BUMETANIDE

General Administration Information
For storage information, see the specific product information in the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer without regard to meals.


Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Updates for coronavirus disease 2019 (COVID-19): The FDA is allowing bumetanide 0.25 mg/mL to be used beyond the labeled in-use time to help ensure access during COVID-related drug shortages. This period should be as short as possible, and for a maximum of 2 hours at room temperature or 4 hours when refrigerated. In-use time is defined as the maximum amount of time allowed to elapse between penetration of a closed-container system or after reconstitution of a lyophilized drug before patient administration.
Intravenous Administration
Intermittent IV Injection
-No dilution necessary.
-Inject slowly over a period of 1 to 2 minutes.

Intermittent IV Infusion
-May administer undiluted (0.25 mg/mL) or further diluted with 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection.
-Storage: Use prepared solution within 24 hours.

Continuous IV Infusion
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 0.04 mg/mL or 0.25 mg/mL.

Intramuscular Administration
-No dilution necessary.
-Inject deeply into a large muscle (e.g., lateral part of the thigh).

Gastrointestinal (GI) adverse reactions reported with bumetanide use in adult patients include abdominal pain (0.2%), nausea (0.6%), and vomiting (0.2%). Other GI adverse reactions that have each occurred in approximately 0.1% of adult patients treated with bumetanide include xerostomia, dyspepsia, and diarrhea.

Muscle cramps (1.1%), dizziness (1.1%), and headache (0.6%) are among the most frequent adverse effects (possibly or probably drug-related) reported during bumetanide therapy in adult patients. Less frequent clinical adverse reactions reported in adults receiving bumetanide include electrocardiogram changes (0.4%), weakness (0.2%), arthralgia (0.2%), and musculoskeletal pain (0.2%). Other adverse reactions that have each occurred in approximately 0.1% of adult patients treated with bumetanide include vertigo, chest pain (unspecified), fatigue, diaphoresis, hyperventilation, and nipple tenderness.

Electrolyte abnormalities are the most common adverse effects associated with bumetanide use and may be severe in some cases. Monitor patients carefully for undesired alterations in serum chemistries. Electrolyte abnormalities reported during bumetanide therapy in adult patients have included hypochloremia (14.9%), hypokalemia (14.7%), and hyponatremia (9.2%). Bumetanide may also increase urinary calcium and phosphate excretion with resultant hypocalcemia and/or hypophosphatemia. Variations in phosphorus (4.5%), carbon dioxide (4.3%), bicarbonate (3.1%), and calcium (2.4%) also can occur. Alterations in serum calcium and phosphorous concentrations may be particularly concerning in neonatal patients, when bone development is crucial. Other loop diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Inform patients and caregivers of the signs and symptoms of electrolyte imbalances (e.g., lassitude, mental confusion, fatigue, faintness, dizziness, muscle cramps, headache, paresthesia, thirst, anorexia, GI upset) and report these signs immediately. Hypokalemia is a particular concern with bumetanide administration, and supplemental therapy with potassium chloride or potassium-sparing diuretics may be necessary. Loop diuretics may also induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement. Bumetanide-induced metabolic alkalosis can be exacerbated in patients with other conditions that cause potassium loss including vomiting, diarrhea, paracentesis, GI drainage, and/or excessive sweating.

Hypotension has been reported in 0.8% of bumetanide-treated adult patients. Hypovolemia and dehydration can occur during bumetanide therapy due to polyuria and excessive electrolyte losses. The risk of such events is increased when large doses are administered or when the drug is given to patients with a restricted sodium intake. The resultant dehydration and hypovolemia can cause orthostatic hypotension and hemoconcentration, which could lead to circulatory collapse, syncope, or thromboembolic events, particularly in chronic cardiac patients.

Renal failure (unspecified), increased serum creatinine, and azotemia (increased blood urea nitrogen) have been reported in 0.1%, 7.4%, and 10.6% of bumetanide-treated adult patients, respectively. Abrupt decreases in glomerular filtration rates and renal blood flow have occurred in patients receiving bumetanide. Reversible azotemia, and/or increased serum creatinine have occurred in dehydrated patients. Bumetanide-induced renal failure (e.g., interstitial nephritis) occurs rarely. Proteinuria (0.3%) has also been observed. Although bumetanide can be used to induce diuresis in renal insufficiency, any marked increase in blood urea nitrogen or serum creatinine, or the development of oliguria during therapy of patients with progressive renal disease, is an indication for discontinuation of treatment with bumetanide.

Bumetanide-induced fluctuations in serum electrolyte concentrations can occur rapidly and may precipitate hepatic encephalopathy and coma in susceptible patients with preexisting hepatic disease. Encephalopathy has been reported in 0.6% of bumetanide-treated adults with preexisting liver disease; asterixis has been reported in approximately 0.1% of patients. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can also predispose patients to developing potassium depletion when bumetanide is administered. Elevated hepatic enzymes (alkaline phosphatase (0.4%), SGOT (0.6%), and SGPT (0.5%)), increased total serum bilirubin (0.8%), and changes in LDH (1%) have also been reported.

Hyperuricemia has been reported in about 18.4% of tested adult patients who were receiving bumetanide. Bumetanide occasionally can cause transient elevations of uric acid concentrations; these elevations are usually asymptomatic.

Impaired hearing and ear discomfort have been reported in 0.5% and 0.1% of bumetanide-treated adult patients, respectively. Ototoxicity, manifested as tinnitus, or reversible or permanent hearing loss rarely occurs during bumetanide therapy and is usually associated with rapid administration of large doses of the drug. Adverse otic effects occur more frequently in patients who are also receiving other ototoxic agents or who have severe renal impairment.

Hyperglycemia, possibly due to potassium depletion, has been reported in 6.6% of bumetanide-treated adult patients. Glycosuria may occur; increases in urinary glucose have been reported in 0.7% of bumetanide-treated adults.

Rarely, adverse hematologic effects have been reported during bumetanide therapy in adult patients and include thrombocytopenia (0.2%) and leukopenia. Deviations in hemoglobin (0.8%), prothrombin time (0.8%), hematocrit (0.6%), WBC (0.3%), and differential counts (0.1%) have also been observed. No causal relationship to the drug has been established. There have been rare spontaneous reports of thrombocytopenia from post-marketing experience.

Diuretics, particularly thiazide and loop diuretics, such as bumetanide, have been shown to cause hypercholesterolemia, hypertriglyceridemia, as well as increased plasma concentrations of LDL. Changes in cholesterol (0.4%) have been reported in adult patients treated with bumetanide. Some studies have suggested that these effects may decrease or cease with long-term therapy, and are not clinically important.

Adverse reactions of the skin associated with bumetanide include pruritus (0.4%), urticaria (0.1%), and rash (unspecified) (0.2%). Other adverse reactions that have each occurred with bumetanide include Stevens-Johnson syndrome and toxic epidermal necrolysis.

Bumetanide is contraindicated in patients with known bumetanide hypersensitivity. Because cross-sensitivity with furosemide has rarely been observed, bumetanide can be substituted for furosemide in patients allergic to furosemide. The risk of an allergic reaction after administration of a loop diuretic in a patient with sulfonamide hypersensitivity or thiazide diuretic hypersensitivity appears to be very low. Although bumetanide is a sulfonamide derivative, sulfonamide cross-sensitivity has been rarely documented. Bumetanide does not contain the N4-aromatic amine or the N1-substituent, which are present in sulfonamide antibiotics. Non-arylamine sulfonamide derivatives, such as loop diuretics, have been proposed to have a lower risk of allergic reactions in patients with sulfonamide allergy, presumably due to lack of an arylamine group at the N4 position (a proposed structural site of action for sulfonamide allergy). One large retrospective cohort study has reported that in patients with the presence of an allergic reaction after exposure to a sulfonamide antibiotic, 9.9% had an allergic reaction after receiving a non-antibiotic sulfonamide derivative, while in patients who lacked an allergic reaction after sulfonamide antibiotic exposure, 1.6% had an allergic reaction after administration of a non-antibiotic sulfonamide derivative (adjusted odds ratio 2.8; 95% CI, 2.1-3.7). A causal relationship between sulfonamide hypersensitivity and allergic reactions with non-arylamine sulfonamide derivatives has not been definitively established and remains controversial. In general, patients with a documented sulfonamide allergy are considered to be predisposed for development of allergic drug reactions.

Bumetanide is a potent diuretic and can cause electrolyte imbalance. Carefully monitor patients; dosage adjustments may be necessary. Because of this, bumetanide is contraindicated in patients with severe electrolyte imbalance until the condition is improved or corrected. Correct significant hyponatremia, hypokalemia, hypocalcemia, hypochloremia, and/or hypomagnesemia before administration. Loop diuretics may induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement.

Bumetanide is contraindicated in patients in hepatic encephalopathy (hepatic coma) until the condition is improved or corrected. Bumetanide-induced fluctuations in serum electrolyte concentrations can occur rapidly and precipitate serious hepatic effects in susceptible patients, including hepatic encephalopathy and/or coma. Use bumetanide with caution in patients with significant hepatic disease such as cirrhosis with ascites.

Monitor blood and/or urine glucose concentrations closely in patients with diabetes mellitus receiving bumetanide because loop diuretics can impair glucose tolerance resulting in hyperglycemia.

Bumetanide can cause dehydration; the dehydration can be profound if bumetanide is given in excessive doses. Monitor patients carefully; dosage adjustments may be necessary. Because of this, bumetanide is contraindicated in any patient with anuria. Use bumetanide with caution in patients with severe renal disease such as severe renal impairment or renal failure. Bumetanide-induced hypovolemia can precipitate oliguria and azotemia in these patients. Although bumetanide can be used to induce diuresis in renal insufficiency, any marked increase in blood urea nitrogen or serum creatinine, or the development of oliguria during therapy of patients with progressive renal disease, is an indication for discontinuation of treatment with bumetanide. Renal failure may reduce drug clearance and warrant the use of higher doses with extended dosing intervals. Bumetanide may be less effective in patients with renal failure and higher doses may be required. Delayed excretion of bumetanide in patients with renal failure may increase the risk of toxicity (e.g., ototoxicity).

Correct pre-existing hypovolemia or hypotension before bumetanide is initiated. Hypotension has been reported with bumetanide and although not specifically reported with bumetanide, orthostatic hypotension has been reported with other loop diuretics. Excessive hypotension can result in syncope.

Like other loop diuretics, bumetanide can reduce the clearance of uric acid; patients with gout or hyperuricemia can have exacerbations of their disease.

Monitor patients with ventricular arrhythmias, heart failure, potassium-losing nephropathy, aldosterone excess, or diarrhea closely since bumetanide-induced hypokalemia can exacerbate these conditions.

High doses and accumulation of bumetanide may cause ototoxicity. Use bumetanide with caution in patients with hearing impairment or tinnitus. Adverse otic effects occur more frequently in patients who are also receiving other ototoxic agents or who have severe renal impairment.

Bumetanide has been reported to cause pancreatitis in adult patients; use with caution in patients with a history of pancreatitis.

In vitro studies using pooled sera from critically ill neonates have shown bumetanide to be a displacer of bilirubin. The administration of bumetanide could present a particular concern if given to critically ill neonates or neonates with jaundice who are at risk for kernicterus.

Description: Bumetanide is a sulfonamide-derived loop diuretic used in the management of edema associated with congestive heart failure, hepatic disease, and renal disease such as nephrotic syndrome. It is structurally related to furosemide, but its diuretic potency is about 40 times greater. Bumetanide may be particularly useful in patients who are unresponsive to other diuretics or who have severe renal impairment and require large doses of loop diuretics. Some data suggest that bumetanide may be associated with lower rates of ototoxicity compared to furosemide and therefore, may be a useful alternative for patients at risk for this adverse event (e.g., those receiving concomitant ototoxic drugs). Although not FDA-approved, bumetanide has been used off-label in pediatric patients as young as neonates for the treatment of edema.

For the treatment of peripheral edema* or edema associated with heart failure* or nephrotic syndrome*:
Oral dosage:
Neonates: 0.01 to 0.05 mg/kg/dose PO every 24 to 48 hours. 0.012 to 0.03 mg/kg/dose PO every 24 to 48 hours was safe and effective for long-term use (2 to 40 weeks) in a study of infants with congenital heart disease and heart failure; 5 patients were younger than 1 month of age at therapy initiation.
Infants, Children, and Adolescents: 0.015 to 0.1 mg/kg/dose PO every 6 to 24 hours; Max initial dose: 2 mg. 0.014 to 0.15 mg/kg/dose PO every 24 to 48 hours was safe and effective for long-term use (4 to 20 weeks) in a study of infants with congenital heart disease and heart failure. Although a maximum dose has not been specified, the maximum dose in adults is 10 mg/day PO.
Intravenous or Intramuscular dosage:
Neonates: 0.01 to 0.05 mg/kg/dose IV or IM every 24 to 48 hours. A dose ranging study in 56 neonates and infants (0 to 6 months of age) assessed diuretic response after single doses of 0.005 to 0.1 mg/kg IV and determined that maximal diuretic response would be achieved with doses of 0.035 to 0.04 mg/kg/dose IV every 6 to 8 hours; neonatal data were not reported separately. However, restricting the dosage interval to a minimum of 12 hours is recommended, especially in premature neonates, due to decreased clearance and risk of accumulation and resultant toxicity.
Infants, Children, and Adolescents: 0.015 to 0.1 mg/kg/dose IV or IM every 6 to 24 hours; Max initial dose: 1 mg. A dose ranging study in 56 infants 6 months or younger assessed diuretic response after single doses of 0.005 to 0.1 mg/kg IV and determined that maximal diuretic response would be achieved with doses of 0.035 to 0.04 mg/kg/dose IV every 6 to 8 hours. Although a maximum dose has not been specified, the maximum dose in adults is 10 mg/day.
Continuous Intravenous Infusion dosage:
Neonates: 1 to 10 mcg/kg/hour continuous IV infusion. The expected dose of bumetanide is 1.25 to 10 mcg/kg/hour continuous IV infusion based on a standard furosemide infusion dose (0.05 to 0.4 mg/kg/hour), taking into account bumetanide IV is 40-fold more potent than furosemide IV. A mean dose of 5.7 +/- 2.2 mcg/kg/hour with a median duration of 3.3 days (range: 0.3 to 18.5 days) was reported in a single-center, retrospective chart review of 95 pediatric critical care patients (median age: 0.2 years, range: 0 to 15.7 years); 54% of patients reached negative fluid balance within 12 hours and 76% of patients reached negative fluid balance within 48 hours. A majority (60%) of patients also received concomitant intermittent diuretics. Another retrospective study (n = 40; mean age: 1.6 years) reported a mean initial and maximum dose of 30 and 50 mcg/kg/hour, respectively (range: 1 to 200 mcg/kg/hour); however, safety was not assessed.
Infants, Children, and Adolescents: 1 to 10 mcg/kg/hour continuous IV infusion. The expected dose of bumetanide is 1.25 to 10 mcg/kg/hour continuous IV infusion based on a standard furosemide infusion dose (0.05 to 0.4 mg/kg/hour), taking into account bumetanide IV is 40-fold more potent than furosemide IV. A mean dose of 5.7 +/- 2.2 mcg/kg/hour with a median duration of 3.3 days (range: 0.3 to 18.5 days) was reported in a single-center, retrospective chart review of 95 pediatric critical care patients (median age: 0.2 years, range: 0 to 15.7 years); 54% of patients reached negative fluid balance within 12 hours and 76% of patients reached negative fluid balance within 48 hours. A majority (60%) of patients also received concomitant intermittent diuretics. Another retrospective study (n = 40; mean age: 1.6 years) reported a mean initial and maximum dose of 30 and 50 mcg/kg/hour, respectively (range: 1 to 200 mcg/kg/hour); however, safety was not assessed.

For the treatment of oliguria* associated with acute renal failure:
Intravenous dosage:
Premature Neonates: 0.01-0.06 mg/kg/dose IV every 12-24 hours was used in a retrospective study of 35 premature neonates (gestational age 24-33 weeks, postnatal age 6-37 days). Mean urinary output increased from 0.6 +/- 0.6 mL/kg/hour to 3 +/- 2.1 mL/kg/hour within 24-48 hours of starting bumetanide (p < 0.0005). Transient increases in serum creatinine also occurred during bumetanide therapy compared to baseline (2.13 vs. 2.31 mg/dL, p = 0.04); however, these elevations began to decline 24-48 hours after the last dose of bumetanide and had returned to normal 4-5 weeks after the last dose in those patients available for follow-up.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 0.06 mg/kg/dose IV have been used off-label for oliguria.
-Infants
Safety and efficacy have not been established; however, doses up to 0.1 mg/kg/dose PO/IV/IM have been used off-label.
-Children
Safety and efficacy have not been established; however, doses up to 0.1 mg/kg/dose PO/IV/IM have been used off-label (Max adult dose: 10 mg/day).
-Adolescents
Safety and efficacy have not been established; however, doses up to 0.1 mg/kg/dose PO/IV/IM have been used off-label (Max adult dose: 10 mg/day).

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; start at the lower end of the dosage range and titrate carefully to desired response. In general, use diuretics with caution in patients with hepatic disease because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; higher doses with extended dosage intervals may be effective in patients with end-stage renal disease (ESRD). Bumetanide is contraindicated in patients with anuria.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Bumetanide is a loop diuretic that inhibits sodium and chloride resorption by competing with chloride for the Na+/K+/2Cl- co-transporter in the ascending limb of the loop of Henle. Bumetanide may also act on the proximal tubule, as phosphate reabsorption occurs primarily in the proximal tubule and phosphaturia occurs with bumetanide therapy. A profound diuresis results from the increased urinary excretion of sodium, chloride, potassium, and hydrogen ions. Additionally, bumetanide causes increased urinary excretion of calcium, magnesium, bicarbonate, ammonium, and phosphate. The diuresis caused by bumetanide can lead to increased aldosterone production, resulting in increased sodium resorption and increased potassium and hydrogen excretion. Excessive loss of these electrolytes can lead to metabolic alkalosis.

Pharmacokinetics: Bumetanide is administered orally, intramuscularly, or intravenously. The duration of action is 3-6 hours. Bumetanide is 94-96% plasma protein-bound. Bumetanide is partially metabolized in the liver to inactive metabolites. The majority of the dose (81%) is excreted in the urine, and approximately 2% of a dose is excreted in the bile. Approximately 45% of a bumetanide dose is excreted unchanged in the urine in adults; however, the percentage is significantly lower in neonates (15-20%), possibly due to immature renal function and higher nonrenal clearance. The elimination half-life in adults is 1-1.5 hours.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, bumetanide is 65-95% absorbed. Food will delay oral absorption but will not alter the diuretic response. Diuresis generally begins 30-60 minutes after oral administration and is usually complete within 4 hours at usual doses. Peak effects occur within 1-2 hours after oral administration.

Intravenous Route
Diuresis generally begins within several minutes after IV administration of bumetanide. Peak effects occur within 15-30 minutes after IV administration.

Intramuscular Route
Diuresis generally begins within 40 minutes after IM administration of bumetanide.


-Special Populations
Pediatrics
Neonates
In neonatal patients, bumetanide elimination is considerably slower than that of adults, possibly because of immature renal and hepatobiliary function in neonates. The mean elimination half-life decreases from approximately 6 hours at birth to 2.4 hours at 1 month of age. A pharmacokinetic study in 53 critically ill neonates and infants (4 days to 6 months of age) showed postnatal age to be a significant determinant of bumetanide clearance and half-life, with both renal and nonrenal clearance increasing with increasing age and half-life decreasing over the first month of life then plateauing. According to the manufacturer, small pharmacokinetic studies of intravenous bumetanide in preterm and full term neonates with respiratory disorders have reported an apparent half-life of approximately 6 hours, with a range up to 15 hours and a serum clearance ranging from 0.2-1.1 ml/min/kg (compared to a mean half-life and serum clearance of 1.07 hours and 1.84 ml/min/70 kg, respectively, in adults). In a population of neonates and infants receiving bumetanide for volume overload, mean serum clearance rates and mean serum half-life were 2.17 ml/min/kg and 2.5 hours in patients < 2 months of age, respectively. The degree of protein binding of bumetanide in cord sera from healthy neonates was approximately 97%, suggesting the potential for bilirubin displacement. A study using pooled sera from critically ill neonates found that bumetanide at concentrations of 0.5-50 mcg/ml, but not 0.25 mcg/ml, caused a linear increase in unbound bilirubin concentrations.

Infants
A pharmacokinetic study in 53 critically ill neonates and infants (4 days to 6 months of age) showed postnatal age to be a significant determinant of bumetanide clearance and half-life, with both renal and nonrenal clearance increasing with increasing age and half-life decreasing over the first month of life then plateauing. In a population of neonates and infants receiving bumetanide for volume overload, mean serum clearance rates were 2.17 ml/min/kg in patients < 2 months of age and 3.8 ml/min/kg in patients 2-6 months of age. Mean serum half-life of bumetanide was 2.5 hours and 1.5 hours in patients < 2 months of age and those 2-6 months of age, respectively. The pharmacodynamic effects of bumetanide doses ranging from 0.005-0.1 mg/kg have been studied in 56 infants aged 4 days-6 months. In these infants, urine flow rates increased at least two-fold in all patients, peaking at one hour in most patients, and returning to or falling below baseline by 6 hours. Maximal increases in electrolyte excretion were seen within 3 hours, which correlated with an increased rate of bumetanide excretion during this time period. Pharmacologic response was best correlated with bumetanide excretion rate and was not necessarily dose-related in these infants.

Children and Adolescents
Limited date are available describing the pharmacokinetics of bumetanide in older pediatric patients. The mean total clearance, renal clearance, and elimination half-life of bumetanide in 9 critically ill patients (3 months to 25 years of age) after a single dose of 0.1 mg/kg IV were 3.9 ml/min/kg, 1.1 ml/min/kg, and 1.65 hours, respectively.