AHFS Class:

• Loop Diuretics 40:28.08

Generic Name(s):

• Furosemide

Furosemide is a sulfonamide, loop-type diuretic and antihypertensive agent.

Edema

Furosemide is used in the management of edema associated with heart failure, nephrotic syndrome, and hepatic cirrhosis. IV furosemide also may be used as an adjunct in the treatment of acute pulmonary edema.

Careful etiologic diagnosis should precede the use of any diuretic. Because the potent diuretic effect of furosemide may result in severe electrolyte imbalance and excessive fluid loss, hospitalization of the patient during initiation of therapy is advisable, especially for patients with hepatic cirrhosis and ascites or chronic renal failure. In prolonged diuretic therapy, intermittent use of the drug for only a few days each week may be advisable. Furosemide may be administered cautiously for additive effect with most other diuretics; however, since furosemide and other loop diuretics (e.g., ethacrynic acid) act in a similar manner, there is no rationale for using these drugs together.

Heart Failure

Furosemide is used in the management of edema associated with heart failure. Most experts state that all patients with symptomatic heart failure who have evidence for, or a history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.524,713,800 Some experts state that because of limited and inconsistent data, it is difficult to make precise recommendations regarding daily sodium intake and whether it should vary with respect to the type of heart failure (e.g., reduced versus preserved ejection fraction), disease severity (e.g., New York Heart Association [NYHA] class), heart failure-related comorbidities (e.g., renal dysfunction), or other patient characteristics (e.g., age, race).524,723,724 The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) state that limiting sodium intake to 1.5 g daily in patients with ACCF/AHA stage A or B heart failure may be reasonable.524 While data currently are lacking to support recommendation of a specific level of sodium intake in patients with ACCF/AHA stage C or D heart failure, ACCF and AHA state that limiting sodium intake to some degree (e.g., less than 3 g daily) in such patients may be considered for symptom improvement.524

Diuretics play a key role in the management of heart failure because they produce symptomatic benefits more rapidly than any other drugs, relieving pulmonary and peripheral edema within hours or days compared with weeks or months for cardiac glycosides, ACE inhibitors, or β-blockers.131 However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality in such patients are not known.524 Although there are patients with heart failure who do not exhibit fluid retention in the absence of diuretic therapy and even may develop severe volume depletion with low doses of diuretics, such patients are rare and the unique pathophysiologic mechanisms regulating their fluid and electrolyte balance have not been elucidated.131

Most experts state that loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are the diuretics of choice for most patients with heart failure.524 If resistance to diuretics occurs, IV administration of a diuretic or concomitant use of 2 or more diuretics (e.g., a loop diuretic and metolazone, a loop diuretic and a thiazide diuretic) may be necessary; alternatively, short-term administration of a drug that increases blood flow (e.g., a positive inotropic agent such as dopamine) may be necessary.524 ACCF and AHA state that IV loop diuretics should be administered promptly to all hospitalized heart failure patients with substantial fluid overload to reduce morbidity.524 In addition, ACCF and AHA state that low-dose dopamine infusions may be considered in combination with loop diuretics to augment diuresis and preserve renal function and renal blood flow in patients with acute decompensated heart failure,524 although data are conflicting and additional study and experience are needed.524,714,715,716,717,718,719,720 For additional information, see Heart Failure under Uses: Edema, in the Thiazides General Statement 40:28.20.

Pulmonary Disease

Furosemide may be administered IV as an adjunct in the treatment of acute pulmonary edema; however, the drug should be used cautiously when pulmonary edema is a complication of cardiogenic shock associated with acute myocardial infarction because diuretic-induced hypovolemia may reduce cardiac output.

Hepatic and Renal Disease

Furosemide also may be used cautiously in the management of edema associated with the nephrotic syndrome and in patients with hepatic cirrhosis, but such edema is frequently refractory to treatment. When metabolic alkalosis may be anticipated, a potassium-rich diet, potassium supplements, or potassium-sparing diuretics may be necessary before and during furosemide therapy to mitigate or prevent hypokalemia in cirrhotic, nephrotic, or digitalized patients. (See Cautions: Fluid, Electrolyte, Cardiovascular, and Renal Effects.)

Large oral or IV doses of furosemide have been employed as an adjunct to other therapy, including peritoneal dialysis or hemodialysis, in patients with acute or chronic renal failure. In some patients, the use of furosemide may delay the need for dialysis, increase the intervals between dialyses, shorten the period of hospitalization, or permit a slightly more liberal fluid intake.

Hypertension

Furosemide may be used alone or in combination with other classes of antihypertensive agents for the management of hypertension, especially when complicated by heart failure or renal disease.1200 Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20) However, some experts state that loop diuretics (e.g., bumetanide, furosemide, torsemide) are preferred over thiazides in patients with moderate to severe chronic kidney disease (CKD)502,504,1200 or symptomatic heart failure.524,1200 Loop diuretics may be particularly useful in patients with heart failure and reduced left ventricular ejection fraction (LVEF) who have evidence of fluid retention; however, some experts state that thiazide diuretics may be considered in hypertensive patients with heart failure and mild fluid retention because of their more persistent antihypertensive effect.524

In most patients, hypertension not controllable by thiazides alone probably will not respond adequately to furosemide alone.

For information on antihypertensive therapy for patients with chronic kidney disease or heart failure, see Chronic Kidney Disease and also see Heart Failure under Hypertension in Adults: Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, in Uses in the Thiazides General Statement 40:28.20.

For further information on the role of diuretics in antihypertensive therapy and information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Hypertensive Crises

IV furosemide has been found useful as an adjunct to hypotensive agents in the treatment of hypertensive crises†, especially when associated with acute pulmonary edema or renal failure. In addition to producing a rapid diuresis, furosemide enhances the effects of other hypotensive drugs and counteracts the sodium retention caused by some of these agents.

Other Uses

Furosemide has been used IV alone or with 0.9% sodium chloride injection or sodium sulfate to increase renal excretion of calcium in patients with hypercalcemia†. Oral furosemide has been suggested for maintenance.

Administration

Furosemide is administered orally; the drug can also be administered by IM or IV injection.

IV Administration

IV injections of furosemide should be given slowly over 1-2 minutes. Parenteral administration of furosemide should be replaced by oral therapy as soon as possible. If high-dose parenteral furosemide therapy is necessary, the manufacturer recommends that the drug be administered as a controlled infusion at a rate not exceeding 4 mg/minute in adults. For IV infusion, furosemide should be diluted with an infusion solution of 0.9% sodium chloride, lactated Ringer's, or 5% dextrose, adjusting the pH to greater than 5.5 when necessary.

Standardize 4 Safety

Standardized concentrations for furosemide have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249,250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249,250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249,250 For additional information on S4S (including updates that may be available), see[Web].249,250

Dosage

Dosage of furosemide injection, in which the drug is present as the sodium salt (see Chemistry and Stability: Chemistry), is expressed in terms of furosemide. Furosemide dosage must be adjusted according to the patient's requirements and response. If furosemide is added to the regimen of a patient stabilized on a potent hypotensive agent, the dosage of the hypotensive agent and possibly both drugs should initially be reduced in order to avoid severe hypotension.

For the management of fluid retention (e.g., edema) associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524

When high-dose furosemide infusions are used, dosage should be individualized according to patient response, titrating the dosage to gain maximum therapeutic effect while using the lowest possible effective dosa the patient should be closely observed during therapy.

Edema

Oral Dosage

The usual initial adult oral dose of furosemide for the management of edema is 20-80 mg given as a single dose, preferably in the morning. In adults who do not respond, the second and each succeeding oral dose may be increased in 20- to 40-mg increments every 6-8 hours until the desired diuretic response (including weight loss) is obtained. The effective dose may be given once or twice daily thereafter, or, in some cases, by intermittent administration on 2-4 consecutive days each week. For maintenance, dosage may be reduced in some patients. Adult oral dosage of furosemide may be carefully titrated up to 600 mg daily in severely edematous patients.

For the management of fluid retention (e.g., edema) associated with heart failure, some experts recommend initiating furosemide at a low dosage (e.g., 20-40 mg once or twice daily) and increasing the dosage (maximum of 600 mg daily) until urine output increases and weight decreases, generally by 0.5-1 kg daily.524

For infants and children, the usual initial oral dose of furosemide for the management of edema is 2 mg/kg administered as a single dose.103,104,105,107,108,151 If necessary, dosage may be increased in increments of 1 or 2 mg/kg every 6-8 hours103,104,105,107,108 to maximum individual doses of 6 mg/kg;103,151 however, it usually is not necessary to exceed individual doses of 4 mg/kg or a dosing frequency of once or twice daily.104 For maintenance, the minimum effective dosage should be employed.

Parenteral Dosage

As a diuretic, the usual adult IM or IV dose is 20-40 mg given as a single injection. In adults who do not respond to the initial parenteral dose of furosemide, the second and each succeeding dose may be increased in 20-mg increments and given not more often than every 2 hours until the desired diuretic response is obtained. The effective single dose may then be given once or twice daily.

For the management of acute pulmonary edema in adults, 40 mg of furosemide may be slowly injected IV over 1-2 minutes. If the initial adult dose does not produce a satisfactory response within 1 hour, the dose may be increased to 80 mg IV given over 1-2 minutes. In adults with hypertensive crises†, who have normal renal function, 40-80 mg of furosemide (administered concomitantly with other hypotensive agents) may be given IV over 1-2 minutes; in patients with reduced renal function higher does may be required.

For infants and children, the usual initial IV or IM dose of furosemide for the management of acute pulmonary edema or edema associated with heart failure or renal disease† is 1 mg/kg.103,104,105,106,107,108 If necessary for resistant forms of edema, the initial dose may be increased by 1 mg/kg103,104,105,108 no more often than every 2 hours until the desired effect has been obtained.103 Adequate response usually is obtained with individual parenteral doses of 1 mg/kg,104,105,107,108 but occasionally individual doses of 2 mg/kg may be required.104,108 Maximum individual parenteral doses recommended by the manufacturer for infants and children are 6 mg/kg;103 however, the potential risks associated with large parenteral doses of the drug should be considered and the patient should be monitored closely.105,107

Literature reports suggest that the recommended maximum dosage of furosemide injection for respiratory distress syndrome (RDS) in premature neonates less than 31 weeks postconception age (gestational age at birth plus postnatal age) should not exceed 1 mg/kg in 24 hours.150 (See Cautions: Pediatric Precautions.)

Large doses of furosemide have been administered orally or IV to adults with acute or chronic renal failure. One investigator recommends beginning therapy in adults with 80 mg of furosemide orally daily and increasing dosage in increments of 80-120 mg daily until the desired effect is achieved. When immediate diuresis is needed, an initial adult dose of 320-400 mg orally daily has been suggested. Some patients have received as much as 4 g orally daily†. Initial IV doses have ranged from 100 mg to 2 g in adults. In some studies, the initial IV doses were doubled at 2- to 24-hour intervals until the desired effect was attained. The highest IV dosage of furosemide was 6 g daily.

Hypertension

Adult Dosage

The manufacturer states that the usual adult oral dosage of furosemide for the management of hypertension is 40 mg twice daily initially and for maintenance. If a satisfactory lowering of blood pressure does not occur, dosage can be increased gradually. Careful monitoring of blood pressure is essential when furosemide is used alone or in combination with other hypotensive agents, especially during initial therapy. If a satisfactory lowering of blood pressure does not occur when 40 mg is administered orally twice daily, the manufacturer recommends adding other antihypertensive agents rather than increasing the dosage of furosemide. Some experts state that the usual oral antihypertensive dosage of furosemide for adults is 20-80 mg daily given in 2 divided doses.1200

Monitoring and Blood Pressure Treatment Goals

The patient's renal function and electrolytes should be assessed 2-4 weeks after initiation of diuretic therapy.1200 Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) In patients who develop unacceptable adverse effects with furosemide, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Pediatric Dosage

For the management of hypertension in children†, some experts have recommended an initial oral dosage of 0.5-2 mg/kg administered once or twice daily. Such experts have suggested that dosage may be increased as necessary up to 6 mg/kg daily.149 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients in the Thiazides General Statement 40:28.20.

Other

In the treatment of hypercalcemia†, adults have been given 80-100 mg of furosemide IV at intervals of 1-2 hours. In one study, total IV dosage ranged from 160 mg to 3.2 g. Slight elevations of blood calcium concentration have been treated with 120 mg of oral furosemide daily.

Dosage in Renal Impairment

Large doses of furosemide have been administered orally or IV to adults with acute or chronic renal failure. One investigator recommends beginning therapy in adults with 80 mg of furosemide orally daily and increasing dosage in increments of 80-120 mg daily until the desired effect is achieved. When immediate diuresis is needed, an initial adult dose of 320-400 mg orally daily has been suggested. Some patients have received as much as 4 g orally daily†. Initial IV doses have ranged from 100 mg to 2 g in adults. In some studies, the initial IV doses were doubled at 2- to 24-hour intervals until the desired effect was attained. The highest IV dosage of furosemide was 6 g daily.

Fluid, Electrolyte, Cardiovascular, and Renal Effects

Furosemide may produce profound diuresis resulting in fluid and electrolyte depletion. Fluid and electrolyte depletion are especially likely to occur when large doses are given and/or in patients with restricted sodium intake.

Too vigorous diuresis, as evidenced by rapid and excessive weight loss, may induce orthostatic hypotension or acute hypotensive episodes, and the patient's blood pressure should be closely monitored. Excessive dehydration is most likely to occur in geriatric patients and/or patients with chronic cardiac disease treated with prolonged sodium restriction or those receiving sympatholytic agents. The resultant hypovolemia may cause hemoconcentration, which could lead to circulatory collapse or thromboembolic episodes such as possibly fatal vascular thromboses and/or emboli. Pronounced reductions in plasma volume associated with rapid or excessive diuresis may also result in an abrupt fall in glomerular filtration rate and renal blood flow, which may be restored by replacement of fluid loss. Rarely, sudden death from cardiac arrest has been reported following IV or IM administration of furosemide.

Potassium depletion occurs frequently in patients with secondary hyperaldosteronism which may be associated with cirrhosis or nephrosis and is particularly important in cirrhotic, nephrotic, or digitalized patients. Hypokalemia and hypochloremia may result in metabolic alkalosis, especially in patients with other losses of potassium and chloride due to vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium-losing renal diseases. In patients with cor pulmonale, alkalosis may cause compensatory respiratory depression. Intermittent administration of furosemide and/or ingestion of potassium-rich foods or administration of a potassium-sparing diuretic may reduce or prevent potassium depletion. However, potassium supplements may be necessary in patients whose serum potassium concentration is less than approximately 3 mEq/L or those receiving digitalis glycosides. To prevent hypokalemic and hypochloremic alkalosis, potassium chloride supplementation should be used. Furosemide increases calcium excretion; rarely, tetany has been reported. Magnesium depletion may also occur.

Furosemide may cause a transient rise in BUN which is usually readily reversible upon withdrawal of the drug. Elevated BUN is especially likely to occur in patients with chronic renal disease. Hyperuricemia may result from furosemide administration and rarely gout has been precipitated; patients with a history of gout or elevated serum uric acid concentrations should be observed closely during therapy. However, large IV doses of furosemide may cause temporary uricosuria. Elevations of BUN and uric acid concentrations may be associated with dehydration, which should be avoided, particularly in patients with renal insufficiency. Allergic interstitial nephritis leading to reversible renal failure has been attributed to furosemide. Blood ammonia concentrations may be increased, especially in patients with preexisting elevations of blood ammonia.

Chronic administration of furosemide 50 mg/kg in rats has caused renal tubular degeneration. Calcification and scarring of the renal parenchyma has occurred in dogs receiving 10 mg/kg for 6 months.

Otic Effects

Tinnitus, reversible or permanent hearing impairment, or reversible deafness have occurred, usually following rapid IV or IM administration of furosemide in doses greatly exceeding the usual therapeutic dose of 20-40 mg. Otic effects are most likely to occur in patients with severe impairment of renal function and/or in patients receiving other ototoxic drugs (e.g., aminoglycosides). (See Drug Interactions: Other Drugs.) It has been postulated that administering furosemide by slow IV infusion rather than as a bolus may reduce the ototoxic effects of the drug by preventing high peak plasma concentrations; if high-dose parenteral furosemide therapy is necessary in patients with severely impaired renal function, the manufacturers recommend that the drug be infused in adults at a rate not exceeding 4 mg/minute.

GI Effects

Adverse GI effects of furosemide include nausea, anorexia, oral and gastric irritation, vomiting, cramping, diarrhea, and constipation. Because furosemide oral solutions contain sorbitol, they may cause diarrhea, especially in children, when high dosages are administered. In children, mild to moderate abdominal pain has been reported after furosemide was administered IV. In addition, rare occurrences of sweet taste have been reported, but a causal relationship to the drug has not been established.

Metabolic Effects

Furosemide may produce hyperglycemia and glycosuria, possibly as a result of hypokalemia, in patients with predisposition to diabetes. Rarely, precipitation of diabetes mellitus has been reported.

Diuretics,110,111,112,113,114,115,116,117,118,119,120,122,123 including furosemide,110,111,119,122,123 can increase serum total cholesterol concentrations in some patients; increases in low-density lipoprotein (LDL)-cholesterol and/or very low-density lipoprotein (VLDL)-cholesterol subfractions appear to be principally responsible for these increases. In addition, the ratio of serum total cholesterol to high-density lipoprotein (HDL)-cholesterol has been increased in some patients in whom total serum cholesterol did not appear to be elevated.117,122 Increases in serum triglyceride concentrations also can occur.110,111,116,119,122,123

Nervous System Effects

Adverse nervous system effects of furosemide include dizziness, lightheadedness, vertigo, headache, xanthopsia, blurred vision, and paresthesias.

Hematologic Effects

Anemia, hemolytic anemia, leukopenia, neutropenia, and thrombocytopenia have occurred in patients receiving furosemide. In addition, rare cases of agranulocytosis and aplastic anemia have been reported.

Dermatologic and Sensitivity Reactions

Adverse dermatologic and/or hypersensitivity reactions to furosemide include purpura, photosensitivity, rash, urticaria, pruritus, exfoliative dermatitis, erythema multiforme, interstitial nephritis, and necrotizing angiitis (vasculitis, cutaneous vasculitis). Patients with known sulfonamide sensitivity may show allergic reactions to furosemide. Anaphylaxis, manifested as urticaria, angioedema, and hypotension, occurred within 5 minutes after IV administration of furosemide in at least one patient; subsequent intradermal skin testing showed sensitivity to furosemide and other sulfonamides.102

Local Effects

Transient pain at the injection site has been reported after IM administration of furosemide. Thrombophlebitis has occurred with IV administration.

Other Adverse Effects

Other adverse effects of furosemide include increased perspiration, weakness, fever, restlessness, muscle spasm, urinary bladder spasm, and urinary frequency. A few cases of flank and loin pain have been reported in adults receiving oral furosemide, possibly resulting from calyceal dilation, increased bladder pressure, or spasms caused by formation of calcium-containing crystals in the urine. Intrahepatic cholestatic jaundice and pancreatitis have also occurred in patients receiving furosemide. Furosemide may possibly exacerbate or activate systemic lupus erythematosus.

Precautions and Contraindications

Patients receiving furosemide must be carefully observed for signs of hypovolemia, hyponatremia, hypokalemia, hypocalcemia, hypochloremia, and hypomagnesemia. Patients should be informed of the signs and symptoms of electrolyte imbalance and instructed to report to their physicians if weakness, dizziness, fatigue, faintness, mental confusion, lassitude, muscle cramps, headache, paresthesia, thirst, anorexia, nausea, and/or vomiting occur. Excessive fluid and electrolyte loss may be minimized by initiating therapy with small doses, careful dosage adjustment, using an intermittent dosage schedule if possible, and monitoring the patient's weight. To prevent hyponatremia and hypochloremia, intake of sodium may be liberalized in most patients; however, patients with cirrhosis usually require at least moderate sodium restriction while on diuretic therapy. Determinations of serum electrolytes, BUN, and carbon dioxide should be performed early in therapy with furosemide and periodically thereafter. If excessive diuresis and/or electrolyte abnormalities occur, the drug should be withdrawn or dosage reduced until homeostasis is restored. Electrolyte abnormalities should be corrected by appropriate measures.

Furosemide should be used with caution in patients with hepatic cirrhosis because rapid alterations in fluid and electrolyte balance may precipitate hepatic precoma or coma.

Periodic blood studies and liver function tests should be performed in patients receiving furosemide, especially in those on prolonged therapy.

Urine and blood glucose concentration determinations should be made periodically in diabetics and suspected latent diabetics receiving furosemide.

Furosemide therapy during the first few weeks of life in premature neonates reportedly may increase the risk of persistent patent ductus arteriosus (PDA), possibly through a prostaglandin E (PGE)-mediated process.

Furosemide is contraindicated in patients with anuria. The drug is contraindicated for further use if increasing azotemia and/or oliguria occur during the treatment of severe, progressive renal disease. In patients with hepatic coma or electrolyte depletion, therapy should not be instituted until the basic condition is improved or corrected. Furosemide is also contraindicated in patients with a history of hypersensitivity to the drug.

Pediatric Precautions

In premature neonates with respiratory distress syndrome (RDS), diuretic therapy with furosemide during the first weeks of life may increase the risk of persistent patent ductus arteriosus (PDA), an effect that may be mediated by prostaglandins, presumably of the E series.103 Hearing loss has been reported in neonates receiving furosemide.103 Ototoxicity may be associated with elevated plasma concentrations of furosemide secondary to renal immaturity in these patients.125,126 Therefore, the manufacturers state that parenteral furosemide dosages should not exceed 1 mg/kg per 24 hours in premature neonates with less than 31 weeks postconception age (gestational age at birth plus postnatal age), because higher dosages may be associated with potentially toxic plasma concentrations of the drug.150

Pregnancy, Fertility, and Lactation

Pregnancy

In reproduction studies in mice, rats, and rabbits, administration of furosemide caused unexplained abortions and maternal and fetal deaths. In addition, an increased incidence of hydronephrosis occurred in fetuses of animals treated with the drug. There are no adequate and well controlled studies in pregnant women. Furosemide should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Reproduction studies in male and female rats using furosemide dosages of 100 mg/kg daily (the maximum effective diuretic dosage in rats and 8 times the maximum human dosage of 600 mg daily) have not revealed evidence of impaired fertility.151

Lactation

Since furosemide is distributed into milk, the manufacturers recommend that nursing be discontinued if administration of the drug is necessary.

Diuretics

Concomitant administration of furosemide and most other diuretics results in enhanced effects, and furosemide should be administered in reduced dosage when the drug is added to an existing diuretic regimen. Spironolactone, triamterene, or amiloride hydrochloride may reduce the potassium loss resulting from furosemide therapy; this effect has been used to therapeutic advantage.

Drugs Affected by or Causing Potassium Depletion

In patients receiving cardiac glycosides, electrolyte disturbances produced by furosemide (principally hypokalemia but also hypomagnesemia) predispose the patient to glycoside toxicity. Possibly fatal cardiac arrhythmias may result. Periodic electrolyte determinations should be performed in patients receiving a cardiac glycoside and furosemide, and correction of hypokalemia undertaken if warranted. (See Cautions: Fluid, Electrolyte, Cardiovascular, and Renal Effects.)

Furosemide reportedly causes prolonged neuromuscular blockade in patients receiving nondepolarizing neuromuscular blocking agents (e.g., tubocurarine chloride, gallamine triethiodide [no longer commercially available in the US]), presumably because of potassium depletion or decreased urinary excretion of the muscle relaxant. Furosemide may also cause decreased arterial responsiveness to pressor amines. Orally administered furosemide should be discontinued 1 week, and parenterally administered furosemide 2 days, prior to elective surgery.

Some drugs such as corticosteroids, corticotropin, and amphotericin B also cause potassium loss, and severe potassium depletion may occur when one of these drugs is administered during furosemide therapy.

Lithium

Renal clearance of lithium is apparently decreased in patients receiving diuretics, and lithium toxicity may result. Furosemide and lithium should generally not be given together. If concomitant therapy is necessary, the patient should be hospitalized. Serum lithium concentrations should be monitored carefully and dosage adjusted accordingly.

Antidiabetic Agents

Administration of furosemide to diabetic patients may interfere with the hypoglycemic effect of insulin or oral antidiabetic agents, possibly as a result of hypokalemia. Patients should be observed for possible decrease of diabetic control. If correction of the potassium deficit does not restore control, dosage adjustments of the antidiabetic agent may be needed.

Hypotensive Agents

The antihypertensive effect of hypotensive agents may be enhanced when given concomitantly with furosemide. This effect is usually used to therapeutic advanta however, orthostatic hypotension may result. Dosage of the hypotensive agent, and possibly both drugs, should be reduced when furosemide is added to an existing regimen.

Indomethacin

In some patients, indomethacin may reduce the natriuretic and hypotensive effects of furosemide. The mechanism(s) of these interactions is uncertain but has been attributed to indomethacin-induced inhibition of prostaglandin synthesis which may result in fluid retention and/or changes in vascular resistance. The clinical importance of these interactions has not been established; however, when indomethacin and furosemide are administered concurrently, patients should be observed closely to determine if the desired diuretic and/or hypotensive effect is obtained. When evaluating plasma renin activity in hypertensive patients, it should be kept in mind that indomethacin blocks the furosemide-induced increase in plasma renin activity.

Ototoxic Drugs

Concomitant administration of furosemide and aminoglycoside antibiotics or other ototoxic drugs may result in increased incidence of ototoxicity and concomitant use of these drugs should be avoided. In addition, the possibility that IV furosemide may increase aminoglycoside toxicity by altering serum and tissue concentrations of the antibiotic should be considered. It has been proposed, but not proven, that furosemide may enhance the nephrotoxicity of neomycin.

Nonsteroidal Anti-inflammatory Agents

Furosemide and salicylates reportedly have competitive renal excretory sites and, therefore, patients receiving high doses of salicylates with furosemide may experience salicylate toxicity at lower dosage than usual. Concomitant administration of furosemide and aspirin reportedly has been associated with a transient reduction in creatinine clearance in a few patients with chronic renal insufficiency. Weight gain and increases in BUN, serum creatinine, and serum potassium concentrations also have been reported in patients receiving furosemide in combination with other nonsteroidal anti-inflammatory agents (NSAIAs).

Anticonvulsants

In one study, epileptic patients receiving chronic anticonvulsant therapy had a reduced diuretic response to furosemide as compared to controls. All of the epileptic patients were receiving phenytoin sodium and phenobarbital and some were also receiving other anticonvulsants. It has been postulated that renal sensitivity to furosemide is diminished by these drugs.

Chloral Hydrate

A reaction characterized by diaphoresis, flushes, variable blood pressure including hypertension, and uneasiness has been reported in some patients with acute myocardial infarction and heart failure who received furosemide IV within 24 hours after administration of an oral hypnotic dose of chloral hydrate (no longer commercially available in the US). Therefore, it may be preferable to use an alternate hypnotic drug (e.g., a benzodiazepine) in patients who require IV furosemide.

Probenecid or Sulfinpyrazone

It has been suggested that furosemide, by increasing serum uric acid concentrations, may interfere with the uricosuric effects of probenecid or sulfinpyrazone. Serum uric acid concentrations should be monitored in patients receiving both drugs, and dosage of the uricosuric drug should be increased if necessary.

Pharmacology

The pharmacologic effects of furosemide are similar to those of ethacrynic acid. The exact mode of action of furosemide has not been clearly defined; in contrast to ethacrynic acid, it does not bind sulfhydryl groups of renal cellular proteins. Furosemide inhibits the reabsorption of electrolytes in the ascending limb of the loop of Henle. The drug also decreases reabsorption of sodium and chloride and increases potassium excretion in the distal renal tubule and exerts a direct effect on electrolyte transport at the proximal tubule. Furosemide does not inhibit carbonic anhydrase and is not an aldosterone antagonist.

Furosemide diuresis results in enhanced excretion of sodium, chloride, potassium, hydrogen, calcium, magnesium, ammonium, bicarbonate, and possibly phosphate. Chloride excretion exceeds that of sodium. In studies in patients with normal renal function, the diuretic response was similar following oral or IV administration of equal doses of furosemide. In one study in uremic patients, however, diuresis and urinary excretion of sodium and potassium were greater after IV administration of furosemide than after equal oral doses. Excessive losses of potassium, hydrogen, and chloride may result in metabolic alkalosis. Urinary pH usually falls after administration of furosemide; however, increased bicarbonate excretion in some patients may temporarily raise urinary pH. Low doses of furosemide promote uric acid retention while large IV doses may cause temporary uricosuria. Maximum diuresis and electrolyte loss is greater with furosemide than with the thiazides or most other diuretics except ethacrynic acid. Like the thiazide diuretics and ethacrynic acid, the effectiveness of furosemide is independent of the acid-base balance of the patient.

Furosemide has some renal vasodilator effect; renal vascular resistance decreases and renal blood flow increases following administration of the drug. A temporary but substantial increase in glomerular filtration rate, as well as decreased peripheral vascular resistance and increased peripheral venous capacitance, has been reported following IV administration of furosemide in patients with heart failure associated with acute myocardial infarction. The renal and peripheral vascular effects may contribute toward the beneficial effects of the drug in these patients, as a decrease in left ventricular filling pressure occurs before the onset of substantial diuresis. In addition, IV administration of furosemide in patients with heart failure results in a decrease in plasma volume, increased hematocrit, and a fall in mean arterial pressure associated with increased cardiac output and decreased peripheral resistance. When large doses of furosemide are administered to patients with chronic renal insufficiency, glomerular filtration rate may be increased temporarily. A fall in renal blood flow and glomerular filtration rate may occur if excessive drug-induced diuresis results in a reduction in plasma volume.

As with other diuretics, a hypotensive effect may result from decreased plasma volume in patients receiving furosemide. However, the drug has been reported to produce only mild decreases in the supine systolic blood pressure and in the erect systolic and diastolic blood pressures when administered alone in the recommended oral dosage.

Furosemide appears to have less effect on carbohydrate metabolism and blood glucose concentrations than do the thiazides; however, the drug may cause elevations of blood glucose, glycosuria, and alterations in glucose tolerance possibly as a result of hypokalemia.

Pharmacokinetics

Absorption

In one study in patients with normal renal function, approximately 60% of a single 80-mg oral dose of furosemide was absorbed from the GI tract. When administered to fasting adults in this dosage, the drug appeared in the serum within 10 minutes, reached a peak concentration of 2.3 mcg/mL in 60-70 minutes, and was almost completely cleared from the serum in 4 hours. When the same dose was given after a meal, the serum concentration of furosemide increased slowly to a peak of about 1 mcg/mL after 2 hours and similar concentrations were present 4 hours after ingestion. However, a similar diuretic response occurred regardless of whether the drug was given with food or to fasting patients. In another study, the rate and extent of absorption varied considerably when 1 g of furosemide was given orally to uremic patients. An average of 76% of a dose was absorbed, and peak plasma concentrations were achieved within 2-9 hours (average 4.4 hours). Serum concentrations required to produce maximum diuresis are not known, and it has been reported that the magnitude of response does not correlate with either the peak or the mean serum concentrations.

The diuretic effect of orally administered furosemide is apparent within 30 minutes to 1 hour and is maximal in the first or second hour. The duration of action is usually 6-8 hours. The maximum hypotensive effect may not be apparent until several days after furosemide therapy is begun. After IV administration of furosemide, diuresis occurs within 5 minutes, reaches a maximum within 20-60 minutes, and persists for approximately 2 hours. After IM administration, peak plasma concentrations are attained within 30 minutes; onset of diuresis occurs somewhat later than after IV administration. In patients with severely impaired renal function, the diuretic response may be prolonged.

Distribution

Only limited information is available on the distribution of furosemide. The drug crosses the placenta and is distributed into milk.

Furosemide is approximately 95% bound to plasma proteins in both normal and azotemic patients.

Elimination

Plasma concentrations of furosemide decline in a biphasic manner. Various investigators have reported a wide range of elimination half-lives for furosemide. In one study, the elimination half-life averaged about 30 minutes in healthy patients who received 20-120 mg of the drug IV. In another study, the elimination half-life averaged 9.7 hours in patients with advanced renal failure who received 1 g of furosemide IV. The elimination half-life was more prolonged in 1 patient with concomitant liver disease.

In patients with normal renal function, a small amount of furosemide is metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid. Furosemide and its metabolite are rapidly excreted in urine by glomerular filtration and by secretion from the proximal tubule. In patients with normal renal function, approximately 50% of an oral dose and 80% of an IV or IM dose are excreted in urine within 24 hours; 69-97% of these amounts is excreted in the first 4 hours. The remainder of the drug is eliminated by nonrenal mechanisms including degradation in the liver and excretion of unchanged drug in the feces. In patients with marked renal impairment without liver disease, nonrenal clearance of furosemide is increased so that up to 98% of the drug is removed from the plasma within 24 hours. One patient with uremia and hepatic cirrhosis eliminated only 58% of an IV dose in 24 hours. Furosemide is not removed by hemodialysis.

Chemistry and Stability

Chemistry

Furosemide is a sulfonamide-type, loop diuretic. The drug occurs as a white to slightly yellow, odorless, crystalline powder with a pK_a of 3.9. Furosemide is insoluble in dilute acids, practically insoluble in water, sparingly soluble in alcohol, and freely soluble in alkali hydroxides.133

Furosemide injection, a nonpyrogenic, sterile solution of the drug, contains the sodium salt of furosemide which is formed in situ by the addition of sodium hydroxide during the manufacturing process. The injection contains 0.162 mEq of sodium per mL and has a pH of 8-9.3.

Stability

Furosemide injection should be stored at a temperature of 15-30°C and protected from light; injections having a yellow color should not be used. Exposure of furosemide tablets to light may cause discoloration; discolored tablets should not be dispensed. Furosemide tablets should be stored and dispensed in well-closed, light-resistant containers at a controlled room temperature of 15-30°C.133 . Commercially available 40-mg furosemide tablets have an expiration date of 5 years and the commercially available injection has an expiration date 42 months following the date of manufacture. The 20-mg tablets do not have a specific expiration dating period. Furosemide oral solutions should be stored at 15-30°C and protected from light and freezing; once opened, unused portions of the oral solution should be discarded after the time period recommended by the manufacturer.

Furosemide injection usually can be mixed with weakly alkaline and neutral solutions having a pH of 7-10, such as 0.9% sodium chloride injection or Ringer's injection, and with some weakly acidic solutions having a low buffer capacity. The injection should not be mixed with strongly acidic solutions (i.e., pH less than 5.5), such as those containing ascorbic acid, tetracycline, epinephrine, or norepinephrine, because furosemide may be precipitated. In addition, furosemide may precipitate at pH less than 7 and should not be used with certain drugs (e.g., amrinone, ciprofloxacin, labetalol, milrinone).150 Other drugs which should not be mixed with furosemide injection include most salts of organic bases including local anesthetics, alkaloids, antihistamines, hypnotics, meperidine, and morphine. Specialized references should be consulted for specific compatibility information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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