Bumetanide (Bumetanide) is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required, and dose and dosage schedule have to be adjusted to the individual patient’s needs. (See )

Bumetanide (Bumetanide) is a loop diuretic, available as scored tablets, 0.5 mg (light green), 1 mg (yellow) and 2 mg (peach) for oral administration; each tablet also contains: anhydrous lactose, magnesium stearate, microcrystalline cellulose, corn starch and talc, with the following colorants: 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 (Ferric oxide red).

Chemically, Bumetanide (Bumetanide) is 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoic acid. It is a practically white powder. It is slightly soluble in water and soluble in alkaline solutions. It has the following structural formula:

Bumetanide (Bumetanide) is a loop diuretic with a rapid onset and short duration of action. Pharmacological and clinical studies have shown that 1 mg Bumetanide (Bumetanide) has a diuretic potency equivalent to approximately 40 mg furosemide. The major site of Bumetanide (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 (Bumetanide) inhibits sodium reabsorption in the ascending limb of the loop of Henle, as shown by marked reduction of free-water clearance (HO) during hydration and tubular free-water reabsorption (THO) during hydropenia. Reabsorption of chloride in the ascending limb is also blocked by Bumetanide (Bumetanide) , and Bumetanide (Bumetanide) is somewhat more chloruretic than natriuretic.

Potassium excretion is also increased by Bumetanide (Bumetanide) , in a dose-related fashion.

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

Bumetanide (Bumetanide) decreases uric acid excretion and increases serum uric acid. Following oral administration of Bumetanide (Bumetanide) the onset of diuresis occurs in 30 to 60 minutes. Peak activity is reached between 1 and 2 hours. At usual doses (1 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 (Bumetanide) , administered orally or parenterally, is eliminated rapidly in humans, with a half-life of between 1 and 1 1/2 hours. Plasma protein-binding is in the range of 94% to 96%.

Oral administration of carbon-14 labeled Bumetanide (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 (Bumetanide) amounted to only 2% of the administered dose.

Bumetanide (Bumetanide) 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 (Bumetanide) . Therefore, if impaired gastrointestinal absorption is suspected or oral administration is not practical, Bumetanide (Bumetanide) should be given by the intramuscular or intravenous route.

Successful treatment with Bumetanide (Bumetanide) following instances of allergic reactions to furosemide suggests a lack of cross-sensitivity.

Bumetanide (Bumetanide) is contraindicated in anuria. Although Bumetanide (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) . 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 (Bumetanide) is contraindicated in patients hypersensitive to this drug.

Hypokalemia can occur as a consequence of Bumetanide (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.

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 (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.

Studies in normal subjects receiving Bumetanide (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 (Bumetanide) use is not certain.

Drugs With Ototoxic Potential (see )

Especially in the presence of impaired renal function, the use of parenterally administered Bumetanide (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 (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 (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 (Bumetanide) . This antagonistic effect of probenecid on Bumetanide (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 (Bumetanide) . Thus, probenecid should not be administered concurrently with Bumetanide (Bumetanide) .

Indomethacin

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

Antihypertensives

Bumetanide (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 (Bumetanide) to have no effect on warfarin metabolism or on plasma prothrombin activity.

Safety and effectiveness in pediatric patients below the age of 18 have not been established.

Clinical studies of Bumetanide (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.

The most frequent clinical adverse reactions considered probably or possibly related to Bumetanide (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 Bumetanide (Bumetanide) -treated patients.

Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in association with Bumetanide (Bumetanide) use.

Less frequent clinical adverse reactions to Bumetanide (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 (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%), C0 content (4.3%), bicarbonate (3.1%) and calcium (2.4%). Although manifestations of the pharmacologic action of Bumetanide (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 (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 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.

Dosage should be individualized with careful monitoring of patient response.

The usual total daily dosage of Bumetanide (Bumetanide) is 0.5 to 2 mg and in most patients is given as a single dose.

If the diuretic response to an initial dose of Bumetanide (Bumetanide) 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 (Bumetanide) 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 (Bumetanide) can be substituted at approximately a 1:40 ratio of Bumetanide (Bumetanide) to furosemide in patients allergic to furosemide.

Bumetanide (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.

Bumetanide (Bumetanide) Tablets USP are available as light green, flat, round, bevel-edged tablets, debossed “0.5” on one side and bisected on the other side with company logo on the upper half and “4232” on the lower, containing 0.5 mg Bumetanide (Bumetanide) , USP packaged in bottles of 100 tablets.

Bumetanide (Bumetanide) Tablets USP are available as yellow, flat, round, bevel-edged tablets, debossed “1” on one side and bisected on the other side with company logo on the upper half and “4233” on the lower, containing 1 mg Bumetanide (Bumetanide) , USP packaged in bottles of 100 and 1000 tablets.

Bumetanide (Bumetanide) Tablets USP are available as peach, flat, round, bevel-edged tablets, debossed “2” on one side and bisected on the other side with company logo on the upper half and “4234” on the lower, containing 2 mg Bumetanide (Bumetanide) , USP packaged in bottles of 100 and 1000 tablets.

PHARMACIST: Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Manufactured In India By:

EMCURE PHARMACEUTICALS LTD.

Hinjwadi, Pune, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. A 3/2010

Bumetanide (Bumetanide) Tablets USP
0.5 mg

Each tablet contains: Bumetanide (Bumetanide) , USP 0.5 mg

Rx only

100 TABLETS

TEVA

Bumetanide (Bumetanide) Tablets USP
1 mg

Each tablet contains: Bumetanide (Bumetanide) , USP 1 mg

Rx only

100 TABLETS

TEVA

Bumetanide (Bumetanide) Tablets USP
2 mg

Each tablet contains: Bumetanide (Bumetanide) , USP 2 mg

Rx only

100 TABLETS

TEVA