FRUSEMIDE
DESCRIPTION:
WARNING
Lasix(R) (FRUSEMIDE) 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 "DOSAGE
AND ADMINISTRATION".)
Lasix(R) is a diuretic which is an anthranilic acid derivative. Lasix(R) tablets
for oral administration contain FRUSEMIDE as the active ingredient and the
following inactive ingredients: lactose USP, magnesium stearate NF, starch NF
and talc USP. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid.
Lasix(R) is available as white tablets for oral administration in dosage
strengths of 40 mg. FRUSEMIDE is a white to off-white odorless
crystalline powder. It is practically insoluble in water, sparingly soluble in
alcohol, freely soluble in dilute alkali solutions and insoluble in dilute
acids.
ACTIONS/CLINICAL PHARMACOLOGY:
Investigations into the mode of action of Lasix(R) 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 Lasix(R)
inhibits primarily the absorption 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 the 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 FRUSEMIDE glucuronide is the only or at least the
major biotransformation product of FRUSEMIDE in man. FRUSEMIDE is extensively
bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from
1 to 400 Mu-g/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 oral administration is within 1 hour. The peak
effect occurs within the first or second hour. The duration of diuretic effect
is 6 to 8 hours.
In fasted normal men, the mean bioavailability of FRUSEMIDE from Lasix(R)
Tablets and Lasix(R) Oral Solution is 64% and 60%, respectively, of that from an
intravenous injection of the drug. Although FRUSEMIDE is more rapidly absorbed
from the oral solution (50 minutes) than from the tablet (87 minutes), 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 FRUSEMIDE is
approximately 2 hours.
Significantly more FRUSEMIDE is excreted in urine following the IV 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
urine.
INDICATIONS AND USAGE:
EDEMA
Lasix(R) 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. Lasix(R) is particularly useful
when an agent with greater diuretic potential is desired.
HYPERTENSION
Oral Lasix(R) may be used in adults for the treatment of hypertension alone or
in combination with other antihypertensive agents. Hypertensive patients who
cannot be adequately controlled with thiazides will probably also not be
adequately controlled with Lasix(R) alone.
CONTRAINDICATIONS:
Lasix(R) is contraindicated in patients with anuria and in patients with a
history of hypersensitivity to FRUSEMIDE.
WARNINGS:
Lasix(R) (FRUSEMIDE) 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 "DOSAGE AND ADMINISTRATION".)
WARNINGS In patients with hepatic cirrhosis and ascites, Lasix(R) 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, Lasix(R) should be discontinued.
Cases of tinnitus and reversible or irreversible hearing impairment have been
reported. Usually, reports indicate that Lasix(R) 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 Lasix(R) per minute has been used).
PRECAUTIONS:
GENERAL
Excessive diuresis may cause dehydration and blood volume reduction with
circulatory collapse and possibly vascular thrombosis and embolism, particularly
in elderly patients. As with any effective diuretic, electrolyte depletion may
occur during Lasix(R) therapy, especially in patients receiving higher doses and
a restricted salt intake. Hypokalemia may develop with Lasix(R), especially with
brisk diuresis, inadequate oral eletrolyte 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 Lasix(R) therapy should be observed for these signs or
symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic
alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): 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 Lasix(R). 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 or kidney damage, or other idiosyncratic
reactions.
INFORMATION FOR PATIENTS
Patients receiving Lasix(R) 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 daibetes mellitus should be told that FRUSEMIDE 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
FRUSEMIDE. 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 (particularly potassium), CO2, creatinine and BUN should be
determined frequently during the first few months of Lasix(R) 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
Lasix(R), even in those suspected of latent diabetes.
Lasix(R) may lower serum levels of calcium (rarely cases of tetany have been
reported) and magnesium. Accordingly, serum levels of these electrolytes should
be determined periodically.
DRUG INTERACTIONS
Lasix(R) may increase the ototoxic potential of aminoglycoside antibiotics,
especially in the presence of impaired renal function. Except in life-
threatening situations, avoid this combination.
Lasix(R) should not be used concomitantly with ethacrynic acid because of the
possibility of ototoxicity. Patients receiving high doses of salicylates
concomitantly with Lasix(R), as in rheumatic disease, may experience salicylate
toxicity at lower doses because of competitive renal excretory sites.
Lasix(R) 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.
Lasix(R) may add to or potentiate the therapeutic effect of other
antihypertensive drugs. Potentiation occurs with ganglionic or peripheral
adrenergic blocking drugs.
Lasix(R) may decrease arterial responsiveness to norepinephrine. However,
norepinephrine may still be used effectively.
Simultaneous administration of sucralfate and Lasix(R) tablets may reduce the
natriuretic and antihypertensive effects of Lasix(R). Patients receiving both
drugs should be observed closely to determine if the desired diuretic and/or
antihypertensive effect of Lasix(R) is achieved. The intake of Lasix(R) and
sucralfate should be separated by at least two hours.
One study in six subjects demonstrated that the combination of FRUSEMIDE 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
FRUSEMIDE was used in conjunction with NSAIDs.
Literature reports indicate that coadministration of indomethacin may reduce the
natriuretic and antihypertensive effects of Lasix(R) (FRUSEMIDE) 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 Lasix(R) should be observed closely to
determine if the desired diuretic and/or antihypertensive effect of Lasix(R) is
achieved.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
FRUSEMIDE was tested for carcinogenicity by oral administration in one strain
of mice and one strain of rats. A small but significantly increased incidence of
mammary gland carcinomas occurred in female mice at a dose 17.5 times the
maximum human dose of 600 mg. There were marginal increases in uncommon tumors
in male rats at a dose of 15 mg/kg (slightly greater than the maximum human
dose) but not at 30 mg/kg.
FRUSEMIDE 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, and questionably positive for gene mutation in mouse lymphoma
cells in the presence of rat liver S9 at the highest dose tested. FRUSEMIDE did
not induce sister chromatid exchange in human cells In Vitro, but other studies
on chromosomal aberrations in human cells In Vitro gave conflicting results. In
Chinese hamster cells it induced chromosomal damage but was questionably
positive for sister chromatic exchange. Studies on the induction by FRUSEMIDE
of chromosomal aberrations in mice were inconclusive. The urine of rats treated
with this drug did not induce gene conversion in SACCHAROMYCES CEREVISIAE.
Lasix(R) produced no impairment of fertility in male or female rats, at 100
mg/kg/day (the maximum effective diuretic dose in the rat and 8 times the
maximal human dose of 600 mg/day).
PREGNANCY
PREGNANCY CATEGORY C-FRUSEMIDE has been shown to cause unexplained maternal
deaths and abortions in rabbits at 2, 4, and 8 times the maximal recommended
human dose. There are no adequate and well-controlled studies in pregnant
women. Lasix(R) should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
The effects of FRUSEMIDE on embryonic and fetal development and on pregnant
dams were studied in mice, rats and rabbits.
FRUSEMIDE caused unexplained maternal deaths and abortions in the rabbit at the
lowest dose of 25 mg/kg (2 times the maximal recommended human dose of 600
mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended
human dose of 600 mg/day) also caused maternal deaths and abortions when
administered to rabbits between Days 12 and 17 of gestation. In a third study,
none of the pregnant rabbits survived a dose of 100 mg/kg. Data from the above
studies indicate fetal lethality that can precede maternal deaths.
The results of the mouse study and one of the three rabbit studies also showed
an increased incidence and severity of hydronephrosis (distention of the renal
pelvis and, in some cases, of the ureters) in fetuses derived from the treated
dams as compared with the incidence in fetuses from the control group.
NURSING MOTHERS
Because it appears in breast milk, caution should be exercised when Lasix(R) is
administered to a nursing mother.
DRUG INTERACTIONS:
Lasix(R) may increase the ototoxic potential of aminoglycoside antibiotics,
especially in the presence of impaired renal function. Except in life-
threatening situations, avoid this combination.
Lasix(R) should not be used concomitantly with ethacrynic acid because of the
possibility of ototoxicity. Patients receiving high doses of salicylates
concomitantly with Lasix(R), as in rheumatic disease, may experience salicylate
toxicity at lower doses because of competitive renal excretory sites.
Lasix(R) 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.
Lasix(R) may add to or potentiate the therapeutic effect of other
antihypertensive drugs. Potentiation occurs with ganglionic or peripheral
adrenergic blocking drugs.
Lasix(R) may decrease arterial responsiveness to norepinephrine. However,
norepinephrine may still be used effectively.
Simultaneous administration of sucralfate and Lasix(R) tablets may reduce the
natriuretic and antihypertensive effects of Lasix(R). Patients receiving both
drugs should be observed closely to determine if the desired diuretic and/or
antihypertensive effect of Lasix(R) is achieved. The intake of Lasix(R) and
sucralfate should be separated by at least two hours.
One study in six subjects demonstrated that the combination of FRUSEMIDE 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
FRUSEMIDE was used in conjunction with NSAIDs.
Literature reports indicate that coadministration of indomethacin may reduce the
natriuretic and antihypertensive effects of Lasix(R) (FRUSEMIDE) 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 Lasix(R) should be observed closely to
determine if the desired diuretic and/or antihypertensive effect of Lasix(R) is
achieved.
ADVERSE REACTIONS:
Adverse reactions are categorized below by organ system and listed by decreasing
severity.
GASTROINTESTINAL SYSTEM REACTIONS
1. pancreatitis 5. cramping
2. jaundice (intrahepatic 6. diarrhea
cholestatic jaundice) 7. constipation
3. anorexia 8. nausea
4. oral and gastric 9. vomiting
irritation
SYSTEMIC HYPERSENSITIVITY REACTIONS
1. systemic vasculitis
2. interstitial nephritis
CENTRAL NERVOUS SYSTEM REACTIONS
1. tinnitus and 4. dizziness
hearing loss 5. headache
2. paresthesias 6. blurred vision
3. vertigo 7. xanthopsia
HEMATOLOGIC REACTIONS
1. aplastic anemia (rare) 4. hemolytic anemia
2. thrombocytopenia 5. leukopenia
3. agranulocytosis (rare) 6. anemia
DERMATOLOGIC- HYPERSENSITIVITY REACTIONS
1. exfoliative dermatitis 5. urticaria
2. erythema multiforme 6. rash
3. purpura 7. pruritus
4. photosensitivity
CARDIOVASCULAR REACTION
Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or
narcotics.
OTHER REACTIONS
1. hyperglycemia 6. restlessness
2. glycosuria 7. urinary bladder spasm
3. hyperuricemia 8. thrombophlebitis
4. muscle spasm 9. fever
5. weakness
Whenever adverse reactions are moderate or severe, Lasix(R) dosage should be
reduced or therapy withdrawn.
OVERDOSAGE:
The principal signs and symptoms of overdose with Lasix(R) are dehydration,
blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and
hypochloremic alkalosis, and are extensions of its diuretic action.
The acute toxicity of Lasix(R) has been determined in mice, rats and dogs. In
all three, the oral LD50 exceeded 1000 mg/kg body weight, while the intravenous
LD50 ranged from 300 to 680mg/kg. The acute intragastric toxicity in neonatal
rats is 7 to 10 times that of adult rats.
The concentration of Lasix(R) in biological fluids associated with toxicity or
death is not known.
Treatment of overdosage is supportive and consists of replacement of excessive
fluid and electrolyte losses. Serum electrolytes, carbon dioxide level and blood
pressure should be determined frequently. Adequate drainage must be assured in
patients with urinary bladder outlet obstruction (such as prostatic
hypertrophy).
Hemodialysis does not accelerate FRUSEMIDE elimination.
DOSAGE AND ADMINISTRATION:
EDEMA
Therapy should be individualized according to patient response to gain maximal
therapeutic response and to determine the minimal dose needed to maintain that
response.
ADULTS--The usual initial dose of Lasix(R) is 20 to 80 mg given as a single
dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be
administered 6 to 8 hours later or the dose may be increased. The dose may be
raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous
dose until the desired diuretic effect has been obtained. The individually
determined single dose should then be given once or twice daily (eg. at 8 am and
2 pm). The dose of Lasix(R) may be carefully titrated up to 600 mg/day in
patients with clinically severe edematous states.
Edema may be most efficiently and safely mobilized by giving Lasix(R) on 2 to 4
consecutive days each week.
When doses exceeding 80 mg/day are given for prolonged periods, careful clinical
observation and laboratory monitoring are particularly advisable. (See
PRECAUTIONS.)
PEDIATRIC PATIENTS--The usual initial dose of oral Lasix(R) in pediatric
patients is 2 mg/kg body weight, given as a single dose. If the diuretic
response is not satisfactory after the initial dose, dosage may be increased by
1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater
than 6 mg/kg body weight are not recommended. For maintenance therapy in
pediatric patients, the dose should be adjusted to the minimum effective level.
HYPERTENSION
Therapy should be individualized according to the patient's response to gain
maximal therapeutic response and to determine the minimal dose needed to
maintain the therapeutic response.
ADULTS - The usual initial dose of Lasix(R) for hypertension is 80 mg, usually
divided into 40 mg twice a day. Dosage should then be adjusted according to
response. If response is not satisfactory add other antihypertensive agents.
Changes in blood pressure must be carefully monitored when Lasix(R) is used with
other antihypertensive drugs, especially during initial therapy. To prevent
excessive drop in blood pressure, the dosage of other agents should be reduced
by at least 50 percent when Lasix(R) is added to the regimen. As the blood
pressure falls under the potentiating effect of Lasix(R), a further reduction in
dosage or even discontinuation of other antihypertensive drugs may be necessary.
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