IMPORTANT SAFETY INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES
- Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA™. Do not administer YESCARTA™ to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].
- Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA™, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA™. Provide supportive care and/or corticosteroids as needed [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.2)].
- YESCARTA™ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA™ REMS [see Warnings and Precautions (5.3)].
Cytokine Release Syndrome (CRS)
CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA™. In Study 1, CRS occurred in 94% (101/108) of patients receiving YESCARTA™, including ≥ Grade 3 (Lee grading system) CRS in 13% (14/108) of patients. Among patients who died after receiving YESCARTA™, four had ongoing CRS events at the time of death. The median time to onset was 2 days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) [see Adverse Reactions (6)].
Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA™. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3)].
Neurologic toxicities, that were fatal or life-threatening, occurred following treatment with YESCARTA™. Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks of YESCARTA™ infusion, with a median time to onset of 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities occurred in 31% of patients.
The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with YESCARTA™. Fatal and serious cases of cerebral edema have occurred in patients treated with YESCARTA™.
Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly [see Management of Severe Adverse Reactions (2.3); Neurologic Toxicities].
Because of the risk of CRS and neurologic toxicities, YESCARTA™ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA™ REMS [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]. The required components of the YESCARTA™ REMS are:
- Healthcare facilities that dispense and administer YESCARTA™ must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within 2 hours after YESCARTA™ infusion, if needed for treatment of CRS.
- Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer YESCARTA™ are trained about the management of CRS and neurologic toxicities.
Further information is available at www.YescartaREMS.com or 1-844-454-KITE (5483).
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™.
Severe or life-threatening infections occurred in patients after YESCARTA™ infusion. In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. YESCARTA™ should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after YESCARTA™ infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines.
Febrile neutropenia was observed in 36% of patients after YESCARTA™ 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.
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA™ infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30 following YESCARTA™ infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after YESCARTA™ infusion.
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with YESCARTA™. In Study 1, hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment with YESCARTA™ and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement.
The safety of immunization 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™.
Patients treated with YESCARTA™ may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events, including altered mental status or seizures, patients receiving YESCARTA™ are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA™ infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia.
The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia, and lung infections.
Please see full Prescribing Information, including BOXED WARNING and Medication Guide.