KYMRIAH

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.

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

2 to 5 × 106 CAR-positive viable T cells per kg body weight. 5 × 108 CAR-positive viable T cells (non-weight based). 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. , 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.

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.

1. DLBCL The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established. 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 […]

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). 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%). 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: […]

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. 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.

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. 8). Other manifestations included depressed level of consciousness, seizures, aphasia and speech […]

4). Contraindications of the lymphodepleting chemotherapy must be considered.