Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Kite Pharma EU B.V., Science Park 408, 1098 XH Amsterdam, 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.
Due to the risks associated with YESCARTA treatment, infusion should be delayed if a patient has any of the following conditions:
Patients treated with YESCARTA should not donate blood, organs, tissues, and cells for transplantation.
YESCARTA is intended solely for autologous use and must not be administered to other patients. Before infusion, the patient’s identity must match the patient identifiers on the YESCARTA infusion bag and cassette. Do not infuse YESCARTA if the information on the patient-specific label does not match the intended patient.
Patients with active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.
There is no experience of use of YESCARTA in patients with primary CNS lymphoma. Therefore, the risk/benefit of YESCARTA has not been established in this population.
Nearly all patients experienced some degree of CRS. Severe CRS, including life-threatening and fatal reactions, was very commonly observed with YESCARTA with a time to onset of 1 to 12 days (see section 4.8).
Ensure that a minimum of 4 doses of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, are available for each patient prior to infusion of YESCARTA.
Monitor patients daily for signs and symptoms of CRS for at least 10 days following infusion at the qualified clinical facility. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion.
Counsel patients to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS occur. Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced by patients on YESCARTA. These include the use of tocilizumab or tocilizumab and corticosteroids for moderate, severe, or life-threatening CRS 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) 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.
YESCARTA should not be administered to patients with active infections or inflammatory disease until these conditions have resolved.
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.
Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.
Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) should be considered in patients with severe or unresponsive CRS.
YESCARTA continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of YESCARTA-associated CRS.
Table 1. CRS grading and management guidance:
Severe neurologic adverse reactions have been very commonly observed in patients treated with YESCARTA, which could be life-threatening or fatal (see section 4.8). Patients with a history of CNS disorders such as seizures or cerebrovascular ischaemia may be at increased risk. Fatal and serious cases of cerebral oedema have been reported in patients treated with YESCARTA. Patients should be monitored for signs and symptoms of neurologic adverse reactions (Table 2). Patients should be monitored at least daily for 10 days at the qualified healthcare facility following infusion for signs and symptoms of neurologic toxicity. After the first 10 days following the infusion, the patient should be monitored at the physician’s discretion. Counsel patients to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of neurologic toxicity occur. Monitoring of vital signs and organ functions should be considered depending on the severity of the reaction.
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 on YESCARTA. 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 grading and management guidance:
Serious infections have been very commonly observed with YESCARTA (see section 4.8). Patients should be monitored for signs and symptoms of infection before, during, and after YESCARTA infusion and treated appropriately. Prophylactic anti-microbials should be administered according to standard institutional guidelines.
Febrile neutropenia has been observed in patients after YESCARTA 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.
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Screening for HBV, HCV, and HIV should be performed in accordance with clinical guidelines before collection of cells for manufacturing of YESCARTA.
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 or higher prolonged cytopenias following YESCARTA infusion occurred very commonly and included thrombocytopenia, neutropenia, and anaemia. Monitor blood counts after YESCARTA infusion.
B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with YESCARTA. Hypogammaglobulinaemia has been very commonly observed in patients treated with YESCARTA. Immunoglobulin levels should be monitored after treatment with YESCARTA and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.
Allergic reactions may occur with the infusion of YESCARTA. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA.
Patients treated with YESCARTA may develop secondary malignancies. Monitor patients 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 YESCARTA infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.
There is limited experience with YESCARTA in patients exposed to prior CD19-directed therapy. YESCARTA 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.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
No interaction studies have been performed with YESCARTA.
The safety of immunisation with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment with YESCARTA.
The pregnancy status of women of child bearing potential must be verified before starting YESCARTA 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 YESCARTA.
There are no available data with YESCARTA use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with YESCARTA to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).
It is not known if YESCARTA 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, YESCARTA 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 YESCARTA therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with YESCARTA should be considered.
It is unknown whether YESCARTA 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.
No clinical data on the effect of YESCARTA on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.
YESCARTA 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 refrain from driving or operating 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 YESCARTA in ZUMA-1, a Phase ½ study in which 108 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) received CAR-positive T cells based on a recommended dose which was weight-based. The median duration of follow up was 27.4 months.
The most significant and frequently occurring adverse reactions were CRS (93%), encephalopathy (58%), and infections (39%).
Serious adverse reactions occurred in 56% of patients. The most common serious adverse reactions included encephalopathy (22%), unspecified pathogen infections (16%), bacterial infections (6%), febrile neutropenia (6%), viral infections (5%), and pyrexia (5%).
The most common Grade 3 or higher adverse reactions included encephalopathy (31%), unspecified pathogen infections (19%), CRS (11%), bacterial infection (9%), aphasia (7%), viral infection (6%), delirium (6%), hypotension (6%), and hypertension (6%).
Adverse reactions reported from clinical trials and post-marketing setting are presented below. 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); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 3. Adverse drug reactions identified with YESCARTA:
Very common: Unspecified pathogen infections, Viral infections, Bacterial infections
Common: Fungal infections
Very common: Leukopenia, Neutropenia, Anaemia, Thrombocytopenia
Common: Coagulopathy
Very common: Cytokine Release Syndrome, Hypogammaglobulinaemia
Common: Hypersensitivity
Histiocytosis Haematophagic
Very common: Dehydration, Decreased appetite, Hypophosphataemia, Hyponatraemia, Weight decrease
Common: Hypocalcaemia, Hypoalbuminaemia
Very common: Delirium, Anxiety
Common: Insomnia
Very common: Encephalopathy, Headache, Tremor, Dizziness, Aphasia
Common: Ataxia, Neuropathy, Seizure, Dyscalculia, Myoclonus
Uncommon: Spinal cord oedema, Myelitis, Quadriplegia
Very common: Tachycardia, Arrhythmia
Common: Cardiac arrest, Cardiac failure
Very common: Hypotension, Hypertension
Common: Thrombosis, Capillary leak syndrome
Very common: Cough, Dyspnoea, Hypoxia, Pleural effusion
Common: Pulmonary oedema
Very common: Diarrhoea, Nausea, Vomiting, Constipation, Abdominal pain, Dry mouth
Common: Dysphagia*
Common: Rash
Very common: Motor dysfunction, Pain in extremity, Back pain, Arthralgia, Muscle pain
Common: Renal insufficiency
Very common: Fatigue, Pyrexia, Oedema, Chills
Very common: Alanine aminotransferase increased, Aspartate aminotransferase increased
Common: Bilirubin increased
CRS occurred in 93% of patients. Eleven percent (11%) of patients experienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was 2 days (range: 1 to 12 days) and the median duration was 7 days (range: 2 to 29 days). Ninety-eight percent (98%) of patients recovered from CRS.
The most common signs or symptoms associated with CRS included pyrexia (83%), hypotension (44%), tachycardia (24%), hypoxia (23%), and chills (20%). Serious adverse reactions that may be associated with CRS included acute kidney injury, atrial fibrillation, ventricular tachycardia, cardiac arrest, cardiac failure, capillary leak syndrome, hypotension, hypoxia, and HLH/MAS. See section 4.4 for monitoring and management guidance.
Neurologic adverse reactions occurred in 67% 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 5 days (range: 1 to 17 days). The median duration was 13 days (range: 1 to 191 days). Most patients recovered from neurologic adverse reactions, with the exception of 4 patients who had ongoing neurologic adverse reactions at the time of death; the deaths were due to other causes.
The most common signs or symptoms associated with neurologic adverse reactions included encephalopathy (58%), headache (40%), tremor (31%), dizziness (21%), aphasia (18%), and delirium (17%). Serious adverse reactions including encephalopathy (22%), aphasia (4%), delirium (4%), and seizures (1%) have been reported in patients administered YESCARTA.
Other neurologic adverse reactions have been reported less frequently in clinical trials and included dysphagia (5%), myelitis (0.2%), and quadriplegia (0.2%).
Spinal cord oedema was reported, in the context of neurologic toxicity in the post-marketing setting.
See section 4.4 for monitoring and management guidance.
Febrile neutropenia was observed in 36% of patients after YESCARTA infusion. Infections occurred in 39% of patients in ZUMA-1. Grade 3 or higher (severe, life-threatening, or fatal) infections occurred in 26% of patients. Grade 3 or higher unspecified pathogen, bacterial, and viral infections occurred in 19%, 9%, and 6% of patients respectively. The most common site of infection was in the respiratory tract. See section 4.4 for monitoring and management guidance.
Grade 3 or higher neutropenia (including febrile neutropenia), anaemia, and thrombocytopenia occurred in 80%, 45%, and 40% of patients, respectively. Prolonged (still present at Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher neutropenia, thrombocytopenia, and anaemia occurred in 26%, 24%, and 10% of patients, respectively. Grade 3 or higher neutropenia, thrombocytopenia, and anaemia present after Day 93 occurred in 11%, 7%, and 3% of patients, respectively. See section 4.4 for management guidance.
In ZUMA-1, hypogammaglobulinaemia occurred in 16% of patients. Cumulatively, 33 (31%) of 108 subjects received intravenous immunoglobulin therapy at the time of the 24-month analysis. See section 4.4 for management guidance.
The immunogenicity of YESCARTA 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. Three patients tested positive for anti-FMC63 prior to being treated with YESCARTA. An impact of these antibodies on efficacy or safety was not discernible.
There is limited experience with YESCARTA in patients ≥75 years of age. Generally, safety and efficacy were similar between patients ≥65 years and patients <65 years of age treated with YESCARTA. Outcomes were consistent between patients with Eastern Cooperative Oncology Group (ECOG) of 0 and 1 and by sex.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
