DO NOT INTERCHANGE ZAROXOLYN TABLETS AND OTHER FORMULATIONS OF
METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE BIOAVAILABILITY AND
ARE THERAPEUTICALLY EQUIVALENT AT THE SAME DOSES TO MYKROX
TABLETS, A MORE RAPIDLY AVAILABLE AND COMPLETELY BIOAVAILABLE
METOLAZONE PRODUCT. FORMULATIONS BIOEQUIVALENT TO ZAROXOLYN AND
FORMULATIONS BIOEQUIVALENT TO MYKROX SHOULD BE INTERCHANGED FOR
Fluid And Electrolytes
All patients receiving therapy with ZAROXOLYN Tablets should have serum electrolyte measurements
done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance:
namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema
accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with
hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important
when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning
signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle
pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare
occasions, may be life threatening.
The risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe
liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or
when excess potassium is being lost extrarenally, such as with vomiting or diarrhea.
Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result
Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in
patients with diabetes or latent diabetes.
ZAROXOLYN regularly causes an increase in serum uric acid and can occasionally precipitate gouty
attacks even in patients without a prior history of them.
Azotemia, presumably prerenal azotemia, may be precipitated during the administration of
ZAROXOLYN. If azotemia and oliguria worsen during treatment of patients with severe renal disease,
ZAROXOLYN should be discontinued.
Use caution when administering ZAROXOLYN Tablets to patients with severely impaired renal
function. As most of the drug is excreted by the renal route, accumulation may occur.
Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or
concurrent therapy with other antihypertensive drugs.
Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of
vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone
should be discontinued before tests for parathyroid function are performed.
Systemic Lupus Erythematosus
Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility
should be considered with ZAROXOLYN Tablets.
Drug/Laboratory Test Interactions
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily
doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small
number of animals examined histologically and poor survival in the mice limit the conclusions that can
be reached from these studies.
Metolazone was not mutagenic in the Ames Test using Salmonella typhimurium strains TA-97, TA-98,
TA-100, TA-102, and TA-1535. in vitro
Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone
possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were
treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with
untreated females, an increased number of resorption sites was observed in dams mated with males from
the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was
reduced in dams mated with males from the 10 and 50 mg/kg groups.
Pregnancy Category B
Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of
gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, ZAROXOLYN Tablets (metolazone
tablets, USP) should be used during pregnancy only if clearly needed. Metolazone crosses the placental
barrier and appears in cord blood.
The use of ZAROXOLYN Tablets in pregnant women requires that the anticipated benefit be weighed
against possible hazards to the fetus. These hazards include fetal or neonatal jaundice,
thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not
known what effect the use of the drug during pregnancy has on the later growth, development, and
functional maturation of the child. No such effects have been reported with metolazone.
Labor And Delivery
Based on clinical studies in which women received metolazone in late pregnancy until the time of
delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or
Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing
infants from metolazone, 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 in controlled clinical trials.
There is limited experience with the use of ZAROXOLYN in pediatric patients with congestive heart
failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes
insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually
resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients
responded and some gained weight. Those patients who did respond did so in the first few days of
treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect
or a return to baseline status and is not recommended.
There is limited experience with the combination of ZAROXOLYN and furosemide in pediatric patients
with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response
with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe
hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after
ZAROXOLYN was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and
laboratory monitoring of all children treated with diuretics is indicated. See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS.
Clinical studies of ZAROXOLYN 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