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WARNING :
Furosemide is a potent diuretic which, if given in excessive
amounts, can lead to a profound diuresis with water and
electrolyte depletion. Therefore, careful medical supervision is
required, and dose and dose schedule must be adjusted to the
individual patient's needs. (See under "DOSAGE AND
ADMINISTRATION.")
DESCRIPTION :
Furosemide is a diuretic which is an anthranilic acid derivative.
Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid.
It is a white to off-white, odorless, crystalline powder,
practically insoluble in water, sparingly soluble in alcohol,
freely soluble in dilute alkali solutions and insoluble in dilute
acids. The structural formula is as follows:
Furosemide Injection is a sterile, nonpyrogenic solution of
furosemide in Water for Injection, prepared with the aid of sodium
hydroxide. The preparation is for intramuscular or intravenous
injection (see DOSAGE and ADMINISTRATION). Each mL contains
furosemide, 10 mg and sodium chloride for isotonicity. The pH
range of the resulting solution is 8.0–9.3. The solution does not
contain any antimicrobial preservatives. The air above the liquid
in the individual containers has been displaced by flushing with
nitrogen during the filling operation.
CLINICAL PHARMACOLOGY :
Investigations into the mode of action of furosemide have utilized
micropuncture studies in rats, stop flow experiments in dogs, and
various clearance studies in both humans and experimental animals.
It has been demonstrated that furosemide inhibits primarily the
reabsorption of sodium and chloride not only in the proximal and
distal tubules but also in the loop of Henle. The high degree of
efficacy is largely due to this unique site of action. The action
on the distal tubule is independent of any inhibitory effect on
carbonic anhydrase and aldosterone.
Recent evidence suggests that furosemide glucuronide is the only
or at least the major bio-transformation product of furosemide in
man. Furosemide is extensively bound to plasma proteins, mainly to
albumin. Plasma concentrations ranging from 1 to 400 µg/mL are 91
to 99% bound in healthy individuals. The unbound fraction averages
2.3 to 4.1% at therapeutic concentrations.
The onset of diuresis following intravenous administration is
within 5 minutes and somewhat later after intramuscular
administration. The peak effect occurs within the first half hour.
The duration of diuretic effect is approximately 2 hours.
In fasted normal men, the mean bioavailability of furosemide from
furosemide tablets and furosemide oral solution is approximately
60% of that from an intravenous injection of the drug. Although
furosemide is more rapidly absorbed from the oral solution than
from the tablet peak plasma levels and area under the plasma
concentration time curves do not differ significantly. Peak plasma
concentrations increase with increasing dose but times-to-peak do
not differ among doses. The terminal half-life of furosemide is
approximately 2 hours.
Significantly more furosemide is excreted in urine following the
I.V. injection than after the tablet or oral solution. There are
no significant differences between the two oral formulations in
the amount of unchanged drug excreted in the urine.
INDICATIONS AND USAGE :
Parenteral therapy should be reserved for patients unable to take
oral medication or for patients in emergency clinical situations.
Edema - Furosemide is indicated in adults and pediatric patients
for the treatment of edema associated with congestive heart
failure, cirrhosis of the liver, and renal disease, including the
nephrotic syndrome. Furosemide is particularly useful when an
agent with greater diuretic potential is desired.
Furosemide is indicated as adjunctive therapy in acute pulmonary
edema. The intravenous administration of furosemide is indicated
when a rapid onset of diuresis is desired, e.g., in acute
pulmonary edema.
If gastrointestinal absorption is impaired or oral medication is
not practical for any reason, furosemide is indicated by the
intravenous or intramuscular route. Parenteral use should be
replaced with oral furosemide as soon as practical.
CONTRAINDICATIONS :
Furosemide is contraindicated in patients with anuria and in
patients with a history of hypersensitivity to furosemide.
WARNINGS
In patients with hepatic cirrhosis and ascites, furosemide therapy
is best initiated in the hospital. In hepatic coma and in states
of electrolyte depletion, therapy should not be instituted until
the basic condition is improved. Sudden alterations of fluid and
electrolyte balance in patients with cirrhosis may precipitate
hepatic coma; therefore, strict observation is necessary during
the period of diuresis. Supplemental potassium chloride and, if
required, an aldosterone antagonist are helpful in preventing
hypokalemia and metabolic alkalosis.
If increasing azotemia and oliguria occur during treatment of
severe progressive renal disease, furosemide should be
discontinued.
Cases of tinnitus and reversible or irreversible hearing
impairment have been reported. Usually, reports indicate that
furosemide ototoxicity is associated with rapid injection, severe
renal impairment, doses exceeding several times the usual
recommended dose, or concomitant therapy with aminoglycoside
antibiotics, ethacrynic acid, or other ototoxic drugs. If the
physician elects to use high dose parenteral therapy, controlled
intravenous infusion is advisable (for adults, an infusion rate
not exceeding 4 mg furosemide per minute has been used.)
Pediatric Use
In premature neonates with respiratory distress syndrome, diuretic
treatment with furosemide in the first few weeks of life may
increase the risk of persistent patent ductus arteriosus (PDA),
possibly through a prostaglandin-E-mediated process.
Literature reports indicate that premature infants with post
conceptual age (gestational plus postnatal) less than 31 weeks
receiving doses exceeding 1 mg/kg/24 hours may develop plasma
levels which could be associated with potential toxic effects
including ototoxicity.
PRECAUTIONS :
General
Excessive diuresis may cause dehydration and blood volume
reduction with circulatory collapse and possible vascular
thrombosis and embolism, particularly in elderly patients. As with
any effective diuretic, electrolyte depletion may occur during
furosemide therapy, especially in patients receiving higher doses
and restricted salt intake. Hypokalemia may develop with
furosemide, especially with brisk diuresis, inadequate oral
electrolyte intake, when cirrhosis is present, or during
concomitant use of corticosteroids or ACTH. Digitalis therapy may
exaggerate metabolic effects of hypokalemia, especially myocardial
effects.
All patients receiving furosemide therapy should be observed for
these signs or symptoms of fluid or electrolyte imbalance (hyponatremia,
hypochloremic alkalosis or hypokalemia): dryness of mouth, thirst,
weakness, lethargy, drowsiness, restlessness, muscle pains or
cramps, muscular fatigue, hypotension, oliguria, tachycardia,
arrhythmia, or gastrointestinal disturbances such as nausea and
vomiting. Increases in blood glucose and alterations in glucose
tolerance tests (with abnormalities of the fasting and 2-hour
postprandial sugar) have been observed, and rarely, precipitation
of diabetes mellitus has been reported.
Asymptomatic hyperuricemia can occur and gout may rarely be
precipitated.
Patients allergic to sulfonamides may also be allergic to
furosemide.
The possibility exists of exacerbation or activation of systemic
lupus erythematosus.
As with many other drugs, patients should be observed regularly
for the possible occurrence of blood dyscrasias, liver damage, or
other idiosyncratic reactions.
Information for Patients
Patients receiving furosemide should be advised that they may
experience symptoms from excessive fluid and/or electrolyte
losses. The postural hypotension that sometimes occurs can usually
be managed by getting up slowly. Potassium supplements and/or
dietary measures may be needed to control or avoid hypokalemia.
Patients with diabetes mellitus should be told that furosemide may
increase blood glucose levels and thereby affect urine glucose
tests. The skin of some patients may be more sensitive to the
effects of sunlight while taking furosemide. Hypertensive patients
should avoid medications that may increase blood pressure,
including over-the-counter products for appetite suppression and
cold symptoms.
Laboratory Tests
Serum electrolytes, CO2 and BUN should be determined frequently
during the first few months of furosemide therapy and periodically
thereafter.
Serum and urine electrolyte determinations are particularly
important when the patient is vomiting profusely or receiving
parenteral fluids. Abnormalities should be corrected or the drug
temporarily withdrawn. Other medications may also influence serum
electrolytes.
Reversible elevations of BUN may occur and are associated with
dehydration, which should be avoided, particularly in patients
with renal insufficiency.
Urine and blood glucose should be checked periodically in
diabetics receiving furosemide, even in those suspected of latent
diabetes.
Furosemide may lower serum calcium levels and tetany has been
reported rarely. Accordingly, serum calcium levels should be
determined periodically.
Drug Interactions
Furosemide may increase the ototoxic potential of aminoglycoside
antibiotics, especially in the presence of impaired renal
function. Except in life-threatening situations, avoid this
combination.
Furosemide should not be used concomitantly with ethacrynic acid
because of the possibility of ototoxicity. Patients receiving high
doses of salicylates concomitantly with furosemide, as in
rheumatic disease, may experience salicylate toxicity at lower
doses because of competitive renal excretory sites.
Furosemide has a tendency to antagonize the skeletal muscle
relaxing effect of tubocurarine and may potentiate the action of
succinylcholine.
Lithium generally should not be given with diuretics because they
reduce lithium's renal clearance and add a high risk of lithium
toxicity.
Furosemide may add to or potentiate the therapeutic effect of
other antihypertensive drugs. Potentiation occurs with ganglionic
or peripheral adrenergic blocking drugs.
Furosemide may decrease arterial responsiveness to norepinephrine.
However, norepinephrine may still be used effectively.
One study in six subjects demonstrated that the combination of
furosemide and acetylsalicylic acid temporarily reduced creatinine
clearance in patients with chronic renal insufficiency. There are
case reports of patients who developed increased BUN, serum
creatinine and serum potassium levels, and weight gain when
furosemide was used in conjunction with NSAIDs.
Literature reports indicate that coadministration of indomethacin
may reduce the natriuretic and antihypertensive effects of
furosemide in some patients by inhibiting prostaglandin synthesis.
Indomethacin may also affect plasma renin levels, aldosterone
excretion, and renin profile evaluation. Patients receiving both
indomethacin and furosemide should be observed closely to
determine if the desired diuretic and/or antihypertensive
effect of furosemide is achieved.
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