Furosemide

Black Box Warnings

Agent is potent diuretic that, if given in excessive amounts, may lead to profound diuresis with water and electrolyte depletion

Careful medical supervision is required; dosing must be adjusted to patient's needs

Contraindications

Documented hypersensitivity to furosemide or sulfonamides

Anuria

Cautions

Use caution in systemic lupus erythematosus, liver disease, renal impairment

Concomitant ethacrynic acid therapy (increases risk of ototoxicity)

Risks of fluid or electrolyte imbalance (including causing hyperglycemia, hyperuricemia, gout), hypotension, metabolic alkalosis, severe hyponatremia, severe hypokalemia, hepatic coma and precoma, hypovolemia (with or without hypotension)

Do not commence therapy in hepatic coma and in electrolyte depletion until improvement is noted

IV route twice as potent as PO

Food delays absorption but not diuretic response

May exacerbate lupus

Possibility of skin sensitivity to sunlight

Prolonged use in premature neonates may cause nephrocalcinosis

Efficacy is diminished and risk of ototoxicity increased in patients with hypoproteinemia (associated with nephrotic syndrome); ototoxicity is associated with rapid injection, severe renal impairment, use of higher than recommended doses, concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs

To prevent oliguria, reversible increases in BUN and creatinine, and azotemia, monitor fluid status and renal function; discontinue therapy if azotemia and oliguria occur during treatment of severe progressive renal disease

FDA-approved product labeling for many medications have included a broad contraindication in patients with a prior allregic reaction to sulfonamides; however, recent studies have suggested that crossreactivity between antibiotic sulfonamides and nonantibiotic sulfonamides is unlikely to occur

In cirrhosis, electrolyte and acid/base imbalances may lead to hepatic encephalopathy; prior to initiation of therapy, correct electrolyte and acid/base imbalances, when hepatic coma is present

High doses (> 80 mg) of furosemide may inhibit binding of thyroid hormones to carrier proteins and result in transient increase in free thyroid hormones, followed by overall decrease in total thyroid hormone levels

In patients at high risk for radiocontrast nephropathy furosemide can lead to higher incidence of deterioration in renal function after receiving radiocontrast compared to high-risk patients who received only intravenous hydration prior to receiving radiocontrast

Observe patients regularly for possible occurrence of blood dyscrasias, liver or kidney damage, or other idiosyncratic reactions

Cases of tinnitus and reversible or irreversible hearing impairment and deafness reported

Hearing loss in neonates has been associated with use of furosemide injection; in premature neonates with respiratory distress syndrome, diuretic treatment with furosemide in the first few weeks of life may increase risk of persistent patent ductus arteriosus (PDA), possibly through a prostaglandin-E-mediated process

Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients

Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of fasting and 2 hour postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus reported

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 initial stages of treatment

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

This medicine is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

The usual starting oral dose for treatment of edema in adults is 20-80 mg as a single dose. The same dose or an increased dose may be administered 6-8 hours later. Doses may be increased 20-40 mg every 6-8 hours until the desired effect occurs. The effective dose may be administered once or twice daily. Some patients may require 600 mg daily.

The starting oral dose for children is 2 mg/kg. The starting dose may be increased by 1-2 mg/kg every 6 hours until the desired effect is achieved. Doses greater than 6 mg/kg are not recommended.

The recommended dose for treating hypertension is 40 mg twice daily. The dose of other blood pressure medications should be reduced by half when furosemide is added.

LASIX® is a diuretic which is an anthranilic acid derivative. LASIX tablets for oral administration contain furosemide as the active ingredient and the following inactive ingredients: lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and colloidal silicon dioxide NF. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. LASIX is available as white tablets for oral administration in dosage strengths of 20, 40 and 80 mg. Furosemide is a white to off-white odorless crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids.

The CAS Registry Number is 54-31-9.

The structural formula is as follows:

Edema

LASIX is indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. LASIX is particularly useful when an agent with greater diuretic potential is desired.

Hypertension

Oral LASIX may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with LASIX alone.

Edema

Management of edema associated with heart failure, hepatic cirrhosis, and renal disease (e.g., nephrotic syndrome).133 e

Considered a diuretic of choice for most patients with heart failure.524

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., 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

IV management of acute pulmonary edema (in combination with oxygen and a cardiac glycoside).150

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).133 500

Not considered a preferred agent for initial management of hypertension;501 502 503 504 however, may be useful in selected patients with renal impairment500 502 504 or heart failure.500 524

Contraindications

• Anuria.133

• Known hypersensitivity to furosemide or any ingredient in the formulation.133

Warnings/Precautions

Warnings

Sudden alterations of electrolyte balance in patients with cirrhosis may precipitate hepatic coma; use with caution in patients with hepatic cirrhosis and ascites.133

Do not initiate therapy in patients with hepatic coma or electrolyte depletion until the basic condition is improved.133 Therapy in such patients is best initiated in the hospital with careful monitoring of clinical status and electrolyte balance.133

If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, discontinue the drug.133 150

Sensitivity Reactions

Anaphylaxis (e.g., urticaria, angioedema, hypotension) within 5 minutes after IV administration reported.102

Possible exacerbation or activation of systemic lupus erythematosus.133 150

Patients sensitive to sulfonamides may show allergic reactions to furosemide.e

Photosensitivity may occur.133

Major Toxicities

Risk of tinnitus, reversible or permanent hearing impairment increased following IV or IM administration, especially at high dosages,133 e after too-rapid administration,133 in patients with severely impaired renal function, and/or in patients receiving other ototoxic drugs (e.g., aminoglycosides).133 e (See Specific Drugs under Interactions.)

If high-dose IV therapy is indicated, administer by slow IV infusion (e.g., at a rate not exceeding 4 mg/minute in adults).133 150

General Precautions

Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients.133 (See Boxed Warning.)

Risk of orthostatic hypotension, especially with brisk diuresis.133 150 151 May be aggravated by concomitant use with alcohol, barbiturates, or narcotics.133 151 e

Risk of hypokalemia, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids or ACTH.133 150 Concomitant therapy with digitalis may exaggerate metabolic effects of hypokalemia, especially myocardial effects.133 150

Observe carefully for manifestations of fluid and electrolyte depletion (e.g., dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, nausea, vomiting).133

Possible increased blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour postprandial sugar); precipitation of diabetes mellitus rarely reported.133 150 Monitor urine and blood glucose concentrations periodically in patients with diabetes and those suspected of latent diabetes.e

Possible hyperuricemia and precipitation of gout;133 150 use with caution in patients with a history of gout or elevated serum uric acid concentrations.e

Monitor regularly for the possible occurrence of blood dyscrasias, liver or kidney damage, or other idiosyncratic reactions.133 150

Serum electrolytes (particularly potassium), CO2, Scr, and BUN should be determined frequently during the first few months of therapy and periodically thereafter.133 150

Discontinue therapy 1 week (oral furosemide) or 2 days (parenteral furosemide) before elective surgery.e

Specific Populations

Category C.133

Distributed into milk.133 Use with caution.133

Risk of persistent patent ductus arteriosus (PDA) may be increased in premature neonates with respiratory distress syndrome (RDS) who receive furosemide during the first weeks of life.103 e

Do not exceed dosage of 1 mg/kg per 24 hours in premature neonates with <31 weeks’ postconception age (gestational age at birth plus postnatal age); risk of potentially toxic furosemide plasma concentrations with higher dosages.150

Renal calcification reported in severely premature infants treated with IV furosemide for edema due to PDA and hyaline membrane disease; concomitant chlorothiazide therapy may decrease hypercalciuria and dissolve some calculi.150

Hearing loss reported in neonates; possibly secondary to renal immaturity.103 125 126 150

Oral solutions contain sorbitol; high dosages may cause diarrhea in children.e

Use with caution.133 e

Use with caution.133 e

Common Adverse Effects

Orthostatic hypotension, dizziness, electrolyte imbalance (hyponatremia, hypokalemia, hypochloremia) tinnitus, photosensitivity.133 e

Absorption

Bioavailability

Mean oral bioavailability of furosemide from commercially available tablets and oral solution is 64% and 60%, respectively.133

Commercially available tablets and oral solution are bioequivalent.133

Onset

Following oral administration, onset of diuresis occurs within 30 minutes to 1 hour; maximal effect after 1–2 hours.133 e

Following IV administration, diuresis occurs within 5 minutes and peaks within 20–60 minutes.150 e

Onset of diuresis after IM administration occurs somewhat later than after IV administration.150

Maximum hypotensive effect may not be apparent until after several days of therapy.e

Duration

Diuretic effect persists 6–8 hours following oral administration and approximately 2 hours following IV administration.133 150 e

Food

Food does not appear to affect diuretic effect.e

Special Populations

In patients with severely impaired renal function, the diuretic response may be prolonged.e

Distribution

Extent

Crosses the placenta and is distributed into milk.e

Plasma Protein Binding

Approximately 95% bound to plasma proteins (mainly albumin) in both normal and azotemic patients.133 e

Elimination

Metabolism

Metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid.e

Elimination Route

Rapidly excreted in urine by glomerular filtration and by secretion from the proximal tubule.e

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.150 e The remainder of the drug is eliminated by nonrenal mechanisms including degradation in the liver and excretion of unchanged drug in the feces.e

Half-life

Biphasic;e terminal half-life is approximately 2 hours.133

Special Populations

Hepatic or renal impairment prolongs the elimination half-life of the drug.e

In patients with marked renal impairment without liver disease, nonrenal clearance is increased to the extent that up to 98% of the drug is cleared within 24 hours.e

Not removed by hemodialysis.133

Storage

Oral

Tight, light resistant containers at 15–30°C.133 151

Parenteral

15–30°C; protect from light.150 Discard unused portion.150

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not mix with strongly acidic solutions (i.e., pH < 5.5), such as those containing ascorbic acid, amrinone, ciprofloxacin, labetalol, tetracycline, milrinone, epinephrine, or norepinephrine, because furosemide may be precipitated.150 e

Edema

Furosemide is indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver and renal disease, including the nephrotic syndrome. Furosemide is particularly useful when an agent with greater diuretic potential is desired.

Hypertension

Oral Furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with Furosemide alone.

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).

• Antihypertensive
• Diuretic, Loop

Monitor I & O (inpatient setting) and weight daily; blood pressure, orthostasis; serum electrolytes, renal function; monitor hearing with high doses or rapid IV administration