Bumetanide

INDICATIONS AND USAGE Bumetanide injection, USP 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 injection, USP following instances of allergic reactions to furosemide suggests a lack of cross-sensitivity.

DOSAGE AND ADMINISTRATION Dosage should be individualized with careful monitoring of patient response. 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. The usual initial dose is 0.5 mg to 1 mg 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, USP (0.25 mg/mL) with 5% Dextrose Injection in Water, 0.9% Sodium Chloride Injection, and Lactated Ringer's Injection in both glass and plasticized PVC (Viaflex) containers have shown no significant absorption effect with either containers, 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.

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.

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. 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 2 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 Aspiro Pharma Limited at 1-866-495-1995, or the 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.

DESCRIPTION Bumetanide is a loop diuretic, available as 4 mL vials and 10 mL vials (0.25 mg/mL) for intravenous or intramuscular injection as a sterile solution. Each mL contains bumetanide USP 0.25 mg, sodium chloride 8.5 mg and ammonium acetate 4 mg as buffers, edetate disodium 0.1 mg and benzyl alcohol 10 mg as preservative in Water for Injection. pH adjusted to 6.8 to 7.8 with sodium hydroxide. Chemically, bumetanide USP is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is a white crystalline powder having a molecular weight of 364.42, soluble in alkaline solutions, acetone, methanol and ethanol (96%), slightly soluble in chloroform and very slightly soluble in water and hexane, and the following structural formula: chemicalstructure

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 INJECTION, USP is supplied in the following dosage forms. NDC 51662-1449-1 BUMETANIDE INJECTION, USP 1mg/4mL (0.25 mg/mL) 4mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Bumetanide Injection, USP, 0.25 mg/mL is a sterile, clear, colorless to slightly yellow solution supplied in amber vials as follows: 4 mL Single Dose Vial packaged in 10s (NDC 0641-6008-10) 10 mL Multiple Dose Vial packaged in 10s (NDC 0641-6007-10) This product, including the packaging components, is free of latex. Storage Store at 20° - 25°C (68° - 77°F), excursions permitted to 15° - 30° C (59° – 86°F) [See USP Controlled Room Temperature]. Protect from light. To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Product Inquiry call 1-877-845-0689. Manufactured by: WEST-WARD PHARMACEUTICALS Eatontown, NJ 07724 USA Revised June 2011 462-485-01 LOGO