Blincyto · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-096980 · has-adverse-reaction-information · PDF-Seite 16

Summary of the safety profile The adverse reactions described in this section were identified in clinical studies of patients with B-cell precursor ALL (N = 1 045). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (22.6%), neurologic events (12.2%), neutropenia/febrile neutropenia (9.1%), cytokine release syndrome (2.7%), and tumour lysis syndrome (0.8%). The most common adverse reactions were: pyrexia (70.8%), infections – pathogen unspecified (41.4%), infusion-related reactions (33.4%), headache (32.7%), nausea (23.9%), anaemia (23.3%), thrombocytopenia (21.6%), oedema (21.4%), neutropenia (20.8%), febrile neutropenia (20.4%), diarrhoea (19.7%), vomiting (19.0%), rash (18.0%), hepatic enzyme increased (17.2%), cough (15.0%), bacterial infectious disorders (14.1%), tremor (14.1%), cytokine release syndrome (13.8%), 16 leukopenia (13.8%), constipation (13.5%), decreased immunoglobulins (13.4%), viral infectious disorders (13.3%), hypotension (13.0%), back pain (12.5%), chills (11.7%), abdominal pain (10.6%), tachycardia (10.6%), insomnia (10.4%), pain in extremity (10.1%), and fungal infectious disorders (9.6%). Tabulated list of adverse reactions Adverse reactions are presented below by system organ class and frequency category. Frequency categories were determined from the crude incidence rate reported for each adverse reaction in clinical studies of patients with B-cell precursor ALL (N = 1 045). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. MedDRA system Very common Common Uncommon organ class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100) Infections and Bacterial infectionsa, b Sepsis infestations Viral infectionsa, b Pneumonia Infections - pathogen Fungal infectionsa, b unspecifieda, b Blood and lymphatic Febrile neutropenia Leukocytosis5 Lymphadenopathy system disorders Anaemia1 Lymphopenia6 Haemophagocytic Neutropenia2 lymphohistiocytosis Thrombocytopenia3 (HLH)

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HOS-096976 · has-contraindication-information · PDF-Seite 12

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

HOS-096975 · has-indication-information · PDF-Seite 2

BLINCYTO is indicated as monotherapy for the treatment of adults with CD19 positive relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL). Patients with Philadelphia chromosome-positive B-cell precursor ALL should have failed treatment with at least 2 tyrosine kinase inhibitors (TKIs) and have no alternative treatment options. BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome- negative CD19 positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 month or older with Philadelphia chromosome-negative CD19 positive B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic haematopoietic stem cell transplantation. BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 month or older with high-risk first relapsed Philadelphia chromosome-negative CD19 positive B-cell precursor ALL as part of the consolidation therapy (see section 4.2). BLINCYTO is indicated as monotherapy as part of consolidation therapy for the treatment of adult patients with newly diagnosed Philadelphia chromosome negative CD19 positive B-cell precursor ALL. 2

HOS-096978 · has-interaction-information · PDF-Seite 15

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.

HOS-096979 · has-pregnancy-information · PDF-Seite 15

Women of childbearing potential/Contraception Women of childbearing potential have to use effective contraception during and for at least 48 hours after treatment with blinatumomab (see section 4.4). 15 Pregnancy Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study conducted in mice, the murine surrogate molecule crossed the placenta and did not induce embryotoxicity, or teratogenicity (see section 5.3). The expected depletions of B- and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses. There are no data from the use of blinatumomab in pregnant women. Blinatumomab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. In case of exposure during pregnancy, depletion of B-cells may be expected in newborns due to the pharmacological properties of the product. Consequently, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered (see section 4.4). Breast-feeding It is unknown whether blinatumomab or metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast-feeding is contraindicated during and for at least 48 hours after treatment with blinatumomab. Fertility No studies have been conducted to evaluate the effects of blinatumomab on fertility. No adverse effects on male or female mouse reproductive organs in 13-week toxicity studies with the murine surrogate molecule (see section 5.3).

HOS-096977 · has-warning-information · PDF-Seite 12

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Neurologic events including ICANS Neurologic events including events with a fatal outcome have been observed. Grade 3 (CTCAE version 4.0) or higher (severe or life-threatening) neurologic events including ICANS following initiation of blinatumomab administration included encephalopathy, seizures, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Among patients that experienced a neurologic event, the median time to the first event was within the first 2 weeks of treatment and the majority of events resolved after treatment interruption and infrequently led to BLINCYTO treatment discontinuation. Elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, encephalopathy, and confusion. Patients with a medical history of neurologic signs and symptoms (such as dizziness, hypoaesthesia, hyporeflexia, tremor, dysaesthesia, paraesthesia and memory impairment) demonstrated a higher rate of neurologic events (such as tremor, dizziness, confusional state, encephalopathy and ataxia). Among these patients, the median time to the first neurologic event was within the first cycle of treatment. There is limited experience in patients with a history or presence of clinically relevant CNS pathology (e.g. epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome and psychosis) as they were excluded from clinical studies. There is a possibility of a higher risk of neurologic events in this population. The potential benefits of treatment should be carefully weighed against the risk of neurologic events and heightened caution should be exercised when administering BLINCYTO to these patients. There is limited experience with blinatumomab in patients with documented active ALL in the CNS or cerebrospinal fluid (CSF). However, patients have been treated with blinatumomab in clinical studies after clearance of CSF blasts with CNS directed therapy (such as intrathecal chemotherapy). Therefore, once the CSF is cleared, treatment with BLINCYTO may be initiated. Patients with Down syndrome may have a higher risk of seizures with BLINCYTO therapy; consider seizure prophylaxis prior to initiation of BLINCYTO for these patien

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