Electrolyte Imbalance and BUN Increases
Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Patients should be observed for clinical signs of fluid or electrolyte imbalance: i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. 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 mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hyponatremia and hypochloremia may occur during the use of thiazides and other diuretics. Any chloride deficit during thiazide therapy is generally mild and may be lessened by the amiloride HCl component of MODURETIC (amiloride and hydrochlorothiazide) . Hypochloremia usually does not require 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 during thiazide therapy, especially with brisk diuresis, when severe cirrhosis is present, during concomitant use of corticosteroids or ACTH, or after prolonged therapy. However, this usually is prevented by the amiloride HCl component of MODURETIC (amiloride and hydrochlorothiazide) .
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Amiloride HCl, a component of MODURETIC (amiloride and hydrochlorothiazide) , has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone.
Increases in BUN levels have been reported with amiloride HCl and with hydrochlorothiazide. These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, when MODURETIC (amiloride and hydrochlorothiazide) is given to such patients, careful monitoring of serum electrolyte and BUN levels is important. In patients with pre-existing severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretic therapy including amiloride HCl and hydrochlorothiazide.
In patients with renal disease, diuretics may precipitate azotemia. Cumulative
effects of the components of MODURETIC (amiloride and hydrochlorothiazide) may develop in patients with impaired
renal function. If renal impairment becomes evident, MODURETIC should be discontinued
(see CONTRAINDICATIONS and WARNINGS).
Carcinogenicity, Mutagenicity, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the effects
upon fertility, mutagenicity or carcinogenic potential of MODURETIC (amiloride and hydrochlorothiazide) .
There was no evidence of a tumorigenic effect when amiloride HCl was administered for 92 weeks to mice at doses up to 10 mg/kg/day (25 times the maximum daily human dose). Amiloride HCl has also been administered for 104 weeks to male and female rats at doses up to 6 and 8 mg/kg/day (15 and 20 times the maximum daily dose for humans, respectively) and showed no evidence of carcinogenicity.
Amiloride HCl was devoid of mutagenic activity in various strains of Salmonella
typhimurium with or without a mammalian liver microsomal activation system
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 vitro in the Ames mutagenicity
assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537,
and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations,
or in vivo in 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 ug/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 conception and throughout
Pregnancy Category B
Teratogenicity studies have been performed with combinations of amiloride
HCl and hydrochlorothiazide in rabbits and mice at doses up to 25 times the
expected maximum daily dose for humans and have revealed no evidence of harm
to the fetus. No evidence of impaired fertility in rats was apparent at dosage
levels up to 25 times the expected maximum human daily dose. A perinatal and
postnatal study in rats showed a reduction in maternal body weight gain during
and after gestation at a daily dose of 25 times the expected maximum daily dose
for humans. The body weights of alive pups at birth and at weaning were also
reduced at this dose level. There are no adequate and well-controlled studies
in pregnant women. Because animal reproduction studies are not always predictive
of human responses, and because of the data listed below with the individual
components, this drug should be used during pregnancy only if clearly needed.
Teratogenicity studies with amiloride HCl in rabbits and mice given 20 and
25 times the maximum human dose, respectively, revealed no evidence of harm
to the fetus, although studies showed that the drug crossed the placenta in
modest amounts. Reproduction studies in rats at 20 times the expected maximum
daily dose for humans showed no evidence of impaired fertility. At approximately
5 or more times the expected maximum daily dose for humans, some toxicity was
seen in adult rats and rabbits and a decrease in rat pup growth and survival
Teratogenic Effects: 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.
Nonteratogenic Effects: Thiazides cross the placental barrier
and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia,
and possibly other adverse reactions that have occurred in adults.
Studies in rats have shown that amiloride is excreted in milk in concentrations
higher than those found in blood, but it is not known whether amiloride HCl
is excreted in human milk. However, thiazides appear in breast milk. Because
of the potential for serious adverse reactions in nursing infants, 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.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of MODURETIC (amiloride and hydrochlorothiazide) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection, and it may be useful to monitor renal
function. (See CONTRAINDICATIONS, Impaired