Cytadren (Aminoglutethimide, Orimeten) ®
Tablets aminoglutethimide tablets USP
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Prescribing Information
Cytadren (Aminoglutethimide, Orimeten), aminoglutethimide tablets USP, is an inhibitor of adrenocortical
steroid synthesis,
available as 250-mg tablets for oral administration. Its chemical name
is 3-(4-aminophenyl)-
3-ethyl-2,6-piperidinedione, and its structural formula is Aminoglutethimide USP is a fine, white or creamy white, crystalline
powder. It is very
slightly soluble in water, and readily soluble in most organic solvents.
It forms water- soluble salts with strong acids. Its molecular weight is 232.28.
Inactive Ingredients. Cellulose compounds, colloidal silicon dioxide,
starch, stearic
acid, and talc. CLINICAL PHARMACOLOGY
Cytadren (Aminoglutethimide, Orimeten) inhibits the enzymatic conversion
of cholesterol to ?
-pregnenolone, resulting in a decrease in the production of
adrenal glucocorticoids, mineralocorticoids, estrogens, and
androgens.
C-21 hydroxylations and the hydroxylations required for the aromatization
of androgens to estrogens, mediated through the binding of Cytadren
(Aminoglutethimide, Orimeten) to cytochrome P-450 complexes.
A decrease in adrenal secretion of cortisol is followed by an increased
secretion of
pituitary adrenocorticotropic hormone (ACTH), which will overcome the
blockade of
adrenocortical steroid synthesis by Cytadren (Aminoglutethimide, Orimeten). The compensatory increase
in ACTH secretion
can be suppressed by the simultaneous administration of hydrocortisone.
Since Cytadren (Aminoglutethimide, Orimeten)
increases the rate of metabolism of dexamethasone but not that of hydrocortisone,
the latter is
preferred as the adrenal glucocorticoid replacement.
Although Cytadren (Aminoglutethimide, Orimeten) inhibits the synthesis of thyroxine by the thyroid
gland, the
compensatory increase in thyroid-stimulating hormone (TSH) is frequently
of sufficient
magnitude to overcome the inhibition of thyroid synthesis due to Cytadren (Aminoglutethimide, Orimeten).
In spite of an
increase in TSH, Cytadren (Aminoglutethimide, Orimeten) has not been associated with increased prolactin
secretion.
Note: Cytadren (Aminoglutethimide, Orimeten) was marketed previously as an anticonvulsant but was
withdrawn
from marketing for that indication in 1966 because of the effects on
the adrenal gland. Pharmacokinetics
Cytadren (Aminoglutethimide, Orimeten) is rapidly and completely absorbed
after oral administration. In 6 healthy male volunteers, maximum plasma
levels of Cytadren (Aminoglutethimide, Orimeten) averaged 5.9 g/mL
at a median of 1.5 hours
after ingestion of two 250-mg tablets. The bioavailability of tablets
is equivalent to equal doses given as a solution. After ingestion of
a single oral dose, 34%-54% is excreted in the
urine as unchanged drug during the first 48 hours, and an additional
fraction as the N-acetyl
derivative.
The half-life of Cytadren (Aminoglutethimide, Orimeten) in normal volunteers
given single oral doses averaged 12.5 ± 1.6 hours.
Upon withdrawal of therapy with Cytadren (Aminoglutethimide, Orimeten), the ability of the adrenal
glands to
synthesize steroid returns, usually within 72 hours. INDICATIONS AND USAGE
Cytadren (Aminoglutethimide, Orimeten) is indicated for the suppression
of adrenal function in selected patients with Cushing‘s
syndrome. Morning levels of plasma cortisol in patients with adrenal
carcinoma
and ectopic ACTH-producing tumors were reduced on the average to about
one half of the pretreatment levels, and in patients with adrenal hyperplasia
to about two thirds of the
pretreatment levels, during 1-3 months of thera py with Cytadren (Aminoglutethimide,
Orimeten). Data available from the few patients with adrenal adenoma
suggest similar reductions in plasma cortisol levels.
Measurements of plasma cortisol showed reductions to at least 50% of
baseline or to normal levels in one third or more of the patients studied,
depending on diagnostic groups and time of
measurement. Because Cytadren (Aminoglutethimide, Orimeten) does not
affect the underlying disease process, it is used primarily as an interim
measure until more definitive therapy such as surgery can be undertaken
or in cases
where such therapy is not appropriate. Only small numbers of patients
have been treated for longer than 3 months. A decreased effect or —escape phenomenon“ seems
to occur more
frequently in patients with pituitary-dependent Cushing‘s syndrome,
probably because of increasing ACTH levels in response to decreasing
glucocorticoid levels.
Cytadren (Aminoglutethimide, Orimeten) should be used only in those patients who are responsive to
treatment.
CONTRAINDICATIONS
Cytadren (Aminoglutethimide, Orimeten) is contraindicated in those
patients with serious forms, and/or more severe manifestations, of
hypersensitivity to glutethimide or aminoglutethimide. WARNINGS
Cytadren (Aminoglutethimide, Orimeten) may cause adrenocortical hypofunction, especially under conditions
of stress, such
as surgery, trauma, or acute illness. Patients should be carefully
monitored and given
hydrocortisone and mineralocorticoid supplements as indicated. Dexamethasone
should not
be used. (See PRECAUTIONS, Drug Interactions.)
Cytadren (Aminoglutethimide, Orimeten) also may suppress aldosterone production by the adrenal cortex
and may
cause orthostatic or persistent hypotension. The blood pressure should
be monitored in all
patients at appropriate intervals. Patients should be advised of the
possible occurrence of
weakness and dizziness as symptoms of hypotension, and of measures
to be taken should they
occur.
The effects of Cytadren (Aminoglutethimide, Orimeten) may be potentiated if it is taken in combination
with alcohol.
Cytadren (Aminoglutethimide, Orimeten) can cause fetal harm when administered to a pregnant woman.
In the earlier
experience with the drug in about 5000 patients, two cases of pseudohermaphroditism
were
reported in female infants whose mothers were treated with Cytadren (Aminoglutethimide, Orimeten)
and concomitant
anticonvulsants. Normal pregnancies have also occurred in patients
treated with Cytadren (Aminoglutethimide, Orimeten).
When administered to rats at doses 1/2 and 1 1/4 times the maximum
daily human
dose, Cytadren (Aminoglutethimide, Orimeten) caused a decrease in fetal implantation, an increase
in fetal deaths, and a
variety of teratogenic effects. The compound also caused pseudohermaphroditism
in rats
treated with approximately 3 times the maximum daily human dose. If
this drug must be used
during pregnancy, or if the patient becomes pregnant while taking the
drug, the patient should
be apprised of the potential hazard to the fetus.
PRECAUTIONS
General
This drug should be administered only by physicians familiar with its
use and hazards.
Therapy should be initiated in a hospital. (See DOSAGE AND ADMINISTRATION.)
Information for Patients
Patients should be warned that drowsiness may occur and that they should
not drive, operate
potentially dangerous machinery, or engage in other activities that
may become hazardous
because of decreased alertness.
Patients should also be warned of the possibility of hypotension and
its symptoms (see
WARNINGS).
Laboratory Tests
Hypothyroidism may occur in association with Cytadren (Aminoglutethimide,
Orimeten); hence, appropriate clinical observations should be made
and laboratory studies of thyroid function performed as
indicated. Supplementary thyroid hormone may be required.
Hematologic abnormalities in patients receiving Cytadren (Aminoglutethimide, Orimeten) have been
reported (see
ADVERSE REACTIONS). Therefore, baseline hematologic studies should
be performed,
followed by periodic hematologic evaluation.
Since elevations in SGOT, alkaline phosphatase, and bilirubin have
been reported,
appropriate clinical observations and regular laboratory studies should
be performed before
and during therapy.
Serum electrolyte levels should be determined periodically. Drug Interactions
Cytadren (Aminoglutethimide, Orimeten) accelerates the metabolism of
dexamethasone; therefore, if glucocorticoid replacement is needed,
hydrocortisone should be prescribed.
Aminoglutethimide diminishes the effect of coumarin and warfarin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year carcinogenicity study of Cytadren (Aminoglutethimide, Orimeten) conducted in rats at doses
of 10-60 mg/kg/day
(approximately 0.04 to 0.2 times the maximum daily therapeutic dose
based on surface area,
mg/m ) revealed a highly statistically significant dose-related
trend in the incidence of benign
and malignant neoplasms of the adrenal cortex and thyroid follicular
cells in both sexes. A
borderline statistically significant increase (0.05 level) in ovarian
tubular adenomas was
observed at 60 mg/kg/day. Urinary bladder papillomas also showed a
statistically significant
dose-related trend in males. Cytadren (Aminoglutethimide, Orimeten)
affects fertility in female rats (see WARNINGS). The relevance of these
findings to humans is not known. Pregnancy Category D
See WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because
many drugs are
excreted in human milk and because of the potential for serious adverse
reactions in nursing
infants from Cytadren (Aminoglutethimide, Orimeten), 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. Pediatric Use
Safety and effectiveness in pediatric patients have not been established
(see CLINICAL
STUDIES IN CHILDREN).
ADVERSE REACTIONS
Untoward effects have been reported in about 2 out of 3 patients with
Cushing‘s syndrome who were treated for 4 or more weeks with
Cytadren (Aminoglutethimide, Orimeten) as the only adrenocortical suppressant.
The most frequent and reversible side effects were drowsiness (approximately
1 in 3 patients), morbilliform skin rash (1 in 6 patients), nausea
and anorexia (each approximately
1 in 8 patients), and dizziness (about 1 in 20 patients). The dizziness
was possibly caused by lowered vascular resistance or orthostasis.
These reactions often disappear spontaneously
with continued therapy. Other Effects Observed Hematologic: Single
instances of neutropenia, leukopenia (patient received concomitant
o,p'-DDD), pancytopenia (patient received concomitant 5-fluorouracil),
and agranulocytosis occurred in 4 of 27 patients with Cushing‘s
syndrome caused by adrenal carcinoma who were
treated for at least 4 weeks. In 1 patient with adrenal hyperplasia,
hemoglobin levels and hematocrit decreased during the course of treatment
with Cytadren (Aminoglutethimide, Orimeten). From the earlier
experience with the drug used as an anticonvulsant in 1,214 patients,
transient leukopenia was the only hematologic effect and was reported once; Coombs‘-negative
hemolytic anemia also
occurred once. In approximately 300 patients with nonadrenal malignancy,
1 in 25 showed
some degree of anemia, and 1 in 150 developed pancytopenia during treatment
with Cytadren (Aminoglutethimide, Orimeten).
Endocrine: Adrenal insufficiency occurred in about 1 in 30 patients
with Cushing‘s syndrome who were treated with Cytadren (Aminoglutethimide,
Orimeten) for 4 or more weeks. This insufficiency tended to
involve glucocorticoids as well as mineralocorticoids. Hypothyroidism
is occasionally associated with thyroid enlargement and may be detected
or confirmed by measuring plasma
levels of the thyroid hormone. Masculinization and hirsutism have occasionally
occurred in females, as has precocious sexual development in males.
Central Nervous System: Headache was reported in a bout 1 in 20 patients.
Cardiovascular: Hypotension, occasionally orthostatic, occurred in
1 in 30 patie nts
receiving Cytadren (Aminoglutethimide, Orimeten). Tachycardia occurred
in 1 in 40 patients. Gastrointestinal and Liver: Vomiting occurred
in 1 in 30 patients. Isolated instances
of abnormal findings on liver function tests were reported. Suspected
hepatotoxicity occurred in less than 1 in 1000 patients.
Skin: In addition to rash (1 in 6 patients, and often reversible with
continued therapy), pruritus was reported in 1 in 20 patients. These
may be allergic or hypersensitive reactions.
Urticaria has occurred rarely. Miscellaneous: Fever was reported
in several patients who were treated with Cytadren (Aminoglutethimide,
Orimeten) for less than 4 weeks; some of these patients also received
other drugs. Myalgia occurred in
1 in 30 patients. Pulmonary hypersensitivity, including allergic alveolitis
and interstitial
alveolar infiltrates, has occurred rarely.
OVERDOSAGE
Acute Toxicity
No deaths due to overdosage with Cytadren (Aminoglutethimide, Orimeten)
have been reported. The
highest known doses that have been survived are 7 g (33-year-old woman), 7.5-10
g (16-year-old girl), and 10 g (10-year-old boy).
Oral LD
Signs and Symptoms
An acute overdose with Cytadren (Aminoglutethimide, Orimeten) may reduce
the production of steroids in the adrenal cortex to a degree that is
clinically relevant. The following manifestations may be expected:
Respiratory Function: Respiratory depression, hypoventilation. Cardiovascular
System: Hypotension, hypovolemic shock due to dehydration.
Central Nervous System/Muscles: Somnolence, lethargy, coma, ataxia,
dizziness, fatigue. (Extreme weakness has been reported with
divided doses of 3 g daily.)
Gastrointestinal System: Nausea, vomiting. Renal Function:
Loss of sodium and water. Laboratory Findings: Hyponatremia,
hypochloremia, hyperkalemia, hypoglycemia. The signs and symptoms
of acute overdosage with Cytadren (Aminoglutethimide, Orimeten) may be aggravated or modified
if alcohol, hypnotics, tranquilizers, or tricyclic antidepressants
have been taken at the same time. Treatment Symptomatic treatment of overdosage is recommended.
Since aminoglutethimide and glutethimide are chemically related, measures
that have
been used in successfully removing glutethimide from the body might
be useful in removing aminoglutethimide.
Gastric lavage and unspecified supportive treatment have been employed.
Full consciousness following deep coma was regained 40 hours
or less after ingestion of 3 or 4 g
without lavage. No evidence of hematologic, renal, or hepatic effects
was subsequently found. Close monitoring should be provided,
and appropriate measures taken to support vital
functions, if necessary.
If deficiency of circulating glucocorticoid develops, an intravenous
infusion of a soluble hydrocortisone preparation (100 mg of
hydrocortisone sodium succinate in 500 mL of
isotonic sodium chloride solution) and 50 mL of 40% glucose solution
should be given within
3 hours. After the initial infusion is completed, an intravenous administration
of
hydrocortisone, 10 mg per hour, should be continued until the patient
is able to take oral cortisone. If hypovolemia or
hypotension occurs, an intravenous administration of
norepinephrine, 10 mg, in 500 mL of isotonic sodium chloride should
be administered according to the patient‘s needs and
response. After rehydration, 500 mL of plasma or blood
should be given for maintenance of sufficient circulatory volume.
Dialysis may be considered in severe intoxication. DOSAGE AND ADMINISTRATION
Adults
Treatment should be instituted in a hospital until a stable dosage
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