The following adverse reactions are discussed in greater detail in other sections of the label:
- Cytokine Release Syndrome [see WARNINGS AND PRECAUTIONS]
- Neurological Toxicities [see WARNINGS AND PRECAUTIONS]
- Infections [see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Neutropenia and Febrile Neutropenia [see WARNINGS AND PRECAUTIONS]
- Effects on Ability to Drive and Use Machines [see WARNINGS AND PRECAUTIONS]
- Elevated Liver Enzymes [see WARNINGS AND PRECAUTIONS]
- Leukoencephalopathy [see WARNINGS AND PRECAUTIONS]
- Preparation and Administration Errors [see WARNINGS AND PRECAUTIONS]
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 data described in this section reflect exposure to BLINCYTO in clinical trials in which 212 patients with relapsed or refractory ALL received up to 28 mcg/day. All patients received at least one dose of BLINCYTO. The median age of the study population was 37 years (range: 18 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American.
The most common adverse reactions ( ≥ 20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (20%).
Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions ( ≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.
Adverse reactions of Grade 3 or higher were reported in 80% of patients. Discontinuation of therapy due to adverse reactions occurred in 18% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 15% of patients. The majority of these events were infections. No fatal adverse events occurred on treatment among patients in remission.
The adverse reactions with ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher are summarized in Table 2.
Table 2: Adverse Reactions With ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher (N = 212)
|Adverse Reaction||Any Grade1 (%)||Grade 3 or Higher1 (%)|
|Blood and lymphatic system disorders|
|General disorders and administration site conditions|
|Peripheral edema||25||< 1|
|Immune system disorders|
|Cytokine release syndrome||11||1|
|Infections and infestations|
|Other pathogen infections||44||25|
|Increased alanine aminotransferase||12||6|
|Increased aspartate aminotransferase||11||4|
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||12||1|
|Nervous system disorders|
|Respiratory, thoracic, and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|1 Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
2 Diarrhea includes the following terms: colitis, diarrhea, enteritis, and neutropenic colitis.
3 Tremor includes the following terms: resting tremor and tremor.
4 Dyspnea includes the following terms: acute respiratory failure, bronchial hyperactivity, bronchospasm, dyspnea, dyspnea exertional, respiratory distress, respiratory failure, and wheezing.
5 Rash includes the following terms: erythema, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, and vesicular rash.
Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were:
Blood and lymphatic system disorders: leukocytosis (2%), lymphopenia (1%)
Cardiac disorders: tachycardia (8%)
General disorders and administration site conditions: edema (5%)
Immune system disorders: cytokine storm (1%)
Investigations: decreased immunoglobulins (9%), increased blood bilirubin (8%), increased gammaglutamyl- transferase (6%), increased liver enzymes (1%)
Metabolism and nutrition disorders: tumor lysis syndrome (4%), hypoalbuminemia (4%)
Nervous system disorders: encephalopathy (5%), paresthesia (5%), aphasia (4%), convulsion (2%), memory impairment (2%), cognitive disorder (1%), speech disorder ( < 1%)
Psychiatric disorders: confusion (7%), disorientation (3%)
Vascular disorders: capillary leak syndrome ( < 1%).
Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm ( < 1%).
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 1% of patients treated with BLINCYTO tested positive for binding antiblinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing anti-blinatumomab antibodies.
Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. No association was seen between antibody development and development of adverse events.
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.