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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 DOSAGE AND ADMINISTRATION .)

DESCRIPTION Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro -N -furfuryl-5-sulfamoylanthranilic acid. Furosemide Injection 10 mg/mL is a sterile, non-pyrogenic solution in vials for intravenous and intramuscular injection. 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 structural formula is as follows: Molecular Formula: Molecular Weight: C 12 H 11 ClN 2 O 5 S 330.74 Each mL contains: Furosemide USP, 10 mg, Water for Injection q.s., Sodium Chloride for isotonicity, Sodium Hydroxide and, if necessary, Hydrochloric Acid to adjust pH between 8.0 and 9.3. structure

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 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 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 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 intravenous 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use .) Pediatric Population Based on PK results obtained from 51 premature infants (23 to 29 weeks gestational age (GA)) receiving repeated doses up to 4 times the maximum recommended total daily dose for intravenous (IV) administration (or 8 times the maximum recommended total daily dose for enteral administration), body weight and postnatal age were found to have an impact on furosemide clearance. Median clearance (normalized by dosing weight) was observed to increase from 8.9 (range: 2.1 to 21.2) mL/h/kg in infants with postnatal age (PNA) <30 days to 25.3 (range: 8.3 to 44.2) mL/h/kg in infants with PNA ≥30 days. In addition, higher clearance was observed in infants with higher body weight. Bioavailability of enteral dose compared to IV dose was estimated to be around 79%.

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.

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 and deafness have been reported. Reports usually indicate that furosemide 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 furosemide per minute has been used). (See PRECAUTIONS, Drug Interactions . ) 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. Hearing loss in neonates has been associated with the use of furosemide injection (see WARNINGS , above).

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 furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, furosemide 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 furosemide 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 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 or kidney 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, (particularly potassium), CO 2 , creatinine and BUN should be determined frequently during the first few months of furosemide therapy and periodically thereafter.

ations that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms. Laboratory Tests Serum electrolytes, (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (See PRECAUTIONS, Pediatric Use .) 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 diseases, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. 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. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide.

y reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion. 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. 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. 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 Teratogenic Effects: Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4, and 8 times the maximal recommended human oral dose. There are no adequate and well-controlled studies in pregnant women. Furosemide 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 fetal 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 oral dose of 600 mg/day).

higher fetal 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 oral dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human oral 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 an oral 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 of fetuses from the control group. Nursing Mothers Because it appears in breast milk, caution should be exercised when furosemide is administered to a nursing mother. Furosemide may inhibit lactation. Pediatric Use In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus. Renal calcifications (from barely visible on x-ray to staghorn) have occurred in some severely premature infants treated with intravenous furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent use of chlorothiazide has been reported to decrease hypercalcinuria and dissolve some calculi. Geriatric Use Controlled clinical studies of furosemide 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 .)

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 furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, furosemide 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 furosemide 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 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 or kidney 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, (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (See PRECAUTIONS, Pediatric Use .)

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 diseases, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. 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. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion. 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.

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.

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. 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 Teratogenic Effects: Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4, and 8 times the maximal recommended human oral dose. There are no adequate and well-controlled studies in pregnant women. Furosemide 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 fetal 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 oral dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human oral 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 an oral 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 of fetuses from the control group.

Pediatric Use In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus. Renal calcifications (from barely visible on x-ray to staghorn) have occurred in some severely premature infants treated with intravenous furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent use of chlorothiazide has been reported to decrease hypercalcinuria and dissolve some calculi.

Geriatric Use Controlled clinical studies of furosemide 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 hepatocellular insufficiency 6. Oral and gastric irritation 7. Cramping 2. Pancreatitis 8. Diarrhea 3. Jaundice (intrahepatic cholestatic jaundice) 9. Constipation 4. Increased liver enzymes 10. Nausea 5. Anorexia 11. Vomiting Systemic Hypersensitivity Reactions 1. Severe anaphylactic or anaphylactoid reactions (e.g. with shock) 3. Interstitial nephritis 4. Necrotizing angiitis 2. Systemic vasculitis Central Nervous System Reactions 1. Tinnitus and hearing loss 5. Headache 2. Paresthesias 6. Blurred vision 3. Vertigo 7. Xanthopsia 4. Dizziness Hematologic Reactions 1. Aplastic anemia 5. Leukopenia 2. Thrombocytopenia 6. Anemia 3. Agranulocytosis 7. Eosinophilia 4. Hemolytic anemia Dermatologic-Hypersensitivity Reactions 1. Exfoliative dermatitis 6. Urticaria 2. Bullous pemphigoid 7. Rash 3. Erythema multiforme 8. Pruritus 4. Purpura 9. Stevens-Johnson Syndrome 5. Photosensitivity 10. Toxic epidermal necrolysis 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 2. Glycosuria 8. Thrombophlebitis 3. Hyperuricemia 4. Muscle spasms 9. Transient injection site pain following intramuscular injection 5. Weakness 10. Fever 6. Restlessness Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

<table ID="ID36" width="100%"><colgroup><col width="50%"/><col width="50%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="center" valign="top"><content styleCode="bold"> Gastrointestinal System Reactions</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">1. Hepatic encephalopathy in patients with hepatocellular insufficiency</td><td styleCode="Botrule Rrule" align="left" valign="top">6. Oral and gastric irritation 7. Cramping</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">2. Pancreatitis</td><td styleCode="Botrule Rrule" align="left" valign="top">8. Diarrhea</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">3. Jaundice (intrahepatic cholestatic jaundice)</td><td styleCode="Botrule Rrule" align="left" valign="top">9. Constipation</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">4. Increased liver enzymes</td><td styleCode="Botrule Rrule" align="left" valign="top">10. Nausea</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">5. Anorexia</td><td styleCode="Botrule Rrule" align="left" valign="top">11. Vomiting</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="top"><content styleCode="bold"> Systemic Hypersensitivity Reactions</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">1. Severe anaphylactic or anaphylactoid reactions (e.g. with shock)</td><td styleCode="Botrule Rrule" align="left" valign="top">3. Interstitial nephritis 4. Necrotizing angiitis</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">2. Systemic vasculitis</td><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold"> Central Nervous System Reactions</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">1. Tinnitus and hearing loss</td><td styleCode="Botrule Rrule" align="left" valign="top">5. Headache</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">2. Paresthesias</td><td styleCode="Botrule Rrule" align="left" valign="top">6. Blurred vision</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">3. Vertigo</td><td styleCode="Botrule Rrule" align="left" valign="top">7. Xanthopsia</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">4. Dizziness</td><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold"> Hematologic Reactions</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">1. Aplastic anemia</td><td styleCode="Botrule Rrule" align="left" valign="top">5. Leukopenia</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">2. Thrombocytopenia</td><td styleCode="Botrule Rrule" align="left" valign="top">6. Anemia</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">3. Agranulocytosis</td><td styleCode="Botrule Rrule" align="left" valign="top">7. Eosinophilia</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">4.

ia</td><td styleCode="Botrule Rrule" align="left" valign="top">6. Anemia</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">3. Agranulocytosis</td><td styleCode="Botrule Rrule" align="left" valign="top">7. Eosinophilia</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">4. Hemolytic anemia</td><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold"> Dermatologic-Hypersensitivity Reactions</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">1. Exfoliative dermatitis</td><td styleCode="Botrule Rrule" align="left" valign="top">6. Urticaria</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">2. Bullous pemphigoid</td><td styleCode="Botrule Rrule" align="left" valign="top">7. Rash</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">3. Erythema multiforme</td><td styleCode="Botrule Rrule" align="left" valign="top">8. Pruritus</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">4. Purpura</td><td styleCode="Botrule Rrule" align="left" valign="top">9. Stevens-Johnson Syndrome</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">5. Photosensitivity</td><td styleCode="Botrule Rrule" align="left" valign="top">10. Toxic epidermal necrolysis</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="top"><content styleCode="bold"> Cardiovascular Reaction</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="top">1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics. 2. Increase in cholesterol and triglyceride serum levels.</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="top"><content styleCode="bold"> Other Reactions</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">1. Hyperglycemia</td><td styleCode="Botrule Rrule" align="left" valign="top">7. Urinary bladder spasm</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">2. Glycosuria</td><td styleCode="Botrule Rrule" align="left" valign="top">8. Thrombophlebitis</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">3. Hyperuricemia 4. Muscle spasms</td><td styleCode="Botrule Rrule" align="left" valign="top">9. Transient injection site pain following intramuscular injection</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">5. Weakness</td><td styleCode="Botrule Rrule" align="left" valign="top">10. Fever</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">6. Restlessness</td><td styleCode="Botrule Rrule" valign="top"/></tr></tbody></table>

OVERDOSAGE The principal signs and symptoms of overdose with furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. The acute toxicity of furosemide has been determined in mice, rats and dogs. In all three, the oral LD 50 exceeded 1000 mg/kg body weight, while the intravenous LD 50 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 furosemide 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 Adults Parenteral therapy with Furosemide Injection should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical. Edema The usual initial dose of furosemide is 20 to 40 mg given as a single dose, injected intramuscularly or intravenously. The intravenous dose should be given slowly (1 to 2 minutes). Ordinarily a prompt diuresis ensues. If needed, another dose may be administered in the same manner 2 hours later or the dose may be increased. The dose may be raised by 20 mg and given not sooner than 2 hours after the previous dose until the desired diuretic effect has been obtained. This individually determined single dose should then be given once or twice daily. Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response. Close medical supervision is necessary. When furosemide is given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable. (See PRECAUTIONS: Laboratory Tests .) If the physician elects to use high dose parenteral therapy, add the furosemide to either Sodium Chloride Injection, USP, Lactated Ringer's Injection, USP, or Dextrose (5%) Injection, USP after pH has been adjusted to above 5.5, and administer as a controlled intravenous infusion at a rate not greater than 4 mg/min. Furosemide Injection is a buffered alkaline solution with a pH of about 9 and drug may precipitate at pH values below 7. Care must be taken to ensure that the pH of the prepared infusion solution is in the weakly alkaline to neutral range. Acid solutions, including other parenteral medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same infusion because they may cause precipitation of the furosemide. In addition, furosemide injection should not be added to a running intravenous line containing any of these acidic products. Acute Pulmonary Edema The usual initial dose of furosemide is 40 mg injected slowly intravenously (over 1 to 2 minutes). If a satisfactory response does not occur within 1 hour, the dose may be increased to 80 mg injected slowly intravenously (over 1 to 2 minutes). If necessary, additional therapy (e.g., digitalis, oxygen) may be administered concomitantly. 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 Parenteral therapy should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical. The usual initial dose of Furosemide Injection (intravenously or intramuscularly) in pediatric patients is 1 mg/kg body weight and should be given slowly under close medical supervision. If the diuretic response to the initial dose is not satisfactory, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended. Literature reports suggest that the maximum dose for premature infants should not exceed 1 mg/kg/day. (See WARNINGS, Pediatric Use .) Furosemide Injection should be inspected visually for particulate matter and discoloration before administration.

en obtained. Doses greater than 6 mg/kg body weight are not recommended. Literature reports suggest that the maximum dose for premature infants should not exceed 1 mg/kg/day. (See WARNINGS, Pediatric Use .) Furosemide Injection should be inspected visually for particulate matter and discoloration before administration. Since the vials are for single-dose only, any unused portion remaining in the vial should be discarded.

HOW SUPPLIED Furosemide Injection, USP is clear, colorless to slightly yellow solution. Furosemide Injection USP, (10 mg/mL) NDC 23155-473-41 2 mL single dose amber colored vial (23155-473-31) packaged in boxes of 25. NDC 23155-473-42 4 mL single dose amber colored vial (23155-473-32) packaged in boxes of 25. NDC 23155-473-43 4 mL single dose amber colored vial (23155-473-32) packaged in boxes of 50. NDC 23155-473-44 10 mL single dose amber colored vial (23155-473-33) packaged in boxes of 25. NDC 23155-473-45 10 mL single dose amber colored vial (23155-473-33) packaged in boxes of 50. Do not use if solution is discolored. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). Protect from light. Manufactured by: Emcure Pharmaceuticals Ltd., Sanand, Ahmedabad – 382110, India. Manufactured for: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Revised:02 /2025 OR Manufactured by: Maiva Pharma Private Limited. No. 32, Sipcot Industrial Complex, Phase -1, Hosur-635126 Tamilnadu, INDIA. Manufactured for: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Revised : 02 /2025 logo

<table ID="ID41" width="100%"><colgroup><col width="50%"/><col width="50%"/></colgroup><tbody><tr><td align="left" valign="top">NDC 23155-473-41</td><td align="left" valign="top">2 mL single dose amber colored vial (23155-473-31) packaged in boxes of 25.</td></tr><tr><td align="left" valign="top">NDC 23155-473-42</td><td align="left" valign="top">4 mL single dose amber colored vial (23155-473-32) packaged in boxes of 25.</td></tr><tr><td align="left" valign="top">NDC 23155-473-43</td><td align="left" valign="top">4 mL single dose amber colored vial (23155-473-32) packaged in boxes of 50.</td></tr><tr><td align="left" valign="top">NDC 23155-473-44</td><td align="left" valign="top">10 mL single dose amber colored vial (23155-473-33) packaged in boxes of 25.</td></tr><tr><td align="left" valign="top">NDC 23155-473-45</td><td align="left" valign="top">10 mL single dose amber colored vial (23155-473-33) packaged in boxes of 50.</td></tr></tbody></table>

1 INDICATIONS AND USAGE FUROSEMIDE INJECTION is a loop diuretic indicated for: • The treatment of edema associated with heart failure, cirrhosis of the liver, and renal disease ( 1.1 ) • Acute pulmonary edema as adjunctive therapy ( 1.2 ) 1.1 Edema Furosemide Injection is indicated in adults and pediatric patients for the treatment of edema associated with heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. 1.2 Acute Pulmonary Edema Furosemide Injection is indicated as adjunctive therapy in acute pulmonary edema.

2 DOSAGE AND ADMINISTRATION Edema : • Initial dose is 20 mg to 40 mg once given intramuscularly or intravenously. The intravenous dose should be administered slowly over 1 minute to 2 minutes ( 2.2 ) • If needed, a second dose may be administered 2 hours after the first dose ( 2.2 ) Acute Pulmonary Edema : • Initial dose is 40 mg injected slowly intravenously over 1 minute to 2 minutes ( 2.2 ) • If needed, a second dose is 80 mg injected intravenously slowly in 1 minute to 2 minutes ( 2.2 ) Pediatric Dosage : • The initial dose in pediatric patients is 1 mg/kg body weight once given slowly intramuscularly or intravenously. If needed, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended ( 2.3 ) 2.1 General Considerations Inspect Furosemide Injection visually for particulate matter and discoloration before administration. 2.2 Recommended Dosage for Adults Edema Individualize therapy according to patient response. The usual initial dose of furosemide is 20 mg to 40 mg given as a single-dose, injected intramuscularly or intravenously. Give the intravenous dose slowly (over 1 minute to 2 minutes). If needed, administer another dose in the same manner 2 hours later or increase the dose. The dose may be raised by 20 mg and administered not sooner than 2 hours after the previous dose until the desired diuretic effect has been obtained. Administer this individually determined single-dose once or twice daily. If the physician elects to use high-dose parenteral therapy, add the furosemide to either 0.9% Sodium Chloride Injection USP, Lactated Ringer's Injection USP, or Dextrose Injection 5%, USP, after pH has been adjusted to above 5.5, and administer as a controlled intravenous infusion at a rate not greater than 4 mg/min. Furosemide Injection is a buffered alkaline solution with a pH of about 9 and the drug may precipitate at pH values below 7. Care must be taken to ensure that the pH of the prepared infusion solution is in the weakly alkaline to neutral range. Acid solutions, including other parenteral medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same infusion because they may cause precipitation of the furosemide. Acute Pulmonary Edema The usual initial dose of furosemide is 40 mg injected slowly intravenously (over 1 minute to 2 minutes). If a satisfactory response does not occur within 1 hour, increase the dose to 80 mg injected slowly intravenously (over 1 minute to 2 minutes). 2.3 Recommended Dosage for Pediatric Patients The usual initial dose of Furosemide Injection (intravenously or intramuscularly) in pediatric patients is 1 mg/kg body weight administered slowly (over 1 minute to 2 minutes). If the diuretic response to the initial dose is not satisfactory, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended. The maximum dose for premature infants should not exceed 1 mg/kg/day [see Use in Specific Populations (8.4) ] .

3 DOSAGE FORMS AND STRENGTHS Injection: Furosemide Injection, USP is supplied as a sterile, colorless solution as • 20 mg/2 mL (10 mg/mL) in a single-dose vial • 40 mg/4 mL (10 mg/mL) in a single-dose vial • 100 mg/10 mL (10 mg/mL) in a single-dose vial Injection: Furosemide Injection, USP is supplied as a sterile, colorless solution as • 20 mg/2 mL (10 mg/mL) in a single-dose vial ( 3 ) • 40 mg/4 mL (10 mg/mL) in a single-dose vial ( 3 ) • 100 mg/10 mL (10 mg/mL) in a single-dose vial ( 3 )

4 CONTRAINDICATIONS • Furosemide Injection is contraindicated in patients with anuria. • Furosemide Injection is contraindicated in patients with a history of hypersensitivity to furosemide. • Anuria ( 4 ) • Hypersensitivity to furosemide ( 4 )

5 WARNINGS AND PRECAUTIONS • Fluid, Electrolyte, and Metabolic Abnormalities : Monitor serum electrolytes, CO 2 , BUN, creatinine, glucose, and uric acid ( 5.1 ) • Worsening Renal Function : Monitor for dehydration and azotemia. ( 5.2 ) • Ototoxicity: Avoid rapid injection and higher than recommended doses. ( 5.3 , 7.1 ) • Acute Urinary Retention : Monitor patients with symptoms of urinary retention. ( 5.4 ) 5.1 Fluid, Electrolyte, and Metabolic Abnormalities Furosemide may cause fluid, electrolyte, and metabolic abnormalities such as hypovolemia, hypokalemia, azotemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypocalcemia, hyperglycemia, or hyperuricemia, particularly in patients receiving higher doses, patients with inadequate oral electrolyte intake, and in elderly patients. Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients. Serum electrolytes, CO 2 , BUN, creatinine, glucose, and uric acid should be monitored frequently during furosemide therapy. In patients with hepatic cirrhosis and ascites, sudden alterations of fluid and electrolyte balance may precipitate hepatic encephalopathy and coma. Treatment in such patients is best initiated in the hospital with small doses and careful monitoring of the patient's clinical status and electrolyte balance. 5.2 Worsening Renal Function Furosemide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, furosemide should be discontinued [see Clinical Pharmacology (12.3) ] . Furosemide use in the first year of life, especially in patients born pre-term, may precipitate nephrocalcinosis/nephrolithiasis. Therefore renal function must be monitored and renal ultrasonography performed in this age group [see Use in Specific Populations (8.4) ] . 5.3 Ototoxicity Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported. Reports usually indicate that furosemide 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 furosemide per minute has been used) [see Drug Interactions (7.1) ] . Hearing loss in neonates, including premature neonates has been associated with the use of Furosemide Injection [see Use in Specific Populations (8.4) ]. 5.4 Acute Urinary Retention 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.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Fluid, Electrolyte, and Metabolic Abnormalities [see Warnings and Precautions (5.1) ] • Ototoxicity [see Warnings and Precautions (5.3) ] The following adverse reactions associated with the use of furosemide were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized below by organ system and listed by decreasing severity. Gastrointestinal System Reactions: pancreatitis, jaundice (intrahepatic cholestatic jaundice), increased liver enzymes, anorexia, oral and gastric irritation, cramping, diarrhea, constipation, nausea, vomiting. Systemic Hypersensitivity Reactions: severe anaphylactic or anaphylactoid reactions (e.g., with shock), systemic vasculitis, interstitial nephritis, necrotizing angiitis. Central Nervous System Reactions: tinnitus and hearing loss, paresthesias, vertigo, dizziness, headache, blurred vision, xanthopsia. Hematologic Reactions: aplastic anemia, thrombocytopenia, agranulocytosis, hemolytic anemia, leukopenia, anemia, eosinophilia. Dermatologic-Hypersensitivity Reactions: toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, exfoliative dermatitis, bullous pemphigoid, purpura, photosensitivity, rash. Cardiovascular Reactions: orthostatic hypotension, increase in cholesterol and triglyceride serum levels. Other Reactions: glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever. Most common adverse reactions are related to fluid and electrolyte imbalance ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS • Aminoglycoside antibiotics : Increased potential ototoxicity of the antibiotics. Avoid combination ( 7.1 ) • Ethacrynic acid : Risk of ototoxicity. Avoid combination ( 7.1 ) • Salicylates : Risk of salicylate toxicity ( 7.1 ) • Cisplatin and nephrotoxic drugs : Risk of ototoxicity and nephrotoxicity ( 7.1 ) • Lithium : Risk of lithium toxicity ( 7.1 ) • Renin-angiotensin inhibitors : Increased risk of hypotension and renal failure.( 7.1 ) • Adrenergic blocking drugs : Risk of potentiation ( 7.1 ) • Drugs undergoing renal tubular secretion : Risk of toxicity potentiation ( 7.1 ) 7.1 Effects of Furosemide on Other Drugs Drug/Substance Class or Name Drug Interaction Effect Recommendations Aminoglycoside antibiotics Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function [see Warnings and Precautions (5.3) ]. Avoid combination except in life-threatening situations. Ethacrynic acid Possibility of ototoxicity [see Warnings and Precautions (5.3) ]. Avoid concomitant use with ethacrynic acid. Salicylates May experience salicylate toxicity at lower doses because of competitive renal excretory sites. Monitor for symptoms of salicylate toxicity. Cisplatin There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly [see Warnings and Precautions (5.3) ]. Cisplatin and nephrotoxic drugs Nephrotoxicity Administer furosemide at lower doses and with postitive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function. Paralytic agents Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine. Monitor for skeletal muscle effect. Lithium Furosemide reduces lithium's renal clearance and add a high-risk of lithium toxicity. Avoid concomitant use with lithium. Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers May lead to severe hypotension and deterioration in renal function, including renal failure. Monitor for changes in blood pressure and renal function and interrupt or reduce the dosage of furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers if needed. Antihypertensive drugs Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs. Monitor for changes in blood pressure and adjust the dose of other antihypertensive drugs if needed. Adrenergic blocking drugs or peripheral adrenergic blocking drugs Potentiation occurs. Monitor for changes in blood pressure and adjust the dose of adrenergic blocking drugs if needed. Norepinephrine Furosemide may decrease arterial responsiveness (vasoconstricting effect) to norepinephrine. Monitor blood pressure (or mean arterial pressure). Chloral hydrate In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Concomitant use with chloral hydrate is not recommended. Methotrexate and other drugs undergoing renal tubular secretion Furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of furosemide may result in elevated serum levels of these drugs and may potentiate their toxicity. Monitor serum levels of drugs undergoing renal tubular secretion and adjust the dose if needed.

bular secretion Furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of furosemide may result in elevated serum levels of these drugs and may potentiate their toxicity. Monitor serum levels of drugs undergoing renal tubular secretion and adjust the dose if needed. Cephalosporin Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Monitor for changes in renal function. Cyclosporine Increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion. Monitor serum urate levels. Thyroid hormones 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. Monitor the total thyroid hormone levels. 7.2 Effects of Other Drugs on Furosemide Drug/Substance Class or Name Drug Interaction Effect Recommendations Phenytoin Interferes directly with renal action of furosemide. Monitor diuretic effects of furosemide and adjust the dose of furosemide if needed. Methotrexate and other drugs undergoing renal tubular secretion May reduce the effect of furosemide. High-dose treatment of methotrexate and these other drugs may result in elevated serum levels of furosemide and may potentiate the toxicity of furosemide. Monitor for enhanced toxicity of furosemide. Indomethacin 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.

<table width="85%"><col width="32%"/><col width="33%"/><col width="32%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Drug/Substance Class or Name</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Drug Interaction Effect</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Recommendations</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Aminoglycoside antibiotics</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function <content styleCode="italics">[see <linkHtml href="#S5.3">Warnings and Precautions (5.3)</linkHtml>].</content></paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Avoid combination except in life-threatening situations. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Ethacrynic acid</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Possibility of ototoxicity <content styleCode="italics">[see <linkHtml href="#S5.3">Warnings and Precautions (5.3)</linkHtml>].</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Avoid concomitant use with ethacrynic acid. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Salicylates</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>May experience salicylate toxicity at lower doses because of competitive renal excretory sites.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for symptoms of salicylate toxicity.</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Cisplatin</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly <content styleCode="italics">[see <linkHtml href="#S5.3">Warnings and Precautions (5.3)</linkHtml>].</content></paragraph></td><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cisplatin and nephrotoxic drugs</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Nephrotoxicity</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Administer furosemide at lower doses and with postitive fluid balance when used to achieve forced diuresis during cisplatin treatment.

platin and nephrotoxic drugs</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Nephrotoxicity</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Administer furosemide at lower doses and with postitive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Paralytic agents</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for skeletal muscle effect.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lithium</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide reduces lithium&apos;s renal clearance and add a high-risk of lithium toxicity.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Avoid concomitant use with lithium.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>May lead to severe hypotension and deterioration in renal function, including renal failure. </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for changes in blood pressure and renal function and interrupt or reduce the dosage of furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers if needed.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antihypertensive drugs</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for changes in blood pressure and adjust the dose of other antihypertensive drugs if needed.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Adrenergic blocking drugs or peripheral adrenergic blocking drugs</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Potentiation occurs.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for changes in blood pressure and adjust the dose of adrenergic blocking drugs if needed.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Norepinephrine</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide may decrease arterial responsiveness (vasoconstricting effect) to norepinephrine. </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor blood pressure (or mean arterial pressure).</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Chloral hydrate</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Concomitant use with chloral hydrate is not recommended.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Methotrexate and other drugs undergoing renal tubular secretion</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide may decrease renal elimination of other drugs that undergo tubular secretion.

commended.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Methotrexate and other drugs undergoing renal tubular secretion</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of furosemide may result in elevated serum levels of these drugs and may potentiate their toxicity.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor serum levels of drugs undergoing renal tubular secretion and adjust the dose if needed.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cephalosporin</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for changes in renal function.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cyclosporine</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor serum urate levels.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Thyroid hormones</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>High-doses (&gt; 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.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor the total thyroid hormone levels.</paragraph></td></tr></tbody></table>

nding 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.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor the total thyroid hormone levels.</paragraph></td></tr></tbody></table> <table width="85%"><col width="32%"/><col width="33%"/><col width="32%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Drug/Substance Class or Name</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Drug Interaction Effect</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Recommendations</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Phenytoin</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Interferes directly with renal action of furosemide. </paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Monitor diuretic effects of furosemide and adjust the dose of furosemide if needed.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Methotrexate and other drugs undergoing renal tubular secretion</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>May reduce the effect of furosemide. High-dose treatment of methotrexate and these other drugs may result in elevated serum levels of furosemide and may potentiate the toxicity of furosemide.</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Monitor for enhanced toxicity of furosemide.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Indomethacin</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>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. </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Patients receiving both indomethacin and furosemide should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved.</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published observational studies, case reports, and postmarketing reports, from decades of use, have not demonstrated a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes with furosemide use during pregnancy. Untreated congestive heart failure and cirrhosis of the liver can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations ) . In animal reproduction studies, furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits when administered orally during organogenesis at 4 times a human i.v. dose of 80 mg based on body surface area (BSA) and oral bioavailability corrections, presumably secondary to volume depletion (see Data ) . The estimated background risk for major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with congestive heart failure are at increased risk for pre-term birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death and/or stillbirth. Closely monitor pregnant patients for destabilization of their heart failure. Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, pre-term delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly. Data Animal Data 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 (approximately 4 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections). In another study, a dose of 50 mg/kg (approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections) 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 an oral 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 of treated dams as compared with the incidence of fetuses from the control group. 8.2 Lactation Risk Summary The presence of furosemide has been reported in human milk. There are no data on the effects on the breastfed infant or the effects on milk production. Doses of furosemide associated with clinically significant diuresis may impair milk production.

incidence of fetuses from the control group. 8.2 Lactation Risk Summary The presence of furosemide has been reported in human milk. There are no data on the effects on the breastfed infant or the effects on milk production. Doses of furosemide associated with clinically significant diuresis may impair milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for furosemide and any potential adverse effects on the breastfed infant from furosemide or from the underlying maternal condition. 8.4 Pediatric Use Published 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 [see Warnings and Precautions (5.3) ] . Furosemide in the first year of life, especially in patients born pre-term, may precipitate nephrocalcinosis/nephrolithiasis [see Warnings and Precautions (5.2) ] . 8.5 Geriatric Use Controlled clinical studies of furosemide 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 Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Available data from published observational studies, case reports, and postmarketing reports, from decades of use, have not demonstrated a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes with furosemide use during pregnancy. Untreated congestive heart failure and cirrhosis of the liver can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations ) . In animal reproduction studies, furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits when administered orally during organogenesis at 4 times a human i.v. dose of 80 mg based on body surface area (BSA) and oral bioavailability corrections, presumably secondary to volume depletion (see Data ) . The estimated background risk for major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with congestive heart failure are at increased risk for pre-term birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death and/or stillbirth. Closely monitor pregnant patients for destabilization of their heart failure. Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, pre-term delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly. Data Animal Data 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 (approximately 4 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections). In another study, a dose of 50 mg/kg (approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections) 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 an oral 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 of treated dams as compared with the incidence of fetuses from the control group.

8.4 Pediatric Use Published 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 [see Warnings and Precautions (5.3) ] . Furosemide in the first year of life, especially in patients born pre-term, may precipitate nephrocalcinosis/nephrolithiasis [see Warnings and Precautions (5.2) ] .

8.5 Geriatric Use Controlled clinical studies of furosemide 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 Clinical Pharmacology (12.3) ] .

10 OVERDOSAGE The principal signs and symptoms of overdose with furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. The concentration of furosemide 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.

11 DESCRIPTION Furosemide Injection contains furosemide as the active pharmaceutical ingredient. Furosemide is a loop diuretic which is an anthranilic acid derivative. Furosemide chemical name is 4-chloro- N -furfuryl-5-sulfamoylanthranilic acid. Furosemide is a white to slightly-yellow crystalline powder. It is 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: Molecular formula: C 12 H 11 CIN 2 O 5 S Molecular weight: 330.74 Furosemide Injection, USP 10 mg/mL is a sterile, non-pyrogenic solution, available in single-dose vials for intravenous and intramuscular injection. Each mL of Furosemide Injection contains: 10 mg of Furosemide, 7.5 mg of Sodium Chloride for isotonicity, 1.34 mg of Sodium Hydroxide, Hydrochloric Acid and Sodium Hydroxide as pH adjusters, in Water for Injection. Furosemide Injection solution pH is between 8.0 and 9.3. It contains no preservative. Chemical Structure

<table styleCode="Noautorules" width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td colspan="2" valign="top"><renderMultiMedia ID="id-1043436074" referencedObject="ID_76ed7953-2d42-4693-808b-6e485eb7e95b"/></td></tr><tr><td align="center" valign="top"><paragraph>Molecular formula: C₁₂H₁₁CIN₂O₅S</paragraph></td><td align="center" valign="top"><paragraph>Molecular weight: 330.74</paragraph></td></tr></tbody></table>

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics Distribution Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 mcg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations. Elimination The terminal half-life of furosemide is approximately 2 hours. Metabolism Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man. Excretion Significantly more furosemide is excreted in urine following the intravenous injection than after the tablet or oral solution. Specific Populations Geriatric Patients 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects [see Use in Specific Populations (8.5) ] . Pediatric Patients Based on PK results obtained from 51 premature infants (23-29 weeks gestational age (GA)) receiving repeated doses up to 4 times the maximum recommended total daily dose for intravenous (IV) administration (or 8 times the maximum recommended total daily dose for enteral administration), body weight and postnatal age were found to have an impact on furosemide clearance. Median clearance (normalized by dosing weight) was observed to increase from 8.9 (range: 2.1-21.2) ml/h/kg in infants with postnatal age (PNA) <30 days to 25.3 (range: 8.3 to 44.2) ml/h/kg in infants with PNA ≥30 days. In addition, higher clearance was observed in infants with higher body weight. Bioavailability of enteral dose compared to IV dose was estimated to be around 79%. Patients with Renal Impairment 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.

12.1 Mechanism of Action 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.

12.2 Pharmacodynamics 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.

12.3 Pharmacokinetics Distribution Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 mcg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations. Elimination The terminal half-life of furosemide is approximately 2 hours. Metabolism Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man. Excretion Significantly more furosemide is excreted in urine following the intravenous injection than after the tablet or oral solution. Specific Populations Geriatric Patients 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects [see Use in Specific Populations (8.5) ] . Pediatric Patients Based on PK results obtained from 51 premature infants (23-29 weeks gestational age (GA)) receiving repeated doses up to 4 times the maximum recommended total daily dose for intravenous (IV) administration (or 8 times the maximum recommended total daily dose for enteral administration), body weight and postnatal age were found to have an impact on furosemide clearance. Median clearance (normalized by dosing weight) was observed to increase from 8.9 (range: 2.1-21.2) ml/h/kg in infants with postnatal age (PNA) <30 days to 25.3 (range: 8.3 to 44.2) ml/h/kg in infants with PNA ≥30 days. In addition, higher clearance was observed in infants with higher body weight. Bioavailability of enteral dose compared to IV dose was estimated to be around 79%. Patients with Renal Impairment 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 approximately 8 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg/kg but not at 30 mg/kg. Mutagenesis 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 . Impairment of Fertility Furosemide produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic dose in the rat), approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 approximately 8 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg/kg but not at 30 mg/kg. Mutagenesis 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 . Impairment of Fertility Furosemide produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic dose in the rat), approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections.

16 HOW SUPPLIED/STORAGE AND HANDLING Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from light. Furosemide Injection, USP is a sterile, colorless solution for injection, available as a single-dose vial that contains 10 mg/mL of furosemide, and is supplied as follows: Unit of Sale Presentations Concentration NDC 55154-2364-5 Overbagged with 5 x 2mL amber glass single-dose vials in each bag 20 mg/2 mL (10 mg/mL) WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Discard unused portion. Do not use if solution is discolored or contains particulate.

<table width="85%"><col width="32%"/><col width="33%"/><col width="33%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Unit of Sale</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Presentations</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Concentration</content></th></tr></thead><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 55154-2364-5</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Overbagged with 5 x 2mL amber glass single-dose vials in each bag</paragraph><paragraph/></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>20 mg/2 mL (10 mg/mL)</paragraph></td></tr></tbody></table>

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from light. Furosemide Injection, USP is a sterile, colorless solution for injection, available as a single-dose vial that contains 10 mg/mL of furosemide, and is supplied as follows: Unit of Sale Presentations Concentration NDC 55154-2364-5 Overbagged with 5 x 2mL amber glass single-dose vials in each bag 20 mg/2 mL (10 mg/mL) WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Discard unused portion. Do not use if solution is discolored or contains particulate.

17 PATIENT COUNSELING INFORMATION Fluid, Electrolyte, and Metabolic Abnormalities Advise patients 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 [see Warnings and Precautions (5.1) ] . Advise patients that furosemide may increase blood glucose levels and thereby affect urine glucose tests [see Warnings and Precautions (5.1) ] . Photosensitivity The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide [see Adverse Reactions (6) ] . Advise hypertensive patients to avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms [see Drug Interactions (7.1) ] .

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For Medical Information about Furosemide Injection, please visit www.pfizermedinfo.com or call 1‑800‑438‑1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Distributed By: Cardinal Health Dublin, OH 43017 L35119041125 LAB-1025-7.0 Logo

Rx Only 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use .) Pediatric Population Based on PK results obtained from 51 premature infants (23 to 29 weeks gestational age (GA)) receiving repeated doses up to 4 times the maximum recommended total daily dose for intravenous (IV) administration (or 8 times the maximum recommended total daily dose for enteral administration), body weight and postnatal age were found to have an impact on furosemide clearance. Median clearance (normalized by dosing weight) was observed to increase from 8.9 (range: 2.1 to 21.2) ml/h/kg in infants with postnatal age (PNA) <30 days to 25.3 (range: 8.3 to 44.2) ml/h/kg in infants with PNA ≥30 days. In addition, higher clearance was observed in infants with higher body weight. Bioavailability of enteral dose compared to IV dose was estimated to be around 79%. Pediatric Patients: Parenteral therapy should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical. The usual initial dose of Furosemide Injection (intravenously or intramuscularly) in pediatric patients is 1 mg/kg body weight and should be given slowly under close medical supervision. If the diuretic response to the initial dose is not satisfactory, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended. Literature reports suggest that the maximum dose for premature infants should not exceed 1 mg/kg/day. (See WARNINGS, Pediatric Use . ) Furosemide Injection should be inspected visually for particulate matter and discoloration before administration.

DESCRIPTION Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro -N -furfuryl-5-sulfamoylanthranilic acid. Furosemide Injection 10 mg/mL is a sterile, non-pyrogenic solution in vials for intravenous and intramuscular injection. 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 structural formula is as follows: Each mL contains: Furosemide 10 mg, Sodium Hydroxide 1.34 mg, Water for Injection q.s., Sodium Chloride for isotonicity, additional Sodium Hydroxide (q.s.) and, if necessary, Hydrochloric Acid (q.s.) to adjust pH between 8.0 and 9.3. spl-image-01-structure.jpg

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 biotransformation product of furosemide in man. Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 mcg/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 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 intravenous 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.

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 and deafness have been reported. Reports usually indicate that furosemide 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 furosemide per minute has been used). (See PRECAUTIONS, Drug Interactions . ) 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. Hearing loss in neonates has been associated with the use of furosemide injection (See WARNINGS , above).

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 furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, furosemide 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 furosemide 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 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 or kidney 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, (particularly potassium), CO 2 , creatinine and BUN should be determined frequently during the first few months of furosemide therapy and periodically thereafter.

tions that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms. Laboratory Tests: Serum electrolytes, (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (See PRECAUTIONS, Pediatric Use . ) 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 diseases, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. 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. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide.

y reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion. 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 co-administration 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. 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. 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: Teratogenic Effects : Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4, and 8 times the maximal recommended human oral dose. There are no adequate and well-controlled studies in pregnant women. Furosemide 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 fetal 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 oral dose of 600 mg/day).

higher fetal 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 oral dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human oral 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 an oral 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 of fetuses from the control group. Nursing Mothers: Because it appears in breast milk, caution should be exercised when furosemide is administered to a nursing mother. Furosemide may inhibit lactation. Pediatric Use: In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus. Renal calcifications (from barely visible on x-ray to staghorn) have occurred in some severely premature infants treated with intravenous furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent use of chlorothiazide has been reported to decrease hypercalcinuria and dissolve some calculi. Geriatric Use: Controlled clinical studies of furosemide 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 .)

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 furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, furosemide 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 furosemide 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 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 or kidney 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, (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (See PRECAUTIONS, Pediatric Use . )

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 diseases, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. 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. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion. 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 co-administration of indomethacin may reduce the natriuretic and antihypertensive effects of furosemide in some patients by inhibiting prostaglandin synthesis.

ncreased BUN, serum creatinine and serum potassium levels, and weight gain when furosemide was used in conjunction with NSAIDs. Literature reports indicate that co-administration 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.

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. 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: Teratogenic Effects : Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4, and 8 times the maximal recommended human oral dose. There are no adequate and well-controlled studies in pregnant women. Furosemide 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 fetal 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 oral dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human oral 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 an oral 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 of fetuses from the control group.

Pediatric Use: In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus. Renal calcifications (from barely visible on x-ray to staghorn) have occurred in some severely premature infants treated with intravenous furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent use of chlorothiazide has been reported to decrease hypercalcinuria and dissolve some calculi.

Geriatric Use: Controlled clinical studies of furosemide 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 hepatocellular insufficiency 2. Pancreatitis 3. Jaundice (intrahepatic cholestatic jaundice) 4. Increased liver enzymes 5. Anorexia 6. Oral and gastric irritation 7. Cramping 8. Diarrhea 9. Constipation 10. Nausea 11. Vomiting Systemic Hypersensitivity Reactions 1. Severe anaphylactic or anaphylactoid reactions (e.g. with shock) 2. Systemic vasculitis 3. Interstitial nephritis 4. Necrotizing angiitis Central Nervous System Reactions 1. Tinnitus and hearing loss 2. Paresthesias 3. Vertigo 4. Dizziness 5. Headache 6. Blurred vision 7. Xanthopsia Hematologic Reactions 1. Aplastic anemia 2. Thrombocytopenia 3. Agranulocytosis 4. Hemolytic anemia 5. Leukopenia 6. Anemia 7. Eosinophilia Dermatologic-Hypersensitivity Reactions 1. Exfoliative dermatitis 2. Bullous pemphigoid 3. Erythema multiforme 4. Purpura 5. Photosensitivity 6. Urticaria 7. Rash 8. Pruritus 9. Stevens-Johnson Syndrome 10. Toxic epidermal necrolysis 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 2. Glycosuria 3. Hyperuricemia 4. Muscle spasms 5. Weakness 6. Restlessness 7. Urinary bladder spasm 8. Thrombophlebitis 9. Transient injection site pain following intramuscular injection 10. Fever Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn. To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation. at 1-877-725-2747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

OVERDOSAGE The principal signs and symptoms of overdose with furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. The acute toxicity of furosemide has been determined in mice, rats and dogs. In all three, the oral LD 50 exceeded 1,000 mg/kg body weight, while the intravenous LD 50 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 furosemide 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 Adults: Parenteral therapy with Furosemide Injection should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical. Edema The usual initial dose of furosemide is 20 to 40 mg given as a single-dose, injected intramuscularly or intravenously. The intravenous dose should be given slowly (1 to 2 minutes). Ordinarily a prompt diuresis ensues. If needed, another dose may be administered in the same manner 2 hours later or the dose may be increased. The dose may be raised by 20 mg and given not sooner than 2 hours after the previous dose until the desired diuretic effect has been obtained. This individually determined single-dose should then be given once or twice daily. Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response. Close medical supervision is necessary. When furosemide is given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable. (See PRECAUTIONS: Laboratory Tests . ) If the physician elects to use high dose parenteral therapy, add the furosemide to either Sodium Chloride Injection USP, Lactated Ringer's Injection USP, or Dextrose (5%) Injection USP after pH has been adjusted to above 5.5, and administer as a controlled intravenous infusion at a rate not greater than 4 mg/min. Furosemide Injection is a buffered alkaline solution with a pH of about 9 and drug may precipitate at pH values below 7. Care must be taken to ensure that the pH of the prepared infusion solution is in the weakly alkaline to neutral range. Acid solutions, including other parenteral medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same infusion because they may cause precipitation of the furosemide. In addition, furosemide injection should not be added to a running intravenous line containing any of these acidic products. Acute Pulmonary Edema The usual initial dose of furosemide is 40 mg injected slowly intravenously (over 1 to 2 minutes). If a satisfactory response does not occur within 1 hour, the dose may be increased to 80 mg injected slowly intravenously (over 1 to 2 minutes). If necessary, additional therapy (e.g., digitalis, oxygen) may be administered concomitantly. 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 .)

HOW SUPPLIED Furosemide Injection, USP (10 mg/mL) Overbagged with 5 x 4 mL single-dose amber colored vials in each bag, NDC 55154-4452-5 WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Do not use if solution is discolored. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15˚ to 30˚C (59˚ to 86˚F) [See USP Controlled Room Temperature]. Protect from light. Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Manufactured by: Baxter Pharmaceuticals India Private Ltd Ahmedabad 382213, India Baxter is a registered trademark of Baxter International Inc. Distributed By: Cardinal Health Dublin, OH 43017 L53164430224 Rev.: 2025-06-30 1400008744

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 DOSAGE AND ADMINISTRATION ). 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 and deafness have been reported. Reports usually indicate that furosemide 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 furosemide per minute has been used) (See PRECAUTIONS: Drug Interactions ).

DESCRIPTION Each tablet for oral administration contains: Furosemide, USP . . . . . . . . . . . . . . . . 20 mg, 40 mg and 80 mg Each mL of Oral Solution for oral administration contains: Furosemide, USP . . . . . . . . . . . . . . . . 10 mg per mL or 8 mg (40 mg per 5 mL) Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro- N -furfuryl-5-sulfamoylanthranilic acid. Furosemide is a white to slightly yellow, crystalline powder. It is practically insoluble in water; freely soluble in acetone, dimethylformamide and in solutions of alkali hydroxides; soluble in methanol; sparingly soluble in alcohol; slightly soluble in ether; very slightly soluble in chloroform. The CAS Registry Number is 54-31-9. The structural formula is as follows: C 12 H 11 ClN 2 O 5 S M.W. 330.74 Furosemide Tablets, USP are available for oral administration containing 20 mg, 40 mg or 80 mg of Furosemide, USP. The tablets meet Dissolution Test 1. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, purified water, sodium lauryl sulfate, sodium starch glycolate and stearic acid. Furosemide Oral Solution, USP is also available for oral administration containing either 10 mg per mL or 40 mg per 5 mL. The oral solution contains the following inactive ingredients: D and C Yellow No. 10, FD and C Yellow No. 6, flavors, potassium carbonate anhydrous, propylene glycol, purified water and sorbitol solution. The 10 mg/mL solution is orange flavored and contains prosweet liquid and saccharin sodium. The 40 mg/5 mL solution is pineapple-peach flavored and contains sweet tone. furosemide structural formula image

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 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 mcg/mL to 400 mcg/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 Furosemide Tablets and Furosemide 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 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 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. Hypertension Oral furosemide 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 furosemide alone.

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 furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, furosemide 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 furosemide 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 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 or kidney 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 (particularly potassium), CO 2 , creatinine and BUN should be determined frequently during the first few months of furosemide therapy and periodically thereafter.

cations that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms. Laboratory Tests Serum electrolytes (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed (See PRECAUTIONS : Pediatric Use ). 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. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and furosemide tablets may reduce the natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved. The intake of furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations.

ardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-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 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. 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 . 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 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.

he maximum effective diuretic dose in the rat and 8 times the maximal human dose of 600 mg/day). Pregnancy 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. Furosemide 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 (two times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (four 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 furosemide is administered to a nursing mother. Furosemide may inhibit lactation. Pediatric Use In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide 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 furosemide 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 ).

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 furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, furosemide 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 furosemide 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 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 or kidney damage, or other idiosyncratic reactions.

Laboratory Tests Serum electrolytes (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed (See PRECAUTIONS : Pediatric Use ).

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. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and furosemide tablets may reduce the natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved. The intake of furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperurecemia and cyclosporine impairment of renal urate excretion.

an increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-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 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.

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 . 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 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. Furosemide 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 (two times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (four 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.

Pediatric Use In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide 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 furosemide 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 hepatocellular insufficiency 2. pancreatitis 3. jaundice (intrahepatic cholestatic jaundice) 4. increased liver enzymes 5. anorexia 6. oral and gastric irritation 7. cramping 8. diarrhea 9. constipation 10. nausea 11. vomiting Systemic Hypersensitivity Reactions: 1. severe anaphylactic or anaphylactoid reactions (e.g. with shock) 2. systemic vasculitis 3. interstitial nephritis 4. necrotizing angiitis Central Nervous System Reactions: 1. tinnitus and hearing loss 2. paresthesias 3. vertigo 4. dizziness 5. headache 6. blurred vision 7. xanthopsia Hematologic Reactions: 1. aplastic anemia 2. thrombocytopenia 3. agranulocytosis 4. hemolytic anemia 5. leukopenia 6. anemia 7. eosinophilia Dermatologic-Hypersensitivity Reactions: 1. toxic epidermal necrolysis 2. Stevens-Johnson Syndrome 3. erythema multiforme 4. drug rash with eosinophilia and systemic symptoms 5. acute generalized exanthematous pustulosis 6. exfoliative dermatitis 7. bullous pemphigoid 8. purpura 9. photosensitivity 10. rash 11. pruritus 12. urticaria 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 2. glycosuria 3. hyperuricemia 4. muscle spasm 5. weakness 6. restlessness 7. urinary bladder spasm 8. thrombophlebitis 9. fever Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 furosemide is 20 mg 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 mg 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 (e.g., at 8 am and 2 pm). The dose of furosemide 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 furosemide 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 furosemide 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 furosemide 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 furosemide 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 furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of furosemide, 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 Furosemide Tablets, USP 20 mg tablets are supplied as white, flat tablets with beveled edges, product identification “54 840” debossed on one side. NDC 0054-8297-25: Unit-Dose (10 x 10) NDC 0054-4297-25: Bottle of 100 Tablets NDC 0054-4297-31: Bottle of 1000 Tablets 40 mg tablets are supplied as white, flat tablets with beveled edges, scored on one side and product identification “54 583” debossed on one side. NDC 0054-8299-25: Unit-Dose (10 x 10) NDC 0054-4299-25: Bottle of 100 Tablets NDC 0054-4299-31: Bottle of 1000 Tablets 80 mg tablets are supplied as white, flat tablets with beveled edges, scored on one side and product identification “54 533” debossed on one side. NDC 0054-8301-25: Unit-Dose (10 x 10) NDC 0054-4301-25: Bottle of 100 Tablets NDC 0054-4301-29: Bottle of 500 Tablets Store and Dispense Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Note: Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF. Exposure to light may cause slight discoloration. Discolored tablets should not be dispensed. Protect From Moisture. PROTECT FROM LIGHT. Furosemide Oral Solution, USP 10 mg per mL oral solution is supplied as a (orange-flavored) clear, orange-colored solution. NDC 0054-3294-46: Bottle of 60 mL Dispense only in this bottle and only with the calibrated oral syringe provided. NDC 0054-3294-50: Bottle of 120 mL Dispense only in this bottle. PROTECT FROM LIGHT. NOTE: DISCARD OPENED BOTTLE AFTER 90 DAYS. 40 mg per 5 mL oral solution is supplied as a (pineapple-peach flavored) clear, orange-colored solution. NDC 0054-3298-63: Bottle of 500 mL Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF PROTECT FROM LIGHT. Store and Dispense Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000360/04 Revised November 2025

<table styleCode="Noautorules" width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">20 mg tablets are supplied as white, flat tablets with beveled edges, product identification &#x201C;54 840&#x201D; debossed on one side.</content></paragraph><paragraph>NDC 0054-8297-25: Unit-Dose (10 x 10)</paragraph><paragraph>NDC 0054-4297-25: Bottle of 100 Tablets NDC 0054-4297-31: Bottle of 1000 Tablets</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">40 mg tablets are supplied as white, flat tablets with beveled edges, scored on one side and product identification &#x201C;54 583&#x201D; debossed on one side.</content></paragraph><paragraph>NDC 0054-8299-25: Unit-Dose (10 x 10)</paragraph><paragraph>NDC 0054-4299-25: Bottle of 100 Tablets NDC 0054-4299-31: Bottle of 1000 Tablets</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">80 mg tablets are supplied as white, flat tablets with beveled edges, scored on one side and product identification &#x201C;54 533&#x201D; debossed on one side.</content></paragraph><paragraph>NDC 0054-8301-25: Unit-Dose (10 x 10)</paragraph><paragraph>NDC 0054-4301-25: Bottle of 100 Tablets NDC 0054-4301-29: Bottle of 500 Tablets</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Store and Dispense</content> Store at 20&#xB0; to 25&#xB0;C (68&#xB0; to 77&#xB0;F). [See USP Controlled Room Temperature.]</paragraph><paragraph><content styleCode="bold">Note:</content> Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF. Exposure to light may cause slight discoloration. Discolored tablets should not be dispensed.</paragraph><paragraph>Protect From Moisture.<content styleCode="bold"> PROTECT FROM LIGHT.</content></paragraph></td></tr></tbody></table>

spense in a tight, light-resistant, child-resistant container as defined in the USP/NF. Exposure to light may cause slight discoloration. Discolored tablets should not be dispensed.</paragraph><paragraph>Protect From Moisture.<content styleCode="bold"> PROTECT FROM LIGHT.</content></paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="98%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">10 mg per mL oral solution is supplied as a</content><content styleCode="bold">(orange-flavored) clear, orange-colored solution.</content></paragraph><paragraph>NDC 0054-3294-46: Bottle of 60 mL Dispense only in this bottle and only with the calibrated oral syringe provided. </paragraph><paragraph>NDC 0054-3294-50: Bottle of 120 mL</paragraph><paragraph>Dispense only in this bottle.</paragraph><paragraph><content styleCode="bold">PROTECT FROM LIGHT.</content> <content styleCode="bold">NOTE: DISCARD OPENED BOTTLE AFTER 90 DAYS.</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">40 mg per 5 mL oral solution is supplied as a</content><content styleCode="bold">(pineapple-peach flavored) clear, orange-colored solution.</content></paragraph><paragraph>NDC 0054-3298-63: Bottle of 500 mL</paragraph><paragraph>Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF</paragraph><paragraph><content styleCode="bold">PROTECT FROM LIGHT.</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Store and Dispense</content> Store at 20&#xB0; to 25&#xB0;C (68&#xB0; to 77&#xB0;F). [See USP Controlled Room Temperature.]</paragraph></td></tr></tbody></table>

R x only Distr. by: West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724 Packaged by: Precision Dose, Inc. South Beloit, IL 61080 For inquiries call Precision Dose, Inc., at 1-800-397-9228 or email druginfo@precisiondose.com LI861 Rev. 05/21

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 DOSAGE AND ADMINISTRATION ). 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 and deafness have been reported. Reports usually indicate that furosemide 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 furosemide per minute has been used) (See PRECAUTIONS: Drug Interactions ).

DESCRIPTION Each mL of Oral Solution for oral administration contains: FurosemideUSP 10mg per mL or 8 mg (40 mg per 5 mL) Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro- N -furfuryl-5-sulfamoylanthranilic acid. Furosemide is a white to slightly yellow, crystalline powder. It is practically insoluble in water; freely soluble in acetone, dimethylformamide and in solutions of alkali hydroxides; soluble in methanol; sparingly soluble in alcohol; slightly soluble in ether; very slightly soluble in chloroform. The CAS Registry Number is 54-31-9. The structural formula is as follows: C 12 H 11 ClN 2 O 5 S M.W. 330.75 Furosemide Oral Solution USP is also available for oral administration containing either 10 mg per mL or 40 mg per 5 mL. The oral solution contains the following inactive ingredients: D and C Yellow No. 10, FD and C Yellow No. 6, flavors, potassium carbonate 1½ hydrate, propylene glycol, purified water and sorbitol solution. The 10 mg/mL solution is orange flavored and contains prosweet liquid and saccharin sodium. The 40 mg/5 mL solution is pineapple-peach flavored and contains sweet tone. Chemical Structure

<table width="55%" styleCode="Noautorules"><col width="40%" align="left" valign="top"/><col width="60%" align="right" valign="top"/><tbody><tr><td>FurosemideUSP</td><td>10mg per mL or 8 mg (40 mg per 5 mL)</td></tr></tbody></table>

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 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 mcg/mL to 400 mcg/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 Furosemide Tablets and Furosemide 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects (See PRECAUTIONS: Geriatric Use ).

cations that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms. Laboratory Tests Serum electrolytes (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed (See PRECAUTIONS: Pediatric Use ). 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. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and furosemide tablets may reduce the natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved. The intake of furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations.

he maximum effective diuretic dose in the rat and 8 times the maximal human dose of 600 mg/day). Pregnancy 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. Furosemide 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 (two times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (four 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 furosemide is administered to a nursing mother. Furosemide may inhibit lactation. Pediatric Use In premature infants furosemide 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 furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide 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 furosemide 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 ).

Laboratory Tests Serum electrolytes (particularly potassium), CO 2 , creatinine 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 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 furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed (See PRECAUTIONS: Pediatric Use ).

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. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and furosemide tablets may reduce the natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved. The intake of furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperurecemia and cyclosporine impairment of renal urate excretion.

Geriatric Use Controlled clinical studies of furosemide 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: hepatic encephalopathy in patients with hepatocellular insufficiency pancreatitis jaundice (intrahepatic cholestatic jaundice) increased liver enzymes anorexia oral and gastric irritation cramping diarrhea constipation nausea vomiting Systemic Hypersensitivity Reactions: severe anaphylactic or anaphylactoid reactions (e.g. with shock) systemic vasculitis interstitial nephritis necrotizing angiitis Central Nervous System Reactions: tinnitus and hearing loss paresthesias vertigo dizziness headache blurred vision xanthopsia Hematologic Reactions: aplastic anemia thrombocytopenia agranulocytosis hemolytic anemia leukopenia anemia eosinophilia Dermatologic-Hypersensitivity Reactions: toxic epidermal necrolysis Stevens-Johnson Syndrome erythema multiforme drug rash with eosinophilia and systemic symptoms acute generalized exanthematous pustulosis exfoliative dermatitis bullous pemphigoid purpura photosensitivity rash pruritus urticaria Cardiovascular Reaction: Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates, or narcotics. Increase in cholesterol and triglyceride serum levels Other Reactions: hyperglycemia glycosuria hyperuricemia muscle spasm weakness restlessness urinary bladder spasm thrombophlebitis fever Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn. To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 furosemide is 20 mg 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 mg 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 (e.g., at 8 am and 2 pm). The dose of furosemide 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 furosemide 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 furosemide 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 furosemide 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 furosemide 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 furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of furosemide, 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 Furosemide Oral Solution USP 10 mg per mL oral solution is supplied as a (orange-flavored) clear, orange-colored solution. NDC 68094-756-62 4 mL per unit dose cup Thirty (30) cups per shipper PROTECT FROM LIGHT. 40 mg per 5 mL oral solution is supplied as a (pineapple-peach flavored) clear, orange-colored solution. NDC 68094-867-62 5 mL per unit dose cup Thirty (30) cups per shipper Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF PROTECT FROM LIGHT. Store and Dispense Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

<table width="65%"><col width="100%" align="left" valign="top"/><tbody><tr><td styleCode="Lrule Rrule"><content styleCode="bold"> 10 mg per mL oral solution is supplied as a (orange-flavored) clear, orange-colored solution.</content></td></tr><tr><td styleCode="Lrule Rrule">NDC 68094-756-62 4 mL per unit dose cup Thirty (30) cups per shipper</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">PROTECT FROM LIGHT.</content></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold"> 40 mg per 5 mL oral solution is supplied as a (pineapple-peach flavored) clear, orange-colored solution.</content></td></tr><tr><td styleCode="Lrule Rrule">NDC 68094-867-62 5 mL per unit dose cup Thirty (30) cups per shipper</td></tr><tr><td styleCode="Lrule Rrule"> Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">PROTECT FROM LIGHT.</content></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Store and Dispense</content></td></tr><tr><td styleCode="Lrule Rrule"> Store at 20&#xB0; to 25&#xB0;C (68&#xB0; to 77&#xB0;F). [See USP Controlled Room Temperature.]</td></tr></tbody></table>

Furosemide Oral Solution USP 10 mg per mL oral solution is supplied as a (orange-flavored) clear, orange-colored solution. NDC 68094-756-62 4 mL per unit dose cup Thirty (30) cups per shipper PROTECT FROM LIGHT. 40 mg per 5 mL oral solution is supplied as a (pineapple-peach flavored) clear, orange-colored solution. NDC 68094-867-62 5 mL per unit dose cup Thirty (30) cups per shipper Dispense in a tight, light-resistant, child-resistant container as defined in the USP/NF PROTECT FROM LIGHT. Store and Dispense Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

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 [ s ee DOSAGE AND ADMINISTRATION ] . 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 and deafness have been reported. Reports usually indicate that Furosemide 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 Furosemide per minute has been used) [see PRECAUTIONS: Drug Interactions ].

DESCRIPTION Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro- N -furfuryl-5-sulfamoylanthranilic acid. 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 structural formula is as follows: Furosemide is available in 20 mg, 40 mg and 80 mg tablets for oral administration. Inactive ingredients include lactose monohydrate, magnesium stearate, pregelatinized starch and starch (corn). Meets USP Dissolution Test 1. furosemide structure

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 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 mcg/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 furosemide tablets and furosemide 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects [see PRECAUTIONS: Geriatric Use ] .

ntravenous administration in older healthy male subjects (60 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects [see PRECAUTIONS: Geriatric Use ] . 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 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 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 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. Hypertension Oral Furosemide 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 Furosemide alone.

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 Furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, Furosemide 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 Furosemide 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 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 or kidney 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 (particularly potassium), CO 2 , creatinine and BUN should be determined frequently during the first few months of Furosemide therapy and periodically thereafter.

cations that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms. Laboratory Tests Serum electrolytes (particularly potassium), CO 2 , creatinine 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 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 Furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed [see PRECAUTIONS: Pediatric Use ] . 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. There is a risk of ototoxic effects if cisplatin and Furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if Furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 Furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and Furosemide tablets may reduce the natriuretic and antihypertensive effects of Furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Furosemide is achieved. The intake of Furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of Furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of Furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of Furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of Furosemide, and consequently to lower peak serum furosemide concentrations.

ardia. Use of Furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of Furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of Furosemide, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like Furosemide, undergo significant renal tubular secretion may reduce the effect of Furosemide. Conversely, Furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both Furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of Furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and Furosemide is associated with increased risk of gouty arthritis secondary to Furosemide-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 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. 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 . 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 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.

the maximum effective diuretic dose in the rat and 8 times the maximal human dose of 600 mg/day). Pregnancy 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. Furosemide 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 Furosemide is administered to a nursing mother. Furosemide may inhibit lactation. Pediatric Use In premature infants Furosemide 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 Furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving Furosemide. If Furosemide 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 Furosemide 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 ] .

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 Furosemide therapy, especially in patients receiving higher doses and a 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, ACTH, licorice in large amounts, or prolonged use of laxatives. 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, 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, Furosemide 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 Furosemide 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 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 or kidney 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 (particularly potassium), CO 2 , creatinine 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 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 Furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed [see PRECAUTIONS: Pediatric Use ] .

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. There is a risk of ototoxic effects if cisplatin and Furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if Furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. 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 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 Furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and Furosemide tablets may reduce the natriuretic and antihypertensive effects of Furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Furosemide is achieved. The intake of Furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of Furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of Furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of Furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of Furosemide, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like Furosemide, undergo significant renal tubular secretion may reduce the effect of Furosemide. Conversely, Furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both Furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of Furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and Furosemide is associated with increased risk of gouty arthritis secondary to Furosemide-induced hyperurecemia and cyclosporine impairment of renal urate excretion.

an increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and Furosemide is associated with increased risk of gouty arthritis secondary to Furosemide-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 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.

Pregnancy 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. Furosemide 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.

Pediatric Use In premature infants Furosemide 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 Furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving Furosemide. If Furosemide 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 Furosemide 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 hepatic encephalopathy in patients with hepatocellular insufficiency pancreatitis jaundice (intrahepatic cholestatic jaundice) increased liver enzymes anorexia oral and gastric irritation cramping diarrhea constipation nausea vomiting Systemic Hypersensitivity Reactions severe anaphylactic or anaphylactoid reactions (e.g., with shock) systemic vasculitis interstitial nephritis necrotizing angiitis Central Nervous System Reactions tinnitus and hearing loss paresthesias vertigo dizziness headache blurred vision xanthopsia Hematologic Reactions aplastic anemia thrombocytopenia agranulocytosis hemolytic anemia leukopenia anemia eosinophilia Dermatologic-Hypersensitivity Reactions toxic epidermal necrolysis Stevens-Johnson Syndrome erythema multiforme drug rash with eosinophilia and systemic symptoms acute generalized exanthematous pustulosis exfoliative dermatitis bullous pemphigoid purpura photosensitivity rash pruritis urticaria Cardiovascular Reaction Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates, or narcotics. Increase in cholesterol and triglyceride serum levels. Other Reactions hyperglycemia glycosuria hyperuricemia muscle spasm weakness restlessness urinary bladder spasm thrombophlebitis fever Whenever adverse reactions are moderate or severe, Furosemide dosage should be reduced or therapy withdrawn. To report SUSPECTED ADVERSE REACTIONS, contact Marlex Pharmaceuticals, Inc. at 1-888-582-1953 or Drugsafety@marlexpharm.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE The principal signs and symptoms of overdose with Furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. The acute toxicity of Furosemide has been determined in mice, rats and dogs. In all three, the oral LD 50 exceeded 1000 mg/kg body weight, while the intravenous LD 50 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 Furosemide 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 Furosemide is 20 mg 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 mg 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 (e.g., at 8 am and 2 pm). The dose of Furosemide 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 Furosemide 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 Test ]. 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 Furosemide 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 Furosemide 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 Furosemide 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 Furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of Furosemide, 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 Furosemide tablets, USP, for oral administration, are available as: 20 mg : White to off-white, round, flat face, radius edge, debossed “G 164” on one side and plain on the other side, and supplied as: NDC 10135-0832-90 bottles of 90 NDC 10135-0832-01 bottles of 100 NDC 10135-0832-10 bottles of 1000 40 mg: White to off-white, round, flat face, radius edge, scored tablet debossed “G” above the score and “165” below the score on one side and plain on the other side, and supplied as: NDC 10135-0833-90 bottles of 90 NDC 10135-0833-01 bottles of 100 NDC 10135-0833-10 bottles of 1000 80 mg: White to off-white, round, flat face, radius edge, scored tablet debossed “G” above the score and “166” below the score on one side and plain on the other side, and supplied as: NDC 10135-0834-90 bottles of 90 NDC 10135-0834-01 bottles of 100 NDC 10135-0834-05 bottles of 500 Dispense in well-closed and light-resistant containers. Exposure to light might cause a slight discoloration. Discolored tablets should not be dispensed. Store at 68º to 77ºF (20º to 25ºC); excursions permitted to 59º to 86ºF (15º to 30ºC) [See USP Controlled Room Temperature]. Manufactured for/ Distributed by: Marlex Pharmaceuticals, Inc. New Castle, DE 19720 Rev. 02/26 GT