Electrolyte Imbalance and BUN Increases
Patients receiving MAXZIDE (triamterene and hydrochlorothiazide) should be
carefully monitored for fluid or electrolyte imbalances, i.e., hyponatremia,
hypochloremic alkalosis, hypokalemia and hypomagnesemia. Determination of serum
electrolytes to detect possible electrolyte imbalance should be performed at
appropriate intervals. Serum and urine electrolyte determinations are especially
important and should be frequently performed when the patient is vomiting or
receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte
imbalance include: dryness of mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Any chloride deficit during thiazide therapy is generally
mild and usually does not require any specific treatment except under
extraordinary circumstances (as in liver disease or renal disease). Dilutional
hyponatremia may occur in edematous patients in hot weather; appropriate
therapy is water restriction, rather than administration of salt, except in
rare instances when the hyponatremia is life threatening. In actual salt
depletion, appropriate replacement is the therapy of choice.
Hypokalemia may develop with thiazide therapy, especially
with brisk diuresis, when severe cirrhosis is present, or during concomitant
use of corticosteroids, ACTH, amphotericin B or after prolonged thiazide
therapy. However, hypokalemia of this type is usually prevented by the
triamterene component of MAXZIDE (triamterene and hydrochlorothiazide).
Interference with adequate oral electrolyte intake will also
contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response
of the heart to the toxic effects of digitalis (e.g., increased ventricular
MAXZIDE (triamterene and hydrochlorothiazide) may produce an
elevated blood urea nitrogen level (BUN), creatinine level or both. This is
probably not the result of renal toxicity but is secondary to a reversible
reduction of the glomerular filtration rate or a depletion of the intravascular
fluid volume. Elevations in BUN and creatinine levels may be more frequent in
patients receiving divided dose diuretic therapy. Periodic BUN and creatinine
determinations should be made especially in elderly patients, patients with
suspected or confirmed hepatic disease or renal insufficiencies. If azotemia
increases, MAXZIDE (triamterene and hydrochlorothiazide) should be
MAXZIDE should be used with caution in patients with
impaired hepatic function or progressive liver disease, since minor alterations
of fluid and electrolyte balance may precipitate hepatic coma.
Triamterene has been reported in renal stones in association
with other calculus components. MAXZIDE should be used with caution in patients
with histories of renal lithiasis.
Folic Acid Deficiency
Triamterene is a weak folic acid antagonist and may
contribute to the appearance of megaloblastosis in instances where folic acid
stores are decreased. In such patients, periodic blood elevations are
Hyperuricemia may occur or acute gout may be precipitated in
certain patients receiving thiazide therapy.
Metabolic and Endocrine Effects
The thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Calcium excretion is decreased by thiazides. Pathological
changes in the parathyroid gland with hypercalcemia and hypophosphatemia have
been observed in a few patients on prolonged thiazide therapy. The common
complications of hyperparathyroidism such as renal lithiasis, bone resorption,
and peptic ulceration have not been seen. Thiazides should be discontinued
before carrying out tests for parathyroid function.
Insulin requirements in diabetic patients may be increased,
decreased or unchanged. Diabetes mellitus which has been latent may become
manifest during thiazide administration.
Sensitivity reactions to thiazides may occur in patients
with or without a history of allergy or bronchial asthma.
Possible exacerbation or activation of systemic lupus
erythematosus by thiazides has been reported.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Long-term studies with MAXZIDE, the
triamterene/hydrochlorothiazide combination, have not been conducted.
In studies conducted under the auspices of the National
Toxicology Program, groups of rats were fed diets containing 0, 150, 300 or 600
ppm triamterene, and groups of mice were fed diets containing 0, 100, 200 or
400 ppm triamterene. Male and female rats exposed to the highest tested
concentration received triamterene at about 25 and 30 mg/kg/day, respectively.
Male and female mice exposed to the highest tested concentration received
triamterene at about 45 and 60 mg/kg/day, respectively.
There was an increased incidence of hepatocellular neoplasia
(primarily adenomas) in male and female mice at the highest dosage level. These
doses represent 7.5 times and 10 times the MRHD of 300 mg/kg (or 6 mg/kg/day
based on a 50 kg patient) for male and female mice, respectively when based on
body-weight and 0.7 times and 0.9 times the MRHD when based on body-surface
area. Although hepatocellular neoplasia (exclusively adenomas) in the rat study
was limited to triamterene-exposed males, incidence was not dose dependent and
there was no statistically significant difference from control incidence at any
Two-year feeding studies in mice and rats, conducted under
the auspices of the National Toxicology Program (NTP), treated mice and rats
with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On
a body-weight basis, these doses are 600 times (in mice) and 100 times (in
rats) the Maximum Recommended Human Dose (MRHD) for the hydrochlorothiazide
component of MAXZIDE (50 mg/day or 1 mg/kg/day based on a 50 kg patient). On
the basis of body-surface area, these doses are 56 times (in mice) and 21 times
(in rats) the MRHD. These studies uncovered no evidence of carcinogenic
potential of hydrochlorothiazide in rats or female mice, but there was
equivocal evidence of hepatocarcinogenicity in male mice.
Studies of the mutagenic potential of MAXZIDE, the
triamterene/hydrochlorothiazide combination, have not been performed.
Triamterene was not mutagenic in bacteria (S. typhimurium
strains TA 98, TA 100, TA 1535 or TA 1537) with or without metabolic
activation. It did not induce chromosomal aberrations in Chinese hamster ovary
(CHO) cells in vitro with or without metabolic activation, but it did induce
sister chromatid exchanges in CHO cells in vitro with and without metabolic
Hydrochlorothiazide was not genotoxic in in vitro assays
using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella
typhimurium (the Ames test), 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 in
the in vitro CHO sister chromatid exchange (clastogenicity) test, and in the
mouse lymphoma cell (mutagenicity) assays, using concentrations of
hydrochlorothiazide of 43 to 1300 mcg/mL. Positive test results were also
obtained in the Aspergillus nidulans nondisjunction assay using an unspecified
concentration of hydrochlorothiazide.
Impairment of Fertility
Studies of the effects of MAXZIDE, the
triamterene/hydrochlorothiazide combination, or of triamterene alone on animal
reproductive function have not been conducted.
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/day, respectively, prior to mating
and throughout gestation. Corresponding multiples of the MRHD are 100 (mice)
and 4 (rats) on the basis of body-weight and 9.4 (mice) and 0.8 (rats) on the
basis of body-surface area.
Category C: MAXZIDE: Animal reproduction studies to
determine the potential for fetal harm by MAXZIDE have not been conducted.
Nevertheless, a One Generation Study in the rat approximated MAXZIDE's
composition by using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30
mg/kg/day). There was no evidence of teratogenicity at those doses that were,
on a body-weight basis, 15 and 30 times, respectively, the MRHD, and, on the
basis of body-surface area, 3.1 and 6.2 times, respectively, the MRHD.
The safe use of MAXZIDE in pregnancy has not been
established since there are no adequate and well controlled studies with
MAXZIDE in pregnant women. MAXZIDE should be used during pregnancy only if the
potential benefit justifies the risk to the fetus.
Reproduction studies have been performed in rats at doses as
high as 20 times the Maximum Recommended Human Dose (MRHD) on the basis of
body-weight, and 6 times the MRHD on the basis of body-surface area without
evidence of harm to the fetus due to triamterene.
Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if
Hydrochlorothiazide was orally administered to pregnant mice
and rats during respective periods of major organogenesis at doses up to 3000
and 1000 mg/kg/day, respectively. At these doses, which are multiples of the
MRHD equal to 3000 for mice and 1000 for rats, based on body-weight, and equal
to 282 for mice and 206 for rats, based on body-surface area, there was no evidence
of harm to the fetus. There are, however, no adequate and well controlled
studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if
Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of thiazides and
triamterene in pregnant women requires that the anticipated benefits be weighed
against possible hazards to the fetus. These hazards include fetal or neonatal
jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions
that have occurred in the adult.
Thiazides and triamterene in combination have not been
studied in nursing mothers. Triamterene appears in animal milk and this may
occur in humans. Thiazides are excreted in human breast milk. If use of the
combination drug product is deemed essential, the patient should stop nursing.
Safety and effectiveness in pediatric patients have not been