Presentation and Status in Health Basket
dispersion for IV
0.4 – 2 × 10^8 cells
For autologous use only.
A single dose of contains 2 × 106 CAR positive viable T cells per kg of body weight (range: 1 x 106–2 x 106 cells/kg), or maximum of 2 × 108 CAR positive viable T cells for patients 100 kg and above in approximately 68 mL dispersion in an infusion bag.
To be infused 3 to 14 days after completion of the lymphodepleting chemotherapy. The availability of the treatment must be confirmed prior to starting the lymphodepleting regimen.
Pre-treatment (lymphodepleting chemotherapy)
A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² and fludarabine 30 mg/m² should be administered intravenously on the 5th, 4th, and 3rd day before infusion of the drug.
– To minimize potential acute infusion reactions, it is recommended that patients be pre medicated with paracetamol 500 to 1,000 mg given orally and diphenhydramine 12.5 to 25 mg intravenous or oral (or equivalent) approximately 1 hour prior to infusion.
– Prophylactic use of systemic corticosteroids is not recommended.
Monitoring after infusion
– Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalization for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurologic events.
– After the first 10 days following the infusion, the patient should be monitored at the physician’s discretion.
– Patients should be instructed to remain within proximity (within 2 hours of travel) of a qualified treatment centre for at least 4 weeks following infusion.
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.
Tecartus is not indicated for children and adolescents under 18 years old.
The safety and efficacy of Tecartus in children and adolescents aged less than 18 years have not yet been established. No data are available.
See prescribing information for full details.
For the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after two or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor unless ineligible to BTK inhibitor.
Limitation of use: not indicated for the treatment of patients with active central nervous system lymphoma
Hypersensitivity to the active substance or to any of the excipients.
Contraindications of the lymphodepleting chemotherapy must be considered.
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 should be kept for a period of 30 years.
Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurologic events. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion.
Counsel patients to remain within the proximity of a qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS or neurological adverse reactions occur. Monitoring of vital signs and organ functions should be considered depending on the severity of the reaction.
Reasons to delay treatment
Due to the risks associated with treatment, infusion should 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. If the infusion is delayed for more than 2 weeks after the patient has received the lymphodepleting chemotherapy, lymphodepleting chemotherapy regimen should be administered again.
Screening for HBV, HCV, and HIV should be performed before collection of cells for manufacturing of the drug.
Blood, organ, tissue and cell donation
Patients treated with anti-CD19 CAR T cells should 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 detectable cerebrospinal fluid malignant cells or brain metastases confirmed by imaging. Therefore, the benefit/risk has not been established in this population. The drug is not indicated for the treatment of patients with active central nervous system lymphoma.
Patients with a history of or active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiac function were excluded from the study. 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 life threatening, was very commonly observed with a median time to onset of 3 days (range: 1 to 13 days). Patients should be closely monitored for signs or symptoms of these events, such as high fever, hypotension, hypoxia, chills, tachycardia and headache. CRS should be managed at the physician’s discretion, based on the patient’s clinical presentation and according to the CRS management algorithm. See prescribing information for full details.
Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection.
Management of cytokine release syndrome associated with anti-CD19 CAR T cells
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 infusion. The qualified treatment centre should have access to an additional dose of tocilizumab within 8 hours of each previous dose.
Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced by patients related with the drug. These include the use of tocilizumab or tocilizumab and corticosteroids. Patients who experience Grade 2 or higher CRS (e.g. hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life threatening CRS, consider intensive care supportive therapy.
CRS has been known to be associated with end organ dysfunction (e.g., 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 should be managed by standards of critical care and measures such as echocardiography should 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) should be considered in patients with severe or unresponsive CRS.
The medication continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of drug associated CRS.
Neurologic adverse reactions
Severe neurologic adverse reactions (encephalopathy, confusional state or delirium, decreased level of consciousness, seizures, aphasia), which could be life threatening, were very commonly observed in patients treated with the drug with a median time to onset of 8 days (range: 1 to 262 days).
Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for severe or life threatening neurologic toxicities. Non sedating, anti-seizure medicines should be considered as clinically indicated for Grade 2 or higher adverse reactions. Treatment algorithms have been developed to ameliorate the neurologic adverse reactions experienced by patients. These include the use of tocilizumab (if concurrent CRS) and/or corticosteroids for moderate, severe, or life threatening neurologic adverse reactions. See prescribing information for full details.
Infections and febrile neutropenia
Severe infections, which could be life threatening, were very commonly observed.
Patients should be monitored for signs and symptoms of infection before, during and after infusion and treated appropriately. Prophylactic antibiotics should be administered according to standard institutional guidelines.
Febrile neutropenia has been observed in patients after infusion 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.
In immunosuppressed patients, life threatening and fatal opportunistic infections including disseminated fungal infections and viral reactivation (e.g., 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 should be performed.
Viral reactivation, e.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.
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and infusion and should be managed according to standard guidelines. Grade 3 or higher prolonged cytopenias following anti-CD19 CAR T cells infusion occurred very commonly and included thrombocytopenia, neutropenia, and anaemia. Patient blood counts should be monitored after infusion.
B cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment. Hypogammaglobulinaemia was very commonly observed in patients treated with anti-CD19 CAR T cells. Hypogammaglobulinaemia predisposes patients to have infections. Immunoglobulin levels should be monitored after treatment and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement in case of recurrent infections and should be taken according standard guidelines.
Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residual gentamicin in the drug.
Patients treated with anti-CD19 CAR T cells may develop secondary malignancies. Patients should be monitored life-long for secondary malignancies. In the event that a secondary malignancy occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.
Tumour lysis syndrome (TLS)
TLS, which may be severe, has occasionally been observed. To minimize 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 events managed according to standard guidelines.
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 worsening GvHD.
Prior treatment with anti CD19 therapy
Treatment is not recommended if the patient has relapsed with CD19 negative disease after prior anti CD19 therapy.
This medicinal product contains 300 mg sodium per infusion, equivalent to 15% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 300 mg sodium.
Each dose contains 0.05 mL of dimethyl sulfoxide (DMSO) per ml.
The most significant and frequently occurring adverse reactions were cytokine release syndrome (91%), infections (56%) and encephalopathy (51%).
Serious adverse reactions occurred in 57% of patients. The most common serious adverse reactions included encephalopathy (26%), infections (28%) and cytokine release syndrome (15%).
Grade 3 or higher adverse reactions were reported in 65% of patients. The most common Grade 3 or higher non haematological adverse reactions included infections (32%) and encephalopathy (24%). The most common Grade 3 or higher haematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anaemia (56%).
No interaction studies have been performed.
Prophylactic use of systemic corticosteroids may interfere with the activity of the medication. Prophylactic use of systemic corticosteroids is therefore not recommended before infusion. Administration of corticosteroids as per the toxicity management guidelines does not impact the expansion and persistence of CAR T cells.
Pregnancy and Lactation
There are no available data with use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted to assess whether it can cause foetal harm when administered to a pregnant woman.
It is not known if this drug 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, it 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 newborn infants of mothers treated with this drug should be considered.
It is unknown whether this drug is excreted in human milk or transferred to the breast feeding child. Breast feeding women should be advised of the potential risk to the breast fed child.
There are no data regarding the signs of overdose.
The drug has major influence on the ability to drive and use machines.
Due to the potential for neurologic events, including altered mental status or seizures, patients should not drive or operate heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.