Special Warning : אזהרת שימוש

4.4   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.
Monitoring after infusion

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.

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. 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)

Serological testing

Screening for HBV, HCV, and HIV must be performed before collection of cells for manufacturing of Tecartus (see section 4.2).

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.
Tecartus is not indicated for the treatment of patients with active central nervous system lymphoma.

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 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.

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.

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 Grade (a)                            Tocilizumab                           Corticosteroids Grade 1                                  If not improving after 24 hours,      N/A Symptoms require symptomatic             administer tocilizumab treatment only (e.g., fever, nausea,     8 mg/kg intravenously over 1 hour fatigue, headache, myalgia,              (not to exceed 800 mg).
malaise).
Grade 2                                  Administer tocilizumab (c) 8 mg/kg    If no improvement within 24 hours Symptoms require and respond to          intravenously over 1 hour (not to     after starting tocilizumab, manage moderate intervention.                   exceed 800 mg).                       as per Grade 3.
Oxygen requirement less than 40%         Repeat tocilizumab every 8 hours      If improving, taper corticosteroids, FiO2 or hypotension responsive to        as needed if not responsive to        and manage as Grade 1.
fluids or low-dose of one                intravenous fluids or increasing vasopressor or Grade 2 organ             supplemental oxygen. Limit to a toxicity (b).                            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.
Grade 3                                  Per Grade 2                           Administer methylprednisolone Symptoms require and respond to                                                1 mg/kg intravenously twice daily aggressive intervention.                                                       or equivalent dexamethasone (e.g., Oxygen requirement greater than or                                             10 mg intravenously every 6 hours) equal to 40% FiO2 or hypotension                                               until Grade 1, then taper requiring high-dose or multiple                                                corticosteroids.
vasopressors or Grade 3 organ                                                  If improving, manage as Grade 2.
toxicity or Grade 4 transaminitis.                                             If not improving, manage as Grade 4.
Grade 4                             Per Grade 2                                Administer methylprednisolone Life-threatening symptoms.                                                     1000 mg intravenously per day for Requirements for ventilator support                                            3 days.
or continuous veno-venous                                                      If improving, taper corticosteroids, haemodialysis or Grade 4 organ                                                 and manage as Grade 3.
toxicity (excluding transaminitis).                                            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.


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. 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 to 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         Concurrent CRS                                 No concurrent CRS assessment
Grade 2         Administer tocilizumab as per Table 1 for       Administer dexamethasone 10 mg management Grade 2 CRS.                         intravenously every 6 hours until the event is If not improving within 24 hours after starting Grade 1 or less.
tocilizumab, administer dexamethasone           If improving, taper corticosteroids 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.
Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 3         Administer tocilizumab as per Table 1 for       Administer dexamethasone 10 mg management of Grade 2 CRS.                      intravenously every 6 hours.
In addition, administer dexamethasone 10 mg Continue dexamethasone use until the event is intravenously with the first dose of            Grade 1 or less, then taper corticosteroids.
tocilizumab and repeat dose every 6 hours.      If not improving, manage as Grade 4.
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.
Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 4         Administer tocilizumab as per Table 1 for       Administer methylprednisolone 1000 mg management of Grade 2 CRS.                      intravenously per day for 3 days.
Administer methylprednisolone 1000 mg           If improving, then manage as Grade 3.
intravenously per day with first dose of        If not improving, consider alternate tocilizumab and continue methylprednisolone immunosuppressants.
1000 mg intravenously per day for 2 more 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.

Infections and febrile neutropenia

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

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.

Prolonged cytopenias

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.

Hypogammaglobulinaemia

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.

Hypersensitivity reactions

Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residual gentamicin in Tecartus.

Secondary malignancies including of T cell 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. 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.

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 allopurinol, or an alternative prophylaxis, prior to Tecartus infusion. Signs and symptoms of TLS must 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 Tecartus worsening GvHD.

Prior treatment with anti-CD19 therapy

Tecartus is not recommended if the patient has relapsed with CD19-negative disease after prior anti-CD19 therapy.

Sodium content

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.

Effects on Driving

4.7    Effects on ability to drive and use machines

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.