Bumetanide tablet

Boxed warning section

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 is a loop diuretic, available as scored tablets. 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:

figure 1

Clinical pharmacology

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.

Contraindications

Bumetanide is contraindicated in anuria. Although bumetanide tablets 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 tablets. 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

Precautions

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.

Drug interactions section

Carcinogenesis, Mutagenesis and Impairment of Fertility

Bumetanide was devoid of mutagenic activity in various strains of Salmonella typhimuriumwhen tested in the presence or absence of an in vitrometabolic 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 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 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 vitrostudies 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%), COcontent (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%), 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 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

Geriatric use section

Individualize dosage with careful monitoring of patient response.

How supplied

Bumetanide Tablets USP, 0.5 mg are light green, round, biconvex, uncoated tablet debossed with '525' on one side separating '5' & '25' with breakline and plain on the other side and are supplied as follows:

NDC 68382-525-06 in bottles of 30 tablets

NDC 68382-525-16 in bottles of 90 tablets

NDC 68382-525-01 in bottles of 100 tablets

NDC 68382-525-05 in bottles of 500 tablets

NDC 68382-525-10 in bottles of 1000 tablets

Bumetanide Tablets USP, 1 mg are light yellow, round, biconvex, uncoated tablet debossed with '526' on one side separating '5' & '26' with breakline and plain on the other side and are supplied as follows:

NDC 68382-526-06 in bottles of 30 tablets

NDC 68382-526-16 in bottles of 90 tablets

NDC 68382-526-01 in bottles of 100 tablets

NDC 68382-526-05 in bottles of 500 tablets

NDC 68382-526-10 in bottles of 1000 tablets

Bumetanide Tablets USP, 2 mg are light orange, round, biconvex, uncoated tablet debossed with '527' on one side separating '5' & '27' with breakline and plain on the other side and are supplied as follows:

NDC 68382-527-06 in bottles of 30 tablets

NDC 68382-527-16 in bottles of 90 tablets

NDC 68382-527-01 in bottles of 100 tablets

NDC 68382-527-05 in bottles of 500 tablets

NDC 68382-527-10 in bottles of 1000 tablets

Storage

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

Dispense in a tight, light-resistant container (USP).

Manufactured by:

Cadila Healthcare Ltd.

Baddi, India

Distributed by:

Zydus Pharmaceuticals( USA) Inc.

Pennington, NJ 08534

Rev.: 05/19

Ingredients and appearance - Product information

Bumetanide tablet- Bumetanide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68382-525
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Bumetanide ( UNII: 0Y2S3XUQ5H)( Bumetanide - UNII: 0Y2S3XUQ5H ) 0.5 mgin 1

Inactive Ingredients

Ingredient Name Code
D&c yellow no. 10 ( UNII: 35SW5USQ3G)
Fd&c blue no. 1 ( UNII: H3R47K3TBD)
Ferrosoferric oxide ( UNII: XM0M87F357)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Povidone k30 ( UNII: U725QWY32X)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Starch, corn ( UNII: O8232NY3SJ)
Talc ( UNII: 7SEV7J4R1U)

Product Characteristics

Color GREEN (light green) Shape ROUND
Size 6 mm Score 2
Imprint Code 5;25

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA202900 USA

Bumetanide tablet- Bumetanide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68382-526
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Bumetanide ( UNII: 0Y2S3XUQ5H)( Bumetanide - UNII: 0Y2S3XUQ5H ) 1 mgin 1

Inactive Ingredients

Ingredient Name Code
D&c yellow no. 10 ( UNII: 35SW5USQ3G)
Ferric oxide red ( UNII: 1K09F3G675)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Povidone k30 ( UNII: U725QWY32X)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Starch, corn ( UNII: O8232NY3SJ)
Talc ( UNII: 7SEV7J4R1U)

Product Characteristics

Color YELLOW (light yellow) Shape ROUND
Size 8 mm Score 2
Imprint Code 5;26

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA202900 USA

Bumetanide tablet- Bumetanide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68382-527
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Bumetanide ( UNII: 0Y2S3XUQ5H)( Bumetanide - UNII: 0Y2S3XUQ5H ) 2 mgin 1

Inactive Ingredients

Ingredient Name Code
D&c yellow no. 10 ( UNII: 35SW5USQ3G)
Ferric oxide red ( UNII: 1K09F3G675)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Povidone k30 ( UNII: U725QWY32X)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Starch, corn ( UNII: O8232NY3SJ)
Talc ( UNII: 7SEV7J4R1U)

Product Characteristics

Color ORANGE (light orange) Shape ROUND
Size 10 mm Score 2
Imprint Code 5;27

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA202900 USA

Labeler - Zydus Pharmaceuticals (USA) Inc.( 156861945)

Establishment

Name ID/FEI Business Operations
Zydus Pharmaceuticals (USA) Inc. 156861945 ANALYSIS( 68382-525, 68382-526, 68382-527), MANUFACTURE( 68382-525, 68382-526, 68382-527)

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