Bumetanide

ENBUMYST is indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease, including the nephrotic syndrome in adults. ENBUMYST is a loop diuretic indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease, including nephrotic syndrome in adults. ( 1 )

Nasal spray: 0.5 mg bumetanide per 0.1 mL spray in a unit-dose nasal spray. Nasal spray: 0.5 mg bumetanide per 0.1 mL spray

Bumetanide is contraindicated in: Patients with anuria. Patients in hepatic coma. Patients with a history of a hypersensitivity reaction to bumetanide. Reactions have included anaphylaxis and anaphylactoid reactions. Anuria. ( 4 ) Hepatic coma. ( 4 ) History of hypersensitivity to bumetanide. ( 4 )

Fluid, Electrolyte, and Metabolic Abnormalities: Monitor serum electrolytes, CO 2 , BUN, creatinine, glucose and uric acid. ( 5.1 ) Worsening Renal Function: Monitor for dehydration and azotemia. ( 5.2 ) Ototoxicity: Avoid higher than recommended doses. ( 5.3 ) Potential Altered Absorption in Patients with Nasal Mucosal or Structural Abnormalities: Avoid use in patients with significant nasal mucosal or structural abnormalities, such as acute episodes of rhinitis or congestion due to any cause. ( 5.4 )

5.1 Fluid, Electrolyte, and Metabolic Abnormalities Bumetanide may cause fluid, electrolyte, and metabolic abnormalities such as hypovolemia, hypokalemia, azotemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypocalcemia, hyperglycemia, or hyperuricemia, particularly in patients receiving higher doses, patients with inadequate oral electrolyte intake, and in elderly patients. Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients. Serum electrolytes, CO2, BUN, creatinine, glucose, and uric acid should be monitored frequently during bumetanide therapy.

5.2 Worsening Renal Function Bumetanide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, discontinue bumetanide [see Clinical Pharmacology (12.3) ].

5.3 Ototoxicity Tinnitus and hearing loss (usually reversible) have been reported with loop diuretics, including bumetanide. Reports indicate that ototoxicity is associated with rapid injection, severe renal impairment, the use of higher than recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs.

5.4 Potential Altered Absorption in Patients with Nasal Mucosal or Structural Abnormalities ENBUMYST has not been assessed in individuals with nasal mucosal or structural abnormalities. Avoid use in patients with significant nasal mucosal or structural abnormalities, such as acute episodes of rhinitis or congestion due to any cause. Consider alternative products or therapies in such patients.

The following clinically significant adverse reactions are described elsewhere in the labeling: Fluid, electrolyte, and metabolic abnormalities [see Warnings and Precautions (5.1) ] Worsening Renal Function [see Warnings and Precautions (5.2) ] Ototoxicity [see Warnings and Precautions (5.3) ] Potential Altered Absorption in Patients with Nasal Mucosal or Structural Abnormalities [see Warnings and Precautions (5.4) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ENBUMYST is supported by clinical trials and postmarketing reports of oral bumetanide, as well as open-label, single- and repeat-dose studies of ENBUMYST in healthy subjects. Adverse Reactions in Two Clinical Pharmacology Studies with ENBUMYST in Adult Subjects In open-label studies of ENBUMYST in healthy subjects (n = 84), the most common adverse reaction that occurred with ENBUMYST was hypovolemia (4.8%) [see Warnings and Precautions (5.1) ] . Headache occurred in 3% of subjects. There were no adverse reactions specifically associated with the nasal route of administration such as nasal irritation or pain. There was a single case of nasal dryness. Adverse Reactions in Studies with Oral Bumetanide The following adverse reactions were identified in clinical studies or postmarketing reports with the use of oral bumetanide. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequent clinical adverse reactions considered probably or possibly related to oral 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 pre-existing liver disease) (0.6%). One or more of these adverse reactions have been reported in approximately 4.1% of patients treated with bumetanide. The following additional adverse reactions have been reported with bumetanide. Blood and Lymphatic System Disorders: Deviations in hemoglobin, prothrombin time, hematocrit, WBC and differential counts, thrombocytopenia Cardiac Disorders: Chest pain, electrocardiogram changes Ear and Labyrinth Disorders: Ear discomfort, impaired hearing, vertigo Gastrointestinal Disorders: Abdominal pain, diarrhea, dry mouth, GI upset, vomiting General Disorders and Administration Site Conditions: Fatigue, weakness Investigations: Changes in LDH, total serum bilirubin, serum proteins, SGOT, SGPT, alkaline phosphatase, cholesterol, creatinine clearance, urinary glucose, and urinary protein Metabolism and Nutrition Disorders: Dehydration Musculoskeletal and Connective Tissue Disorders: Arthritic pain, musculoskeletal pain Nervous System Disorders: Asterixis Renal and Urinary Disorders: Renal failure Reproductive System and Breast Disorders: Erectile dysfunction, nipple tenderness, premature ejaculation Respiratory, Thoracic and Mediastinal Disorders: Hyperventilation Skin and Subcutaneous Tissue Disorders: Pruritus, rash, Stevens-Johnson syndrome, sweating, toxic epidermal necrolysis Most common adverse reactions (incidence > 0.5%) are hypovolemia, headache, muscle cramps, dizziness, hypotension, nausea and encephalopathy (in patients with pre-existing liver disease). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Corstasis Therapeutics at 1-877-300-5339 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Lithium may reduce renal clearance of bumetanide and add a high risk of lithium toxicity. ( 7 ) Probenecid reduces both the natriuresis and hyperreninemia. ( 7 ) Indomethacin blunts the increase in urine volume and sodium excretion. ( 7 ) Drugs with ototoxic potential: avoid parenteral bumetanide in patients receiving aminoglycoside antibiotics. ( 7 ) Drugs with nephrotoxic potential: the simultaneous administration of ENBUMYST with drugs of nephrotoxic potential should be avoided. ( 7 ) Antihypertensive effects may be potentiated by bumetanide. ( 7 )

7.1 Effects of Other Drugs on Bumetanide 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 Probenecid should not be administered concurrently with bumetanide. 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. Indomethacin Concurrent therapy with bumetanide is not recommended. Indomethacin blunts the increases in urine volume and sodium excretion seen during bumetanide treatment and inhibits the bumetanide-induced increase in plasma renin activity.

7.2 Effects of Bumetanide on Other Drugs Drugs with Ototoxic Potential [ see Warnings and Precautions (5.3) ] 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 Monitor renal function. Concomitant use may worsen renal function and increase the risk of nephrotoxicity. 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.

Lactation: A lactating woman treated with ENBUMYST should monitor her infant for excessive urine output, dehydration, and lethargy. ( 8.2 )

8.1 Pregnancy Risk Summary The available data on bumetanide use in pregnant women from scientific review publications have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Untreated congestive heart failure, hepatic disease such as cirrhosis and chronic kidney disease can lead to adverse outcomes for the mother and fetus (see Clinical Considerations ). In animal reproduction studies, no malformations were observed with oral administration of bumetanide to pregnant rats and rabbits during organogenesis at doses approximately 485 times and equivalent to a human dose of 2 mg once daily, respectively (see Data ) . The background risk for major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with congestive heart failure are at increased risk for pre-term birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death and/or stillbirth. Closely monitor pregnant patients for destabilization of their heart failure. Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, pre-term delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly. Chronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery, polyhydramnios, still birth, and low birth weight infants. Data Animal Data Bumetanide has been shown to be nonteratogenic, but it has a slight embryocidal effect in rats when given at a dose approximately 485 times and in rabbits at a dose equivalent to a 2 mg/day human dose, based on body surface area (BSA). 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, approximately 485 times a 2 mg/day human dose, based on BSA. These effects were associated with maternal weight reductions noted during dosing. No such adverse effects were observed at 30 mg/kg/day (approximately 146 times a 2 mg/day human dose, based on BSA). No fetotoxicity was observed at dose up to approximately 292 times a 2 mg/day human dose, based on BSA. 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 (approximately equivalent to 3 times a 2 mg/day human dose, based on BSA). 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 (approximately 3 times a 2 mg/day human dose, based on BSA).

8.2 Lactation Risk Summary There are no data on the presence of bumetanide in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because there have been no reports of adverse events in breastfed infants over decades of bumetanide use, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bumetanide and any potential adverse effects on the breastfed infant from bumetanide or from the underlying maternal condition. Clinical Considerations Monitor infants potentially exposed to ENBUMYST through breast milk for excessive urine output, dehydration and lethargy.

8.4 Pediatric Use The safety and effectiveness of ENBUMYST (bumetanide nasal spray) have not been established in pediatric patients. In vitro studies 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. ENBUMYST (bumetanide nasal spray) is not approved for use in pediatric patients, including neonates.

8.5 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 .

Bumetanide primarily inhibits the reabsorption of sodium and chloride in the proximal and distal tubules and in the loop of Henle. The high degree of diuresis is largely due to the unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase and aldosterone.