blinatumomab: prescribing information – dosing, contraindications, interactions, side effects

BLINCYTO is indicated as monotherapy for the treatment of adults with CD19 positive relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL). Patients with Philadelphia chromosome-positive B-cell precursor ALL should have failed treatment with at least 2 tyrosine kinase inhibitors (TKIs) and have no alternative treatment options.

BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome- negative CD19 positive B-cell 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 paediatric patients aged 1 month or older with Philadelphia chromosome-negative CD19 positive B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic haematopoietic stem cell transplantation.

BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 month or older with high-risk first relapsed Philadelphia chromosome-negative CD19 positive B-cell precursor ALL as part of the consolidation therapy (see section 4.2).

BLINCYTO is indicated as monotherapy as part of consolidation therapy for the treatment of adult patients with newly diagnosed Philadelphia chromosome negative CD19 positive B-cell precursor ALL.

Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of haematological malignancies. Patients treated with BLINCYTO should be given the Educational Brochure for Patients and Caregivers and the Patient Card.

For the treatment of relapsed or refractory B-cell precursor ALL, 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.

For the treatment of Philadelphia chromosome-negative MRD positive B-cell precursor ALL, hospitalisation is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles.

For the treatment of B-cell precursor ALL in the consolidation phase, hospitalisation is recommended for the first 3 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 judgement should be based on tolerance to BLINCYTO 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 hospitalisation is recommended.

Posology

Relapsed or refractory B-cell precursor ALL

Patients with relapsed or refractory B-cell 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 weeks) 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 body weight (see table 1). 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).

Table 1. BLINCYTO recommended dosage for relapsed or refractory B-cell precursor ALL

Body weight
Cycle 1
Subsequent cycles
Days 1-7
Days 8-28
Days 29-42
Days 1-28
Days 29-42
Greater than or equal to
45 kg
(fixed-dose)
9 mcg/day via continuous infusion
28 mcg/day via continuous infusion
14-day treatment- free interval
28 mcg/day via continuous infusion
14-day treatment-free interval
Less than
45 kg
(BSA-based dose)
5 mcg/m2/day via continuous infusion
(not to exceed
9 mcg/day)
15 mcg/m2/day via continuous infusion
(not to exceed
28 mcg/day)
15 mcg/m2/day via continuous infusion
(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 BLINCYTO therapy.

In paediatric 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 tumour burden

For patients with ≥ 50% leukaemic blasts in bone marrow or > 15 000/microlitre peripheral blood leukaemic blast counts treat with dexamethasone (not to exceed 24 mg/day).

MRD positive B-cell precursor ALL

When considering the use of BLINCYTO as a treatment for Philadelphia chromosome-negative MRD positive B-cell precursor ALL, quantifiable MRD should be confirmed in a validated assay with minimum sensitivity of 10-4 (see section 5.1). 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 weeks) treatment-free interval (total 42 days). The majority of patients who respond to blinatumomab achieve a response after 1 cycle (see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 1 treatment cycle should be assessed by the treating physician. See table 2 for the recommended daily dose.

Table 2. BLINCYTO recommended dosage for adult patients with MRD-positive B-cell precursor ALL

Body weight
Treatment cycle(s)
Days 1-28
Days 29-42
Greater than or equal to 45 kg
(fixed-dose)
28 mcg/day
14-day treatment free interval
Less than 45 kg
(BSA-based dose)
15 mcg/m2/day
(not to exceed 28 mcg/day)
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.

B-cell precursor ALL in the consolidation phase

BLINCYTO is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump. A single cycle of treatment is 28 days (4 weeks) of continuous infusion followed by a 14-day (2-week) treatment-free interval. Patients may receive up to 4 cycles of BLINCYTO consolidation treatment.

See table 3 for the recommended daily dose by body weight for adults. Patients weighing greater than or equal to 45 kg receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).

Table 3. BLINCYTO recommended dosage for B-cell precursor ALL for Adults in the consolidation phase

Body weight
Consolidation cycles (Cycles 1-4)

Days 1-28
Days 29-42
Greater than or equal to 45 kg
(fixed-dose)
28 mcg/day

14 day treatment-free interval

Less than 45 kg
(BSA-based dose)
15 mcg/m2/day
(not to exceed 28 mcg/day)
14 day treatment-free interval

Premedication and additional medication recommendations

In adult patients, dexamethasone 20 mg intravenous should be administered within 1 hour prior to initiation of each cycle of BLINCYTO therapy.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.

High-risk first relapsed B-cell precursor ALL

Paediatric patients with high-risk first relapsed B-cell precursor ALL may receive 1 cycle of BLINCYTO treatment after induction and 2 blocks of consolidation chemotherapy. A single cycle of treatment is 28 days (4 weeks) of continuous infusion. See table 4 for the recommended daily dose by body weight for paediatric patients.

Table 4. BLINCYTO recommended dosage for paediatric patients with high-risk first relapsed B-cell precursor ALL post-induction chemotherapy

One consolidation cycle
Body weight greater than or equal to 45 kg
(fixed-dose)
Body weight less than 45 kg
(BSA-based dose)
Days 1-28
28 mcg/day
15 mcg/m2/day
(not to exceed 28 mcg/day)

Premedication and additional medication recommendations

In paediatric patients, dexamethasone 5 mg/m2 (not to exceed 20 mg) should be administered prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.

Dose adjustments for all indications

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 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 BLINCYTO permanently, except if described differently in the table 5 below.

Table 5. Recommendations for toxicity management (excluding ICANS)

Toxicity
Grade*
Action for patients weighing greater than or equal to 45 kg
Action for patients weighing less than 45 kg
Cytokine release syndrome, tumour lysis syndrome
Grade 3
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.
Interrupt BLINCYTO until resolved, then restart
BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after
7 days if the toxicity does not recur.
Grade 4
Discontinue BLINCYTO permanently.
Discontinue BLINCYTO permanently.
Neurological toxicity
(excluding
ICANS)
Grade 3
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 reinitiation, 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.
Interrupt BLINCYTO until no more than grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after
7 days if the toxicity does not recur. If the toxicity occurred at
5 mcg/m2/day, or if the toxicity takes more than 7 days to resolve, discontinue
BLINCYTO permanently.
Grade 4
Discontinue BLINCYTO permanently.
Discontinue BLINCYTO permanently.
Elevated liver enzymes
Grade 3
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.
If clinically relevant, interrupt
BLINCYTO until no more than grade 1 (mild), then restart
BLINCYTO at 5 mcg/m2/day.
Escalate to 15 mcg/m2/day after
7 days if the toxicity does not recur.
Grade 4
Consider discontinuing
BLINCYTO permanently.
Consider discontinuing
BLINCYTO permanently.

Toxicity
Grade*
Action for patients weighing greater than or equal to 45 kg
Action for patients weighing less than 45 kg
Other clinically relevant (as determined by treating physician) adverse reactions Grade 3 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.
Interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at
5 mcg/m2/day. Escalate to
15 mcg/m2/day after 7 days if the toxicity does not recur.
Grade 4
Consider discontinuing
BLINCYTO permanently.
Consider discontinuing
BLINCYTO permanently.
* Based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 is severe, and grade 4 is life-threatening.

Table 6. Recommendations for management of immune effector cell-associated neurotoxicity syndrome (ICANS)

Gradea
Presenting symptomsb
Actions
Grade 1
ICE score 7-9c
CAPD score 1-8* or depressed level of consciousnessd: awakens spontaneously.
Interrupt BLINCYTO until ICANS resolves.

Monitor neurologic symptoms and consider consultation with a neurologist for further evaluation and management.

Consider non-sedating, antiseizure medicinal products (e.g. levetiracetam) for seizure prophylaxis.

Action for patients ≥ 45 kg:
Consider treatment with dexamethasone up to
8 mg/dose up to 3 doses administered over
24 hours. For reinitiation, premedicate with up to
20 mg dexamethasone 1-3 hours before
BLINCYTO restart.

Action for patients < 45 kg:
Consider treatment with dexamethasone at a total daily dose up to 0.2-0.4 mg/kg/day (up to a maximum 24 mg/day). For reinitiation, premedicate with 5 mg/m2 dexamethasone (maximum 20 mg dose) 1-3 hours before BLINCYTO restart.

Gradea
Presenting symptomsb
Actions
Grade 2
ICE score 3-6c
CAPD score 1-8* or depressed level of consciousnessd: awakens to voice.
Interrupt BLINCYTO.
Administer dexamethasone:

For patients ≥ 45 kg:
Administer dexamethasone 8 mg/dose up to
3 doses/day (24 mg/day maximum) for up to
2 days or until event resolution, whichever is sooner.

For patients < 45 kg:
Administer dexamethasone at a total daily dose of at least 0.2-0.4 mg/kg/day (maximum 24 mg per day) administered over 3 doses for up to 2 days or until event resolution, whichever is sooner.

Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management.

Consider non-sedating, antiseizure medicinal products (e.g. levetiracetam) for seizure prophylaxis.

Action for patients ≥ 45 kg:
Interrupt BLINCYTO until ICANS resolves, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. For reinitiation, premedicate with up to 20 mg dexamethasone 1-3 hours before BLINCYTO restart.

Action for patients < 45 kg:
Interrupt BLINCYTO until ICANS resolve, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur. For reinitiation, premedicate with 5 mg/m2 dexamethasone (maximum 20 mg dose) 1-3 hours before BLINCYTO restart.

Gradea
Presenting symptomsb
Actions
Grade 3
ICE score 0-2c
CAPD ≥ 9 or depressed level of consciousnessd:
- awakens only to tactile stimulus,

or seizuresd, either:
- any clinical seizure, focal or generalised, that resolves rapidly, or
- non-convulsive seizures on electroencephalogram
(EEG) that resolve with intervention,

or raised intracranial pressure:
- focal/local oedema on neuroimagingd
Interrupt BLINCYTO.
Administer dexamethasone:

For patients ≥ 45 kg:
Administer dexamethasone 8 mg/dose 3 doses/day
(24 mg/day maximum) until event resolution to grade 1 or less and then taper as clinically indicated.

For patients < 45 kg:
Administer dexamethasone at a total daily dose of at least 0.2-0.4 mg/kg/day (maximum 24 mg per day) until event resolution to grade 1 or less and then taper as clinically indicated.

Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management.

Consider non-sedating, antiseizure medicinal products (e.g. levetiracetam) for seizure prophylaxis.

Provide supportive therapy, which may include intensive care.

Action for patients ≥ 45 kg:
Interrupt BLINCYTO until ICANS resolves, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. For reinitiation, premedicate with up to 20 mg dexamethasone 1-3 hours before BLINCYTO restart. If the toxicity occurred at 9 mcg/day, or if the toxicity takes more than 7 days to resolve, discontinue BLINCYTO permanently.

Action for patients < 45 kg:
Interrupt BLINCYTO until ICANS resolves, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur. For reinitiation, premedicate with 5 mg/m2 dexamethasone (maximum 20 mg/dose) 1-3 hours before BLINCYTO restart. If the toxicity occurred at 5 mcg/m2/day, or if the toxicity takes more than 7 days to resolve, discontinue BLINCYTO permanently.

Action for all patients:
Permanently discontinue BLINCYTO if more than one seizure occurs.

Gradea
Presenting symptomsb
Actions
Grade 4
ICE score 0c
Unable to perform CAPD* or, depressed level of consciousnessd either:
- patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or
- stupor or coma,

or seizuresd, either:
- life-threatening prolonged seizure (> 5 minutes), or
- repetitive clinical or electrical seizures without return to baseline in between,

or motor findingsd:
- deep focal motor weakness such as hemiparesis or paraparesis,

or raised intracranial pressure/cerebral oedemad, with signs/symptoms such as:
- diffuse cerebral oedema on neuroimaging, or
- decerebrate or decorticate posturing, or
- cranial nerve VI palsy, or
- papilledema, or
- Cushing’s triad
Permanently discontinue BLINCYTO.
Administer dexamethasone:

For patients ≥ 45 kg:
Administer dexamethasone 8 mg/dose 3 doses/day until event resolution to grade 1 or less and then taper as clinically indicated.
Alternatively, consider administration of methylprednisolone 1000 mg per day intravenously for 3 days; taper as clinically indicated.

For patients < 45 kg:
Administer dexamethasone at a total daily dose of at least 0.2-0.4 mg/kg/day until event resolution to grade 1 or less and then taper as clinically indicated.
Alternatively, consider administration of methylprednisolone 30 mg/kg/day (maximum 1000 mg/day) in divided doses intravenously for 3 days; taper as clinically indicated.

Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management.

Consider non-sedating, antiseizure medicinal products (e.g. levetiracetam) for seizure prophylaxis.

Provide supportive therapy, which may include intensive care.
Utilise ICE-Immune effector cell-associated encephalopathy score for patients aged ≥ 12 years of age.
Utilise the CAPD-Cornell Assessment of Paediatric Delirium tool for patients aged < 12 years of age. For details on CAPD assessment please refer to Lee, et al, 2019.
a Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.
b Management is determined by the most severe event, not attributable to any other cause.
c If patient is arousable and able to perform ICE assessment, assess:
Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g. point to clock, pen, button = 3 points); Following commands (e.g. “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE assessment (Grade 4 ICANS) = 0 points.
d Not attributable to any other cause.
e All references to dexamethasone administration are dexamethasone or equivalent medicinal products.
* Scores between 1-8 may represent no impairment, grade 1 or grade 2 ICANS and must be combined with clinical assessment.

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

There is limited experience with BLINCYTO in children < 1 year of age. Currently available data in children are described in sections 4.8 and 5.1.

Method of administration

BLINCYTO is for intravenous use.

For instructions on the handling and preparation of the medicinal product before administration, see section 6.6.

Administer BLINCYTO as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump over a period of up to 96 hours. The pump should be programmable, lockable, non-elastomeric, and have an alarm.

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 prepared BLINCYTO final infusion 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

Administer prepared BLINCYTO final infusion solution using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter.

Important note: Do not flush the BLINCYTO infusion line, 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.

The choice of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes and the weight of the patient. 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.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Breast-feeding (see section 4.6).

Summary of the safety profile

The adverse reactions described in this section were identified in clinical studies of patients with B-cell precursor ALL (N = 1 045).

The most serious adverse reactions that may occur during blinatumomab treatment include: infections (22.6%), neurologic events (12.2%), neutropenia/febrile neutropenia (9.1%), cytokine release syndrome (2.7%), and tumour lysis syndrome (0.8%).

The most common adverse reactions were: pyrexia (70.8%), infections – pathogen unspecified (41.4%), infusion-related reactions (33.4%), headache (32.7%), nausea (23.9%), anaemia (23.3%), thrombocytopenia (21.6%), oedema (21.4%), neutropenia (20.8%), febrile neutropenia (20.4%), diarrhoea (19.7%), vomiting (19.0%), rash (18.0%), hepatic enzyme increased (17.2%), cough (15.0%), bacterial infectious disorders (14.1%), tremor (14.1%), cytokine release syndrome (13.8%),

leukopenia (13.8%), constipation (13.5%), decreased immunoglobulins (13.4%), viral infectious disorders (13.3%), hypotension (13.0%), back pain (12.5%), chills (11.7%), abdominal pain (10.6%), tachycardia (10.6%), insomnia (10.4%), pain in extremity (10.1%), and fungal infectious disorders (9.6%).

Tabulated list of adverse reactions

Adverse reactions are presented below by system organ class and frequency category. Frequency categories were determined from the crude incidence rate reported for each adverse reaction in clinical studies of patients with B-cell precursor ALL (N = 1 045). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA system organ class
Very common
(≥ 1/10)
Common
(≥ 1/100 to < 1/10)
Uncommon
(≥ 1/1 000 to < 1/100)
Infections and infestations
Bacterial infectionsa, b
Viral infectionsa, b
Infections - pathogen unspecifieda, b
Sepsis
Pneumonia
Fungal infectionsa, b

Blood and lymphatic system disorders
Febrile neutropenia
Anaemia1
Neutropenia2
Thrombocytopenia3
Leukopenia4
Leukocytosis5
Lymphopenia6

Lymphadenopathy
Haemophagocytic lymphohistiocytosis
(HLH)

Immune system disorders
Cytokine release syndromea
Hypersensitivity
Cytokine storm
Metabolism and nutrition disorders

Tumour lysis syndrome

Psychiatric disordersa
Insomnia18
Confusional state18
Disorientation18

Nervous system disordersa
Headache18
Tremor18
Encephalopathy18
Aphasia18
Paraesthesia18
Seizure18
Cognitive disorder18
Memory impairment
Dizziness18
Somnolence18
Hypoaesthesia18
Cranial nerve disorderb
Ataxia18
Immune effector cell- associated neurotoxicity syndrome (ICANS)
Speech disorder18
Cardiac disorders
Tachycardia7

Vascular disorders
Hypotension8
Hypertension9
Flushing
Capillary leak syndrome
Respiratory, thoracic and mediastinal disorders
Cough
Dyspnoea
Productive cough
Respiratory failure
Wheezing
Dyspnoea exertional
Acute respiratory failure
Gastrointestinal disorders
Nausea
Diarrhoea
Vomiting
Constipation
Abdominal pain

Pancreatitisa
Hepatobiliary disorders

Hyperbilirubinaemiaa, 10

MedDRA system organ class
Very common
(≥ 1/10)
Common
(≥ 1/100 to < 1/10)
Uncommon
(≥ 1/1 000 to < 1/100)
Skin and subcutaneous tissue disorders
Rash11

Musculoskeletal and connective tissue disorders
Back pain
Pain in extremity
Bone pain

General disorders and administration site conditions
Pyrexia12
Chills
Oedema13
Chest pain14
Pain

Investigations
Hepatic enzyme increaseda, 15
Decreased immunoglobulins16
Weight increased
Blood alkaline phosphatase increased

Injury, poisoning and procedural complications
Infusion-related reactions17

a Additional information is provided in “Description of selected adverse reactions”.
b MedDRA high level group terms (MedDRA version 23.0).

Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above. The terms contributing to the relevant adverse reaction are indicated below:
1 Anaemia includes anaemia and haemoglobin decreased.
2 Neutropenia includes neutropenia and neutrophil count decreased.
3 Thrombocytopenia includes platelet count decreased and thrombocytopenia.
4 Leukopenia includes leukopenia and white blood cell count decreased.
5 Leukocytosis includes leukocytosis and white blood cell count increased.
6 Lymphopenia includes lymphocyte count decreased and lymphopenia.
7 Tachycardia includes sinus tachycardia, supraventricular tachycardia, tachycardia, atrial tachycardia and ventricular tachycardia.
8 Hypotension includes blood pressure decreased and hypotension.
9 Hypertension includes blood pressure increased and hypertension.
10 Hyperbilirubinaemia includes blood bilirubin increased and hyperbilirubinaemia.
11 Rash includes erythema, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash pruritic, catheter site rash, rash pustular, genital rash, rash papular and rash vesicular.
12 Pyrexia includes body temperature increased and pyrexia.
13 Oedema includes bone marrow oedema, periorbital oedema, eyelid oedema, eye oedema, lip oedema, face oedema, localised oedema, generalised oedema, oedema, oedema peripheral, infusion site oedema, oedematous kidney, scrotal oedema, oedema genital, pulmonary oedema, laryngeal oedema, angioedema, circumoral oedema and lymphoedema.
14 Chest pain includes chest discomfort, chest pain, musculoskeletal chest pain and non-cardiac chest pain.
15 Hepatic enzyme increased includes alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hepatic enzyme increased, liver function test increased and transaminases increased.
16 Decreased immunoglobulins includes blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, globulins decreased, hypogammaglobulinaemia, hypoglobulinaemia and immunoglobulins decreased.
17 Infusion-related reactions is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and event lasted ≤ 2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, rash, tachypnoea, swelling face, face oedema and rash erythematous.
18 Events may represent ICANS.

Description of selected adverse reactions

Neurologic events including ICANS

In the randomised phase III clinical study (N = 267) and the single-arm phase II clinical study (N = 189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL treated with BLINCYTO, 66.0% of patients experienced one or more neurologic adverse

reactions (including psychiatric disorders), primarily involving the CNS. Serious and grade ≥ 3 neurologic adverse reactions were observed in 11.6% and 12.1% of patients respectively, of which the most common serious adverse reactions were encephalopathy, tremor, aphasia, and confusional state.
The majority of neurologic events (80.5%) were clinically reversible and resolved following interruption of BLINCYTO. The median time to the first event was within the first 2 weeks of treatment. One case of fatal encephalopathy has been reported in an earlier phase II clinical single-arm study.

Neurologic events were reported for 62.2% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL (N = 45). Serious and grade ≥ 3 neurologic events were reported at 13.3% each in adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL.

Neurologic events were reported for 71.5% of adult patients with MRD positive B-cell precursor ALL (N = 137), 22.6% of patients experienced serious events. Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 16.1% and 2.2% of adult patients with MRD positive B-cell precursor ALL.

Neurologic events were reported in 61.2% of adult patients in CD19-positive B-cell precursor ALL in the consolidation phase where BLINCYTO was administered alternating with chemotherapy (N = 147). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 28.6% and 2.0% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase.

ICANS, including Grade 3 and higher ICANS, were reported in clinical trials and with post-marketing experience. The most frequent clinical manifestations of ICANS were confusional state, aphasia, disorientation, altered state of consciousness, dysarthria, encephalopathy, seizure, mental status changes, somnolence and dysgraphia.

The observed time to onset of ICANS ranged from 0 to 299 days with the majority of ICANS occurring within the first three weeks.

For clinical management of neurologic events and ICANS, see section 4.2.

Infections

Life-threatening or fatal (grade ≥ 4) viral, bacterial and fungal infections have been reported in patients treated with BLINCYTO. In addition, reactivations of virus infection (e.g. Polyoma (BK)) have been observed in the phase II clinical study in adults with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL. Patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL with ECOG performance status at baseline of 2 experienced a higher incidence of serious infections compared to patients with ECOG performance status of < 2.

Infections were reported in 34.7% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase where BLINCYTO was administered alternating with chemotherapy (N = 147).
Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 28.6% and 10.2% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase.

For clinical management of infections, see section 4.4.

Cytokine release syndrome (CRS)

In the randomised phase III clinical study (N = 267) and the single-arm phase II clinical study (N = 189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL treated with BLINCYTO, 14.7% of patients experienced CRS. Serious CRS reactions were reported in 2.4% of patients with a median time to onset of 2 days.

Cytokine release syndrome was reported in 8.9% of adult patients with Philadelphia chromosome- positive relapsed or refractory B-cell precursor ALL (N = 45), 2.2% of patients experienced serious events. No grade ≥ 3 or ≥ 4 events were reported.

Cytokine release syndrome was reported in 2.9% of adult patients with MRD positive B-cell precursor ALL (N = 137). Grade 3 and serious events were reported for 1.5% each of adult patients with MRD positive B-cell precursor ALL; no grade ≥ 4 events were reported.

Cytokine release syndrome was reported in 15.6% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase where BLINCYTO was administered alternating with chemotherapy (N = 147). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 4.1% and 0.7% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase.

Capillary leak syndrome was observed in 1 patient in the phase II clinical study in adult patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL and in 1 patient in the phase II clinical study in adult patients with MRD positive B-cell precursor ALL. Capillary leak syndrome was not observed in adult patients in the phase II clinical study in patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. Capillary leak syndrome was reported in 1 patient (0.7%) with CD19-positive B-cell precursor ALL in the consolidation phase where BLINCYTO was administered alternating with chemotherapy (N = 147); the event was grade 3.

For clinical management of CRS, see section 4.4.

Elevated liver enzymes

In the randomised phase III clinical study (N = 267) and the single-arm phase II clinical study (N = 189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL treated with BLINCYTO, 22.4% of patients reported elevated liver enzymes and associated signs/symptoms. Serious and grade ≥ 3 adverse reactions (such as ALT increased, AST increased, and blood bilirubin increased) were observed in 1.5% and 13.6% of patients respectively. The median time to onset to the first event was 4 days from the start of BLINCYTO treatment initiation.

Elevated liver enzyme events were reported for 17.8% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL (N = 45), 2.2% of patients experienced serious events. Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 13.3% and 6.7% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL.

Elevated liver enzyme events were reported for 12.4% of adult patients with MRD positive B-cell precursor ALL (N = 137). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 8.0% and 4.4% of adult patients with MRD positive B-cell precursor ALL.

Elevated liver enzyme events were reported in 15.6% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase where BLINCYTO was administered alternating with chemotherapy (N = 147). Grade ≥ 3 and Grade ≥ 4 events, respectively, were reported -for 8.8% and 2.7% of adult patients with CD-19 positive B-cell precursor ALL in the consolidation phase.

The duration of hepatic adverse reactions has generally been brief and with rapid resolution, often when continuing uninterrupted treatment with BLINCYTO.

For clinical management of elevated liver enzymes, see section 4.4.

Pancreatitis

Pancreatitis, life-threatening or fatal, has been reported in patients receiving BLINCYTO in the clinical studies and the post-marketing settings. The median time to onset was 7.5 days. For clinical management of pancreatitis, see section 4.4.

Leukoencephalopathy including progressive multifocal leukoencephalopathy

Leukoencephalopathy has been reported. Patients with brain MRI/CT findings consistent with leukoencephalopathy experienced concurrent serious adverse reactions including confusional state, tremor, cognitive disorder, encephalopathy, and convulsion. Although there is a potential for the development of progressive multifocal leukoencephalopathy (PML), no confirmed case of PML has been reported in the clinical studies.

Paediatric population

The safety and effectiveness of BLINCYTO have been evaluated in paediatric patients with Philadelphia chromosome negative relapsed or refractory B-cell precursor ALL in two open label studies: a single-arm phase I/II study (MT103-205) and a randomised, controlled phase III study (20120215).

Study MT103-205 was a dose escalation/evaluation study in paediatric patients with relapsed or refractory B-cell precursor ALL in a phase I/II, single-arm dose escalation/evaluation study (MT103-205), in which 70 patients, aged 7 months to 17 years, were treated with the recommended dosage regimen.

The most frequently reported serious adverse reactions were pyrexia (11.4%), febrile neutropenia (11.4%), cytokine release syndrome (5.7%), sepsis (4.3%), device-related infection (4.3%), overdose (4.3%), convulsion (2.9%), respiratory failure (2.9%), hypoxia (2.9%), pneumonia (2.9%), and multi-organ failure (2.9%).

The adverse reactions in BLINCYTO-treated paediatric patients were similar in type to those seen in adult patients. Adverse reactions that were observed more frequently (≥ 10% difference) in the paediatric population compared to the adult population were anaemia, thrombocytopenia, leukopenia, pyrexia, infusion-related reactions, weight increase, and hypertension.

The type and frequency of adverse reactions were similar across different paediatric subgroups (gender, age and geographic region).

At a dose higher than the recommended dose in study MT103-205, a case of fatal cardiac failure occurred in the setting of life-threatening cytokine release syndrome (CRS) and tumour lysis syndrome (TLS), see section 4.4.

BLINCYTO has also been evaluated in paediatric patients with high-risk first relapsed B-cell precursor ALL in a randomised, controlled, open-label phase III study (20120215), in which 54 patients, aged 1 to 18 years, were treated with the recommended dosage regimen for high-risk first relapsed B-cell precursor ALL. The safety profile of BLINCYTO in study 20120215 is consistent with that of the studied paediatric relapsed or refractory B-cell precursor ALL population.

Other special populations

There is limited experience with BLINCYTO in patients ≥ 75 years of age. Generally, safety was similar between elderly patients (≥ 65 years of age) and patients less than 65 years of age treated with BLINCYTO. However, elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, encephalopathy and confusion.

Elderly patients with MRD positive ALL treated with BLINCYTO may have an increased risk of hypogammaglobulinaemia compared to younger patients. It is recommended that immunoglobulin levels are monitored in elderly patients during treatment with BLINCYTO.

The safety of BLINCYTO has not been studied in patients with severe renal impairment.

Immunogenicity

In clinical studies of adult ALL patients treated with BLINCYTO, less than 2% tested positive for anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, the majority had in vitro neutralising activity. No anti-blinatumomab antibodies were detected in clinical studies of paediatric patients with relapsed or refractory ALL treated with blinatumomab.

Anti-blinatumomab antibody formation may affect the pharmacokinetics of BLINCYTO.

Overall, the totality of clinical evidence supports the finding that anti-blinatumomab antibodies are not suggestive of any clinical impact on the safety or effectiveness of BLINCYTO.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 including ICANS

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 including ICANS 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 2 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, hypoaesthesia, hyporeflexia, tremor, dysaesthesia, paraesthesia 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.

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.

Patients with Down syndrome may have a higher risk of seizures with BLINCYTO therapy; consider seizure prophylaxis prior to initiation of BLINCYTO for these patients.

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 including ICANS (e.g. writing test which could be part of a comprehensive neurological assessment). Management of these signs and symptoms to resolution may require either temporary interruption or permanent discontinuation of BLINCYTO and/or treatment with corticosteroids (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. 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, 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 (HLH)/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).

Haemophagocytic lymphohistiocytosis/Immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS)

Haemophagocytic lymphohistiocytosis (HLH)/Immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) have been observed in patients receiving BLINCYTO.
HLH is a life-threatening syndrome characterized by fever, hyperferritinaemia, hepato- and/or splenomegaly, cytopenias, coagulopathy with hypofibrinogenaemia, haemophagocytosis and transaminitis. IEC-HS refers to the occurrence of HLH-like toxicities associated with immune effector cell therapies, characterized by excessive immune activation and dysregulated cytokine production leading to multisystem inflammation and organ dysfunction. HLH/IEC-HS should be considered when the presentation of CRS is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH/IEC-HS. For suspected HLH/IEC-HS, BLINCYTO must be interrupted for diagnostic workup, including evaluation for alternative causes of HLH such as infections, malignancies and autoimmune diseases. Prompt initiation of treatment for HLH/IEC-HS (e.g.
corticosteroids, immunosuppressive or cytokine-directed therapy, and supportive care) should follow institutional or published guidelines.

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 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-leukaemic 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-cell 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 leukaemia (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.

Immunisations

The safety of immunisation 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 minimise 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’.

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 (see section 4.4).

Pregnancy

Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study conducted in mice, the murine surrogate molecule crossed the placenta and did not induce embryotoxicity, or teratogenicity (see section 5.3). The expected depletions of B- and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses.

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 foetus.

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 (see section 4.4).

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 (see section 5.3).

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.

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 (see section 4.2).

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX07.

Mechanism of action

Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on T-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal in nature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing proteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.

Pharmacodynamic effects

Consistent immune-pharmacodynamic responses were observed in patients studied. During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterised by T-cell activation and initial redistribution, rapid peripheral B-cell depletion, and transient cytokine elevation.

Peripheral T-cell redistribution (i.e. T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of blinatumomab infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients.

Peripheral B-cell counts decreased rapidly to an undetectable level during treatment at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week treatment-free period between treatment cycles. Incomplete depletion of B-cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few non-responders at higher doses.

Peripheral lymphocytes were not measured in paediatric subjects.

Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α and IFN-γ were measured and, IL-6, IL-10 and IFN-γ were most elevated. Transient elevation of cytokines was observed in the first 2 days following start of blinatumomab infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.

Clinical efficacy and safety

Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9-162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory ALL, the mean (SD) Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively. The pharmacokinetics of blinatumomab in patients with MRD positive B-cell precursor ALL were similar to patients with relapsed or refractory ALL. The pharmacokinetics of blinatumomab in the consolidation phase in adults with B-cell precursor ALL, including patients with newly diagnosed ALL and first relapsed ALL, were similar to adult patients with relapsed or refractory ALL.

Distribution

The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 5.27 (4.37) L with the continuous intravenous infusion of blinatumomab.

Biotransformation

The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination

The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 3.10 (2.94) L/hour. The mean (SD) half-life was 2.20 (1.34) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.

Specific populations