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BESPONSA™ (inotuzumab ozogamicin) Adverse Reactions

6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

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 adverse reactions described in this section reflect exposure to BESPONSA in 164 patients with relapsed or refractory ALL who participated in a randomized clinical study of BESPONSA versus Investigator's choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (INO-VATE ALL Trial [NCT01564784]) [see Clinical Studies (14)].

Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18–78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.

In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1–26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 treatment cycle started in each patient.

In patients who received BESPONSA, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

In patients who received BESPONSA, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).

VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].

Table 6 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 6. Adverse Reactions With ≥ 10% Incidence* in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
Body System
  Adverse Reaction
BESPONSA
(N=164)
FLAG, MXN/Ara-C, or HIDAC
(N=143)
All Grades ≥ Grade 3 All Grades ≥ Grade 3
% % % %
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the last dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Severity grade of adverse reactions were according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
*
Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included.
19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations.
§
Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia.
Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased.
#
Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased.
Þ
Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased.
ß
Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia.
à
Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache.
è
Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage.
ð
Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain.
ø
Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis.
ý
Fatigue includes the following reported preferred terms: Asthenia and Fatigue.
£
Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.
Infections
  Infection 48 28 76 54
Blood and lymphatic system disorders
  Thrombocytopenia§ 51 42 61 59
  Neutropenia 49 48 45 43
  Anemia# 36 24 59 47
  LeukopeniaÞ 35 33 43 42
  Febrile neutropenia 26 26 53 53
  Lymphopeniaß 18 16 27 26
Metabolism and nutrition disorders
  Decreased appetite 12 1 13 2
Nervous system disorders
  Headacheà 28 2 27 1
Vascular disorders
  Hemorrhageè 33 5 28 5
Gastrointestinal disorders
  Nausea 31 2 46 0
  Abdominal painð 23 3 23 1
  Diarrhea 17 1 38 1
  Constipation 16 0 24 0
  Vomiting 15 1 24 0
  Stomatitisø 13 2 26 3
Hepatobiliary disorders
  Hyperbilirubinemia 21 5 17 6
General disorders and administration site conditions
  Fatigueý 35 5 25 3
  Pyrexia 32 3 42 6
  Chills 11 0 11 0
Investigations
  Transaminases increased£ 26 7 13 5
  Gamma-glutamyltransferase increased 21 10 8 4
  Alkaline phosphatase increased 13 2 7 0

Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).

Table 7 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 7. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
BESPONSA FLAG, MXN/Ara-C, or HIDAC
All Grades Grade 3/4 All Grades Grade 3/4
Laboratory Abnormality* N % % N % %
Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
*
Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
Hematology
Platelet count decreased 161 98 76 142 100 99
Hemoglobin decreased 161 94 40 142 100 70
Leukocytes decreased 161 95 82 142 99 98
Neutrophil count decreased 160 94 86 130 93 88
Lymphocytes (absolute) decreased 160 93 71 127 97 91
Chemistry
GGT increased 148 67 18 111 68 17
AST increased 160 71 4 134 38 4
ALP increased 158 57 1 133 52 3
ALT increased 161 49 4 137 46 4
Blood bilirubin increased 161 36 5 138 35 6
Lipase increased 139 32 13 90 20 2
Hyperuricemia 158 16 3 122 11 0
Amylase increased 143 15 2 102 9 1

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of 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 inotuzumab ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In clinical studies of BESPONSA in patients with relapsed or refractory ALL, the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.

In clinical studies of BESPONSA in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.

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