Bumex ®(bumetanide) is a loop diuretic available as 0.5 mg (light green), 1 mg (yellow) and 2 mg (peach) tablets for oral administration; each tablet also contains anhydrous lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch and talc, with the following dye systems: 0.5 mg—D&C Yellow No. 10 aluminum lake and FD&C Blue No. 1 aluminum lake; 1 mg—D&C Yellow No. 10 aluminum lake; 2 mg—red iron oxide.

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:

FDA-approved impurity specifications differ from the USP.

Bumex – Clinical Pharmacology

Bumex is a loop diuretic with a rapid onset and short duration of action. Pharmacological and clinical studies have shown that 1 mg Bumex has a diuretic potency equivalent to approximately 40 mg furosemide. The major site of Bumex action is the ascending limb of the loop of Henle.

The mode of action has been determined through various clearance studies in both humans and experimental animals. Bumex inhibits sodium reabsorption in the ascending limb of the loop of Henle, as shown by marked reduction of free-water clearance (CH 2O) during hydration and tubular free-water reabsorption (T CH 2O) during hydropenia. Reabsorption of chloride in the ascending limb is also blocked by Bumex, and Bumex is somewhat more chloruretic than natriuretic.

Potassium excretion is also increased by Bumex, in a dose-related fashion.

Bumex may have an additional action in the proximal tubule. Since phosphate reabsorption takes place largely in the proximal tubule, phosphaturia during Bumex induced diuresis is indicative of this additional action. This is further supported by the reduction in the renal clearance of Bumex 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. Bumex does not appear to have a noticeable action on the distal tubule.

Bumex decreases uric acid excretion and increases serum uric acid. Following oral administration of Bumex 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 Bumex 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 Bumex 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 μg/L at 1 hour to 57 μg/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 μg/mL to 50 μg/mL, but not 0.25 μg/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 μg/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.

Indications and Usage for Bumex

Bumex tablets 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 Bumex tablets following instances of allergic reactions to furosemide suggests a lack of cross-sensitivity.

Contraindications

Bumex is contraindicated in anuria. Although Bumex 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 Bumex. Bumex is also contraindicated in patients in hepatic coma or in states of severe electrolyte depletion until the condition is improved or corrected. Bumex is contraindicated in patients hypersensitive to this drug.

Warnings

Volume and Electrolyte Depletion

The dose of Bumex 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 Bumex 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 Bumex.

Thrombocytopenia

Since there have been rare spontaneous reports of thrombocytopenia from postmarketing experience, patients should be observed regularly for possible occurrence of thrombocytopenia.

Precautions

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. Bumex 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 Bumex 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 Bumex use is not certain.

Drug Interactions

Drugs with Ototoxic Potential 

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 Bumex 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 Bumex) 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 Bumex. This antagonistic effect of probenecid on Bumex 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 Bumex.

Indomethacin

Indomethacin blunts the increases in urine volume and sodium excretion seen during Bumex treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent therapy with Bumex is thus not recommended.

Antihypertensives

Bumex 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 Bumex to have no effect on warfarin metabolism or on plasma prothrombin activity.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Bumex was devoid of mutagenic activity in various strains of Salmonella typhimurium when 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, 30, 60 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

Bumex is neither teratogenic nor embryocidal in mice when given in doses up to 3400 times the maximum human therapeutic dose.

Bumex 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 Bumex parallels the marked pharmacologic and toxicologic effects of the drug in this species.

Bumex 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 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. Bumex 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 Bumex 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 . 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 Bumex 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/Side Effects

The most frequent clinical adverse reactions considered probably or possibly related to Bumex 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 Bumex.

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 Bumex 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 Bumex.

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 Bumex, 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 Bumex 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.

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.

Bumex Dosage and Administration

Individualize dosage with careful monitoring of patient response.

Oral Administration

The usual total daily dosage of Bumex 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 Bumex 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 Bumex tablets are 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.

How is Bumex supplied

Bumex Tablets for oral administration are elliptical, flat-faced, and bevel-edged, available as:

Store at 68° to 77°F (20° to 25°C); excursions permitted between 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature].

Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.

Manufactured for andDistributed by:
Validus Pharmaceuticals LLC
Parsippany, NJ 07054
info@validuspharma.com
www.validuspharma.com
1-866-982-5438

Product of Italy

© 2023 Validus Pharmaceuticals LLC

60018-05 November 2023

PRINCIPAL DISPLAY PANEL

NDC 30698-630-01
Bumex ®
(bumetanide) Tablets
0.5 mg
100 Tablets
Rx Only

PRINCIPAL DISPLAY PANEL

NDC 30698-631-01
Bumex ®
(bumetanide) Tablets
1 mg
100 Tablets
Rx Only

NDC 30698-631-05
Bumex ®
(bumetanide) Tablets
1 mg
500 Tablets
Rx Only

PRINCIPAL DISPLAY PANEL

NDC 30698-632-01
Bumex ®
(bumetanide) Tablets
2 mg
100 Tablets
Rx Only

NDC 30698-632-05
Bumex ®
(bumetanide) Tablets
2 mg
500 Tablets
Rx Only

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 0.25 mg bumetanide compounded with 0.85% sodium chloride and 0.4% ammonium acetate as buffers; 0.01% edetate disodium; 1% benzyl alcohol as preservative in water for injection and pH adjusted to 6.8 to 7.8 with sodium hydroxide.

Chemically, bumetanide is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is a practically white or almost white, crystalline powder having a calculated molecular weight of 364.42, and the following structural formula:

Bumetanide – Clinical Pharmacology

Bumetanide is a loop diuretic with a rapid onset and short duration of action. Pharmacological and clinical studies have shown that 1 mg bumetanide has a diuretic potency equivalent to approximately 40 mg furosemide. The major site of bumetanide action is the ascending limb of the loop of Henle.

The mode of action has been determined through various clearance studies in both humans and experimental animals. Bumetanide inhibits sodium reabsorption in the ascending limb of the loop of Henle, as shown by marked reduction of free-water clearance (CH2O) during hydration and tubular free-water reabsorption (TcH2O) during hydropenia. Reabsorption of chloride in the ascending limb is also blocked by bumetanide, and bumetanide is somewhat more chloruretic than natriuretic.

Potassium excretion is also increased by bumetanide, in a dose-related fashion.

Bumetanide may have an additional action in the proximal tubule. Since phosphate reabsorption takes place largely in 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. 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 to 1.1 mL/min/kg. In a population of neonates receiving bumetanide for volume overload, mean serum clearance rates were 2.17 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 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 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.

Indications and Usage for Bumetanide

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.

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.

Warnings

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.

Precautions

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

Drugs with Ototoxic Potential

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, 30, 60 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 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 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.

Adverse Reactions/Side Effects

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%), CO2 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.

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.

Bumetanide 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 with 5% dextrose in water, 0.9% sodium chloride and lactated Ringer’s solution 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.

How is Bumetanide supplied

Bumetanide Injection USP, 0.25 mg/mL is a sterile, clear, colorless to slightly yellow solution free from visible particulate matter supplied in amber vials as follows:

4 mL Single Dose Vial packaged in 10s (NDC 70748-323-10)

Discard unused portion.

10 mL Multiple Dose Vial packaged in 10s (NDC 70748-323-11)

This container closure is not made with natural rubber latex.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30° C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light.

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Naples, FL 34108

United States

Manufactured by:

Lupin Limited

Nagpur – 441108

India

Revised: November 2024 #ID: 278600

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Bumetanide Injection, USP

1 mg/4 mL (0.25 mg/mL)

4 mL Single Dose Vial

NDC 70748-323-01

Bumetanide Injection, USP

1 mg/4 mL (0.25 mg/mL)

10 x 4 mL Single Dose Vials

NDC 70748-323-10

Bumetanide Injection, USP

2.5 mg/10 mL (0.25 mg/mL)

10 mL Multiple Dose Vial

NDC 70748-323-02

Bumetanide Injection, USP

2.5 mg/10 mL (0.25 mg/mL)

10 x 10 mL Multiple Dose Vials

NDC 70748-323-11

Bisoprolol is a beta-blocker that affects the heart and circulation (blood flow through arteries and veins).

Bisoprolol is used to treat hypertension (high blood pressure).

Bisoprolol may also be used for purposes not listed in this medication guide.

Warnings

Do not skip doses or stop taking bisoprolol without first talking to your doctor. Stopping suddenly may make your condition worse or cause other serious heart problems.

If you need to have any type of surgery, tell the surgeon ahead of time that you are using this medicine.

You should not use bisoprolol if you have a serious heart condition such as “AV block,” severe heart failure, or slow heartbeats that have caused you to faint.

Keep using bisoprolol as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Before taking this medicine

You should not use bisoprolol if you you are allergic to it, or if you have a serious heart condition such as:

• “AV block”;
• severe heart failure; or
• slow heartbeats that have caused you to faint.

To make sure bisoprolol is safe for you, tell your doctor if you have:

• congestive heart failure or other heart problems;
• coronary artery disease;
• circulation problems (such as Peripheral Vascular Disease or Raynaud’s syndrome);
• asthma, chronic obstructive pulmonary disease (COPD), or other breathing disorder;
• diabetes (taking bisoprolol can make it harder for you to tell when you have low blood sugar);
• liver or kidney disease;
• a thyroid disorder; or
• a history of allergies.

It is not known whether bisoprolol is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether bisoprolol passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Bisoprolol is not approved for use by anyone younger than 18 years old.

How should I take bisoprolol?

Take bisoprolol exactly as it was prescribed for you. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Do not skip doses or stop taking bisoprolol without first talking to your doctor. Stopping suddenly may make your condition worse or cause other serious heart problems.

If you need surgery, tell the surgeon ahead of time that you are using bisoprolol.

Your blood pressure will need to be checked often.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store bisoprolol at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What to avoid

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Minimize drinking alcohol. It can increase some of the side effects of bisoprolol.

Bisoprolol side effects

Get emergency medical help if you have signs of an allergic reaction to bisoprolol: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• shortness of breath (even with mild exertion), swelling, rapid weight gain;
• slow heart rate;
• pounding heartbeats or fluttering in your chest;
• numbness, tingling, or cold feeling in your hands or feet;
• a light-headed feeling, like you might pass out;
• eye pain, vision problems; or
• bronchospasm (wheezing, chest tightness, trouble breathing).

Common bisoprolol side effects may include:

• headache;
• feeling tired;
• sleep problems (insomnia);
• joint pain;
• swelling; or
• cold symptoms such as stuffy nose, runny nose, cough, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

What other drugs will affect bisoprolol?

Tell your doctor about all your current medicines and any you start or stop using, especially:

• insulin or oral diabetes medicine;
• rifampin; or
• heart or blood pressure medicine–clonidine, digitalis, digoxin, diltiazem, reserpine, or verapamil.

Benazepril is used alone or in combination with other medications to treat high blood pressure in adults and children at least 6 years old.

Lowering blood pressure may lower your risk of a stroke or heart attack.

Benazepril may also be used for purposes not listed in this medication guide.

Benazepril side effects

Get emergency medical help if you have signs of an allergic reaction: hives, severe stomach pain, difficulty breathing, swelling of your face, lips, tongue, or throat.

Benazepril may cause serious side effects. Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;
• kidney problems–swelling, urinating less, feeling tired or short of breath;
• high blood potassium–nausea, weakness, tingly feeling, chest pain, irregular heartbeats, loss of movement; or
• liver problems–loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects of benazepril may include:

• headache; or
• cough.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Warnings

Do not use if you are pregnant. Stop using benazepril and tell your doctor right away if you become pregnant.

Tell your doctor about all your other medicines. Some drugs should not be used with benazepril.

Before taking this medicine

You should not use benazepril if you are allergic to it or to any other ACE (angiotensin converting enzyme) inhibitor such as captopril, fosinopril, enalapril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

Do not take benazepril within 36 hours before or after taking medicine that contains sacubitril (such as Entresto).

If you have diabetes, do not use benazepril together with any medication that contains aliskiren (a blood pressure medicine).

Do not take benazepril if you have a history of angioedema (severe allergic reaction).

Tell your doctor if you have ever had:

• heart disease, heart problems such as a recent heart attack;
• stomach pain;
• low blood pressure;
• if you are on a low-salt diet;
• diabetes;
• liver disease; or
• kidney disease (or if you are on dialysis).

You may also need to avoid taking benazepril with aliskiren if you have kidney disease.

Stop using this medicine and tell your doctor right away if you become pregnant. Benazepril can cause injury or death to the unborn baby if you use the medicine during your second or third trimester.

Do not breastfeed.

How should I take benazepril?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

You may take benazepril with or without food.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking benazepril. This can lead to very low blood pressure, an electrolyte imbalance, or kidney failure.

Your blood pressure will need to be checked often and you may need frequent blood tests. Your treatment may also include diet, exercise, lifestyle changes, and other medications. Follow your doctor’s instructions very carefully.

Tell your doctor if you have a planned surgery.

Keep using benazepril even if you feel well. High blood pressure often has no symptoms.

Store tightly closed at room temperature, away from moisture and heat.

Benazepril dosing information

Usual Adult Dose for Hypertension:

Initial dose: With a diuretic: 5 mg orally once a day; without a diuretic: 10 mg orally once a day
Maintenance dose: 20 to 40 mg/day orally as a single dose or in two equally divided doses
Maximum dose: 80 mg/day

Comments:
-The divided dose regimen was more effective in controlling pre-dosing blood pressure.
-If discontinuing a diuretic prior to initiating this drug to reduce the likelihood of hypotension, conclude diuretic therapy 2 to 3 days prior to starting this drug.

Usual Pediatric Dose for Hypertension:

6 YEARS OR OLDER:
Initial dose: 0.2 mg/kg orally once a day as monotherapy
Maximum dose: 0.6 mg/kg; 40 mg/day

Comments:
-Doses between 0.1 and 0.6 mg/kg once a day have been studied; doses greater than 0.1 mg/kg were shown to reduce blood pressure; doses above 0.6 mg/kg or 40 mg/day have not been studied in pediatric patients.
-Prepare a suspension for pediatric patients who cannot swallow tablets or for whom the calculated dosage does not correspond to available tablet strengths.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line .

What should I avoid while taking benazepril?

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Do not take potassium supplements or use salt substitutes, unless your doctor has told you to.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids. Follow your doctor’s instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

What other drugs will affect benazepril?

Benazepril can harm your kidneys, especially if you also use certain medicines for infections, cancer, or osteoporosis.

Tell your doctor about all your other medicines, especially:

• a diuretic or “water pill” that may increase blood potassium such as spironolactone, triamterene, or amiloride;
• NSAIDs (nonsteroidal anti-inflammatory drugs)–aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;
• insulin or diabetes medications;
• medicine to prevent organ transplant rejection such as temsirolimus, sirolimus, or everolimus; or
• heart or blood pressure medication.