Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Kite Pharma EU B.V., Tufsteen 1, 2132 NT Hoofddorp, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 must be kept for a period of 30 years.
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 patientspecific cassette label does not match the intended patient’s identity.
Warnings and precautions of lymphodepleting chemotherapy must be considered.
Patients must 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 is to 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 must be considered depending on the severity of the reaction.
Due to the risks associated with Tecartus treatment, infusion must be delayed if a patient has any of the following conditions:
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 must be administered again (see section 4.2).
Screening for HBV, HCV, and HIV must be performed before collection of cells for manufacturing of Tecartus (see section 4.2).
Patients treated with Tecartus must not donate blood, organs, tissues, or cells for transplantation.
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.
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.
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 these events, such as high fever, hypotension, hypoxia, chills, tachycardia and headache (see section 4.8). CRS is to be managed at the physician’s discretion, based on the patient’s clinical presentation and according to the CRS management algorithm provided in Table 1.
Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection.
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 European Medicines Agency shortage catalogue, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS.
Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced by patients on Tecartus. These include the use of tocilizumab or tocilizumab and corticosteroids, as summarised in Table 1. Patients who experience Grade 2 or higher CRS (e.g. hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) must 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 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.
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.
Table 1. CRS grading and management guidance:
| CRS Gradea | Tocilizumab | Corticosteroids |
|---|---|---|
| Grade 1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise). | If not improving after 24 hours, administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). | N/A |
| Grade 2 Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low-dose of one vasopressor or Grade 2 organ toxicityb. | Administer tocilizumabc 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24 hour period; maximum total of 4 doses if no clinical improvement in the signs and symptoms of CRS, or if no response to second or subsequent doses of tocilizumab, consider alternative measures for treatment of CRS. If improving, discontinue tocilizumab. | If no improvement within 24 hours after starting tocilizumab, manage as per Grade 3. If improving, taper corticosteroids, and manage as Grade 1. |
| Grade 3 Symptoms require and respond to aggressive intervention. Oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis. | Per Grade 2 | Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (e.g., 10 mg intravenously every 6 hours) until Grade 1, then taper corticosteroids. If improving, manage as Grade 2. If not improving, manage as Grade 4. |
| Grade 4 Life-threatening symptoms. Requirements for ventilator support or continuous veno-venous haemodialysis or Grade 4 organ toxicity (excluding transaminitis). | Per Grade 2 | Administer methylprednisolone 1000 mg intravenously per day for 3 days. If improving, taper corticosteroids, and manage as Grade 3. If not improving, consider alternate immunosuppressants. |
N/A = not available/not applicable
a Lee et al 2014.
b Refer to Table 2 for management of neurologic adverse reactions.
c Refer to tocilizumab summary of product characteristics for details.
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 lifethreatening or fatal. The median time to onset was 7 days (range: 1 to 262 days) following Tecartus infusion (see section 4.8).
Patients who experience Grade 2 or higher neurologic toxicity/ICANS must be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive-care supportive therapy for severe or life-threatening neurologic toxicity/ICANS. Non-sedating, anti-seizure medicines are 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 on Tecartus. These include the use of tocilizumab (if concurrent CRS) and/or corticosteroids for moderate, severe, or life-threatening neurologic adverse reactions as summarised in Table 2.
Table 2. Neurologic adverse reaction/ICANS grading and management guidance:
| Grading assessment | Concurrent CRS | No concurrent CRS |
|---|---|---|
| Grade 2 | Administer tocilizumab as per Table 1 for management Grade 2 CRS. If not improving within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less, then taper corticosteroids. If improving, discontinue tocilizumab. If still not improving, manage as Grade 3. | Administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less. If improving, taper corticosteroids. |
| Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. | ||
| Grade 3 | Administer tocilizumab as per Table 1 for management of Grade 2 CRS. In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids. If improving, discontinue tocilizumab and manage as Grade 2. If still not improving, manage as Grade 4. | Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids. If not improving, manage as Grade 4. |
| Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. | ||
| Grade 4 | Administer tocilizumab as per Table 1 for management of Grade 2 CRS. Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days. If improving, then manage as Grade 3. If not improving, consider alternate immunosuppressants. | Administer methylprednisolone 1000 mg intravenously per day for 3 days. If improving, then manage as Grade 3. If not improving, consider alternate immunosuppressants. |
| Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. | ||
Severe infections, which could be life-threatening, were very commonly observed with Tecartus (see section 4.8).
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.
Febrile neutropenia has been observed in patients after Tecartus infusion (see section 4.8) 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.
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 must 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 Tecartus infusion and must be managed according to standard guidelines. Grade 3 or higher prolonged cytopenias following Tecartus infusion occurred very commonly and included thrombocytopenia, neutropenia, and anaemia (see section 4.8). Patient blood counts must be monitored after Tecartus infusion.
B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinaemia was very commonly observed in patients treated with Tecartus (see section 4.8). 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.
Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residual gentamicin in Tecartus.
Patients treated with Tecartus may develop secondary malignancies. Patients must be monitored life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact the company to obtain instructions on patient samples to collect for testing.
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 allopurinol, or an alternative prophylaxis, prior to Tecartus infusion. Signs and symptoms of TLS must be monitored, and events managed according to standard guidelines.
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 Tecartus worsening GvHD.
Tecartus 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.
Patients are expected to enrol in a registry and will be followed in the registry in order to better understand the long-term safety and efficacy of Tecartus.
No interaction studies have been performed.
Prophylactic use of systemic corticosteroids may interfere with the activity of Tecartus. Prophylactic use of systemic corticosteroids is therefore not recommended before infusion (see section 4.2).
Administration of corticosteroids as per the toxicity management guidelines does not impact the expansion and persistence of CAR T cells.
The safety of immunisation with live viral vaccines during or following Tecartus treatment has not been studied. As a precautionary measure, vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, and until immune recovery following treatment.
The pregnancy status of women of childbearing potential must be verified before starting Tecartus treatment.
See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Tecartus.
There are no available data with Tecartus use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with Tecartus to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).
It is not known if Tecartus 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, Tecartus 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 Tecartus therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels and B-cells in newborn infants of mothers treated with Tecartus must be considered.
It is unknown whether Tecartus is excreted in human milk or transferred to the breast-feeding child.
Breast-feeding women must be advised of the potential risk to the breast-fed child.
No clinical data on the effect of Tecartus on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.
Tecartus 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 must not drive or operate heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.
The safety data described in this section reflect exposure to Tecartus in ZUMA-2, a Phase 2 study in which a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positive viable T cells (2 × 106 or 0.5 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight-based.
The most significant and frequently occurring adverse reactions were CRS (91%), infections (55%) and encephalopathy (51%).
Serious adverse reactions occurred in 56% 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 67% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (34%) 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%).
The safety data described in this section reflect exposure to Tecartus in ZUMA-3, a Phase ½ study in which a total of 100 patients with relapsed/refractory B-cell precursor ALL received a single dose of CAR-positive viable T cells (0.5 × 106, 1 × 106, or 2 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight based.
The most significant and frequently occurring adverse reactions were CRS (91%), encephalopathy (57%), and infections (41%).
Serious adverse reactions occurred in 70% of patients. The most common serious adverse reactions included CRS (25%), infections (22%) and encephalopathy (21%).
Grade 3 or higher adverse reactions were reported in 76% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (27%), CRS (25%) and encephalopathy (22%).
Adverse reactions described in this section were identified in a total of 182 patients exposed to Tecartus in two multi-centre pivotal clinical studies, ZUMA-2 (n=82) and ZUMA-3 (n=100). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 3. Adverse drug reactions identified with Tecartus:
| System Organ Class (SOC) | Frequency | Adverse reactions |
|---|---|---|
| Infections and infestations | ||
| Very common | Unspecified pathogen infections Bacterial infections Fungal infections Viral Infections | |
| Blood and lymphatic system disorders | ||
| Very common | Leukopeniaa Neutropeniaa Lymphopeniaa Thrombocytopeniaa Anaemiaa Febrile neutropenia | |
| Common | Coagulopathy | |
| Immune system disorders | ||
| Very common | Cytokine Release Syndromeb Hypogammaglobulinaemia | |
| Common | Hypersensitivity Haemophagocytic lymphohistiocytosis | |
| Metabolism and nutrition disorders | ||
| Very common | Hypophosphataemiaa Decreased appetite Hypomagnesaemia Hyperglycaemiaa | |
| Common | Hypoalbuminemiaa Dehydration | |
| Psychiatric disorders | ||
| Very common | Delirium Anxiety Insomnia | |
| Nervous system disorders | ||
| Very common | Encephalopathy Tremor Headache Aphasia Dizziness Neuropathy | |
| Common | Seizure Ataxia Increased intracranial pressure | |
| Cardiac disorders | ||
| Very common | Tachycardias Bradycardias | |
| Common | Non-ventricular arrhythmias | |
| Vascular disorders | ||
| Very common | Hypotension Hypertension Haemorrhage | |
| Common | Thrombosis | |
| Respiratory, thoracic and mediastinal disorders | ||
| Very common | Cough Dyspnoea Pleural effusion Hypoxia | |
| Common | Respiratory failure Pulmonary oedema | |
| Gastrointestinal disorders | ||
| Very common | Nausea Diarrhoea Constipation Abdominal pain Vomiting Oral pain | |
| Common | Dry mouth Dysphagia | |
| Skin and subcutaneous tissue disorders | ||
| Very common | Rash Skin disorder | |
| Musculoskeletal and connective tissue disorders | ||
| Very common | Musculoskeletal pain Motor dysfunction | |
| Renal and urinary disorders | ||
| Very common | Renal insufficiency | |
| Common | Urine output decreased | |
| General disorders and administration site conditions | ||
| Very common | Oedema Fatigue Pyrexia Pain Chills | |
| Eye Disorders | ||
| Common | Visual impairment | |
| Investigations | ||
| Very common | Alanine aminotransferase increaseda Blood uric acid increaseda Aspartate aminotransferase increaseda Hypocalcaemiaa Hyponatraemiaa Direct bilirubin increaseda Hypokalaemiaa | |
| Common | Bilirubin increaseda | |
Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment in current therapy are included in Table 3.
a Frequency based on Grade 3 or higher laboratory parameter.
b See section Description of selected adverse reactions.
ZUMA-2 data cutoff: 24 July 2021; ZUMA-3 data cutoff: 23 July 2021
CRS occurred in 91% of patients. Twenty percent (20%) of patients experienced Grade 3 or higher (severe or life-threatening) CRS. The median time to onset was 3 days (range: 1 to 13 days) and the median duration was 9 days (range: 1 to 63 days). Ninety-seven percent (97%) of patients recovered from CRS.
The most common signs or symptoms associated with CRS among the patients who experienced CRS included pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinus tachycardia (23%), headache (22%), fatigue (16%), and nausea (13%). Serious adverse reactions that may be associated with CRS included hypotension (22%), pyrexia (15%), hypoxia (9%), tachycardia (3%), dyspnoea (2%) and sinus tachycardia (2%). See section 4.4 for monitoring and management guidance.
Neurologic adverse reactions occurred in 69% of patients. Thirty-two percent (32%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onset was 7 days (range: 1 to 262 days). Neurologic events resolved for 113 out of 125 patients (90.4%) with a median duration of 12 days (range: 1 to 708 days). Three patients had ongoing neurologic events at the time of death, including one patient with the reported event of serious encephalopathy and another patient with the reported event of serious confusional state. The remaining unresolved neurologic events were Grade 2. Ninety-three percent of all treated patients experienced the first CRS or neurological event within the first 7 days after Tecartus infusion.
The most common neurologic adverse reactions included tremor (32%), confusional state (27%), encephalopathy (27%), aphasia (21%), and agitation (11%). Serious adverse reactions including encephalopathy (15%), aphasia (6%) and confusional state (5%) have been reported in patients administered Tecartus. ICANS was reported as a serious adverse neurologic reaction at a low frequency (2%) in clinical trials. ICANS observed during clinical studies are represented under the adverse reaction encephalopathy. Serious cases of cerebral oedema which may become fatal have occurred in patients treated with Tecartus. See section 4.4 for monitoring and management guidance.
ICANS was reported in the context of neurologic toxicity in the post marketing setting.
Febrile neutropenia was observed in 12% of patients after Tecartus infusion. Infections occurred in 87 of the 182 patients treated with Tecartus in ZUMA-2 and ZUMA-3. Grade 3 or higher (severe, life-threatening or fatal) infections occurred in 30% of patients including unspecified pathogen, bacterial, fungal and viral infections in 23%, 8%, 2% and 4% of patients respectively. See section 4.4 for monitoring and management guidance.
Cytopenias are very common following prior lymphodepleting chemotherapy and Tecartus therapy.
Prolonged (present on or beyond Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher cytopenias occurred in 48% of patients and included neutropenia (34%), thrombocytopenia (27%) and anaemia (15%). See section 4.4 for management guidance.
Hypogammaglobulinaemia occurred in 12% of patients. Grade 3 or higher hypogammaglobulinemia occurred in 1% of patients. See section 4.4 for management guidance.
The immunogenicity of Tecartus has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. To date, no anti-CD19 CAR T-cell antibody immunogenicity has been observed in MCL patients. Based on an initial screening assay, 17 patients in ZUMA-2 at any time point tested positive for antibodies; however, a confirmatory orthogonal cell-based assay demonstrated that all 17 patients in ZUMA-2 were antibody negative at all time points tested. Based on an initial screening assay, 16 patients in ZUMA-3 tested positive for antibodies at any timepoint. Among patients with evaluable samples for confirmatory testing, two patients were confirmed to be antibody-positive after treatment. One of the two patients had a confirmed positive antibody result at Month 6. The second patient had a confirmed positive antibody result at retreatment Day 28 and Month 3. There is no evidence that the kinetics of initial expansion, CAR T-cell function and persistence of Tecartus, or the safety or effectiveness of Tecartus, were altered in these patients.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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