6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cytokine Release Syndrome [see Warnings and Precautions ( 5.1 )] Neurological Toxicities [see Warnings and Precautions ( 5.2 )] Infections [see Warnings and Precautions ( 5.3 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] Neutropenia and Febrile Neutropenia [see Warnings and Precautions ( 5.5 )] Effects on Ability to Drive and Use Machines [see Warnings and Precautions ( 5.6 )] Elevated Liver Enzymes [see Warnings and Precautions ( 5.7 )] Pancreatitis [see Warnings and Precautions ( 5.8 )] Leukoencephalopathy [see Warnings and Precautions ( 5.9 )] The most common adverse reactions (≥ 20%) were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) 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. Philadelphia Chromosome -negative Relapsed or Refractory B -cell Precursor ALL The safety data described below reflect exposure to BLINCYTO in a randomized, open-label, active-controlled clinical study (TOWER Study) in which 376 patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL were treated with BLINCYTO (n = 267) or standard of care (SOC) chemotherapy (n = 109). The median age of BLINCYTO-treated patients was 37 years (range: 18 to 80 years), 60% were male, 84% were White, 7% Asian, 2% were Black or African American, 2% were American Indian or Alaska Native, and 5% were Multiple/Other. The most common adverse reactions (≥ 20%) in the BLINCYTO arm were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia. Adverse reactions of Grade 3 or higher were reported in 87% of patients. Discontinuation of therapy due to adverse reactions occurred in 12% of patients treated with BLINCYTO; neurologic events and infections were the most frequently reported reasons for discontinuation of treatment due to an adverse reaction. Fatal adverse events occurred in 16% of patients. The majority of the fatal events were infections. The adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher in the BLINCYTO-treated patients in first cycle of therapy are summarized in Table 7. Table 7. Adverse Reactions Occurring at ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher in BLINCYTO-treated Patients in First Cycle of Therapy Adverse Reaction BLINCYTO (N = 267) Standard of Care (SOC) Chemotherapy (N = 109) Any Grade* n (%) ≥ Grade 3* n (%) Any Grade* n (%) ≥ Grade 3* n (%) Blood and lymphatic system disorders Neutropenia1 84 (31) 76 (28) 67 (61) 61 (56) Anemia2 68 (25) 52 (19) 45 (41) 37 (34) Thromobocytopenia3 57 (21) 47 (18) 42 (39) 40 (37) Leukopenia4 21 (8) 18 (7) 9 (8) 9 (8) Cardiac disorders Arrhythmia5 37 (14) 5 (2) 18 (17) 0 (0) General disorders and administration site conditions Pyrexia 147 (55) 15 (6) 43 (39) 4 (4) Edema6 48 (18) 3 (1) 20 (18) 1 (1) Immune system disorders Cytokine release syndrome7 37 (14) 8 (3) 0 (0) 0 (0) Infections and infestations Infections - pathogen unspecified 74 (28) 40 (15) 50 (46) 35 (32) Bacterial infectious disorders 38 (14) 19 (7) 35 (32) 21 (19) Viral infectious disorders 30 (11) 4 (1) 14 (13) 0 (0) Fungal infectious disorders 27 (10) 13 (5) 15 (14) 9 (8) Injury, poisoning and procedural complications Infusion-related reaction8 79 (30) 9 (3) 9 (8) 1 (1) Investigations Hypertransaminasemia9 40 (15) 22 (8) 13 (12) 7 (6) Nervous system disorders Headache 61 (23) 1 (<1) 30 (28) 3 (3) Skin and subcutaneous tissue disorders Rash10 31 (12) 2 (1) 21 (19) 0 (0) * Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 1 Neutropenia includes agranulocytosis, febrile neutropenia, neutropenia, and neutrophil count decreased 2 Anemia includes anemia and hemoglobin decreased 3 Thrombocytopenia includes platelet count decreased and thrombocytopenia 4 Leukopenia includes leukopenia and white blood cell count decreased 5 Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia 6 Edema includes face edema, fluid retention, edema, edema peripheral, peripheral swelling, and swelling face 7 Cytokine release syndrome includes cytokine release syndrome and cytokine storm 8 Infusion-related reaction is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and the event lasted ≤ 2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, and rash erythematous 9 Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased 10 Rash includes erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash pruritic, skin exfoliation, and toxic skin eruption. Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 in first cycle of therapy are shown in Table 8. Table 8. Selected Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Treatment-related Maximal Grade 3-4* in First Cycle of Therapy BLINCYTO Grade 3 or 4 (%) SOC Chemotherapy Grade 3 or 4 (%) Hematology Decreased lymphocyte count Decreased white blood cell count Decreased hemoglobin Decreased neutrophil count Decreased platelet count 80 53 29 57 47 83 97 43 68 85 Chemistry Increased ALT Increased bilirubin Increased AST 11 5 8 11 4 4 * Includes only patients who had both baseline and at least one laboratory measurement during first cycle of therapy available. R elapsed or Refractory B -cell Precursor ALL Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were: Blood and lymphatic system disorders: lymphadenopathy, hematophagic histiocytosis, and leukocytosis (includes leukocytosis and white blood cell count increased) General disorders and administration site conditions: chills, chest pain (includes chest discomfort, chest pain, musculoskeletal chest pain, and non-cardiac chest pain), pain, body temperature increased, hyperthermia, and systemic inflammatory response syndrome Hepatobiliary disorders: hyperbilirubinemia (includes blood bilirubin increased and hyperbilirubinemia) Immune system disorders: hypersensitivity (includes hypersensitivity, anaphylactic reaction, angioedema, dermatitis allergic, drug eruption, drug hypersensitivity, erythema multiforme, and urticaria) Injury, poisoning and procedural complications: medication error and overdose (includes overdose, medication error, and accidental overdose) Investigations: weight increased, decreased immunoglobulins (includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, and hypogammaglobulinemia), blood alkaline phosphatase increased, and hypertransaminasemia Metabolism and nutrition disorders: tumor lysis syndrome Musculoskeletal and connective tissue disorders: back pain, bone pain, and pain in extremity Nervous system disorders: tremor (resting tremor, intention tremor, essential tremor, and tremor), altered state of consciousness (includes altered state of consciousness, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, stupor, and somnolence), dizziness, memory impairment, seizure (includes seizure and atonic seizure), aphasia, cognitive disorder, speech disorder, hypoesthesia, encephalopathy and cranial nerve disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, cranial nerve disorder, facial nerve disorder, and facial paresis). Psychiatric disorders: insomnia, disorientation, confusional state, and depression (includes depressed mood, depression, suicidal ideation, and completed suicide) Respiratory, thoracic and mediastinal disorders: dyspnea (includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough Vascular disorders: hypotension (includes blood pressure decreased, hypotension, hypovolemic shock, and circulatory collapse), hypertension (includes blood pressure increased, hypertension, and hypertensive crisis), flushing (includes flushing and hot flush), and capillary leak syndrome 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of BLINCYTO. Because these reactions are 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. Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone [see Warnings and Precautions ( 5.8 )]. 6.3 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In clinical studies, less than 2% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, 7 out of 9 (78%) had in vitro neutralizing activity. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing. The detection of anti-blinatumomab antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to blinatumomab with the incidence of antibodies to other products may be misleading.