BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion.
One vial of powder contains 38.5 micrograms blinatumomab.
Reconstitution with water for injections results in a final blinatumomab concentration of 12.5 micrograms/mL.
Blinatumomab is produced in Chinese hamster ovary cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
Powder for concentrate and solution for solution for infusion.
BLINCYTO powder (powder for concentrate): White to off-white powder.
Solution (stabiliser): Colourless-to-slightly yellow, clear solution with a pH of 7.0.
BLINCYTO is indicated for the treatment of adults with Philadelphia chromosome negative relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL).
Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of haematological malignancies.
Hospitalisation 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.
In patients with a history or presence of clinically relevant central nervous system (CNS) pathology (see section 4.4), hospitalisation is recommended at a minimum for the first 14 days of the first cycle. In the second cycle, hospitalisation is recommended at a minimum for 2 days, and clinical judgment should be based on tolerance to BLINCYTO 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 hospitalisation is recommended.
Posology
Patients may receive 2 cycles of treatment. A single cycle of treatment is 4 weeks of continuous infusion. Each cycle of treatment is separated by a 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 dose (for patients at least 45 kg in weight):
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Cycle 1
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2 week-treatment free interval
(Days 29 – 42)
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Cycle 2 and subsequent cycles
(Days 1 - 28)
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Starting dose
Days 1 - 7
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Subsequent dose
Days 8 - 28
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9 mcg/day via continuous infusion
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28 mcg/day via continuous infusion
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28 mcg/day via continuous infusion
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Premedication and additional medication recommendations
Dexamethasone 20 mg intravenous 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.
Pre-phase treatment for patients with high tumour burden
For patients with ≥ 50% leukaemic blasts or > 15,000/microlitre peripheral blood leukaemic blast counts treat with dexamethasone (not to exceed 24 mg/day).
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 (see section 4.4): cytokine release syndrome, tumour 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 below.
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Toxicity
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Grade*
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Action
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Cytokine release syndrome, tumour lysis syndrome
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Grade 3
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Interrupt BLINCYTO until resolved, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur.
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Grade 4
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Discontinue BLINCYTO permanently.
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Neurological toxicity
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Convulsion
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Discontinue BLINCYTO permanently if more than one convulsion occurs.
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Grade 3
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Interrupt BLINCYTO until no more than grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. For re-initiation, premedicate with a 24 mg dose of dexamethasone. Then reduce dexamethasone step-wise over 4 days. If the toxicity occurred at 9 mcg/day, or if the toxicity takes more than 7 days to resolve, discontinue BLINCYTO permanently.
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Grade 4
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Discontinue BLINCYTO permanently.
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Elevated liver enzymes
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Grade 3
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If clinically relevant, interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur.
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Grade 4
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Consider discontinuing BLINCYTO permanently.
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Other clinically relevant (as determined by treating physician) adverse reactions
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Grade 3
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Interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur.
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Grade 4
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Consider discontinuing BLINCYTO permanently.
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*Based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 is severe, and grade 4 is life-threatening.
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Special populations
Elderly
No dose adjustment is necessary in elderly patients (≥ 65 years of age), see section 5.1. There is limited experience with BLINCYTO in patients ≥ 75 years of age.
Renal impairment
Based on pharmacokinetic analyses, dose adjustment is not necessary in patients with mild to moderate renal dysfunction (see section 5.2). The safety and efficacy of BLINCYTO have not been studied in patients with severe renal impairment.
Hepatic impairment
Based on pharmacokinetic analyses, no effect of baseline liver function on blinatumomab exposure is expected and adjustment of the initial dose is not necessary (see section 5.2). The safety and efficacy of BLINCYTO have not been studied in patients with severe hepatic impairment.
Paediatric population
The safety and efficacy of BLINCYTO in paediatric patients have not yet been established.
Currently available data are described in section 4.8 but no recommendation on a posology can be made.
Method of administration
Important note: Do not flush infusion lines into the patient, as it will cause an inadvertent bolus of BLINCYTO to be administered. 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.
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 an in-line, sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter.
A therapeutic dose of 9 mcg/day or 28 mcg/day should be administered to the patient by infusing a total of 240 mL BLINCYTO solution for infusion at one of 4 constant infusion rates and associated infusion durations:
• 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 health care professional for sterility reasons.
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Breast-feeding (see section 4.6).
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, hypoaesthesia, hyporeflexia, tremor, dysaesthesia, paraesthesia, 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.
There is limited experience 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) 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 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, bacteraemia, 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 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 events 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, hypoalbuminaemia, oedema and haemoconcentration) have been commonly associated with CRS (see section 4.8). Patients experiencing capillary leak syndrome should be managed promptly.
Haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/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. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).
Tumour lysis syndrome
Tumour 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-hyperuricaemic 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 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 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 c
