Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Neurologic events

Neurologic events including events with a fatal outcome have been observed. Grade 3 (CTCAE version 4.0) or higher (severe or life-threatening) neurologic events following initiation of blinatumomab administration included encephalopathy, seizures, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Among patients that experienced a neurologic event, the median time to the first event was within the first two weeks of treatment and the majority of events resolved after treatment interruption and infrequently led to BLINCYTO treatment discontinuation.

Elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, encephalopathy, and confusion.

Patients with a medical history of neurologic signs and symptoms (such as dizziness, hypoesthesia, hyporeflexia, tremor, dysesthesia, paresthesia and memory impairment) demonstrated a higher rate of neurologic events (such as tremor, dizziness, confusional state, encephalopathy and ataxia). Among these patients, the median time to the first neurologic event was within the first cycle of treatment.

BLINCYTO is indicated:
• as monotherapy for the treatment of adults with CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL). Patients with Philadelphia chromosome positive B-precursor ALL should have failed treatment with at least 2 tyrosine kinase inhibitors (TKIs) and have no alternative treatment options.
• as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
• as monotherapy for the treatment of pediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
• as monotherapy for the treatment of pediatric patients aged 1 year or older with high-risk first relapsed Philadelphia chromosome negative CD19 positive B-precursor ALL as part of the consolidation therapy.
with no CNS involvement.


There is limited experience in patients with a history or presence of clinically relevant CNS pathology (e.g. epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome and psychosis) as they were excluded from clinical studies.
There is a possibility of a higher risk of neurologic events in this population. The potential benefits of treatment should be carefully weighed against the risk of neurologic events and heightened caution should be exercised when administering BLINCYTO to these patients.

There is limited experience with blinatumomab in patients with documented active ALL in the CNS or cerebrospinal fluid (CSF). However, patients have been treated with blinatumomab in clinical studies after clearance of CSF blasts with CNS directed therapy (such as intrathecal chemotherapy).
Therefore, once the CSF is cleared, treatment with BLINCYTO may be initiated.

It is recommended that a neurological examination be performed in patients prior to starting BLINCYTO therapy and that patients be clinically monitored for signs and symptoms of neurologic events (e.g. writing test). Management of these signs and symptoms to resolution may require either temporary interruption or permanent discontinuation of BLINCYTO (see section 4.2). In the event of a seizure, secondary prophylaxis with appropriate anticonvulsant medicinal products (e.g. levetiracetam) is recommended.

Infections

In patients receiving blinatumomab, serious infections, including sepsis, pneumonia, bacteremia, opportunistic infections and catheter site infections have been observed, some of which were life-threatening or fatal. Adult patients with Eastern Cooperative Oncology Group (ECOG) performance status at baseline of 2 experienced a higher incidence of serious infections compared to patients with ECOG performance status of < 2. There is limited experience with BLINCYTO in patients with an active uncontrolled infection.

Patients receiving BLINCYTO should be clinically monitored for signs and symptoms of infection and treated appropriately. Management of infections may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).

Cytokine release syndrome and infusion reactions

Cytokine release syndrome (CRS) which may be life-threatening or fatal (grade ≥ 4) has been reported in patients receiving BLINCYTO (see section 4.8).

Serious adverse reactions that may be signs and symptoms of CRS included pyrexia, asthenia, headache, hypotension, total bilirubin increased, and nausea; uncommonly, these events led to BLINCYTO discontinuation. The median time to onset of a CRS event was 2 days. Patients should be closely monitored for signs or symptoms of these events.

Disseminated intravascular coagulation (DIC) and capillary leak syndrome (CLS, e.g. hypotension, hypoalbuminemia, edema and hemoconcentration) have been commonly associated with CRS (see section 4.8). Patients experiencing capillary leak syndrome should be managed promptly.

Hemophagocytic histiocytosis/macrophage activation syndrome (MAS) has been uncommonly reported in the setting of CRS.

Infusion reactions may be clinically indistinguishable from manifestations of CRS (see section 4.8).
The infusion reactions were generally rapid, occurring within 48 hours after initiating infusion.
However, some patients reported delayed onset of infusion reactions or in later cycles. Patients should be observed closely for infusion reactions, especially during the initiation of the first and second treatment cycles and treated appropriately. Anti-pyretic use (e.g. paracetamol) is recommended to help reduce pyrexia during the first 48 hours of each cycle. To mitigate the risk of CRS, it is important to initiate BLINCYTO (cycle 1, days 1-7) at the recommended starting dose in section 4.2.

Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).

Tumor lysis syndrome

Tumor lysis syndrome (TLS), which may be life-threatening or fatal (grade ≥ 4) has been observed in patients receiving BLINCYTO.

Appropriate prophylactic measures including aggressive hydration and anti-hyperuricemic therapy (such as allopurinol or rasburicase) should be used for the prevention and treatment of TLS during BLINCYTO treatment, especially in patients with higher leukocytosis or a high tumor burden. Patients should be closely monitored for signs or symptoms of TLS, including renal function and fluid balance in the first 48 hours after the first infusion. In clinical studies, patients with moderate renal impairment showed an increased incidence of TLS compared with patients with mild renal impairment or normal renal function. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).

Neutropenia and febrile neutropenia

Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Laboratory parameters (including, but not limited to white blood cell count and absolute neutrophil count) should be monitored routinely during BLINCYTO infusion, especially during the first 9 days of the first cycle, and treated appropriately.

Elevated liver enzymes

Treatment with BLINCYTO was associated with transient elevations in liver enzymes. The majority of the events were observed within the first week of treatment initiation and did not require interruption or discontinuation of BLINCYTO (see section 4.8).

Monitoring of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment especially during the first 48 hours of the first 2 cycles should be performed. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).

Pancreatitis

Pancreatitis, life-threatening or fatal, has been reported in patients receiving BLINCYTO in clinical studies and the post-marketing setting. High-dose steroid therapy may have contributed, in some cases, to the pancreatitis.

Patients should be closely monitored for signs and symptoms of pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).

Leukoencephalopathy including progressive multifocal 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 anti-leukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.

Due to the potential for progressive multifocal leukoencephalopathy (PML), patients should be monitored for signs and symptoms. In case of suspicious events consider consultation with a neurologist, brain MRI and examination of cerebral spinal fluid (CSF), see section 4.8.
CD19-negative relapse

CD19-negative B-precursor ALL has been reported in relapsed patients receiving BLINCYTO.
Particular attention should be given to assessment of CD19 expression at the time of bone marrow testing.

Lineage switch from ALL to acute myeloid leukemia (AML)

Lineage switch from ALL to AML has been rarely reported in relapsed patients receiving BLINCYTO, including those with no immunophenotypic and/or cytogenetic abnormalities at initial diagnosis. All relapsed patients should be monitored for presence of AML.

Immunizations

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 recovery of B-lymphocytes to normal ranges following last treatment cycle.

Due to the potential depletion of B-cells in newborns following exposure to blinatumomab during pregnancy, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered (see section 4.6).

Contraception

Women of childbearing potential have to use effective contraception during and for at least 48 hours, after treatment with BLINCYTO (see section 4.6).

Medication errors

Medication errors have been observed with BLINCYTO treatment. It is very important that the instructions for preparation (including reconstitution and dilution) and administration are strictly followed to minimize medication errors (including underdose and overdose) (see section 4.2).

Excipients with known effect

This medicinal product contains less than 1 mmol (23 mg) sodium over a 24 hour infusion, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Blinatumomab has major influence on the ability to drive and use machines. Confusion and disorientation, coordination and balance disorders, risk of seizures and disturbances in consciousness can occur (see section 4.4). Due to the potential for neurologic events, patients receiving blinatumomab should refrain from driving, engaging in hazardous occupations or activities such as driving or operating heavy or potentially dangerous machinery while blinatumomab is being administered. Patients must be advised that they may experience neurologic events.