BUMETANIDE- bumetanide tablet
Aphena Pharma Solutions - Tennessee, LLC
Bumetanide Tablets, USP
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 patient’s
needs (see DOSAGE AND ADMINISTRATION).
Bumetanide is a loop diuretic, available as scored tablets. Each tablet for oral administration contains
0.5 mg, 1 mg or 2 mg of bumetanide. In addition, each tablet contains the following inactive ingredients:
anhydrous lactose, corn starch, magnesium stearate, microcrystalline cellulose, pregelatinized starch
(corn), talc, with the following dye systems: 0.5 mg- D&C yellow No. 10 aluminum lake, FD&C blue
No. 1 aluminum lake and FD&C red No. 40 aluminum lake; 1 mg- D&C yellow No. 10 aluminum lake; 2
mg- synthetic black iron oxide, synthetic red iron oxide and synthetic yellow iron oxide.
Chemically, bumetanide is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is a practically white
powder having a calculated molecular weight of 364.42, and the following structural formula:
H N O S
Bumetanide is a loop diuretic with a rapid onset and short duration of action. Pharmacological and
clinical studies have shown that 1 mg bumetanide has a diuretic potency equivalent to approximately 40
mg furosemide. The major site of bumetanide action is the ascending limb of the loop of Henle.
The mode of action has been determined through various clearance studies in both humans and
experimental animals. Bumetanide inhibits sodium reabsorption in the ascending limb of the loop of
Henle, as shown by marked reduction of free-water clearance ( H O) during hydration and tubular free-
water reabsorption (T H O) during hydropenia. Reabsorption of chloride in the ascending limb is also
blocked by bumetanide, and bumetanide is somewhat more chloruretic than natriuretic.
Potassium excretion is also increased by bumetanide, in a dose-related fashion.
Bumetanide may have an additional action in the proximal tubule. Since phosphate reabsorption takes
place largely in the proximal tubule, phosphaturia during bumetanide-induced diuresis is indicative of
this additional action. This is further supported by the reduction in the renal clearance of bumetanide by
probenecid, associated with diminution in the natriuretic response. This proximal tubular activity does
not seem to be related to an inhibition of carbonic anhydrase. Bumetanide does not appear to have a
noticeable action on the distal tubule.
Bumetanide decreases uric acid excretion and increases serum uric acid. Following oral administration
of bumetanide the onset of diuresis occurs in 30 to 60 minutes. Peak activity is reached between 1 and 2
hours. At usual doses (1 mg to 2 mg) diuresis is largely complete within 4 hours; with higher doses, the
diuretic action lasts for 4 to 6 hours. Diuresis starts within minutes following an intravenous injection
and reaches maximum levels within 15 to 30 minutes.
Several pharmacokinetic studies have shown that bumetanide, administered orally or parenterally, is
eliminated rapidly in humans, with a half-life of between 1 and 1½ hours. Plasma protein-binding is in
the range of 94% to 96%.
Oral administration of carbon-14 labeled bumetanide to human volunteers revealed that 81% of the
administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Urinary and biliary
metabolites identified in this study were formed by oxidation of the N-butyl side chain. Biliary
excretion of bumetanide amounted to only 2% of the administered dose.
Elimination of bumetanide appears to be considerably slower in neonatal patients compared with adults,
possibly because of immature renal and hepatobiliary function in this population. 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 mL/min/kg to 1.1 mL/min/kg. In a population of neonates receiving
bumetanide for volume overload, mean serum clearance rates were 2.17 mL/min/kg in patients less than 2
months of age and 3.8 mL/min/kg in patients aged 2 to 6 months. Mean serum half-life of bumetanide was
2.5 hours and 1.5 hours in patients aged less than 2 months and those aged 2 to 6 months, respectively.
Elimination half-life decreased considerably during the first month of life, from a mean of
approximately 6 hours at birth to approximately 2.4 hours at 1 month of age.
In preterm neonates, mean serum concentrations following a single 0.05 mg/kg dose ranged from 126
mcg/L at 1 hour to 57 mcg/L at 8 hours. In another study, mean serum concentrations following a single
0.05 mg/kg dose were 338 ng/mL at 30 minutes and 176 ng/mL after 4 hours. A single dose of 0.1 mg/kg
produced mean serum levels of 314 ng/mL at 1 hour, and 195 ng/mL at 6 hours. Mean volume of
distribution in neonates and infants has been reported to range from 0.26 L/kg to 0.39 L/kg.
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 µg/mL to 50 mcg/mL, but not 0.25 mcg/mL,
caused a linear increase in unbound bilirubin concentrations.
In 56 infants aged 4 days to 6 months, bumetanide doses ranging from 0.005 mg/kg to 0.1 mg/kg were
studied for pharmacodynamic effect. Peak bumetanide excretion rates increased linearly with increasing
doses of drug. Maximal diuretic effect was observed at a bumetanide excretion rate of about 7
mcg/kg/hr, corresponding to doses of 0.035 mg/kg to 0.040 mg/kg. Higher doses produced a higher
bumetanide excretion rate but no increase in diuretic effect. Urine flow rate peaked during the first hour
after drug administration in 80% of patients and by 3 hours in all patients.
In a group of ten geriatric subjects between the ages of 65 and 73 years, total bumetanide clearance was
significantly lower (1.8 ± 0.3 mL/minkg) compared with younger subjects (2.9 ± 0.2 mL/minkg) after a
single oral bumetanide 0.5 mg dose. Maximum plasma concentrations were higher in geriatric subjects
(16.9 ± 1.8 ng/mL) compared with younger subjects (10.3 ± 1.5 ng/mL). Urine flow rate and total
excretion of sodium and potassium were increased less in the geriatric subjects compared with younger
subjects, although potassium excretion and fractional sodium excretion were similar between the two
age groups. Nonrenal clearance, bioavailability, and volume of distribution were not significantly
different between the two groups.
INDICATIONS AND USAGE
Bumetanide tablets, USP are indicated for the treatment of edema associated with congestive heart
failure, hepatic and renal disease, including the nephrotic syndrome.
Almost equal diuretic response occurs after oral and parenteral administration of bumetanide.
Therefore, if impaired gastrointestinal absorption is suspected or oral administration is not practical,
bumetanide should be given by the intramuscular or intravenous route.
Successful treatment with bumetanide tablets, USP following instances of allergic reactions to
furosemide suggests a lack of cross-sensitivity.
Bumetanide is contraindicated in anuria. Although bumetanide can be used to induce diuresis in renal
insufficiency, any marked increase in blood urea nitrogen or creatinine, or the development of oliguria
during therapy of patients with progressive renal disease, is an indication for discontinuation of
treatment with bumetanide. Bumetanide is also contraindicated in patients in hepatic coma or in states of
severe electrolyte depletion until the condition is improved or corrected. Bumetanide is contraindicated
in patients hypersensitive to this drug.
Volume and Electrolyte Depletion
The dose of bumetanide should be adjusted to the patient’s need. Excessive doses or too frequent
administration can lead to profound water loss, electrolyte depletion, dehydration, reduction in blood
volume and circulatory collapse with the possibility of vascular thrombosis and embolism, particularly
in elderly patients.
Hypokalemia can occur as a consequence of bumetanide administration. Prevention of hypokalemia
requires particular attention in the following conditions: patients receiving digitalis and diuretics for
congestive heart failure, hepatic cirrhosis and ascites, states of aldosterone excess with normal renal
function, potassium-losing nephropathy, certain diarrheal states, or other states where hypokalemia is
thought to represent particular added risks to the patient, i.e., history of ventricular arrhythmias.
In patients with hepatic cirrhosis and ascites, sudden alterations of electrolyte balance may precipitate
hepatic encephalopathy and coma. Treatment in such patients is best initiated in the hospital with small
doses and careful monitoring of the patient’s clinical status and electrolyte balance. Supplemental
potassium and/or spironolactone may prevent hypokalemia and metabolic alkalosis in these patients.
In cats, dogs and guinea pigs, bumetanide has been shown to produce ototoxicity. In these test animals
bumetanide was 5 to 6 times more potent than furosemide and, since the diuretic potency of bumetanide
is about 40 to 60 times furosemide, it is anticipated that blood levels necessary to produce ototoxicity
will rarely be achieved. The potential exists, however, and must be considered a risk of intravenous
therapy, especially at high doses, repeated frequently in the face of renal excretory function impairment.
Potentiation of aminoglycoside ototoxicity has not been tested for bumetanide. Like other members of
this class of diuretics, bumetanide probably shares this risk.
Allergy to Sulfonamides
Patients allergic to sulfonamides may show hypersensitivity to bumetanide.
Since there have been rare spontaneous reports of thrombocytopenia from postmarketing experience,
patients should be observed regularly for possible occurrence of thrombocytopenia.
Serum potassium should be measured periodically and potassium supplements or potassium-sparing
diuretics added if necessary. Periodic determinations of other electrolytes are advised in patients
treated with high doses or for prolonged periods, particularly in those on low-salt diets.
Hyperuricemia may occur; it has been asymptomatic in cases reported to date. Reversible elevations of
the BUN and creatinine may also occur, especially in association with dehydration and particularly in
patients with renal insufficiency. Bumetanide may increase urinary calcium excretion with resultant
Diuretics have been shown to increase the urinary excretion of magnesium; this may result in
Studies in normal subjects receiving bumetanide revealed no adverse effects on glucose tolerance,
plasma insulin, glucagon and growth hormone levels, but the possibility of an effect on glucose
metabolism exists. Periodic determinations of blood sugar should be done, particularly in patients with
diabetes or suspected latent diabetes.
Patients under treatment should be observed regularly for possible occurrence of blood dyscrasias,
liver damage or idiosyncratic reactions, which have been reported occasionally in foreign marketing
experience. The relationship of these occurrences to bumetanide use is not certain.
Drugs with Ototoxic Potential
Especially in the presence of impaired renal function, the use of parenterally administered bumetanide in
patients to whom aminoglycoside antibiotics are also being given should be avoided, except in life-
Drugs with Nephrotoxic Potential
There has been no experience with the concurrent use of bumetanide with drugs known to have a
nephrotoxic potential. Therefore, the simultaneous administration of these drugs should be avoided.
Lithium should generally not be given with diuretics (such as bumetanide) because they reduce its renal
clearance and add a high risk of lithium toxicity.
Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by bumetanide.
This antagonistic effect of probenecid on bumetanide natriuresis is not due to a direct action on sodium
excretion but is probably secondary to its inhibitory effect on renal tubular secretion of bumetanide.
Thus, probenecid should not be administered concurrently with bumetanide.
Indomethacin blunts the increases in urine volume and sodium excretion seen during bumetanide
treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent therapy with
bumetanide is thus not recommended.
Bumetanide may potentiate the effect of various antihypertensive drugs, necessitating a reduction in the
dosage of these drugs.
Interaction studies in humans have shown no effect on digoxin blood levels.
Interaction studies in humans have shown bumetanide to have no effect on warfarin metabolism or on
plasma prothrombin activity.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Bumetanide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested
in the presence or absence of an in vitro metabolic activation system. An 18-month study showed an
increase in mammary adenomas of questionable significance in female rats receiving oral doses of 60
mg/kg/day (2000 times a 2-mg human dose). A repeat study at the same doses failed to duplicate this
Reproduction studies were performed to evaluate general reproductive performance and fertility in rats
at oral dose levels of 10 mg/kg/day, 30 mg/kg/day, 60 mg/kg/day or 100 mg/kg/day. The pregnancy rate
was slightly decreased in the treated animals; however, the differences were small and not statistically
Pregnancy Category C
Bumetanide is neither teratogenic nor embryocidal in mice when given in doses up to 3400 times the
maximum human therapeutic dose.
Bumetanide has been shown to be nonteratogenic, but it has a slight embryocidal effect in rats when
given in doses of 3400 times the maximum human therapeutic dose and in rabbits at doses of 3.4 times
the maximum human therapeutic dose. In one study, moderate growth retardation and increased incidence
of delayed ossification of sternebrae were observed in rats at oral doses of 100 mg/kg/day, 3400 times
the maximum human therapeutic dose. These effects were associated with maternal weight reductions
noted during dosing. No such adverse effects were observed at 30 mg/kg/day (1000 times the maximum
human therapeutic dose). No fetotoxicity was observed at 1000 to 2000 times the human therapeutic
In rabbits, a dose-related decrease in litter size and an increase in resorption rate were noted at oral
doses of 0.1 mg/kg/day and 0.3 mg/kg/day (3.4 and 10 times the maximum human therapeutic dose). A
slightly increased incidence of delayed ossification of sternebrae occurred at 0.3 mg/kg/day; however,
no such adverse effects were observed at the dose of 0.03 mg/kg/day. The sensitivity of the rabbit to
bumetanide parallels the marked pharmacologic and toxicologic effects of the drug in this species.
Bumetanide was not teratogenic in the hamster at an oral dose of 0.5 mg/kg/day (17 times the maximum
human therapeutic dose). Bumetanide was not teratogenic when given intravenously to mice and rats at
doses up to 140 times the maximum human therapeutic dose.
There are no adequate and well-controlled studies in pregnant women. A small investigational
experience in the United States and marketing experience in other countries to date have not indicated
any evidence of adverse effects on the fetus, but these data do not rule out the possibility of harmful
effects. Bumetanide should be given to a pregnant woman only if the potential benefit justifies the
potential risk to the fetus.
It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be
undertaken while the patient is on bumetanide since it may be excreted in human milk.
Safety and effectiveness in pediatric patients below the age of 18 have not been established.
In vitro studies using pooled sera from critically ill neonates have shown bumetanide to be a potent
displacer of bilirubin (see CLINICAL PHARMACOLOGY, Pediatric Pharmacology). The
administration of bumetanide could present a particular concern if given to critically ill or jaundiced
neonates at risk for kernicterus.
Clinical studies of bumetanide did not include sufficient numbers of subjects aged 65 and over to
determine whether they responded differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of
concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal
The most frequent clinical adverse reactions considered probably or possibly related to bumetanide are
muscle cramps (seen in 1.1% of treated patients), dizziness (1.1%), hypotension (0.8%), headache
(0.6%), nausea (0.6%) and encephalopathy (in patients with preexisting liver disease) (0.6%). One or
more of these adverse reactions have been reported in approximately 4.1% of patients treated with
Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported
in association with bumetanide use.
Less frequent clinical adverse reactions to bumetanide are impaired hearing (0.5%), pruritus (0.4%),
electrocardiogram changes (0.4%), weakness (0.2%), hives (0.2%), abdominal pain (0.2%), arthritic
pain (0.2%), musculoskeletal pain (0.2%), rash (0.2%) and vomiting (0.2%). One or more of these
adverse reactions have been reported in approximately 2.9% of patients treated with bumetanide.
Other clinical adverse reactions, which have each occurred in approximately 0.1% of patients, are
vertigo, chest pain, ear discomfort, fatigue, dehydration, sweating, hyperventilation, dry mouth, upset
stomach, renal failure, asterixis, itching, nipple tenderness, diarrhea, premature ejaculation and
difficulty maintaining an erection.
Laboratory abnormalities reported have included hyperuricemia (in 18.4% of patients tested),
hypochloremia (14.9%), hypokalemia (14.7%), azotemia (10.6%), hyponatremia (9.2%), increased serum
creatinine (7.4%), hyperglycemia (6.6%), and variations in phosphorus (4.5%), CO content (4.3%),
bicarbonate (3.1%) and calcium (2.4%). Although manifestations of the pharmacologic action of
bumetanide, these conditions may become more pronounced by intensive therapy.
Also reported have been thrombocytopenia (0.2%) and deviations in hemoglobin (0.8%), prothrombin
time (0.8%), hematocrit (0.6%), WBC (0.3%) and differential counts (0.1%). There have been rare
spontaneous reports of thrombocytopenia from post-marketing experience.
Diuresis induced by bumetanide may also rarely be accompanied by changes in LDH (1.0%), total serum
bilirubin (0.8%), serum proteins (0.7%), SGOT (0.6%), SGPT (0.5%), alkaline phosphatase (0.4%),
cholesterol (0.4%) and creatinine clearance (0.3%). Increases in urinary glucose (0.7%) and urinary
protein (0.3%) have also been seen.
Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration,
reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and
embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia,
lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by
careful monitoring of the urine and electrolyte output and serum electrolyte levels.
DOSAGE AND ADMINISTRATION
Dosage should be individualized with careful monitoring of patient response.
The usual total daily dosage of bumetanide tablets is 0.5 mg to 2 mg and in most patients is given as a
If the diuretic response to an initial dose of bumetanide tablets is not adequate, in view of its rapid onset
and short duration of action, a second or third dose may be given at 4 to 5 hour intervals up to a
maximum daily dose of 10 mg. An intermittent dose schedule, whereby bumetanide tablets is given on
alternate days or for 3 to 4 days with rest periods of 1 to 2 days in between, is recommended as the
safest and most effective method for the continued control of edema. In patients with hepatic failure, the
dosage should be kept to a minimum, and if necessary, dosage increased very carefully.
Because cross-sensitivity with furosemide has rarely been observed, bumetanide tablets can be
substituted at approximately a 1:40 ratio of bumetanide tablets to furosemide in patients allergic to
Bumetanide injection may be administered parenterally (IV or IM) to patients in whom gastrointestinal
absorption may be impaired or in whom oral administration is not practical.
Parenteral treatment should be terminated and oral treatment instituted as soon as possible.
Bumetanide Tablets, USP, for oral administration, are available as
Green, round, biconvex, bisected and debossed “E” above and “128” below the bisect on one side and
plain on the reverse side and supplied as:
NDC 0185-0128-01 bottles of 100
NDC 0185-0128-05 bottles of 500
Yellow, round, biconvex, bisected and debossed “E” above and “129” below the bisect on one side and
plain on the reverse side and supplied as:
NDC 0185-0129-01 bottles of 100
NDC 0185-0129-05 bottles of 500
Beige to light brown, round, biconvex, bisected and debossed “E” above and “130” below the bisect on
one side and plain on the reverse side and supplied as:
NDC 0185-0130-01 bottles of 100
NDC 0185-0130-05 bottles of 500
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant
closure, as required.
KEEP TIGHTLY CLOSED.
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Princeton, NJ 08540
Rev. September 2016
Please reference the How Supplied section listed above for a description of individual tablets. This
drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged
configuration and repackaged in full compliance with all applicable cGMP regulations. The package
configurations available from Aphena are listed below:
Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-
resistant container as defined by USP. Keep this and all drugs out of the reach of children.
Cookeville, TN 38506
PRINCIPAL DISPLAY PANEL - 2mg
NDC 43353-292 Bumetanide 2mg - Rx Only
Product T ype
HUMAN PRESCRIPTION DRUG
Ite m Code (Source )
NDC:43353-29 2(NDC:0 18 5-0 130 )
Route of Administration
Active Ingredient/Active Moiety
Basis of Strength
Stre ng th
BUMETANIDE (UNII: 0 Y2S3XUQ5H) (BUMETANIDE - UNII:0 Y2S3XUQ5H)
Stre ng th
ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)
STARCH, CO RN (UNII: O8 232NY3SJ)
MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )
CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)
FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)
FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)
FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)
TALC (UNII: 7SEV7J4R1U)
Aphena Pharma Solutions - Tennessee, LLC
S hap e
S iz e
Marketing Start Date
Marketing End Date
6 0 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct
0 3/10 /20 17
Marke ting Cate gory
Application Numbe r or Monograph Citation
Marke ting Start Date
Marke ting End Date
ANDA0 7470 0
11/21/19 9 6
Aphena Pharma Solutions - T ennessee, LLC (128385585)
Ad d re s s
Busine ss Ope rations
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