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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(byoo MET a nide)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of edema secondary to heart failure or hepatic or renal disease (including nephrotic syndrome)
Use: Unlabeled
Treatment of hypertension
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events have been observed in some animal studies.
Lactation
Excretion in breast milk unknown/not recommended
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
Warnings/Precautions
Boxed warnings:
• Fluid/electrolyte loss: See “Concerns related to adverse effects” below.
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.
• 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 I.V. administration, renal impairment, excessive doses, and concurrent use of other ototoxins (eg, aminoglycosides).
• Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid); the manufacturer's labeling states that bumetanide may be used in patients allergic to furosemide. Use in patients with sulfonylurea allergy is not specifically contraindicated in product labeling; however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
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.
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.
Adverse Reactions
>10%:
Endocrine & metabolic: Hyperuricemia (18%), hypochloremia (15%), hypokalemia (15%)
Renal: Azotemia (11%)
1% to 10%:
Central nervous system: Dizziness (1%)
Endocrine & metabolic: Hyponatremia (9%), hyperglycemia (7%), phosphorus altered (5%), CO2 content altered (4%), bicarbonate altered (3%), calcium altered (2%)
Neuromuscular & skeletal: Muscle cramps (1%)
Renal: Serum creatinine increased (7%)
Miscellaneous: LDH altered (1%)
<1%, postmarketing, and/or case reports: Abdominal pain, alkaline phosphatase altered, arthritic pain, asterixis, bilirubin altered, chest pain, cholesterol altered, creatinine clearance altered, dehydration, diaphoresis, diarrhea, ear discomfort, ECG changes, encephalopathy (in patients with pre-existing liver disease), erectile dysfunction, fatigue, headache, hearing impaired, hemoglobin/hematocrit altered, hives, hypernatremia, hyperventilation, hypotension, musculoskeletal pain, nausea, nipple tenderness, orthostatic hypotension, ototoxicity, premature ejaculation, prothrombin time altered, pruritus, rash, renal failure, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, transaminase altered, upset stomach, urine glucose increased, urine protein increased, vertigo, vomiting, WBC altered, weakness, xerostomia
Metabolism/Transport Effects
None known.
Drug Interactions
ACE Inhibitors: Loop Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: 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. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Aminoglycosides: Loop Diuretics may enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Loop Diuretics. Risk D: Consider therapy modification
Cardiac Glycosides: Loop Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. This by increasing the risk of hypokalemia. Risk C: Monitor therapy
CISplatin: Loop Diuretics may enhance the nephrotoxic effect of CISplatin. Loop Diuretics may enhance the ototoxic effect of CISplatin. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
CycloSPORINE (Systemic): May enhance the adverse/toxic effect of Loop Diuretics. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Dofetilide: Loop Diuretics may enhance the QTc-prolonging effect of Dofetilide. Risk C: Monitor therapy
Fosphenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Licorice: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Lithium: Loop Diuretics may decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methotrexate: May diminish the therapeutic effect of Loop Diuretics. Methotrexate may increase the serum concentration of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. 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. Risk D: Consider therapy modification
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: 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. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the diuretic effect of Loop Diuretics. Management: Monitor for decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concomitant use of these agents in CHF or cirrhosis with ascites. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: 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. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: 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. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates. Risk C: 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. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Bumetanide serum levels may be decreased if taken with food. It has been recommended that bumetanide be administered without food (Bard, 2004).
Herb/Nutraceutical: Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid dong quai if using for hypertension (has estrogenic activity). Avoid garlic (may have increased antihypertensive effect).
Storage
I.V.: Store vials at 15°C to 30°C (59°F to 86°F). Infusion solutions 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).
Compatibility
Stable in D5W, NS, LR.
Y-site administration: Compatible: Allopurinol, amifostine, aztreonam, bivalirudin, caspofungin, cefepime, cisatracurium, cladribine, dexmedetomidine, diltiazem, docetaxel, doripenem, etoposide phosphate, filgrastim, gemcitabine, granisetron, hetastarch in lactate electrolyte injection (Hextend®), lorazepam, melphalan, meperidine, micafungin, milrinone, morphine, oxaliplatin, pemetrexed, piperacillin/tazobactam, propofol, remifentanil, teniposide, thiotepa, vinorelbine. Incompatible: Fenoldopam, midazolam, nesiritide.
Compatibility in syringe: Compatible: Doxapram.
Mechanism of Action
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
Pharmacodynamics/Kinetics
Onset of action: Oral, I.M.: 0.5-1 hour; I.V.: 2-3 minutes
Peak effect: Oral: 1-2 hours; I.V.: 15-30 minutes
Duration: 4-6 hours
Distribution: Vd: Neonates and Infants: 0.26-0.39 L/kg; Adults: 9-25 L
Protein binding: 94% to 96%
Metabolism: Partially hepatic
Bioavailability: 59% to 89% (median: 80%)
Half-life elimination: Neonates: ~6 hours; Infants (1 month): ~2.4 hours; Adults: 1-1.5 hours
Excretion: Urine (81% of total dose; 45% of which is unchanged drug); feces (2% of total dose)
Dosage
Infants and Children: Oral, I.M., I.V.: 0.015-0.1 mg/kg/dose every 6-24 hours (maximum dose: 10 mg/day)
Adults:
Edema:
Oral: 0.5-2 mg/dose 1-2 times/day; if diuretic response to initial dose is not adequate, may repeat in 4-5 hours for up to 2 doses (maximum dose: 10 mg/day)
I.M., I.V.: 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/day)
Continuous I.V. infusion (unlabeled dose): Initial: 1 mg I.V. load then 0.5-2 mg/hour (Hunt, 2009)
Hypertension (unlabeled use): Oral: 0.5 mg daily (maximum dose: 5 mg/day); usual dosage range (JNC 7): 0.5-2 mg/day in 2 divided doses (Chobanian, 2003)
Administration: 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.
Administration: I.V.
Administer slowly, over 1-2 minutes.
Administration: I.V. Detail
pH: 6.8-7.8 (adjusted)
Monitoring Parameters
Blood pressure; serum electrolytes, renal function; fluid status (weight and I & O), blood pressure
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.
Patient Education
May be taken with food to reduce GI effects. If taking one dose daily, take single dose early in day; if taking twice daily, take last dose early in afternoon to prevent sleep interruptions. Include potassium-rich foods in your daily diet, but do not take supplemental potassium without consulting prescriber. May cause dizziness or weakness. Report palpitations or chest pain, swelling of ankles or feet, weight increase, increased fatigue, muscle cramps, trembling, and any changes in hearing.
Geriatric Considerations
Loop diuretics are potent diuretics; excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation is required, particularly in the elderly. Severe loss of sodium and/or increases in BUN can cause confusion; for any change in mental status in patients on bumetanide, monitor electrolytes and renal function.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: If given the morning of surgery, bumetanide may render the patient volume depleted and blood pressure may be labile during general anesthesia.
Patients with impaired hepatic function must be monitored carefully due to increased risk of hepatic encephalopathy, often requiring reduced doses. Larger doses may be necessary in patients with impaired renal function to obtain the same therapeutic response.
Cardiovascular Considerations
Loop diuretic therapy has been a mainstay in the treatment of heart failure. Although loop diuretics have not demonstrated reduction in mortality associated with heart failure, they improve symptomatology associated with congestion (eg, edema, dyspnea). Due to rapid onset and predictability, intravenous loop diuretic therapy is routinely used to treat patients with acutely decompensated heart failure (ADHF). Intravenous therapy may also improve pulmonary congestion since it dilates veins and reduces preload. Until recently, prospective clinical trial data has been lacking in the treatment of ADHF. The DOSE trial prospectively evaluated the use of furosemide in a 2-by-2 factorially designed trial. Patients with ADHF (n=308) were randomized in a 1:1:1:1 fashion to either low-dose (total I.V. furosemide dose equal to total daily oral dosing) or high-dose (total I.V. furosemide dose equal to 2.5 times total daily oral dosing) and to administration of an I.V. bolus dose every 12 hours or a continuous infusion. No significant differences were seen between groups with respect to patient-assessed symptoms or change in renal function; therefore, in patients with ADHF, use of either administration method may be appropriate (Felker, 2011).
The use of loop diuretics can lead to hypokalemia and/or hypomagnesemia. Electrolyte disturbances can predispose a patient to serious cardiac arrhythmias, particularly if the patient is concurrently receiving digoxin. Fluid depletion, hypotension, and azotemia can also result from excessive use of diuretics. In contrast to thiazide diuretics, a loop diuretic can also lower serum calcium concentrations. 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.
Dose equivalency (approximate): Bumetanide 1 mg = furosemide 40 mg = torsemide 20 mg = ethacrynic acid 50 mg
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness
Mental Health: Effects on Psychiatric Treatment
Lithium excretion may be decreased; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Assess history of allergies and renal, electrolyte, hepatic, and pregnancy status prior to beginning treatment. Blood pressure, weight, and fluid status should be monitored at beginning of therapy and periodically during therapy. Assess electrolytes, renal function, and therapeutic effectiveness (reduced edema and cardiopulmonary symptoms). Monitor for hypotension, electrolyte imbalance, and ototoxicity.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 0.25 mg/mL (2 mL, 4 mL, 10 mL)
Tablet, oral: 0.5 mg, 1 mg, 2 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Bumetanide)
0.5 mg (90): $18.99
1 mg (90): $28.97
2 mg (30): $20.99
References
Bard RL, Bleske BE, and Nicklas JM, “Food: An Unrecognized Source of Loop Diuretic Resistance,” Pharmacotherapy, 2004, 24(5):630-7.
Brater DC, “Clinical Pharmacology of Loop Diuretics,” Drugs, 1991, 41(Suppl 3):14-22.
Chobanian AV, Bakris GL, Black HR, et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,” JAMA, 2003, 289(19):2560-71.
Cook JA, Smith DE, Cornish LA, et al, “Kinetics, Dynamics, and Bioavailability of Bumetanide in Healthy Subjects and Patients With Congestive Heart Failure,” Clin Pharmacol Ther, 1988, 44(5):487-500.
Felker GM, Lee KL, Bull DA, et al, "Diuretic Strategies in Patients With Acute Decompensated Heart Failure," N Engl J Med, 2011, 364(9):797-805.
Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-e90.
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
Montgomery PA and Christen C, “Policy to Restrict Use of I.V. Bumetanide,” Am J Health Syst Pharm, 1995, 52(16):1802-4.
Ward A and Heel RC, “Bumetanide: A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use,” Drugs, 1984, 28(5):426-64.
Wells TG, “The Pharmacology and Therapeutics of Diuretics in the Pediatric Patient,” Pediatr Clin North Am, 1990, 37(2):463-504.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
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