1 INDICATIONS AND USAGE BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adult and pediatric patients one month and older with: CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.

( 1.1 ) Relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL).

( 1.2 ) CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy.

( 1.3 ) 1.1 MRD-positive B-cell Precursor ALL BLINCYTO is indicated for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adult and pediatric patients one month and older.

1.2 Relapsed or Refractory B-cell Precursor ALL BLINCYTO is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one month and older.

1.3 B-cell Precursor ALL in the Consolidation Phase BLINCYTO is indicated for the treatment of CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy in adult and pediatric patients one month and older.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome [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%) are pyrexia, infusion-related reactions, headache, infection, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea.

( 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.

The safety of BLINCYTO in adult and pediatric patients one month and older with MRD-positive B-cell precursor ALL (n = 137), relapsed or refractory B-cell precursor ALL (n = 267), and Philadelphia chromosome-negative B-cell precursor ALL in consolidation (n = 165) was evaluated in clinical studies.

The most common adverse reactions (≥ 20%) to BLINCYTO in this pooled population were pyrexia, infusion-related reactions, headache, infection, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea.

MRD-positive B-cell Precursor ALL The safety of BLINCYTO in patients with MRD-positive B-cell precursor ALL was evaluated in two single-arm clinical studies in which 137 adult patients were treated with BLINCYTO.

The median age of the study population was 45 years (range: 18 to 77 years).

The most common adverse reactions (≥ 20%) were pyrexia, infusion-related reactions, headache, infections (pathogen unspecified), tremor, and chills.

Serious adverse reactions were reported in 61% of patients.

The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.

Adverse reactions of Grade 3 or higher were reported in 64% of patients.

Discontinuation of therapy due to adverse reactions occurred in 17% of patients; neurologic events were the most frequently reported reasons for discontinuation.

There were 2 fatal adverse reactions that occurred within 30 days of the end of BLINCYTO treatment (atypical pneumonia and subdural hemorrhage).

Table 6 summarizes the adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher.

Table 6.

Adverse Reactions Occurring at ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher in BLINCYTO-treated Adult Patients with MRD-Positive B-cell Precursor ALL Adverse Reaction BLINCYTO (N = 137) Any Grade Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

n (%) Grade ≥ 3 n (%) Blood and lymphatic system disorders Neutropenia Neutropenia includes febrile neutropenia, neutropenia, and neutrophil count decreased.

21 (15) 21 (15) Leukopenia Leukopenia includes leukopenia and white blood cell count decreased.

19 (14) 13 (9) Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia.

14 (10) 8 (6) Cardiac disorders Arrhythmia Arrhythmia includes bradycardia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, tachycardia and ventricular extrasystoles.

17 (12) 3 (2) General disorders and administration site conditions Pyrexia Pyrexia includes body temperature increased and pyrexia.

125 (91) 9 (7) Chills 39 (28) 0 (0) Infections and infestations Infections - pathogen unspecified 53 (39) 11 (8) Injury, poisoning and procedural complications Infusion-related reaction 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: cytokine release syndrome, eye swelling, hypertension, hypotension, myalgia, periorbital edema, pruritus generalized, pyrexia, and rash.

105 (77) 7 (5) Investigations Decreased immunoglobulins Decreased immunoglobulins includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinemia, hypoglobulinemia, and immunoglobulins decreased.

25 (18) 7 (5) Weight increased 14 (10) 1 (< 1) Hypertransaminasemia Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased.

13 (9) 9 (7) Musculoskeletal and connective tissue disorders Back pain 16 (12) 1 (< 1) Nervous system disorders Headache May represent ICANS.

54 (39) 5 (4) Tremor , Tremor includes essential tremor, intention tremor, and tremor.

43 (31) 6 (4) Aphasia 16 (12) 1 (< 1) Dizziness 14 (10) 1 (< 1) Encephalopathy , Encephalopathy includes cognitive disorder, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, leukoencephalopathy, memory impairment, somnolence, and toxic encephalopathy.

14 (10) 6 (4) Psychiatric disorders Insomnia , Insomnia includes initial insomnia, insomnia, and terminal insomnia.

24 (18) 1 (< 1) Respiratory, thoracic and mediastinal disorders Cough 18 (13) 0 (0) Skin and subcutaneous tissue disorders Rash Rash includes dermatitis contact, eczema, erythema, rash, and rash maculopapular.

22 (16) 1 (< 1) Vascular disorders Hypotension 19 (14) 1 (< 1) Additional adverse reactions in adult patients with MRD-positive ALL that did not meet the threshold criteria for inclusion in Table 6 were: Blood and lymphatic system disorders: anemia General disorders and administration site conditions: edema peripheral, pain, and chest pain (includes chest pain and musculoskeletal chest pain) Hepatobiliary disorders: blood bilirubin increased Immune system disorders: hypersensitivity and cytokine release syndrome Infections and infestations: viral infectious disorders, bacterial infectious disorders, and fungal infectious disorders Injury, poisoning and procedural complications: medication error and overdose (includes overdose and accidental overdose) Investigations: blood alkaline phosphatase increased Musculoskeletal and connective tissue disorders: pain in extremity and bone pain Nervous system disorders: seizure (includes seizure and generalized tonic-clonic seizure), speech disorder, and hypoesthesia Psychiatric disorders: confusional state, disorientation, and depression Respiratory, thoracic and mediastinal disorders: dyspnea and productive cough Vascular disorders: hypertension (includes blood pressure increased and hypertension) flushing (includes flushing and hot flush), and capillary leak syndrome Relapsed or Refractory B-cell Precursor ALL The safety of BLINCYTO was evaluated in a randomized, open-label, active-controlled clinical study (TOWER Study) in which 376 adult 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 for Adult Patients with Relapsed or Refractory B-cell Precursor ALL (TOWER Study) Adverse Reaction BLINCYTO (N = 267) Standard of Care (SOC) Chemotherapy (N = 109) Any Grade Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

n (%) Grade ≥ 3 n (%) Any Grade n (%) Grade ≥ 3 n (%) Blood and lymphatic system disorders Neutropenia Neutropenia includes agranulocytosis, febrile neutropenia, neutropenia, and neutrophil count decreased.

84 (31) 76 (28) 67 (61) 61 (56) Anemia Anemia includes anemia and hemoglobin decreased.

68 (25) 52 (19) 45 (41) 37 (34) Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia.

57 (21) 47 (18) 42 (39) 40 (37) Leukopenia Leukopenia includes leukopenia and white blood cell count decreased.

21 (8) 18 (7) 9 (8) 9 (8) Cardiac disorders Arrhythmia Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia.

37 (14) 5 (2) 18 (17) 0 (0) General disorders and administration site conditions Pyrexia 147 (55) 15 (6) 43 (39) 4 (4) Edema Edema includes face edema, fluid retention, edema, edema peripheral, peripheral swelling, and swelling face.

48 (18) 3 (1) 20 (18) 1 (1) Immune system disorders Cytokine release syndrome Cytokine release syndrome includes cytokine release syndrome and cytokine storm.

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 reaction 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.

79 (30) 9 (3) 9 (8) 1 (1) Investigations Hypertransaminasemia Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased.

40 (15) 22 (8) 13 (12) 7 (6) Nervous system disorders Headache May represent ICANS.

61 (23) 1 (< 1) 30 (28) 3 (3) Skin and subcutaneous tissue disorders Rash Rash includes erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash pruritic, skin exfoliation, and toxic skin eruption.

31 (12) 2 (1) 21 (19) 0 (0) 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 Includes only patients who had both baseline and at least one laboratory measurement during first cycle of therapy available.

in First Cycle of Therapy for Adult Patients with Relapsed or Refractory B-cell Precursor ALL (TOWER Study) BLINCYTO Grade 3 or 4 (%) SOC Chemotherapy Grade 3 or 4 (%) Hematology Decreased lymphocyte count 80 83 Decreased white blood cell count 53 97 Decreased hemoglobin 29 43 Decreased neutrophil count 57 68 Decreased platelet count 47 85 Chemistry Increased ALT 11 11 Increased bilirubin 5 4 Increased AST 8 4 Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were: Blood and lymphatic system disorders: lymphadenopathy, hemophagocytic lymphohistiocytosis, 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, paresthesia, 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 B-cell Precursor ALL in the Consolidation Phase Study E1910 The safety of a consolidation regimen comprised of multiple cycles of BLINCYTO monotherapy in addition to multiple cycles of chemotherapy (BLINCYTO arm) was evaluated in a randomized trial in adult patients with newly diagnosed Philadelphia chromosome-negative B-cell precursor ALL (Study E1910) [NCT02003222] [see Clinical Studies (14.3) ] which included 111 patients treated in the BLINCYTO arm and 112 patients treated in the chemotherapy alone arm.

In the BLINCYTO arm, the median (range) of cycles was 8 (1-8) (4 cycles of BLINCYTO and 4 cycles of chemotherapy).

In the chemotherapy alone arm, the median (range) of cycles was 4 (1-4).

Fatal adverse reactions occurred in 2 patients (2%) during BLINCYTO cycles and were due to infection (n = 1) and coagulopathy (n = 1).

Permanent discontinuation of BLINCYTO due to an adverse reaction occurred in 2% of patients.

Dosage interruptions of BLINCYTO due to an adverse reaction occurred in 5% of patients.

Dose reductions of BLINCYTO due to an adverse reaction occurred in 28% of patients.

The most common (≥ 20%) adverse reactions during consolidation cycles in the BLINCYTO arm were neutropenia, thrombocytopenia, anemia, leukopenia, headache, infection, nausea, lymphopenia, diarrhea, musculoskeletal pain, and tremor.

The adverse reactions occurring at a difference between arms in incidence of ≥ 10% for All Grades or ≥ 5% for Grade 3 or higher are summarized in Table 9.

Table 9.

Adverse Reactions with a Difference Between Arms of ≥ 10% for Any Grade or ≥ 5% for Grade 3 or 4 during Consolidation (Study E1910) Consolidation Consisting of Adverse Reaction BLINCYTO Cycles + Chemotherapy Cycles (n = 111) Chemotherapy Cycles Alone (n = 112) All Grades (%) Includes the following fatal adverse reaction: infection (n = 1).

Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and lymphatic system disorders Neutropenia Other related adverse reactions included: 82 77 89 89 Thrombocytopenia 75 57 75 71 Anemia 59 29 50 38 Leukopenia 43 41 57 56 Lymphopenia 32 30 25 23 Febrile neutropenia 19 19 25 25 Gastrointestinal disorders Nausea Nausea: vomiting; 32 5 22 4 Diarrhea 29 3 15 3 Immune system disorders Cytokine release syndrome Cytokine release syndrome: capillary leak syndrome; 16 4 0 0 Infections and infestations Infection – pathogen unspecified 35 31 22 21 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: pain in extremity, back pain, arthralgia, myalgia, neck pain, flank pain, bone pain, non-cardiac chest pain; 23 5 5 4 Nervous system disorders Headache May represent ICANS.

41 5 30 5 Tremor 23 3 3 0 Aphasia Aphasia: dysarthria.

, 10 8 0 0 Vascular disorders Hypertension 12 10 5 3 Study 20120215 The safety of BLINCYTO as the 3rd cycle of the consolidation phase was evaluated in a randomized, open-label study (Study 20120215) following induction and two cycles of consolidation chemotherapy in pediatric and young adult patients with high-risk first-relapsed B-cell precursor ALL [see Clinical Studies (14.3) ] .

The study included 54 patients treated with one cycle of BLINCYTO and 52 patients treated with one cycle of chemotherapy.

Serious adverse reactions occurred in 28% of patients who received BLINCYTO.

Permanent discontinuation of BLINCYTO due to an adverse reaction occurred in 4% of patients.

Adverse reactions that led to discontinuation included nervous system disorder and seizure.

Dosage interruptions of BLINCYTO due to an adverse reaction occurred in 11% of patients.

Adverse reactions which required dosage interruption in > 2% of patients included nervous system disorder.

The most common (≥ 20%) adverse reactions in the BLINCYTO arm were pyrexia, nausea, headache, rash, hypogammaglobulinemia, and anemia.

The adverse reactions occurring at a difference of ≥ 10% incidence for any grade or at a difference of ≥ 5% incidence for Grade 3 or 4 between the BLINCYTO arm and chemotherapy arm are summarized in Table 10.

Table 10.

Adverse Reactions with a Difference Between Arms of ≥ 10% for Any Grade or ≥ 5% for Grade 3 or 4 during Consolidation Cycle 3 (Study 20120215) Adverse Reaction BLINCYTO (n = 54) Chemotherapy (n = 52) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and lymphatic system disorders Anemia Other related adverse reactions included: 24 15 46 42 Neutropenia 19 17 35 31 Thrombocytopenia 15 15 39 35 Febrile neutropenia 2 2 25 25 Gastrointestinal disorders Nausea Nausea: vomiting; 43 2 31 2 Abdominal pain 13 0 23 2 Stomatitis Stomatitis: mouth ulceration, mucosal inflammation; 11 4 60 29 General disorders and administration site conditions Pyrexia 76 6 19 0 Hepatobiliary disorders Liver function test abnormal Liver function test abnormal: alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hypertransaminasemia; 9 6 27 17 Immune system disorders Hypogammaglobulinemia 24 2 12 2 Infections and infestations Infection – pathogen unspecified 13 6 29 10 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: back pain, pain in extremity, bone pain; 9 0 29 2 Nervous system disorders Headache May represent ICANS.

37 0 15 0 Skin and subcutaneous disorders Rash 22 2 12 0 Vascular disorders Hemorrhage Hemorrhage: Epistaxis, petechiae, hemarthrosis, hematoma, hematuria.

11 2 23 6 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 in patients receiving BLINCYTO in combination with dexamethasone.