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Diuretics, Loop (Systemic)

This monograph includes information on the following:

1) Bumetanide  
2) Ethacrynic Acid
3) Furosemide


INN:
Ethacrynic Acid—Etacrynic acid


JAN:
Ethacrynic Acid—Etacrynic acid

VA CLASSIFICATION
Primary: CV702
Secondary: CV409; TN900

Commonly used brand name(s): Apo-Furosemide3; Bumex1; Edecrin2; Furoside3; Lasix3; Lasix Special3; Myrosemide3; Novosemide3; Uritol3.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Diagnostic aid adjunct (renal disease)—Furosemide;

Diuretic—Bumetanide; Ethacrynic Acid; Furosemide;

Antihypertensive—Bumetanide; Ethacrynic Acid; Furosemide;

Antihypercalcemic—Bumetanide; Ethacrynic Acid; Furosemide;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Edema (treatment)—Bumetanide, ethacrynic acid, and furosemide are indicated in the treatment of edema associated with congestive heart failure, hepatic cirrhosis, and renal disease (including nephrotic syndrome). {01} {03} {06} {32} {34}
—Bumetanide, ethacrynic acid, and furosemide are indicated as adjuncts in the treatment of acute pulmonary edema. {02} {03} {06}
—Ethacrynic acid is indicated in the short-term management of ascites due to malignancy, idiopathic edema, and lymphedema; and in the short-term management of hospitalized pediatric patients with congenital heart disease or nephrotic syndrome. {03} {04}
—Bumetanide, ethacrynic acid, and furosemide are especially useful in patients refractory to other diuretics or with existing acid-base disorders, congestive heart failure, or renal disease.

Hypertension (treatment)—[Bumetanide ], [ethacrynic acid]1 , and furosemide are indicated in the treatment of mild to moderate hypertension , usually in combination with other antihypertensive agents, and as adjuncts in the treatment of hypertensive crisis. {05} {14}
—Bumetanide, ethacrynic acid, and furosemide are not considered to be primary agents in the treatment of essential hypertension. However, they may be indicated in combination with other antihypertensives in the treatment of hypertension associated with impaired renal function. In the stepped-care approach to antihypertensive treatment, bumetanide, ethacrynic acid, or furosemide may be substituted for a thiazide diuretic in patients with renal function impairment.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

Hypercalcemia (treatment)—[Bumetanide ], [ethacrynic acid]1 , and [furosemide]1 are used in the treatment of hypercalcemia.

[Renography, adjunct]1 and
[Renal imaging, radionuclide, adjunct ]1—Furosemide augments radionuclide renography and renal scintigraphy by stimulating the flow of urine and thereby aiding in the differentiation of mechanical obstruction from nonobstructive dilatation in patients with hydroureteronephrosis. {17} {18} {19} {20}

Acceptance not established
Pharmacokinetic studies demonstrated efficacy in the use of bumetanide for the treatment of edema in infant and pediatric patients.{37}{38}{39}{40}{41}{42} However, data are insufficient to determine an optimal dose for safe and effective use in pediatric patients.{37}{38}{39}{40}{41}{42}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Bumetanide: 364.42 {35}
    Ethacrynic acid: 303.14 {35}
    Furosemide: 330.74 {35}

pKa—
    Ethacrynic acid: 3.5
    Furosemide: 3.9

Mechanism of action/Effect:

Diuretic—Bumetanide, ethacrynic acid, and furosemide inhibit reabsorption of sodium and water in the ascending limb of the loop of Henle by interfering with the chloride binding site of the 1Na+, 1K+, 2Cl- cotransport system. Loop diuretics increase the rate of delivery of tubular fluid and electrolytes to the distal sites of hydrogen and potassium ion secretion, while plasma volume contraction increases aldosterone production. The increased delivery and high aldosterone levels promote sodium reabsorption at the distal tubules, thus increasing the loss of potassium and hydrogen ions. {02} Bumetanide may have a small additional action on sodium reabsorption in the proximal tubule since phosphate reabsorption is reduced.

Antihypertensive—Diuretics lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases. Eventually, cardiac output returns to normal with an accompanying decrease in peripheral resistance. {07} {08}

Antihypercalcemic—Loop diuretics increase the urinary excretion of calcium. {02}

Absorption:

Bumetanide—Almost completely absorbed from gastrointestinal tract. Absorption is probably reduced in patients with edematous bowel caused by congestive heart failure or nephrotic syndrome; parenteral administration may be preferable in these patients.

Furosemide—Approximately 60 to 70% of an oral dose of furosemide is absorbed. Food may slow the rate of absorption but does not appear to alter the bioavailability or diuretic effect. Absorption is reduced to 43 to 46% in patients with end-stage renal disease, and is probably reduced also in patients with edematous bowel caused by congestive heart failure or nephrotic syndrome; parenteral administration may be preferable in these patients.

Protein binding:

Bumetanide—Very high (94 to 96%). {01} {34}

Ethacrynic acid—High.

Furosemide—Very high (91 to 97%; almost totally to albumin).

Biotransformation:

Hepatic; metabolism of bumetanide is limited and produces inactive metabolites.

Half-life:


Bumetanide:

1 to 11/2 hours. {01}



Furosemide:

Wide variation among individuals.


Normal—

1/2 to 1 hour.



Anuric—

75 to 155 minutes.

In patients with both renal and hepatic insufficiency, half-lives of 11 to 20 hours have been reported.

In neonates, reported half-lives are prolonged, probably due to low renal and hepatic clearance.



Onset of action:


Diuretic:


Bumetanide—

Oral—30 to 60 minutes. {01}

Intravenous—Within minutes. {01}



Ethacrynic acid—

Oral—30 minutes. {03}

Intravenous—5 minutes. {03}



Furosemide—

Oral—20 to 60 minutes. {05} {21}

Intravenous—5 minutes. {06}



Time to peak effect:


Diuretic:


Bumetanide—

Oral—1 to 2 hours. {01}

Intravenous—15 to 30 minutes. {01}



Ethacrynic acid—

Oral—2 hours. {03}

Intravenous—15 to 30 minutes.



Furosemide—

Oral—1 to 2 hours. {05}

Intravenous—Within 30 minutes. {06}



Note: The maximum antihypertensive effect may not occur until several days after initiation of loop diuretic therapy.


Duration of action:


Diuretic:


Bumetanide—

Oral—4 hours with usual doses (1 to 2 mg); 4 to 6 hours with higher doses. {01}

Intravenous—3.5 to 4 hours.



Ethacrynic acid—

Oral—6 to 8 hours. {03}

Intravenous—2 hours.



Furosemide—

Oral—6 to 8 hours. {05}

Intravenous—2 hours. {06}



Elimination:


Bumetanide—
        Renal (81%; 45% unchanged); biliary/fecal (2%).



Ethacrynic acid—
        Renal (67%); biliary/fecal (33%); 20% excreted unchanged.



Furosemide—
        Renal (88%); biliary/fecal (12%).
        In patients with severe renal impairment, renal clearance is reduced but overall plasma clearance may be unchanged because nonrenal clearance is increased. In patients with uremia, both renal and nonrenal clearance are reduced, and elimination is delayed.
        In dialysis: Not dialyzable.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to sulfonamides (including thiazide diuretics) may be sensitive to bumetanide or furosemide also.

Carcinogenicity/Tumorigenicity

Bumetanide—One study in female rats given 60 mg per kg of body weight (mg/kg) of bumetanide for 18 months found an increase in mammary adenomas; repetition of the same study did not result in the same findings. {34}

Ethacrynic acid—A 79-week study in rats at doses up to 45 times the human dose revealed no evidence of a tumorigenic effect. {04}

Mutagenicity

Bumetanide—Studies with bumetanide in various strains of Salmonella typhimurium in the presence or absence of an in vitro metabolic activation system found no evidence of mutagenicity. {34}

Furosemide—Mutagenicity studies have not been conducted. {32}

Pregnancy/Reproduction

Pregnancy—
Pregnant women should be advised to contact physician before taking this medication, since routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of toxemia. Diuretics are indicated only in the treatment of edema due to pathologic causes or as a short course of treatment in patients with severe hypervolemia.


Bumetanide

Adequate and well-controlled studies in humans have not been done.

Some studies in animals have shown that bumetanide may cause adverse effects on the fetus. Bumetanide has not been shown to be teratogenic in mice or hamsters; {34} however, one study in rats showed moderate growth retardation and increased incidence of delayed ossification of sternebrae at doses 3400 times the maximum human therapeutic dose. {34} These effects in the rat were associated with maternal weight reductions during dosing and were not observed at doses 1000 times the maximum human therapeutic dose. Delayed ossification of sternebrae was also noted in rabbits at doses 10 times the maximum human therapeutic dose. A slight embryocidal effect in rats and rabbits was evident at doses 3400 and 3.4 times the maximum human therapeutic dose, respectively. In rabbits, a dose-related decrease in litter size and an increase in resorption rate were noted at doses of 3.4 and 10 times the maximum human therapeutic dose. {01} {34}

FDA Pregnancy Category C. {01} {34}



Ethacrynic acid

Adequate and well-controlled studies in humans have not been done.

Studies in mice and rabbits using doses up to 50 times the human dose have not shown evidence of external abnormalities of the fetus. In rats, a decrease in mean body weights of the fetuses was noted at doses 50 times the maximum human dose. {03} {04}

FDA Pregnancy Category B. {03} {04}



Furosemide

Furosemide crosses the placenta. Studies in humans have not been done.

Studies in rabbits and mice have shown that furosemide causes an increased incidence of hydronephrosis in the fetus. In rabbits, unexplained maternal deaths and abortions have occurred at doses 2 to 8 times the maximum recommended human dose. {32}

FDA Pregnancy Category C. {32}


Breast-feeding

Furosemide is distributed into breast milk; {32} it is not known whether bumetanide or ethacrynic acid is distributed into breast milk. {01} {04} {05} {34}

Pediatrics

Caution is required in neonates because of the prolonged half-life of furosemide. Usual pediatric doses may be used, but the dosing interval should be extended.


Geriatrics


Although appropriate studies on the relationship of age to the effects of loop diuretics have not been performed in the geriatric population, the elderly may be more sensitive to the hypotensive and electrolyte effects. In addition, elderly patients are at greater risk of developing circulatory collapse and thromboembolic episodes. Elderly patients are also more likely to have age-related renal function impairment, which may require adjustment of dosage or dosing interval in patients receiving loop diuretics.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol or
Hypotension-producing medications, other (See Appendix II )    (hypotensive and/or diuretic effects may be potentiated when these medications are used concurrently with loop diuretics; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, when used concurrently dosage adjustments may be necessary {01} {03})


Amiodarone    (concurrent use of loop diuretics with amiodarone may lead to an increased risk of arrhythmias associated with hypokalemia {11})


» Amphotericin B, parenteral    (concurrent and/or sequential administration with loop diuretics should be avoided since the potential for ototoxicity and nephrotoxicity may be increased, especially in the presence of renal function impairment; in addition, concurrent use with loop diuretics may intensify electrolyte imbalance, particularly hypokalemia; frequent electrolyte determinations are recommended and potassium supplementation may be required {13})


Angiotensin-converting enzyme (ACE) inhibitors    (sudden and severe hypotension may occur within the first 1 to 5 hours after the initial dose of captopril, enalapril, or lisinopril, particularly in patients who are sodium- and volume-depleted as a result of diuretic therapy. Withdrawal of the diuretic or increase of salt intake approximately 1 week before start of captopril therapy or 2 to 3 days before start of benazepril, enalapril, fosinopril, lisinopril, quinapril, or ramipril therapy, or initiating ACE inhibitor therapy in lower doses, will minimize the reaction; this reaction does not usually recur with subsequent doses, although caution in increasing doses is recommended; diuretics may be reinstituted as necessary {10} {25} {26} {27})

    (risk of renal failure may be increased in patients who are sodium- and volume-depleted as a result of diuretic therapy {28})

    (ACE inhibitors may reduce the secondary aldosteronism and hypokalemia caused by diuretics)


» Anticoagulants, coumarin- or indandione-derivative or{01}{03}{10}
Heparin or
Streptokinase or
Urokinase    (anticoagulant effects may be decreased when these medications are used concurrently with loop diuretics, as a result of reduction of plasma volume leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function, resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary)

    (anticoagulant effects may be potentiated when these medications are used concurrently with ethacrynic acid as a result of displacement of anticoagulant from protein-binding sites; dosage adjustments of the anticoagulant may be necessary during and after ethacrynic acid therapy or, alternatively, use of furosemide is recommended)

    (gastrointestinal ulcerative or hemorrhagic potential of ethacrynic acid may increase the risk of hemorrhage in patients receiving anticoagulant or thrombolytic therapy; use of a different diuretic is recommended)


Antidiabetic agents, oral or
Insulin    (furosemide, and possibly bumetanide or ethacrynic acid {24}, may rarely raise blood glucose concentrations or interfere with the hypoglycemic effects of these agents; {24} for adult-onset diabetics, dosage adjustment of hypoglycemic medications may be necessary during and after therapy {01} {04})


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin{03}{14}    (may antagonize the natriuresis and increase in plasma renin activity [PRA] caused by loop diuretics; indomethacin, and possibly other NSAIDs with the exception of diflunisal, may also reduce the increase in urine volume caused by loop diuretics, possibly by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention {14})

    (in addition, concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis)

    (in the premature neonate, administration of 1 mg/kg of furosemide immediately following indomethacin has been shown to prevent or reduce indomethacin-induced adverse renal effects without interfering with ductus arteriosus closure {23})


Digitalis glycosides    (concurrent use with loop diuretics may enhance the possibility of digitalis toxicity associated with hypokalemia and hypomagnesemia {01} {15} {16})


» Hypokalemia-causing medications, other (See Appendix II ){10}{30}    (risk of severe hypokalemia due to other hypokalemia-causing medications may be increased; monitoring of serum potassium concentrations and cardiac function and potassium supplementation may be required {29})


» Lithium    (concurrent use with loop diuretics may provoke lithium toxicity because of reduced renal clearance and is not recommended unless patient can be closely monitored {01} {03} {06} {10})


» Nephrotoxic medications, other (See Appendix II ) or{01}
Ototoxic medications, other (See Appendix II ){01}{03}    (concurrent and/or sequential administration with loop diuretics should be avoided since the potential for ototoxicity and nephrotoxicity may be increased, especially in the presence of renal function impairment)


Neuromuscular blocking agents, nondepolarizing    (loop diuretics may induce hypokalemia, which may enhance the blockade of nondepolarizing neuromuscular blocking agents; serum potassium determinations may be necessary prior to administration of nondepolarizing neuromuscular blocking agents; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade {06} {10})


Sympathomimetics    (concurrent use may reduce the antihypertensive effects of the loop diuretics; the patient should be carefully monitored to confirm that the desired effect is being obtained {22})


For furosemide only (in addition to those listed above)
Chloral hydrate    (administration of chloral hydrate followed by intravenous furosemide may result in diaphoresis, hot flashes, and variable blood pressure, including hypertension due to a hypermetabolic state caused by displacement of thyroxine from its bound state {10} {12} {31})


Probenecid    (probenecid has been found to increase serum concentrations of furosemide by inhibiting active renal tubular secretion {10} {14})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values

For bumetanide, ethacrynic acid, and furosemide
Blood glucose concentrations and{01}{03}{32}{34}
Urine glucose concentrations{01}{03}    (may be increased; ethacrynic acid increases blood glucose only rarely, especially in diabetics, prediabetics, or patients with compensated cirrhosis; in patients with uremia, large doses of ethacrynic acid may cause severe hypoglycemia; the effect of bumetanide is controversial and possibly variable)


Blood urea nitrogen (BUN) and{01}{32}
Uric acid, serum{01}{34}    (concentrations may be increased)


Calcium and
Chloride and
Magnesium and
Potassium and
Sodium    (serum concentrations may be decreased {01} {32} {34})


For bumetanide only (in addition to the above)
Phosphate    (urinary concentrations may be increased {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist

For bumetanide, ethacrynic acid, and furosemide:
» Anuria or{01}{03}{06}{32}{34}
» Renal function impairment, severe{01}    (impaired effectiveness and possible delayed excretion with increased risk of toxicity. Although bumetanide, ethacrynic acid, and furosemide are effective diuretics in patients with renal function impairment, reduced clearance may necessitate use of higher doses combined with more prolonged dosing intervals to prevent accumulation and reduce the risk of ototoxicity)


Diabetes mellitus    (loop diuretics cause impaired glucose tolerance {01} {32} {34})


Gout, history of or{03}{32}{34}
Hyperuricemia{01}{03}{32}{34}    (loop diuretics may elevate serum uric acid concentrations)


Hearing function impairment{01}
Hepatic function impairment, including cirrhosis and ascites    (risk of dehydration and electrolyte imbalance, which may precipitate hepatic coma and death; hospitalization during initiation of therapy is recommended {01} {04} {32} {34})


Myocardial infarction, acute    (excessive diuresis should be avoided because of the danger of precipitating shock)


Pancreatitis, or history of    (pancreatitis has been reported with bumetanide, ethacrynic acid, and furosemide {03})


Sensitivity to loop diuretic prescribed
Caution is recommended also in patients who are at increased risk if hypokalemia occurs, including those taking digitalis and diuretics and those with:{01}
Certain diarrheal states
Congestive heart failure
Hepatic cirrhosis and ascites
History of ventricular arrhythmias
Potassium-losing nephropathy
States of aldosterone excess with normal renal function{01}
For ethacrynic acid and furosemide only (in addition to the above):
Lupus erythematosus, history of    (exacerbation or activation by ethacrynic acid and furosemide has been reported)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure measurements    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be taught to monitor their blood pressure at home and report the results at regular physician visits)


Blood urea nitrogen (BUN) and{01}{03}{06}{32}{34}
Carbon dioxide (CO 2){01}{03}    (determinations recommended at periodic intervals during therapy)


Electrolyte concentrations    (determinations recommended at periodic intervals, especially if patients are also taking cardiac glycosides or systemic steroids, or when severe hepatic cirrhosis is present {01})


Glucose, serum and{01}{03}{32}{34}
Hepatic function and{01}
Renal function and
Uric acid, serum{01}{32}{34}    (determinations recommended at periodic intervals)


Hearing examinations    (recommended at periodic intervals in patients receiving prolonged high-dose intravenous therapy {01})


Weight measurement    (recommended prior to initiation of therapy and at periodic intervals during therapy to monitor water loss {03})




Side/Adverse Effects

Table 1. Side/Adverse Effects*


Note: Nephrocalcinosis or nephrolithiasis may occur with furosemide administration if hypercalciuria is present.
Ethacrynic acid appears to be more likely to cause ototoxicity than bumetanide or furosemide and less likely to cause hyperglycemia than furosemide.



The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Legend
I=Bumetanide
II=Ethacrynic acid
III =Furosemide

I
 
II
 
III
 
Those indicating need for medical attention
 
     
Allergic reaction (skin rash) {01} {03} {06}
R
R
R
Blood in urine—associated with parenteral use
U
R
U
Electrolyte imbalance such as hyponatremia, hypochloremic alkalosis, and hypokalemia—occurs frequently, up to 10 to 15% of patients receiving ethacrynic acid (usually not symptomatic; symptoms include dry mouth, increased thirst, irregular heartbeat, mood or mental changes, muscle cramps or pain, nausea or vomiting, unusual tiredness or weakness, weak pulse) {01} {03}
L
L
L
Gastrointestinal bleeding (black, tarry stools)—associated with parenteral use
U
R
U
Gout (joint pain, lower back or side pain) {04}
R
R
R
Hepatic dysfunction (yellow eyes or skin) {01} {03} {06}
R
R
R
Leukopenia or agranulocytosis (fever or chills, cough or hoarseness, lower back or side pain, painful or difficult urination) {01} {03} {06}
R
R
R
Ototoxicity—more frequent with renal function impairment and in rapid {09} parenteral administration of large doses (ringing or buzzing in ears or any loss of hearing; usually transient, but permanent deafness has occurred, especially in patients receiving other ototoxic drugs) {01} {03} {06}
R
L
R
Pancreatitis (severe stomach pain with nausea and vomiting) {04}
R
R
R
Thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin) {01} {04}
R
R
R
Xanthopsia (yellow vision) {06}
U
U
R
Those indicating need for medical attention only if they continue or are bothersome
 
     
Blurred vision {04}
 
L
L
L
Chest pain
 
L
U
U
Confusion {03}
 
U
L
U
Diarrhea {03} {06}
 
L
M
L
Headache {01} {03} {06}
 
L
L
L
Increased sensitivity of skin to sunlight {06}
 
U
U
L
Local irritation (redness or pain at site of injection) {03}
R
R
R
Loss of appetite {04}
 
L
M
L
Nervousness
 
U
L
U
Orthostatic hypotension as a result of massive diuresis (dizziness or lightheadedness when getting up from a lying or sitting position) {01} {04}
M
M
M
Premature ejaculation or difficulty in keeping an erection {01}
 
L
U
U
Stomach cramps or pain {01}
 
L
L
L
* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents (although their basic pharmacologic similarity suggests that side effects occurring with one may occur with the others). M = more frequent; L = less frequent; R = rare; U = unknown.
 Dose-related.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diuretics, Loop (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to the loop diuretic prescribed, or to sulfonamides (for bumetanide and furosemide)

Pregnancy—Not recommended for routine use; reported to cause harmful effects, including birth defects, in animals





Breast-feeding—Furosemide distributed into breast milk





Use in the elderly—Elderly patients may be more sensitive to hypotensive and electrolyte effects, and may be at greater risk of developing circulatory collapse and thromboembolic episodes
Other medications, especially parenteral amphotericin B, oral anticoagulants, other hypokalemia-causing medications, lithium, or other nephrotoxic medications
Other medical problems, especially anuria or severe renal function impairment

Proper use of this medication
Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis

Compliance with therapy; taking medication at the same time(s) each day to maintain the therapeutic effect

Taking with food or milk to reduce gastrointestinal irritation

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but controls hypertension; possible need for lifelong therapy; serious consequences of untreated hypertension

For oral solution dosage form of furosemide (in addition to the above)
Taking orally, even if in dropper bottle; importance of accurate measurement

Precautions while using this medication
Making regular visits to physician to check progress

» Possibility of hypokalemia; possible need for additional potassium in diet; not changing diet without first checking with physician

To prevent dehydration, notifying physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution if any kind of surgery (including dental surgery) is required

» Caution when getting up suddenly from a lying or sitting position

» Caution in using alcohol, while standing for long periods or exercising, and during hot weather because of enhanced orthostatic hypotensive effects

Diabetics: May increase blood sugar levels

For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician

For furosemide (in addition to the above)
» Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth


Side/adverse effects
Signs of potential side effects, especially allergic reaction, blood in urine, electrolyte imbalance, gastrointestinal bleeding, gout, hepatic dysfunction, leukopenia, agranulocytosis, ototoxicity, pancreatitis, thrombocytopenia, and xanthopsia


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response. The lowest effective dosage should be utilized to minimize potential fluid and electrolyte imbalance.

When loop diuretics are used to promote diuresis, intermittent dosage schedules may reduce the possibility of electrolyte imbalance or hyperuricemia resulting from therapy.

Concurrent administration of potassium supplements or potassium-sparing diuretics may be indicated in patients considered to be at higher risk for developing hypokalemia.

If a single daily dose is indicated, it is preferably taken on arising in order to minimize the effect of increased frequency of urination on sleep.

When bumetanide, ethacrynic acid, or furosemide is added to an antihypertensive regimen, the dose of other antihypertensive agents may have to be reduced in order to prevent an excessive drop in blood pressure.

It is recommended that bumetanide, ethacrynic acid, and furosemide be discontinued if oliguria persists for more than 24 hours at maximal dosage.

BUMETANIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effect—May have additional action on proximal tubule.

Biotransformation and elimination—Excreted largely unchanged.



Side/adverse effects:
Muscle pain may occur with large doses. Chest pain, premature ejaculation, and difficulty in keeping an erection have also been reported.



Additional Dosing Information
See also General Dosing Information .

For parenteral dosage forms only
Intravenous administration is generally preferred over intramuscular administration.

Intravenous administration should be at a slow, controlled rate over a 2-minute period.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

BUMETANIDE TABLETS USP

Usual adult dose
[Antihypertensive or]
Diuretic
Oral, 500 mcg (0.5 mg) to 2 mg a day as a single daily dose. {34} The dose may be increased, if necessary, by addition of a second or third daily dose with intervals of four to five hours between doses. An intermittent dosage schedule (administration on alternate days for three or four days, with one or two days in between) may also be used. {01} {34}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual adult prescribing limits
10 mg a day. {01} {34}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


500 mcg (0.5 mg) (Rx) [Bumex (lactose)][Generic]


1 mg (Rx) [Bumex (lactose)][Generic]


2 mg (Rx) [Bumex (lactose)][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

BUMETANIDE INJECTION USP

Usual adult dose
[Antihypertensive or]
Diuretic
Intravenous or intramuscular, 500 mcg (0.5 mg) to 1 mg, repeated at intervals of two to three hours, if necessary. {01} {34}


Usual adult prescribing limits
10 mg a day. {01} {34}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


250 mcg (0.25 mg) per mL (Rx) [Bumex (benzyl alcohol 1%)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. Protect from light.

Stability:
Infusion solutions should be freshly prepared and used within a 24-hour period. {01}


ETHACRYNIC ACID

Summary of Differences


Indications:
Also indicated for short-term management of ascites due to malignancy, idiopathic edema, and lymphedema, and for treatment of hypercalcemia.



Side/adverse effects:
Greatest risk of ototoxicity. Gastrointestinal bleeding and blood in urine may occur with parenteral use. Higher incidence of gastrointestinal upset. Confusion, loss of appetite, and nervousness were reported more often than with other loop diuretics.



Additional Dosing Information
See also General Dosing Information.

Concurrent administration of ammonium chloride or arginine chloride may be indicated in patients considered to be at higher risk of developing metabolic alkalosis as a result of the chloruretic effect.

Because of the profound effect of ethacrynic acid on sodium excretion, rigid dietary salt restriction is not necessary in most patients and may in fact increase the risk of adverse effects due to hyponatremia.

In patients with renal edema, administration of salt-poor albumin may be helpful in preventing reduced response to ethacrynic acid because of hypoproteinemia.

If severe, watery diarrhea occurs, it is recommended that ethacrynic acid be permanently withdrawn.

For parenteral dosage forms only
Intramuscular or subcutaneous administration is not recommended because of local pain and irritation.

Intravenous administration should be at a slow, controlled rate over a period of about 30 minutes.

If a second injection is required, use of a different injection site is recommended to prevent thrombophlebitis.


Oral Dosage Forms

ETHACRYNIC ACID ORAL SOLUTION

Usual adult dose
Diuretic
Initial: Oral, 50 to 100 mg a day, in single or divided daily doses with increments of 25 to 50 mg a day as needed. {03}

Maintenance: Oral, reduced to meet individual requirements once dry weight is achieved; usually 50 to 200 mg a day. {03}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual adult prescribing limits
400 mg a day.

Usual pediatric dose
Diuretic
Initial: Oral, 25 mg a day, with increments of 25 mg a day as needed. {03}

Maintenance: Oral, adjusted to meet individual requirements. {03}


Note: Use in infants is not recommended.


Strength(s) usually available
U.S.—
Dosage form not commercially available in the U.S. Compounding required for prescriptions.

Canada—
Dosage form not commercially available in Canada. Compounding required for prescriptions.

Packaging and storage:
Store at or below 24 °C (75 °F). Protect from freezing.

Preparation of dosage form:
An oral liquid dosage form of ethacrynic acid has been prepared by dissolving ethacrynic acid powder in 10% alcohol in water, then bringing it to volume (to produce a solution containing 1 mg of ethacrynic acid per mL) with a 50% aqueous sorbitol solution (with added 0.005% methylparaben and 0.002% propylparaben as preservatives), and adjusting the pH to 7 with sodium hydroxide.

Stability:
This product was found to be stable for several weeks when stored at 24 °C (75 °F).

Auxiliary labeling:
   • Take with meals or milk.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



ETHACRYNIC ACID TABLETS USP

Usual adult dose
See Ethacrynic Acid Oral Solution.

Usual adult prescribing limits
400 mg a day. {03}

Usual pediatric dose
See Ethacrynic Acid Oral Solution.

Strength(s) usually available
U.S.—


25 mg (Rx) [Edecrin (lactose)]


50 mg (Rx) [Edecrin (lactose)]

Canada—


50 mg (Rx) [Edecrin (scored) (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Take with meals or milk.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.




Parenteral Dosage Forms

ETHACRYNATE SODIUM FOR INJECTION USP

Usual adult dose
Diuretic
Intravenous, 50 mg (base), or 500 mcg (0.5 mg) to 1 mg per kg of body weight; {03} {04} may be repeated in two to four hours if necessary, then every four to six hours if the patient is responsive. In some emergency situations, the injection may be repeated every hour.


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual adult prescribing limits
100 mg (base). {03}

Usual pediatric dose
Diuretic
Intravenous, 1 mg (base) per kg of body weight.


Size(s) usually available:
U.S.—


50 mg (base) (Rx) [Edecrin (mannitol 62.5 mg)]

Canada—


50 mg (base) (Rx) [Edecrin (mannitol 62.5 mg)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
Infusion solutions can be prepared using 0.9% sodium chloride injection or 5% dextrose injection, after pH has been adjusted when necessary. {03}

Stability:
A hazy or opalescent solution may result from use of a diluent with a low pH (below 5); use of such a solution is not recommended. {03}

Unused, reconstituted solution should be discarded after 24 hours at room temperature. {03}

Incompatibilities:
The solution is physically incompatible with whole blood or its derivatives. {03}


FUROSEMIDE

Summary of Differences


Category:
Furosemide is used as a diagnostic aid adjunct in renal disease.



Precautions:
Breast-feeding—Distributed into breast milk.

Pediatrics—Prolonged half-life in neonates.

Drug interactions and/or related problems—Also interacts with chloral hydrate and probenecid.



Side/adverse effects:
Also causes xanthopsia and increased sensitivity of skin to sunlight.



Additional Dosing Information
See also General Dosing Information .

When furosemide is used as an antihypercalcemic, body fluid and sodium chloride should be replaced in order to maintain extracellular fluid volume and increase calcium excretion effectively.

For parenteral dosage forms only
Intravenous administration is generally preferred over intramuscular administration.

Intravenous administration should be at a slow, controlled rate over a 1- to 2-minute period.

If high-dose parenteral therapy is indicated, administration should be by controlled intravenous infusion at a rate not exceeding 4 mg per minute.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

FUROSEMIDE ORAL SOLUTION

Usual adult dose
Diuretic
Oral, initially 20 to 80 mg as a single dose, the dosage then being increased by an additional 20 to 40 mg at six- to eight-hour intervals, until the desired response is obtained. The maintenance dose as determined by titration is then given daily as a single dose or divided into two or three doses, given once a day every other day, or given once a day for two to four consecutive days out of each week. {05}

Antihypertensive
Oral, initially 40 mg two times a day, the dosage then being adjusted according to patient response. {05}

[Antihypercalcemic]1
Oral, 120 mg a day as a single dose or divided into two or three doses.


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual adult prescribing limits
600 mg a day. {05}

Note: In chronic renal failure, doses of up to 4 grams a day have been used.


Usual pediatric dose
Diuretic
Oral, initially 2 mg per kg of body weight as a single dose, the dosage then being increased by an additional 1 to 2 mg per kg of body weight at six- to eight-hour intervals, until the desired response is obtained. {05}


Note: Doses as large as 5 mg per kg of body weight may be required in some children with nephrotic syndrome.
Doses greater than 6 mg per kg of body weight are not recommended. {05}
Dosing interval should be extended in neonates because of prolonged half-life.


Strength(s) usually available
U.S.—


8 mg per mL (Rx)[Generic]


10 mg per mL (Rx) [Lasix (alcohol 11.5%)] [Myrosemide (alcohol 11.5%)][Generic]

Canada—


10 mg per mL (Rx) [Lasix (sugar-free)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Auxiliary labeling:
   • Take by mouth only (when dispensed with graduated dropper).
   • Do not take other medicines without your doctor's advice.

Note: Do not dispense discolored solution.
When dispensing, include the manufacturer-provided graduated dropper or measuring spoon.
Explain administration technique when dispensed with graduated dropper.
Check refill frequency to determine compliance in hypertensive patients.



FUROSEMIDE TABLETS USP

Usual adult dose
See Furosemide Oral Solution.

Usual adult prescribing limits
600 mg a day. {06}

Note: In chronic renal failure, doses of up to 4 grams a day have been used.


Usual pediatric dose
See Furosemide Oral Solution.

Strength(s) usually available
U.S.—


20 mg (Rx) [Lasix][Generic] (may be scored)


40 mg (Rx) [Lasix (scored)][Generic] (may be scored)


80 mg (Rx) [Lasix][Generic] (may be scored)

Canada—


20 mg (Rx) [Apo-Furosemide] [Furoside (scored)] [Lasix] [Novosemide (scored)] [Uritol (scored)]


40 mg (Rx) [Apo-Furosemide (scored)] [Furoside (scored)] [Lasix (scored)] [Novosemide (scored)] [Uritol (scored)]


80 mg (Rx) [Apo-Furosemide (scored)] [Novosemide (scored)] [Lasix (scored)]


500 mg (Rx) [Lasix Special (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. Protect from light.

Stability:
Exposure to light may cause discoloration. Do not dispense discolored tablets.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Since variations in bioavailability have been found among brands, try to avoid switching brands when dispensing refills.
Check refill frequency to determine compliance in hypertensive patients.




Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

FUROSEMIDE INJECTION USP

Usual adult dose
Diuretic
Intramuscular or intravenous, initially 20 to 40 mg as a single dose, the dosage then being increased by an additional 20 mg at two-hour intervals until the desired response is obtained. The maintenance dose as determined by titration is then given one or two times a day. {06} {33}

Note: In acute pulmonary edema (not accompanied by hypertensive crisis), the usual initial dose is 40 mg intravenously, followed by 80 mg in one hour if a satisfactory response is not obtained. {06} {33}


Antihypertensive
Hypertensive crisis in patients with normal renal function: Intravenous, 40 to 80 mg.

Hypertensive crisis accompanied by pulmonary edema or acute renal failure: Intravenous, 100 to 200 mg.

[Antihypercalcemic]1
Intramuscular or intravenous, 80 to 100 mg in severe cases, the dosage being repeated if necessary every one to two hours until the desired response is obtained. In less severe cases, smaller doses may be given every two to four hours.

[Diagnostic aid adjunct (renal disease)]
Intravenous, 0.3 to 0.5 mg per kg of body weight to a maximum of 40 mg. {17}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual adult prescribing limits
Although controversial, doses of up to 6 grams a day administered by slow intravenous infusion have been used in acute renal failure by some clinicians.

Usual pediatric dose
Diuretic
Intramuscular or intravenous, initially 1 mg per kg of body weight as a single dose, the dosage then being increased by an additional 1 mg per kg of body weight at two-hour intervals until the desired response is obtained. {06} {33}

[Antihypercalcemic]1
Intramuscular or intravenous, 25 to 50 mg, the dosage being repeated if necessary every four hours until the desired response is obtained.


Note: Doses greater than 6 mg per kg of body weight are not recommended. {06} {33}
Dosing interval should be extended in neonates because of prolonged half-life.


Strength(s) usually available
U.S.—


10 mg per mL (Rx) [Lasix][Generic]

Canada—


10 mg per mL (Rx) [Lasix (benzyl alcohol)] [Lasix Special] [Uritol][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Preparation of dosage form:
Infusion solutions can be prepared using 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose injection, after pH has been adjusted when necessary. {06}

Stability:
Infusion solutions should be freshly prepared and used within a 24-hour period.

Incompatibilities:
Furosemide Injection USP is a mildly buffered alkaline solution and should not be mixed with highly acidic solutions.



Revised: 08/08/2000



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Bumetanide package insert (Bumex, Roche—US), Rev 11/85.
  1. Drug evaluations subscription. Chicago: American Medical Association, Spring 1990.
  1. Ethacrynic acid package insert (Edecrin, MSD—US), Rev 10/85.
  1. Ethacrynic acid (Edecrin, MSD—US). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1452-3.
  1. Furosemide oral solution product information (Lasix, Hoechst-Roussel—US), Rev 1/87, Rec 12/88.
  1. Furosemide product information (Lasix, Hoechst-Roussel). In: PDR Physicians' desk reference. 44th ed. 1990. Montvale, NJ: Medical Economics Data Production Company, 1990.
  1. Aranda P, Novales E. Diuretics and the treatment of systemic hypertension. Am J Cardiol 1990; 65: 72H-76H.
  1. Lant A. Diuretic drugs. Drugs 1986; 31(suppl 4): 40-55.
  1. Reviewer comment, 1989 revision cycle.
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea & Febiger, 1989.
  1. Cordarone package insert (Wyeth—US), Rev 9/90, Rec 2/91.
  1. Noctec package insert (US), Rev 12/86, Rec 2/89.
  1. Fungizone intravenous package insert (Squibb—US), Rev 11/87, Rec 3/89.
  1. Ponto L, Schoenwald R. Furosemide (Frusemide) A pharmacokinetic/pharmacodynamic review (part 1). Clin Pharmacokinet 1990; 18(5): 381-408.
  1. Whang R, Osi T, Watanabe A. Frequency of hypomagnesemia in hospitalized patients receiving digitalis. Arch Intern Med 1985; 145: 655-6.
  1. Leary W, Reyes A. Diuretic-induced magnesium losses. Drugs 1984; 28(suppl 1): 182-7.
  1. Reviewer comment, 1990 revision cycle.
  1. Essentials of Nuclear Medicine, 1987: 219.
  1. Clorius J, Dreikorn K, Zelt J, Raptan E, Weber D, Rubinstein K, et al. Renal graft evaluation with pertechnetate and I-131 hippuran, a comparative clinical study. J Nucl Med 1979; 20: 1029-37.
  1. Thrall J, Koff S, Keyes J. Diuretic radionuclide renography and scintigraphy in the differential diagnosis of hydroureteronephrosis. Semin Nucl Med 1981; 11(2): 89-104.
  1. Manufacturer comment, 1990.
  1. Epinephrine product information (IMS—Canada), Rev 1/88, Rec 11/88.
  1. Yeh T, Wilks A, Singh J, Betkerur M, Lilien L, Pildes R. Furosemide prevents the renal side effects of indomethacin therapy in premature infants with patent ductus arteriosus. J Pediatr 1982; 101(3): 433-7.
  1. O'Byrne S, Feely J. Effects of drugs on glucose tolerance in non-insulin-dependent diabetes (part 1). Drugs 1990; 4(1): 6-18.
  1. Panel comments, 1989 revision of Angiotension-converting Enzyme Inhibitors monograph.
  1. Atkinson A, Brown J, Leckie B, Lever A, Morton J, Fraser R. Captopril in a hyponatremic hypertensive: need for caution in initiating therapy. Lancet 1979 (Mar); 557-8.
  1. Hodsman G, Isles C, Murray G, Usherwood T, Webb D, Robertson J. Factors related to first dose hypotensive effect of captopril prediction and treatment. Br Med J; 286: 832-4.
  1. Funck-Brentano C, Chatellier G, Alexandre J. Reversible renal failure after combined treatment with enalapril and furosemide in a patient with congestive heart failure. Br Heart J 1986; 55: 596-8.
  1. Stanaszek W, Romankiewicz J. Current approaches to management of potassium deficiency. DICP 1985; 19: 176-83.
  1. Florinef acetate package insert (Squibb—US), Rev 12/87, Rec 3/89.
  1. Dean R, Rudinsky B, Kelleher M. Interaction of chloral hydrate and intravenous furosemide in a child. Clin Pharm 1991; 10: 385-7.
  1. Furosemide package insert (Lasix, Hoechst-Roussel—US), Rev 7/93, Rec 1/94.
  1. Furosemide injection package insert (Lasix, Hoechst-Roussel—US), Rev 8/93, Rec 12/93.
  1. Bumetanide package insert (Bumex, Roche—US), Rev 2/91, Rec 7/93.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 102, 259, 302.
  1. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153(2): 154-83.
  1. Panel consensus, 3/2000.
  1. Marshall JD, Wells TG, Letzig L, et al. Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients. J Clin Pharmacol 1998, 38: 994-1002.
  1. Sullivan JE, Witte MK, Yamashita TS, et al. Analysis and variability in the pharmacokinetics and pharmacodynamics of bumetanide in critically ill infants. Clin Pharmacol Ther 1996 Oct; 60: 414-23.
  1. Sullivan JE, Witte MK, Yamashita TS, et al. Pharmacokinetics of bumetanide in critically ill infants. Clin Pharmacol Ther Oct 1996; 60: 405-13.
  1. Sullivan JE, Witte MK, Yamashita TS, et al. Dose-ranging evaluation of bumetanide pharmacodynamics in critically ill infants. Clin Pharmacol Ther Oct 1996; 60: 424-34.
  1. Lopez-Samblas AM, Adams JA, Goldberg RN, et al. The pharmacokinetics of bumetanide in the newborn infant. Biol Neonate 1997; 72: 265-72.
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