WARNINGS
Spironolactone has been shown
to be a tumorigen in chronic toxicity studies in rats
(see
PRECAUTIONS
). Aldactone should be used only in those conditions
described under INDICATIONS AND USAGE. Unnecessary
use of this drug should be avoided. |
Potassium supplementation, either in the form of medication
or as a diet rich in potassium, should not ordinarily
be given in association with Aldactone therapy. Excessive
potassium intake may cause hyperkalemia in patients receiving
Aldactone (see
PRECAUTIONS
: General). Aldactone should not be administered
concurrently with other potassium-sparing diuretics. Aldactone,
when used with ACE inhibitors or indomethacin, even in
the presence of a diuretic, has been associated with severe
hyperkalemia. Extreme caution should be exercised when
Aldactone is given concomitantly with these drugs.
Aldactone should be used with caution in patients with
impaired hepatic function because minor alterations of
fluid and electrolyte balance may precipitate hepatic
coma.
Lithium generally should not be given with diuretics
(see DRUG INTERACTIONS).
PRECAUTIONS
General
All patients receiving diuretic therapy should be observed
for evidence of fluid or electrolyte imbalance, eg, hypomagnesemia,
hyponatremia, hypochloremic alkalosis, and hyperkalemia.
Serum and urine electrolyte determinations are particularly
important when the patient is vomiting excessively or
receiving parenteral fluids. Warning signs or symptoms
of fluid and electrolyte imbalance, irrespective of cause,
include dryness of the mouth, thirst, weakness, lethargy,
drowsiness, restlessness, muscle pains or cramps, muscular
fatigue, hypotension, oliguria, tachycardia, and gastrointestinal
disturbances such as nausea and vomiting. Hyperkalemia
may occur in patients with impaired renal function or
excessive potassium intake and can cause cardiac irregularities,
which may be fatal. Consequently, no potassium supplement
should ordinarily be given with Aldactone.
Concomitant administration of potassium-sparing diuretics
and ACE inhibitors or nonsteroidal anti-inflammatory drugs
(NSAIDs), eg, indomethacin, has been associated with severe
hyperkalemia.
If hyperkalemia is suspected (warning signs include paresthesia,
muscle weakness, fatigue, flaccid paralysis of the extremities,
bradycardia and shock) an electrocardiogram (ECG) should
be obtained. However, it is important to monitor serum
potassium levels because mild hyperkalemia may not be
associated with ECG changes.
If hyperkalemia is present, Aldactone should be discontinued
immediately. With severe hyperkalemia, the clinical situation
dictates the procedures to be employed. These include
the intravenous administration of calcium chloride solution,
sodium bicarbonate solution and/or the oral or parenteral
administration of glucose with a rapid-acting insulin
preparation. These are temporary measures to be repeated
as required. Cationic exchange resins such as sodium polystyrene
sulfonate may be orally or rectally administered. Persistent
hyperkalemia may require dialysis.
Reversible hyperchloremic metabolic acidosis, usually
in association with hyperkalemia, has been reported to
occur in some patients with decompensated hepatic cirrhosis,
even in the presence of normal renal function.
Dilutional hyponatremia, manifested by dryness of the
mouth, thirst, lethargy, and drowsiness, and confirmed
by a low serum sodium level, may be caused or aggravated,
especially when Aldactone is administered in combination
with other diuretics, and dilutional hyponatremia may
occur in edematous patients in hot weather; appropriate
therapy is water restriction rather than administration
of sodium, except in rare instances when the hyponatremia
is life-threatening.
Aldactone therapy may cause a transient elevation of
BUN, especially in patients with preexisting renal impairment.
Aldactone may cause mild acidosis.
Gynecomastia may develop in association with the use
of spironolactone; physicians should be alert to its possible
onset. The development of gynecomastia appears to be related
to both dosage level and duration of therapy and is normally
reversible when Aldactone is discontinued. In rare instances
some breast enlargement may persist when Aldactone is
discontinued.
Information for Patients
Patients who receive Aldactone should be advised to avoid
potassium supplements and foods containing high levels
of potassium including salt substitutes.
Laboratory Tests
Periodic determination of serum electrolytes to detect
possible electrolyte imbalance should be done at appropriate
intervals, particularly in the elderly and those with
significant renal or hepatic impairments.
Drug Interactions
See DRUG INTERACTIONS section.
Drug/Laboratory Test Interactions
Several reports of possible interference with digoxin
radioimmunoassays by spironolactone, or its metabolites,
have appeared in the literature. Neither the extent nor
the potential clinical significance of its interference
(which may be assay-specific) has been fully established.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Orally administered spironolactone has been shown to
be a tumorigen in dietary administration studies performed
in rats, with its proliferative effects manifested on
endocrine organs and the liver. In an 18-month study using
doses of about 50, 150 and 500 mg/kg/day, there were statistically
significant increases in benign adenomas of the thyroid
and testes and in male rats, a dose-related increase in
proliferative changes in the liver (including hepatocytomegaly
and hyperplastic nodules). In a 24-month study in which
the same strain of rat was administered doses of about
10, 30, 100 and 150 mg spironolactone/kg/day, the range
of proliferative effects included significant increases
in hepatocellular adenomas and testicular interstitial
cell tumors in males, and significant increases in thyroid
follicular cell adenomas and carcinomas in both sexes.
There was also a statistically significant, but not dose-related,
increase in benign uterine endometrial stromal polyps
in females.
A dose-related (above 20 mg/kg/day) incidence of myelocytic
leukemia was observed in rats fed daily doses of potassium
canrenoate (a compound chemically similar to spironolactone
and whose primary metabolite, canrenone, is also a major
product of spironolactone in man) for a period of one
year. In two year studies in the rat, oral administration
of potassium canrenoate was associated with myelocytic
leukemia and hepatic, thyroid, testicular and mammary
tumors.
Neither spironolactone nor potassium canrenoate produced
mutagenic effects in tests using bacteria or yeast. In
the absence of metabolic activation, neither spironolactone
nor potassium canrenoate has been shown to be mutagenic
in mammalian tests in vitro. In the presence of metabolic
activation, spironolactone has been reported to be negative
in some mammalian mutagenicity tests in vitro and inconclusive
(but slightly positive) for mutagenicity in other mammalian
tests in vitro. In the presence of metabolic activation,
potassium canrenoate has been reported to test positive
for mutagenicity in some mammalian tests in vitro, inconclusive
in others, and negative in still others.
In a three-litter reproduction study in which female
rats received dietary doses of 15 and 50 mg spironolactone/kg/day,
there were no effects on mating and fertility, but there
was a small increase in incidence of stillborn pups at
50 mg/kg/day. When injected into female rats (100 mg/kg/day
for 7 days, i.p.), spironolactone was found to increase
the length of the estrous cycle by prolonging diestrus
during treatment and inducing constant diestrus during
a two week posttreatment observation period. These effects
were associated with retarded ovarian follicle development
and a reduction in circulating estrogen levels, which
would be expected to impair mating, fertility and fecundity.
Spironolactone (100 mg/kg/day), administered i.p. to female
mice during a two week cohabitation period with untreated
males, decreased the number of mated mice that conceived
(effect shown to be caused by an inhibition of ovulation)
and decreased the number of implanted embryos in those
that became pregnant (effect shown to be caused by an
inhibition of implantation), and at 200 mg/kg, also increased
the latency period to mating.
Pregnancy
Teratogenic Effects: Pregnancy Category C.
Teratology studies with spironolactone have been carried
out in mice and rabbits at doses of up to 20 mg/kg/day.
On a body surface area basis, this dose in the mouse is
substantially below the maximum recommended human dose
and, in the rabbit, approximates the maximum recommended
human dose. No teratogenic or other embryotoxic effects
were observed in mice, but the 20 mg/kg dose caused an
increased rate of resorption and a lower number of live
fetuses in rabbits. Because of its anti-androgenic activity
and the requirement of testosterone for male morphogenesis,
Aldactone may have the potential for adversely affecting
sex differentiation of the male during embryogenesis.
When administered to rats at 200 mg/kg/day between gestation
days 13 and 21 (late embryogenesis and fetal development),
feminization of male fetuses was observed. Offspring exposed
during late pregnancy to 50 and 100 mg/kg/day doses of
spironolactone exhibited changes in the reproductive tract
including dose-dependent decreases in weights of the ventral
prostate and seminal vesicle in males, ovaries and uteri
that were enlarged in females, and other indications of
endocrine dysfunction, that persisted into adulthood.
There are no adequate and well-controlled studies with
Aldactone in pregnant women. Spironolactone has known
endocrine effects in animals including progestational
and antiandrogenic effects. The antiandrogenic effects
can result in apparent estrogenic side effects in humans,
such as gynecomastia. Therefore, the use of Aldactone
in pregnant women requires that the anticipated benefit
be weighed against the possible hazards to the fetus.
Nursing Mothers
Canrenone, a major (and active) metabolite of spironolactone,
appears in human breast milk. Because spironolactone has
been found to be tumorigenic in rats, a decision should
be made whether to discontinue the drug, taking into account
the importance of the drug to the mother. If use of the
drug is deemed essential, an alternative method of infant
feeding should be instituted.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
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