WARNINGS
Spironolactone, an ingredient
of Aldactazide, has been shown to be a tumorigen in
chronic toxicity studies in rats (see
PRECAUTIONS
). Aldactazide should be used only in those conditions
described under INDICATIONS AND USAGE.
Unnecessary use of this drug should be avoided.
Fixed-dose combination drugs are
not indicated for initial therapy of edema or hypertension.
Edema or hypertension requires therapy titrated
to the individual patient. If the fixed combination
represents the dosage so determined, its use may
be more convenient in patient management. The treatment
of hypertension and edema is not static but must
be reevaluated as conditions in each patient warrant.
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Potassium supplementation, either in the form of medication
or as a diet rich in potassium, should not ordinarily
be given in association with Aldactazide therapy. Excessive
potassium intake may cause hyperkalemia in patients receiving
Aldactazide (see
PRECAUTIONS
: General). Aldactazide should not be administered concurrently
with other potassium-sparing diuretics. Spironolactone,
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
Aldactazide is given concomitantly with these drugs (see
DRUG INTERACTIONS).
Aldactazide 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).
Thiazides should be used with caution in severe renal
disease. In patients with renal disease, thiazides may
precipitate azotemia. Cumulative effects of the drug may
develop in patients with impaired renal function.
Thiazides may add to or potentiate the action of other
antihypertensive drugs.
Sensitivity reactions to thiazides may occur in patients
with or without a history of allergy or bronchial asthma.
Sulfonamide derivatives, including thiazides, have been
reported to exacerbate or activate systemic lupus erythematosus.
PRECAUTIONS
General
All patients receiving diuretic therapy should be observed
for evidence of fluid or electrolyte imbalance, eg, hypomagnesemia,
hyponatremia, hypochloremic alkalosis, and hypokalemia
or 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 Aldactazide.
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, Aldactazide 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.
Hypokalemia may develop as a result of profound diuresis,
particularly when Aldactazide is used concomitantly with
loop diuretics, glucocorticoids, or ACTH, when severe
cirrhosis is present or after prolonged therapy. Interference
with adequate oral electrolyte intake will also contribute
to hypokalemia. Hypokalemia may cause cardiac arrhythmias
and may exaggerate the effects of digitalis therapy. Potassium
depletion may induce signs of digitalis intoxication at
previously tolerated dosage levels. Although any chloride
deficit is generally mild and usually does not require
specific treatment except under extraordinary circumstances
(as in liver disease or renal disease), chloride replacement
may be required in the treatment of metabolic alkalosis.
Aldactazide therapy may cause a transient elevation of
BUN. This appears to represent a concentration phenomenon
rather than renal toxicity, since the BUN level returns
to normal after use of Aldactazide is discontinued. Progressive
elevation of BUN is suggestive of the presence of preexisting
renal impairment.
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 induced, especially
when Aldactazide 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.
A true low-salt syndrome may rarely develop with Aldactazide
therapy and may be manifested by increasing mental confusion
similar to that observed with hepatic coma. This syndrome
is differentiated from dilutional hyponatremia in that
it does not occur with obvious fluid retention. Its treatment
requires that diuretic therapy be discontinued and sodium
administered.
Hyperuricemia may occur or acute gout may be precipitated
in certain patients receiving thiazides. Thiazides have
been shown to increase the urinary excretion of magnesium;
this may result in hypomagnesemia. Increases in cholesterol
and triglyceride levels may be associated with thiazide
diuretic therapy.
In diabetic patients, dosage adjustments of insulin or
oral hypoglycemic agents may be required. Hyperglycemia
may occur with thiazide diuretics. Thus, latent diabetes
mellitus may become manifest during thiazide therapy.
The antihypertensive effects of Aldactazide may be enhanced
in the post-sympathetectomy patient. If progressive renal
impairment becomes evident, consider withholding or discontinuing
diuretic therapy.
Thiazides may decrease urinary calcium excretion. Thiazides
may cause intermittent and slight elevation of serum calcium
in the absence of known disorders of calcium metabolism.
Marked hypercalcemia may be evidence of hidden hyperparathyroidism.
Thiazides should be discontinued before carrying out tests
for parathyroid function. Pathologic changes in the parathyroid
gland with hypercalcemia and hypophosphatemia have been
observed in patients on prolonged thiazide therapy.
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 Aldactazide is discontinued. In rare instances
some breast enlargement may persist when Aldactazide is
discontinued.
Information for Patients
Patients who receive Aldactazide 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
Thiazides should be discontinued before carrying out
tests for parathyroid function (see
PRECAUTIONS
: General). Thiazides may also decrease
serum PBI levels without evidence of alteration of thyroid
function.
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
Spironolactone: 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.
Hydrochlorothiazide: Two-year feeding
studies in mice and rats conducted under the auspices
of the National Toxicology Program (NTP) uncovered no
evidence of a carcinogenic potential of hydrochlorothiazide
in female mice (at doses of up to approximately 600 mg/kg/day)
or in male and female rats (at doses of up to approximately
100 mg/kg/day). The NTP, however, found equivocal evidence
for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in in vitro assays
using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538
of Salmonella typhimurium (Ames assay) and in the Chinese
Hamster Ovary (CHO) test for chromosomal aberrations,
or in in vivo assays using mouse germinal cell chromosomes,
Chinese hamster bone marrow chromosomes, and the Drosophila
sex-linked recessive lethal trait gene. Positive test
results were obtained only in the in vitro CHO Sister
Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma
Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide
from 43 to 1300 µg/ml, and in the Aspergillus nidulans
non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility
of mice and rats of either sex in studies wherein these
species were exposed, via their diet, to doses of up to
100 and 4 mg/kg, respectively, prior to mating and throughout
gestation.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
Hydrochlorothiazide: Studies in which
hydrochlorothiazide was orally administered to pregnant
mice and rats during their respective periods of major
organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg,
respectively, provided no evidence of harm to the fetus.
There are, however, no adequate and well controlled studies
in pregnant women.
Spironolactone: 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, spironolactone 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 Aldactazide 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 Aldactazide
in pregnant women requires that the anticipated benefit
be weighed against the possible hazards to the fetus.
Non-Teratogenic Effects
Spironolactone or its metabolites may, and hydrochlorothiazide
does, cross the placental barrier and appear in cord blood.
Therefore, the use of Aldactazide in pregnant women requires
that the anticipated benefit be weighed against possible
hazards to the fetus. The hazards include fetal or neonatal
jaundice, thrombocytopenia, and possibly other adverse
reactions that have occurred in adults.
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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