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/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.

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.

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

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.

Pregnancy

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.

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, 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.