Yescarta

/ Gilead

A single dose of Yescarta contains 2 × 10⁶ CAR-positive viable T cells per kg of body weight (or maximum of 2 × 10⁸ CAR-positive viable T cells for patients 100 kg and above) in approximately 68 mL dispersion in an infusion bag.
The availability of Yescarta must be confirmed prior to starting the lymphodepleting regimen.
Pre-treatment (lymphodepleting chemotherapy)
A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² intravenous and fludarabine 30 mg/m² intravenous must be administered on the 5^th, 4^th, and 3^rd day before infusion of Yescarta.
Pre-medication
Paracetamol 500‑1,000 mg given orally and diphenhydramine 12.5 to 25 mg intravenous or oral (or equivalent) approximately 1 hour before Yescarta infusion is recommended.
Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the activity of Yescarta.
Monitoring
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 or symptoms of CRS and/or neurologic events.
After the first 10 days following the infusion, the patient is to be monitored at the physician’s discretion.
Patients must be instructed to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion.
Special populations:
Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection: There is no clinical experience in patients with active HIV, HBV or HCV infection.
Paediatric population
The safety and efficacy of YESCARTA in children and adolescents below 18 years of age have not yet been established.  No data are available.
Elderly: No dose adjustment is required in patients ≥ 65 years of age.  Efficacy was consistent with the overall treated patient population.
Method of administration:
YESCARTA is to be administered via intravenous infusion.
YESCARTA must not be irradiated.  Do NOT use a leukodepleting filter.
Precautions to be taken before handling or administering the medicinal product:
This medicinal product contains genetically modified human blood cells.  Healthcare professionals handling Yescarta must take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases.
Preparation of Yescarta:
Verify that the patient’s identity (ID) matches the patient identifiers on the Yescarta cassette.
The Yescarta bag must not be removed from the metal cassette if the information on the patient-specific label does not match the intended patient.
Once the patient ID is confirmed, remove the Yescarta bag from the metal cassette.
Check that the patient information on the metal cassette label matches that on the bag label.
Inspect the product bag for any breaches of container integrity before thawing.  If the bag is compromised, follow the local guidelines for the handling of waste of human-derived material (or immediately contact Kite).
Place the infusion bag inside a second bag.
Thaw Yescarta at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material.  If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing.  Yescarta must not be washed, spun down, and/or re‑suspended in new medium prior to infusion. Thawing takes approximately 3 to 5 minutes.
Once thawed, Yescarta is stable at room temperature (20°C‑25°C) for up to 3 hours. However, Yescarta infusion must begin within 30 minutes of thaw completion.
Administration: For autologous use only.
Tocilizumab and emergency equipment must be available prior to infusion and during the monitoring period.
A leukodepleting filter must not be used.
Central venous access is recommended for the administration of Yescarta.
Verify the patient ID again to match the patient identifiers on the Yescarta bag.
Prime the tubing with 0.9% sodium chloride solution (0.154 mmol sodium per mL) prior to infusion.
Infuse the entire content of the Yescarta bag within 30 minutes by either gravity or a peristaltic pump.
Gently agitate the bag during Yescarta infusion to prevent cell clumping.
After the entire content of the bag is infused, rinse the tubing at the same infusion rate with 0.9% sodium chloride solution (0.154 mmol sodium per mL) to ensure all Yescarta is delivered.

Treatment of adult patients with relapsed or refractory diffuse  Large B cell lymphoma (DLBCL) and primary mediastinal Large B cell lymphoma (PMBCL) after two or more lines of systemic therapy.
Limitation of Use: Yescarta not indicated for the treatment of patients with primary or secondary central nervous system lymphoma.

Hypersensitivity to the active substance or to any of the excipients.
Contraindications of the lymphodepleting chemotherapy must be considered.

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 after expiry date of the product.
General:
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 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 Yescarta 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.
Active graft‑versus‑host disease (GVHD).
Serological testing:
Screening for HBV, HCV, and HIV must be performed before collection of cells for manufacturing of Yescarta.
Blood, organ, tissue and cell donation:
Patients treated with Yescarta must not donate blood, organs, tissues, or cells for transplantation.
Concomitant disease:
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.
Primary central nervous system (CNS) lymphoma:
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. Yescarta is not indicated for the treatment of patients with primary or secondary central nervous system lymphoma.
Cytokine release syndrome:
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 in ZUMA-1 and 1 to 11 days in ZUMA-5. CRS should 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. Interleukin-6 (IL-6) receptor inhibitor based therapy such as tocilizumab has been administered for moderate or severe CRS associated with Yescarta.
At least 1 dose of tocilizumab per patient must be on site and available for administration prior to Yescarta infusion. The treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose.
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 is to 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) 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.
Yescarta must 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 must be managed by standards of critical care and measures such as echocardiography are to 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) is to 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.
Neurologic adverse reactions:
Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicity syndrome (ICANS) have been very commonly observed in patients treated with Yescarta, which could be life-threatening or fatal. 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 must be monitored for signs and symptoms of neurologic adverse reactions. Patients must be monitored at least daily for 10 days at the qualified healthcare facility following infusion for signs and symptoms of neurologic toxicity/ICANS. After the first 10 days following the infusion, the patient is to 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/ICANS occur.  Monitoring of vital signs and organ functions must be considered depending on the severity of the reaction.
Patients who experience Grade 2 or higher neurologic toxicities /ICANS must 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 are to be considered for seizure prophylaxis 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: See prescribing information for full details.
Infections and febrile neutropenia:
Serious infections have been very commonly observed with Yescarta. Patients must 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 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:
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 must be performed before collection of cells for manufacturing of Yescarta.
Prolonged cytopenias:
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.
Hypogammaglobulinaemia:
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.
Hypersensitivity reactions:
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.
Secondary malignancies:
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.
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 Yescarta infusion. Signs and symptoms of TLS must be monitored and events managed according to standard guidelines.
Prior treatment with anti‑CD19 therapy:
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.
Excipients:
This medicinal product contains 300 mg sodium per infusion bag, equivalent to 15% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
See prescribing information for full details.

Very common: Unspecified pathogen infections, viral infections, bacterial infections, febrile neutropenia, neutropenia, lymphopenia, leukopenia, anaemia, thrombocytopenia, cytokine Release Syndrome, hypogammaglobulinaemia, hyponatraemia, hypophosphatemia, hyperuricemia, decreased appetite, weight decrease, delirium , insomnia, encephalopathy, tremor, headache, dizziness, tachycardia, arrhythmia, hypotension, hypertension, dyspnoea, cough, nausea, vomiting, constipation, abdominal pain, diarrhoea, rash, motor dysfunction, musculoskeletal pain, fever, oedema, fatigue, chills, transaminases increased.
Common:  Fungal infections, coagulopathy, hypersensitivity, hypokalemia,
hypocalcaemia, hypoalbuminaemia, dehydration, affective disorder, seizure
hemiparesis, ataxia, neuropathy peripheral, cardiac arrest, cardiac failure, thrombosis, hypoxia, pleural effusion, nasal inflammation, dysphagia,
dry mouth, renal impairment, pain, visual impairment, hyperbilirubinemia.
See prescribing information for full details.

No interaction studies have been performed with Yescarta.

Pregnancy:
Women of childbearing potential/Contraception
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.
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
Lactation:
It is unknown whether Yescatra 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.

There are no data regarding the signs of overdose.

Storage:
The expiry date of the product is indicated on the packaging materials.
Yescarta must be stored frozen in the vapour phase of liquid nitrogen (≤ -150 ˚C).
The stability of Yescarta upon completion of thawing is up to 3 hours at room temperature (20 ˚C to 25 °C).  However, Yescarta infusion must begin within 30 minutes of thaw completion and the total Yescarta infusion time must not exceed 30 minutes.  Thawed product must not be refrozen.
The Yescarta bag must be stored in the vapour phase of liquid nitrogen (≤ -150 ˚C) and Yescarta must remain frozen until the patient is ready for treatment to ensure viable live autologous cells are administered to the patient.
Effects on ability to drive and use machines
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 must refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.