WARNING: CAPILLARY LEAK SYNDROME Capillary Leak Syndrome (CLS) which may be life-threatening or fatal, can occur in patients receiving ELZONRIS. Monitor for signs and symptoms of CLS and take actions as recommended [see Warnings and Precautions ( 5.1 )] . WARNING: CAPILLARY LEAK SYNDROME See full prescribing information for complete boxed warning. Capillary Leak Syndrome (CLS), which may be life-threatening or fatal if not properly managed, can occur in patients receiving ELZONRIS. ( 5.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity: Monitor patients for signs/symptoms and treat appropriately. ( 5.2 ) Hepatotoxicity: Monitor ALT and AST. Interrupt ELZONRIS if the transaminases rise to greater than 5 times the upper limit of normal. ( 5.3 ) 5.1 Capillary Leak Syndrome Capillary leak syndrome (CLS), including life-threatening and fatal cases, has been reported among patients treated with ELZONRIS. In patients receiving ELZONRIS in clinical trials, the overall incidence of CLS was 53% (65/122), including Grade 1 or 2 in 43% (52/122) of patients, Grade 3 in 7% (8/122) of patients, Grade 4 in 1% (1/122) of patients, and four fatalities (3%) [see Adverse Reactions (6.1) ] . The median time to onset was 4 days (range - 1 to 46 days), and all but 5 patients experienced an event in Cycle 1. Before initiating therapy with ELZONRIS, ensure that the patient has adequate cardiac function and serum albumin is greater than or equal to 3.2 g/dL. During treatment with ELZONRIS, monitor serum albumin levels prior to the initiation of each dose of ELZONRIS and as indicated clinically thereafter, and assess patients for other signs or symptoms of CLS, including weight gain, new onset or worsening edema, including pulmonary edema, hypotension or hemodynamic instability [see Dosage and Administration (2.2) ]. 5.2 Hypersensitivity Reactions ELZONRIS can cause severe hypersensitivity reactions. In patients receiving ELZONRIS in clinical trials, hypersensitivity reactions were reported in 43% (53/122) of patients treated with ELZONRIS and were Grade ≥ 3 in 7% (9/122) [see Adverse Reactions (6.1) ] . Manifestations of hypersensitivity reported in ≥ 5% of patients include rash, pruritus, and stomatitis. Monitor patients for hypersensitivity reactions during treatment with ELZONRIS. Interrupt ELZONRIS infusion and provide supportive care as needed if a hypersensitivity reaction should occur [see Dosage and Administration (2.2) ] . 5.3 Hepatotoxicity Treatment with ELZONRIS was associated with elevations in liver enzymes. In patients receiving ELZONRIS in clinical trials, elevations in ALT occurred in 79% (96/122) and elevations in AST occurred in 76% (93/122) [see Adverse Reactions (6.1) ] . Grade 3 ALT elevations were reported in 26% (32/122) of patients. Grade 3 AST elevations were reported in 30% (36/122) and Grade 4 AST elevations were reported in 3% (4/122) of patients. Elevated liver enzymes occurred in the majority of patients in Cycle 1 and were reversible following dose interruption. Monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) prior to each infusion with ELZONRIS. Withhold ELZONRIS temporarily if the transaminases rise to greater than 5 times the upper limit of normal and resume treatment upon normalization or when resolved [see Dosage and Administration (2.2) ] .
6 ADVERSE REACTIONS The following serious adverse drug reactions are described elsewhere in the labeling: Capillary Leak Syndrome [see Warnings and Precautions ( 5.1 ) ] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [see Warnings and Precautions ( 5.3 ) ] Most common adverse reactions (incidence ≥ 30%) are capillary leak syndrome, nausea, fatigue, pyrexia, peripheral edema, and weight increase. Most common laboratory abnormalities (incidence ≥ 50%) are decreases in albumin, platelets, hemoglobin, calcium, and sodium, and increases in glucose, ALT and AST. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Safety of ELZONRIS was assessed in a single-arm clinical trial that included 122 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 86 with BPDCN, treated with ELZONRIS 12 mcg/kg daily for 5 days of a 21-day cycle. The overall median number of cycles started was 2.5 (range, 1-76), and 4 in patients with BPDCN (range, 1-76). Four (3%) patients (4/122) had fatal adverse reactions, all of which were related to capillary leak syndrome. Overall, 8% (10/122) of patients discontinued treatment with ELZONRIS due to an adverse reaction; the most common adverse reactions resulting in treatment discontinuation were hepatic toxicities, hypoalbuminemia and CLS (2% each). Table 3 summarizes the common (≥ 10%) adverse reactions with ELZONRIS in patients with myeloid malignancies. The rate of any given adverse reaction or lab abnormality was derived from all the reported events of that type. Table 3. Adverse Reactions in ≥ 10% of Patients Receiving 12 mcg/kg of ELZONRIS 1 Capillary leak syndrome defined as any event reported as CLS during treatment with ELZONRIS or the occurrence of at least 2 of the following CLS manifestations within 7 days of each other: hypoalbuminemia (including albumin value less than 3.0 g/dL), edema (including weight increase of 5 kg or more), hypotension (including systolic blood pressure less than 90 mmHg). N=122 All Grades % Grade ≥ 3 % Vascular disorders Capillary leak syndrome 1 53 11 Hypotension 25 7 Hypertension 14 6 General disorders and administration site conditions Fatigue 45 7 Pyrexia 43 0 Peripheral edema 39 1 Chills 26 1 Gastrointestinal disorders Nausea 45 0 Constipation 24 0 Diarrhea 21 0 Vomiting 19 0 Investigations Weight increase 31 0 Nervous system disorders Headache 28 0 Dizziness 21 0 Metabolism and nutrition disorders Decreased appetite 22 0 Respiratory, thoracic and mediastinal disorders Dyspnea 20 3 Epistaxis 12 1 Cough 12 0 Blood and lymphatic system disorders Febrile neutropenia 19 16 Musculoskeletal and connective tissue disorders Back pain 19 2 Pain in extremity 10 2 Cardiac disorders Tachycardia 17 0 Psychiatric disorders Insomnia 16 0 Anxiety 15 0 Skin and subcutaneous tissue disorders Pruritus 10 0 Clinically relevant adverse reactions occurring in less than 10% of patients treated with ELZONRIS included tumor lysis syndrome. Table 4 summarizes the clinically important laboratory abnormalities that occurred in ≥ 10% patients with myeloid malignancies treated with ELZONRIS. Table 4. Selected Laboratory Abnormalities in Patients Receiving 12 mcg/kg of ELZONRIS Treatment-Emergent Laboratory Abnormalities All Grades % Grade ≥ 3 % Hematology Platelets decrease 68 49 Hemoglobin decrease 61 30 Neutrophils decrease 38 29 Chemistry Glucose increase 89 21 ALT increase 79 26 AST increase 76 33 Albumin decrease 72 1 Calcium decrease 57 2 Sodium decrease 52 9 Potassium decrease 36 6 Phosphate decrease 32 10 Creatinine increase 26 0 Magnesium decrease 25 0 Alkaline phosphatase increase 22 1 Potassium increase 20 3 Magnesium increase 13 4 Bilirubin increase 11 0 Glucose decrease 10 0