Furosemide

Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.

• 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.
• 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.
• 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.
• 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.
• Nursing Mothers Because it appears in breast milk, caution should be exercised when furosemide is administered to a nursing mother.
• Pediatric Use In premature infants furosemide may precipitate nephrocalcinosis/nephrolithiasis.
• 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.
• 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.

• 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.
• Because it appears in breast milk, caution should be exercised when furosemide is administered to a nursing mother. Furosemide may inhibit lactation.

• 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.
• 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.

• 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.