TECARTUS

Tecartus must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with Tecartus. At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion.

The qualified treatment centre 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 due to a shortage that is listed in the MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

4). Mantle cell lymphoma Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag. The target dose is 2 × 106 CAR-positive viable T cells per kg of body weight (range: 1 x 106–2 x 106 cells/kg), with a maximum of 2 × 108 CAR-positive viable T cells for patients 100 kg and above.

Tecartus is recommended to be infused 3 to 14 days after completion of the lymphodepleting chemotherapy for MCL patients. e. date of product availability for shipment). Pre-treatment (lymphodepleting chemotherapy) for MCL patients • A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously must be administered prior to infusing Tecartus.

The recommended days are on the 5th, 4th, and 3rd day before infusion of Tecartus. Acute lymphoblastic leukaemia Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag.

The target dose is 1 × 106 CAR-positive viable T cells per kg of body weight, with a maximum of 1 × 108 CAR-positive viable T cells for patients 100 kg and above. Tecartus is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy for ALL patients.

e. date of product availability for shipment). Pre-treatment (lymphodepleting chemotherapy) for ALL patients A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 900 mg/m2 intravenously over 60 minutes must be administered prior to infusing Tecartus.

This is recommended on the 2nd day before infusion of Tecartus. Fludarabine 25 mg/m2 intravenously over 30 minutes must be administered prior to infusing Tecartus. The recommended days are on the 4th, 3rd, and 2nd day before infusion of Tecartus.

5 to 25 mg intravenously or orally (or equivalent medicinal products) approximately 1 hour before the infusion of Tecartus. 5). Monitoring prior to infusion • In some patient groups at risk, a delay of the Tecartus infusion may be indicated (see section

8 Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection. Management of cytokine release syndrome associated with Tecartus At least 1 dose per patient of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, must be on site and available for administration prior to Tecartus infusion.

The qualified treatment centre 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 due to a shortage that is listed in the MHRA Central Alerting System, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS.

The management of patients should be conducted based on the patient’s clinical presentation and in accordance with applicable local institutional and/or national or European/international clinical guidelines. Physicians are advised to exercise clinical judgment consistent with these standards.

, hepatic, renal, cardiac, and pulmonary). In addition, worsening of underlying organ pathologies can occur in the setting of CRS. Patients with medically significant cardiac dysfunction must be managed by standards of critical care and measures such as echocardiography is to be considered.

In some cases, macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of CRS. Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is to be considered in patients with severe or unresponsive CRS.

HLH/MAS should be managed per local institutional and/or national or European/international clinical guidelines. Tecartus continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of Tecartus-associated CRS.

Neurologic adverse reactions Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicity syndrome (ICANS), have been observed in patients treated with Tecartus, which could be life-threatening or fatal.

8). The management of patients should be conducted based on the patient’s clinical presentation and in accordance with applicable local institutional and/or national or European/international clinical guidelines. Physicians are advised to exercise clinical judgment consistent with these standards.

8). Patients must be monitored for signs and symptoms of infection before, during and after infusion and treated appropriately. Prophylactic antibiotics must be administered according to standard institutional guidelines. 8) and may be concurrent with CRS.

In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. , HHV-6 and progressive multifocal leukoencephalopathy) have been reported.

The possibility of these infections should be considered in patients with neurologic events and appropriate diagnostic evaluations must be performed. g. Hepatitis B virus (HBV) reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure, and death.

Prolonged cytopenias Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion and must be managed according to standard guidelines. 8). Patient blood counts must be monitored after Tecartus infusion.

Hypogammaglobulinaemia B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Tecartus. 8). Hypogammaglobulinaemia predisposes patients to have infections. Immunoglobulin levels should be monitored after treatment with Tecartus and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement in case of recurrent infections and must be taken according to standard guidelines.

Hypersensitivity reactions Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residual gentamicin in Tecartus. Secondary malignancies including of T cell and myeloid origin Patients treated with Tecartus 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. 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. In the event that a secondary malignancy occurs, contact the company to obtain instructions on patient samples to collect for testing. Myelodysplastic syndrome and acute myeloid leukaemia, including cases with fatal outcomes, have occurred in patients following treatment with Tecartus.

Patients must be monitored life-long for secondary malignancies. Tumour lysis syndrome (TLS) TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive […]

4 Reasons to delay treatment). Monitoring after infusion • Patients must be monitored daily for the first 7 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for the first 7 days or at the first signs or symptoms of CRS and/or neurologic events.

• After the first 7 days following the infusion, the patient is to be monitored at the physician’s discretion. • Patients must remain within proximity of a qualified treatment centre for at least 4 weeks following infusion. Special populations Elderly No dose adjustment is required in patients ≥65 years of age.

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) There is no experience with manufacturing Tecartus for patients with a positive test for HIV, active HBV, or active HCV infection.

Therefore, the benefit/risk has not yet been established in this population. Paediatric population The safety and efficacy of Tecartus in children and adolescents aged less than 18 years have not yet been established. No data are available.

Method of administration Tecartus is for intravenous use only. Tecartus must not be irradiated. Do NOT use a leukodepleting filter. Before administration, it must be confirmed that the patient’s identity matches the unique patient information on the Tecartus infusion bag and cassette.

Administration • A leukodepleting filter must not be used. • Tocilizumab and emergency equipment must be available prior to infusion and during the monitoring period. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

• For autologous use only, verify the patient ID to match the patient identifiers on the Tecartus infusion bag. • Once tubing has been primed, infuse the entire content of the Tecartus infusion bag within 30 minutes by either gravity or a peristaltic pump.

6. 1. Contraindications of the lymphodepleting chemotherapy must be considered. 4 Special warnings and precautions for use 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.

Autologous use Tecartus is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Before infusion, the patient’s identity must match the patient identifiers on the Tecartus infusion bag and cassette.

Do not infuse Tecartus if the information on the patient-specific cassette label does not match the intended patient’s identity. General Warnings and precautions of lymphodepleting chemotherapy must be considered. Reasons to delay treatment Due to the risks associated with Tecartus treatment, infusion must be delayed if a patient has any of the following conditions: • Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) including from preceding chemotherapies.

• Active uncontrolled infection or inflammatory disease. • Active graft-versus-host disease (GvHD). In some cases, the treatment may be delayed after administration of the lymphodepleting chemotherapy regimen. 2) Monitoring after infusion Patients must be monitored daily for the first 7 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities.

Physicians can consider hospitalisation for the first 7 days or at the first signs or symptoms of CRS and/or neurologic events. After the first 7 days following infusion, the patient is to be monitored at the physician’s discretion.

Patients must remain within proximity of a qualified treatment centre for at least 4 weeks following infusion and seek immediate medical attention should signs or symptoms of CRS or neurological adverse reactions occur. Monitoring of vital signs and organ functions must be considered depending on the severity of the reaction.

2). Blood, organ, tissue and cell donation Patients treated with Tecartus must not donate blood, organs, tissues, or cells for transplantation. Active central nervous system (CNS) lymphoma There is no experience of use of this medicinal product in patients with active CNS lymphoma defined as brain metastases confirmed by imaging.

In ALL, asymptomatic patients with a maximum of CNS-2 disease (defined as white blood cells <5/μL in cerebral spinal fluid with presence of lymphoblasts) without clinically evident neurological changes were treated with Tecartus, however, data is limited in this population.

Therefore, the benefit/risk of Tecartus has not been established in these populations. Concomitant disease Patients with a history of or active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiac function were excluded from the studies.

These patients are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention. Cytokine release syndrome Nearly all patients experienced some degree of CRS. Severe CRS, which can be fatal, was observed with Tecartus with a median time to onset of 3 days (range: 1 to 13 days).

Patients must be closely monitored for signs or symptoms of […]

1. Contraindications of the lymphodepleting chemotherapy must be considered.