AHFS Class:

• Loop Diuretics 40:28.08

Generic Name(s):

• Bumetanide

Bumetanide is a sulfonamide loop-type diuretic and antihypertensive agent.

Edema

Bumetanide is used for the management of edema associated with heart failure or hepatic or renal disease (including nephrotic syndrome).3,4,524 The drug may be effective in some patients whose condition is unresponsive or refractory to other diuretics.5,47,52 In a limited number of patients, approximately 60% of those with edema refractory to other diuretic therapy showed an improved diuretic response with bumetanide.47 Patients who had received 80-160 mg of furosemide daily with little or no diuretic response showed a marked diuresis with 2-6 mg of bumetanide daily;47 however, in some of these patients, improvement observed during initial therapy did not continue during maintenance therapy with bumetanide.47 Further study is needed to determine the role of bumetanide in the management of edema refractory to other diuretics.2

Careful etiologic diagnosis should precede the use of any diuretic. Because the potent diuretic effect of loop diuretics 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 loop diuretics for only a few days each week may be advisable.

Heart Failure

Bumetanide is effective for the short- and long-term management of edema associated with heart failure.2,25,35,39,44,45,46,73 In addition to decreasing edema, the drug relieves other signs and symptoms of heart failure such as dyspnea, rales, and hepatomegaly.2,45,46 Bumetanide appears to be as effective as furosemide in reducing edema, body weight, abdominal girth, rales, hepatomegaly, blood pressure, and heart rate in patients with heart failure.2,45,46

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-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.524,700,713 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.116 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.116

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 However, thiazides may be preferred in some patients with concomitant hypertension because of their sustained antihypertensive effects.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, 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.

Hepatic Disease

Bumetanide is used for the short- and long-term management of edema and ascites associated with hepatic disease (e.g., cirrhosis).2,31,36,48,49,50 Short-term administration of 2-4 mg of bumetanide daily or long-term administration of up to 6 mg daily has produced appreciable diuretic and natriuretic effects without substantial serum electrolyte disturbance in some patients with this condition.36 Patients with hepatic ascites reportedly have responded to an initial bumetanide dosage of 1 mg daily with weight loss averaging about 0.6 kg daily and a marked increase in urinary volume and natriuresis.48 The major complications observed during bumetanide therapy in these patients included hypokalemia and hyponatremia; however, electrolyte disturbances are commonly observed in patients with severe hepatic disease who are receiving diuretic therapy.48 Some patients developed encephalopathy during bumetanide administration.48

Bumetanide appears to be as effective as furosemide in reducing body weight and in causing diuresis and increased urinary excretion of sodium, potassium, and chloride in patients with hepatic cirrhosis and ascites.31,50,53 Following IV administration, single 0.5-mg doses of bumetanide were as effective as 20-mg doses of furosemide in patients with refractory ascites.49

In most clinical studies in patients with hepatic cirrhosis and ascites, patients received concomitant therapy with bumetanide and potassium salts or potassium-sparing diuretics to prevent hypokalemia.31,48,50

Renal Disease

Bumetanide is used for the management of edema in patients with impaired renal function.34,37,54,55,56 In patients with severe renal impairment (i.e., GFR less than 10 mL/minute), high dosages of the drug may be needed to produce an adequate diuretic response.5

Bumetanide (1-10 mg orally daily) appears to be as effective as furosemide (40-400 mg orally daily) in reducing edema, body weight, and abdominal girth in patients with edema secondary to renal disease.34 However, in one study, substantial reductions in body weight, edema, and mean arterial pressure were observed in patients with severe renal impairment who received oral bumetanide dosages of 1-18 mg daily but not in those who received oral furosemide dosages of 20-480 mg daily.55

Oral bumetanide dosages of 2-6 mg daily appear to be as effective as oral furosemide dosages of 40-160 mg daily in reducing edema in patients with nephrotic syndrome;70 however, in some patients with nephrotic syndrome and moderately impaired renal function (i.e., creatinine clearance of 4-34 mL/minute), a decreased response compared with that of patients with nephrotic syndrome and normal renal function has been reported.70

Other Edematous Conditions

Bumetanide has been used for the management of postoperative† or premenstrual edema† and edema associated with disseminated carcinoma†.5

Hypertension

Bumetanide has been used alone or in combination with other classes of antihypertensive agents for the management of hypertension†,5,43,57,92,94,1200 especially when complicated by heart failure, acute pulmonary edema, or renal disease.5,113 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., furosemide, bumetanide, 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 my be considered in hypertensive patients with heart failure and mild fluid retention because of their more persistent antihypertensive effect.524

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

Other Uses

Bumetanide has been used to enhance the elimination of drugs or toxic substances following intoxication.5,58 Like furosemide,58,74 bumetanide has been used as an adjunct in forced alkaline diuresis to enhance salicylate elimination following acute aspirin intoxication.58 (See Measures to Enhance Salicylate Elimination in Acute Toxicity: Treatment, in the Salicylates General Statement 28:08.04.24.) IV bumetanide and IV sodium bicarbonate have reportedly produced a more rapid decrease in blood salicylate concentration compared with parenteral fluid therapy alone.58

Administration

Oral Administration

Bumetanide is usually administered orally as a single daily dose in the morning.4 Bumetanide may also be given by intermittent administration on alternate days or on 3 or 4 consecutive days alternating with drug-free periods of 1 or 2 days.4 For optimum therapeutic effect in some patients, it may be necessary to administer bumetanide in 2 divided doses in the morning and evening.67 Administration of bumetanide in 2 divided doses daily has been reported to be more effective in increasing urinary sodium output and urinary volume than administration of the drug as a single daily dose,67 and the evening dose appeared to have a greater diuretic effect than the morning dose.67 Therefore, some clinicians suggest that, when the drug is administered once daily, it may be preferable to administer the dose in the evening.24,67,81 Further study is needed to determine the optimum dosage schedule for oral bumetanide administration.67

IV Administration

When the patient is unable to take oral medication or GI absorption is impaired, bumetanide may be administered by IM or IV injection or by IV infusion.4 Parenteral administration of bumetanide should be replaced by oral therapy as soon as possible.4 Bumetanide injection should be inspected visually for particulate matter and discoloration prior to administration.4

For IV injection, bumetanide should be given slowly over a period of 1-2 minutes.4 For IV infusion, bumetanide injection should be diluted in 5% dextrose, 0.9% sodium chloride, or lactated Ringer's injection.4 IV infusions should be freshly prepared and used within 24 hours.4

Standardize 4 Safety

Standardized concentrations for IV bumetanide 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 bumetanide should be adjusted according to individual requirements and response.4 Since the diuretic response following oral or parenteral administration is similar, bumetanide dosage is identical for oral, IV, or IM administration.4 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 The manufacturer states that, in furosemide-allergic patients, bumetanide may be substituted for furosemide at approximately a 1:40 ratio since cross-sensitivity between the drugs does not appear to occur;4 however, some clinicians question the safety of bumetanide administration in furosemide-sensitive patients.2

Edema

Oral Dosage

For the management of edema, the usual initial adult oral dosage of bumetanide recommended by the manufacturers is 0.5-2 mg daily.4 If the diuretic response to an initial dose of the drug is inadequate, repeated doses may be given at 4- to 5-hour intervals until the desired response is obtained or a maximum dosage of 10 mg daily is reached.4 For maintenance therapy, the effective dose of bumetanide may be administered intermittently.4 For the management of fluid retention (e.g., edema) associated with heart failure, some experts recommend initiating bumetanide at a low dosage (e.g., 0.5-1 mg once or twice daily) and increasing the dosage (maximum of 10 mg daily) until urine output increases and weight decreases, generally by 0.5-1 kg daily.524 (See Dosage and Administration: Administration.)

Parenteral Dosage

The usual initial adult IV or IM dose of bumetanide for the management of edema is 0.5-1 mg.4 In patients with inadequate response to the initial parenteral dose of bumetanide, repeated doses may be given at 2- to 3-hour intervals until the desired diuretic response is obtained or a maximum dosage of 10 mg daily is reached.4

Hypertension

Oral Dosage

For the management of hypertension† in adults, the usual oral dosage of bumetanide is 0.5-2 mg daily, administered 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 bumetanide, 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

Although the manufacturer states that safety and efficacy have not been established, dosages of 0.015 mg/kg on alternate days to 0.1 mg/kg daily have been used safely and effectively in a limited number of children with heart failure†.42 For information on overall principles for treatment of hypertension and overall expert recommendations for such disease in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Dosage in Renal and Hepatic Impairment

Although the manufacturer recommends that maximum oral or parenteral dosage of bumetanide not exceed 10 mg daily,4 oral or IV dosages up to 20 mg daily have been administered to patients with impaired renal function for the management of edema.37,55 Single-dose studies have shown that IV doses greater than 2 mg are needed to achieve a diuretic response in patients with creatinine clearances less than 5 mL/minute.2,54

In patients with impaired hepatic function, bumetanide dosage should be kept to a minimum;4 if bumetanide dosage must be increased in these patients, it should be adjusted carefully.4

Adverse effects occurring frequently during bumetanide therapy include muscle cramps, dizziness, hypotension, headache, nausea, and encephalopathy; these adverse effects may be related to bumetanide.4 The manufacturer states that one or more of these adverse effects occurs in 4.1% of bumetanide-treated patients.4 Laboratory test alterations, including electrolyte, hematologic, renal, and hepatic abnormalities, occur in approximately 49% of patients receiving the drug.38 Many of the adverse effects associated with bumetanide therapy may be caused by diuresis38 or the underlying disease being treated.81,82

Fluid, Electrolyte, Cardiovascular, and Renal Effects

Bumetanide may produce profound diuresis resulting in fluid and electrolyte depletion.4 Fluid and electrolyte depletion is more likely to occur with excessive doses or too frequent administration of the drug or in those with restricted sodium intake.4

Too vigorous diuresis may result in profound water loss and dehydration, especially in geriatric patients.4 The resultant hypovolemia may lead to circulatory collapse or thromboembolic episodes such as vascular thromboses and/or emboli.4 Pronounced reductions in plasma volume associated with rapid or excessive diuresis may also result in an abrupt fall in glomerular filtration rate, as evidenced by increased BUN and serum creatinine concentration.4 Hypotension reportedly occurs in less than 1% of patients receiving bumetanide.4,34 Orthostatic hypotension has occurred during concomitant therapy with other hypotensive agents.34

Hypokalemia and hypochloremia reportedly occur in about 15% of patients receiving bumetanide and hyponatremia occurs in about 10% of patients.4 Hypophosphatemia and hypocalcemia have been reported less frequently.4,31 Potassium depletion is particularly likely to occur in patients with hyperaldosteronism with normal renal function, hepatic cirrhosis and ascites, potassium-losing renal diseases, or certain diarrheal conditions and may require particular attention in patients with heart failure receiving cardiac glycosides and diuretics, those with a history of ventricular arrhythmias, and those with other conditions in which hypokalemia is considered to represent a risk.4 Prevention of hypokalemia is particularly important in these patients.4 Diuretic-induced hypokalemia and hypochloremia may result in metabolic alkalosis,77 especially in patients with other losses of potassium and chloride secondary to vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium-losing renal diseases.81,82 Metabolic alkalosis, with increased serum bicarbonate concentration25,35 and changes in total CO₂ content,4 has been reported in patients receiving bumetanide. Sudden changes in electrolyte balance may precipitate hepatic encephalopathy and coma in patients with hepatic cirrhosis and ascites.4 Supplemental therapy with potassium chloride or potassium-sparing diuretics (e.g., spironolactone) may be necessary for the prevention of hypokalemia and/or metabolic alkalosis in some patients.4 Diuretics also have shown to increase urinary excretion of magnesium, which may result in hypomagnesemia.4

Other adverse cardiovascular effects of bumetanide include ECG changes4 and chest pain.4,34

Hyperuricemia has been reported in about 20% of patients receiving bumetanide;4 however, most reported cases to date have been asymptomatic.4,25,31,32,43 Gouty arthritis has occurred in at least one patient receiving the drug.25 Serum uric acid concentrations have returned to pretreatment levels in some patients during continued therapy with the drug.81 Serum uric acid concentrations have increased to more than 12 mg/dL in a few patients receiving bumetanide but have returned to within normal limits following discontinuance of the drug.14

Reversible azotemia and increased serum creatinine concentration have been reported in 10% or less of bumetanide-treated patients.4 These adverse renal effects are especially likely to occur in patients with impaired renal function and appear to be associated with dehydration.4 Decreased creatinine clearance reportedly has been observed in less than 1% of patients receiving the drug.4,81 Bumetanide-induced renal failure has occurred rarely.4 Although acute interstitial nephritis has been reported rarely with furosemide, there are no reports to date of this adverse renal effect with bumetanide.2

Otic Effects

Ototoxicity has been reported in cats,4,40 dogs,4,40 and guinea pigs receiving bumetanide.4 On a weight basis, the ototoxic potential of bumetanide in these animals was 5-6 times greater than that of furosemide;4 however, the relative ototoxic potential of bumetanide at equivalent diuretic dosages was 0.11-0.16 times that of furosemide,40 since bumetanide has about 40-60 times the diuretic potency of furosemide.4 The likelihood of serum bumetanide concentrations achieving a level necessary to produce ototoxicity in humans is small; however, the possibility of bumetanide-induced ototoxicity must be considered following IV administration of the drug, especially at high dosages,4 after too rapid administration,81 in patients with impaired renal function, and/or in patients receiving other ototoxic drugs (e.g., aminoglycosides).4 Impaired hearing and otic discomfort have reportedly occurred rarely in patients receiving bumetanide.4 Combined data from comparative studies indicate that the frequency of drug-related hearing loss based on audiometric testing was 1.1% in patients receiving oral bumetanide dosages of 0.5-18 mg daily and 6.4% in patients receiving oral furosemide dosages of 20-640 mg daily.38,81 In addition, there are reports of furosemide-induced ototoxicity that improved following substitution of bumetanide therapy.41

Metabolic Effects

Although changes in plasma insulin, glucagon, or growth hormone concentration or in glucose tolerance generally have not been observed to date in patients receiving bumetanide, the possibility that the drug may adversely affect glucose metabolism should be considered.4 Hyperglycemia has reportedly occurred in about 7% of patients receiving the drug.2,4 Although comparative differences have not been fully determined, the frequency of bumetanide-induced hyperglycemia has been reported to be lower than that of furosemide.2 Bumetanide has also been associated with glycosuria and proteinuria in less than 1% of patients.4 The drug has been associated with decreased glucose tolerance without glycosuria in at least one patient.3,14 In general, diabetic control has not been adversely affected in patients with diabetes mellitus who were receiving bumetanide for the management of edema.3,24

Diuretics,94,96,97,98,99,100,102,103,104,105,106,107,108,109 including bumetanide,4,94 can increase serum total cholesterol concentrations in some patients; increases in low-density lipoprotein cholesterol and/or very low-density lipoprotein cholesterol subfractions appear to be principally responsible for these increases.

Musculoskeletal Effects

Adverse musculoskeletal effects reportedly occurring in about 1% or less of patients receiving bumetanide4 include muscle cramps,4,34,35,36 arthritic pain,4 musculoskeletal pain,4,33,34 muscle stiffness and tenderness,37 and asterixis.4 Musculoskeletal pain (sometimes severe)33 generally develops about 4 hours following oral administration or 1-2 hours following IV administration of the drug and persists for about 6-12 hours.33 In most patients, musculoskeletal pain is more severe in the extremities.33 The development of musculoskeletal pain appears to be a dose-related effect but varies among individuals.33,37 Some clinicians suggest that bumetanide-induced musculoskeletal pain may be related to electrolyte disturbances.37

Nervous System Effects

Adverse nervous system effects occurring in 1% or less of patients receiving bumetanide4 include dizziness,4,33 headache,4,34 weakness,4 vertigo,4,34 and fatigue.4

Hepatic Effects

Adverse hepatic effects of bumetanide include alteration of liver function test results and encephalopathy (in patients with preexisting hepatic disease).4 Increased total serum bilirubin, serum LDH, AST (SGOT), ALT (SGPT), or alkaline phosphatase concentration and increased or decreased cholesterol concentration have occurred in 1% or less of patients receiving bumetanide.4,81 Although these adverse hepatic effects have been associated with bumetanide, a causal relationship to the drug has not been established.4

Hematologic Effects

Adverse hematologic effects of bumetanide reportedly occurring in less than 1% of patients include increased or decreased hemoglobin concentration, prothrombin time, or hematocrit.4,81 Thrombocytopenia,4,33 increased or decreased leukocyte count,4,33,81 and changes in the differential leukocyte count,4 including eosinophilia,31 have occurred rarely.4 Bumetanide-induced leukopenia and thrombocytopenia have usually been transient and not associated with serious adverse systemic effects;33 however, one patient developed purpura alone and another developed purpura, epistaxis, and intestinal hemorrhage which proved fatal.33 Although the development of blood dyscrasias has been associated with bumetanide, a causal relationship to the drug has not been established.4

GI Effects

Adverse GI effects reportedly occurring in less than 1% of patients receiving bumetanide include nausea,4,33 abdominal pain,4,33 vomiting,4,24 xerostomia,4 dyspepsia,4 diarrhea,4 and stomach cramps.39

Dermatologic Effects

Adverse dermatologic effects reportedly occurring rarely in patients receiving bumetanide include pruritus,4 urticaria,4,34,39 and rash.4,24 The drug has been associated with Stevens-Johnson syndrome in at least one patient;36 a causal relationship to bumetanide has been suggested since the condition resolved following discontinuance of the drug.36

Other Adverse Effects

Premature ejaculation, erectile impotence, and nipple tenderness have occurred rarely in patients receiving bumetanide.4 Bumetanide has been associated with the development of mammary tenderness31 or gynecomastia in a few patients;33,34 however, a causal relationship to the drug has not been established38 and some of these patients were receiving concomitant therapy with spironolactone.31,34

Other adverse effects of bumetanide include sweating, hyperventilation, and increased or decreased serum protein concentrations.4,81

Precautions and Contraindications

Bumetanide is a potent diuretic that may produce profound diuresis with fluid and electrolyte depletion, especially when administered at high dosages or for prolonged periods.4 Patients receiving bumetanide should be carefully observed for signs of electrolyte depletion, especially hypokalemia.4 Patients should be informed of the signs and symptoms of electrolyte imbalance and instructed to report to their physician if weakness, dizziness, fatigue, faintness, mental confusion, lassitude, muscle cramps, headache, paresthesia, thirst, anorexia, nausea, and/or vomiting occur.3,75,76,81,82 Excessive fluid and electrolyte loss may be minimized by monitoring the patient carefully and by initiating therapy with small doses, adjusting dosage carefully, and using an intermittent dosage schedule if possible.4 Careful monitoring, including hospitalization during initiation of therapy, and dosage adjustment are especially important in patients with hepatic cirrhosis and ascites.4

Serum potassium concentration should be measured periodically during therapy with bumetanide.4 Supplemental therapy with potassium chloride4,82 or potassium-sparing diuretics may be used if necessary to prevent or treat hypokalemia and/or metabolic alkalosis.4 Prevention of hypokalemia is particularly important for patients with heart failure receiving cardiac glycosides and diuretics or for those with hepatic cirrhosis and ascites, hyperaldosteronism with normal renal function, potassium-losing renal diseases, certain diarrheal conditions, or other conditions (e.g., history of ventricular arrhythmias) in which hypokalemia is considered to represent a risk.4 Periodic determination of other serum electrolyte concentrations is recommended for patients receiving therapy at high dosages or for prolonged periods, especially in those with restricted sodium intake.4 Administration of bumetanide at high dosages or for prolonged periods may cause profound water loss, electrolyte depletion, dehydration, or hypovolemia and circulatory collapse with the possibility of vascular thrombosis and embolism, especially in geriatric patients.4 If excessive diuresis and/or electrolyte abnormalities occur, the drug should be withdrawn or dosage reduced until homeostasis is restored.76,81,82 Electrolyte abnormalities should be corrected by appropriate measures.76,81,82

Bumetanide should be used with caution in patients with hepatic cirrhosis and ascites, since sudden alterations in fluid and electrolyte balance may precipitate hepatic encephalopathy and/or coma.4 Bumetanide administration in these patients should be initiated at low dosages in a hospital setting with careful monitoring of the patient's fluid and electrolyte balance and clinical status.4 Supplemental therapy with potassium chloride4,82 or potassium-sparing diuretics may be used to prevent hypokalemia and metabolic alkalosis in these patients.4

Although changes in plasma insulin, glucagon, or growth hormone concentration or in glucose tolerance generally have not been observed during therapy with bumetanide, the possibility of an adverse effect on glucose metabolism cannot be excluded.4 Blood glucose concentration should be determined periodically, especially in patients with known or suspected (e.g., marginally impaired glucose tolerance) diabetes mellitus.4

Patients receiving bumetanide should be observed carefully for the development of blood dyscrasias (especially thrombocytopenia), liver damage, or idiosyncratic reactions which have been reported occasionally during therapy with the drug.4

Although bumetanide's potential for producing ototoxicity is small compared with furosemide, the possibility of bumetanide-induced ototoxicity must be considered following IV administration of the drug, especially at high dosages,4 after too rapid administration,81 in patients with impaired renal function, and/or in patients receiving other ototoxic drugs.4

Bumetanide should be used with extreme caution, if at all, in patients who are allergic to sulfonamides, since these patients may show hypersensitivity to bumetanide.4 Although the manufacturer states that bumetanide does not appear to exhibit cross-sensitivity in patients allergic to furosemide,4,69 the drugs are structurally similar and some clinicians believe that there is insufficient evidence to support a lack of cross-sensitivity.2 Bumetanide is contraindicated in patients with known hypersensitivity to the drug.4

Bumetanide is contraindicated in patients with anuria.4 Although bumetanide may be used to produce diuresis in patients with impaired renal function, the drug is contraindicated for further use when marked increases in BUN or serum creatinine concentration or oliguria occur during treatment of progressive renal disease.4 In patients with hepatic coma or severe electrolyte depletion, bumetanide therapy should not be instituted until the basic condition is improved or corrected.4

Pediatric Precautions

Safety and efficacy of bumetanide in children younger than 18 years of age have not been established.4 Bumetanide has been used effectively as a diuretic for up to 40 weeks in a limited number of infants ranging from 2 weeks to 7 months of age who had congenital heart disease and heart failure†.42 However, in vitro studies using pooled serum from critically ill neonates have shown substantial displacement of bilirubin from albumin by bumetanide.4 Therefore, bumetanide should be used with caution in critically ill or jaundiced neonates who are at risk for kernicterus.4 In addition, the elimination of bumetanide appears to be slower in neonates than in adults, possibly because of immature renal and hepatobiliary functions.4 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.

Mutagenicity and Carcinogenicity

It is not known whether bumetanide is mutagenic or carcinogenic in humans.4 Bumetanide did not produce mutagenic activity in various strains of Salmonella typhimurium when tested with or without metabolic activation.4 Following oral administration of bumetanide, an increased number of mammary tumors was observed in female rats receiving 2000 times the maximum recommended human dosage for 18 months; however, these findings could not be duplicated when the study was repeated with the same dosage.4

Pregnancy, Fertility, and Lactation

Pregnancy

Limited clinical experience with bumetanide in pregnant women to date has not revealed evidence of harm to the fetus; however, the possibility of adverse fetal effects cannot be excluded.4 Bumetanide should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.4

Although there are no adequate and controlled studies to date in humans, bumetanide has been shown to have a slight embryocidal effect in rats when given at a dosage 3400 times the maximum recommended human dosa 4 evidence of moderate growth retardation and delayed ossification of sternebrae in fetal offspring and maternal weight loss also occurred.4 Fetotoxic effects were not observed in rats when bumetanide was administered at 1000-2000 times the maximum recommended human dosage.4 Reproduction studies in mice using dosages up to 3400 times the maximum recommended human dosage have not revealed evidence of teratogenic or embryocidal effects.4 Bumetanide was not teratogenic in hamsters following oral administration of 0.5 mg/kg daily (17 times the maximum recommended human dosage) or in mice or rats at IV dosages up to 140 times the maximum recommended human dosage.4 A dose-related decrease in litter size and increase in fetal resorption rate occurred in rabbits receiving oral dosages of 0.1 and 0.3 mg/kg daily (3.4 and 10 times the maximum recommended human dosage, respectively); a slight embryocidal effect occurred in those receiving 0.1 mg/kg daily, and an increased frequency of delayed ossification of the sternebrae also occurred in those receiving 0.3 mg/kg daily.4 Adverse fetal effects were not observed in rabbits receiving 0.03 mg/kg daily.4

Fertility

The effect of bumetanide on fertility in humans is not known.4 Reproduction studies in rats using bumetanide dosages of 10, 30, 60, or 100 mg/kg daily showed a slightly decreased rate of pregnancy; however, the differences were small and not statistically significant.4

Lactation

Since it is not known if bumetanide is distributed into milk,4 the manufacturer cautions that nursing should not be undertaken in women receiving the drug.4

Diuretics

Concomitant administration of bumetanide and most other diuretics results in enhanced diuretic and natriuretic effects.3,25 Spironolactone, triamterene, or amiloride hydrochloride may reduce the potassium loss resulting from bumetanide therapy; this effect has been used to therapeutic advantage.3,25

Drugs Affected by or Causing Potassium Depletion

In patients receiving a cardiac glycoside (e.g., digoxin), electrolyte disturbances produced by bumetanide (principally hypokalemia but also hypomagnesemia) predispose the patient to digitalis toxicity;3 possibly fatal cardiac arrhythmias may result.77,79 Therefore, it is particularly important that hypokalemia be prevented in patients receiving bumetanide and a cardiac glycoside concomitantly.4 Periodic electrolyte determinations should be performed in patients receiving a cardiac glycoside and bumetanide, and correction of hypokalemia undertaken if warranted.79,80 Bumetanide does not affect serum digoxin concentrations3,4 or renal excretion of digoxin when the drugs are used concomitantly.59

Like furosemide, bumetanide potentially can cause prolonged neuromuscular blockade in patients receiving nondepolarizing neuromuscular blocking agents (e.g., tubocurarine chloride, gallamine triethiodide [no longer commercially available in the US]),79,85 presumably because of potassium depletion or decreased urinary excretion of the muscle relaxant.86 Although there are no reports to date of prolonged neuromuscular blockade during concomitant administration of bumetanide and nondepolarizing neuromuscular blocking agents, the possibility of this drug interaction should be considered.81

Some drugs such as corticosteroids, corticotropin, and amphotericin B also cause potassium loss,79 and severe potassium depletion may occur when one of these drugs is administered during bumetanide therapy.81

Lithium

Renal clearance of lithium is apparently decreased in patients receiving diuretics, and lithium toxicity may result.3,4 Bumetanide and lithium should generally not be given together.3,4 If concomitant therapy is necessary, serum lithium concentrations should be monitored carefully and dosage adjusted accordingly.81

Hypotensive Agents

The antihypertensive effect of hypotensive agents may be enhanced during concomitant bumetanide administration.3,4 This effect is usually used to therapeutic advanta however, orthostatic hypotension may result.34 Dosage of the hypotensive agent, and possibly both drugs, should be reduced when bumetanide is added to an existing antihypertensive regimen.3,4

Indomethacin

Indomethacin may reduce the diuretic and natriuretic effects of bumetanide.3,4,60,61,62 The mechanism(s) of these interactions has not been established but has been attributed to indomethacin-induced inhibition of prostaglandin synthesis61 which may result in fluid retention and/or changes in vascular resistance.78 Indomethacin also inhibits the bumetanide-induced increase in plasma renin activity.4 Although the clinical importance of these interactions has not been determined, the manufacturer states that concomitant therapy with bumetanide and indomethacin is not recommended.4 However, some clinicians suggest that, if concomitant therapy is necessary, an increase in bumetanide dosage may overcome an indomethacin-induced decrease in diuretic activity.82

Probenecid

Probenecid may reduce the diuretic and natriuretic effects of bumetanide.3,4,8,62,63 Probenecid may also inhibit the bumetanide-induced increase in plasma renin activity.4,63 The mechanism(s) of these interactions does not appear to result from direct inhibition of sodium excretion but probably involves inhibition by probenecid of the renal tubular secretion of bumetanide.4,63 Although the clinical importance of these interactions has not been determined, the manufacturer recommends that probenecid not be administered concomitantly with bumetanide.4

Ototoxic Drugs

Concomitant parenteral administration of bumetanide and aminoglycoside antibiotics or other ototoxic drugs (e.g., cisplatin) may result in increased risk of ototoxicity, especially in patients with impaired renal function.4 Although potentiation of aminoglycoside-induced ototoxicity with bumetanide has not been reported to date in humans,4 permanent changes in cochlear activity have occurred following administration of bumetanide in animals pretreated with kanamycin.64 Concomitant parenteral administration of bumetanide and aminoglycoside antibiotics should be avoided, except in life-threatening conditions.4

Nephrotoxic Drugs

Although there is no clinical experience to date with concomitant administration of bumetanide and nephrotoxic agents, concomitant use of these drugs should be avoided since bumetanide may enhance the nephrotoxic effects.4

Anticoagulants

Bumetanide does not appear to affect the plasma prothrombin activity or the metabolism of oral anticoagulants (e.g., warfarin).4,65,66 In 2 studies in healthy individuals, no substantial differences in prothrombin time or in plasma concentration or half-life of warfarin were observed when a single dose of warfarin (40-65 mg) was administered alone or concomitantly with 1 or 2 mg of bumetanide daily.65,66

Acute Toxicity

Pathogenesis

The LD₅₀ of bumetanide following IV administration has been reported to be 330 mg/kg in mice and 70 mg/kg in rabbits.3 The oral LD₅₀ of the drug in rabbits has been reported to be 350 mg/kg.3 However, mice and rats have survived oral doses of 2000 mg/kg in one study and 6000 mg/kg in another study.3

Manifestations

Overdosage of bumetanide may result in acute, profound water loss, volume and electrolyte depletion, and hypovolemia and circulatory collapse with a possibility of vascular thrombosis and embolism.4 Electrolyte depletion may be manifested as weakness, dizziness, mental confusion, anorexia, lethargy, vomiting, and cramps.4

Following intraperitoneal administration of 300 mg/kg of bumetanide to mice, ataxia, reduced muscle tone, tremors, and seizures occurred and persisted for 1 day.3 In dogs receiving 0.5 mg/kg of the drug IV, leg muscle fasciculations, opisthotonos, and trismus occurred and were present from 10 seconds to 2 minutes followed by complete recovery.3

Treatment

In acute bumetanide overdose, supportive and symptomatic treatment consisting of fluid and electrolyte replacement should be initiated.4 Urinary output and serum and urinary electrolyte concentrations should be carefully monitored.4

Pharmacology

The pharmacologic effects of bumetanide are similar to those of furosemide.2,5

Renal Effects

Bumetanide acts directly on the ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption.4,6,7,8,13 Although the exact mechanism(s) of action has not been established, bumetanide decreases electrolyte reabsorption by inhibiting the active chloride13,51,89 and, possibly, sodium8 transport systems in the ascending limb of the loop of Henle. Bumetanide may interfere with renal cyclic 3',5'-adenosine monophosphate (cAMP) activity or with binding of cAMP to renal tissue.7 Inhibition of cAMP-dependent protein kinase5,7,8 or sodium-potassium adenosine triphosphatase (ATPase), an enzyme with high activity in the ascending limb of the loop of Henle, may be involved.7,8 Unlike ethacrynic acid, bumetanide does not bind sulfhydryl groups of renal cellular proteins.72 Bumetanide also appears to inhibit electrolyte reabsorption in the proximal renal tubule.2,3,4,5,6,7,8,9 Since phosphate and bicarbonate reabsorption occur mainly in the proximal tubule,87 phosphaturia and increased bicarbonate excretion during bumetanide-induced diuresis are indicative of this additional effect.4,6,8,9,10,14 Inhibition of electrolyte reabsorption in the proximal tubule may result from inhibition of sodium phosphate-linked transport, but is apparently not related to inhibition of carbonic anhydrase activity.4,6,9 Bumetanide indirectly increases potassium secretion in the distal renal tubule7,72 secondary to an increased sodium load in the tubule;7 the drug does not appear to have a direct effect on electrolyte reabsorption in the distal tubule.3,4,5,7,10,90 The drug is not an aldosterone antagonist. Although bumetanide reportedly has about 40 times the diuretic activity of furosemide on a weight basis,2,3,4,5,11,25 the relative potency may vary when different dosages3,12 and/or routes of administration73 are compared.

Bumetanide increases urinary excretion of sodium, chloride, potassium,3,4,6,7,13,14,15 hydrogen,3,6,9 calcium,3,7,8,14 magnesium,3,4,7,8,14 and ammonium;3,6,9 excretion of phosphate6,7,8,9,10,14 and bicarbonate6,8,9,10,14 may also be increased. The chloruretic effect of the drug is greater than its natriuretic effect3,4,6,7,13,15 and its effect on urinary calcium and magnesium excretion is less than that on sodium excretion.3,8,14 Although urinary excretion of calcium and magnesium is initially (4-6 hours after administration) increased, retention of these electrolytes subsequently occurs and no substantial net loss of calcium or magnesium is observed over a 24-hour period.3,8,14 Bumetanide-induced increases in urinary excretion of hydrogen and ammonium ions are generally associated with little or no effect on urinary pH;3,6,9,90 however, in one study, urinary pH decreased from 6.1 to 5.1 following administration of the drug.68 The drug decreases free water clearance in humans during hydration and tubular free water reabsorption during hydropenia.2,3,4,10 The decrease in free water clearance results from inhibition of electrolyte reabsorption4 and active transport3,7 at the ascending limb of the loop of Henle.4

Bumetanide decreases uric acid excretion4,8,14 and increases serum uric acid concentration.4,7,14,25 Hyperuricemia has been reported in some patients receiving the drug.7,14,25 (See Cautions: Renal Effects.) The overall decrease in uric acid excretion appears to be less than that attributed to therapeutically equivalent doses of furosemide.8

Bumetanide produces renal vascular dilation7 and substantially increases renal blood flow.3,16 Maximum increases in renal blood flow have ranged from 30-40% during bumetanide therapy.3,16 In animals, the drug causes redistribution of renal blood flow to the midcortical and juxtamedullary regions of the kidney.3,16 Increased urinary prostaglandin E concentrations have been observed in bumetanide-treated animals.3 It has been suggested that the drug's effect on renal prostaglandin activity may result in changes in renal hemodynamics.3,82,90 Although the effect of bumetanide on prostaglandin activity in humans has not been determined,3 the drug's effects on renal blood flow and renal cortical redistribution in animals are inhibited by prior treatment with a prostaglandin synthetase inhibitor (e.g., indomethacin).3,7,71 Bumetanide has a variable effect on glomerular filtration rate (GFR) in humans.3,17

Bumetanide produces variable but substantial increases in plasma renin activity (PRA).13 In one study in healthy adults, increased PRA was observed 1 hour after bumetanide administration and persisted for up to 12 hours.13

Cardiovascular Effects

Bumetanide may produce hypotensive effects resulting from decreased plasma volume.4 Substantial reductions in blood pressure and in body weight have been observed in patients with hypertensive cardiovascular disease and heart failure who received the drug.3 Reductions in mean pulmonary venous pressure, left ventricular end-diastolic pressure (LVEDP), mean pulmonary artery pressure, and mean right atrial pressure have also been observed in patients with valvular heart disease receiving bumetanide; pulmonary and systemic arteriolar resistance were slightly reduced.3 Following administration of the drug in patients with coronary artery disease, reductions in cardiac output, cardiac index, stroke volume, stroke index, and in diastolic pressures (beginning, mean, and end) have occurred.3

Metabolic Effects

There is conflicting evidence to date on bumetanide's effect on carbohydrate metabolism.2,3,4,5,18,19 In healthy individuals receiving the drug, changes in plasma insulin, glucagon, or growth hormone concentration or in glucose tolerance generally have not been observed.3,4 However, hyperglycemia reportedly has occurred in some patients receiving the drug.4 Diuretic-induced hyperglycemia may result from potassium depletion which has been associated with impaired insulin secretion.83,84 In one study in healthy individuals, a single 1-mg IV dose of bumetanide did not alter insulin response to IV glucose or the rate of decrease in blood glucose concentration.18 In individuals with impaired glucose tolerance (chemical, latent, or borderline diabetes mellitus), 1 mg of the drug daily for 10 days did not impair glucose tolerance further.18 When the effects of bumetanide and furosemide on oral glucose tolerance and insulin response to glucose were compared in another study, similar effects on carbohydrate metabolism were observed in bumetanide- and in furosemide-treated patients.2,5 Further study is needed to fully characterize the effects of bumetanide on carbohydrate metabolism; however, the drug does not appear to be associated with consistent or clinically important changes in blood glucose concentration.5

Pharmacokinetics

Absorption

Bumetanide is rapidly and almost completely absorbed from the GI tract.3,20,21,22 In several studies in healthy individuals, at least 85-95% of a single oral dose of the drug was absorbed;2,3,20,21,22 however, in one study, the bioavailability of bumetanide tablets reportedly was only 72%.2 The oral bioavailability of the drug in patients with impaired renal or hepatic function does not appear to differ substantially from that in healthy individuals.23 Limited data suggest that food may delay the absorption of oral bumetanide.22 The drug appears to be completely absorbed following IM administration.2

Following oral administration, bumetanide appears in plasma within 15-20 minutes22,23 and peak plasma concentrations of the drug generally occur within 0.5-2 hours.3,13,14,20,21,22,23 Following oral administration of a single 1-mg dose of the drug in healthy adults, peak plasma or serum bumetanide concentrations have reportedly averaged 31-48 ng/mL;3,22 after a single 2-mg dose in one study, the peak plasma concentration averaged 73 ng/mL.3,13

Bumetanide-induced diuresis begins within 30-60 minutes following oral administration,3,4 about 40 minutes following IM administration,73 and within a few minutes following IV administration;4 peak diuretic activity generally occurs within 1-2 hours following oral or IM administration14,20,22,24,25,73 and within 15-30 minutes after IV administration.4,21,22 Diuresis is generally complete within 4 hours following oral or IM administration of 1-2 mg of the drug;3,4,20,24,25,73 however, diuretic activity may persist for up to 5-6 hours, particularly when doses greater than 2 mg are used.4,14,20,24,25,73 Following IV administration, diuresis generally persists for 2-3 hours.21

Distribution

Distribution of bumetanide into human body tissues and fluids has not been fully characterized.2,3,20 Following IV administration of bumetanide in dogs, highest concentrations of the drug were observed in kidney, liver, and plasma, with lowest concentrations in heart, lung, muscle, and adipose tissue;26 bumetanide showed 3 times the affinity for renal tissue compared with that of furosemide.26 Following IV administration of bumetanide in healthy adults, the steady-state volume of distribution (V_ss) has been reported to range from 9.45-19.7 L and the volume of distribution of the central compartment (V_c) has been reported to range from 3.26-5.84 L.14,21,22,29 Following IV administration of bumetanide in neonates, the mean volume of distribution has been reported to range from 0.26-0.38 L/kg.4 V_ss may be decreased in patients with hepatic impairment.23 V_ss may be increased in patients with renal impairment.91 In one study in patients with varying degrees of renal dysfunction, V_ss, but not V_c, was increased compared with that of individuals with normal renal function (V_ss: 22 versus 17 L).91

Approximately 94-97% of bumetanide is bound to plasma proteins in vitro.3,4,27,28 In vivo, approximately 92.6 or 96% of the drug is bound to plasma proteins based on Sephadex batch or ultrafiltration method, respectively.21,29 Protein binding may be decreased in patients with renal impairment; binding appears to be correlated with plasma albumin concentration in these patients.91 In one study, when bumetanide or furosemide was added to pooled human serum (adult or neonatal) in equimolar concentrations, bumetanide's displacement of bilirubin from albumin-binding sites was equivalent to that of furosemide in adult serum but less than that of furosemide in neonatal cord serum.28 In addition, results of an vitro study of pooled serum from critically ill neonates indicate that serum concentrations of free (unbound) bilirubin increased in a linear manner at bumetanide concentrations of 0.5-50 mcg/mL; however, such a correlation was not observed at bumetanide concentrations of 0.25 mcg/mL.4 Bumetanide does not appear to bind to erythrocytes.2,3,21

Bumetanide and its metabolites are distributed into bile.3,4,20 Following oral administration of radiolabeled bumetanide in one patient with a biliary T tube in place, 1.8% of the dose was distributed into bile as unchanged drug and 12.6% as metabolites.20

It is not known whether bumetanide crosses the blood-brain barrier or the placenta3 or is distributed into milk.3,4

Elimination

Plasma concentrations of bumetanide have generally been reported to decline in a monophasic or biphasic manner;2,14,20,21,22 however, studies using sensitive assay methods indicate that plasma concentrations may decline in a triphasic manner following IV administration.22,29

Following oral administration, the terminal elimination half-life of bumetanide reportedly ranges from 1-1.5 hours in healthy adults.3,4,20 Following IV administration in adults with normal renal and hepatic function, the half-life in the initial phase (t_½α) averages 5-6.9 minutes, the half-life in the secondary phase (t_½β) averages 46-47 minutes, and the half-life in the terminal phase (t_½γ) averages 3.1-3.4 hours.22,29 Serum concentrations of bumetanide may be higher and the terminal elimination half-life prolonged in patients with impaired renal and/or hepatic function.23,91 In neonates and infants, the elimination of bumetanide appears to be slower than in older pediatric patients and adults, possibly because of immature renal and hepatobiliary functions.4 The mean serum elimination half-life of bumetanide reportedly is 2.5 and 1.5 hours in infants younger than 2 months of age and in those 2-6 months of age, respectively.4 In addition, limited data indicate that the apparent half-life of the drug may be prolonged to about 6 hours (with a range up to 15 hours) in premature or full-term neonates with respiratory disorders receiving IV bumetanide.4

Total body clearance of bumetanide from plasma reportedly averages 120-250 mL/minute in adults with normal renal and hepatic function;3,22,29,88 renal clearance of the drug is about 50-65% of the total body clearance.3,22,29,88,101 Total body clearance of bumetanide is decreased in patients with impaired renal function, with or without concomitant hepatic impairment;29,91,101 in patients with only renal impairment, nonrenal clearance of the drug is about 90% or more of the total body clearance.29,91,101 Clearance also may be decreased in neonates and infants possibly, because of immature renal and hepatobiliary functions.4 In neonates with volume overload, mean serum clearance of bumetanide reportedly was about 2.2 and 3.8 mL/minute per kg in those younger than 2 months of age and 2-6 months of age, respectively.4 In addition, limited data indicate that serum clearance of the drug may be decreased to about 0.2-1.1 mL/minute per kg in premature or full-term neonates with respiratory disorders receiving IV bumetanide.4

Bumetanide is partially metabolized in the liver to at least 5 metabolites.3,20,21 Metabolism apparently occurs only by oxidation of the N -butyl side chain of the bumetanide molecule; the phenyl ring structures do not appear to be metabolized.20 Hydroxylation occurs at each carbon of the N -butyl side chain.20 The major urinary metabolite is the 3'-alcohol derivative.20 The major metabolite excreted in bile and/or feces is the 2'-alcohol derivative.20 Minor metabolites include the 4'-alcohol, N -desbutyl, and 3'-acid derivatives.20 Bumetanide metabolites in urine and bile are present as conjugates, principally glucuronide conjugates.20 Conjugates of the drug and its metabolites do not appear in feces.20

Bumetanide and its metabolites are excreted principally in urine.3,4,20,21,22,29 Renal excretion of the drug appears to occur mainly via glomerular filtration;3,22,29,91 tubular secretion may also occur.22,29,91 Following oral or IV administration in healthy adults, about 80% of a dose is excreted in urine and 10-20% in feces within 48 hours;3,20,21,29 about 50% of a dose is excreted unchanged in urine.3,20,21,29 Bumetanide is excreted in feces almost completely as metabolites, apparently via biliary elimination;20 less than 2% of a dose is excreted unchanged in feces within 48 hours.20 Following IV administration of radiolabeled bumetanide in one study in patients with varying degrees of renal dysfunction, about 25% of a dose was excreted in urine within 48 hours and about 40% (range: 4-94%) was excreted in feces within 7 days.91

Chemistry and Stability

Chemistry

Bumetanide is a sulfonamide-type, loop diuretic.1 The drug is a derivative of metanilamide and is structurally related to furosemide.1,2 Bumetanide differs structurally from furosemide by the presence of 4-phenoxy and 5-butylamino substituents.1

Bumetanide occurs as a practically white, crystalline powder with a slightly bitter taste.3 The drug has solubilities of 0.1 mg/mL in water and 30.6 mg/mL in alcohol at 25°C.3 Bumetanide has pK_as of 0.3, 4, and 10.3 Commercially available bumetanide injection is a sterile solution of the drug containing 0.85% sodium chloride and 0.4% ammonium acetate as buffers, 1% benzyl alcohol as a preservative, and 0.01% disodium edetate.3,4 Sodium hydroxide is added during the manufacture of the injection to adjust the pH to 6.8-7.8.95

Stability

Bumetanide is photosensitive and will discolor when exposed to light.3 Commercially available preparations of bumetanide should be protected from light and stored at 15-30°C.3 Bumetanide tablets should be stored in tight, light-resistant containers.3,95 The commercially available tablets are stable for 5 years and the injection is stable for 3 years after the date of manufacture.3

Bumetanide injection is reportedly stable at a pH of 4-10.3 Substantial adsorption of the drug to glass or PVC containers reportedly does not occur.3,4 Bumetanide injection is physically and chemically compatible in glass and PVC containers with the following IV solutions: 5% dextrose, 0.9% sodium chloride, or lactated Ringer's injection.4 Bumetanide injection that has been diluted with one of these compatible IV solutions should be used within 24 hours after preparation.4

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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4. Roche Laboratories. Bumex^® (bumetanide) tablets and injection prescribing information. Nutley, NJ; 1999 Feb.

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