DO NOT INTERCHANGE: DO NOT INTERCHANGE ZAROXOLYN®
TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE
BIOAVAILABILITY AND ARE NOT 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 NOT BE INTERCHANGED FOR ONE
Fluid and Electrolytes
All patients receiving therapy with metolazone 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 in hypomagnesemia.
Metolazone may raise blood glucose concentrations
possibly causing hyperglycemia and glycosuria in patients with diabetes or
Metolazone 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 metolazone. If azotemia and oliguria
worsen during treatment of patients with severe renal disease, metolazone
should be discontinued.
Use caution when administering metolazone 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 metolazone
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 vitro in the Ames Test
using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535.
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,
metolazone tablets should be used during pregnancy only if clearly needed.
Metolazone crosses the placental barrier and appears in cord blood.
The use of metolazone 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 delivery.
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 metolazone 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
metolazone 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 metolazone 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 metolazone 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.