teroids, ACTH, licorice in large amounts, or prolonged use of laxatives. Digitalis therapy may
(furosemide) Tablets 20, 40, and 80 mg
exaggerate metabolic effects of hypokalemia, especially myocardial effects.
All patients receiving LASIX therapy should be observed for these signs or symptoms of fluid or
LASIX® (furosemide) is a potent diuretic which, if given in excessive amounts, can lead to a
electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or
profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision
hypocalcemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains
is required and dose and dose schedule must be adjusted to the individual patient’s needs. (See
or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or gastrointestinal distur-
DOSAGE AND ADMINISTRATION.)
bances 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,
LASIX® is a diuretic which is an anthranilic acid derivative. LASIX tablets for oral administration contain
precipitation of diabetes mellitus has been reported.
furosemide as the active ingredient and the following inactive ingredients: lactose monohydrate NF,
In patients with severe symptoms of urinary retention (because of bladder emptying disorders, prostatic
magnesium stearate NF, starch NF, talc USP, and colloidal silicon dioxide NF. Chemically, it is
hyperplasia, urethral narrowing), the administration of furosemide can cause acute urinary retention
4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. LASIX is available as white tablets for oral
related to increased production and retention of urine. Thus, these patients require careful monitoring,
administration in dosage strengths of 20, 40 and 80 mg. Furosemide is a white to off-white odorless
especially during the initial stages of treatment.
crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in dilute
In patients at high risk for radiocontrast nephropathy LASIX can lead to a higher incidence of
alkali solutions and insoluble in dilute acids.
deterioration in renal function after receiving radiocontrast compared to high-risk patients who received
only intravenous hydration prior to receiving radiocontrast.
In patients with hypoproteinemia (e.g., associated with nephrotic syndrome) the effect of LASIX may be weakened and its ototoxicity potentiated. Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Patients allergic to sulfonamides may also be allergic to LASIX. 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 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 CLINICAL PHARMACOLOGY
Investigations into the mode of action of LASIX have utilized micropuncture studies in rats, stop flow
Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and
experiments in dogs and various clearance studies in both humans and experimental animals. It has
thereby affect urine glucose tests. The skin of some patients may be more sensitive to the effects of
been demonstrated that LASIX 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
Hypertensive patients should avoid medications that may increase blood pressure, including over-
to the unique site of action. The action on the distal tubule is independent of any inhibitory effect on
the-counter products for appetite suppression and cold symptoms. Laboratory Tests
Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransfor-
Serum electrolytes (particularly potassium), CO , creatinine and BUN should be determined frequently
mation product of furosemide in man. Furosemide is extensively bound to plasma proteins, mainly to
during the first few months of LASIX therapy and periodically thereafter. Serum and urine electrolyte
albumin. Plasma concentrations ranging from 1 to 400 µg/mL are 91 to 99% bound in healthy
determinations are particularly important when the patient is vomiting profusely or receiving parenteral
individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations.
fluids. Abnormalities should be corrected or the drug temporarily withdrawn. Other medications may
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.
Reversible elevations of BUN may occur and are associated with dehydration, which should be avoided,
In fasted normal men, the mean bioavailability of furosemide from LASIX Tablets and LASIX Oral
particularly in patients with renal insufficiency.
Solution is 64% and 60%, respectively, of that from an intravenous injection of the drug. Although
Urine and blood glucose should be checked periodically in diabetics receiving LASIX, even in those
furosemide 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
LASIX may lower serum levels of calcium (rarely cases of tetany have been reported) and magnesium.
significantly. Peak plasma concentrations increase with increasing dose but times-to-peak do not differ
Accordingly, serum levels of these electrolytes should be determined periodically.
among doses. The terminal half-life of furosemide is approximately 2 hours.
In premature infants LASIX may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function
Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral
must be monitored and renal ultrasonography performed. (See PRECAUTIONS: Pediatric Use)
solution. There are no significant differences between the two oral formulations in the amount of
LASIX 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 binding to albumin may be reduced in elderly patients. Furosemide is predominantly
LASIX should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity.
excreted unchanged in the urine. The renal clearance of furosemide after intravenous administration
Patients receiving high doses of salicylates concomitantly with LASIX, as in rheumatic disease, may
in older healthy male subjects (60–70 years of age) is statistically significantly smaller than in younger
experience salicylate toxicity at lower doses because of competitive renal excretory sites.
healthy male subjects (20–35 years of age). The initial diuretic effect of furosemide in older subjects
There is a risk of ototoxic effects if cisplatin and LASIX are given concomitantly. In addition,
is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use.)
nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if LASIX is not given in lower
INDICATIONS AND USAGE
doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.
LASIX has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may
LASIX is indicated in adults and pediatric patients for the treatment of edema associated with
potentiate the action of succinylcholine.
congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome.
Lithium generally should not be given with diuretics because they reduce lithium’s renal clearance and
LASIX is particularly useful when an agent with greater diuretic potential is desired.
add a high risk of lithium toxicity. Hypertension
LASIX combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may
Oral LASIX may be used in adults for the treatment of hypertension alone or in combination with other
lead to severe hypotension and deterioration in renal function, including renal failure. An interruption
antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will
or reduction in the dosage of LASIX, angiotensin converting enzyme inhibitors, or angiotensin receptor
probably also not be adequately controlled with LASIX alone. CONTRAINDICATIONS
Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
LASIX is contraindicated in patients with anuria and in patients with a history of hypersensitivity to
LASIX may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be
Simultaneous administration of sucralfate and LASIX tablets may reduce the natriuretic and antihy-
In patients with hepatic cirrhosis and ascites, LASIX therapy is best initiated in the hospital. In hepatic
pertensive effects of LASIX. Patients receiving both drugs should be observed closely to determine if
coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition
the desired diuretic and/or antihypertensive effect of LASIX is achieved. The intake of LASIX and
is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate
sucralfate should be separated by at least two hours.
hepatic coma; therefore, strict observation is necessary during the period of diuresis. Supplemental
In isolated cases, intravenous administration of LASIX within 24 hours of taking chloral hydrate may
potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia
lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure and tachycardia.
Use of LASIX concomitantly with chloral hydrate is, therefore, not recommended.
If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, LASIX
Phenytoin interferes directly with renal action of LASIX. There is evidence that treatment with phenytoin
leads to decrease intestinal absorption of LASIX, and consequently to lower peak serum furosemide
Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported.
Reports usually indicate that LASIX ototoxicity is associated with rapid injection, severe renal
Methotrexate and other drugs that, like LASIX, undergo significant renal tubular secretion may reduce
impairment, the use of higher than recommended doses, hypoproteinemia or concomitant therapy with
the effect of LASIX. Conversely, LASIX may decrease renal elimination of other drugs that undergo
aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs. If the physician elects to use high
tubular secretion. High-dose treatment of both LASIX and these other drugs may result in elevated
dose parenteral therapy, controlled intravenous infusion is advisable (for adults, an infusion rate not
serum levels of these drugs and may potentiate their toxicity as well as the toxicity of LASIX.
exceeding 4 mg LASIX per minute has been used). (See PRECAUTIONS: Drug Interactions)
LASIX can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or
Concomitant use of cyclosporine and LASIX is associated with increased risk of gouty arthritis
Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and
secondary to LASIX-induced hyperurecemia and cyclosporine impairment of renal urate excretion.
possibly vascular thrombosis and embolism, particularly in elderly patients. As with any effective
One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid
diuretic, electrolyte depletion may occur during LASIX therapy, especially in patients receiving higher
temporarily reduced creatinine clearance in patients with chronic renal insufficiency. There are case
doses and a restricted salt intake. Hypokalemia may develop with LASIX, especially with brisk diuresis,
reports of patients who developed increased BUN, serum creatinine and serum potassium levels, and
inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticos-
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 LASIX (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 LASIX should be observed closely to determine if the desired
diuretic and/or antihypertensive effect of LASIX is achieved. Carcinogenesis, Mutagenesis, Impairment of Fertility
Furosemide 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)
Furosemide 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
4. drug rash with eosinophilia and systemic symptoms
mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest dose tested.
5. acute generalized exanthematous pustulosis
Furosemide 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 chromatid exchange. Studies
on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of
rats treated with this drug did not induce gene conversion in Saccharomyces cerevisiae.
LASIX (furosemide) 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 Cardiovascular Reaction PREGNANCY CATEGORY C - Furosemide has been shown to cause unexplained maternal deaths
1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics.
and abortions in rabbits at 2, 4 and 8 times the maximal recommended human dose. There are no
2. Increase in cholesterol and triglyceride serum levels
adequate and well-controlled studies in pregnant women. LASIX should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Treatment during pregnancy requires monitoring of fetal growth because of the potential for higher birth
The effects of furosemide on embryonic and fetal development and on pregnant dams were studied
Furosemide 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
Whenever adverse reactions are moderate or severe, LASIX dosage should be reduced or therapy
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
The principal signs and symptoms of overdose with LASIX are dehydration, blood volume reduction,
fetuses derived from the treated dams as compared with the incidence in fetuses from the control group.
hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of
Because it appears in breast milk, caution should be exercised when LASIX is administered to a nursing
The acute toxicity of LASIX has been determined in mice, rats and dogs. In all three, the oral LD
exceeded 1000 mg/kg body weight, while the intravenous LD ranged from 300 to 680 mg/kg. The
acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats. Pediatric Use In premature infants LASIX may precipitate nephrocalcinosis/nephrolithiasis.
The concentration of LASIX in biological fluids associated with toxicity or death is not known.
Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no
Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte
history of prematurity who have been treated chronically with LASIX. Monitor renal function, and renal
losses. Serum electrolytes, carbon dioxide level and blood pressure should be determined frequently.
ultrasonography should be considered, in pediatric patients receiving LASIX.
Adequate drainage must be assured in patients with urinary bladder outlet obstruction (such as prostatic
If LASIX is administered to premature infants during the first weeks of life, it may increase the risk of
Hemodialysis does not accelerate furosemide elimination. Geriatric Use DOSAGE AND ADMINISTRATION
Controlled clinical studies of LASIX did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical experience
Therapy should be individualized according to patient response to gain maximal therapeutic response
has not identified differences in responses between the elderly and younger patients. In general, dose
and to determine the minimal dose needed to maintain that response.
selection for the 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
The usual initial dose of LASIX 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.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
dose until the desired diuretic effect has been obtained. The individually determined single dose should
to have decreased renal function, care should be taken in dose selection and it may be useful to monitor
then be given once or twice daily (eg, at 8 am and 2 pm). The dose of LASIX may be carefully titrated
renal function. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)
up to 600 mg/day in patients with clinically severe edematous states. ADVERSE REACTIONS
Edema may be most efficiently and safely mobilized by giving LASIX on 2 to 4 consecutive days each
Adverse reactions are categorized below by organ system and listed by decreasing severity. Gastrointestinal System Reactions
When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and
1. hepatic encephalopathy in patients with hepatocellular insufficiency
laboratory monitoring are particularly advisable. (See PRECAUTIONS: Laboratory Tests.)
3. jaundice (intrahepatic cholestatic jaundice)
In general, dose selection for the elderly patient should be cautious, usually starting at the low end of
the dosing range (see PRECAUTIONS: Geriatric Use).
The usual initial dose of oral LASIX 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
Hypertension Systemic Hypersensitivity Reactions
Therapy should be individualized according to the patient’s response to gain maximal therapeuticresponse and to determine the minimal dose needed to maintain the therapeutic response.
1. Severe anaphylactic or anaphylactoid reactions (e.g. with shock)
The usual initial dose of LASIX 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
Central Nervous System Reactions
Changes in blood pressure must be carefully monitored when LASIX 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 is added to the regimen. As the blood
pressure falls under the potentiating effect of LASIX, a further reduction in dosage or even
discontinuation of other antihypertensive drugs may be necessary.
In general, dose selection and dose adjustment for the elderly patient should be cautious, usually
starting at the low end of the dosing range (see PRECAUTIONS: Geriatric Use). HOW SUPPLIED LASIX (furosemide) Tablets 20 mg are supplied as white, oval, monogrammed tablets in Bottles of 100 (NDC 0039-0067-10), and 1000 (NDC 0039-0067-70). The 20 mg tablets are imprinted with ″Lasix®″
on one side. LASIX Tablets 40 mg are supplied as white, round, monogrammed, scored tablets in Bottles of 100(NDC 0039-0060-13), 500 (NDC 0039-0060-50), and 1000 (NDC 0039-0060-70). The 40 mg tabletsare imprinted with ″Lasix® 40″ on one side. LASIX Tablets 80 mg are supplied as white, round, monogrammed, facetted edge tablets in Bottles of50 (NDC 0039-0066-05) and 500 (NDC 0039-0066-50). The 80 mg tablets are imprinted with ″Lasix®
80″ on one side. Note: Dispense in well-closed, light-resistant containers. Exposure to light might cause a slight discoloration. Discolored tablets should not be dispensed. Tested by USP Dissolution Test 2 Store at 25° C (77° F); excursions permitted to 15 – 30° C (59 – 86° F). [See USP Controlled Room Temperature.]
sanofi-aventis U.S. LLCBridgewater, NJ 08807
b o l l e t t i n o d ’ i n f o r m a z i o n e s u i f a r m a c i AGGIORNAMENTI Progetto Cronos: i risultati dello studio osservazionale Riassunto 7 treated patients, and 36% of these patients discontinuedthe treatment. Background. L’immissione in commercio degli ini- Conclusions. The response to therapy is modest. There is bitori reversibili dell’acetilcolinesterasi
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