Blinatumomab interacts in the following cases:
Initiation of blinatumomab 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.
The safety and efficacy of blinatumomab have not been studied in patients with severe renal impairment.
The safety and efficacy of blinatumomab have not been studied in patients with severe hepatic impairment.
The safety of immunisation with live viral vaccines during or following blinatumomab therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of blinatumomab 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.
There is limited experience in patients with a history or presence of clinically relevant CNS pathology (e.g. epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome and psychosis) as they were excluded from clinical studies. There is a possibility of a higher risk of neurologic events in this population. The potential benefits of treatment should be carefully weighed against the risk of neurologic events and heightened caution should be exercised when administering blinatumomab to these patients.
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. The expected depletions of B- and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses.
There are no data from the use of blinatumomab in pregnant women.
Blinatumomab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.
In case of exposure during pregnancy, depletion of B-cells may be expected in newborns due to the pharmacological properties of the product. Consequently, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered.
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.
Women of childbearing potential have to use effective contraception during and for at least 48 hours after treatment with blinatumomab.
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.
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. 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.
The adverse reactions described in this section were identified in clinical studies of patients with B-cell precursor ALL (N=1 045).
The most serious adverse reactions that may occur during blinatumomab treatment include: infections (22.6%), neurologic events (12.2%), neutropenia/febrile neutropenia (9.1%), cytokine release syndrome (2.7%), and tumour lysis syndrome (0.8%).
The most common adverse reactions were: pyrexia (70.8%), infections – pathogen unspecified (41.4%), infusion-related reactions (33.4%), headache (32.7%), nausea (23.9%), anaemia (23.3%), thrombocytopenia (21.6%), oedema (21.4%), neutropenia (20.8%), febrile neutropenia (20.4%), diarrhoea (19.7%), vomiting (19.0%), rash (18.0%), hepatic enzyme increased (17.2%), cough (15.0%), bacterial infectious disorders (14.1%), tremor (14.1%), cytokine release syndrome (13.8%), leukopenia (13.8%), constipation (13.5%), decreased immunoglobulins (13.4%), viral infectious disorders (13.3%), hypotension (13.0%), back pain (12.5%), chills (11.7%), abdominal pain (10.6%), tachycardia (10.6%), insomnia (10.4%), pain in extremity (10.1%), and fungal infectious disorders (9.6%).
Adverse reactions are presented below by system organ class and frequency category. Frequency categories were determined from the crude incidence rate reported for each adverse reaction in clinical studies of patients with B-cell precursor ALL (N=1 045). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| MedDRA system organ class | Very common (≥1/10) | Common (≥1/100 to <1/10) | Uncommon (≥1/1 000 to <1/100) |
|---|---|---|---|
| Infections and infestations | Bacterial infectionsa,b Viral infectionsa,b Infections – pathogen unspecifieda,b | Sepsis Pneumonia Fungal infectionsa,b | |
| Blood and lymphatic system disorders | Febrile neutropenia Anaemia1 Neutropenia2 Thrombocytopenia3 Leukopenia4 | Leukocytosis5 Lymphopenia6 | Lymphadenopathy 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 | |
| Investigations | Hepatic enzyme increaseda,15 Decreased immunoglobulins16 | Weight increased Blood alkaline phosphatase increased | |
| Injury, poisoning and procedural complications | Infusion-related reactions17 |
a Additional information is provided in “Description of selected adverse reactions”.
b MedDRA high level group terms (MedDRA version 23.0).
Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above. The terms contributing to the relevant adverse reaction are indicated below:
1 Anaemia includes anaemia and haemoglobin decreased.
2 Neutropenia includes neutropenia and neutrophil count decreased.
3 Thrombocytopenia includes platelet count decreased and thrombocytopenia.
4 Leukopenia includes leukopenia and white blood cell count decreased.
5 Leukocytosis includes leukocytosis and white blood cell count increased.
6 Lymphopenia includes lymphocyte count decreased and lymphopenia.
7 Tachycardia includes sinus tachycardia, supraventricular tachycardia, tachycardia, atrial tachycardia and ventricular tachycardia.
8 Hypotension includes blood pressure decreased and hypotension.
9 Hypertension includes blood pressure increased and hypertension.
10 Hyperbilirubinaemia includes blood bilirubin increased and hyperbilirubinaemia.
11 Rash includes erythema, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash pruritic, catheter site rash, rash pustular, genital rash, rash papular and rash vesicular.
12 Pyrexia includes body temperature increased and pyrexia.
13 Oedema includes bone marrow oedema, periorbital oedema, eyelid oedema, eye oedema, lip oedema, face oedema, localised oedema, generalised oedema, oedema, oedema peripheral, infusion site oedema, oedematous kidney, scrotal oedema, oedema genital, pulmonary oedema, laryngeal oedema, angioedema, circumoral oedema and lymphoedema.
14 Chest pain includes chest discomfort, chest pain, musculoskeletal chest pain and non-cardiac chest pain.
15 Hepatic enzyme increased includes alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hepatic enzyme increased, liver function test increased and transaminases increased.
16 Decreased immunoglobulins includes blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, globulins decreased, hypogammaglobulinaemia, hypoglobulinaemia and immunoglobulins decreased.
17 Infusion-related reactions is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and event lasted ≤2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, rash, tachypnea, swelling face, face oedema and rash erythematous.
In the randomised phase III clinical study (N=267) and the single-arm phase II clinical study (N=189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL treated with blinatumomab, 66.0% of patients experienced one or more neurologic adverse reactions (including psychiatric disorders), primarily involving the CNS. Serious and grade ≥3 neurologic adverse reactions were observed in 11.6% and 12.1% of patients respectively, of which the most common serious adverse reactions were encephalopathy, tremor, aphasia, and confusional state. The majority of neurologic events (80.5%) were clinically reversible and resolved following interruption of blinatumomab. The median time to the first event was within the first 2 weeks of treatment. One case of fatal encephalopathy has been reported in an earlier phase II clinical single-arm study.
Neurologic events were reported for 62.2% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL (N=45). Serious and grade ≥3 neurologic events were reported at 13.3% each in adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL.
Neurologic events were reported for 71.5% of adult patients with MRD positive B-cell precursor ALL (N=137), 22.6% of patients experienced serious events. Grade ≥3 and grade ≥4 events, respectively, were reported for 16.1% and 2.2% of adult patients with MRD positive B-cell precursor ALL.
Life-threatening or fatal (grade ≥ 4) viral, bacterial and fungal infections have been reported in patients treated with blinatumomab. In addition, reactivations of virus infection (e.g. Polyoma (BK)) have been observed in the phase II clinical study in adults with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL. Patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL with ECOG performance status at baseline of 2 experienced a higher incidence of serious infections compared to patients with ECOG performance status of <2.
In the randomised phase III clinical study (N=267) and the single-arm phase II clinical study (N=189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL treated with blinatumomab, 14.7% of patients experienced CRS. Serious CRS reactions were reported in 2.4% of patients with a median time to onset of 2 days.
Cytokine release syndrome was reported in 8.9% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL (N=45), 2.2% of patients experienced serious events. No grade ≥3 or ≥4 events were reported.
Cytokine release syndrome was reported in 2.9% of adult patients with MRD positive B-cell precursor ALL (N=137). Grade 3 and serious events were reported for 1.5% each of adult patients with MRD positive B-cell precursor ALL; no grade ≥4 events were reported.
Capillary leak syndrome was observed in 1 patient in the phase II clinical study in adult patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL and in 1 patient in the phase II clinical study in adult patients with MRD positive B-cell precursor ALL. Capillary leak syndrome was not observed in adult patients in the phase II clinical study in patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL.
In the randomised phase III clinical study (N=267) and the single-arm phase II clinical study (N=189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL treated with blinatumomab, 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 blinatumomab treatment initiation.
Elevated liver enzyme events were reported for 17.8% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL (N=45), 2.2% of patients experienced serious events. Grade ≥3 and grade ≥4 events, respectively, were reported for 13.3% and 6.7% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL.
Elevated liver enzyme events were reported for 12.4% of adult patients with MRD positive B-cell precursor ALL (N=137). Grade ≥3 and grade ≥4 events, respectively, were reported for 8.0% and 4.4% of adult patients with MRD positive B-cell precursor ALL. The duration of hepatic adverse reactions has generally been brief and with rapid resolution, often when continuing uninterrupted treatment with blinatumomab.
Pancreatitis, life-threatening or fatal, has been reported in patients receiving blinatumomab in the clinical studies and the post-marketing settings. The median time to onset was 7.5 days.
Leukoencephalopathy has been reported. Patients with brain MRI/CT findings consistent with leukoencephalopathy experienced concurrent serious adverse reactions including confusional state, tremor, cognitive disorder, encephalopathy, and convulsion. Although there is a potential for the development of progressive multifocal leukoencephalopathy (PML), no confirmed case of PML has been reported in the clinical studies.
Blinatumomab has been evaluated in paediatric patients with relapsed or refractory B-cell precursor ALL in a phase I/II, single-arm dose escalation/evaluation study (MT103-205), in which 70 paediatric patients, aged 7 months to 17 years, were treated with the recommended dosage regimen.
The most frequently reported serious adverse reactions were pyrexia (11.4%), febrile neutropenia (11.4%), cytokine release syndrome (5.7%), sepsis (4.3%), device-related infection (4.3%), overdose (4.3%), convulsion (2.9%), respiratory failure (2.9%), hypoxia (2.9%), pneumonia (2.9%), and multi-organ failure (2.9%).
The adverse reactions in blinatumomab-treated paediatric patients were similar in type to those seen in adult patients. Adverse reactions that were observed more frequently (≥ 10% difference) in the paediatric population compared to the adult population were anaemia, thrombocytopenia, leukopenia, pyrexia, infusion-related reactions, weight increase, and hypertension.
The type and frequency of adverse reactions were similar across different paediatric subgroups (gender, age and geographic region).
At a dose higher than the recommended dose in study MT103-205, a case of fatal cardiac failure occurred in the setting of life-threatening cytokine release syndrome (CRS) and tumour lysis syndrome (TLS).
Blinatumomab has also been evaluated in paediatric patients with high-risk first relapsed B-cell precursor ALL in a randomised, controlled, open-label phase III study (20120215), in which 54 patients, aged 1 to 18 years, were treated with the recommended dosage regimen for high-risk first relapsed B-cell precursor ALL. The safety profile of blinatumomab in study 20120215 is consistent with that of the studied paediatric relapsed or refractory B-cell precursor ALL population.
There is limited experience with blinatumomab 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 blinatumomab. 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 blinatumomab 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 blinatumomab.
The safety of blinatumomab has not been studied in patients with severe renal impairment.
In clinical studies of adult ALL patients treated with blinatumomab, less than 2% tested positive for anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, the majority had in vitro neutralizing activity. No anti-blinatumomab antibodies were detected in clinical studies of paediatric patients with relapsed or refractory ALL treated with blinatumomab.
Anti-blinatumomab antibody formation may affect the pharmacokinetics of blinatumomab.
Overall, the totality of clinical evidence supports the finding that anti-blinatumomab antibodies are not suggestive of any clinical impact on the safety or effectiveness of blinatumomab.
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