Blincyto

/ Amgen

Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of hematological malignancies. Patients treated with this dru should be given the Educational Brochure for Patients and Caregivers and the Patient Card.
For the treatment of relapsed or refractory B-precursor ALL, hospitalization is recommended for initiation at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.
For the treatment of Philadelphia chromosome negative MRD positive B-precursor ALL, hospitalization is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles.
For pediatric patients with high-risk first relapsed B-precursor ALL, hospitalization is recommended at a minimum for the first 3 days of the cycle.
In patients with a history or presence of clinically relevant central nervous system (CNS) pathology, hospitalization is recommended at a minimum for the first 14 days of the first cycle. In the second cycle, hospitalization is recommended at a minimum for 2 days, and clinical judgment should be based on tolerance in the first cycle. Caution should be exercised as cases of late occurrence of first neurological events have been observed.
For all subsequent cycle starts and reinitiation (e.g. if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
Relapsed or refractory B-precursor ALL
Patients with relapsed or refractory B-precursor ALL, may receive 2 cycles of treatment. A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval.
Patients who have achieved complete remission (CR/CRh*) after 2 treatment cycles may receive up to 3 additional cycles of consolidation treatment, based on an individual benefits-risks assessment.
Recommended daily dose is by patient weight. Patients greater than or equal to 45 kg receive a fixed dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).
Patient weight greater than or equal to 45 kg (fixed-dose):
Cycle 1:
Days 1 – 7: 9 mcg/day via continuous infusion.
Days 8 – 28: 28 mcg/day via continuous infusion.
Days 29 – 42: 14 day treatment-free interval.
Subsequent cycles:
Days 1 – 28: 28 mcg/day via continuous infusion.
Days 29–42: 14 day treatment-free interval.
Patient weight less than 45 kg (BSA-based dose):
Cycle 1:
Days 1 – 7: 5 mcg/m²/day via continuous infusion (not to exceed 9 mcg/day)
Days 8 – 28: 15 mcg/m²/day via continuous infusion (not to exceed 28 mcg/day)
Days 29 – 42: 14 day treatment-free interval.
Subsequent cycles:
Days 1 – 28: 15 mcg/m²/day via continuous infusion (not to exceed 28 mcg/day)
Days 29–42: 14 day treatment-free interval.
High-risk first relapsed B-precursor ALL
Pediatric patients with high-risk first relapsed B-precursor ALL may receive 1 cycle of treatment after induction and 2 blocks of consolidation chemotherapy. A single cycle of treatment is 28 days (4 weeks) of continuous infusion.
One consolidation cycle (1-28 days) for patients with weight greater than or equal to 45 kg: 28 mcg/d
For patients with weight less than 45 kg:  Days 1 -28 dose is 15 mcg/m2/day (not to exceed 28 mcg/day).
Premedication and additional medication recommendations
In adult patients, dexamethasone 20 mg intravenous should be administered 1 hour prior to initiation of each cycle of therapy.
In pediatric patients, dexamethasone 10 mg/m2 (not to exceed 20 mg) should be administered orally or intravenously 6 to 12 hours prior to the start of this therapy (cycle 1, day 1). This should be followed by dexamethasone 5 mg/m2 orally or intravenously within 30 minutes prior to the start (cycle 1, day 1).
Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of each treatment cycle.
Intrathecal chemotherapy prophylaxis is recommended before and during this therapy to prevent central nervous system ALL relapse.
Pre-phase treatment for patients with high tumor burden
For patients with ≥ 50% leukemic blasts in bone marrow or > 15,000/microliter peripheral blood leukemic blast counts treat with dexamethasone (not to exceed 24 mg/day).
MRD positive B-precursor ALL
When considering the use of this drug as a treatment for Philadelphia chromosome negative MRD positive B-precursor ALL, quantifiable MRD should be confirmed in a validated assay with minimum sensitivity of 10-4. Clinical testing of MRD, regardless of the choice of technique, should be performed by a qualified laboratory familiar with the technique, following well established technical guidelines.
Patients may receive 1 cycle of induction treatment followed by up to 3 additional cycles of consolidation treatment. A single cycle of treatment of induction or consolidation is 28 days (4 weeks) of continuous intravenous infusion followed by a 14 day (2 week) treatment-free interval (total 42 days). The majority of patients who respond to blinatumomab achieve a response after 1 cycle. Therefore, the potential benefit and risks associated with continued therapy in patients who do not show hematological and/or clinical improvement after 1 treatment cycle should be assessed by the treating physician.
Recommended dose (for patients at least 45 kg in weight):
Induction Cycle (1)  (Days 1-28) dose: 28 mcg/day. Days 29-42: 14  day treatment-free interval
Consolidation Cycles (2-4) : as Cycle 1
Premedication and additional medication recommendations
Prednisone 100 mg intravenously or equivalent (e.g. dexamethasone 16 mg) should be administered 1 hour prior to initiation of each cycle of therapy.
Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of each treatment cycle.
Intrathecal chemotherapy prophylaxis is recommended before and during this therapy to prevent central nervous system ALL relapse.
Dose adjustments
For patients with Philadelphia chromosome negative relapsed or refractory B precursor ALL and patients with Philadelphia chromosome negative MRD positive B precursor ALL receiving this therapy, consideration to discontinue temporarily or permanently as appropriate should be made in the case of the following severe (grade 3) or life-threatening (grade 4) toxicities: cytokine release syndrome, tumor lysis syndrome, neurological toxicity, elevated liver enzymes and any other clinically relevant toxicities.
If the interruption of treatment after an adverse reaction is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse reaction is longer than 7 days, start a new cycle. If the toxicity takes more than 14 days to resolve, discontinue this drug permanently, except if described differently in the table at the attached doctor’s leaflet.  See prescribing information for full details.

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.
Indicated 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%.
Indicated 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.
Indicated 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.
Limitations of use:
After failure of two previous treatments and with no CNS involvement.

Hypersensitivity to the active substance or to any of the excipients.
Breast-feeding.

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 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.
This drug 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.

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 trials. 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 this drug 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 may be initiated.
It is recommended that a neurological examination be performed in patients prior to starting this 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. 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 this drug in patients with an active uncontrolled infection.
Patients receiving this treatment should be clinically monitored for signs and symptoms of infection and treated appropriately. Management of infections may require either temporary interruption or discontinuation.
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 this drug.
Serious adverse events that may be signs and symptoms of CRS included pyrexia, asthenia, headache, hypotension, total bilirubin increased, and nausea; uncommonly, these events led to 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. 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 .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 this treatment (cycle 1, days 1-7) at the recommended starting dose.
Management of these events may require either temporary interruption or discontinuation.

Tumor lysis syndrome
Tumor lysis syndrome (TLS), which may be life-threatening or fatal (grade ≥ 4) has been observed in patients receiving this drug.
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 this 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.
Neutropenia and febrile neutropenia
Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving this drug. Laboratory parameters (including, but not limited to white blood cell count and absolute neutrophil count) should be monitored routinely during infusion, especially during the first 9 days of the first cycle, and treated appropriately.
Elevated liver enzymes
Treatment with this drug 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.
Monitoring of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during 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.
Pancreatitis
Pancreatitis, life-threatening or fatal, has been reported in patients receiving this drug in clinical trials 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.
Leukoencephalopathy including progressive multifocal leukoencephalopathy
Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving this drug, 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).
CD19-negative relapse
CD19-negative B-precursor ALL has been reported in relapsed patients receiving this drug. 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 this drug, 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 this therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start 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.
Medication errors
Medication errors have been observed with this 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 prescribing information for full details.

Very common: Bacterial infections,Viral infections, Febrile neutropenia,
Anemia, Neutropenia,Thrombocytopenia, Leukopenia, Cytokine release syndrome, Insomnia, Headache,Tremor,Tachycardia ,Hypotension, Hypertension, Cough, Nausea, Diarrhea, Vomiting, Constipation, Abdominal pain, Rash, Back pain, Pain in extremity, Pyrexia, Chills, Edema, Hepatic enzyme increased, Decreased immunoglobulins, Infusion-related reactions.
Common: Sepsis, Pneumonia, Leukocytosis, Lymphopenia, Hypersensitivity,Tumor lysis syndrome, Confusional state, Disorientation, Encephalopathy, Aphasia Paresthesia, Seizure, Cognitive disorder,  Memory impairment, Dizziness, Somnolence, Hypoesthesia, Cranial nerve disorder, Ataxia, Flushing, Dyspnea, Productive cough, Respiratory failure, Wheezing, Hyperbilirubinemia, Bone pain, Chest pain, Pain, Weight increased, Blood alkaline phosphatase increased.
See prescribing information for full details.

No formal drug interaction studies have been performed. Results from an in vitro test in human hepatocytes suggest that blinatumomab did not affect CYP450 enzyme activities.
Initiation of BLINCYTO treatment causes transient release of cytokines during the first days of treatment that may suppress CYP450 enzymes. Patients who are receiving medicinal products that are CYP450 and transporter substrates with a narrow therapeutic index should be monitored for adverse effects (e.g. warfarin) or drug concentrations (e.g. cyclosporine) during this time. The dose of the concomitant medicinal product should be adjusted as needed.

Women of childbearing potential/Contraception
Women of childbearing potential have to use effective contraception during and for at least 48 hours after treatment with blinatumomab.
Pregnancy
Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-fetal developmental toxicity study conducted in mice, the murine surrogate molecule crossed the placenta and did not induce embryotoxicity, or teratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice but hematological effects were not assessed in fetuses.
There are no data from the use of blinatumomab in pregnant women.
Blinatumomab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus.
In case of exposure during pregnancy, depletion of B-cells may be expected in newborns due to the pharmacological properties of the product. Consequently, 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.
Breast-feeding
It is unknown whether blinatumomab or metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast-feeding is contraindicated during and for at least 48 hours after treatment with blinatumomab.
Fertility
No studies have been conducted to evaluate the effects of blinatumomab on fertility. No adverse effects on male or female mouse reproductive organs in 13-week toxicity studies with the murine surrogate molecule.

Overdoses have been observed including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, the infusion should be temporarily interrupted and patients should be monitored. Reinitiation of BLINCYTO at the correct therapeutic dose should be considered when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion.

Storage:  Store and transport refrigerated (2°C – 8°C). Do not freeze. Store the vials in the original package in order to protect from light. After removal from the refrigerator, this drug may be stored at room temperature (23-27°C) and used within 8 hours.