BUMETANIDE
WARNING
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, 0.5 mg
(light green), 1 mg (yellow) and 2 mg (peach) for oral administration; each
tablet also contains lactose, magnesium stearate, microcrystalline cellulose,
corn starch and talc, with the following dye systems: 0.5 mg--D&C Yellow No. 10
and FD&C Blue No. 1; 1 mg--D&C Yellow No. 10; 2 mg--red iron oxide. Also as 2-mL
ampuls, 2-mL vials, 4-mL vials and 10-mL vials (0.25 mg/mL) for intravenous or
intramuscular injection as a sterile solution, each 2 mL of which contains 0.5
mg (0.25 mg/mL) bumetanide compounded with 0.85% sodium chloride and 0.4%
ammonium acetate as buffers; 0.01% edetate disodium; 1% benzyl alcohol as
preservative, and pH adjusted to approximately 7 with sodium hydroxide.
Chemically, bumetanide is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It
is a practically white powder having a calculated molecular weight of 364.41.
ACTIONS/CLINICAL PHARMACOLOGY:
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 (CH2O) during hydration and tubular free-water reabsorption (TCH2O)
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 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
1 1/2 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.
INDICATIONS AND USAGE:
BUMETANIDE is 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 following instances of allergic reactions to
furosemide suggests a lack of cross-sensitivity.
CONTRAINDICATIONS:
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.
WARNINGS:
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.)
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1. 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.
2. Hypokalemia. 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, ie, 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.
3. Ototoxicity. 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.
4. Allergy to sulfonamides. Patients allergic to sulfonamides may show
hypersensitivity to BUMETANIDE.
5. Thrombocytopenia. Since there have been rare spontaneous reports of
thrombocytopenia from postmarketing experience, patients should be observed
regularly for possible occurrence of thrombocytopenia.
PRECAUTIONS:
General: 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
hypocalcemia.
Diuretics have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia. Laboratory Tests: 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.
Drug Interactions:
1. Drugs with ototoxic potential (see WARNINGS): 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-threatening conditions.
2. Drugs with nephrotoxic potential: There has been no experience on the
concurrent use of BUMETANIDE with drugs known to have a nephrotoxic potential.
Therefore, the simultaneous administration of these drugs should be avoided.
3. Lithium: 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.
4. Probenecid: 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.
5. Indomethacin: 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.
6. Antihypertensives: BUMETANIDE may potentiate the effect of various
antihypertensive drugs, necessitating a reduction in the dosage of these drugs.
7. Digoxin: Interaction studies in humans have shown no effect on digoxin blood
levels.
8. Anticoagulants: Interaction studies in humans have shown BUMETANIDE to have no
effect on warfarin metabolism or on plasma prothrombin activity.
Carcinogenesis, Mutagenesis, 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 finding.
Reproduction studies were performed to evaluate general reproductive performance
and fertility in rats at oral dose levels of 10, 30, 60 or 100 mg/kg/day. The
pregnancy rate was slightly decreased in the treated animals; however, the
differences were small and not statistically significant.
Pregnancy: Teratogenic Effects: 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 dose.
In rabbits, a dose-related decrease in litter size and an increase in resorption
rate were noted at oral doses of 0.1 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.
Nursing Mothers: 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.
Pediatric Use: Safety and effectiveness in children below the age of 18 have
not been established.
DRUG INTERACTIONS:
1. Drugs with ototoxic potential (see WARNINGS): 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-threatening conditions.
2. Drugs with nephrotoxic potential: There has been no experience on the
concurrent use of BUMETANIDE with drugs known to have a nephrotoxic potential.
Therefore, the simultaneous administration of these drugs should be avoided.
3. Lithium: 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.
4. Probenecid: 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.
5. Indomethacin: 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.
6. Antihypertensives: BUMETANIDE may potentiate the effect of various
antihypertensive drugs, necessitating a reduction in the dosage of these drugs.
7. Digoxin: Interaction studies in humans have shown no effect on digoxin blood
levels.
8. Anticoagulants: Interaction studies in humans have shown BUMETANIDE to have no
effect on warfarin metabolism or on plasma prothrombin activity.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
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 BUMETANIDE-treated
patients.
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 BUMETANIDE-treated patients.
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%), CO2 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
postmarketing 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:
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.
Oral Administration: The usual total daily dosage of BUMETANIDE is 0.5 to 2 mg and
in most patients is given as a single dose.
If the diuretic response to an initial dose of BUMETANIDE 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 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 can be
substituted at approximately a 1:40 ratio of BUMETANIDE to furosemide in patients
allergic to furosemide.
Parenteral Administration: BUMETANIDE 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.
The usual initial dose is 0.5 to 1mg intravenously or intramuscularly.
Intravenous administration should be given over a period of 1 to 2 minutes. If
the response to an initial dose is deemed insufficient, a second or third dose
may be given at intervals of 2 to 3 hours, but should not exceed a daily dosage
of 10 mg.
Miscibility And Parenteral Solutions: The compatibility tests of BUMETANIDE
injection (0.25 mg/mL, 2-mL ampuls) with 5% dextrose in water, 0.9% sodium
chloride, and lactated Ringer's solution in both glass and plasticized PVC
(Viaflex) containers have shown no significant absorption effect with either
container, nor a measurable loss of potency due to degradation of the drug.
However, solutions should be freshly prepared and used within 24 hours.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
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