CONTRAINDICATIONS
Hyperkalemia
Amiloride HCl; hydrochlorothiazide should not be used in the presence of elevated serum potassium
levels (greater than 5.5 mEq per liter).
Antikaliuretic Therapy or Potassium Supplementation
Amiloride HCl; hydrochlorothiazide should not be given to patients receiving other
potassium-conserving agents, such as spironolactone or triamterene. Potassium supplementation in
the form of medication, potassium-containing salt substitutes or a potassium-rich diet should not be
used with amiloride HCl; hydrochlorothiazide except in severe and/or refractory cases of
hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium
levels. If potassium supplementation is used, careful monitoring of the serum potassium level is
necessary.
Impaired Renal Function
Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are
contraindications to the use of amiloride HCl; hydrochlorothiazide. Patients with evidence of renal
functional impairment (blood urea nitrogen [BUN] levels over 30 mg per 100 ml or serum creatinine
levels over 1.5 mg per 100 ml) or diabetes mellitus should not receive the drug without careful,
frequent and continuing monitoring of serum electrolytes, creatinine, and BUN levels. Potassium
retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal
impairment and may result in the rapid development of hyperkalemia.
Hypersensitivity
Amiloride HCl; hydrochlorothiazide is contraindicated in patients who are hypersensitive to this
product, or to other sulfonamide-derived drugs.
WARNINGS
Hyperkalemia
Like other potassium-conserving diuretic combinations, amiloride HCl; hydrochlorothiazide may
cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter). In patients without
renal impairment or diabetes mellitus, the risk of hyperkalemia with amiloride HCl;
hydrochlorothiazide is about 1-2 percent. This risk is higher in patients with renal impairment or
diabetes mellitus (even without recognized diabetic nephropathy). Since hyperkalemia, if
uncorrected, is potentially fatal, it is essential to monitor serum potassium levels carefully in any
patient receiving amiloride HCl; hydrochlorothiazide, particularly when it is first introduced, at the
time of dosage adjustments, and during any illness that could affect renal function.
The risk of hyperkalemia may be increased when potassium-conserving agents, including amiloride
HCl; hydrochlorothiazide, are administered concomitantly with an angiotensin-converting enzyme
inhibitor. (See DRUG INTERACTIONS) Warning signs or symptoms of hyperkalemia include
paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock,
and ECG abnormalities. Monitoring of the serum potassium level is essential because mild
hyperkalemia is not usually associated with an abnormal ECG.
When abnormal, the ECG in hyperkalemia is characterized primarily by tall, peaked T waves or
elevations from previous tracings. There may also be lowering of the R wave and increased depth
of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS
complex, prolongation of the PR interval, and ST depression.
Treatment of Hyperkalemia: If hyperkalemia occurs in patients taking amiloride HCl;
hydrochlorothiazide, the drug should be discontinued immediately. If the serum potassium level
exceeds 6.5 mEq per liter, active measures should be taken to reduce it. Such measures include the
intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a
rapid-acting insulin preparation. If needed, a cation exchange resin such as sodium polystyrene
sulfonate may be given orally or by enema. Patients with persistent hyperkalemia may require
dialysis.
Diabetes Mellitus
In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving
diuretics, including amiloride HCl, even in patients without evidence of diabetic nephropathy.
Therefore, amiloride HCl; hydrochlorothiazide should be avoided, if possible, in diabetic patients and,
if it is used, serum electrolytes and renal function must be monitored frequently.
Amiloride HCl; hydrochlorothiazide should be discontinued at least three days before glucose
tolerance testing.
Metabolic or Respiratory Acidosis
Antikaliuretic therapy should be instituted only with caution in severely ill patients in whom
respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or
poorly controlled diabetes. If amiloride HCl; hydrochlorothiazide is given to these patients, frequent
monitoring of acid-base balance is necessary. Shifts in acid-base balance alter the ratio of
extracellular/intracellular potassium, and the development of acidosis may be associated with rapid
increases in serum potassium levels.
PRECAUTIONS
General
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 amiloride HCl; 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 amiloride HCl;
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 amiloride HCl; 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 amiloride HCl;
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 amiloride HCl; hydrochlorothiazide may develop in patients with impaired renal
function. If renal impairment becomes evident, amiloride HCl; hydrochlorothiazide should be
discontinued (see CONTRAINDICATIONS and WARNINGS).
Other Precautions
In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or
bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has
been reported with the use of thiazides.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the effects upon fertility,
mutagenicity or carcinogenic potential of amiloride HCl; hydrochlorothiazide.
Amiloride HCl
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 (Ames test).
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 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 mcg/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 gestation.
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 material 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.
Amiloride HCl
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 occurred.
Hydrochlorothiazide
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.
Nursing Mothers
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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.