4.1. Therapeutic indications

Yescarta is indicated for the treatment of adult patients with diffuse large B‑cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy.

Yescarta is indicated for the treatment of adult patients with relapsed or refractory (r/r) DLBCL and primary mediastinal large B‑cell lymphoma (PMBCL), after two or more lines of systemic therapy.

Yescarta is indicated for the treatment of adult patients with r/r follicular lymphoma (FL) after three or more lines of systemic therapy.

4.2. Posology and method of administration

Yescarta must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with the medicinal product.

In the event of cytokine release syndrome (CRS), at least 1 dose of tocilizumab, and emergency equipment must be available prior to infusion. The qualified treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

Posology

Yescarta is intended for autologous use (see section 4.4).

Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag. The target dose is 2 × 106 CAR-positive viable T cells per kg of body weight (within a range of 1 × 106 – 2 × 106 cells/kg), with a maximum of 2 × 108 CAR-positive viable T cells for patients 100 kg and above.

The availability of Yescarta must be confirmed prior to starting the lymphodepleting regimen (i.e. date of product availability for shipment).

Pre-treatment (lymphodepleting chemotherapy)

• A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously must be administered prior to infusing Yescarta. The recommended days are on the 5th, 4th, and 3rd day before infusion of Yescarta.

Pre-medication

• It is recommended that pre-medication with paracetamol 500‑1 000 mg given orally and diphenhydramine 12.5 to 25 mg intravenously or oral or equivalent medicinal products, be administered approximately 1 hour before the infusion of Yescarta to reduce the possibility of an infusion reaction.

• Prophylactic use of systemic corticosteroids is not recommended (see section 4.5).

Monitoring

• Patients must be monitored daily for the first 7 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for the first 7 days or at the first signs or symptoms of CRS and/or neurologic events.

• After the first 7 days following the infusion, the patient is to be monitored at the physician's discretion.

• Patients must 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 limited clinical experience in patients with active HIV, HBV or HCV infection.

Elderly

No dose adjustment is required in patients ≥ 65 years of age.

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.

Method of administration

Yescarta is to be administered via intravenous infusion.

Yescarta must not be irradiated. A leukodepleting filter must not be used.

Before administration, it must be confirmed that the patient's identity matches the unique patient information on the Yescarta infusion bag and cassette.

Administration

• A leukodepleting filter must not be used.

• Tocilizumab and emergency equipment must be available prior to infusion and during the monitoring period. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

• Yescarta is intended for autologous use only, it must be confirmed that the patient's identity matches the patient identifiers on the Yescarta infusion bag.

• Once the tubing has been primed, the entire content of the Yescarta infusion bag must be infused within 30 minutes by either gravity or a peristaltic pump.

For detailed instructions on preparation, administration, measures to take in case of accidental exposure and disposal of Yescarta, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to gentamicin (a possible trace residue).

Contraindications of the lymphodepleting chemotherapy must be considered.

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 after expiry date of the medicinal product.

Autologous use

Yescarta 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 Yescarta infusion bag and cassette. Yescarta must not be administered if the information on the patient‑specific infusion bag and cassette label does not match the patient's identity.

General

Warnings and precautions of lymphodepleting chemotherapy must be considered.

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).

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)

Monitoring after infusion

Patients must be monitored daily for the first 7 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for the first 7 days or at the first signs or symptoms of CRS and/or neurologic events. After the first 7 days following infusion, the patient is to be monitored at the physician's discretion.

Patients must remain within proximity of a qualified treatment centre for at least 4 weeks following infusion and seek immediate medical attention should signs or symptoms of CRS or neurological adverse reactions occur. Vital signs and organ function must be monitored depending on the severity of the reaction.

Transmission of an infectious agent

Although Yescarta is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Yescarta must, therefore, monitor patients for signs and symptoms of infection after treatment and treat appropriately, if needed.

Serological testing

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

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 central nervous system (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 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.

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 ZUMA-7, and 1 to 11 days in ZUMA-5 (see section 4.8).

Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection.

Management of cytokine release syndrome associated with Yescarta

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 Yescarta infusion. The qualified treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS.

The management of patients should be conducted based on the patient's clinical presentation and in accordance with applicable local institutional and/or national or European/international clinical guidelines. Physicians are advised to exercise clinical judgment consistent with these standards.

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.

Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is to be considered in patients with severe or unresponsive CRS. HLH/MAS should be managed per local institutional and/or national or European/international clinical guidelines.

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. The median time to onset was 6 days (range: 1 to 133 days) in ZUMA-1 and ZUMA-7, and 7 days (range: 1 to 177 days) in ZUMA-5 following Yescarta infusion (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 with most cases occurring in patients with ICANS. The risk for cerebral oedema may be higher in PMBCL patients (section 4.8).

The management of patients should be conducted based on the patient's clinical presentation and in accordance with applicable local institutional and/or national or European/international clinical guidelines. Physicians are advised to exercise clinical judgment consistent with these standards.

Infections and febrile neutropenia

Serious infections have been very commonly observed with Yescarta (see section 4.8). In immunosuppressed patients, life-threatening and fatal opportunistic infections including disseminated fungal infections have been reported.

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 (see section 4.8) and may be concurrent with CRS. In the event of febrile neutropenia, infection is to be considered and managed with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Viral 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.

Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy (PML), has been reported in patients treated with Yescarta who have also received prior treatment with other immunosuppressive medications. Cases with fatal outcome have been reported. The possibility of PML should be considered in immunosuppressed patients with new onset or worsening neurological symptoms and appropriate diagnostic evaluations should be performed.

Other life-threatening and fatal cases of viral reactivation with HHV-6 have been reported.

Prolonged cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion and must be managed according to standard guidelines. Grade 3 or higher prolonged cytopenias following Yescarta infusion occurred very commonly and included thrombocytopenia, neutropenia, and anaemia. Patient blood counts must be monitored with Yescarta infusion.

Hypogammaglobulinaemia

B‑cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Yescarta. Hypogammaglobulinaemia predisposes patients to have infections. Hypogammaglobulinaemia has been very commonly observed in patients treated with Yescarta (see section 4.8). Immunoglobulin levels should be monitored after treatment with Yescarta 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

Allergic reactions may occur with the infusion of Yescarta. Serious hypersensitivity reactions including anaphylaxis, may be due to DMSO or residual gentamicin in Yescarta.

Secondary malignancies including of T-cell and myeloid origin

Patients treated with Yescarta may develop secondary malignancies. T-cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CART-cell therapy, including Yescarta. 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. In the event that a secondary malignancy occurs, the company is to be contacted to obtain instructions on patient samples to collect for testing.

Myelodysplastic syndrome and acute myeloid leukaemia, including cases with fatal outcomes, have occurred in patients following treatment with Yescarta.

Patients are to be monitored life-long for secondary malignancies.

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.

CD19-negative disease

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.

There are limited data available on CD19-negative patients treated with Yescarta and it is possible that CD19-negative patients may have less benefit compared with CD19-positive patients. Patients with CD19-negative status by immunohistochemistry may still express CD19 and have been shown to benefit from treatment with Yescarta. The potential risks and benefits associated with treatment of CD19-negative patients with Yescarta should be considered.

Long-term follow-up

Patients are expected to enrol in a registry in order to better understand the long-term safety and efficacy of Yescarta.

Excipients (sodium)

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.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Yescarta.

Prophylactic use of systemic corticosteroids may interfere with the activity of Yescarta. Prophylactic use of systemic corticosteroids is therefore not recommended before infusion (see section 4.2).

Administration of corticosteroids as per the toxicity management guidelines does not impact the expansion and persistence of CAR T cells.

Live vaccines

The safety of immunisation with live viral vaccines during or following treatment with Yescarta has not been studied. As a precautionary measure, vaccination with live 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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.

Pregnancy

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 must be advised on the potential risks to the foetus. Pregnancy after Yescarta therapy must be discussed with the treating physician.

Assessment of immunoglobulin levels and B‑cells in newborns of mothers treated with Yescarta must be considered.

Breast-feeding

It is unknown whether Yescarta is excreted in human milk or transferred to the breast‑feeding child. A risk to the breast fed infant cannot be excluded. Breast‑feeding women must be advised of the potential risk to the breast‑fed child. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Yescarta therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

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.

4.7. 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.

4.8. Undesirable effects

Summary of the safety profile

The safety data described in this section are from a total of 397 adult patients treated with Yescarta in three multi-centre pivotal clinical studies (ZUMA-1, ZUMA-5 and ZUMA-7) and post-marketing experience. Adverse reactions are adverse events from pivotal clinical studies and post-marketing experience medically assessed as reasonably attributed to axicabtagene ciloleucel.

Relapsed or refractory DLBCL, PMBCL and DLBCL arising from follicular lymphoma after two or more lines of systemic therapy

Safety data from ZUMA-1 reflects exposure to Yescarta in a Phase 1/2 study in which 108 patients received CAR‑positive T cells based on a recommended dose which was weight-based. The data described are from the 54-month follow-up analysis where the median actual duration of follow-up was 23.5 months (range: 0.3 to 68.2 months).

The most significant and frequently occurring adverse reactions were CRS (93%), encephalopathy (60%), and infections (40%).

Serious adverse reactions occurred in 51% of patients. The most common (≥ 5%) serious adverse reactions included encephalopathy (22%), unspecified pathogen infections (15%), bacterial infection (6%), viral infection (6%), febrile neutropenia (5%), and fever (5%).

The most common (≥ 5%) Grade 3 or higher non-haematological adverse reactions included encephalopathy (31%), unspecified pathogen infections (19%), CRS (11%), bacterial infection (9%), delirium (6%), hypertension (6%), hypotension (6%), transaminases increased (6%), and viral infection (6%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%), leukopenia (96%), neutropenia (94%), anaemia (65%), and thrombocytopenia (56%).

DLBCL and HGBL that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy

Safety data from ZUMA-7 reflects exposure to Yescarta in a Phase 3 study in which 170 patients received CAR‑positive T cells based on a recommended dose which was weight‑based. The data described are from an analysis where the median actual duration of follow-up was 23.2 months (range: 1.5 to 41.3 months).

The most significant and frequently occurring adverse reactions were CRS (92%), encephalopathy (49%), and infections (45%).

Serious adverse reactions occurred in 54% of patients. The most common (≥ 5%) serious adverse reactions included CRS (17%), encephalopathy (16%), unspecified pathogen infections (8%), fever (6%) and viral infection (5%).

The most common (≥ 5%) Grade 3 or higher non-haematological adverse reactions included encephalopathy (19%), unspecified pathogen infections (8%), CRS (6%), and bacterial infection (5%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%), leukopenia (95%), neutropenia (94%), anaemia (41%), and thrombocytopenia (26%).

Follicular lymphoma after three or more lines of systemic therapy

Safety data from ZUMA-5 reflects exposure to Yescarta in a Phase 2 study in which 119 patients with relapsed/refractory FL, received CAR-positive T cells based on a recommended dose which was weight-based. The data described are from the 24-month follow-up analysis where the median actual duration of follow-up was 25.9 months (range: 0.3 to 44.3 months).

The most significant and frequently occurring adverse reactions were CRS (77%), infections (59%), and encephalopathy (47%).

Serious adverse reactions occurred in 45% of patients. The most common (≥ 5%) serious adverse reactions included encephalopathy (16%), unspecified pathogen infections (12%), CRS (12%), and bacterial infection (5%).

The most common (≥ 5%) Grade 3 or higher non-haematological adverse reactions included encephalopathy (14%), unspecified pathogen infections (11%), CRS (6%), and bacterial infection (5%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%), leukopenia (94%), neutropenia (92%), thrombocytopenia (34%), and anaemia (33%).

Tabulated list of adverse reactions

Adverse reactions described in this section were identified in patients exposed to Yescarta in ZUMA-1 (n=108), ZUMA-5 (n=119), and ZUMA-7 (n=170) and from post-marketing reports. 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1: Adverse drug reactions identified with Yescarta

System Organ Class (SOC)

Frequency

Adverse reactions

Infections and infestations

Very common

Unspecified pathogen infections

Viral infection

Bacterial infection

Common

Fungal infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon

Secondary malignancy of T-cell origin

Blood and lymphatic system disorders

Very common

Febrile neutropenia#

Neutropenia#

Lymphopenia#

Leukopenia#

Anaemia#

Thrombocytopenia#

Common

Coagulopathya

Immune system disorders

Very common

Cytokine Release Syndrome

Immunoglobulins decreasedb

Common

Hypersensitivity

Uncommon

Haemophagocytic lymphohistiocytosis*

Metabolism and nutrition disorders

Very common

Hyponatraemia#

Hypophosphataemia#

Hyperuricemia#**

Hyperglycaemia#

Decreased appetitec

Common

Hypokalaemia#

Hypocalcaemia#

Hypoalbuminaemia#

Dehydrationd

Weight decreased

Psychiatric disorders

Very common

Deliriume

Insomnia

Common

Anxiety

Affective disorderf

Nervous system disorders

Very common

Encephalopathyg

Tremorh

Headachei

Dizzinessj

Common

Ataxiak

Seizures, including status epilepticus

Hemiparesis

Facial paralysisl

Neuropathy peripheralm

Myoclonus

Uncommon

Quadriplegia

Spinal cord oedema

Myelitis

Dyscalculia

Cerebral oedeman

Eye disorders

Common

Visual impairmento

Cardiac disorders

Very common

Tachycardiap

Arrhythmiaq

Common

Cardiac arrest

Cardiac failurer

Vascular disorders

Very common

Hypotensions

Hypertension

Common

Thrombosist

Haemorrhageu

Respiratory, thoracic and mediastinal disorders

Very common

Coughv

Common

Respiratory failurew

Hypoxiax

Pleural effusion

Pulmonary oedema

Dyspnoeay

Nasal inflammationz

Gastrointestinal disorders

Very common

Vomiting

Diarrhoeaaa

Constipation

Abdominal painbb

Nausea

Common

Dysphagia***

Dry mouthcc

Hepatobiliary disorders

Very common

Transaminases increaseddd

Common

Hyperbilirubinaemiaee

Skin and subcutaneous tissue disorders

Very common

Rashff

Musculoskeletal and connective tissue disorders

Very common

Motor dysfunctiongg

Musculoskeletal painhh

Uncommon

Rhabdomyolysis

Renal and urinary disorders

Common

Renal impairmentii

General disorders and administration site conditions

Very common

Feverjj

Oedemakk

Fatiguell

Chills

Common

Infusion related reaction

Pain

Uncommon

Multiple organ dysfunction syndrome

* Haemophagocytic lymphohistiocytosis has been reported in the setting of CRS

** Hyperuricemia was identified from a pooled analysis of 227 adult patients treated with Yescarta in ZUMA-1 and ZUMA-5

*** Dysphagia has been reported in the setting of neurologic toxicity and encephalopathy

# Frequency based on Grade 3 or higher laboratory parameter

a. Coagulopathy includes coagulopathy, blood fibrinogen decreased, blood fibrinogen increased, disseminated intravascular coagulation, hypofibrinogenaemia, international normalized ratio increased, prothrombin level decreased, prothrombin time prolonged

b. Immunoglobulins decreased includes blood immunoglobulin G decreased, hypogammaglobulinaemia

c. Decreased appetite includes decreased appetite, hypophagia

d. Dehydration includes dehydration, hypovolaemia

e. Delirium includes delirium, agitation, delusion, disorientation, hallucination, restlessness

f. Affective disorder includes impulsive behavior, mood altered, depression, panic attack

g. Encephalopathy includes encephalopathy, agraphia, altered state of consciousness, amnesia, aphasia, aphonia, apraxia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, dyskinesia, dyspraxia, hypersomnia, immune effector cell-associated neurotoxicity syndrome, lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, neurotoxicity, slow speech, somnolence, speech disorder, stupor, toxic encephalopathy

h. Tremor includes tremor, head titubation

i. Headache includes headache, head discomfort, tension headache

j. Dizziness includes dizziness, dizziness postural, presyncope, syncope, vertigo

k. Ataxia includes ataxia, balance disorder, gait disturbance

l. Facial paralysis includes facial paralysis, facial paresis

m. Neuropathy peripheral includes neuropathy peripheral, allodynia, cervical radiculopathy, hyperaesthesia, hypoaesthesia, lumbar radiculopathy, paraesthesia, peripheral sensory neuropathy, peroneal nerve palsy

n. Most cases of cerebral oedema occurred in patients with ICANS

o. Visual impairment includes visual impairment, hemianopia, vision blurred, visual acuity reduced

p. Tachycardia includes tachycardia, postural orthostatic tachycardia syndrome, sinus tachycardia

q. Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, bundle branch block right, electrocardiogram QT prolonged, extrasystoles, heart rate increased, heart rate irregular, sinus bradycardia, supraventricular extrasystoles, supraventricular tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular tachycardia

r. Cardiac failure includes cardiac failure, acute left ventricular failure, ejection fraction decreased, stress cardiomyopathy

s. Hypotension includes hypotension, capillary leak syndrome, diastolic hypotension, hypoperfusion, orthostatic hypotension

t. Thrombosis includes thrombosis, axillary vein thrombosis, brachiocephalic vein thrombosis, deep vein thrombosis, device occlusion, embolism, jugular vein thrombosis, peripheral embolism, peripheral ischaemia, pulmonary embolism, splenic vein thrombosis, thrombosis in device

u. Haemorrhage includes serious and potentially fatal haemorrhagic events such as gastrointestinal haemorrhage, pulmonary haemorrhage and intracranial haemorrhage

v. Cough includes cough, productive cough, upper-airway cough syndrome

w. Respiratory failure includes respiratory failure, acute respiratory failure

x. Hypoxia includes hypoxia, oxygen saturation decreased

y. Dyspnoea includes dyspnoea, dyspnoea exertional

z. Nasal inflammation includes rhinitis allergic, rhinorrhoea

aa. Diarrhoea includes diarrhoea, colitis, enteritis

bb. Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, dyspepsia, epigastric discomfort

cc. Dry mouth includes dry mouth, lip dry

dd. Transaminases increased includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasaemia

ee. Hyperbilirubinaemia increased includes hyperbilirubinemia, blood bilirubin increased

ff. Rash includes rash, application site rash, dermatitis, dermatitis allergic, dermatitis bullous, erythema, pruritus, rash erythematous, rash macular, rash maculo-papular, rash pruritic, rash pustular, urticaria

gg. Motor dysfunction includes motor dysfunction, muscle contractions involuntary, muscle rigidity, muscle spasms, muscle spasticity, muscle strain, muscle tightness, muscle twitching, muscular weakness

hh. Musculoskeletal pain includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, pain in extremity

ii. Renal impairment includes acute kidney injury, blood creatinine increased, renal failure

jj. Fever includes hyperthermia, pyrexia

kk. Oedema includes oedema, face oedema, generalized oedema, localized oedema, oedema genital, oedema peripheral, peripheral swelling, swelling

ll. Fatigue includes fatigue, asthenia, decreased activity, malaise

Description of selected adverse reactions

Cytokine release syndrome

In ZUMA-1 and ZUMA-7, CRS occurred in 92% of patients. Eight percent (8%) of patients experienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was 3 days (range: 1 to 12 days) and the median duration was 7 days (range: 2 to 58 days). Ninety-nine percent (99%) of patients recovered from CRS. No CRS was reported by patients treated with standard of care therapy (SOCT) in ZUMA-7.

In ZUMA-5, CRS occurred in 77% of patients. Six percent (6%) of patients experienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was 4 days (range: 1 to 11 days) and the median duration was 6 days (range: 1 to 27 days). Ninety-nine percent (99%) of patients recovered from CRS.

The most common adverse reactions (≥ 20%) that may be associated with CRS included pyrexia (89%), hypotension (50%), tachycardia (47%), chills (30%), and hypoxia (24%). Serious adverse reactions that may be associated with CRS included pyrexia (12%), hypotension (5%), hypoxia (3%), arrhythmia (3%), cardiac failure (2%), fatigue (2%), headache (2%), tachycardia (2%), cardiac arrest (1%), dyspnoea (1%), and tachypnoea (1%). See section 4.4 for monitoring and management guidance.

Neurologic adverse reactions

In ZUMA-1 and ZUMA-7, neurologic adverse reactions occurred in 63% of patients. Twenty-five percent (25%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. Neurologic toxicities occurred within the first 7 days of infusion for 75% of patients. The median time to onset was 6 days (range: 1 to 133 days). The median duration was 10 days, with resolution occurring within 3 weeks for 66% of patients following infusion.

In ZUMA-5, neurologic adverse reactions occurred in 57% of patients. Sixteen percent (16%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. Neurologic toxicities occurred within the first 7 days of infusion for 65% of patients. The median time to onset was 7 days (range: 1 to 177 days). The median duration was 14 days, with resolution occurring within 3 weeks for 60% of patients following infusion.

The most common (≥ 5%) neurologic adverse reactions included encephalopathy (51%), tremor (28%), and delirium (14%). Serious neurologic adverse reactions reported in patients included encephalopathy (18%), tremor (2%), delirium (2%), hemiparesis (1%) and seizure (1%). In ZUMA-7, encephalopathy and tremor were reported in 49% and 25% of patients treated with Yescarta compared to 8% and 1% treated with SOCT, respectively.

Other neurologic adverse reactions have been reported less frequently in clinical trials and included dysphagia (3%), myelitis (0.2%), and quadriplegia (0.1%).

In registries, the cerebral oedema event rate in the PMBCL indication was 1.6% overall (2 cases in 129 exposed) compared with 0.7% overall in DLBCL and other lymphoma indications (28 cases in 3876 exposed).

See section 4.4 for monitoring and management guidance.

Febrile neutropenia and infections

Febrile neutropenia was observed in 10% of patients after Yescarta infusion. Infections occurred in 48% of patients. Grade 3 or higher (severe, life-threatening, or fatal) infections occurred in 19% of patients. Grade 3 or higher unspecified pathogen, bacterial, and viral infections occurred in 12%, 6%, and 5% of patients respectively. The most common site of unspecified pathogen infection was in the respiratory tract. In ZUMA-7, febrile neutropenia and viral infection were reported in 2% and 16% of patients treated with Yescarta compared to 27% and 5% treated with SOCT, respectively. See section 4.4 for monitoring and management guidance.

Prolonged cytopenias

Grade 3 or higher neutropenia (including febrile neutropenia), anaemia, and thrombocytopenia occurred in 68%, 31%, and 23% 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%, 12%, and 6% of patients, respectively. In ZUMA-1, at the time of the 24-month follow-up analysis, Grade 3 or higher neutropenia, thrombocytopenia, and anaemia present after Day 93 occurred in 11%, 7%, and 3% of patients, respectively. In ZUMA-7, Grade 3 or higher neutropenia and thrombocytopenia were reported in 94% and 26% of patients treated with Yescarta compared to 51% and 63% treated with SOCT, respectively. See section 4.4 for management guidance.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 15% of patients treated with Yescarta. Cumulatively, 36 (33%) of 108 patients in ZUMA-1 received intravenous immunoglobulin therapy by the time of the 54‑month analysis, 28 (16%) of 170 patients in ZUMA‑7 received intravenous immunoglobulin therapy by the time of the 23.2 month analysis and 33 (28%) of 119 subjects in ZUMA-5 received intravenous immunoglobulin therapy at the time of the 24-month follow-up analysis. In ZUMA-7, immunoglobulins decreased was reported in 11% of patients treated with Yescarta compared to 1% of patients treated with SOCT. See section 4.4 for management guidance.

Immunogenicity

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. Eleven out of 278 patients (4%) tested positive for anti‑FMC63 antibodies prior to being treated with Yescarta in ZUMA-1 and ZUMA-7, and 1 patient (1%) in ZUMA-7 who had a negative test result prior to treatment, had a positive test result after treatment in the screening ELISA. Results of a confirmatory cell-based assay, leveraging a properly folded and expressed extracellular portion of the CAR (ScFv, hinge and linker) demonstrated that all patients treated with Yescarta that had a positive result in the screening ELISA were antibody negative at all time points tested. There is no evidence that the kinetics of initial expansion and persistence of Yescarta, or the safety or effectiveness of Yescarta, was altered in these patients. In ZUMA-5, 13 out of 116 patients (11%) tested positive for antibodies in the ELISA screening assay prior to being treated with Yescarta, and 2 subjects who had negative results prior to treatment had positive test results after treatment. Results of a confirmatory cell-based assay demonstrated that all patients treated with Yescarta that had an ELISA positive result were antibody negative, before, during and after treatment.

Special population

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 of suspected adverse reactions

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No data from clinical studies are available regarding overdose of Yescarta.