BLINCYTO Powder for concentrate solution Ref.[6566] Active ingredients: Blinatumomab

Source: European Medicines Agency (EU)  Revision Year: 2019  Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands

Contraindications

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

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 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.

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.

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”.

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.

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).

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).

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.

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.

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)

Infections and infestations

Very common: Bacterial infectionsa,b, Fungal infectionsa,b, Viral infectionsa,b, Infections – pathogen, unspecifieda,b

Common: Sepsis, Pneumonia

Blood and lymphatic system disorders

Very common: Febrile neutropenia, Anaemia1, Neutropenia2, Thrombocytopenia3, Leukopenia4

Common: Leukocytosis5, Lymphopenia6

Uncommon: Lymphadenopathy, Histiocytosis haematophagic

Immune system disorders

Very common: Cytokine release syndromea

Common: Hypersensitivity

Uncommon: Cytokine storm

Metabolism and nutrition disorders

Common: Tumour lysis syndrome

Psychiatric disordersa

Very common: Insomnia

Common: Confusional state, Disorientation

Nervous system disordersa

Very common: Headache, Tremor

Common: Encephalopathy, Aphasia, Paraesthesia, Seizure, Cognitive disorder, Memory impairment, Dizziness, Somnolence, Hypoaesthesia, Cranial nerve disorderb, Ataxia

Uncommon: Speech disorder

Cardiac disorders

Very common: Tachycardia7

Vascular disorders

Very common: Hypotension8

Common: Hypertension9, Flushing

Uncommon: Capillary leak syndrome

Respiratory, thoracic and mediastinal disorders

Very common: Cough

Common: Dyspnoea, Productive cough, Respiratory failure, Wheezing

Uncommon: Dyspnoea exertional, Acute respiratory failure

Gastrointestinal disorders

Very common: Nausea, Diarrhoea, Vomiting, Constipation, Abdominal pain

Uncommon: Pancreatitisa

Hepatobiliary disorders

Common: Hyperbilirubinaemiaa,10

Skin and subcutaneous tissue disorders

Very common: Rash11

Musculoskeletal and connective tissue disorders

Very common: Back pain, Pain in extremity

Common: Bone pain

General disorders and administration site conditions

Very common: Pyrexia12, Chills, Oedema13

Common: Chest pain14, Pain

Investigations

Very common: Hepatic enzyme increaseda,15, Decreased immunoglobulins16

Common: Weight increased, Blood alkaline phosphatase increased

Injury, poisoning and procedural complications

Very common: 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.

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.

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.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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