Included as part of the PRECAUTIONS section.
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 system1) 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].
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 INFORMATION]. At the
first sign of CRS, institute treatment with supportive care, tocilizumab or
tocilizumab and corticosteroids as indicated [see DOSAGE AND ADMINISTRATION].
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; 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 Cytokine Release Syndrome (CRS) and Neurologic Toxicities sections). The required components of the YESCARTA
- 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
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Ensure that patients understand the risk of manufacturing
failure (1% in clinical trial). In case of a manufacturing failure, a second
manufacturing of YESCARTA may be attempted. In addition, while the patient
awaits the product, additional chemotherapy (not the lymphodepletion) may be
necessary and may increase the risk of adverse events during the pre-infusion
Advise patients to seek immediate attention for any of
- Cytokine Release Syndrome (CRS) – Signs or symptoms
associated with CRS including fever chills, fatigue, tachycardia, nausea,
hypoxia and hypotension. [see WARNINGS AND PRECAUTIONS and ADVERSE
- Neurologic Toxicities – Signs or symptoms associated with
neurologic events including encephalopathy, seizures, changes in level of
consciousness, speech disorders, tremors, and confusion [see WARNINGS AND
PRECAUTIONS and ADVERSE REACTIONS].
- Serious Infections – Signs or symptoms associated with
infection [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
- Prolonged Cytopenia – Signs or symptoms associated with
bone marrow suppression including neutropenia, anemia, thrombocytopenia, or
febrile neutropenia [see WARNINGS AND PRECAUTIONS and ADVERSE
Advise patients for the need to:
- Refrain from driving or operating heavy or potentially
dangerous machinery after YESCARTA infusion until at least 8 weeks after
infusion. [see WARNINGS AND PRECAUTIONS].
- Have periodic monitoring of blood counts.
- Contact Kite at 1-844-454-KITE (5483) if they are
diagnosed with a secondary malignancy [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity or genotoxicity studies have been
conducted with YESCARTA. No studies have been conducted to evaluate the effects
of YESCARTA on fertility.
Use In Specific Populations
There are no available data with YESCARTA use in pregnant
women. No animal reproductive and developmental toxicity studies have been
conducted with YESCARTA to assess whether it can cause fetal harm when
administered to a pregnant woman. It is not known if YESCARTA has the potential
to be transferred to the fetus. Based on the mechanism of action, if the
transduced cells cross the placenta, they may cause fetal toxicity, including
B-cell lymphocytopenia. Therefore, YESCARTA is not recommended for women who
are pregnant, and pregnancy after YESCARTA infusion should be discussed with
the treating physician.
In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2%-4% and 15%-20%, respectively.
There is no information regarding the presence of
YESCARTA in human milk, the effect on the breastfed infant, and the effects on
milk production. The developmental and health benefits of breastfeeding should
be considered along with the mother’s clinical need for YESCARTA and any
potential adverse effects on the breastfed infant from YESCARTA or from the
underlying maternal condition.
Females And Males Of Reproductive Potential
Pregnancy status of females with reproductive potential should
be verified. Sexually-active females of reproductive potential should have a
pregnancy test prior to starting treatment with YESCARTA.
See the prescribing information for fludarabine and
cyclophosphamide 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
There are no data on the effect of YESCARTA on fertility.
The safety and efficacy of YESCARTA have not been
established in pediatric patients.
Clinical trials of YESCARTA did not include sufficient
numbers of patients aged 65 years and older to determine whether they respond
differently or have different safety outcomes as compared to younger patients.
1 Lee DW et al (2014). Current concepts in the diagnosis
and management of cytokine release syndrome. Blood. 2014 Jul 10; 124(2):