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Microsoft word - 60031-01 lasix pi with fda and validus changes clean 07apr2016.docx

LASIX®
(furosemide)
Tablets 20, 40, and 80 mg

WARNING
LASIX® (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 DOSAGE AND ADMINISTRATION.)

DESCRIPTION
LASIX® is a diuretic which is an anthranilic acid derivative. LASIX tablets for oral
administration contain furosemide as the active ingredient and the following inactive ingredients:
lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and colloidal silicon
dioxide NF. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. LASIX is
available as white tablets for oral administration in dosage strengths of 20, 40 and 80 mg.
Furosemide 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.
The CAS Registry Number is 54-31-9.
The structural formula is as follows:

CLINICAL PHARMACOLOGY
Investigations into the mode of action of LASIX 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 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 furosemide glucuronide is the only or at least the major
biotransformation 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 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 furosemide from LASIX Tablets and LASIX
Oral Solution is 64% and 60%, respectively, of that from an intravenous injection of the drug.
Although 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 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 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.
Geriatric Population
Furosemide binding to albumin may be reduced in elderly patients. Furosemide is predominantly
excreted unchanged in the urine. The renal clearance of furosemide after intravenous
administration in older healthy male subjects (60-70 years of age) is statistically significantly
smaller than in younger healthy male subjects (20-35 years of age). The initial diuretic effect of
furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS:
Geriatric Use
.)
INDICATIONS AND USAGE
Edema
LASIX 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 is particularly useful when an agent with greater diuretic potential is desired.
Hypertension
Oral LASIX 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 alone.
CONTRAINDICATIONS
LASIX is contraindicated in patients with anuria and in patients with a history of hypersensitivity
to furosemide.
WARNINGS
In patients with hepatic cirrhosis and ascites, LASIX 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 should be discontinued.
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 impairment, the use of higher than recommended doses, hypoproteinemia 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 per minute has been used).
(See PRECAUTIONS: Drug Interactions)

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 therapy, especially in patients
receiving higher doses and a restricted salt intake. Hypokalemia may develop with LASIX,
especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or
during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of
laxatives. Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially
myocardial effects.
All patients receiving LASIX 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.
In patients with severe symptoms of urinary retention (because of bladder emptying disorders,
prostatic hyperplasia, urethral narrowing), the administration of furosemide can cause acute
urinary retention related to increased production and retention of urine. Thus, these patients
require careful monitoring, especially during the initial stages of treatment.
In patients at high risk for radiocontrast nephropathy, LASIX can lead to a higher incidence of
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 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 (particularly potassium), CO2, creatinine and BUN should be determined
frequently during the first few months of LASIX 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, even in
those suspected of latent diabetes.
LASIX 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.
In premature infants LASIX may precipitate nephrocalcinosis/nephrolithiasis, therefore renal
function must be monitored and renal ultrasonography performed. (See PRECAUTIONS:
Pediatric Use
)

Drug Interactions
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.
LASIX should not be used concomitantly with ethacrynic acid because of the possibility of
ototoxicity. Patients receiving high doses of salicylates concomitantly with LASIX, as in
rheumatic disease, may experience salicylate toxicity at lower doses because of competitive renal
excretory sites.
There is a risk of ototoxic effects if cisplatin and LASIX are given concomitantly. In addition,
nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if LASIX is not given in
lower 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 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 combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may lead to severe hypotension and deterioration in renal function, including renal failure. An interruption or reduction in the dosage of LASIX, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. LASIX may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and LASIX tablets may reduce the natriuretic and antihypertensive effects of LASIX. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of LASIX is achieved. The intake of LASIX and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of LASIX within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of LASIX concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of LASIX. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of LASIX, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like LASIX, undergo significant renal tubular secretion may reduce the effect of LASIX. Conversely, LASIX may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both LASIX and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of LASIX. LASIX can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and LASIX is associated with increased risk of gouty arthritis secondary to LASIX-induced hyperurecemia and cyclosporine impairment of renal urate excretion. High doses (>80 mg) of furosemide may inhibit the binding of thyroid hormones to carrier
proteins and result in transient increase in free thyroid hormones, followed by an overall
decrease in total thyroid hormone levels.
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 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) but not at 30 mg/kg.
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 mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest
dose tested. 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
PREGNANCY CATEGORY C - Furosemide 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 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 weights.
The effects of furosemide on embryonic and fetal development and on pregnant dams were
studied in mice, rats and rabbits.
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 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 is administered to a
nursing mother.
LASIX may inhibit lactation.
Pediatric Use
In premature infants LASIX may precipitate nephrocalcinosis/nephrolithiasis.
Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no
history of prematurity who have been treated chronically with LASIX. Monitor renal function,
and renal ultrasonography should be considered, in pediatric patients receiving LASIX.
If LASIX is administered to premature infants during the first weeks of life, it may increase the
risk of persistence of patent ductus arteriosus
Geriatric Use
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 has not identified differences in responses between the elderly and younger
patients. In general, dose 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 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. (See PRECAUTIONS: General and DOSAGE AND
ADMINISTRATION
.)
ADVERSE REACTIONS
Adverse reactions are categorized below by organ system and listed by decreasing severity.

Gastrointestinal System Reactions
1. hepatic encephalopathy in patients with
6. oral and gastric irritation hepatocellular insufficiency 3. jaundice (intrahepatic cholestatic jaundice) 4. increased liver enzymes Systemic Hypersensitivity Reactions
1. Severe anaphylactic or anaphylactoid
3. interstitial nephritis reactions (e.g. with shock) 4. necrotizing angiitis 2. systemic vasculitis Central Nervous System Reactions
1. tinnitus and hearing loss
6. blurred vision Hematologic Reactions
1. aplastic anemia
2. thrombocytopenia 3. agranulocytosis 4. hemolytic anemia Dermatologic-Hypersensitivity Reactions
1. toxic epidermal necrolysis
7. bullous pemphigoid 2. Stevens-Johnson Syndrome 3. erythema multiforme 9. photosensitivity 4. drug rash with eosinophilia and systemic 5. acute generalized exanthematous pustulosis 12. urticaria 6. exfoliative dermatitis Cardiovascular Reaction
1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics.
2. Increase in cholesterol and triglyceride serum levels
Other Reactions
1. hyperglycemia
7. urinary bladder spasm 3. hyperuricemia 8. thrombophlebitis Whenever adverse reactions are moderate or severe, LASIX dosage should be reduced or therapy
withdrawn.
OVERDOSAGE
The principal signs and symptoms of overdose with LASIX are dehydration, blood volume
reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and
are extensions of its diuretic action.
The acute toxicity of LASIX 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 680
mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats.
The concentration of LASIX 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 furosemide 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 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 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 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: Laboratory
Tests.
)
Geriatric patients -- 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).
Pediatric patients -- 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 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 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 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% 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.
Geriatric patients -- 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 30698-067-01) and 1000 (NDC 30698-067-10). 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 30698-060-01), 500 (NDC 30698-060-50), and 1000 (NDC 30698-060-10). The 40
mg tablets are imprinted with "Lasix® 40" on one side.
LASIX Tablets 80 mg are supplied as white, round, monogrammed, facetted edge tablets in
Bottles of 50 (NDC 30698-066-05) and 500 (NDC 30698-066-50). 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 25º C (77º F); excursions permitted to 15 - 30º C (59 - 86º F). [See USP Controlled
Room Temperature.]
Origin Canada


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