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  • Blincyto
    / Amgen


    Active Ingredient
    Blinatumomab 12.5 mcg/ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    1 X 35 mcg

    partial basket chart 32804 54312

    Related information


    Dosage

    Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of hematological malignancies.
    For the treatment of Philadelphia chromosome negative 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.
    In patients with a history 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 to Blinatumomab in the first cycle. Caution should be exercised as cases of late occurrence of first neurological events in the second cycle 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.
    Blinatumomab infusion bags should be prepared to infuse over 24 hours, 48 hours, 72 hours, or 96 hours.
    Philadelphia chromosome negative relapsed or refractory B-precursor ALL:
    Patients 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 BLINCYTO 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 2942: 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 2942: 14 day treatment-free interval.
    Premedication and additional medication recommendations: In adult patients, dexamethasone 20 mg intravenous should be administered 1 hour prior to initiation of each cycle of BLINCYTO 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 BLINCYTO (cycle 1, day 1). This should be followed by dexamethasone 5 mg/m²
    orally or intravenously within 30 minutes prior to the start of BLINCYTO (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 BLINCYTO 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 BLINCYTO 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 BLINCYTO consolidation treatment. A single cycle of treatment of BLINCYTO 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: 28 mcg/day; Days 29-42: 14-day treatment-free interval.
    Consolidation Cycles 2-4: Days 1-28: 28 mcg/day; Days 29-42: 14-day treatment-free interval.
    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 BLINCYTO 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 BLINCYTO therapy to prevent central nervous system ALL relapse.
    Dose adjustments: Consideration to discontinue BLINCYTO 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 event 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 event is longer than 7 days, start a new cycle. If the toxicity takes more than 14 days to resolve, discontinue BLINCYTO permanently, except if described differently in the table at the attached doctor’s leaflet.
    Elderly: No dose adjustment is necessary in elderly patients (≥ 65 years of age). There is limited experience with BLINCYTO in patients ≥ 75 years of age.
    Renal impairment: Based on pharmacokinetic analyzes, dose adjustment is not necessary in patients with mild to moderate renal dysfunction. The safety and efficacy of BLINCYTO have not been studied in patients with severe renal impairment.
    Hepatic impairment: Based on pharmacokinetic analyzes, no effect of baseline liver function on blinatumomab exposure is expected and adjustment of the initial dose is not necessary. The safety and efficacy of BLINCYTO have not been studied in patients with severe hepatic impairment.
    Pediatric population: The safety and efficacy of BLINCYTO in children < 1 year of age have not yet been established.
    There are no data for children < 7 months of age. Currently available data in children are described in sections 4.8 and 5.1 at the attached doctor’s leaflet.
    Method of administration:
    Important note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, BLINCYTO should be infused through a dedicated lumen.
    For instructions on the handling and preparation of the medicinal product before administration, see section 6.6 at the attached doctor’s leaflet.
    BLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump over a period of up to 96 hours.
    The BLINCYTO solution for infusion must be administered using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding 0.2 micrometer in-line filter.
    The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO.
    Infuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates:
    – Infusion rate of 10 mL/h for a duration of 24 hours
    – Infusion rate of 5 mL/h for a duration of 48 hours
    – Infusion rate of 3.3 mL/h for a duration of 72 hours
    – Infusion rate of 2.5 mL/h for a duration of 96 hours
    The choice of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes. The target therapeutic dose of BLINCYTO delivered does not change.
    Change of infusion bag: The infusion bag must be changed at least every 96 hours by a healthcare professional for sterility reasons.


    Indications

    BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
    BLINCYTO is 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%.
    BLINCYTO is 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.
    Limitations of use: After failure of two previous treatments and with no CNS involvement.


    Contra-Indications

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


    Special Precautions

    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. The median time from initiation of blinatumomab to onset of a neurologic event was 9 days. The majority of events resolved after treatment interruption.
    Elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, and confusion. Patients with a medical history of neurologic signs and symptoms (such as dizziness, hypoesthesia, hyporeflexia, tremor, dysesthesia, paresthesia, memory impairment) demonstrated a higher rate of neurologic events (such as tremor, dizziness, confusional state, encephalopathy and ataxia). The median time to onset of a neurologic event in these patients was 12 days.
    Blincyto is indicated for treatment of adult patients with Philadelphia chromosome-negative relapsed or refractory B‑cell precursor acute lymphoblastic leukemia (ALL) with no CNS involvement.
    There is a possibility of a higher risk of neurologic events in patients with a history or presence of clinically relevant central nervous system (CNS) pathology (e.g. epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis). There is limited experience in these patients as they were excluded from clinical trials. 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 blinatumomab may be initiated.
    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. 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 blinatumomab in patients with an active uncontrolled infection.
    Tumor lysis syndrome: Tumor lysis syndrome (TLS), which may be life-threatening or fatal (grade ≥ 4) has been observed in patients receiving blinatumomab.
    Appropriate prophylactic measures including aggressive hydration and anti-hyperuricaemia therapy (such as allopurinol or rasburicase) should be used for the prevention and treatment of TLS during blinatumomab treatment, especially in patients with higher leukocytosis or a high tumour 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 blinatumomab.
    Neutropenia and febrile neutropenia: Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving blinatumomab. Laboratory parameters (including, but not limited to white blood cell count and absolute neutrophil count) should be monitored routinely during blinatumomab infusion, especially during the first 9 days of the first cycle, and treated appropriately.
    Elevated liver enzymes: Treatment with blinatumomab 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 blinatumomab.
    Pancreatitis: Pancreatitis, life-threatening or fatal, has been reported in patients receiving blinatumomab in clinical trials and the post-marketing setting. High-dose steroid therapy may have contributed, in some cases, to the pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of blinatumomab.
    Leukoencephalopathy including progressive multifocal leukoencephalopathy: Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, 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.
    See prescribing information for full details.


    Side Effects

    The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumor lysis syndrome (0.7%).
    The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), edema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%).
    See prescribing information for full details.


    Drug interactions

    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.


    Pregnancy and Lactation

    Pregnancy: 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.
    Women of childbearing potential have to use effective contraception during and for at least 48 hours after treatment with blinatumomab.
    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.
    Lactation: 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 contra-indicated during and for at least 48 hours after treatment with blinatumomab.
    See prescribing information for full details.


    Overdose

    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.


    Important notes

    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.


    Manufacturer
    Amgen Europe B.V., Breda, Netherlands.
    Licence holder
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