglycemia may recur after apparent clinical recovery.
Monitor the patient's vital signs, blood gases, glucose, serum electrolytes, etc. Absorption of drugs from the gastrointestinal
tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider
charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some
drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.
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DOSAGE AND ADMINISTRATION
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There is no fixed dosage regimen for the management of diabetes mellitus with acetohexamide 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 a patient; to detect primary failure, i.e., inadequate lowering of blood glucose with the 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 acetohexamide may be sufficient during periods of transient loss of control in patients usually
well controlled on diet.
Daily oral dosage of acetohexamide may range between 250 mg and 1.5 g.
No loading dose is required. Patients who do not respond to 1.5 g daily usually will not respond to a higher dose. For this
reason, doses in excess of 1.5 g daily are not recommended.
The majority of patients receiving 1 g or less/ day can be controlled on a convenient once- daily dosage. Patients who need
1.5 g/ day usually benefit from twice- daily dosage, given before the morning and evening meals.
Various measures have been employed to establish patients on acetohexamide, and the following procedures are suggested.
Patients Not Previously Receiving Insulin or Drug Therapy
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In mild, stable diabetes (after dietary regulation), therapy may be initiated with 250 mg daily before breakfast; subsequent
adjustment of the dosage may be made by increments of 250- 500 mg every 5- 7 days as necessary. The 250 or 500 mg tablet (scored
and easily broken in half) may be used.
Because of reports of hyperresponsiveness to acetohexamide of some elderly patients with diabetes, patients in this group
should be started with a single dose of 250 mg before breakfast, and their blood and urine sugars should be checked during
the first 24 hours of therapy. If control appears to be satisfactory, this dose may be continued on a daily basis or, if necessary,
gradually increased. If, however, there appears to be a tendency toward hypoglycemia, this dose should be reduced or the drug
should be discontinued.
|
Patients Receiving Other Oral Agents
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When transfer is made from tolbutamide, the initial dose of acetohexamide should be about half the tolbutamide dose ( e.g., 250 mg of acetohexamide in place of 500 mg of tolbutamide), up to a maximum of 1.5 g of acetohexamide.
When transfer is made from chlorpropamide, the initial dose of acetohexamide should be about double the chlorpropamide dose
( e.g., 500 mg of acetohexamide in place of 250 mg of chlorpropamide).
A transition period usually is required because of the long half- life of chlorpropamide. Subsequent adjustment of dosage
should be made according to clinical response. The maximum recommended dose of acetohexamide is 1.5 g.
Clinical reports on the efficacy of once- daily dosage of acetohexamide indicate that its effect on the blood sugar is better
sustained than that of tolbutamide. However, patients requiring more than 1 g of acetohexamide daily should be treated with
divided doses.
|
Patients Receiving Insulin
|
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In general, patients who were previously maintained on insulin in small dosage ( e.g., up to 20 units/ day) may be placed on acetohexamide directly and their insulin administration abruptly discontinued. Patients
receiving larger doses of insulin, such as 20- 40 units or more/ day, should have an initial reduction of insulin dosage by
25- 30% daily or every other day and subsequent further reduction depending on the response to acetohexamide. An initial dose
of 250 mg of acetohexamide can be used, with readjustment depending on response to therapy. Because of the potential hazards
of hypoglycemia in the elderly, patients in this age group should be carefully observed during the transition from insulin
to acetohexamide.
During the period of insulin withdrawal, the patient should test his/ her blood or urine for sugar and urine for acetone at
least 3 times a day and report the results frequently to his/ her physician so that appropriate adjustments of therapy may
be made. In some cases, it may be advisable to consider hospitalization during the transition period from insulin to acetohexamide.
It should be noted that, as with other sulfonylureas, primary and secondary failures may occur with acetohexamide.
In elderly, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance
doses should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS ).
|
Store at controlled room temperature, 59- 86°F (15- 30°C).
|
PRODUCT LISTING - RATED THERAPEUTICALLY EQUIVALENT
|
| |
| tablet - oral - 250 mg -
|
| 100.0's |
$74.16 |
GENERIC
Barr Laboratories Inc
|
00555044202 |
| tablet - oral - 500 mg -
|
| 100.0's |
$127.50 |
GENERIC
Barr Laboratories Inc
|
00555044302 |
|
|