BUMETANIDE tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
BUMETANIDE (UNII: 0Y2S3XUQ5H) (BUMETANIDE - UNII:0Y2S3XUQ5H)
Available from:
NCS HealthCare of KY, LLC dba Vangard Labs
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Bumetanide tablets 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 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 cond
Product summary:
Bumetanide Tablets USP are available as green, round, flat-faced, beveled edge, plain on one side and debossed with " 700" on other side, containing 0.5 mg bumetanide, USP. Bumetanide Tablets USP are available as yellow, round, flat-faced, beveled edge, plain on one side and debossed with" 701" on other side, containing 1 mg bumetanide, USP packaged in blistercards of 30 tablets (NDC 0615-8361-39). Bumetanide Tablets USP are available as peach, round, flat-faced, beveled edge, plain on one side and debossed with " 702" on other side, containing 2 mg bumetanide, USP packaged in blistercards of 30 tablets (NDC 0615-8362-39). Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Manufactured by: Centaur Pharmaceuticals Pvt. Ltd. Hinjewadi, Pune-411057, India. Manufactured for: Heritage Pharma Labs Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Iss. 05/19
Authorization status:
Abbreviated New Drug Application
Authorization number:
0615-8361-39, 0615-8362-39

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BUMETANIDE- bumetanide tablet

NCS HealthCare of KY, LLC dba Vangard Labs

----------

Rx only

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).

DESCRIPTION

Bumetanide Tablets USP are a loop diuretic available as 0.5 mg (green), 1 mg (yellow)

and 2 mg (peach) tablets for oral administration; each tablet also contains: anhydrous

lactose, corn starch, magnesium stearate, microcrystalline cellulose and talc, with the

following colorants: 0.5 mg (D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1

Aluminum Lake); 1 mg (D&C Yellow No. 10 Aluminum Lake); 2 mg (Ferric oxide red).

Chemically, bumetanide, USP is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is

a practically white powder. It is slightly soluble in water and soluble in alkaline solutions. It

has the following structural formula:

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 (CH 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.

Pediatric Pharmacology

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 2.2 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

mcg/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.

Geriatric Pharmacology

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 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 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

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

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.

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.

Allergy to Sulfonamides

Patients allergic to sulfonamides may show hypersensitivity to bumetanide.

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

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.

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

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.

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.

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.

Antihypertensives

Bumetanide may potentiate the effect of various antihypertensive drugs, necessitating a

reduction in the dosage of these drugs.

Digoxin

Interaction studies in humans have shown no effect on digoxin blood levels.

Anticoagulants

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 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

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 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.

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 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.

Geriatric Use

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 function.

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 patients treated with bumetanide.

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 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.

To report SUSPECTED ADVERSE REACTIONS, contact Heritage

Pharmaceuticals at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

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

Individualize dosage with careful monitoring of patient response.

Oral Administration

The usual total daily dosage of bumetanide tablets is 0.5 mg to 2 mg and in most

patients is given as a single dose.

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 are 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,

keep the dosage to a minimum.

Because cross-sensitivity with furosemide has rarely been observed, bumetanide can be

substituted at approximately a 1:40 ratio of bumetanide in proportion to furosemide in

patients allergic to furosemide.

Parenteral Administration

Bumetanide injection may be administered parenterally (intravenously and

intramuscularly) to patients in whom gastrointestinal absorption may be impaired or in

whom oral administration is not practical.

Terminate parenteral treatment and institute oral treatment as soon as possible.

HOW SUPPLIED

Bumetanide Tablets USP are available as green, round, flat-faced, beveled edge, plain on

one side and debossed with " 700" on other side, containing 0.5 mg bumetanide, USP.

Bumetanide Tablets USP are available as yellow, round, flat-faced, beveled edge, plain on

one side and debossed with" 701" on other side, containing 1 mg bumetanide, USP

packaged in blistercards of 30 tablets (NDC 0615-8361-39).

Bumetanide Tablets USP are available as peach, round, flat-faced, beveled edge, plain on

one side and debossed with " 702" on other side, containing 2 mg bumetanide, USP

packaged in blistercards of 30 tablets (NDC 0615-8362-39).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant

closure (as required).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Manufactured by:

Centaur Pharmaceuticals Pvt. Ltd.

Hinjewadi, Pune-411057, India.

Manufactured for:

Heritage Pharma Labs Inc.

East Brunswick, NJ 08816

1.866.901.DRUG (3784)

Iss. 05/19

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 1 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 2 mg

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