General
All patients receiving diuretic therapy should be observed for evidence of
fluid or electrolyte imbalance, e.g., 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), e.g., 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 Aldactone; 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.
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.
Carcinogenesis, mutagenesis, impairment of fertility
Orally administered Aldactone 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 Aldactone/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 Aldactone and whose primary metabolite, canrenone, is also a major product of Aldactone 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 Aldactone nor potassium canrenoate produced mutagenic effects in tests
using bacteria or yeast. In the absence of metabolic activation, neither Aldactone
nor potassium canrenoate has been shown to be mutagenic in mammalian tests in
vitro. In the presence of metabolic activation, Aldactone 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 Aldactone/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.),
Aldactone was found to increase the length of the estrous cycle by prolonging
diestrus during treatment and inducing constant diestrus during a two-week post-treatment
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. Aldactone (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 Aldactone 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 Aldactone
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. Aldactone 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 Aldactone, appears in human
breast milk. Because Aldactone 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.
Last updated on RxList: 8/19/2009