Cytokine Release Syndrome: Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO.
Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS.
Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was reported in patients receiving BLINCYTO. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS.
Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see Dosage & Administration).
Neurological Toxicities: In patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 64% of patients. The median time to onset of any neurological toxicity was 4 days. The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness; the neurological toxicity profile varied by age group (see Use in Specific Populations as follows). Grade 3 or higher (severe, life-threatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 17% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation.
There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical trials.
Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, and interrupt or discontinue BLINCYTO as recommended (see Dosage & Administration).
Infections: In patients receiving BLINCYTO in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately.
Tumor Lysis Syndrome: Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see Dosage & Administration).
Neutropenia and Febrile Neutropenia: Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs.
Elevated Liver: Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes. In clinical trials, the median time to onset of elevated liver enzymes was 3 days.
In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients.
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the postmarketing setting.
Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone (see Dosage & Administration).
Leukoencephalopathy: Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.
Preparation and Administration Errors: Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) (see Dosage & Administration).
Immunization: The safety of immunization with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness (see Precautions). Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Use in Specific Populations: Pediatric Use: The safety and efficacy of BLINCYTO have been established in pediatric patients. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups.
In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients (see Adverse Reactions). Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adult population were anemia (41% vs 18%), thrombocytopenia (21% vs.11%), vomiting (24% vs. 13%), pyrexia (80% vs. 62%), and hypertension (26% vs. 8%). In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (23%).
The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on BSA-based regimens.
Geriatric Use: Of the total number of patients with relapsed or refractory ALL in clinical studies of BLINCYTO, treated at the recommended dose and schedule, approximately 10% were 65 and over, while 1% were 75 and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections (see Precautions).