Blincyto

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

  



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion. 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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. 

 

 

3. PHARMACEUTICAL FORM 

 
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. 

 
 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome 

negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (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 paediatric 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. 

 

4.2 Posology and method of administration 

 

Treatment should be initiated under the direction of and supervised by physicians experienced in the 

treatment of haematological malignancies.  

 

For the treatment of Philadelphia chromosome negative relapsed or refractory B-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. 

 

 



3 

For the treatment of Philadelphia chromosome negative MRD positive B-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. 

 

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 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. 

 

BLINCYTO infusion bags should be prepared to infuse over 24 hours, 48 hours, 72 hours, or 

96 hours. See method of administration. 

 

Posology  

 

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 

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). 

 



4 

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-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 (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 week) 

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. 

 

Recommended dose (for patients at least 45 kg in weight): 

 

Treatment cycle(s) 

Induction Cycle 1 

Days 1-28 Days 29-42 

28 mcg/day 14-day treatment-free interval 

Consolidation Cycles 2-4 

Days 1-28 Days 29-42 

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. 

 

Dose adjustments 

 

For patients with Philadelphia chromosome negative relapsed or refractory B-precursor ALL and 

patients with MRD positive B-precursor ALL receiving BLINCYTO, 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, 



5 

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. 

 

Toxicity Grade* Action for patients greater 

than or equal to 45 kg 

Action for patients 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 

Convulsion  Discontinue BLINCYTO 

permanently if more than one 

convulsion occurs. 

 

Discontinue BLINCYTO 

permanently if more than one 

convulsion occurs. 

 

 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.  



6 

Toxicity Grade* Action for patients greater 

than or equal to 45 kg 

Action for patients 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. 

 

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 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 section 4.8 and 5.1. 

 

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. 

 

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 micrometre in-line filter. 

 



7 

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. 

 

4.3 Contraindications 

 

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

4.4 Special warnings and precautions for use 

 

Neurologic events 

 

Neurologic events including events with a fatal outcome have been observed. Grade 3 (CTCAE 

version 4.0) or higher (severe or life-threatening) neurologic events following initiation of 

blinatumomab administration included encephalopathy, seizures, speech disorders, disturbances in 

consciousness, confusion and disorientation, and coordination and balance disorders. Among patients 

that experienced a neurologic event, the median time to the first event was within the first two weeks 

of treatment and the majority of events resolved after treatment interruption and infrequently led to 

BLINCYTO treatment discontinuation. 

 

Elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, 

encephalopathy, and confusion.  

 

Patients with a medical history of neurologic signs and symptoms (such as dizziness, hypoaesthesia, 

hyporeflexia, tremor, dysaesthesia, paraesthesia, 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 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 



8 

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. 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 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 histiocytosis/macrophage activation syndrome (MAS) has been uncommonly 

reported in the setting of CRS.  

 

Infusion reactions may be clinically indistinguishable from manifestations of CRS (see section 4.8). 

The infusion reactions were generally rapid, occurring within 48 hours after initiating infusion. 

However some patients reported delayed onset of infusion reactions or in later cycles. Patients 

should be observed closely for infusion reactions, especially during the initiation of the first and 

second treatment cycles and treated appropriately. Anti-pyretic use (e.g. paracetamol) is 

recommended to help reduce pyrexia during the first 48 hours of each cycle. To mitigate the risk of 

CRS, it is important to initiate BLINCYTO (cycle 1, days 1-7) at the recommended starting dose in 

section 4.2.  

 

Management of these events may require either temporary interruption or discontinuation of 

BLINCYTO (see section 4.2). 

 

Tumour lysis syndrome 

 

Tumour lysis syndrome (TLS), which may be life-threatening or fatal (grade ≥ 4) has been observed 

in patients receiving BLINCYTO.  

 



9 

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 

trials and the post-marketing setting. High-dose steroid therapy may have contributed, in some cases, 

to the pancreatitis. 

 

Patients should be closely monitored for signs and symptoms of pancreatitis. Patient evaluation may 

include physical examination, laboratory evaluation for serum amylase and serum lipase, and 

abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Management of 

pancreatitis may require either temporary interruption or discontinuation 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. 

 

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. 

 



10 

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 provides less than 1 mmol (23 mg) sodium over a 24 hour infusion i.e. 

“essentially sodium-free”. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

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. 

 

4.6 Fertility, pregnancy and lactation 

 

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.  

 

Women of childbearing potential have to use effective contraception during and for at least 48 hours 

after treatment with blinatumomab (see section 4.4). 

 

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). 

 



11 

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). 

 

4.7 Effects on ability to drive and use machines 

 

Blinatumomab has major influence on the ability to drive and use machines. Confusion and 

disorientation, coordination and balance disorders, risk of seizures and disturbances in consciousness 

can occur (see section 4.4). Due to the potential for neurologic events, patients receiving 

blinatumomab should refrain from driving, engaging in hazardous occupations or activities such as 

driving or operating heavy or potentially dangerous machinery while blinatumomab is being 

administered. Patients must be advised that they may experience neurologic events.  

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

The adverse reactions described in this section were identified in clinical studies of patients with 

B-precursor ALL (N = 843). 

 

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 tumour 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%), anaemia (22.8%), thrombocytopenia 

(20.9%), febrile neutropenia (20.2%), oedema (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%). 

 

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-precursor ALL (N = 843). Within each system organ class, adverse 

reactions are presented in order of decreasing seriousness. 

 



12 

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 

Fungal infectionsa, b 

Viral infectionsa, b 

Infections - pathogen 

unspecifieda, b 

Sepsis 

Pneumonia 

 

 

Blood and lymphatic 

system disorders 

Febrile neutropenia 

Anaemia1 

Neutropenia2 

Thrombocytopenia3 

Leukopenia4 

Leukocytosis5 

Lymphopenia6 

 

Lymphadenopathy 

Histiocytosis 

haematophagic 

Immune system 

disorders 

Cytokine release 

syndromea 

Hypersensitivity Cytokine storm 

Metabolism and 

nutrition disorders 

 Tumour lysis 

syndrome 

 

Psychiatric disordersa Insomnia Confusional state 

Disorientation 

 

Nervous system 

disordersa 

Headache  

Tremor 

 

Encephalopathy 

Aphasia 

Paraesthesia  

Seizure  

Cognitive disorder 

Memory impairment 

Dizziness  

Somnolence 

Hypoaesthesia  

Cranial nerve disorderb 

Ataxia 

Speech disorder 

 

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 

 

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 

 



13 

MedDRA system 

organ class 

Very common 

(≥ 1/10) 

Common 

(≥ 1/100 to < 1/10) 

Uncommon 

(≥ 1/1,000 to < 1/100) 

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 18.1). 

 
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 and 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 and 

rash pruritic. 
12 Pyrexia includes body temperature increased and pyrexia. 
13 Oedema includes face oedema, generalised oedema, oedema and oedema peripheral. 
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-glutamyltransferase increased, hepatic enzyme increased and transaminases increased.  
16 Decreased immunoglobulins includes blood immunoglobulin G 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, tachypnea, swelling face, 

face oedema and rash erythematous. 
 

Description of selected adverse reactions 

 

Neurologic events 

 

In BLINCYTO-treated patients in the randomised phase III clinical study (N = 267) and the single 

arm phase II clinical study (N = 189), 66.0% of patients experienced one or more neurologic adverse 

reactions (including psychiatric disorders), primarily involving the central nervous system. 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 two 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 71.5% of adult patients with MRD positive B-precursor ALL 

(N = 137) of which 22.6% were considered serious. Grade ≥ 3 and grade ≥ 4 events, respectively, 

were reported for 16.1% and 2.2% of adult patients with MRD positive B-precursor ALL. 

 

For clinical management of neurologic events, see section 4.4. 

 



14 

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-precursor ALL. Patients with Philadelphia chromosome negative relapsed or 

refractory B-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. For 

clinical management of infections, see section 4.4. 

 

Cytokine release syndrome (CRS) 

 

In BLINCYTO-treated patients in the randomised phase III clinical study (N = 267) and the single 

arm phase II clinical study (N = 189), 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 2.9% of adult patients with MRD positive B-precursor 

ALL (N = 137). Grade 3 and serious events were reported for 1.5% each of adult patients with MRD 

positive B-precursor ALL; no grade ≥ 4 events were reported. 

 

Capillary leak syndrome was observed in 1 patient in the phase II clinical study in adult patients with 

relapsed or refractory B-precursor ALL and in 1 patient in the phase 2 clinical study in adult patients 

with MRD positive B-precursor ALL. 

 

For clinical management of CRS, see section 4.4. 

 

Elevated liver enzymes 

 

In BLINCYTO-treated patients in the randomised phase III clinical study (N = 267) and the single 

arm phase II clinical study (N = 189), 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 12.4% of adult patients with MRD positive 

B-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-precursor ALL. 

 

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 trials 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 events 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.  



15 

 

Paediatric population 

 

BLINCYTO has been evaluated in paediatric patients with relapsed or refractory B-precursor ALL in 

a phase I/II dose escalation/evaluation study, in which 70 paediatric patients, aged 7 months to 

17 years, were treated with the recommended dosage regimen. 

 

The most frequently reported serious adverse events 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 events were similar across different paediatric sub-groups 

(gender, age, geographic region). 

 

At a dose higher than the recommended dose, 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. 

 

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 3% tested positive for 

anti-blinatumomab antibodies. Six of those patients had anti-blinatumomab antibodies with in vitro 

neutralising activity. No anti-blinatumomab antibodies were detected in clinical studies of paediatric 

patients with relapsed or refractory ALL treated with blinatumomab. 

 

If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact 

the Marketing Authorisation Holder to discuss antibody testing. Contact details are provided in 

section 6 of the package leaflet. 

 

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. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


16 

4.9 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 (see section 4.2). 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Antineoplastic agents, other Antineoplastic agents, ATC code: 

L01XC19. 

 

Mechanism of action 

 

Blinatumomab is a bispecific T-cell engager antibody construct 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 two 

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 



17 

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-precursor ALL 

 

A total of 456 patients aged ≥ 18 years of age with relapsed or refractory B-precursor ALL were 

exposed to BLINCYTO during the phase II and phase III clinical studies described below.  

 

The safety and efficacy of BLINCYTO compared to standard of care (SOC) chemotherapy were 

evaluated in a randomised, open-label, multicentre, phase III study. Eligible patients were ≥ 18 years 

of age and ECOG status ≤ 2 with relapsed or refractory B-cell precursor ALL (had > 5% blasts in the 

bone marrow and either relapse at any time after allogeneic HSCT, untreated first relapse with first 

remission duration < 12 months, or refractory to last therapy). 

 

Patients were randomised 2:1 to receive BLINCYTO or 1 of 4 prespecified, investigator-selected, 

SOC backbone chemotherapy regimens. Randomisation was stratified by age (< 35 years versus 

≥ 35 years of age), prior salvage therapy (yes versus no), and prior allogeneic HSCT (yes versus no) 

as assessed at the time of consent. The demographics and baseline characteristics were well-balanced 

between the two arms (see table 1). 

 

Table 1. Demographics and baseline characteristics in phase III study 

 

Characteristic 
BLINCYTO 

(N = 271) 

SOC chemotherapy 

(N = 134) 

Age 

 Median, years (min, max) 37 (18, 80) 37 (18, 78) 

 Mean, years (SD) 40.8 (17.1) 41.1 (17.3)  

 ≥ 65 Years, n (%) 33 (12.2) 15 (11.2) 

Prior salvage therapy 164 (60.5) 80 (59.7) 

 0 114 (42.1) 65 (48.5) 

 1 91 (33.6) 43 (32.1) 

 ≥ 2 66 (24.3) 26 (19.4) 

Prior alloHSCT  94 (34.7) 46 (34.3) 

ECOG status - n (%)   

0 96 (35.4) 52 (38.8) 

1 134 (49.4) 61 (45.5) 

2 41 (15.1) 20 (14.9) 

Refractory status - n (%)   

 Primary refractory 46 (17.0) 27 (20.1) 

 Refractory to salvage therapy 87 (32.1) 34 (25.4) 

Maximum of central/local bone marrow 

blasts - n (%) 
  

 ≥ 50% 201 (74.2) 104 (77.6) 
AlloHSCT = allogeneic haematopoietic stem cell transplantation 

SOC = standard of care 

 

BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose 

was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 

28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose 

adjustment was possible in case of adverse events. Of the 267 patients who received BLINCYTO, 

the mean number of completed treatment cycles was 2.0; of the 109 patients who received SOC 

chemotherapy, the mean number of treatment cycles was 1.3. 

 



18 

The primary endpoint was overall survival (OS). The median OS was 4.0 months (95% CI: 2.9, 5.3) 

in the SOC chemotherapy arm compared with 7.7 months (95% CI: 5.6, 9.6) in the BLINCYTO arm. 

The hazard ratio (95% CI) was 0.71 (0.55, 0.93) between treatment arms favouring BLINCYTO, 

indicated a 29% reduction in hazard rate in the BLINCYTO arm (p-value = 0.012 (stratified log-rank 

test)), see figure 1. Consistency in OS results was shown in subgroups by stratification factors. 

 

Consistent results were observed after censoring at the time of HSCT; median OS, censored at the 

time of HSCT, was 6.9 months (95% CI: 5.3, 8.8) in the BLINCYTO group and 3.9 months 

(95% CI: 2.8, 4.9) in the SOC group (HR, 0.66; 95% CI: 0.50, 0.88; p value = 0.004). The mortality 

rate following alloHSCT among all responders who did not receive anti-leukemic therapy was 

10/38 (26.3%; 95% CI: 13.4, 43.1) in the BLINCYTO group and 3/12 (25%; 95% CI: 5.5, 57.2) in 

the SOC group; such mortality rate at 100 days post alloHSCT was 4/38 (12.4%; 95% CI: 4.8%, 

29.9%) in the BLINCYTO group and 0/12 (0%; 95% CI: not estimable) in the SOC group. Efficacy 

results from other key endpoints in the study are summarised in table 2. 

 

Figure 1. Kaplan-Meier curve of overall survival 

 

 
 

 

 

Table 2. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome negative 

relapsed or refractory B-cell precursor ALL 

 

 BLINCYTO 

(N = 271) 

SOC chemotherapy  

(N = 134) 

Complete remission (CR) 

CRa/CRh*b/CRic, n (%) [95% CI] 
119 (43.9) (37.9, 50.0) 33 (24.6) (17.6, 32.8) 

Treatment difference [95% CI] 19.3 (9.9, 28.7) 

p-value  < 0.001 

CR, n (%) [95% CI] 91 (33.6) (28.0, 39.5) 21 (15.7) (10.0, 23.0) 

Treatment difference [95% CI] 17.9 (9.6 - 26.2) 

p-value  < 0.001 

Event-free survivald 

6-month estimate % [95% CI] 30.7 (25.0, 36.5) 12.5 (7.2, 19.2) 

18-months estimate % [95% CI] 9.5 (5.1, 15.6) 7.9 (3.7, 14.2) 

HR [95% CI] 0.55 (0.43, 0.71) 

 

Number of subjects at Risk 

Months 

1.0 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0.0 

 

S
ur

vi
va

l P
ro

ba
bi

lit
y 

Median OS, mo 7.7 (5.6, 9.6)  4.0 (2.9, 5.3) 
HR (BLINCYTO/SOC Chemo) (95% CI) 0.71 (0.55, 0.93)  
p-value (2-sided) 0.012  

 

BLINCYTO 271 176 124 79 45 27 9 4 0 0 

SOC Chemo 134 71 41 27 17 7 4 1 0 0 

 

0 3 6 9 12 15 18 21 24 27 

 

BLINCYTO (N=271) SOC Chemo (N=134) 

 BLINCYTO  SOC Chemo 

A censored subject is indicated by a Vertical Bar l. GRH0358 v1 



19 

 BLINCYTO 

(N = 271) 

SOC chemotherapy  

(N = 134) 

Duration of haematological response- 

Median time to event [95% CI] 

CR 8.3 (5.7, 10.7) 7.8 (2.2, 19.0) 

CR/CRh*/CRi 7.3 (5.8, 9.9) 4.6 (1.8, 19.0) 

MRDe response for CR/CRh*/CRi  

MRD evaluable patients (%) 

[95% CI]f 
74/97 (76.3) (66.6, 84.3) 

16/33 (48.5) (30.8, 

66.5) 

Duration of MRD response- 

Median time to event [95% CI] 
4.5 months (3.6, 9.0) 3.8 months (1.9, 19.0) 

Postbaseline alloHSCT - n (%) 

Overall subjects 65 (24) 32 (23.9) 

Hematological responders 

(CR/CRh*/CRi) 
50 (42.0) 18 (54.5) 

Time to alloHSCT among all 

transplanted patients 

Median time to event 

(Interquartile range) 

3.7 months (3.0, 5.3) 

(N = 65) 

3.1 months (2.6, 4.3) 

(N = 32) 

Time to alloHSCT among 

CR/CRh*/CRi responders 

Median time to event [95% CI] 

(KM estimate) 

11.3 months (5.2, NE) 

(N = 119) 

3.6 months (2.3, 7.2) 

(N = 33) 

100 day mortality after alloHSCT 

n/N (%), [95% CI] 4/38, 12.4% (4.8, 29.9) 0/12, 0.0% (0.0, NE) 
a. CR was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral 

blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre). 
b. CRh* (complete remission with partial haematologic recovery) was defined as ≤ 5% blasts in the bone 

marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre 

and ANC > 500/microlitre). 
c. CRi (complete remission with incomplete haematologic recovery) was defined as ≤ 5% blasts in the bone 

marrow, no evidence of disease, and incomplete recovery of peripheral blood counts (platelets 

> 100,000/microlitre or ANC > 1,000/microlitre). 
d. EFS time was calculated from the time of randomisation until the date of disease assessment indicating a 

relapse after achieving a CR/CRh*/CRi or death, whichever is earlier. Subjects who fail to achieve a 

CR/CRh*/CRi within 12 weeks of treatment initiation are considered treatment failures and assigned an EFS 

duration of 1 day. 
e. MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 x 10-4.  
f. Patients who achieved CR/CRh*/CRi and had an evaluable post baseline MRD assessment. 
 

Health related quality of life 

 

In this open-label study, Health related quality of life (HRQoL) reported by patients were measured 

using the European Organisation for Research and Treatment of Cancer Quality of Life 

Questionnaire - Core 30 (EORTC QLQ-C30). In a post-hoc sensitivity analysis, compared to SOC, 

BLINCYTO consistently delayed the time to clinically meaningful deterioration of HRQoL 

(≥ 10-point worsening from baseline) for global health status [median BLINCYTO versus SOC: 

8.1 months versus 1.0 month; HR = 0.60 (95% CI = 0.42, 0.85)], functional scales, symptom scales 

and individual items. Because the health-related quality of life results are based on a post-hoc 

sensitivity analysis, the results should be interpreted with caution.  

 

BLINCYTO was also evaluated in an open-label, multicentre, single-arm phase II study of 

189 patients. Eligible patients were ≥ 18 years of age with Philadelphia chromosome negative 

relapsed or refractory B-precursor ALL (relapsed with first remission duration of ≤ 12 months in first 

salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of 

allogeneic HSCT, and had ≥ 10% blasts in bone marrow).  

 



20 

Premedication, BLINCYTO dose per treatment cycle and route of administration were identical to 

those in the phase III study. Patients were premedicated with a mandatory cerebrospinal fluid 

prophylaxis consisting of an intrathecal regimen according to institutional or national guidelines 

within 1 week prior to start of BLINCYTO treatment. BLINCYTO was administered as a continuous 

intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day 

for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and 

subsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in the case of 

adverse events. The treated population included 189 patients who received at least 1 infusion of 

BLINCYTO; the mean number of cycles per patient was 1.6. Patients who responded to BLINCYTO 

but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the 

median age was 39 years (range: 18 to 79 years, including 25 patients ≥ 65 years of age), 64 of 

189 (33.9%) had undergone HSCT prior to receiving BLINCYTO and 32 of 189 (16.9%) had 

received more than 2 prior salvage therapies.  

 

The primary endpoint was the complete remission/complete remission with partial haematological 

recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eighty-one of 189 (42.9%) 

patients achieved CR/CRh* within the first 2 treatment cycles with the majority of responses (64 of 

81) occurring within 1 cycle of treatment. In the elderly population (≥ 65 years of age) 11 of 

25 patients (44.0%) achieved CR/CRh* within the first 2 treatment cycles (see section 4.8 for safety 

in elderly). Four patients achieved CR during consolidation cycles, resulting in a cumulative CR rate 

of 35.4% (67/189; 95% CI: 28.6% - 42.7%). Thirty-two of 189 (17%) patients underwent allogeneic 

HSCT in CR/CRh* induced with BLINCYTO (see table 3).  

 

Table 3. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome negative 

relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL) 
 

 n (%) 

n = 189 

95% CI 

Complete remission (CR)1/Complete remission 

with partial haematological recovery (CRh*)2 

81 (42.9%)  [35.7% - 50.2%] 

CR  63 (33.3%)  [26.7% - 40.5%] 

CRh* 18 (9.5%)  [5.7% - 14.6%] 

Blast free hypoplastic or aplastic bone marrow3  17 (9%)  [5.3% - 14.0%] 

Partial remission4 5 (2.6%)  [0.9% - 6.1%] 

Relapse5-free survival (RFS) for CR/CRh*  5.9 months  [4.8 to 8.3 months] 

Overall survival 6.1 months  [4.2 to 7.5 months] 
1. CR was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral 

blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre). 
2. CRh* was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of 

peripheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre). 
3. Blast free hypoplastic or aplastic bone marrow was defined as bone marrow blasts ≤ 5%, no evidence of 

disease, insufficient recovery of peripheral blood counts: platelets ≤ 50,000/microlitre and/or ANC 

≤ 500/microlitre. 
4. Partial remission was defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline. 
5. Relapse was defined as haematological relapse (blasts in bone marrow greater than 5% following CR) or an 

extramedullary relapse. 
 

In a prespecified exploratory analysis, 60 of 73 MRD evaluable patients with CR/CRh* (82.2%) also 

had a MRD response (defined as MRD by PCR < 1 x 10-4).  

 

Patients with prior allogeneic HSCT had similar response rates to those without prior HSCT, older 

patients had similar response rates to younger patients, and no substantial difference was observed in 

remission rates based on the number of lines of prior salvage treatment.  

 

In patients with non-CNS/non-testes extramedullary disease (defined as at least 1 lesion ≥ 1.5 cm) at 

screening (N = 8/189) clinical response rates (25% [95% CI: 3.2-65.1] were lower compared with 

patients with no evidence of extramedullary disease (N = 181, 43.6% [95% CI: 36.3 - 51.2]) (see 

figure 2). 



21 

 

Patients with the highest tumour burden as measured by the percentage of bone marrow blast cells at 

baseline (≥ 90%) still had a clinically meaningful response with a CR/CRh* rate of 21.6% (CI 

12.9 - 32.7) (see figure 2). Patients with low tumour burden (< 50%) responded best to BLINCYTO 

treatment with CR/CRh* rate of 72.9% (CI 59.7 - 83.6). 

 

Figure 2. Forest plot of CR/CRh* rate during the first two cycles for study MT103-211 

(primary analysis set)  

 

 
n = number of patients who achieved CR or CRh* in the first two cycles of treatment in the specified subgroup. 

N = total number of patients in the specified subgroup. 

 

There is limited data in patients with late first relapse of B-precursor ALL defined as a relapse 

occurring more than 12 months after first remission or more than 12 months after HSCT in the first 

remission. In clinical phase II studies, 88.9% (8/9) of patients with late first relapse as defined in the 

individual studies achieved CR/CRh* within the first 2 treatment cycles with 62.5% (6/9) achieving 

MRD response and 37.5% (3/9) undergoing allogeneic HSCT after treatment with BLINCYTO. The 

median overall survival (OS) was 17.7 months (CI 3.1 - not estimable).  

 

In the randomised, open-label, multicentre, phase III study, 70% (7/10) of post-transplant patients in 

late first relapse treated with BLINCYTO compared to 20% (1/5) treated with SOC chemotherapy 

achieved CR/CRh* within the first 2 treatment cycles. Fifty percent (5/10) compared to 0% (0/5) 

achieved MRD response and 20% (2/10) compared to 40% (2/5) underwent allogeneic HSCT after 

treatment. The median OS was 15.6 months (CI 5.5 – not estimable) for the BLINCYTO group and 

5.3 months (CI 1.1 – not estimable) for the SOC chemotherapy group. 

 

MRD positive B-precursor ALL  

 

The safety and efficacy of BLINCYTO in adult patients with MRD positive B-precursor ALL were 

evaluated in an open-label, multicentre, single-arm study. Eligible patients were ≥ 18 years of age 

with no prior HSCT, had received at least 3 blocks of standard ALL induction therapy, were in 

complete haematologic remission (defined as < 5% blasts in bone marrow, absolute neutrophil count 

≥ 1,000/microlitres, platelets ≥ 50,000/microlitres, and haemoglobin level ≥ 9 g/dL) and had 

molecular failure or molecular relapse (defined as MRD ≥ 10-3), see table 4. MRD status at screening 

was determined from bone marrow aspirations using flow cytometry or polymerase chain reaction 

(PCR) at a minimum sensitivity of 10-4 based on local site evaluations. A central laboratory 

subsequently confirmed MRD levels by PCR. Final interpretation of MRD results followed 

EuroMRD Consortium guidelines. 

0 20 40 60 80 100 

 

Subgroup 

Bone Marrow Blast Infiltration  
(Central Lab) 

<50% 

≥50% to <75% 
 

≥75% to <90% 
 

≥90% 

Extramedullary Disease at Baseline 

Yes 

No 

 

Overall 

 

Percent Achieving CR/CRh* 

Rate and 95% Confidence Interval (CI) n/N Rate (95% CI) 

  

43/59 72.9% (59.7%-83.6%) 

8/25 32.0% (14.9%-53.5%) 
  

14/31 45.2% (27.3%-64.0%) 
  

16/74 21.6% (12.9%-32.7%) 

  

2/8 25.0% (3.2%-65.1%) 

79/181 43.6% (36.3%-51.2%) 

  

81/189 42.9% (35.7%-50.2%) 

 

GRH0148v2 



22 

 

Table 4. Demographics and baseline characteristics in MRD study 

 

Characteristic 
BLINCYTO 

(N = 116) 

Age  

Median, years (min, max) 45 (18, 76) 

Mean, years (SD) 44.6 (16.4) 

≥ 65 years, n (%) 15 (12.9) 

Males, n (%) 68 (58.6) 

Race, n (%)  

 Asian 1 (0.9) 

 Other (mixed) 1 (0.9) 

 White 102 (87.9) 

 Unknown 12 (10.3) 

Relapse history n (%)  

Patients in 1st CR 75 (64.7) 

Patients in 2nd CR 39 (33.6) 

Patients in 3rd CR 2 (1.7) 

MRD level at baseline* n (%)  

≥ 10-1 and < 1 9 (7.8) 

≥ 10-2 and < 10-1 45 (38.8) 

≥ 10-3 and < 10-2 52 (44.8) 

< 10-3 3 (2.6) 

Below lower limit of quantification 5 (4.3) 

Unknown 2 (1.7) 
* Centrally assessed in an assay with minimum sensitivity of 10-4 

 

BLINCYTO was administered as a continuous intravenous infusion. Patients received BLINCYTO 

at a constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) for all 

treatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case 

of adverse events. The treated population included 116 patients who received at least one infusion of 

BLINCYTO; the mean number of completed treatment cycles was 1.8 (range: 1 to 4). 

 

The primary endpoint was the proportion of patients who achieved a complete MRD response within 

one cycle of BLINCYTO treatment. Eighty-eight out of 113 (77.9%) evaluable patients achieved a 

complete MRD response after one cycle of treatment; see table 5. Two subjects achieved a complete 

MRD response with 1 additional cycle of BLINCYTO. MRD response rates by age and MRD level 

at baseline subgroups were consistent with the results in the overall population. RFS in patients with 

Philadelphia chromosome negative B-precursor ALL at 18 months censored at HSCT or post-

BLINCYTO chemotherapy was 54% (33%, 70%). RFS at 18 months not censored at HSCT or post-

BLINCYTO chemotherapy was 53% (44%, 62%). 

 

Table 5. Efficacy results in patients ≥ 18 years of age with MRD positive B-precursor ALL 

 

Complete MRD responsea, n/N (%), [95% CI]  88/113b (77.9) [69.1, 85.1] 

≥ 65 years old 12/15 (80.0) [51.9-95.7] 

Patients in 1st CR 60/73 (82.2) [71.5-90.2] 

Patients in 2nd CR 27/38 (71.1) [54.1-84.6] 

Patients in 3rd CR 1/2 (50.0) [1.3-98.7] 

Duration of complete MRD response [95% CI] 17.3 months [12.6, 23.3] 
a Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity 

of 10-4 
b One hundred thirteen patients (97.4%; 113/116) were included in the primary endpoint full analysis set 

 



23 

Paediatric population 

 

The safety and efficacy of BLINCYTO were evaluated in an open-label, multicentre, single-arm 

study in 93 paediatric patients with relapsed or refractory B-precursor ALL (second or later bone 

marrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments, and 

also with > 25% blasts in bone marrow). This was a two-part study, a dose-finding part to determine 

the appropriate dosing regimen, followed by a single-arm efficacy part using this regimen. 

 

BLINCYTO was administered as a continuous intravenous infusion. In the dose-finding part of the 

study, doses of up to 30 mcg/m2/day were evaluated. The recommended dose for the PK expansion 

and efficacy parts of the study was determined to be 5 mcg/m2/day on days 1-7 and 15 mcg/m2/day 

on days 8-28 for cycle 1, and 15 mcg/m2/day on days 1-28 for subsequent cycles. Dose adjustment 

was possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had 

the option to be retreated with BLINCYTO.  

 

The treated population (in the dose-finding, PK expansion, and efficacy parts) included 70 patients 

who received at least 1 infusion of BLINCYTO at the recommended dose; the mean number of 

treatment cycles was 1.5. Among treated patients, the median age was 8 years (range: 7 months to 

17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 

39 out of 70 (55.7%) had refractory disease. Most patients had a high tumour burden (≥ 50% 

leukaemic blasts in bone marrow) at baseline with a median of 75.5% bone marrow blasts. 

 

Twenty out of 70 (28.6%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out 

of 20 (85%) occurring within cycle 1 of treatment. Four patients achieved M1 bone marrow but did 

not meet the peripheral blood count recovery criteria for CR or CRh*. Eleven of the 20 patients 

(55%) who achieved CR/CRh* received an allogeneic HSCT. The CR/CRh* for patients less than 

2 years of age was 40% (4/10), for patients 2 to 6 years was 30.0% (6/20); and for patients aged 7 to 

17 years was 25% (10/40). 3 patients < 1 year of age refractory to prior treatment and without prior 

alloHSCT received one cycle of Blincyto at a dose of 5-15 µg/m2/day. None of the 3 subjects 

< 1 year old achieved a CR/CRh*, 1 patient had progressive disease (OS 2.3 months) and 2 were 

non-responders (OS 1.1 months and 8.7 months, respectively). The type of adverse events observed 

in infants were similar to those observed in the overall paediatric population. See table 6 for the 

efficacy results. 

 

Table 6. Efficacy results in patients < 18 years of age with relapsed or refractory B-cell 

precursor ALL 

 

 N = 70 

CRa/CRh*b, n (%) [95% CI] 20 (28.6%) [18.4% – 40.6%] 

CR, n (%) [95% CI] 11 (15.7%) [8.1% – 26.4%] 

CRh*, n (%) [95% CI] 9 (12.9%) [6.1% – 23.0%] 

Complete MRD response for CR /CRh*c, n1/n2d (%) [95% CI] 11/20 (55.0%) [31.5 – 76.9] 

CR, n1/n2d (%) [95% CI] 6/11 (54.5%) [23.4 – 83.3] 

CRh*, n1/n2d (%) [95% CI] 5/9 (55.6%) [21.2 – 86.3] 

Median relapsee-free survival (RFS)e for CR /CRh* [95% CI] 6.8 months [2.2 to 12.0 months] 

Median overall survival [95% CI] 7.5 months [4.0 to 11.8 months] 

100-day mortality after alloHSCTf  

n/N (%), [95% CI] 1/6 (16.7%) [2.5% – 72.7%] 
a. CR was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary 

disease, and full recovery of peripheral blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] 

> 1,000/microlitre) and no relapse within 28 days. 
b. CRh*was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary 

disease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre) and no 

relapse within 28 days. 
c. Complete MRD response No detectable signal for leukemic cells either by PCR or flow cytometry.  



24 

d. n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who 

achieved the respective remission status. One CR /CRh*responder with missing MRD data was considered as a MRD-

nonresponder. 

e. Relapse was defined as haematological relapse (blasts in bone marrow greater than 25% following CR) or an 

extramedullary relapse. 

f. Only patients with HSCT in CR/CRh* remission (with no anti-leukemia agents used prior to HSCT) are included. 

 

5.2 Pharmacokinetic properties 

 

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/refractory 

ALL, the mean (SD) Css was 230 (359) pg/mL and 612 (532) pg/mL, respectively. The 

pharmacokinetics of blinatumomab in patients with MRD positive B-precursor ALL was similar to 

patients with relapsed or refractory ALL. 

 

Distribution 

 

The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) 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 2.92 (2.83) L/hour. The mean (SD) half-life was 

2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested 

clinical doses.  

 

Body surface area, gender and age 

 

A population pharmacokinetic analysis was performed to evaluate the effects of demographic 

characteristics on blinatumomab pharmacokinetics. Results suggest that age (7 months to 80 years) 

and gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.37 to 

2.70 m2) influences the pharmacokinetics of blinatumomab. However the influence is negligible in 

adults and body surface area based dosing is recommended in the paediatric population. 

 

Renal impairment 

 

No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal 

impairment.  

 

Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab 

clearance values between patients with moderate renal dysfunction and normal renal function. 

However high inter-patient variability was discerned (CV% up to 95.6%), and clearance values in 

renal impaired patients were essentially within the range observed in patients with normal renal 

function, no clinically meaningful impact of renal function on clinical outcomes is expected. 

 



25 

Hepatic impairment 

 

No formal pharmacokinetic studies of blinatumomab have been conducted in patients with hepatic 

impairment. Baseline ALT and AST levels were used to assess the effect of hepatic impairment on 

the clearance of blinatumomab. Population pharmacokinetic analysis suggested that there was no 

association between ALT or AST levels and the clearance of blinatumomab.  

 

Paediatric population 

 

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day in 

paediatric patients. At the recommended doses, the mean (SD) steady state concentration (Css) 

values were 162 (179) and 533 (392) pg/mL at 5 and 15 mcg/m2/day doses, respectively. The 

estimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were 

3.91 (3.36) L/m2, 1.88 (1.90) L/hr/m2 and 2.19 (1.53) hours, respectively. 

 

5.3 Preclinical safety data 

 

Repeat-dose toxicity studies conducted with blinatumomab and the murine surrogate revealed the 

expected pharmacologic effects (including release of cytokines, decreases in leukocyte counts, 

depletion of B-cells, decreases in T-cells, decreased cellularity in lymphoid tissues). These changes 

reversed after cessation of treatment.  

 

Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal 

developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited 

extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or 

teratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice but 

haematological effects were not assessed in foetuses. No studies have been conducted to evaluate 

treatment-related effects on fertility. There were no effects on male or female reproductive organs in 

toxicity studies with the murine surrogate. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Powder 

 

Citric acid monohydrate (E330) 

Trehalose dihydrate 

Lysine hydrochloride 

Polysorbate 80 

Sodium hydroxide (for pH-adjustment) 

 

Solution (stabiliser) 

 

Citric acid monohydrate (E330) 

Lysine hydrochloride 

Polysorbate 80 

Sodium hydroxide (for pH-adjustment) 

Water for injections 

 

6.2 Incompatibilities 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6. 

 



26 

6.3 Shelf life 

 

Unopened vials 

 

5 years 

 

Reconstituted solution  

 

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours at 

or below 27°C. 

 

From a microbiological point of view, unless the method of reconstituting precludes the risks of 

microbial contamination, the reconstituted solution should be diluted immediately. If not diluted 

immediately, in-use storage times and conditions are the responsibility of the user. 

 

Diluted solution (prepared infusion bag)  

 

Chemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours at 

or below 27°C. 

 

From a microbiological point of view, the prepared infusion bags should be used immediately. If not 

used immediately, in-use storage times and conditions prior to use are the responsibility of the user 

and would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in 

controlled and validated aseptic conditions. 

 

6.4 Special precautions for 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. 

 

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 

 

Each BLINCYTO pack contains 1 vial of powder for concentrate for solution for infusion and 1 vial 

of solution (stabiliser): 

• 38.5 micrograms blinatumomab powder in a vial (type I glass) with a stopper (elastomeric 
rubber), seal (aluminium) and a flip off cap and 

• 10 mL solution in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) 
and a flip off cap. 

 

6.6 Special precautions for disposal and other handling 

 

Aseptic preparation 
 

Aseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should 

be:  
- performed under aseptic conditions by trained personnel in accordance with good practice 

rules especially with respect to the aseptic preparation of parenteral products. 
- prepared in a laminar flow hood or biological safety cabinet using standard precautions for the 

safe handling of intravenous agents. 

 

It is very important that the instructions for preparation and administration provided in this section 

are strictly followed to minimise medication errors (including underdose and overdose).  

 



27 

Special instructions to support accurate preparation 

 

• A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the pre-
filled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution 

(stabiliser) for reconstitution of BLINCYTO powder for concentrate. 

• The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume 
to be administered to the patient (240 mL). This is to account for intravenous infusion line loss 

and to assure that the patient will receive the full dose of BLINCYTO.  

• When preparing an infusion bag, remove all air from infusion bag. This is particularly 
important when using an ambulatory infusion pump.  

• Use the specific volumes described in the reconstitution and dilution instructions below to 
minimise errors in calculation.  

 

Other instructions 

 

• BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or 
ethyl vinyl acetate (EVA) infusion bags/pump cassettes.  

• Pump specifications: The infusion pump to administer BLINCYTO solution for infusion 
should be programmable, lockable and have an alarm. Elastomeric pumps should not be used. 

• Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements.  

 

Preparation of the solution for infusion  

 

Specific reconstitution and dilution instructions are provided for each dose and infusion time. Verify 

the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation 

section listed below. Table 7 provides instructions for patients weighing greater than or equal to 

45 kg, whereas table 8 and table 9 provide instructions for patients weighing less than 45 kg. Follow 

the steps for reconstituting BLINCYTO and preparing the infusion bag detailed below table 9. 

 

Table 7. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride 

9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to 

add to infusion bag 

 

Sodium chloride 9 mg/mL (0.9%) solution for injection (starting volume)  

250 mL 

(usual overfill 

volume of 265 to 

275 mL) 

Solution (stabiliser) 5.5 mL 

Dose Infusion duration Infusion rate 

Reconstituted  

BLINCYTO  

(number of 

packages) 

9 mcg/day  

24 hours 10 mL/hour 0.83 mL (1) 

48 hours 5 mL/hour 1.7 mL (1) 

72 hours 3.3 mL/hour 2.5 mL (1) 

96 hours 2.5 mL/hour 3.3 mL (2) 

28 mcg/day 

24 hours 10 mL/hour 2.6 mL (1) 

48 hours 5 mL/hour 5.2 mL (2) 

72 hours 3.3 mL/hour 8 mL (3) 

96 hours 2.5 mL/hour 10.7 mL (4) 

 



28 

Table 8. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) 

solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion 

bag for 5 mcg/m2/day dose  

 

Sodium chloride 9 mg/mL (0.9%) solution for injection (starting 

volume) 

250 mL (usual overfill volume 

of 265 to 275 mL) 

Solution (stabiliser) 5.5 mL 

Dose Infusion duration Infusion rate BSA (m2) 
Reconstituted BLINCYTO 

(number of packages) 

5 mcg/m2/day 

24 hours 10 mL/hour 

1.50 – 1.59 0.70 mL (1) 

1.40 – 1.49 0.66 mL (1) 

1.30 – 1.39 0.61 mL (1) 

1.20 – 1.29 0.56 mL (1) 

1.10 – 1.19 0.52 mL (1) 

1.00 – 1.09 0.47 mL (1) 

0.90 – 0.99 0.43 mL (1) 

0.80 – 0.89 0.38 mL (1) 

0.70 – 0.79 0.33 mL (1) 

0.60 – 0.69 0.29 mL (1) 

0.50 – 0.59 0.24 mL (1) 

0.40 – 0.49 0.20 mL (1)  

 

48 hours 5 mL/hour 

1.50 – 1.59 1.4 mL (1) 

1.40 – 1.49 1.3 mL (1) 

1.30 – 1.39 1.2 mL (1) 

1.20 – 1.29 1.1 mL (1) 

1.10 – 1.19 1.0 mL (1) 

1.00 – 1.09 0.94 mL (1) 

0.90 – 0.99 0.85 mL (1) 

0.80 – 0.89 0.76 mL (1) 

0.70 – 0.79 0.67 mL (1) 

0.60 – 0.69 0.57 mL (1) 

0.50 – 0.59 0.48 mL (1) 

0.40 – 0.49 0.39 mL (1) 

 

72 hours 3.3 mL/hour 

1.50 – 1.59 2.1 mL (1) 

1.40 – 1.49 2.0 mL (1) 

1.30 – 1.39 1.8 mL (1) 

1.20 – 1.29 1.7 mL (1) 

1.10 – 1.19 1.6 mL (1) 

1.00 – 1.09 1.4 mL (1) 

0.90 – 0.99 1.3 mL (1) 

0.80 – 0.89 1.1 mL (1) 

0.70 – 0.79 1 mL (1) 

0.60 – 0.69 0.86 mL (1) 

0.50 – 0.59 0.72 mL (1) 

0.40 – 0.49 0.59 mL (1) 

 

96 hours 2.5 mL/hour 

1.50 – 1.59 2.8 mL (1) 

1.40 – 1.49 2.6 mL (1) 

1.30 – 1.39 2.4 mL (1) 

1.20 – 1.29 2.3 mL (1) 

1.10 – 1.19 2.1 mL (1) 

1.00 – 1.09 1.9 mL (1) 

0.90 – 0.99 1.7 mL (1) 

0.80 – 0.89 1.5 mL (1) 

0.70 – 0.79 1.3 mL (1) 

0.60 – 0.69 1.2 mL (1) 

0.50 – 0.59 0.97 mL (1) 

0.40 – 0.49 0.78 mL (1) 



29 

Table 9. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) 

solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion 

bag for 15 mcg/m2/day dose  

 

Sodium chloride 9 mg/mL (0.9%) (starting volume) 250 mL (usual overfill volume 

of 265 to 275 mL) 

Solution (stabiliser) 5.5 mL 

Dose Infusion duration Infusion rate BSA (m2) 
Reconstituted BLINCYTO 

(number of packages) 

15 mcg/m2/day 

24 hours 10 mL/hour 

1.50 – 1.59 2.1 mL (1) 

1.40 – 1.49 2.0 mL (1) 

1.30 – 1.39 1.8 mL (1) 

1.20 – 1.29 1.7 mL (1) 

1.10 – 1.19 1.6 mL (1) 

1.00 – 1.09 1.4 mL (1) 

0.90 – 0.99 1.3 mL (1) 

0.80 – 0.89 1.1 mL (1) 

0.70 – 0.79 1.00 mL (1) 

0.60 – 0.69 0.86 mL (1) 

0.50 – 0.59 0.72 mL (1) 

0.40 – 0.49 0.59 mL (1) 

 

48 hours 5 mL/hour 

1.50 – 1.59 4.2 mL (2) 

1.40 – 1.49 3.9 mL (2) 

1.30 – 1.39 3.7 mL (2) 

1.20 – 1.29 3.4 mL (2) 

1.10 – 1.19 3.1 mL (2) 

1.00 – 1.09 2.8 mL (1) 

0.90 – 0.99 2.6 mL (1) 

0.80 – 0.89 2.3 mL (1) 

0.70 – 0.79 2.0 mL (1) 

0.60 – 0.69 1.7 mL (1) 

0.50 – 0.59 1.4 mL (1) 

0.40 – 0.49 1.2 mL (1) 

 

72 hours 3.3 mL/hour 

1.50 – 1.59 6.3 mL (3) 

1.40 – 1.49 5.9 mL (3) 

1.30 – 1.39 5.5 mL (2) 

1.20 – 1.29 5.1 mL (2) 

1.10 – 1.19 4.7 mL (2) 

1.00 – 1.09 4.2 mL (2) 

0.90 – 0.99 3.8 mL (2) 

0.80 – 0.89 3.4 mL (2) 

0.70 – 0.79 3.0 mL (2) 

0.60 – 0.69 2.6 mL (1) 

0.50 – 0.59 2.2 mL (1) 

0.40 – 0.49 1.8 mL (1) 

 

96 hours 2.5 mL/hour 

1.50 – 1.59 8.4 mL (3) 

1.40 – 1.49 7.9 mL (3) 

1.30 – 1.39 7.3 mL (3) 

1.20 – 1.29 6.8 mL (3) 

1.10 – 1.19 6.2 mL (3) 

1.00 – 1.09 5.7 mL (3) 

0.90 – 0.99 5.1 mL (2) 

0.80 – 0.89 4.6 mL (2) 

0.70 – 0.79 4.0 mL (2) 

0.60 – 0.69 3.4 mL (2) 

0.50 – 0.59 2.9 mL (2) 

0.40 – 0.49 2.3 mL (1) 



30 

BSA = body surface area 

 

These supplies are also required, but not included in the package  

• Sterile single-use disposable syringes  

• 21-23 gauge needle(s) (recommended)  

• Water for injections  

• Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection; 
o To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. 

BLINCYTO dose calculations are based on a usual overfill volume of 265 to 

275 mL sodium chloride 9 mg/mL (0.9%) solution for injection.  

o Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl 
acetate (EVA) infusion bags/pump cassettes. 

• Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low 
protein-binding 0.2 micrometre in-line filter. 

o Ensure that the tubing is compatible with the infusion pump. 
 

Reconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled 

with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection  

 

1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for 
injection that usually contains a total volume of 265 to 275 mL.  

2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution 
(stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard 

the remaining solution (stabiliser) vial.  

3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of 
water for injections. Direct the water for injections toward the side of the vial during 

reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. 

• Do not reconstitute BLINCYTO powder for concentrate with the solution 
(stabiliser).  

• The addition of water for injections to the powder for concentrate results in a total 
volume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL.  

4. Visually inspect the reconstituted solution for particulate matter and discolouration during 
reconstitution and prior to infusion. The resulting solution should be clear to slightly 

opalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has 

precipitated.  

5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to 
table 7 to table 9 for the specific volume of reconstituted BLINCYTO). Gently mix the 

contents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted 

solution. 

6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile 
0.2 micron in-line filter.  

7. Remove air from the infusion bag and prime the intravenous infusion line only with the 
prepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) 

solution for injection.  

8. Store at 2°C - 8°C if not used immediately. 
 

 

7. MARKETING AUTHORISATION HOLDER 

 

Amgen Europe B.V. 

Minervum 7061 

4817 ZK Breda 

The Netherlands  

 

 



31 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1047/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 23 November 2015 

Date of last renewal: 19 April 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

 

Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/
http://www.ema.europa.eu/


32 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURERS RESPONSIBLE 

FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



33 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance 

 

Lonza Biologics plc 

228 Bath Road 

Slough 

Berkshire, SL1 4DX 

UK 

 

Name and address of the manufacturers responsible for batch release 

 

Amgen Europe B.V. 

Minervum 7061 

4817 ZK Breda 

The Netherlands 

 

Amgen NV 

Telecomlaan 5-7 

1831 Diegem 

Belgium 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product 

are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) 

of Directive 2001/83/EC and any subsequent updates published on the European medicines 

web-portal. 

 

The marketing authorisation holder shall submit the first periodic safety update report for this 

product within 6 months following authorisation. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed 

in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

 



34 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result 

of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

• Additional risk minimisation measures 
 

Prior to launch of BLINCYTO in each Member State, the Marketing Authorisation Holder (MAH) 

must agree about the content and format of the educational programme, including communication 

media, distribution modalities, and any other aspects of the programme, with the National Competent 

Authority.  

 

The MAH shall ensure that in each Member State where BLINCYTO is marketed, all healthcare 

professionals (HCP) and patients / caregivers who are expected to prescribe, dispense and use 

BLINCYTO are provided with the following educational packages: 

• Physician educational material 

• Pharmacist educational material 

• Nurse educational material  

• Patient / caregivers educational material  

• Patient alert card 
 

The physician educational material should contain: 

1. A link to the Summary of Product Characteristics (SmPC) 
2. The guide for physicians shall contain the following key elements: 

• Remarks on the importance of reporting ADRs 

• Information on treatment with BLINCYTO, administration and posology, duration of 
hospitalisation, interruption and / or permanent discontinuation of the treatment  

Medication errors (ME) 

• Data from clinical trials, causes of ME, frequency, severity and outcomes. 

• Reminder to counsel the patients on how to reduce the risk of ME while using the 
infusion pump.  

Neurologic events 

• Data from clinical trials, frequency and severity (grade 3 and 4 neurological toxicities 
were observed) 

• Recommendation to monitor patients for signs and symptoms of neurotoxicity 

• Management of neurotoxicity (including dose adjustment and dose interruption)  

• Recommendation for patients not to drive while receiving BLINCYTO and to contact 
immediately the treating physician if they experience neurological symptoms 

 

The pharmacist educational material should contain: 

1. A link to the Summary of Product Characteristics (SmPC) 
2. The guide for pharmacists, containing the following key elements: 

• Remarks on the importance of reporting ADRs 

• Detailed description of the reconstitution and preparation procedures of BLINCYTO 
infusion solution for intravenous administration under aseptic conditions, using aseptic 

techniques. 

 

The nurse educational material should contain: 

1. A link to the Summary of Product Characteristics (SmPC) 
2. The nurse educational guide, including the following key elements: 

• Remarks on the importance of reporting ADRs  

• Description of the administration procedures of BLINCYTO 



35 

• Description on patient’s monitoring and management of early signs and symptoms of 
neurological events  

• Recommendation for patients not to drive while receiving BLINCYTO and to contact 
immediately the treating physician/nurse if they experience neurological symptoms 

 

The patient (including caregivers) educational material should contain: 

1. The patient information guide, including the following key elements: 

• Remarks on the importance of reporting ADRs 

• Description of the administration procedures of BLINCYTO and how to reduce the risk 
of ME while using the infusion pump. 

• Description of the main signs and / or symptoms of neurologic events and the 
importance of notifying the treating physician or nurse immediately if symptoms occur  

• Recommendation for patients not to drive while receiving BLINCYTO  
2. A link to the package leaflet 
 

The patient alert card should contain: 

• A warning message for HCPs treating the patient at any time, including emergency 
conditions, that the patient is using BLINCYTO 

• Contact details of the BLINCYTO prescriber 

• BLINCYTO treatment start date 

• Remarks on the importance of reporting ADRs 
 

• Obligation to complete post-authorisation measures 
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Description Due date 

Non-interventional post-authorisation safety study (PASS): Study 20150136: an 

observational study of blinatumomab safety and effectiveness, utilisation, and 

treatment practices* 

Q42021 

* The study protocol needs to be developed and presented for PRAC review within 2 months after the EU 

Commission Decision. 

 

Description Due date 

Non-interventional post-authorisation safety study (PASS): The applicant 

should submit the final results of a follow-up observational study to further 

characterise the long-term safety of BLINCYTO including developmental 

aspects, HSCT and secondary malignancy in high-risk paediatric patients 

enrolled in Study 20120215*. 

Q42036 

* The study protocol needs to be developed and presented for PRAC review within 3 months after the EU 

Commission Decision. 

 

  



36 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



38 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion 

blinatumomab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One vial of powder contains 38.5 micrograms of blinatumomab.  

After reconstitution with water for injections each vial contains 12.5 micrograms/mL of 

blinatumomab. 

 

 

3. LIST OF EXCIPIENTS 

 

Powder: citric acid monohydrate (E330), trehalose dihydrate, lysine hydrochloride, polysorbate 80 

and sodium hydroxide. 

Solution (stabiliser): citric acid monohydrate (E330), lysine hydrochloride, polysorbate 80, sodium 

hydroxide and water for injections. 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for concentrate and solution for solution for infusion 

1 vial of powder. 

1 vial of solution (stabiliser). Add to the sodium chloride bag only. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Intravenous use after reconstitution and dilution. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Do not shake the reconstituted solution. 

 

 

8. EXPIRY DATE 

 

EXP 



39 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store and transport refrigerated. 

Do not freeze. 

Store in the original carton in order to protect from light.  

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Amgen Europe B.V. 

Minervum 7061 

4817 ZK Breda 

The Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1047/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 



40 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

POWDER VIAL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

BLINCYTO 38.5 mcg powder for concentrate 

blinatumomab  

IV after reconstitution and dilution 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

 

6. OTHER 

 

 

 

  



41 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

SOLUTION (STABILISER) VIAL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Solution (stabiliser).  

BLINCYTO 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

10 ml 

 

 

6. OTHER 

 

Add to the sodium chloride bag only. 

  



42 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 



43 

Package leaflet: Information for the patient 

 

BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion 

blinatumomab 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What BLINCYTO is and what it is used for  
2. What you need to know before you use BLINCYTO  
3. How to use BLINCYTO  
4. Possible side effects  
5. How to store BLINCYTO  
6. Contents of the pack and other information 
 

 

1. What BLINCYTO is and what it is used for 

 

The active ingredient in BLINCYTO is blinatumomab. This belongs to a group of medicines called 

antineoplastic agents which target cancer cells.  

 

BLINCYTO is used to treat adults with acute lymphoblastic leukaemia. Acute lymphoblastic 

leukaemia is a cancer of the blood in which a particular kind of white blood cell called 

“B-lymphocyte” is growing out of control. This medicine works by enabling your immune system to 

attack and destroy these abnormal white blood cancer cells. BLINCYTO is used when acute 

lymphoblastic leukaemia has come back or has not responded to previous treatment (referred to as 

relapsed/refractory acute lymphoblastic leukaemia).  

 

It is also used in patients with acute lymphoblastic leukaemia who still have a small number of 

cancer cells remaining after previous treatment (referred to as minimal residual disease). 

 

BLINCYTO is used to treat children (≥ 1 year old), teenagers and young adults with acute 

lymphoblastic leukaemia (ALL) when previous treatments have not worked or have stopped 

working. 

 

 

2. What you need to know before you use BLINCYTO  

 

Do not use BLINCYTO: 

- if you are allergic to blinatumomab or any of the other ingredients of this medicine (listed in 
section 6).  

- if you are breast-feeding. 
 



44 

Warnings and precautions  

 

Talk to your doctor, pharmacist or nurse before using BLINCYTO if any of these apply to you. 

BLINCYTO may not be suitable for you:  

• if you have ever had neurological problems, for example, shaking (or tremor), abnormal 
sensations, seizures, memory loss, confusion, disorientation, loss of balance, or difficulty in 

speaking. If you are still suffering from active neurological problems or conditions, tell your 

doctor. If your leukaemia has spread to your brain and/or spinal cord, your doctor may have to 

treat this first before you can start treatment with BLINCYTO. Your doctor will assess your 

nervous system and conduct tests before deciding if you should receive BLINCYTO. Your 

doctor may need to take special care of you during your treatment with BLINCYTO.  
• if you have an active infection. 

• if you have ever had an infusion reaction after previously using BLINCYTO. Symptoms may 
include wheezing, flushing, face swelling, difficulty breathing, low or high blood pressure. 

• if you think you may need any vaccinations in the near future, including those needed to travel 
to other countries. Some vaccines must not be given within two weeks before, at the same time 

as or in the months after you receive treatment with BLINCYTO. Your doctor will check if 

you should have the vaccination. 

 

Tell your doctor, pharmacist or nurse immediately if you experience any of the following 

reactions whilst receiving BLINCYTO as these may need to be treated and your dose adjusted:  

• if you experience seizures, difficulty in speaking or slurred speech, confusion and 
disorientation, or loss of balance. 

• if you develop chills or shivering, or feel warm; you should take your temperature as you may 
have a fever - these may be symptoms of an infection. 

• if you develop a reaction at any time during your infusion, which may include dizziness, 
feeling faint, nauseated, face swelling, difficulty breathing, wheezing, or rash. 

• if you have severe and persistent stomach pain, with or without nausea and vomiting, as these 
may be symptoms of a serious and potentially fatal condition known as pancreatitis 

(inflammation of the pancreas). 

 

Your doctor or nurse will monitor you for signs and symptoms of these reactions. 

 

Tell your doctor, pharmacist or nurse immediately if you became pregnant whilst receiving 

BLINCYTO. Your doctor will talk to you about precautions in using vaccinations for your baby. 

 

Before each infusion cycle of BLINCYTO, you will be given medicines which help reduce a 

potentially life-threatening complication known as tumour lysis syndrome, which is caused by 

chemical disturbances in the blood due to the breakdown of dying cancer cells. You may also be 

given medicines to reduce fever. 

 

During treatment, especially in the first few days after treatment start, you may experience a severe 

low white blood cell count (neutropenia), severe low white blood cell count with a fever (febrile 

neutropenia), elevated liver enzymes, or elevated uric acid. Your doctor will take regular blood tests 

to monitor your blood counts during treatment with BLINCYTO. 

 

Children and adolescents 

 

BLINCYTO should not be used in children below 1 year of age. 

 

Other medicines and BLINCYTO 

 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. 

 



45 

Pregnancy and breast-feeding  

 

If you are pregnant, are breast-feeding, think you may be pregnant or are planning to have a baby, 

ask your doctor or nurse for advice before taking this medicine. 

 

Contraception 

 

Women who are able to become pregnant have to use effective contraception during treatment and 

for at least 48 hours after your last treatment. Talk to your doctor or nurse about suitable methods of 

contraception. 

 

Pregnancy 

 

The effects of BLINCYTO in pregnant women are not known but based on its mechanism of action, 

BLINCYTO may harm your unborn baby. You should not use BLINCYTO during pregnancy, unless 

your doctor thinks that it is the best medicine for you. 

 

If you become pregnant during BLINCYTO treatment, please inform your doctor or nurse. Your 

doctor will talk to you about precautions in using vaccinations for your baby.  

 

Breast-feeding 

 

You must not breast-feed during and for at least 48 hours after your last treatment. It is not known 

whether BLINCYTO is excreted in breast milk but a risk for suckling baby cannot be excluded.  

 

Driving and using machines 

 

Do not drive, use heavy machines, or engage in hazardous activities while you are being given 

BLINCYTO. BLINCYTO can cause neurological problems such as dizziness, seizures, confusion, 

coordination and balance disorders. 

 

BLINCYTO contains sodium 

 

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’. 

 

 

3. How to use BLINCYTO 

 

Always use this medicine exactly as your doctor, pharmacist or nurse have told you. Check with 

your doctor, pharmacist or nurse if you are not sure. 

 

How BLINCYTO is given 

 

BLINCYTO will be given to you through a vein (intravenous) continuously for 4 weeks using an 

infusion pump (this is 1 treatment cycle). You will then have a 2-week break where you will not be 

given the infusion. Your infusion catheter will be attached to you at all times during each cycle of 

your treatment. 

 

BLINCYTO is usually given for 2 treatment cycles if you have relapsed/refractory acute 

lymphoblastic leukaemia, or for 1 treatment cycle if you have minimal residual disease acute 

lymphoblastic leukaemia. If you respond to this treatment, your doctor may decide to give you up to 

3 additional cycles of treatment. The number of treatment cycles and the dose which you will be 

given will depend on how you tolerate and respond to BLINCYTO. Your doctor will discuss with 

you how long your treatment will last. Your treatment may also be interrupted depending on how 

you tolerate BLINCYTO.  

 



46 

If you have relapsed/refractory acute lymphoblastic leukaemia it is recommended that the first 9 days 

of treatment and the first two days of the second cycle will be given to you in a hospital or clinic 

under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines.  

 

If you have minimal residual disease acute lymphoblastic leukaemia, it is recommended that the first 

3 days of treatment and the first 2 days of subsequent cycles will be given to you in a hospital or 

clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. 

 

If you have or had neurological problems, it is recommended that the first 14 days of treatment will 

be given to you in a hospital or clinic. Your doctor will discuss with you if you can continue 

treatment at home after your initial hospital stay. Treatment may include a bag change by a nurse.  

 

Your doctor will determine when your BLINCYTO infusion bag will be changed, which may range 

from every day to every 4 days. The infusion rate may be faster or slower depending on how often 

the bag is changed. 

 

Your first cycle 

 

If you have relapsed/refractory acute lymphoblastic leukaemia and your body weight is greater than 

or equal to 45 kilograms the recommended initial dose in your first cycle is 9 micrograms per day for 

1 week. Your doctor may decide to then increase your dose to 28 micrograms per day for weeks 2, 3, 

and 4 of your treatment.  

 

If your body weight is less than 45 kilograms, the recommended initial dose in your first cycle will 

be based on your weight and height. Your doctor may decide to then increase your dose for weeks 2, 

3, and 4 of your treatment.  

 

If you have minimal residual disease acute lymphoblastic leukaemia, your dose of BLINCYTO will 

be 28 micrograms per day throughout the first cycle. 

 

Your next cycles 

 

If your doctor determines that you should be given more cycles of BLINCYTO and if your body 

weight is greater than or equal to 45 kilograms, your pump will be set to infuse a dose of 

28 micrograms per day.  

 

If your doctor determines that you should be given more cycles of BLINCYTO and if your body 

weight is less than 45 kilograms, your pump will be set to infuse a dose based on your weight and 

height. 

 

Medicines given before each cycle of BLINCYTO  

 

Before your treatment with BLINCYTO, you will be given other medicines (pre-medication) to help 

reduce infusion reactions and other possible side effects. These may include corticosteroids (e.g. 

dexamethasone). 

 

Infusion catheter 

 

If you have a catheter for infusion, it is very important to keep the area around the catheter clean; 

otherwise you could get an infection. Your doctor or nurse will show you how to care for your 

catheter site. 

 

Infusion pump and intravenous tubing 

 

Do not adjust the settings on the pump, even if there is a problem or the pump alarm sounds. Any 

changes to the pump settings may result in a dose that is too high or too low. 

 



47 

Contact your doctor or nurse immediately if: 

• there is a problem with the pump or the pump alarm sounds 

• the infusion bag empties before the scheduled bag change 

• if the infusion pump stops unexpectedly. Do not try to restart your pump. 
 

Your doctor or nurse will advise you on how to manage your daily activities around your infusion 

pump. Contact your doctor or nurse if you have questions. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of 

these side effects may be serious. 

 

Tell your doctor immediately if you get any of the following or combination of the following side 

effects: 

• chills, shivering, fever, rapid heart rate, decreased blood pressure, aching muscles, feeling 
tired, coughing, difficulty breathing, confusion, redness, swelling or discharge in the affected 

area or at the site of the infusion line - these may be signs of an infection. 

• neurologic events: shaking (or tremor), confusion, disturbances of brain function 
(encephalopathy), difficulty in communicating (aphasia), seizure (convulsion). 

• fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may 
become severe - these may be signs of a so-called cytokine release syndrome. 

• if you have severe and persistent stomach pain, with or without nausea and vomiting, as these 
may be symptoms of a serious and potentially fatal condition known as pancreatitis 

(inflammation of the pancreas). 

 

Treatment with BLINCYTO can cause a decrease in the levels of certain white blood cells with or 

without fever (febrile neutropenia or neutropenia) or can lead to increased blood levels of potassium, 

uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome). Your 

doctor will take regular blood tests during treatment with BLINCYTO. 

 

Other side effects include: 

 

Very common side effects (may affect more than 1 in 10 people): 

• infections in the blood including bacteria, fungi, viruses, or other types of infection  

• decreased levels of certain white blood cells with or without fever ((febrile) neutropenia, 
leukopenia), decreased levels of red blood cells, decreased levels of platelets 

• fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may 
become severe (cytokine release syndrome) 

• not being able to sleep 

• headache, shaking (or tremor) 

• rapid heart rate (tachycardia) 

• low blood pressure 

• cough 

• nausea, diarrhoea, vomiting, constipation, abdominal pain 

• rash 

• back pain, pain in extremity 

• fever (pyrexia), swelling of the face, lips, mouth, tongue or throat which may cause difficulty 
in swallowing or breathing (oedema), chills 

• low levels of antibodies called “immunoglobulins” which help the immune system fight 
infection (decreased immunoglobulins) 

• increased levels of liver enzymes (ALT, AST, GGT) 

• reactions related to infusion may include, wheezing, flushing, face swelling, difficulty 
breathing, low blood pressure, high blood pressure. 

 



48 

Common side effects (may affect up to 1 in 10 people): 

• serious infection which can result in organ failure, shock or can be fatal (sepsis) 

• lung infection (pneumonia)  

• increased levels of white blood cell count (leucocytosis), decreased levels of certain white 
blood cells (lymphopenia)  

• allergic reaction 

• complications occurring after cancer treatment leading to increased blood levels of potassium, 
uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome)  

• confusion, disorientation 

• disturbances of brain function (encephalopathy) such as difficulty in communicating (aphasia), 
tingling of skin (paraesthesia), seizure, difficulty thinking or processing thoughts, difficulty 

remembering, difficulty in controlling movement (ataxia) 

• feeling sleepy (somnolence), numbness, dizziness  

• nerve problems affecting the head and neck such as visual disturbances, drooping eyelid 
and/or sagging muscles on one side of the face, difficulty hearing or trouble swallowing 

(cranial nerve disorders) 

• wheezing or difficulty in breathing (dyspnoea), breathlessness (respiratory failure) 

• high blood pressure (hypertension) 

• flushing 

• coughing with phlegm 

• increased bilirubin in the blood 

• bone pain 

• chest pain or other pain 

• high levels of some enzymes including blood enzymes 

• increase in your weight 
 

Uncommon side effects (may affect up to 1 in 100 people): 

• excessive activation of white blood cells associated with inflammation (hemophagocytic 
histiocytosis) 

• swollen lymph nodes (lymphadenopathy) 

• fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may 
be severe and can be fatal (cytokine storm) 

• a condition which causes fluid to leak from the small blood vessels into your body (capillary 
leak syndrome) 

• difficulty in speaking 
 

Additionally, the side effects that happened more often in adolescents and children include: 

• decreased levels of red blood cells (anaemia), decreased levels of platelets 
(thrombocytopenia), decreased levels of certain white blood cells (leukopenia) 

• fever (pyrexia) 

• reactions related to infusion may include face swelling, low blood pressure, high blood 
pressure (infusion-related reaction) 

• increase in your weight 

• high blood pressure (hypertension) 
 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


49 

5. How to store BLINCYTO 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 

expiry date refers to the last day of that month. 

 

Unopened vials: 

- Store and transport refrigerated (2°C - 8°C). 
- Do not freeze.  
- Store in the original carton in order to protect from light. 
 

Reconstituted solution (BLINCYTO solution):  

- When refrigerated, the reconstituted solution must be used within 24 hours. Alternatively the 
vials can be stored at room temperature (up to 27°C) for up to 4 hours. 

 

Diluted solution (prepared infusion bag):  

If your infusion bag is changed at home: 

- Infusion bags containing BLINCYTO solution for infusion will arrive in special packaging 
containing cooling packs.  

• Do not open the package.  

• Store the package at room temperature (up to 27°C).  

• Do not refrigerate or freeze the package.  
- The package will be opened by your nurse and the infusion bags will be stored in a refrigerator 

until infusion.  

- When refrigerated, the infusion bags must be used within 10 days of preparation. 
- Once at room temperature (up to 27°C) the solution will be infused within 96 hours. 
 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What BLINCYTO contains 

 

- The active substance is blinatumomab. Each vial of powder contains 38.5 micrograms of 
blinatumomab. Reconstitution with water for injections results in a final blinatumomab 

concentration of 12.5 micrograms/mL. 

- The other ingredients in the powder are citric acid monohydrate (E330), trehalose dihydrate, 
lysine hydrochloride, polysorbate 80, and sodium hydroxide. 

- The solution (stabiliser) contains citric acid monohydrate (E330), lysine hydrochloride, 
polysorbate 80, sodium hydroxide and water for injections. 

 

What BLINCYTO looks like and contents of the pack 

 

BLINCYTO is a powder for concentrate and solution for solution for infusion. 

Each pack of BLINCYTO contains: 

• 1 glass vial containing a white to off-white powder.  

• 1 glass vial containing a colourless-to-slightly yellow, clear solution.  
 

Marketing Authorisation Holder and Manufacturer 

Amgen Europe B.V. 

Minervum 7061 

4817 ZK Breda 

The Netherlands  

 



50 

Marketing Authorisation Holder 

Amgen Europe B.V. 

Minervum 7061 

4817 ZK Breda 

The Netherlands 

 

Manufacturer 

Amgen NV 

Telecomlaan 5-7 

1831 Diegem 

Belgium 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien 

s.a. Amgen n.v. 

Tel/Tél: +32 (0)2 7752711 

 

Lietuva 

Amgen Switzerland AG Vilniaus filialas 

Tel: +370 5 219 7474 

 

България 

Амджен България ЕООД 

Тел.: +359 (0)2 424 7440 

 

Luxembourg/Luxemburg 

s.a. Amgen  

Belgique/Belgien 

Tel/Tél: +32 (0)2 7752711 

 

Česká republika 

Amgen s.r.o. 

Tel: +420 221 773 500 

 

Magyarország 

Amgen Kft. 

Tel.: +36 1 35 44 700 

 

Danmark 

Amgen, filial af Amgen AB, Sverige 

Tlf: +45 39617500 

 

Malta 

Amgen B.V. 

The Netherlands 

Tel: +31 (0)76 5732500 

 

Deutschland 

AMGEN GmbH 

Tel.: +49 89 1490960 

 

Nederland 

Amgen B.V. 

Tel: +31 (0)76 5732500 

 

Eesti 

Amgen Switzerland AG Vilniaus filialas 

Tel: +372 586 09553 

 

Norge 

Amgen AB 

Tel: +47 23308000 

 

Ελλάδα 

Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε.  

Τηλ.: +30 210 3447000 

 

Österreich 

Amgen GmbH  

Tel: +43 (0)1 50 217 

 

España 

Amgen S.A. 

Tel: +34 93 600 18 60  
 

Polska 

Amgen Biotechnologia Sp. z o.o. 

Tel.: +48 22 581 3000 

 

France 

Amgen S.A.S. 

Tél: +33 (0)9 69 363 363 

 

Portugal 

Amgen Biofarmacêutica, Lda. 

Tel: +351 21 422 0606 

 

Hrvatska 

Amgen d.o.o. 

Tel: +385 (0)1 562 57 20 

 

România 

Amgen România SRL 

Tel: +4021 527 3000 

 



51 

Ireland  

Amgen Ireland Limited 

Tel: +353 1 8527400 
 

Slovenija 

AMGEN zdravila d.o.o. 

Tel: +386 (0)1 585 1767 

 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Amgen Slovakia s.r.o. 

Tel: +421 2 321 114 49 

 

Italia 

Amgen S.r.l. 

Tel: +39 02 6241121 

 

Suomi/Finland 

Amgen AB, sivuliike Suomessa/Amgen AB, filial 

i Finland 

Puh/Tel: +358 (0)9 54900500 

 

Kύπρος 

C.A. Papaellinas Ltd 

Τηλ.: +357 22741 741 

 

Sverige 

Amgen AB  

Tel: +46 (0)8 6951100 

 

Latvija 

Amgen Switzerland AG Rīgas filiāle 

Tel: +371 257 25888 

 

United Kingdom 

Amgen Limited 

Tel: +44 (0)1223 420305 

 

 

This leaflet was last revised in 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. 

 

 

The following information is intended for healthcare professionals only: 

 

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. 

 

Philadelphia chromosome negative relapsed or refractory B-precursor ALL 

 

Recommended daily dose 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). 

 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


52 

Patient 

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/da

y via 

continuous 

infusion  

(not to exceed 

28 mcg/day) 

 

 

MRD positive B-precursor ALL 

 

The recommended dose of BLINCYTO throughout each 4-week treatment cycle is 28 mcg/day. 

 

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. 

 

Aseptic preparation 
 

Aseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should 

be:  
- performed under aseptic conditions by trained personnel in accordance with good practice 

rules especially with respect to the aseptic preparation of parenteral products. 
- prepared in a laminar flow hood or biological safety cabinet using standard precautions for the 

safe handling of intravenous agents. 

 

It is very important that the instructions for preparation and administration provided in this section 

are strictly followed to minimise medication errors (including underdose and overdose).  

 

Special instructions to support accurate preparation 

 

• A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the 
pre-filled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution 

(stabiliser) for reconstitution of BLINCYTO powder for concentrate. 

• The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume 
to be administered to the patient (240 mL). This is to account for intravenous infusion line loss 

and to assure that the patient will receive the full dose of BLINCYTO.  



53 

• When preparing an infusion bag, remove all air from infusion bag. This is particularly 
important when using an ambulatory infusion pump.  

• Use the specific volumes described in the reconstitution and dilution instructions below to 
minimise errors in calculation.  

 

Other instructions 

 

• BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or 
ethyl vinyl acetate (EVA) infusion bags/pump cassettes.  

• Pump specifications: The infusion pump to administer BLINCYTO solution for infusion 
should be programmable, lockable and have an alarm. Elastomeric pumps should not be used. 

• Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements.  

 

Preparation of the solution for infusion  

 

Specific reconstitution and dilution instructions are provided for each dose and infusion time. Verify 

the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation 

in the relevant table below. Table 1 provides instructions for patients weighing greater than or equal 

to 45 kg whereas table 2 and table 3 provide instructions for patients weighing less than 45 kg. 

Follow the steps for reconstituting BLINCYTO and preparing the infusion bag detailed below 

table 3. 

 

Table 1. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride 

9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to 

add to infusion bag 

 

Pre-filled bag containing sodium chloride 9 mg/mL (0.9%) solution for 

injection 

250 mL 

(usual overfill volume 

of 265 to 275 mL) 

Solution (stabiliser) 5.5 mL 

 

Dose 
Infusion duration 

(hours) 

Infusion rate 

(mL/hour) 

Reconstituted 

BLINCYTO 

(number of 

packages) 

9 mcg/day  

24 10 0.83 mL (1) 

48 5 1.7 mL (1) 

72  3.3 2.5 mL (1) 

96  2.5 3.3 mL (2) 

28 mcg/day 

24  10 2.6 mL (1) 

48  5 5.2 mL (2) 

72  3.3 8 mL (3) 

96  2.5 10.7 mL (4) 

 



54 

Table 2. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) 

solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion 

bag for 5 mcg/m2/day dose  

 

Sodium chloride 9 mg/mL (0.9%) solution for injection (starting 

volume) 

250 mL (usual overfill volume 

of 265 to 275 mL) 

Solution (stabiliser) 5.5 mL 

Dose Infusion duration Infusion rate BSA (m2) 
Reconstituted BLINCYTO 

(number of packages) 

5 mcg/m2/day 

24 hours 10 mL/hour 

1.50 – 1.59 0.70 mL (1) 

1.40 – 1.49 0.66 mL (1) 

1.30 – 1.39 0.61 mL (1) 

1.20 – 1.29 0.56 mL (1) 

1.10 – 1.19 0.52 mL (1) 

1.00 – 1.09 0.47 mL (1) 

0.90 – 0.99 0.43 mL (1) 

0.80 – 0.89 0.38 mL (1) 

0.70 – 0.79 0.33 mL (1) 

0.60 – 0.69 0.29 mL (1) 

0.50 – 0.59 0.24 mL (1) 

0.40 – 0.49 0.20 mL (1)  

 

48 hours 5 mL/hour 

1.50 – 1.59 1.4 mL (1) 

1.40 – 1.49 1.3 mL (1) 

1.30 – 1.39 1.2 mL (1) 

1.20 – 1.29 1.1 mL (1) 

1.10 – 1.19 1.0 mL (1) 

1.00 – 1.09 0.94 mL (1) 

0.90 – 0.99 0.85 mL (1) 

0.80 – 0.89 0.76 mL (1) 

0.70 – 0.79 0.67 mL (1) 

0.60 – 0.69 0.57 mL (1) 

0.50 – 0.59 0.48 mL (1) 

0.40 – 0.49 0.39 mL (1) 

 

72 hours 3.3 mL/hour 

1.50 – 1.59 2.1 mL (1) 

1.40 – 1.49 2.0 mL (1) 

1.30 – 1.39 1.8 mL (1) 

1.20 – 1.29 1.7 mL (1) 

1.10 – 1.19 1.6 mL (1) 

1.00 – 1.09 1.4 mL (1) 

0.90 – 0.99 1.3 mL (1) 

0.80 – 0.89 1.1 mL (1) 

0.70 – 0.79 1 mL (1) 

0.60 – 0.69 0.86 mL (1) 

0.50 – 0.59 0.72 mL (1) 

0.40 – 0.49 0.59 mL (1) 

 

96 hours 2.5 mL/hour 

1.50 – 1.59 2.8 mL (1) 

1.40 – 1.49 2.6 mL (1) 

1.30 – 1.39 2.4 mL (1) 

1.20 – 1.29 2.3 mL (1) 

1.10 – 1.19 2.1 mL (1) 

1.00 – 1.09 1.9 mL (1) 

0.90 – 0.99 1.7 mL (1) 

0.80 – 0.89 1.5 mL (1) 

0.70 – 0.79 1.3 mL (1) 

0.60 – 0.69 1.2 mL (1) 

0.50 – 0.59 0.97 mL (1) 

0.40 – 0.49 0.78 mL (1) 



55 

Table 3. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) 

solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion 

bag for 15 mcg/m2/day dose  

 

Sodium chloride 9 mg/mL (0.9%) solution for injection (starting 

volume) 

250 mL (usual overfill volume 

of 265 to 275 mL) 

Solution (stabiliser) 5.5 mL 

Dose Infusion duration Infusion rate BSA (m2) 
Reconstituted BLINCYTO 

(number of packages) 

15 mcg/m2/day 

24 hours 10 mL/hour 

1.50 – 1.59 2.1 mL (1) 

1.40 – 1.49 2.0 mL (1) 

1.30 – 1.39 1.8 mL (1) 

1.20 – 1.29 1.7 mL (1) 

1.10 – 1.19 1.6 mL (1) 

1.00 – 1.09 1.4 mL (1) 

0.90 – 0.99 1.3 mL (1) 

0.80 – 0.89 1.1 mL (1) 

0.70 – 0.79 1.00 mL (1) 

0.60 – 0.69 0.86 mL (1) 

0.50 – 0.59 0.72 mL (1) 

0.40 – 0.49 0.59 mL (1) 

 

48 hours 5 mL/hour 

1.50 – 1.59 4.2 mL (2) 

1.40 – 1.49 3.9 mL (2) 

1.30 – 1.39 3.7 mL (2) 

1.20 – 1.29 3.4 mL (2) 

1.10 – 1.19 3.1 mL (2) 

1.00 – 1.09 2.8 mL (1) 

0.90 – 0.99 2.6 mL (1) 

0.80 – 0.89 2.3 mL (1) 

0.70 – 0.79 2.0 mL (1) 

0.60 – 0.69 1.7 mL (1) 

0.50 – 0.59 1.4 mL (1) 

0.40 – 0.49 1.2 mL (1) 

 

72 hours 3.3 mL/hour 

1.50 – 1.59 6.3 mL (3) 

1.40 – 1.49 5.9 mL (3) 

1.30 – 1.39 5.5 mL (2) 

1.20 – 1.29 5.1 mL (2) 

1.10 – 1.19 4.7 mL (2) 

1.00 – 1.09 4.2 mL (2) 

0.90 – 0.99 3.8 mL (2) 

0.80 – 0.89 3.4 mL (2) 

0.70 – 0.79 3.0 mL (2) 

0.60 – 0.69 2.6 mL (1) 

0.50 – 0.59 2.2 mL (1) 

0.40 – 0.49 1.8 mL (1) 

 

96 hours 2.5 mL/hour 

1.50 – 1.59 8.4 mL (3) 

1.40 – 1.49 7.9 mL (3) 

1.30 – 1.39 7.3 mL (3) 

1.20 – 1.29 6.8 mL (3) 

1.10 – 1.19 6.2 mL (3) 

1.00 – 1.09 5.7 mL (3) 

0.90 – 0.99 5.1 mL (2) 

0.80 – 0.89 4.6 mL (2) 

0.70 – 0.79 4.0 mL (2) 

0.60 – 0.69 3.4 mL (2) 

0.50 – 0.59 2.9 mL (2) 

0.40 – 0.49 2.3 mL (1) 



56 

 

These supplies are also required, but not included in the package  

• Sterile single-use disposable syringes  

• 21-23 gauge needle(s) (recommended)  

• Water for injections  

• Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection; 
o To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. 

BLINCYTO dose calculations are based on a usual overfill volume of 265 to 

275 mL sodium chloride 9 mg/mL (0.9%) solution for injection.  

o Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl 
acetate (EVA) infusion bags/pump cassettes. 

• Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low 
protein-binding 0.2 micrometre in-line filter. 

o Ensure that the tubing is compatible with the infusion pump. 
 

Reconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled 

with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection 

 

1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for 
injection that usually contains a total volume of 265 to 275 mL.  

2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution 
(stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard 

the remaining solution (stabiliser) vial.  

3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of 
water for injections. Direct the water for injections toward the side of the vial during 

reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. 

• Do not reconstitute BLINCYTO powder for concentrate with the solution 
(stabiliser).  

• The addition of water for injections to the powder for concentrate results in a total 
volume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL.  

4. Visually inspect the reconstituted solution for particulate matter and discolouration during 
reconstitution and prior to infusion. The resulting solution should be clear to slightly 

opalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has 

precipitated.  

5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to 
table 1 to table 3 for the specific volume of reconstituted BLINCYTO). Gently mix the 

contents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted 

solution. 

6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile 
0.2 micron in-line filter.  

7. Remove air from the infusion bag and prime the intravenous infusion line only with the 
prepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) 

solution for injection.  

8. Store at 2°C – 8°C if not used immediately. 
 

For instructions on administration, see Summary of Product Characteristics section 4.2. 
 

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 multi-lumen venous 

catheter, BLINCYTO should be infused through a dedicated lumen.  

 

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.  

 



57 

The BLINCYTO solution for infusion must be administered using intravenous tubing that contains a 

sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. 

 

The infusion bag must be changed at least every 96 hours by a healthcare professional for sterility 

reasons. 

 

Storage conditions and shelf life 

 

Unopened vials:  

 

5 years (2°C - 8°C) 

 

Reconstituted solution: 

 

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours at 

or below 27°C. 

 

From a microbiological point of view, unless the method of reconstituting precludes the risks of 

microbial contamination, the reconstituted solution should be diluted immediately. If not diluted 

immediately, in-use storage times and conditions are the responsibility of the user. 

 

Diluted solution (prepared infusion bag)  

 

Chemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours at 

or below 27°C. 

 

From a microbiological point of view, the prepared infusion bags should be used immediately. If not 

used immediately, in-use storage times and conditions prior to use are the responsibility of the user 

and would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in 

controlled and validated aseptic conditions. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET