Bumetanide

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.

DOSAGE AND ADMINISTRATION Dosage should be individualized 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 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 furosemide. Parenteral Administration 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.

CONTRAINDICATIONS Bumetanide tablets are 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 tablets are also contraindicated in patients in hepatic coma or in states of severe electrolyte depletion until the condition is improved or corrected. Bumetanide tablets are contraindicated in patients hypersensitive to this drug.

ADVERSE REACTIONS The most frequent clinical adverse reactions considered probably or possibly related to bumetanide tablets 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 pre-existing liver disease) (0.6%). One or more of these adverse reactions have been reported in approximately 4.1% of patients treated with bumetanide tablets. 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 tablets 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 tablets. 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 tablets, 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 tablets 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 First Nation Group, LLC at 1-855-221-5332 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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.

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: Each bumetanide tablet intended for oral administration contains 0.5 mg, 1 mg or 2 mg of bumetanide. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone and talc. In addition, each 0.5 mg tablet contains D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake and ferric oxide black; each 1 mg tablet contains D&C Yellow No. 10 aluminum lake and ferric oxide red; each 2 mg tablet contains mg D&C Yellow No. 10 aluminum lake and ferric oxide red. Bumetanide tablet meets USP Dissolution Test 2. figure 1

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.

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 with child-resistance closure NDC 68382-525-16 in bottles of 90 tablets with child-resistance closure 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 with child-resistance closure NDC 68382-526-16 in bottles of 90 tablets with child-resistance closure 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 with child-resistance closure NDC 68382-527-16 in bottles of 90 tablets with child-resistance closure 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 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP). Manufactured by: Zydus Lifesciences Ltd., Baddi, India Distributed by: Zydus Pharmaceuticals ( USA) Inc. Pennington, NJ 08534 Rev.: 01/23