ENBUMYST

ENBUMYST contains bumetanide, a loop diuretic. Chemically, bumetanide is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is a practically white powder with a calculated molecular weight of 364.42 g/mol, and the following structural formula: ENBUMYST is supplied as a unit-dose nasal spray containing 0.5 mg of bumetanide (equivalent to about 0.554 mg of potassium salt of bumetanide) per 0.1 mL. ENBUMYST contains the following inactive ingredients: benzyl alcohol (0.5 mg per 0.1 mL spray), carboxymethylcellulose sodium (viscosity control agent), mannitol, potassium hydroxide (pH modifier), hydrochloric acid (to adjust pH) and water for injection. Chemical Structure

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 )

ENBUMYST is for nasal route only. ( 2 ) Individualize dosage based on patient response. The recommended total daily dosage of ENBUMYST is 0.5 mg to 2 mg administered once daily. ( 2.1 ) ENBUMYST is not intended for chronic use; replace with oral diuretics as soon as practical. ( 2.1 ) 2.1 Recommended Dosage Each unit-dose nasal spray contains 0.5 mg of bumetanide. The usual total daily dosage of ENBUMYST is 0.5 mg to 2 mg once daily. The number of nasal spray devices needed for a single dose depends upon the prescribed dose. Individualize dosage based on patient response up to a maximum dose of 2 mg/day. ENBUMYST is not intended for chronic use and should be replaced with oral diuretics as soon as practical. ENBUMYST can be substituted at approximately a 1:40 ratio to oral furosemide and a 1:20 ratio to intravenous furosemide. 2.2 Administration Instructions ENBUMYST is for nasal use only. Each ENBUMYST unit is for single use and delivers 0.5 mg bumetanide upon actuation. Do not prime or attempt to reuse ENBUMYST for more than one administration. Administer ENBUMYST directly into the nose and not against the wall of the nose. If prescribed dose requires more than one nasal spray, alternate between right and left nostrils. Refer patients and caregivers to the Instructions for Use for detailed administration instructions.

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 )

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.

Storage and Handling Store at room temperature 59°F to 77°F (15°C to 25°C). Short-term excursions permitted between 39°F to 104°F (4°C to 40°C). Do not freeze. Dispense in the original sealed carton.