4.1. Therapeutic indications

Kymriah is indicated for the treatment of:

• Paediatric and young adult patients up to and including 25 years of age with B‑cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post‑transplant or in second or later relapse.

• Adult patients with relapsed or refractory diffuse large B‑cell lymphoma (DLBCL) after two or more lines of systemic therapy.

• Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

4.2. Posology and method of administration

Kymriah must be administered in a qualified treatment centre. Therapy should be initiated under the direction of and supervised by a healthcare professional experienced 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 one dose of tocilizumab and emergency equipment must be available per patient prior to infusion. The treatment centre must have access to additional doses of tocilizumab within 8 hours. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortage catalogue, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

Manufacture and release of Kymriah usually takes about 3‑4 weeks.

Posology

Kymriah is intended for autologous use only (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 or more infusion bags.

Dose in paediatric and young adult B‑cell ALL patients

The concentration of CAR‑positive viable T cells is dependent on indication and patient body weight.

- For patients 50 kg and below: The dose is within a range of 0.2 to 5 × 106 CAR‑positive viable T cells per kg body weight.

- For patients above 50 kg: The dose is within a range of 0.1 to 2.5 × 108 CAR‑positive viable T cells (non‑weight based).

Dose in adult DLBCL and FL patients

- The dose is within a range of 0.6 to 6 × 108 CAR‑positive viable T cells (non‑weight based).

See the accompanying batch specific documentation for additional information pertaining to dose.

Pre‑treatment conditioning (lymphodepleting chemotherapy)

The availability of Kymriah must be confirmed prior to starting the lymphodepleting regimen. For B‑cell ALL and DLBCL indications, Kymriah is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy. For FL, Kymriah is recommended to be infused 2 to 6 days after completion of the lymphodepleting chemotherapy.

Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count ≤1 000 cells/µL within one week prior to infusion.

If there is a delay of more than 4 weeks between completing lymphodepleting chemotherapy and the infusion and the WBC count is >1 000 cells/μL, then the patient should be re‑treated with lymphodepleting chemotherapy prior to receiving Kymriah.

B‑cell ALL

The recommended lymphodepleting chemotherapy regimen is:

- Fludarabine (30 mg/m2 intravenous daily for 4 days) and cyclophosphamide (500 mg/m2 intravenous daily for 2 days starting with the first dose of fludarabine).

If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide‑containing regimen administered shortly before lymphodepleting chemotherapy, then the following should be used:

- Cytarabine (500 mg/m2 intravenous daily for 2 days) and etoposide (150 mg/m2 intravenous daily for 3 days starting with the first dose of cytarabine).

DLBCL and FL

The recommended lymphodepleting chemotherapy regimen is:

- Fludarabine (25 mg/m2 intravenous daily for 3 days) and cyclophosphamide (250 mg/m2 intravenous daily for 3 days starting with the first dose of fludarabine).

If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide‑containing regimen administered shortly before lymphodepleting chemotherapy, then the following should be used:

- Bendamustine (90 mg/m2 intravenous daily for 2 days).

Pre‑medication

To minimise potential acute infusion reactions, it is recommended that patients be pre‑medicated with paracetamol and diphenhydramine or another H1 antihistamine within approximately 30 to 60 minutes prior to Kymriah infusion. Corticosteroids should not be used at any time except in the case of a life‑threatening emergency (see section 4.4).

Clinical assessment prior to infusion

Kymriah treatment should be delayed in some patient groups at risk (see section 4.4).

Monitoring after infusion

- In the first week following infusion, patients should be monitored 2 to 3 times, or more frequently at the physician's discretion, for signs and symptoms of potential cytokine release syndrome, neurological events and other toxicities.

- After the first week following the infusion, the patient should be monitored at the physician's discretion.

- Physicians should consider hospitalisation at the first signs/symptoms of cytokine release syndrome and/or neurological events.

- Patients should be instructed to remain within proximity (within 2 hours of travel) of a qualified clinical facility for at least 4 weeks following infusion.

Special populations

Elderly

B‑cell ALL

The safety and efficacy of Kymriah in this population have not been established.

DLBCL and FL

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

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

There is no experience with manufacturing Kymriah for patients with a positive test for HIV, active HBV, or active HCV infection. Leukapheresis material from these patients will not be accepted for Kymriah manufacturing. Screening for HBV, HCV, and HIV must be performed in accordance with clinical guidelines before collection of cells for manufacturing.

Paediatric population

B-cell ALL

There is limited experience with Kymriah in paediatric patients below the age of 3 years. Currently available data in this age group are described in sections 4.8 and 5.1.

DLBCL

The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

FL

The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established. No data are available.

Method of administration

Kymriah is for intravenous use only.

Preparation for infusion

Kymriah is intended for autologous use only. Before administration, it must be confirmed that the patient's identity matches the unique patient information on the Kymriah infusion bags and accompanying documentation. The total number of infusion bags to be administered should also be confirmed with the patient-specific information on the batch-specific documentation (see section 4.4).

The timing of thaw of Kymriah and infusion should be coordinated (please refer to section 6.6).

Administration

Kymriah should be administered as an intravenous infusion through latex‑free intravenous tubing without a leukocyte depleting filter, at approximately 10 to 20 mL per minute by gravity flow.

If the volume of Kymriah to be administered is ≤20 mL, intravenous push may be used as an alternative method of administration.

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

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

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 medicinal 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

Kymriah is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Kymriah must not be administered if the information on the product labels and batch specific documentation do not match the patient's identity.

Reasons to delay treatment

Due to the risks associated with tisagenlecleucel treatment, infusion should be delayed if a patient has any of the following conditions:

- Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies.

- Active uncontrolled infection.

- Active graft‑versus‑host disease (GVHD).

- Significant clinical worsening of leukaemia burden or rapid progression of lymphoma following lymphodepleting chemotherapy.

Transmission of an infectious agent

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

Blood, organ, tissue and cell donation

Patients treated with Kymriah must not donate blood, organs, tissues or cells for transplantation. This information is provided in the Patient Alert Card which should be given to the patient after treatment.

Active central nervous system (CNS) leukaemia or lymphoma

There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore, the risk/benefit of Kymriah has not been established in these populations.

Cytokine release syndrome

Cytokine release syndrome (CRS), including fatal or life‑threatening events, has been frequently observed after Kymriah infusion (see section 4.8). In almost all cases, development of CRS occurred between 1 to 10 days (median onset 3 days) after Kymriah infusion in paediatric and young adult B-cell ALL patients, between 1 and 9 days (median onset 3 days) after Kymriah infusion in adult DLBCL patients and between 1 to 14 days (median onset 4 days) after Kymriah infusion in adult FL patients. In some cases onset of CRS occurred after that period. The median time to resolution of cytokine release syndrome was 8 days in B-cell ALL patients, 7 days in DLBCL patients and 4 days in FL patients.

Patients should be closely monitored for signs or symptoms of CRS and patients and caregivers should be informed about potential late onset of signs or symptoms and instructed accordingly. Symptoms of CRS may include high fever, rigors, myalgia, arthralgia, nausea, vomiting, diarrhoea, diaphoresis, rash, anorexia, fatigue, headache, hypotension, dyspnoea, tachypnoea, hypoxia, and tachycardia. Organ dysfunction, including cardiac insufficiency, renal insufficiency and liver injury with accompanying elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) or elevated total bilirubin may also be observed. In some cases, disseminated intravascular coagulation (DIC) with low fibrinogen levels, capillary leak syndrome (CLS), macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of CRS.

Risk factors for severe CRS in paediatric and young adult B‑cell ALL patients are: high pre‑infusion tumour burden, uncontrolled or accelerating tumour burden following lymphodepleting chemotherapy, active infection and early onset of fever or CRS following Kymriah infusion. High tumour burden prior to Kymriah infusion was identified as a risk factor for developing severe cytokine release syndrome in adult DLBCL patients.

Prior to administration of Kymriah in paediatric and young adult B-cell ALL patients, efforts should be made to lower and control the patient's tumour burden.

In all indications, appropriate prophylactic and therapeutic treatment for infections should be provided, and complete resolution of any existing infections should be ensured. Infections may also occur during cytokine release syndrome and may increase the risk of a fatal event.

Management of cytokine release syndrome associated with Kymriah

To reduce the risk of or manage CRS complications (see above), patients treated with Kymriah may receive anti-interleukin-6-based intervention (e.g. tocilizumab) with or without a corticosteroid-based therapy. CRS management strategies may be implemented based on the most recent relevant treatment guidelines, including appropriate local institutional/academic guidelines.

One dose of tocilizumab per patient must be on site and available for administration prior to Kymriah infusion. The treatment centre should have access to additional doses of tocilizumab within 8 hours. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortage catalogue, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS.

Tisagenlecleucel continues to expand and persist following administration of tocilizumab and corticosteroids. Patients with medically significant cardiac dysfunction should be managed by standards of critical care and measures such as echocardiography should be considered. Tumour necrosis factor (TNF) antagonists are not recommended for management of Kymriah‑associated CRS.

Neurological adverse reactions

Neurological events (also known as immune effector cell-associated neurotoxicity syndrome [ICANS]), in particular encephalopathy, confusional state or delirium, occur frequently with Kymriah and can be severe or life‑threatening (see section 4.8). Other manifestations included depressed level of consciousness, seizures, aphasia and speech disorder. The majority of neurological events occurred within 8 weeks following Kymriah infusion and were transient. In some cases onset of neurological events occurred after that period. The median time to onset of the first neurological events occurring at any time following Kymriah infusion was 9 days in B‑cell ALL, 6 days in DLBCL, and 9 days in FL. The median time to resolution was 7 days for B‑cell ALL, 13 days for DLBCL, and 2 days for FL. Neurological events can be concurrent with cytokine release syndrome, following resolution of cytokine release syndrome or in the absence of cytokine release syndrome.

Patients should be monitored for neurological events and patients and caregivers should be informed about the potential late onset of events and instructed accordingly. To reduce the risk of or manage neurological toxicities (including ICANS) (see above), patients treated with Kymriah may receive supportive treatment based on the most recent relevant guidelines, including appropriate local institutional/academic guidelines.

Infections and febrile neutropenia

Patients with active, uncontrolled infection should not start Kymriah treatment until the infection is resolved. Prior to Kymriah infusion, infection prophylaxis should follow standard guidelines based on the degree of preceding immunosuppression.

Serious infections, including life‑threatening or fatal infections, in some cases with late onset, occurred frequently in patients after Kymriah infusion (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated appropriately. As appropriate, prophylactic antibiotics should be administered and surveillance testing should be employed prior to and during treatment with Kymriah. Infections are known to complicate the course and management of concurrent cytokine release syndrome. The possibility of opportunistic infections of the central nervous system should be considered in patients with neurological adverse events and appropriate diagnostic evaluations should be performed.

Febrile neutropenia was frequently observed in patients after Kymriah infusion (see section 4.8) and may be concurrent with cytokine release syndrome. In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad‑spectrum antibiotics, fluids and other supportive care, as medically indicated.

In patients achieving complete remission following Kymriah, resulting low immunoglobulin levels can increase the risk for infections. Attention to signs and symptoms of infection should be implemented according to age and standard specific guidelines.

Prolonged cytopenias

Patients may continue to exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Kymriah infusion and should be managed according to standard guidelines. The majority of patients who had cytopenias at day 28 following Kymriah treatment resolved to Grade 2 or below within three months after treatment for paediatric ALL and DLBCL patients, and within six months for FL patients. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly granulocyte macrophage‑colony stimulating factor (GM‑CSF), have the potential to worsen cytokine release syndrome symptoms and are not recommended during the first 3 weeks after Kymriah infusion or until cytokine release syndrome has resolved.

Secondary malignancies including of T-cell origin

Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. T-cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T-cell therapy, including Kymriah. 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. Patients should be monitored life‑long for secondary malignancies. In the event that a secondary malignancy occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.

Hypogammaglobulinaemia

Hypogammaglobulinaemia and agammaglobulinaemia can occur in patients after Kymriah infusion. Immunoglobulin levels should be monitored after treatment with Kymriah. In patients with low immunoglobulin levels pre‑emptive measures such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be taken according to age and standard guidelines.

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 Kymriah infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.

Concomitant disease

Patients with a history of active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function were excluded from the studies. These patient are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

Prior stem cell transplantation

It is not recommended that patients receive Kymriah within 4 months of undergoing an allogeneic stem cell transplant (SCT) because of the potential risk of Kymriah worsening GVHD. Leukapheresis for Kymriah manufacturing should be performed at least 12 weeks after allogeneic SCT.

Serological testing

There is currently no experience with manufacturing Kymriah for patients testing positive for HBV, HCV and HIV.

Screening for HBV, HCV and HIV must be performed in accordance with clinical guidelines before collection of cells for manufacturing.

Viral reactivation

Hepatitis B virus (HBV) reactivation can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure and death.

Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy (PML), has been reported in patients treated with Kymriah who have also received prior treatment with other immunosuppressive medications. Cases with fatal outcome have been reported

CD19-negative B-cell ALL disease

Kymriah is not recommended if the B-cell ALL patient has CD19-negative disease or an unconfirmed CD19 status.

Prior treatment with anti‑CD19 therapy

There is limited experience with Kymriah in patients exposed to prior CD19‑directed therapy. While activity of tisagenlecleucel has been observed, data are currently too limited to make an adequate assessment of the benefit-risk profile in these patients. Kymriah is not recommended if the patient has relapsed with CD19‑negative leukaemia after prior anti‑CD19 therapy.

Interference with virological testing

Due to limited and short spans of identical genetic information between the lentiviral vector used to create Kymriah and HIV, some commercial HIV nucleic acid tests (NAT) may give a false positive result.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis, have been reported and may be due to dimethyl sulfoxide (DMSO) and dextran 40 in Kymriah. All patients should be observed closely during the infusion period.

Long-term follow‑up

Patients are expected to be enrolled in a registry in order to better understand the long‑term safety and efficacy of Kymriah.

Sodium and potassium content

This medicinal product contains 24.3 to 121.5 mg sodium per dose, equivalent to 1 to 6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially “potassium‑free”.

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

No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been performed in either the paediatric or adult population. The co‑administration of agents known to inhibit T‑cell function has not been formally studied. Administration of low‑dose steroids as per the cytokine release syndrome treatment algorithm does not impact the expansion and persistence of CAR‑T cells. The co‑administration of agents known to stimulate T‑cell function has not been investigated and the effects are unknown.

Live vaccines

The safety of immunisation with live vaccines during or following Kymriah treatment 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 Kymriah treatment, and until immune recovery following treatment.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Pregnancy status for females of childbearing age should be verified prior to starting treatment with Kymriah.

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 Kymriah.

Pregnancy

There are no data from the use of tisagenlecleucel in pregnant women. No animal studies have been conducted with tisagenlecleucel to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3). It is not known whether tisagenlecleucel has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B‑cell lymphocytopenia. Kymriah is not recommended during pregnancy and in women of childbearing potential not using contraception.

Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Kymriah therapy should be discussed with the treating physician. Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah.

Breast‑feeding

It is unknown whether tisagenlecleucel cells are excreted in human milk. A risk to the breast‑fed infant cannot be excluded. Women who are breast‑feeding should be advised of the potential risk to the breast‑fed infant.

Following administration of Kymriah, breast‑feeding should be discussed with the treating physician.

Fertility

There are no data on the effect of Kymriah on fertility. Effects of Kymriah on male and female fertility have not been evaluated in animal studies.

4.7. Effects on ability to drive and use machines

Kymriah has major influence on the ability to drive and use machines.

Due to the potential for neurological events, including altered mental status or seizures, patients receiving Kymriah are at risk for altered or decreased consciousness or coordination and must refrain from driving or operating heavy or potentially dangerous machines for 8 weeks following Kymriah infusion.

4.8. Undesirable effects

Summary of the safety profile

Safety assessment was based on a total of 424 patients (with paediatric and young adult B-cell ALL, DLBCL and FL) who received Kymriah in three multicentre pivotal clinical studies.

B‑cell ALL

The adverse reactions described in this section were characterised in 212 patients infused with Kymriah in the pivotal clinical study CCTL019B2202 and in the supportive studies CCTL019B2205J and CCTL019B2001X.

The most common non‑haematological adverse reactions were cytokine release syndrome (75%), infections (70%), hypogammaglobulinaemia (49%), pyrexia (43%) and decreased appetite (28%).

The most common haematological laboratory abnormalities were decreased white blood cells (100%), decreased haemoglobin (99%), decreased neutrophils (98%), decreased lymphocytes (98%) and decreased platelets (95%).

Grade 3 and 4 adverse reactions were reported in 86% of patients. The most common Grade 3 and 4 non‑haematological adverse reaction was cytokine release syndrome (37%).

The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cells decreased (97%), lymphocytes decreased (94%), neutrophils decreased (96%), platelets decreased (70%) and haemoglobin decreased (46%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion (78% of patients) compared to after 8 weeks post infusion (49% of patients).

DLBCL

The adverse reactions described in this section were characterised in 115 patients infused with Kymriah in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019C2201.

The most common non‑haematological adverse reactions were cytokine release syndrome (57%), infections (58%), pyrexia (35%), diarrhoea (31%), nausea (29%), fatigue (27%) and hypotension (25%).

The most common haematological laboratory abnormalities were decreased lymphocytes (100%), decreased white blood cells (99%), decreased haemoglobin (99%), decreased neutrophils (97%), and decreased platelets (95%).

Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common Grade 3 and 4 non‑haematological adverse reactions were infections (34%) and cytokine release syndrome (23%).

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count decreased (95%), neutrophil count decreased (82%), white blood cell count decreased (78%), haemoglobin decreased (59%) and platelet count decreased (56%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion (82%) compared to after 8 weeks post infusion (48%).

FL

The adverse reactions described in this section were characterised in 97 patients infused with Kymriah in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019E2202.

The most common non‑haematological adverse reactions (>25%) were cytokine release syndrome (50%), infections (50%) and headache (26%).

The most common haematological laboratory abnormalities were decreased haemoglobin (94%), decreased lymphocytes (92%), decreased white blood cells (91%), decreased neutrophils (89%) and decreased platelets (89%).

Grade 3 and 4 adverse reactions were reported in 75% of patients. The most common Grade 3 and 4 non‑haematological adverse reactions were infections (16%).

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count decreased (87%), white blood cell count decreased (74%), neutrophil count decreased (71%), platelet count decreased (26%) and haemoglobin decreased (25%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion (70%) compared to after 8 weeks post infusion (40%).

Tabulated list of adverse reactions

The adverse reactions described in this section were identified in 79, 115 and 97 patients in the ongoing multicentre pivotal clinical studies (CCTL019B2202, CCTL019C2201 and CCTL019E2202), as well as 64 and 69 patients in the supportive studies (CCTL019B2205J and CCTL019B2001X), and from post-marketing reporting. Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first, using the following convention: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 1 Adverse drug reactions

Infections and infestations1)

Very common:

Infections ‑ pathogen unspecified, viral infections, bacterial infections

Common:

Fungal infections

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

Rare:

Secondary malignancy of T-cell origin

Blood and lymphatic system disorders

Very common:

Anaemia, febrile neutropenia, neutropenia, thrombocytopenia

Common:

Leukopenia, pancytopenia, coagulopathy, lymphopenia

Uncommon:

B-cell aplasia

Immune system disorders

Very common:

Cytokine release syndrome, hypogammaglobulinaemia2)

Common:

Infusion-related reaction, graft‑versus‑host disease3), haemophagocytic lymphohistiocytosis

Not known:

Anaphylactic reaction

Metabolism and nutrition disorders

Very common:

Decreased appetite, hypokalaemia, hypophosphataemia

Common:

Hypomagnesaemia, hypoalbuminaemia4), hyperglycaemia, hyponatraemia, hyperuricaemia5), hypercalcaemia, tumour lysis syndrome, hyperkalaemia, hyperphosphataemia6), hypernatraemia, hyperferritinaemia7), hypocalcaemia

Uncommon:

Hypermagnesaemia

Psychiatric disorders

Common:

Anxiety, delirium8), sleep disorder9)

Nervous system disorders

Very common:

Headache10), encephalopathy11)

Common:

Dizziness12), peripheral neuropathy13), tremor14), motor dysfunction15), seizure16), immune effector cell-associated neurotoxicity syndrome**, speech disorders17), neuralgia18)

Uncommon:

Ischaemic cerebral infarction, ataxia19)

Not known:

Neurotoxicity

Eye disorders

Common:

Visual impairment20)

Cardiac disorders

Very common:

Tachycardia21)

Common:

Cardiac failure22), cardiac arrest, atrial fibrillation

Uncommon:

Ventricular extrasystoles

Vascular disorders

Very common:

Haemorrhage23), hypotension24), hypertension

Common:

Thrombosis25), capillary leak syndrome

Uncommon:

Flushing

Respiratory, thoracic and mediastinal disorders

Very common:

Cough26), dyspnoea27), hypoxia

Common:

Oropharyngeal pain28), pulmonary oedema29), nasal congestion, pleural effusion, tachypnoea

Uncommon:

Acute respiratory distress syndrome, lung infiltration

Gastrointestinal disorders

Very common:

Diarrhoea, nausea, vomiting, constipation, abdominal pain30)

Common:

Stomatitis, abdominal distension, dry mouth, ascites

Hepatobiliary disorders

Common:

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Very common:

Rash31)

Common:

Pruritus, erythema, hyperhidrosis, night sweats

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, musculoskeletal pain32)

Common:

Myalgia

Renal and urinary disorders

Very common:

Acute kidney injury33)

General disorders and administration site conditions

Very common:

Pyrexia, fatigue34), oedema35), pain36)

Common:

Influenza‑like illness, asthenia, multiple organ dysfunction syndrome, chills

Investigations

Very common:

Lymphocyte count decreased*, white blood cell count decreased*, haemoglobin decreased*, neutrophil count decreased*, platelet count decreased*, hepatic enzyme increased37)

Common:

Blood bilirubin increased, weight decreased, blood fibrinogen decreased, international normalised ratio increased, fibrin D dimer increased, activated partial thromboplastin time prolonged, prothrombin time prolonged

1) Infections and infestations presented reflect high-level group terms.

2) Hypogammaglobulinaemia includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinaemia, immunodeficiency, immunodeficiency common variable and immunoglobulins decreased.

3) Graft-versus-host disease (GvHD) includes GvHD, GvHD in gastrointestinal tract, GvHD in skin

4) Hypoalbuminaemia includes blood albumin decreased, hypoalbuminaemia

5) Hyperuricaemia includes blood uric acid increased, hyperuricaemia

6) Hyperphosphataemia includes blood phosphorus increased, hyperphosphataemia

7) Hyperferritinaemia includes hyperferritinaemia, serum ferritin increased

8) Delirium includes agitation, delirium, hallucination, hallucination visual, irritability and restlessness.

9) Sleep disorder includes insomnia, nightmare and sleep disorder.

10) Headache includes headache and migraine.

11) Encephalopathy includes automatism, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, metabolic encephalopathy, somnolence and thinking abnormal. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms.

12) Dizziness includes dizziness, presyncope and syncope.

13) Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.

14) Tremor includes dyskinesia and tremor.

15) Motor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy.

16) Seizure includes generalised tonic-clonic seizures, seizure and status epilepticus.

17) Speech disorders includes aphasia, dysarthria and speech disorders.

18) Neuralgia includes neuralgia and sciatica.

19) Ataxia includes ataxia and dysmetria.

20) Visual impairment includes vision blurred and visual impairment.

21) Tachycardia includes sinus tachycardia, supraventricular tachycardia, tachycardia

22) Cardiac failure includes cardiac failure, cardiac failure congestive, left ventricular dysfunction and right ventricular dysfunction.

23) Haemorrhage includes anal haemorrhage, blood blister, blood urine present, catheter site haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, contusion, cystitis haemorrhagic, disseminated intravascular coagulation, duodenal ulcer haemorrhage, ecchymosis, epistaxis, eye contusion, gastrointestinal haemorrhage, gingival bleeding, haemarthrosis, haematemesis, haematochezia, haematoma, haematuria, haemoptysis, heavy menstrual bleeding, injection site haematoma, intermenstrual bleeding, large intestinal haemorrhage, lip haemorrhage, melaena, mouth haemorrhage, mucosal haemorrhage, oral blood blister, periorbital haematoma, peritoneal haematoma, petechiae, pharyngeal haemorrhage, post-procedural haemorrhage, pulmonary haemorrhage, purpura, rectal haemorrhage, retinal haemorrhage, stoma site haemorrhage, subcutaneous haematoma, subdural haematoma, subdural haemorrhage, tooth socket haemorrhage, tracheal haemorrhage, traumatic haematoma, tumour haemorrhage, upper gastrointestinal haemorrhage and vaginal haemorrhage.

24) Hypotension includes hypotension and orthostatic hypotension.

25) Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava thrombosis and venous thrombosis.

26) Cough includes cough, productive cough and upper-airway cough syndrome.

27) Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory distress and respiratory failure.

28) Oropharyngeal pain includes oral pain and oropharyngeal pain.

29) Pulmonary oedema includes acute pulmonary oedema and pulmonary oedema.

30) Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain.

31) Rash includes dermatitis, dermatitis acneiform, dermatitis contact, rash, rash maculo‑papular, rash papular and rash pruritic.

32) Musculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, neck pain, non-cardiac chest pain.

33) Acute kidney injury includes acute kidney injury, anuria, azotaemia, blood creatinine abnormal, blood creatinine increased, blood urea increased, renal failure, renal tubular dysfunction and renal tubular necrosis.

34) Fatigue includes fatigue and malaise.

35) Oedema includes face oedema, fluid retention, generalised oedema, hypervolaemia, localised oedema, oedema peripheral, periorbital oedema and peripheral swelling.

36) Pain includes pain and pain in extremity.

37) Hepatic enzyme increased includes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, hepatic enzyme increased, transaminases increased.

* Frequency is based on laboratory values. Patients are counted only for the worst grade observed post baseline.

** Abbreviated as ICANS. Symptoms or signs can be progressive and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral oedema.

Description of selected adverse drug reactions

Cytokine release syndrome

In the clinical studies in paediatric and young adult B‑cell ALL (N=212), cytokine release syndrome was reported in 75% of patients (37% with Grade 3 or 4; 0.5% [1 patient] with fatal outcome).

In the ongoing clinical study in DLBCL (N=115), cytokine release syndrome was reported in 57% of patients (23% with Grade 3 or 4).

In the ongoing clinical study in FL (N=97), cytokine release syndrome was reported in 50% of patients. No Grade 3 or 4 events were reported.

Cytokine release syndrome was graded per Penn criteria in the paediatric and young adult B-cell ALL and DLBCL studies as follows: Grade 1: mild reactions, reactions requiring supportive care; Grade 2: moderate reactions, reactions requiring intravenous therapies; Grade 3: severe reactions, reactions requiring low‑dose vasopressors or supplemental oxygen; Grade 4: life‑threatening reactions, those requiring high‑dose vasopressors or intubation; Grade 5: death.

Cytokine release syndrome was graded per the Lee criteria in the FL study as follows: Grade 1: mild general symptoms requiring symptomatic treatment; Grade 2: symptoms requiring moderate intervention such as low-flow oxygen supplementation or low-dose vasopressor; Grade 3: symptoms requiring aggressive intervention, such as high-flow oxygen supplementation and high-dose vasopressor; Grade 4: life‑threatening symptoms requiring intubation; Grade 5: death.

For clinical management of cytokine release syndrome, see section 4.4.

Infections and febrile neutropenia

In B‑cell ALL patients severe infections (Grade 3 and higher), which can be life‑threatening or fatal, occurred in 36% of patients after Kymriah infusion. The overall incidence (all grades) was 70% (unspecified 55%, viral 31%, bacterial 24% and fungal 12%) (see section 4.4). 41% of the patients experienced an infection of any type within 8 weeks after Kymriah infusion.

In DLBCL patients severe infections (Grade 3 and higher), which can be life‑threatening or fatal, occurred in 34% of patients. The overall incidence (all grades) was 58% (unspecified 48%, bacterial 15%, fungal 11% and viral 11%) (see section 4.4). 37% of the patients experienced an infection of any type within 8 weeks.

In FL patients severe infections (Grade 3 or 4), occurred in 16% of patients. The overall incidence (all grades) was 50% (unspecified 36%, viral 17%, bacterial 6%, and fungal 2%) (see section 4.4). 19% of the patients experienced an infection of any type within 8 weeks.

Severe febrile neutropenia (Grade 3 or 4) was observed in 26% of paediatric and young adult B‑cell ALL patients, 17% of DLBCL patients and 12% of FL patients. See section 4.4 for the management of febrile neutropenia before and after Kymriah infusion.

Prolonged cytopenias

Cytopenias are very common based on prior chemotherapies and Kymriah therapy.

All paediatric and young adult B‑cell ALL patients had a Grade 3 or 4 cytopenia at some time after Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based on laboratory findings included decreased count of white blood cells (50%), neutrophils (56%), lymphocytes (43%), and thrombocytes (32%) and decreased haemoglobin (11%).

All adult DLBCL patients had Grade 3 and 4 cytopenias at some time after Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 based on laboratory findings included decreased count of thrombocytes (39%), lymphocytes (29%), neutrophils (25%), and white blood cells (21%) and decreased haemoglobin (14%).

In adult patients with FL, 99% had Grade 3 and 4 cytopenias at any time post Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based on laboratory findings included a decreased count of lymphocytes (23%), thrombocytes (17%), neutrophils (16%), white blood cells (13%) and decreased haemoglobin (3%).

Neurological adverse reactions

The majority of neurotoxic events occurred within 8 weeks following infusion and were transient.

In paediatric and young adult B‑cell ALL patients, serious neurological adverse reactions including manifestations of encephalopathy and/or delirium occurred in 32% of patients (10% were Grade 3 or 4) within 8 weeks after Kymriah infusion. In DLBCL patients, manifestations of encephalopathy and/or delirium occurred in 20% of patients (11% were Grade 3 or 4) within 8 weeks after Kymriah infusion. In FL patients, these occurred in 9% of patients (1% Grade 3 or 4) within 8 weeks after Kymriah infusion. Among the neurotoxic events in FL patients, immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% of patients (1% Grade 3 or 4), all within 8 weeks of Kymriah infusion.

For clinical management of neurological adverse reactions, see section 4.4.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 49% of patients treated with Kymriah for r/r ALL, 17% of patients with r/r DLBCL and 17% of patients with r/r FL.

Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Immunoglobulin levels should be assessed in newborns of mothers treated with Kymriah.

Immunogenicity

In clinical studies, humoral immunogenicity of tisagenlecleucel was measured by determination of anti‑murine CAR19 antibodies (anti‑mCAR19) in serum pre‑ and post‑administration. The majority of patients tested positive for pre‑dose anti‑mCAR19 antibodies in paediatric and young adult ALL (B2202, B2205J, B2001X, 84.0%), adult DLBCL (C2201, 93.9%) and adult FL (E2202, 66.0%) patients.

Treatment‑induced anti‑mCAR19 antibodies were found in 40.5% of paediatric and young adult ALL (B2202), 8.7% of adult DLBCL and 28.7% of adult FL patients. Pre‑existing and treatment‑induced antibodies were not associated with an impact on clinical response nor did they have an impact on the expansion and persistence of tisagenlecleucel. There is no evidence that the presence of pre‑existing and treatment‑induced anti‑mCAR19 antibodies impacts the safety or effectiveness of Kymriah.

T‑cell immunogenicity responses were not observed in paediatric and young adult B‑cell ALL, adult r/r DLBCL and adult FL patients.

Paediatric population

The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients from 3 years of age and older was assessed in 212 patients in the pivotal study B2202 and the supportive studies B2205J and B2001X in which the majority of patients (81%) were under 18 years old (65/79 in B2202, 54/64 in B2205 and 52/69 in B2001X). The frequency, type and severity of adverse reactions in paediatric patients are reflected in “Summary of the safety profile” and in Table 1 above.

The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients below 3 years of age was assessed in the observational study B2401 (n=43) where the overall safety experience was generally consistent with the known safety profile of tisagenlecleucel.

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

4.9. Overdose

Overdose has not been reported.

In case of overdose, the potential risk is an increased probability of developing CRS including severe CRS. For close monitoring, see section 4.2; for symptoms and management of CRS, see section 4.4.