FUROSEMIDE: 51,843 Adverse Event Reports & Safety Profile

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

INDICATIONS AND USAGE Edema Furosemide tablets are 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 tablets are 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.

Edema

Furosemide tablets are 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 tablets are 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.

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 tablets is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (e.g., at 8 am and 2 pm). The dose of furosemide tablets 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 tablets 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 tablets 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 tablets are used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when furosemide tablets are added to the regimen. As the blood pressure falls under the potentiating effect of furosemide tablets, 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 ).

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 tablets is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (e.g., at 8 am and 2 pm). The dose of furosemide tablets 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 tablets 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.

Adults - The usual initial dose of furosemide tablets is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (e.g., at 8 am and 2 pm). The dose of furosemide tablets 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 tablets 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 ).

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 tablets 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 tablets are used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when furosemide tablets are added to the regimen. As the blood pressure falls under the potentiating effect of furosemide tablets, 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 ).

Adults - The usual initial dose of furosemide tablets 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 tablets are used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when furosemide tablets are added to the regimen. As the blood pressure falls under the potentiating effect of furosemide tablets, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary.

Lasix ONYU is contraindicated in patients with anuria. Lasix ONYU is contraindicated in patients with a history of hypersensitivity to furosemide, any component of the Lasix ONYU formulation, or medical adhesives. Anuria. ( 4 ) Hypersensitivity to furosemide or medical adhesives. ( 4 )

REACTIONS The following important adverse reactions are discussed 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 trials or post-marketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably, or to 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.

Administration

Site and Skin Reactions : erythema, bruising, edema, infusion site pain.

Other

Reactions : glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever. The most common adverse reactions during treatment with the Furoscix Infusor were administration site and skin reactions: erythema, bruising, edema and infusion site pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact scPharmaceuticals, Inc. at 1-855-727-4276 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 higher than recommended doses. ( 5.3 , 7.1 )

Acute Urinary

Retention : Monitor patients with symptoms of urinary retention. ( 5.4 )

Incomplete

Dosing : Fluid contact and certain patient movements during treatment may cause the On-body Infusor to prematurely terminate infusion. Ensure the patient or caregiver can detect and respond to alarms. ( 5.5 )

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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

5.2 Worsening Renal Function Furosemide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, discontinue furosemide <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

5.3 Ototoxicity Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported with furosemide. 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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

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. These patients require careful monitoring, especially during the initial stages of treatment.

5.5 Incomplete Dosing The On-body Infusor should not be allowed to get wet from water or any other fluids (blood or drug product). Fluid contact with the circuit board can lead to device errors and premature termination of infusion. The On-body Infusor is intended for use in a setting where the patient can limit their activity for the duration of administration. Certain patient movements may cause interruption of device adherence to skin and premature termination of infusion. The On-body Infusor for FUROSCIX should only be administered in settings where alarms can be detected and responded to in order to ensure a complete dose is administered <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

5.2 Worsening Renal Function Furosemide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, discontinue furosemide <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

5.3 Ototoxicity Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported with furosemide. 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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

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. These patients require careful monitoring, especially during the initial stages of treatment.

5.5 Incomplete Dosing The On-body Infusor should not be allowed to get wet from water or any other fluids (blood or drug product). Fluid contact with the circuit board can lead to device errors and premature termination of infusion. The On-body Infusor is intended for use in a setting where the patient can limit their activity for the duration of administration. Certain patient movements may cause interruption of device adherence to skin and premature termination of infusion. The On-body Infusor for FUROSCIX should only be administered in settings where alarms can be detected and responded to in order to ensure a complete dose is administered <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

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 tablets therapy, especially in patients receiving higher doses and a restricted salt intake. Hypokalemia may develop with Furosemide tablets, 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 tablets 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 tablets 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 tablets 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 tablets. 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 tablets 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. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Laboratory Tests Serum electrolytes (particularly potassium), CO 2 , creatinine and BUN should be determined frequently during the first few months of Furosemide tablets 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 tablets, even in those suspected of latent diabetes. Furosemide tablets 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 tablets may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (see PRECAUTIONS: Pediatric Use)

Drug Interactions

Furosemide tablets 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 tablets should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity. Patients receiving high doses of salicylates concomitantly with Furosemide tablets, 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 tablets are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if Furosemide tablets are not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. Furosemide tablets have 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 tablets 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 tablets, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide tablets 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 tablets. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Furosemide tablets is achieved. The intake of Furosemide tablets and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of Furosemide tablets within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of Furosemide tablets concomitantly with chloral hydrate is, therefore, not recommended. Phenytoin interferes directly with renal action of Furosemide tablets. There is evidence that treatment with phenytoin leads to decrease intestinal absorption of Furosemide tablets, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like Furosemide tablets, undergo significant renal tubular secretion may reduce the effect of Furosemide tablets. Conversely, Furosemide tablets may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both Furosemide tablets 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 tablets. Furosemide tablets can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and Furosemide tablets is associated with increased risk of gouty arthritis secondary to Furosemide tablets-induced hyperurecemia and cyclosporine impairment of renal urate excretion. High doses (>80mg) 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 tablets (furesomide) 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 tablets should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Furosemide tablets 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 tablets (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 tablets 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 tablets 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 tablets. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving Furosemide tablets.

If

Furosemide tablets are 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 tablets 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 .)

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 Table 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. Avoid combination except in life-threatening situations. Ethacrynic acid Possibility of ototoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. 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

Cisplatin and nephrotoxic drugs There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly [see Warnings and Precautions ( 5.3 )].

Nephrotoxicity

Administer furosemide at lower doses and with positive 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 adds 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.

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 Effect of Other Drugs on Furosemide Table 2: Effect of Other Drugs on Furosemide Drug/Substance Class or Name Drug Interaction Effect Recommendations Phenytoin 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.

7.1 Effects of Furosemide on Other Drugs Table 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. Avoid combination except in life-threatening situations. Ethacrynic acid Possibility of ototoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. 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

Cisplatin and nephrotoxic drugs There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly [see Warnings and Precautions ( 5.3 )].

Nephrotoxicity

Administer furosemide at lower doses and with positive 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 adds 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.

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 Effect of Other Drugs on Furosemide Table 2: Effect of Other Drugs on Furosemide Drug/Substance Class or Name Drug Interaction Effect Recommendations Phenytoin 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.