Enbumyst

5 WARNINGS AND PRECAUTIONS 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.

6 ADVERSE REACTIONS 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.