WARNINGS
The effects of EDECRIN on electrolytes are related to
its renal pharmacologic activity and are dose dependent.
The possibility of profound electrolyte and water loss
may be avoided by weighing the patient throughout the
treatment period, by careful adjustment of dosage, by
initiating treatment with small doses, and by using the
drug on an intermittent schedule when possible. When excessive
diuresis occurs, the drug should be withdrawn until homeostasis
is restored. When excessive electrolyte loss occurs, the
dosage should be reduced or the drug temporarily withdrawn.
Initiation of diuretic therapy with EDECRIN in the cirrhotic
patient with ascites is best carried out in the hospital.
When maintenance therapy has been established, the individual
can be satisfactorily followed as an outpatient.
EDECRIN should be given with caution to patients with
advanced cirrhosis of the liver, particularly those with
a history of previous episodes of electrolyte imbalance
or hepatic encephalopathy. Like other diuretics it may
precipitate hepatic coma and death.
Too vigorous a diuresis, as evidenced by rapid and excessive
weight loss, may induce an acute hypotensive episode.
In elderly cardiac patients, rapid contraction of plasma
volume and the resultant hemoconcentration should be avoided
to prevent the development of thromboembolic episodes,
such as cerebral vascular thromboses and pulmonary emboli
which may be fatal. Excessive loss of potassium in patients
receiving digitalis glycosides may precipitate digitalis
toxicity. Care should also be exercised in patients receiving
potassium-depleting steroids.
A number of possibly drug-related deaths have occurred
in critically ill patients refractory to other diuretics.
These generally have fallen into two categories: (1) patients
with severe myocardial disease who have been receiving
digitalis and presumably developed acute hypokalemia with
fatal arrhythmia; (2) patients with severely decompensated
hepatic cirrhosis with ascites, with or without accompanying
encephalopathy, who were in electrolyte imbalance and
died because of intensification of the electrolyte defect.
Deafness, tinnitus, and vertigo with a sense of fullness
in the ears have occurred, most frequently in patients
with severe impairment of renal function. These symptoms
have been associated most often with intravenous administration
and with doses in excess of those recommended. The deafness
has usually been reversible and of short duration (one
to 24 hours). However, in some patients the hearing loss
has been permanent. A number of these patients were also
receiving drugs known to be ototoxic. EDECRIN may increase
the ototoxic potential of other drugs (see
PRECAUTIONS
, subsection DRUG INTERACTIONS).
Lithium generally should not be given with diuretics
(see
PRECAUTIONS
, subsection DRUG INTERACTIONS).
PRECAUTIONS
General
Weakness, muscle cramps, paresthesias, thirst, anorexia,
and signs of hyponatremia, hypokalemia, and/or hypochloremic
alkalosis may occur following vigorous or excessive diuresis
and these may be accentuated by rigid salt restriction.
Rarely tetany has been reported following vigorous diuresis.
During therapy with ethacrynic acid, liberalization of
salt intake and supplementary potassium chloride are often
necessary.
When a metabolic alkalosis may be anticipated, e.g.,
in cirrhosis with ascites, the use of potassium chloride
or a potassium-sparing agent before and during therapy
with EDECRIN may mitigate or prevent the hypokalemia.
Loop diuretics have been shown to increase the urinary
excretion of magnesium; this may result in hypomagnesemia.
The safety and efficacy of ethacrynic acid in hypertension
have not been established. However, the dosage of coadministered
antihypertensive agents may require adjustment.
Orthostatic hypotension may occur in patients receiving
other antihypertensive agents when given ethacrynic acid.
EDECRIN has little or no effect on glomerular filtration
or on renal blood flow, except following pronounced reductions
in plasma volume when associated with rapid diuresis.
A transient increase in serum urea nitrogen may occur.
Usually, this is readily reversible when the drug is discontinued.
As with other diuretics used in the treatment of renal
edema, hypoproteinemia may reduce responsiveness to ethacrynic
acid and the use of salt-poor albumin should be considered.
A number of drugs, including ethacrynic acid, have been
shown to displace warfarin from plasma protein; a reduction
in the usual anticoagulant dosage may be required in patients
receiving both drugs.
EDECRIN may increase the risk of gastric hemorrhage associated
with corticosteroid treatment.
Laboratory Tests
Frequent serum electrolyte, CO 2 and BUN determinations
should be performed early in therapy and periodically
thereafter during active diuresis. Any electrolyte abnormalities
should be corrected or the drug temporarily withdrawn.
Increases in blood glucose and alterations in glucose
tolerance tests have been observed in patients receiving
EDECRIN.
Drug Interactions
Lithium generally should not be given with diuretics
because they reduce its renal clearance and add a high
risk of lithium toxicity. Read circulars for lithium preparations
before use of such concomitant therapy.
EDECRIN may increase the ototoxic potential of other
drugs such as aminoglycoside and some cephalosporin antibiotics.
Their concurrent use should be avoided.
A number of drugs, including ethacrynic acid, have been
shown to displace warfarin from plasma protein; a reduction
in the usual anticoagulant dosage may be required in patients
receiving both drugs.
In some patients, the administration of a non-steroidal
antiinflammatory agent can reduce the diuretic, natriuretic,
and antihypertensive effects of loop, potassium-sparing
and thiazide diuretics. Therefore, when EDECRIN and non-steroidal
anti-inflammatory agents are used concomitantly, the patient
should be observed closely to determine if the desired
effect of the diuretic is obtained.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect in a 79-week
oral chronic toxicity study in rats at doses up to 45
times the human dose.
Ethacrynic acid had no effect on fertility in a two-litter
study in rats or a two-generation study in mice at 10
times the human dose.
Pregnancy
Pregnancy Category B: Reproduction studies in the mouse
and rabbit at doses up to 50 times the human dose showed
no evidence of external abnormalities of the fetus due
to EDECRIN.
In a two-litter study in the dog and rat, oral doses
of 5 or 20 mg/kg/day (2Y2 or 10 times the human dose),
respectively, did not interfere with pregnancy or with
growth and development of the pups. Although there was
reduction in the mean body weights of the fetuses in a
teratogenic study in the rat at a dose level of 100 mg/kg
(50 times the human dose), there was no effect on mortality
or postnatal development. Functional and morphologic abnormalities
were not observed.
There are, however, no adequate and well-controlled studies
in pregnant women. Since animal reproduction studies are
not always predictive of human response, EDECRIN should
be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human
milk. Because many drugs are excreted in human milk and
because of the potential for serious adverse reactions
in nursing infants from EDECRIN, 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
There are no well-controlled clinical trials in pediatric
patients. The information on oral dosing in pediatric
patients, other than infants, is supported by evidence
from empiric use in this age group.
For information on oral use in pediatric patients, other
than infants, see INDICATIONS AND USAGE and DOSAGE AND
ADMINISTRATION.
Safety and effectiveness of oral and parenteral use in
infants have not been established (see CONTRAINDICATIONS).
Safety and effectiveness of intravenous use in pediatric
patients have not been established (see DOSAGE AND ADMINISTRATION:
Intravenous Use).
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