Serum potassium should be measured periodically and
potassium supplements or potassium sparing diuretics added if necessary.
Periodic determinations of other electrolytes are advised in patients treated
with high doses or for prolonged periods, particularly in those on low-salt
Hyperuricemia may occur; it has been asymptomatic in
cases reported to date. Reversible elevations of the BUN and creatinine may
also occur, especially in association with dehydration and particularly in
patients with renal insufficiency. Bumex may increase urinary calcium excretion
with resultant hypocalcemia.
Diuretics have been shown to increase the urinary
excretion of magnesium; this may result in hypomagnesemia.
Studies in normal subjects receiving Bumex revealed no
adverse effects on glucose tolerance, plasma insulin, glucagon and growth
hormone levels, but the possibility of an effect on glucose metabolism exists.
Periodic determinations of blood sugar should be done, particularly in patients
with diabetes or suspected latent diabetes.
Patients under treatment should be observed regularly for
possible occurrence of blood dyscrasias, liver damage or idiosyncratic
reactions, which have been reported occasionally in foreign marketing
experience. The relationship of these occurrences to Bumex use is not certain.
Carcinogenesis, Mutagenesis and Impairment Of Fertility
Bumex was devoid of mutagenic activity in various strains
of Salmonella typhimurium when tested in the presence or absence of an in vitro
metabolic activation system. An 18month study showed an increase in mammary
adenomas of questionable significance in female rats receiving oral doses of 60
mg/kg/day (2000 times a 2-mg human dose). A repeat study at the same doses failed
to duplicate this finding.
Reproduction studies were performed to evaluate general
reproductive performance and fertility in rats at oral dose levels of 10, 30,
60 or 100 mg/kg/day. The pregnancy rate was slightly decreased in the treated
animals; however, the differences were small and not statistically significant.
Pregnancy Category C. Bumex is neither teratogenic nor
embryocidal in mice when given in doses up to 3400 times the maximum human
Bumex has been shown to be nonteratogenic, but it has a
slight embryocidal effect in rats when given in doses of 3400 times the maximum
human therapeutic dose and in rabbits at doses of 3.4 times the maximum human
therapeutic dose. In one study, moderate growth retardation and increased
incidence of delayed ossification of sternebrae were observed in rats at oral
doses of 100 mg/kg/day, 3400 times the maximum human therapeutic dose. These
effects were associated with maternal weight reductions noted during dosing. No
such adverse effects were observed at 30 mg/kg/day (1000 times the maximum
human therapeutic dose). No fetotoxicity was observed at 1000 to 2000 times the
human therapeutic dose.
In rabbits, a dose-related decrease in litter size and an
increase in resorption rate were noted at oral doses of 0.1 and 0.3 mg/kg/day
(3.4 and 10 times the maximum human therapeutic dose). A slightly increased
incidence of delayed ossification of sternebrae occurred at 0.3 mg/kg/day;
however, no such adverse effects were observed at the dose of 0.03 mg/kg/day.
The sensitivity of the rabbit to Bumex parallels the marked pharmacologic and
toxicologic effects of the drug in this species.
Bumex was not teratogenic in the hamster at an oral dose
of 0.5 mg/kg/day (17 times the maximum human therapeutic dose). Bumetanide was
not teratogenic when given intravenously to mice and rats at doses up to 140
times the maximum human therapeutic dose.
There are no adequate and well-controlled studies in
pregnant women. A small investigational experience in the United States and
marketing experience in other countries to date have not indicated any evidence
of adverse effects on the fetus, but these data do not rule out the possibility
of harmful effects. Bumex should be given to a pregnant woman only if the
potential benefit justifies the potential risk to the fetus.
It is not known whether this drug is excreted in human
milk. As a general rule, nursing should not be undertaken while the patient is
on Bumex since it may be excreted in human milk.
Safety and effectiveness in pediatric patients below the
age of 18 have not been established.
In vitro studies using pooled sera from critically ill
neonates have shown bumetanide to be a potent displacer of bilirubin (see CLINICAL
PHARMACOLOGY: Pediatric Pharmacology). The administration of
bumetanide could present a particular concern if given to critically ill or
jaundiced neonates at risk for kernicterus.
Clinical studies of Bumex did not include sufficient
numbers of subjects aged 65 and over to determine whether they responded
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.