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Bumetanide


General


Pronunciation

(byoo MET a nide)


Brand Names: U.S.

  • Bumex

Indications


Use: Labeled Indications

Management of edema secondary to heart failure or hepatic or renal disease (including nephrotic syndrome)


Contraindications


Hypersensitivity to bumetanide or any component of the formulation; anuria; patients with hepatic coma or in states of severe electrolyte depletion until the condition improves or is corrected


ALERT: U.S. Boxed Warning

Fluid/electrolyte loss:

Bumetanide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required and dose and dosage schedule have to be adjusted to the individual patients needs.


Dosing and Administration


Dosing: Adult

Note: Dose equivalency for patients with normal renal function (approximate): Bumetanide 1 mg = furosemide 40 mg = torsemide 20 mg = ethacrynic acid 50 mg

Edema, heart failure:

Oral: 0.5-2 mg/dose 1-2 times daily; if diuretic response to initial dose is not adequate, may repeat in 4-5 hours for up to 2 doses (maximum dose: 10 mg daily). ACCF/AHA 2013 heart failure guidelines recommend initial dosing of 0.5-1 mg once or twice daily and a maximum total daily dose of 10 mg (Yancy, 2013).

IM, IV: 0.5-1 mg/dose; if diuretic response to initial dose is not adequate, may repeat in 2-3 hours for up to 2 doses (maximum dose: 10 mg daily)

Continuous IV infusion (off-label dose): Initial: 1 mg IV load then 0.5-2 mg/hour; repeat loading dose before increasing infusion rate (ACCF/AHA [Yancy, 2013]; Brater, 1998). Note: With lower baseline CrCl (eg, CrCl <25 mL/minute), the upper end of the initial infusion dosage range should be considered.


Dosing: Geriatric

Refer to adult dosing.


Dosing: Pediatric

Edema: Oral, IM, IV: Infants and Children: 0.015-0.1 mg/kg/dose every 6-24 hours (maximum dose: 10 mg/day)


Dosing: Renal Impairment

Use is contraindicated in anuria. Use with caution in renal insufficiency due to increased risk of adverse effects.


Dosing: Hepatic Impairment

Use is contraindicated in hepatic coma. Use with caution in cirrhosis and ascites due to increased risk of precipitating hepatic coma; initiate with conservative doses and monitoring.


Administration

IV: Administer slowly, over 1-2 minutes.

Oral: An alternate-day schedule or a 3-4 daily dosing regimen with rest periods of 1-2 days in between may be the most tolerable and effective regimen for the continued control of edema.


Dietary Considerations

Administration with food slows the rate and reduces the extent of absorption and may reduce diuretic efficacy (Bard, 2004). May require increased intake of potassium-rich foods.


Storage

IV: Store vials at 15 � �C to 30 � �C (59 � �F to 86 � �F). Infusion solutions in D5W, NS, or LR should be used within 24 hours after preparation. Light sensitive; discoloration may occur when exposed to light.

Tablet: Store at 15 � �C to 30 � �C (59 � �F to 86 � �F); protect from light.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 0.25 mg/mL (2 mL, 4 mL, 10 mL)

Tablet, Oral:

Bumex: 0.5 mg [contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Bumex: 1 mg [contains fd&c yellow #10 (quinoline yellow)]

Bumex: 2 mg

Generic: 0.5 mg, 1 mg, 2 mg


Compatibility

Stable in D5W, NS, LR.

Y-site administration: Incompatible with fenoldopam, midazolam, nesiritide.


Drug Interactions

ACE Inhibitors: Loop Diuretics may enhance the hypotensive effect of ACE Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Allopurinol: Loop Diuretics may enhance the adverse/toxic effect of Allopurinol. Loop Diuretics may increase the serum concentration of Allopurinol. Specifically, Loop Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminoglycosides: Loop Diuretics may enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Analgesics (Opioid): May enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: May enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Loop Diuretics. Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hypotensive effect of Loop Diuretics. Management: If canagliflozin is combined with a loop diuretic, monitor for symptoms of intravascular volume depletion and hypotension. Canadian product labeling recommends avoiding the combination of canagliflozin and loop diuretics. Consider therapy modification

Cardiac Glycosides: Loop Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of loop diuretics. Monitor therapy

Cefazedone: May enhance the nephrotoxic effect of Loop Diuretics. Monitor therapy

Cefotiam: Loop Diuretics may enhance the nephrotoxic effect of Cefotiam. Monitor therapy

Ceftizoxime: Loop Diuretics may enhance the nephrotoxic effect of Ceftizoxime. Monitor therapy

Cephalothin: Loop Diuretics may enhance the nephrotoxic effect of Cephalothin. Monitor therapy

Cephradine: May enhance the nephrotoxic effect of Loop Diuretics. Monitor therapy

CISplatin: Loop Diuretics may enhance the nephrotoxic effect of CISplatin. Loop Diuretics may enhance the ototoxic effect of CISplatin. Monitor therapy

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

CycloSPORINE (Systemic): May enhance the adverse/toxic effect of Loop Diuretics. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dofetilide: Loop Diuretics may enhance the QTc-prolonging effect of Dofetilide. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Empagliflozin: May enhance the hypotensive effect of Loop Diuretics. Monitor therapy

Foscarnet: Loop Diuretics may increase the serum concentration of Foscarnet. Consider therapy modification

Fosphenytoin: May diminish the diuretic effect of Loop Diuretics. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Ivabradine: Loop Diuretics may enhance the arrhythmogenic effect of Ivabradine. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Levosulpiride: Loop Diuretics may enhance the adverse/toxic effect of Levosulpiride. Avoid combination

Licorice: May enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Lithium: Loop Diuretics may decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Methotrexate: May diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics. Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic dose reductions may be necessary. Consider therapy modification

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Neuromuscular-Blocking Agents: Loop Diuretics may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Loop Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Consider therapy modification

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phenytoin: May diminish the diuretic effect of Loop Diuretics. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Probenecid: May enhance the adverse/toxic effect of Loop Diuretics. Probenecid may diminish the diuretic effect of Loop Diuretics. Probenecid may increase the serum concentration of Loop Diuretics. Management: Monitor for decreased diuretic effects or increased adverse effects of loop diuretics with concomitant use of probenecid. Bumetanide prescribing information recommends against concomitant use of probenecid. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Reboxetine: May enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

RisperiDONE: Loop Diuretics may enhance the adverse/toxic effect of RisperiDONE. Management: Consider alternative diuretic therapy (e.g., thiazides) to more potent diuretics (e.g., furosemide) in elderly patients receiving risperidone. Patients who require use of more potent diuretic therapy should be closely monitored and adequately hydrated. Consider therapy modification

Salicylates: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates. Monitor therapy

Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Consider therapy modification

Tobramycin (Oral Inhalation): Loop Diuretics may enhance the nephrotoxic effect of Tobramycin (Oral Inhalation). Loop Diuretics may enhance the ototoxic effect of Tobramycin (Oral Inhalation). Monitor therapy

Topiramate: Loop Diuretics may enhance the hypokalemic effect of Topiramate. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy


Monitoring Parameters

Blood pressure; serum electrolytes, renal function; fluid status (weight and I & O), blood pressure


Adverse Reactions


>10%:

Endocrine & metabolic: Hyperuricemia (18%), hypochloremia (15%), hypokalemia (15%)

Genitourinary: Azotemia (11%)

1% to 10%:

Central nervous system: Dizziness (1%)

Endocrine & metabolic: Hyponatremia (9%), hyperglycemia (7%), phosphorus change (5%), variations in bicarbonate (3%), abnormal serum calcium (2%), abnormal lactate dehydrogenase (1%)

Neuromuscular & skeletal: Muscle cramps (1%)

Renal: Increased serum creatinine (7%)

Respiratory: Variations in CO2 content (4%)

<1% (Limited to important or life-threatening): Abdominal pain, abnormal alkaline phosphatase, abnormal bilirubin levels, abnormal hematocrit, abnormal hemoglobin level, abnormal transaminase, arthritic pain, asterixis, auditory impairment, blood cholesterol abnormal, brain disease (in patients with preexisting liver disease), change in creatinine clearance, change in prothrombin time, change in WBC count, chest pain, dehydration, diaphoresis, diarrhea, dyspepsia, ECG changes, erectile dysfunction, fatigue, glycosuria, headache, hyperventilation, hypotension, musculoskeletal pain, nausea, nipple tenderness, orthostatic hypotension, otalgia, ototoxicity, premature ejaculation, proteinuria, pruritus, renal failure, skin rash, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, urticaria, vertigo, vomiting, weakness, xerostomia


Warnings/Precautions


Special Populations: Renal Function Impairment

The half-life is prolonged.


Warnings/Precautions

Concerns related to adverse effects:

- Fluid/electrolyte loss: [U.S. Boxed Warning]: Loop diuretics are potent diuretics; excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Potassium supplementation and/or use of potassium-sparing diuretics may be necessary to prevent hypokalemia. In contrast to thiazide diuretics, a loop diuretic can also lower serum calcium concentrations. Electrolyte disturbances can predispose a patient to serious cardiac arrhythmias.

- Hyperuricemia: Asymptomatic hyperuricemia has been reported with use.

- Nephrotoxicity: Monitor fluid status and renal function in an attempt to prevent oliguria, azotemia, and reversible increases in BUN and creatinine; close medical supervision of aggressive diuresis required.

- Ototoxicity: Bumetanide-induced ototoxicity (usually transient) may occur with rapid IV administration, renal impairment, excessive doses, and concurrent use of other ototoxins (eg, aminoglycosides).

- Sulfonamide ( "sulfa " �) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

- Cirrhosis: Use caution in patients with cirrhosis; initiate bumetanide therapy with conservative dosing and close monitoring of electrolytes; avoid sudden changes in fluid and electrolyte balance and acid/base status which may lead to hepatic encephalopathy.

- Renal impairment: Larger doses may be necessary in patients with impaired renal function to obtain the same therapeutic response (Brater, 1998).

Concurrent drug therapy issues:

- Antihypertensives: Coadministration of antihypertensives may increase the risk of hypotension.

Special populations:

- Neonates: In vitro studies using pooled sera from critically-ill neonates have shown bumetanide to be a potent displacer of bilirubin; avoid use in neonates at risk for kernicterus.

- Surgical patients: If given the morning of surgery, bumetanide may render the patient volume depleted and blood pressure may be labile during general anesthesia.

Dosage form specific issues:

- Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity ( "gasping syndrome " �) in neonates; the "gasping syndrome " � consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP [Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer 's labeling.

Other warnings and precautions:

- Diuretic resistance: For some patients, despite higher doses of loop diuretic treatment, an adequate diuretic response cannot be attained. Diuretic resistance can usually be overcome by intravenous administration, the use of two diuretics together (eg, furosemide and chlorothiazide), or the use of a diuretic with a positive inotropic agent. When such combinations are used, serum electrolytes need to be monitored even more closely (Cody, 1994; ACC/AHA [Yancy, 2013]; HFSA, 2010).


Pregnancy Risk Factor

C


Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies.


Actions


Pharmacology

Inhibits reabsorption of sodium and chloride in the ascending loop of Henle and proximal renal tubule, interfering with the chloride-binding cotransport system, thus causing increased excretion of water, sodium, chloride, magnesium, phosphate, and calcium; it does not appear to act on the distal tubule


Distribution

Vd: Neonates and Infants: 0.26 to 0.39 L/kg; Adults: 9 to 25 L


Metabolism

Partially hepatic


Excretion

Urine (81% of total dose; 45% of which is unchanged drug); feces (2% of total dose)

Clearance:

Preterm and full term neonates: 0.2 to 1.1 mL/minute/kg

Infants <2 months: 2.17 mL/minute/kg

Infants 2 to 6 months: 3.8 mL/minute/kg

Adults: 2.9 � � 0.2 mL/minute/kg


Onset of Action

Oral, IM: 0.5 to 1 hour; IV: 2 to 3 minutes

Peak effect: Oral: 1 to 2 hours; IV: 15 to 30 minutes


Duration of Action

Oral: 4 to 6 hours; IV: 2 to 3 hours


Half-Life Elimination

Premature and full term neonates: 6 hours (range up to 15 hours)

Infants <2 months: 2.5 hours

Infants 2 to 6 months: 1.5 hours

Adults: 1 to 1.5 hours


Protein Binding

94% to 96%; Neonates: 97%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience headache, itching, or nausea. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea or vomiting), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), severe dizziness, passing out, severe diarrhea, hearing impairment, tinnitus, or injection site pain or irritation (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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