epatic 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.

ation 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.

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 sandoz inc. at 1-800-525-8747 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

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.

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/h, 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/min•kg) compared with younger subjects (2.9 ± 0.2 ml/min•kg) 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.