BREYANZI

/ BMS

At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available per patient prior to infusion. The treatment center must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.
This medical product is intended for autologous use.
Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one or more vials.
The target dose is 100 x 10^6 CAR-positive viable T cells (consisting of a target 1:1 ratio of CD4+ and CD8+ cell components) within a range of 44-120 x 10^6 CAR-positive viable T cells.
The availability of this medical product must be confirmed before starting lymphodepleting chemotherapy regimen.
Patients should be clinically re-assessed prior to administration of lymphodepleting chemotherapy and this medical product to ensure no reasons to delay therapy.
See prescribing information for full details.
Pre-treatment (lymphodepleting chemotherapy)
Lymphodepleting chemotherapy consisting of cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day, administered intravenously for three days.
This medical product is to be administered 2 to 7 days after completion of lymphodepleting chemotherapy. If there is a delay of more than 2 weeks between completing lymphodepleting chemotherapy and the infusion of this medical product, then the patient should be re-treated with lymphodepleting chemotherapy prior to receiving the infusion.
Pre-medication
It is recommended that premedication with paracetamol and diphenhydramine (25-50 mg, intravenously or orally) or another H1-antihistamine, be administered 30 to 60 minutes before the infusion to reduce the possibility of an infusion reaction.
Prophylactic use of systemic corticosteroids should be avoided, as the use may interfere with the activity of this medical product.
See prescribing information for full details.

Treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising
from indolent lymphoma), high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B who have:
* Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line
chemoimmunotherapy; or
* Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligibale for hematopoetic stem cell transplanatation (HSCT) due to comorbidities or age.
Treatment of adult patients with relapsed or refractory diffuse large B-cell
lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma
grade 3B (FL3B), after two or more lines of systemic therapy.

* Hypersensitivity to the active substance or to any of the excipients
* Contraindications of the lymphodepleting chemotherapy must be considered

Traceability
The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the product.
Autologous use
Intended solely for autologous use and must not under any circumstances be administered to other patients.
Reasons to delay treatment
Due to the risks associated with this treatment, infusion should be delayed if a patient has any of the following conditions:
* Unresolved serious adverse events (especially pulmonary events, cardiac events, or hypotension), including those after preceding chemotherapies.
* Active uncontrolled infections, or inflammatory disorders.
* Active graft-versus-host disease (GVHD).
Cytokine release syndrome
CRS including fatal or life-threatening reactions can occur following this medical product infusion. For patients who received one prior line of therapy for large B-cell lymphoma (LBCL), the median time to onset was 4 days (range: 1 to 63 days, with the upper limit due to CRS onset, without fever, reported in one patient). For patients who received two or more prior lines of therapy for LBCL, the median time to onset was 4 days (range: 1 to 14 days). Less than half of all patients treated with this medical product experienced some degree of CRS.
In clinical studies high tumour burden prior to infusion this medical product was associated with a higher incidence of CRS.
Patients should be monitored 2-3 times during the first week following infusion at the qualified treatment center for signs and symptoms of CRS.
Neurologic adverse reactions
Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with this medical product, including concurrently with CRS, after CRS resolution, or in the absence of CRS. For patients who received one prior line of therapy for LBCL, the median time to onset of the first event was 8 days (range: 1 to 63 days) and for patients who received two or more prior lines of therapy for LBCL, the median time to onset of the first event was 9 days (range: 1 to 66 days). The most common neurologic symptoms included encephalopathy, tremor, aphasia, delirium, dizziness and headache.
Infections and febrile neutropenia
This medical product should not be administered to patients with a clinically significant active infection or inflammatory disorder. Severe infections including life-threatening or fatal infections, have occurred in patients after receiving this medicinal product. Patients should be monitored for signs and symptoms of infection before and after administration and treated appropriately.
Prophylactic anti-microbials should be administered according to standard institutional guidelines.
Febrile neutropenia has been observed in patients after treatment with this medical product and may be concurrent with CRS. In the event of febrile neutropenia, infection should be evaluated and managed with broad-spectrum antibiotics, fluids and other supportive care as medically indicated.
Viral reactivation
Viral reactivation occurs in immunosuppressed patients.
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against B cells. For patients with a prior history of HBV, prophylactic antiviral suppressive therapy is recommended to prevent HBV reactivation during and after therapy.
Reactivation of JC virus, leading to progressive multifocal leukoencephalopathy (PML), has been reported in patients treated with this medical product who have also received prior treatment with other immunosuppressive medicinal products. Cases with fatal outcome have been reported.
Serological testing
Screening for HBV, HCV, and HIV should be performed before collection of cells for manufacturing.
Prolonged cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and this medical product. Blood counts should be monitored prior to and after administration. Prolonged cytopenias should be managed according to clinical guidelines.
Hypogammaglobulinaemia
B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with this medical product. Hypogammaglobulinaemia has been very commonly observed in patients treated with this medical produt. Immunoglobulin levels should be monitored after treatment and managed per clinical guidelines including infection precautions, antibiotic prophylaxis and/or immunoglobulin replacement.
Secondary malignancies including of T-cell origin
Patients treated with this medical product may develop secondary malignancies. T-cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T-cell therapy, including this medical product. T-cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-, directed CAR T-cell therapy. There have been fatal outcomes. Patients should be monitored life-long for secondary malignancies. In the event that a secondary malignancy of T-cell origin occurs, the company should be contacted to obtain instructions on the collection of tumor samples for testing.
Tumour lysis syndrome (TLS)
TLS may occur in patients treated with CAR T therapies. To minimise the risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to infusion. Signs and symptoms of TLS should be monitored and managed in accordance with clinical guidelines.
Hypersensitivity reactions
Allergic reactions may occur with the infusion of this medical product. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide.
Transmission of an infectious agent
Although this medical product is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists, Therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.
Interference with virological testing
Due to limited and short spans of identical genetic information between the lentiviral vector used to create this medical product and HIV, some HIV nucleic acid tests (NAT) may give a false positive result.
Prior stem cell transplantation (GVHD)
It is not recommended that patients who underwent an allogeneic stem cell transplant and suffer from active acute or chronic GVHD receive treatment because of the potential risk of this medical product worsening GVHD.
See prescribing information for full details.

Very common: Infections – pathogen unspecified, Neutropenia, Anaemia, Thrombocytopenia, Leukopenia, Lymphopenia, Cytokine release syndrome, Insomnia, Headache, Encephalopathy, Dizziness, Tremor, Tachycardia, Hypotension, Cough, Nausea, Diarrhoea, Constipation, Abdominal pain, Vomiting, Rash, Fatigue, Pyrexia, Oedema.
Common: Bacterial infectious disorders, Viral infectious disorders, Fungal infections disorders, Febrile neutropenia, Hypofibrinogenaemia, Hypogammaglobulinaemia, Hypophosphataemia, Delirium, Anxiety, Aphasia, Peripheral neuropathy, Visual disturbance, Ataxia, Taste disorder, Cerebellar syndrome, Arrhythmia, Hypertension
Thrombosis, Dyspnoea, Pleural effusion, Hypoxia, Gastrointestinal haemorrhage, Acute kidney injury, Chills, Infusion related reaction.

No interaction studies have been performed in humans.
See prescribing information for full details.

Pregnancy: It is not known if lisocabtagene maraleucel has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, this medical product is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with should be considered.
Lactation: It is unknown whether lisocabtagene maraleucel is excreted in human milk or transferred to the breastfeeding child. Women who are breast-feeding should be advised of the potential risk to the breast-fed child.

No data from clinical studies are available regarding overdose

Unopened vial when stored in the vapour phase of liquid nitrogen (≤ -130°C)
After thawing
The product should be administered immediately after thawing. In-use storage times and conditions should not exceed 2 hours at room temperature (15 °C-25 °C).
Do not refreeze.