Kymriah

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Kymriah 1.2 x 106 – 6 x 108 cells dispersion for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

2.1 General description 
 

Kymriah is an immunocellular therapy containing tisagenlecleucel, autologous T cells genetically 

modified ex vivo using a lentiviral vector encoding an anti-CD19 chimeric antigen receptor (CAR). 

 

2.2 Qualitative and quantitative composition 

 

Each ethylene vinyl acetate (EVA) infusion bag of Kymriah contains tisagenlecleucel cell dispersion 

at a batch-dependent concentration of autologous T cells genetically modified to express an anti-CD19 

chimeric antigen receptor (CAR-positive viable T cells) (see section 4.2). 

 

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

(for B-cell acute lymphoblastic leukaemia [ALL]). The cellular composition and the final cell number 

varies between individual patient batches. In addition to T cells, NK cells may be present. The 

quantitative information regarding CAR-positive viable T cells/mL and total cells in the product is 

presented in the batch-specific documentation accompanying Kymriah. 

 

1 or more infusion bags containing a total of 1.2 x 106 to 6 x 108 CAR-positive viable T cells. 

 

Excipient with known effect 

 

This medicinal product contains 2.43 mg sodium per mL and 24.3 to 121.5 mg sodium per dose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Dispersion for infusion. 

 

A colourless to slightly yellow dispersion. 

 

 

4. CLINICAL PARTICULARS 
 

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. 

 



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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 

Kymriah. Tocilizumab for use in the event of cytokine release syndrome 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. 

 

Kymriah is intended for autologous use only (see section 4.4). Manufacture and release of Kymriah 

usually takes about 3-4 weeks. 

 

Posology 

 

Dosage in paediatric and young adult B-cell ALL patients 

- For patients 50 kg and below: 0.2 to 5 x 106 CAR-positive viable T cells/kg body weight. 
- For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells (non-weight based). 
 

Dosage in adult DLBCL patients 

- 0.6 to 6 x 108 CAR-positive viable T cells (non-weight based). 
 

Pre-treatment conditioning (lymphodepleting chemotherapy) 

 

Lymphodepleting chemotherapy is recommended to be administered before Kymriah infusion unless 

the white blood cell (WBC) count within one week prior to infusion is ≤1,000 cells/μL. 

 

Kymriah is recommended to be infused 2 to 14 days after completion of the lymphodepleting 

chemotherapy. The availability of Kymriah must be confirmed prior to starting the lymphodepleting 

regimen. 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 

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). 
 

Lymphodepleting chemotherapy may be omitted if a patient’s white blood cell (WBC) count is 

≤1,000 cells/µL within 1 week prior to Kymriah infusion. 

 



4 

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 

- Patients should be monitored daily for the first 10 days following infusion for signs and 
symptoms of potential cytokine release syndrome, neurological events and other toxicities. 

Physicians should consider hospitalisation for the first 10 days post infusion or at the first 

signs/symptoms of cytokine release syndrome and/or neurological events. 

- After the first 10 days following the infusion, the patient should be monitored at the physician’s 
discretion. 

- 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 

 

Paediatric population 

B-cell ALL: No formal studies have been performed in paediatric patients below 3 years of age. 

DLBCL: The safety and efficacy of Kymriah in children and adolescents below 18 years of age have 

not yet been established. No data are available. 

 

Elderly 

B-cell ALL: The safety and efficacy of Kymriah in this population have not been established. 

DLBCL: 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. 

 

Method of administration 

 

Kymriah is for intravenous use only. 

 

Precautions to be taken before handling or administering the medicinal product 
This medicinal product contains genetically modified human blood cells. Healthcare professionals 

handling Kymriah should take appropriate precautions (wearing gloves and glasses) to avoid potential 

transmission of infectious diseases as for any human-derived material. 

 

Preparation for infusion 

Prior to Kymriah infusion, it must be confirmed that the patient’s identity matches the essential unique 

patient information on the infusion bag(s). 

 

The timing of thaw of Kymriah and infusion should be coordinated. Please refer to section 6.6 for 

details on inspection and thawing of the infusion bag. The infusion start time should be confirmed in 

advance and adjusted for thaw so that Kymriah is available for infusion when the recipient is ready. 

Once Kymriah has been thawed and is at room temperature (20°C -25°C), it should be infused within 

30 minutes to maintain maximum product viability, including any interruption during the infusion. 

 



5 

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. All 

contents of the infusion bag(s) should be infused. Sodium chloride 9 mg/mL (0.9%) solution for 

injection should be used to prime the tubing prior to infusion and to rinse it after infusion. When the 

full volume of Kymriah has been infused, the infusion bag should be rinsed with 10 to 30 mL sodium 

chloride 9 mg/mL (0.9%) solution for injection by back priming to ensure as many cells as possible 

are infused into the patient. 

 

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

alternative method of administration. 

 

For special precautions for disposal see section 6.6. 

 

4.3 Contraindications 
 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

Contraindications of the lymphodepleting chemotherapy must be considered. 

 

4.4 Special warnings and precautions for use 
 

Traceability 

 

To ensure traceability the name of the product, the batch number and the name of the treated patient 

should be kept for a period of 30 years. 

 

Reasons to delay treatment 

 

Due to the risks associated with Kymriah 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. 

 

Blood, organ, tissue and cell donation 

 

Patients treated with Kymriah should not donate blood, organs, tissues or cells. 

 

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. 

 

  



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Cytokine release syndrome 

 

Cytokine release syndrome, including fatal or life-threatening events, has been frequently observed 

after Kymriah infusion (see section 4.8). In almost all cases, development of cytokine release 

syndrome occurred between 1 to 10 days (median onset 3 days) after Kymriah infusion. The median 

time to resolution of cytokine release syndrome was 8 days. 

 

Symptoms of cytokine release syndrome may include high fever, rigors, myalgia, arthralgia, nausea, 

vomiting, diarrhoea, diaphoresis, rash, anorexia, fatigue, headache, hypotension, dyspnoea, 

tachypnoea, and hypoxia. Organ dysfunction, including cardiac insufficiency and arrhythmia, 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 cytokine release syndrome. Patients should be closely monitored for signs 

or symptoms of these events, including fever. 

 

Risk factors for severe cytokine release syndrome 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 cytokine release syndrome 

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. 

 

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 

Cytokine release syndrome should be managed solely based on the patient’s clinical presentation and 

according to the cytokine release syndrome management algorithm provided in Table 1. Anti-IL-6 

based therapy such as tocilizumab has been administered for moderate or severe cytokine release 

syndrome associated with Kymriah. 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. Corticosteroids may be administered in cases of life-threatening 

emergencies. 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 cytokine release syndrome. 

 



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Table 1 Cytokine release syndrome management algorithm 

 

Cytokine release syndrome severity Management 

Prodromal syndrome: 

Low-grade fever, fatigue, anorexia 

Observe in person; exclude infection; administer 

antibiotics per local guidelines if neutropenic; provide 

symptomatic support. 

Cytokine release syndrome requiring 

mild intervention - one or more of the 

following: 

 High fever 

 Hypoxia 

 Mild hypotension 

Administer antipyretics, oxygen, intravenous fluids 

and/or low-dose vasopressors as needed. 

Cytokine release syndrome requiring 

moderate to aggressive 

intervention - one or more of the 

following: 

 Haemodynamic instability despite 
intravenous fluids and vasopressor 

support 

 Worsening respiratory distress, 
including pulmonary infiltrates, 

increasing oxygen requirement 

including high-flow oxygen and/or 

need for mechanical ventilation 

 Rapid clinical deterioration 

 Administer high-dose or multiple vasopressors, 
oxygen, mechanical ventilation and/or other 

supportive care as needed. 

 

 Administer tocilizumab. 
- Patient weight less than 30 kg: 12 mg/kg 

intravenously over 1 hour 

- Patient weight ≥30 kg: 8 mg/kg intravenously 
over 1 hour (maximum dose 800 mg) 

 

Repeat tocilizumab as needed at a minimum interval of 

8 hours if there is no clinical improvement. 

 

If no response to second dose of tocilizumab, consider a 

third dose of tocilizumab or pursue alternative measures 

for treatment of cytokine release syndrome. 

 

Limit to a maximum total of 4 tocilizumab doses. 

 

 If no clinical improvement within 12 to 18 hours of 
the first tocilizumab dose, or worsening at any time, 

administer methylprednisolone 2 mg/kg as an initial 

dose, then 2 mg/kg per day until vasopressors and 

high-flow oxygen are no longer needed, then taper. 

 

  



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Neurological adverse reactions 

 

Neurological events, 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. The median time to 

onset of the first neurological events was 8 days in B-cell ALL and 6 days in DLBCL. The median 

time to resolution was 7 days for B-cell ALL and 13 days for DLBCL. 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. In case of neurological events, patients should 

be diagnostically worked up and managed depending on the underlying pathophysiology and in 

accordance with local standard of care. 

 

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, 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. 

 

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. 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 

 

Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. 

They 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. 

 



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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. 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. 

 

Prior treatment with anti-CD19 therapy 

 

There is limited experience with Kymriah in patients exposed to prior CD19-directed therapy. 

Kymriah is not recommended if the patient has relapsed with CD19-negative leukaemia after prior 

anti-CD19 therapy. 

 

Interference with serological 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. 

 

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”. 

 



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Content of dextran 40 and dimethyl sulfoxide (DMSO) 

 

This medicinal product contains 11 mg dextran 40 and 82.5 mg dimethyl sulfoxide (DMSO) per mL. 

Each of these excipients are known to possibly cause anaphylactic reaction following parenteral 

administration. Patients not previously exposed to dextran and DMSO should be observed closely 

during the first minutes of the infusion period. 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been 

performed. 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. 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 with Kymriah. 

 

4.6 Fertility, pregnancy and lactation 
 

Women of childbearing potential/Contraception in males and females 

 

Pregnancy status for females of child-bearing 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 Kymriah in pregnant women. No animal studies have been 

conducted with Kymriah to assess whether it can cause foetal harm when administered to a pregnant 

woman (see section 5.3). It is not known whether Kymriah 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 Kymriah 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. 

 



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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 in the 8 weeks 

following infusion. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Safety assessment was based on a total of 194 patients (with paediatric and young adult B-cell ALL 

and DLBCL) who received Kymriah in two multi-centre pivotal clinical studies. 
 

B-cell ALL 

The adverse reactions described in this section were characterised in 79 patients infused with Kymriah 

in the multi-centre, pivotal clinical study CCTL019B2202. 

 

The most common non-haematological adverse reactions were cytokine release syndrome (77%), 

infections (73%), hypogammaglobulinaemia (53%), pyrexia (42%) and decreased appetite (38%). 

 

The most common haematological adverse reactions were decreased white blood cells (100%), 

decreased haemoglobin (100%), decreased neutrophils (100%), decreased lymphocytes (100%) and 

decreased platelets (97%). 

 

Grade 3 and 4 adverse reactions were reported in 89% of patients. The most common Grade 3 and 4 

non-haematological adverse reaction was cytokine release syndrome (48%). 

 

The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cells 

decreased (97%), lymphocytes decreased (96%), neutrophils decreased (95%), platelets decreased 

(77%) and haemoglobin decreased (48%). 

 

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post-infusion 

(82% of patients) compared to after 8 weeks post-infusion (51% 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 adverse reactions 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%). 

 



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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%). 

 

Tabulated list of adverse drug reactions 

The adverse reactions described in this section were identified in 79 and 115 patients in the ongoing 

multicentre pivotal clinical studies (CCTL019B2202 and CCTL019C2201). Adverse drug reactions 

from these clinical studies (Table 2) 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 2 Adverse drug reactions observed in clinical studies 

 
Adverse drug 

reaction 

(MedDRA 

system organ 

class) 

Studies B2202 (N=79) + C2201 (N=115) 

Very common 

(≥1/10) 

Common 

(≥1/100 to <1/10) 

Uncommon 

(≥1/1000 to <1/100) 

Infections and 

infestations1) 

Infections - pathogen 

unspecified 

Viral infections 

Bacterial infections 

Fungal infections 

  

Blood and 

lymphatic 

system disorders 

Anaemia 

Haemorrhage2) 

Febrile neutropenia 

Neutropenia 

Thrombocytopenia 

Haemophagocytic 

lymphohistiocytosis 

Leukopenia 

Pancytopenia 

Coagulopathy 

Lymphopenia 

B-cell aplasia 

Immune system 

disorders 

Cytokine release syndrome 

Hypogammaglobulinaemia3) 

Infusion-related reaction 

Graft-versus-host disease 

 

Metabolism and 

nutrition 

disorders 

Decreased appetite 

Hypokalaemia 

Hypophosphataemia 

Hypomagnesaemia 

Hypocalcaemia 

Hypoalbuminaemia 

Hyperglycaemia 

Hyponatraemia 

Hyperuricaemia 

Fluid overload 

Hypercalcaemia 

Tumour lysis syndrome 

Hyperkalaemia 

Hyperphosphataemia 

Hypernatraemia 

Hypermagnesaemia 

 

Psychiatric 

disorders 

Anxiety 

Delirium4) 

Sleep disorder5) 

  

Nervous system 

disorders 

Headache6) 

Encephalopathy7) 

Dizziness8) 

Peripheral neuropathy9) 

Tremor10) 

Motor dysfunction11) 

Seizure12) 

Speech disorders13) 

Neuralgia14) 

Ataxia15) 

Ischaemic cerebral 

infarction 

Eye disorders  Visual impairment16)  



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Cardiac 

disorders 

Arrhythmia17) Cardiac failure18) 

Cardiac arrest 

 

Vascular 

disorders 

Hypotension19) 

Hypertension 

Thrombosis20) 

Capillary leak syndrome 

Flushing 

Respiratory, 

thoracic and 

mediastinal 

disorders 

Cough21) 

Dyspnoea22) 

Hypoxia 

Oropharyngeal pain23) 

Pulmonary oedema24) 

Nasal congestion 

Pleural effusion 

Tachypnoea 

Acute respiratory distress 

syndrome 

Lung infiltration 

Gastrointestinal 

disorders 

Diarrhoea 

Nausea 

Vomiting 

Constipation 

Abdominal pain25) 

Stomatitis 

Abdominal distension 

Dry mouth 

Ascites 

 

Hepatobiliary 

disorders 

 Hyperbilirubinaemia  

Skin and 

subcutaneous 

tissue disorders 

Rash26) Pruritus 

Erythema 

Hyperhidrosis 

Night sweats 

 

Musculoskeletal 

and connective 

tissue disorders 

Arthralgia Back pain 

Myalgia 

Musculoskeletal pain 

 

Renal and 

urinary disorders 

Acute kidney injury27)   

General 

disorders and 

administration 

site conditions 

Pyrexia 

Fatigue28) 

Oedema29) 

Pain30) 

Chills 

Influenza-like illness 

Asthenia 

Multiple organ dysfunction 

syndrome 

 

Investigations Lymphocyte count decreased* 

White blood cell count 

decreased* 

Haemoglobin decreased* 

Neutrophil count decreased* 

Platelet count decreased* 

Aspartate aminotransferase 

increased 

Alanine aminotransferase 

increased 

Blood bilirubin increased 

Weight decreased 

Serum ferritin increased 

Blood fibrinogen decreased 

International normalised 

ratio increased 

Fibrin D dimer increased 

Activated partial 

thromboplastin time 

prolonged 

Blood alkaline phosphatase 

increased 

Prothrombin time prolonged 

 

1) Infections and infestations presented reflect high-level group terms. 
2) Haemorrhage includes anal haemorrhage, blood urine present, catheter site haemorrhage, cerebral 

haemorrhage, conjunctival haemorrhage, contusion, cystitis haemorrhagic, duodenal ulcer 

haemorrhage, disseminated intravascular coagulation, epistaxis, eye contusion, gastrointestinal 

haemorrhage, gingival bleeding, haematochezia, haemarthrosis, haematemesis, haematuria, 

haemoptysis, large intestinal haemorrhage, melaena, menorrhagia, mouth haemorrhage, peritoneal 

haematoma, petechiae, pharyngeal haemorrhage, post-procedural haemorrhage, pulmonary 

haemorrhage, purpura, retinal haemorrhage, traumatic haematoma, tumour haemorrhage, upper 

gastrointestinal haemorrhage and vaginal haemorrhage. 
3) Hypogammaglobulinaemia includes immunoglobulins decreased, blood immunoglobulin A decreased, 

blood immunoglobulin G decreased, blood immunoglobulin M decreased, immunodeficiency, 

immunodeficiency common variable and hypogammaglobulinaemia. 
4) Delirium includes agitation, delirium, hallucination, hallucination visual, irritability and restlessness. 
5) Sleep disorder includes sleep disorder, insomnia and nightmare. 
6) Headache includes headache and migraine. 



14 

7) Encephalopathy includes depressed level of consciousness, mental status changes, automatism, 

cognitive disorder, confusional state, disturbance in attention, encephalopathy, somnolence, lethargy, 

memory impairment, metabolic encephalopathy and thinking abnormal. 
8) Dizziness includes dizziness, presyncope and syncope. 
9) Peripheral neuropathy includes paraesthesia, peripheral sensory neuropathy, neuropathy peripheral, 

hyperaesthesia and hypoaesthesia. 
10) Tremor includes dyskinesia and tremor. 
11) Motor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy. 
12) Seizure includes seizure, generalised tonic-clonic seizures and status epilepticus. 
13) Speech disorders includes speech disorders, dysarthria and aphasia. 
14) Neuralgia includes neuralgia and sciatica. 
15) Ataxia includes ataxia and dysmetria. 
16) Visual impairment includes vision blurred and visual impairment. 
17) Arrhythmia includes atrial fibrillation, supraventricular tachycardia, tachycardia and ventricular 

extrasystoles. 
18) Cardiac failure includes cardiac failure, left ventricular dysfunction, cardiac failure congestive and 

right ventricular dysfunction. 
19) Hypotension includes hypotension and orthostatic hypotension. 
20) Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava 

thrombosis and venous thrombosis. 
21) Cough includes cough, productive cough and upper-airway cough syndrome. 
22) Dyspnoea includes dyspnoea, dyspnoea exertional, respiratory distress and respiratory failure. 
23) Oropharyngeal pain includes oral pain and oropharyngeal pain. 
24) Pulmonary oedema includes acute pulmonary oedema and pulmonary oedema 
25) Abdominal pain includes abdominal pain, abdominal pain upper and abdominal discomfort. 
26) Rash includes dermatitis, dermatitis acneiform, dermatitis contact, rash, rash maculo-papular, rash 

papular and rash pruritic. 
27) Acute kidney injury includes acute kidney injury, anuria, azotaemia, blood creatinine abnormal, blood 

creatinine increased, renal failure, renal tubular dysfunction and renal tubular necrosis. 
28) Fatigue includes fatigue and malaise. 
29) Oedema includes oedema peripheral, generalised oedema, localised oedema, face oedema and 

peripheral swelling. 
30) Pain includes pain and pain in extremity. 

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

 

Description of selected adverse drug reactions 

 

Cytokine release syndrome 

In the ongoing clinical study in paediatric and young adult B-cell ALL (N=79), cytokine release 

syndrome was reported in 77% of patients (48% with Grade 3 or 4). Two deaths occurred within 

30 days of tisagenlecleucel infusion, including one patient, who died from progressive leukaemia in 

the setting of possible cytokine release syndrome and one patient who experienced fatal intracranial 

haemorrhage that developed during the course of resolved cytokine release syndrome, abdominal 

compartment syndrome, coagulopathy and renal failure. 

 

In the ongoing clinical study in DLBCL (N=115), cytokine release syndrome was reported in 57% of 

patients (23% with Grade 3 or 4). 

 

Cytokine release syndrome was graded with the Penn scale 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. 

 

For clinical management of cytokine release syndrome, see section 4.4 and Table 1. 

 



15 

Infections and febrile neutropenia 

In B-cell ALL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, 

occurred in 48% of patients after Kymriah infusion. The overall incidence (all grades) was 73% 

(unspecified 57%, viral 38%, bacterial 27% and fungal 15%) (see section 4.4). 43% 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. 

 

Severe febrile neutropenia (Grade 3 or 4) was observed in 34% of paediatric and young adult B-cell 

ALL patients and 17% of DLBCL 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 (57%), neutrophils (54%), 

lymphocytes (44%), and thrombocytes (42%) and decreased haemoglobin (13%). 

 

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%). 

 

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, manifestations of encephalopathy and/or delirium 

occurred in 39% 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. 

 

Hypogammaglobulinaemia 

Hypogammaglobulinaemia was reported in 53% of patients treated with Kymriah for r/r ALL and 17% 

of patients with r/r DLBCL. 

 

Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Immunoglobulin 

levels should be assessed in newborns of mothers treated with Kymriah. 

 

  



16 

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, 91.1%) and adult DLBCL (C2201, 93.9%) patients. 

 

Treatment-induced anti-mCAR19 antibodies were found in 40.5% of paediatric and young adult ALL 

and 8.7% of adult DLBCL 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 and 

adult r/r DLBCL patients. 

 

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 national reporting system 

listed in Appendix V. 

 

4.9 Overdose 
 

Not applicable. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: other antineoplastic agents, ATC code: not yet assigned 

 

Mechanism of action 

 

Tisagenlecleucel is an autologous, immunocellular cancer therapy which involves reprogramming a 

patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and 

eliminate CD19 expressing cells. The CAR is comprised of a murine single chain antibody fragment 

which recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and 

CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and antitumour activity, 

while 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to 

CD19-expressing cells, the CAR transmits a signal promoting T-cell expansion and persistence of 

tisagenlecleucel. 

 

Clinical efficacy and safety 

 

Acute lymphoblastic leukaemia (ALL) 

The safety and efficacy of Kymriah treatment in paediatric and young adult patients with relapsed or 

refractory (r/r) B-cell ALL were evaluated in one pivotal (B2202, N=79) and two supportive (B2205J 

and B2101J) open-label, single-arm studies (160 patients in total, up to 25 years of age). All patients 

had leukapheresis products collected and cryopreserved prior to or during study entry. 

 



17 

The pivotal study (B2202) is a multicentre, single-arm phase II study in paediatric and young adult 

patients with r/r B-cell acute lymphoblastic leukaemia. Of 97 patients enrolled, 79 received infusion 

with Kymriah; for 8 patients (8%) Kymriah could not be manufactured; reasons for discontinuation 

prior to Kymriah infusion included death (n=7; 7%) or adverse events (n=3; 3%) while awaiting 

Kymriah manufacturing in the clinical study. 

 

Key baseline information for enrolled and infused patients is presented in Table 3. The majority of 

patients (69/79, 87%) received bridging therapy while waiting for Kymriah. A total of 76 out of 

79 patients who received Kymriah infusion also received lymphodepleting chemotherapy after 

enrolment and prior to infusion of a single dose of Kymriah (see section 4.2 for condition of 

lymphodepleting chemotherapy). 

 

Table 3 Study B2202: Baseline information across the enrolled and the infused patient 

population 

 

 Enrolled 

N=97 

n (%) 

Infused 

N=79 

n (%) 

Age (years)   

 Mean (standard deviation) 12 (5.48) 12 (5.38) 

 Median (minimum – maximum) 11 (3 – 27) 11 (3 – 24) 

Age category (years) - n (%)   

 <10 years 40 (41.2) 32 (40.5) 

 ≥10 years and <18 years 40 (41.2) 33 (41.8) 

 ≥18 years 17 (17.5) 14 (17.7) 

Sex - n (%)   

 Male 54 (55.7)  45 (57.0) 

 Female 43 (44.3) 34 (43) 

Disease status (%)   

 Primary refractory1 8 (8.2) 6 (7.6) 

 Relapsed disease2 89 (91.8) 73 (92.4) 

Prior stem-cell transplantation - n (%)   

 0 39 (40.2) 31 (39.2) 

 1 50 (51.5) 42 (53.2) 

 2 8 (8.2) 6 (7.6) 
1Primary refractory: Never had a morphologic complete remission (CR) prior to the study; 
2Relapsed disease: Had at least one relapse prior to the study 

 

Efficacy was established through the primary endpoint of overall remission rate (ORR), which 

includes best overall response as complete remission (CR) or complete remission with incomplete 

blood count recovery (CRi) within 3 months post infusion, as determined by Independent Review 

Committee (IRC) assessment, as well as secondary endpoints including duration of remission (DOR) 

and the proportion of patients who achieved CR or CRi with minimal residual disease (MRD) <0.01% 

by flow cytometry (MRD-negative). See Table 4 for efficacy results from this study. ORR was 

consistent across all subgroups. Eight patients who achieved CR/CRi after Kymriah infusion went to 

transplant while in remission. Kymriah was administered in a qualified Kymriah treatment centre in an 

inpatient and outpatient setting. 

 

Health-related quality of life (HRQoL) was evaluated by PedsQL™ and EQ-5D questionnaires 

completed by patients aged 8 years and above (n=61). Among patients responding (n=51), the mean 

(SD) change from baseline in the PedsQL total score was 13.1 (13.45) at month 3, 15.4 (16.81) at 

month 6 and 25.0 (19.09) at month 12, and the mean (SD) change from baseline in the EQ-5D VAS 

score was 16.0 (16.45) at month 3, 15.3 (18.33) at month 6 and 21.7 (17.14) at month 12, indicating 

overall clinically meaningful improvement in HRQoL following Kymriah infusion. 

 



18 

Special populations 

No differences in efficacy or safety were observed between different age subgroups. 

 

Patients with active CNS leukaemia 

Of four patients with active CNS leukaemia (i.e. CNS-3) included in study B2101J, three experienced 

cytokine release syndrome (Grade 2-4) and transient neurological abnormalities (Grade 1-3) that 

resolved within 1-3 months of infusion. One patient died due to disease progression and the remaining 

three patients achieved a CR or CRi and remain alive 1.5-2 years after infusion. 

 

Table 4 Study B2202: Efficacy results in paediatric and young adult patients with 

relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL) 

 

Primary endpoint 
Enrolled patients 

N=97 

Infused patients 

N=79 

Overall remission rate (ORR)1,2, n (%) 

95% CI 
65 (67.0) 

(56.7, 76.2) 

p<0.0001 

65 (82.3) 

(72.1, 90.0) 

p<0.0001 

 CR3, n (%) 49 (50.5) 49 (62.0) 

 CRi4, n (%) 16 (16.5) 16 (20.3) 

Key secondary endpoint N=97 N=79 

CR or CRi with MRD negative bone marrow5,6, n 

(%) 

95% CI 

64 (66.0) 

(55.7, 75.3) 

p<0.0001 

64 (81.0) 

(70.6, 89.0) 

p<0.0001 

Duration of remission (DOR)7 N=65 N=65 

% event free probability at 12 months 66.3 66.3 

% event free probability at 18 months 66.3 66.3 

Median (months) (95% CI) Not reached (20.0, 

NE9) 

Not reached (20.0, 

NE) 

Other secondary endpoint N=97 N=79 

Overall survival (OS)8   

 % survival probability at 12 months 69.8 76.4 

% survival probability at 24 months 56.9 66.3 

 Median (months) (95% CI) Not reached (19.4, 

NE) 

Not reached (28.2, 

NE) 
1 Requires remission status to be maintained for at least 28 days without clinical evidence of 

relapse. 
2 Nominal one-sided exact p-value based on H0: ORR ≤20% vs. Ha: ORR >20% 
3 CR (complete remission) was defined as <5% of blasts in the bone marrow, circulating blasts 

in blood should be <1%, no evidence of extramedullary disease, and full recovery of 

peripheral blood counts (platelets >100,000/μL and absolute neutrophil counts [ANC] 

>1,000/μL) without blood transfusion. 
4 CRi (complete remission with incomplete blood count recovery) was defined as <5% of 

blasts in the bone marrow, circulating blasts in blood should be <1%, no evidence of 

extramedullary disease, and without full recovery of peripheral blood counts with or without 

blood transfusion. 
5 MRD (minimal residual disease) negative was defined as MRD by flow cytometry <0.01%. 
6 Nominal one-sided exact p-value based on H0: Rate of MRD negative remission ≤15% vs. 

Ha: >15%. 
7 DOR was defined as time since onset of CR or CRi to relapse or death due to underlying 

indication, whichever is earlier (N=65). 
8 OS was defined as time from date of Kymriah infusion to the date of death due to any cause 

for infused patients and from time of date of enrolment to the date of death due to any cause 

for enrolled patients. 
9 Not estimable 

 



19 

Diffuse large B-cell lymphoma (DLBCL) 

The safety and efficacy of Kymriah treatment in adult patients with relapsed or refractory (r/r) diffuse 

large B-cell lymphoma (DLBCL) who received ≥2 lines of chemotherapy, including rituximab and 

anthracycline, or relapsed following autologous haematopoietic stem cell transplantation (HSCT), was 

evaluated in an open-label, pivotal, single-arm study. Patients with T-cell rich/histiocyte-rich large 

B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell 

lymphoma (PMBCL), EBV-positive DLBCL of the elderly, Richter’s transformation, and Burkitt 

lymphoma were not enrolled in study C2201. 

 

The pivotal study (C2201) is a multicentre, single-arm phase II study in adult patients with relapsed or 

refractory DLBCL. Of 167 patients enrolled, 115 patients received infusion with Kymriah. 

Approximately 31% of patients discontinued the study prior to Kymriah infusion. For 13 patients (8%) 

Kymriah could not be manufactured. Other reasons for discontinuation prior to Kymriah infusion 

included death (n=16; 10%), physician decision/primary disease progression (n=16; 10%), patient 

decision (n=2; 1%), protocol deviation (n=1; 1%) or adverse events (n=4; 2%) while awaiting 

Kymriah manufacturing in the clinical study. 

 

Key baseline information for enrolled and infused patients is presented in Table 5. All patients had 

leukapheresis starting material collected and cryopreserved prior to or during study entry. The 

majority of patients (103/115, 90%) received bridging therapy for disease stabilisation. The type and 

duration of bridging therapy was left to the discretion of the physician. 107/115 patients (93%) 

received lymphodepleting chemotherapy prior to Kymriah infusion. Kymriah was given as a 

single-dose (0.6-6.0 x 108 CAR-positive viable T cells) intravenous infusion in a qualified Kymriah 

treatment centre in an inpatient and outpatient setting. 

 

Table 5 Study C2201: Baseline information across the enrolled and the infused patient 

populations 

 

 Enrolled 

N=167 

n (%) 

Infused 

N=115 

n (%) 

Age (years)   

 Mean (standard deviation) 56 (12.9) 54 (13.1) 

 Median (minimum – maximum) 58 (22 - 76) 56 (22 - 76) 

Age category (years) - n (%)   

 <65 years 120 (71.9) 89 (77.4) 

 ≥65 years 47 (28.1) 26 (22.6) 

Sex - n (%)   

 Male 105 (62.9) 71 (61.7) 

 Female 62 (37.1) 44 (38.3) 

Prior haematopoietic stem cell transplant 

(SCT) - n (%) 

  

 No 93 (55.7) 59 (51.3) 

 Yes 74 (44.3) 56 (48.7) 

Stage III/IV disease at study entry - n (%)   

 No 36 (21.6) 27 (23.5) 

 Yes 131 (78.4) 88 (76.5) 

Number of prior lines of antineoplastic 

therapy – n (%) 

  

 1 6 (3.6) 5 (4.3) 

 2 73 (43.7) 51 (44.3) 

 3 52 (31.1) 36 (31.3) 

 ≥4 36 (21.6) 23 (20.0) 

Disease status (%)   

 Refractory to last line of therapy 98 (58.7) 63 (54.8) 

 Relapse to last line of therapy 69 (41.3) 52 (45.2) 



20 

 

The efficacy of Kymriah was evaluated through the primary endpoint of best overall response rate 

(ORR), which includes complete response (CR) and partial response (PR) as determined by 

Independent Review Committee (IRC) assessment as well as secondary endpoints including duration 

of response (Table 6). 
 

Table 6 Study C2201: Efficacy results in adult patients with relapsed or refractory diffuse 

large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy 

 

 Enrolled patients 

N=167 

Infused patients 

N=115 

Primary endpoint1 N=147 N=99 

Overall response rate (ORR) (CR+PR)2, n (%) 

95% CI 
53 (36.1) 

(28.3, 44.4) 
53 (53.5) 

(43.2, 63.6) 

CR, n (%) 40 (27.2) 40(40.4) 

PR, n (%) 13 (8.8) 13 (13.1) 

Response at month 3 N=147 N=99 

ORR (%) 39 (26.5) 39 (39.4) 

CR (%) 34 (23.1) 34 (34.3) 

Response at month 6 N=147 N=99 

ORR (%) 34 (23.1) 34 (34.3) 

CR (%) 31 (21.1) 31 (31.3) 

Duration of response (DOR)3 N=53 N=53 

Median (months) (95% CI) Not reached (10.0, NE5) Not reached (10.0, NE5) 

% relapse free probability at 12 months 63.2 63.2 

% relapse free probability at 18 months 63.2 63.2 

Other secondary endpoints N=167 N=115 

Overall survival (OS)4   

% survival probability at 12 months 40.9 47.9 

% survival probability at 24 months 32.5 39.1 

Median (months) (95% CI) 8.2 (5.8, 11.7) 10.3 (6.6, 21.1) 
1 The primary endpoint was analysed on all patients whose Kymriah was manufactured at the Novartis 

US facility. 
2 ORR is the proportion of patients with best overall response (BOR) of CR or PR based on the 

Lugano response criteria (Cheson 2014); non-infused patients were assigned BOR=Unknown (i.e. 

non-responders). 
3 DOR was defined as time from achievement of CR or PR to relapse or death due to DLBCL, 

whichever occurs first. 
4 OS was defined as time from date of Kymriah infusion to the date of death due to any cause (N=115) 

and time from date of enrolment to the date of death due to any cause for enrolled patients (N=167). 
5 Not estimable. 

 

Among the 40 patients who achieved CR, 15 patients initially had an overall disease response of PR 

which improved to CR over time; most patients (13/15) achieved PR to CR conversion within 

6 months post-tisagenlecleucel infusion. ORR was consistent across subgroups. 
 

Special populations 

 

There are not enough data to determine whether there are any differences in efficacy or safety between 

different age subgroups, although the clinical benefit and safety experience in elderly patients with 

DLBCL above the age of 65 years (23% of the study population) were comparable to the overall 

population. 

 



21 

Paediatric population 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Kymriah in one or more subsets of the paediatric population in the following conditions: a) treatment 

of B-cell lymphoblastic lymphoma, and b) treatment of mature B-cell neoplasms (see section 4.2 for 

information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 
Following infusion of Kymriah into paediatric and young adult r/r B-cell ALL and r/r DLBCL 

patients, tisagenlecleucel typically exhibited an initial rapid expansion followed by a slower 

bi-exponential decline. 

 

Cellular kinetics in paediatric and young adult B-cell ALL patients 

 

A summary of cellular kinetic parameters of tisagenlecleucel in paediatric and young adult B-cell ALL 

patients is provided in Table 7 below. The maximal expansion (Cmax) was approximately 1.6-fold 

higher in CR/CRi patients (n=103) compared with non-responding (NR) patients (n=10) as measured 

by qPCR. Delayed and lower expansion was observed in NR patients compared to CR/CRi patients. 

 

Table 7 Cellular kinetic parameters of tisagenlecleucel in paediatric and young adult r/r 

B-cell ALL (Studies B2202 and B2205J) 

 

Parameter Summary statistics Responding patients 

(CR/CRi) 

N=105 

Non-responding 

patients (NR) 

N=12 

Cmax (copies/μg) Geometric mean 

(CV%), n 

35,300 (154.0), 103 21,900 (80.7), 10 

Tmax‡ (day) Median [min;max], n 9.83 [5.70; 27.8], 103 20.1 [12.6; 62.7], 10 

AUC0-28d 
(copies/μg*day) 

Geometric mean 

(CV%), n 

309,000 (178.1), 103 232,000 (104.5), 8 

T½ (day) Geometric mean 

(CV%), n 

25.2 (307.8), 71 3.80 (182.4), 4 

Tlast Median [min;max], n 166 [20.9; 916], 103 28.8 [26.7; 742], 9 

 

 

Cellular kinetics in adult DLBCL patients 

 

A summary of cellular kinetic parameters of tisagenlecleucel in DLBCL patients is provided in 

Table 8 below. 

 

Table 8 Cellular kinetic parameters of tisagenlecleucel in r/r DLBCL patients 

 

Parameter Summary statistics Responding patients 

(CR and PR) 

N=43 

Non-responding patients 

(SD/PD/Unknown) 

N=72 

Cmax (copies/μg) Geometric mean 

(CV%), n 

5,840 (254.3), 43 5,460 (326.89), 65 

Tmax (day) Median [min;max], n 9.00 [5.78; 19.8], 35 8.84 [3.04; 27.7], 65 

AUC0-28d 
(copies/μg*day) 

Geometric mean 

(CV%), n 

61,200 (177.7), 40 67,000 (275.2), 56 

T½ (day) Geometric mean 

(CV%), n 

129 (199.2), 33 14.7 (147.1), 44 

Tlast Median [min;max], n 551 [17.1; 1030], 43 61.4 [19.8; 685], 56 

 



22 

Distribution 

 

In paediatric and young adult B-cell ALL patients, tisagenlecleucel has been shown to be present in 

the blood and bone marrow beyond 2 years. The blood to bone marrow partitioning of tisagenlecleucel 

in bone marrow was 47.2% of that present in blood at day 28 while at months 3 and 6 it distributes at 

68.3% and 69%, respectively (Studies B2202 and B2205J). Tisagenlecleucel also traffics and persists 

in cerebrospinal fluid in paediatric and young adult B-cell ALL patients (Study B2101J) for up to 

1 year. 

 

In adult DLBCL patients (Study C2201), tisagenlecleucel has been detected for up to 3 years in 

peripheral blood and up to month 9 in bone marrow for complete responder patients. The blood to 

bone marrow partitioning in bone marrow was nearly 70% of that present in blood at day 28 and 50% 

at month 3 in both responder and non-responder patients. 

 

Elimination 

 

The elimination profile of Kymriah includes a bi-exponential decline in peripheral blood and bone 

marrow. 

 

Linearity/non-linearity 

 

There is no apparent relationship between dose and AUC0-28d or Cmax. 

 

Special populations 

 

Elderly 

The scatter plots of cellular kinetic parameters versus age (22-76 years) revealed no relevant 

relationship between cellular kinetic parameters (AUC0-28d and Cmax) with age. 

 

Gender 

Gender is not a significant characteristic influencing tisagenlecleucel expansion in B-cell ALL and 

DLBCL patients. In Study B2202, there were 43% female and 57% male patients and in Study C2201 

38% female and 62% male patients who received Kymriah. 

 

Race/ethnicity 

There is limited evidence that race/ethnicity impact the expansion of Kymriah in paediatric and young 

adult ALL and DLBCL patients. In Studies B2202 there were 73.4% Caucasian, 12.7% Asian and 

13.9% other ethnic patients. In Study C2201 there were 85% Caucasian, 9% Asian, 4% Black or 

African American patients, and 3 patients (3%) of unknown race. 

 

Body weight 

In ALL and DLBCL patients, across the weight ranges (ALL; 14.4 to 137 kg; DLBCL: 38.4 to 

186.7 kg), the scatter plots of qPCR cellular kinetic parameters versus weight revealed no apparent 

relationship between cellular kinetic parameters with weight. 

 

Prior transplantation 

Prior transplantation did not impact the expansion/persistence of Kymriah in paediatric and young 

adult B-Cell ALL patients or DLBCL patients. 

 

  



23 

5.3 Preclinical safety data 
 

Non-clinical safety assessment of Kymriah addressed the safety concerns of potential uncontrolled cell 

growth of transduced T cells in vitro and in vivo as well as dose-related toxicity, biodistribution and 

persistence. No such risks were identified based on these studies. 

 

Carcinogenicity and mutagenicity 

 

Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of 

insertional mutagenesis for genetically-modified cell therapy products. No alternative adequate animal 

models are available. 

 

In vitro expansion studies with CAR-positive T cells (Kymriah) from healthy donors and patients 

showed no evidence for transformation and/or immortalisation of T cells. In vivo studies in 

immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell 

expansion for up to 7 months, which represents the longest meaningful observation period for 

immunocompromised mouse models. A genomic insertion site analysis of the lentiviral vector was 

performed on Kymriah products from 14 individual donors (12 patients and 2 healthy volunteers). 

There was no evidence for preferential integration near genes of concern or preferential outgrowth of 

cells harbouring integration sites of concern. 

 

Reproductive toxicity 

 

No non-clinical reproductive safety studies were conducted as no adequate animal model is available. 

 

Juvenile animal studies 

 

Juvenile toxicity studies were not conducted. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Glucose 

Sodium chloride 

Human albumin solution 

Dextran 40 for injection 

Dimethylsulfoxide 

Sodium gluconate 

Sodium acetate 

Potassium chloride 

Magnesium chloride 

Sodium-N-acetyltryptophanate 

Sodium caprylate 

Aluminium 

Water for injections 

 

6.2 Incompatibilities 
 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 

products. 

 



24 

6.3 Shelf life 
 

9 months. 

 

The product should be administered immediately after thawing. After thawing, the product should be 

kept at room temperature (20°C-25°C) and infused within 30 minutes to maintain maximum product 

viability, including any interruption during the infusion. 

 

6.4 Special precautions for storage 

 

Store and transport below -120°C, e.g. in a container for cryogenic storage (Dewar) in the vapour 

phase of liquid nitrogen. 

 

Store in the original protective envelope (Tyvek) containing the cassette protecting the infusion bag. 

 

For storage conditions after thawing of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container and special equipment for use, administration or 

implantation 

 

Ethylene vinyl acetate (EVA) infusion bag with polyvinyl chloride (PVC) tubing and a luer spike 

interconnector closed by a luer-lock cap containing either 10–30 mL (50 mL bags) or 30–50 mL 

(250 mL bags) cell dispersion. 

 

Each infusion bag is placed into an aluminum cassette, then put in a plastic overwrap bag with 

absorbent sheets and sealed in a protective envelope (Tyvek). 

 

One individual treatment dose comprises 1 or more infusion bags. 

 

6.6 Special precautions for disposal and other handling 
 

Inspection and thawing of the infusion bag(s) 

 

Do not thaw the product until it is ready to be used. 

 

The infusion bag should be placed inside a second sterile bag during thawing to protect ports from 

contamination and avoid spills in the unlikely event of the bag leaking. Kymriah should be thawed at 

37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. The 

bag should be removed immediately from the thawing device and kept at room temperature 

(20°C-25°C) until infusion. If more than one infusion bag has been received for the treatment dose, the 

next bag should only be thawed after the contents of the preceding bag have been infused. 

 

Kymriah should not be manipulated. For example, Kymriah should not be washed (spun down and 

resuspended in new media) prior to infusion. 

 

The infusion bag(s) should be examined for any breaks or cracks prior to thawing. If the infusion bag 

appears to have been damaged or to be leaking, it should not be infused and should be disposed of 

according to local procedures on handling of biological waste (see section 4.2.). 

 

Precautions to be taken for transport and disposal of the medicinal product 

 

Kymriah should be transported within the facility in closed, break-proof, leak-proof containers. 

 

Kymriah contains genetically-modified human blood cells. Local guidelines on handling of biological 

waste should be followed for unused medicinal product or waste material. All material that has been in 

contact with Kymriah (solid and liquid waste) should be handled and disposed in accordance with 

local guidelines on handling of biological waste. 



25 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1297/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

23 August 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu 

 

  



26 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



27 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturers of the biological active substance 

 

Fraunhofer Institut für Zelltherapie und Immunologie 

Perlickstrasse 1 

Hauptgebäude und Erweiterungsbau 1 

D-04103 Leipzig 

Germany 

 

Novartis Pharmaceutical Corporation 

220 East Hanover Avenue 

Morris Plains 

New Jersey 

NJ07950 

United States 

 

Novartis Pharma Stein AG 

Novartis Technical Operations Schweiz 

Stein Cell and Gene Therapy, 

Schaffhauserstrasse 

4332 Stein 

Switzerland 

 

CELLFORCURE 

ZA de Courtabœuf 

11 avenue des Tropiques 

91940 Les Ulis 

France 

 

Name and address of the manufacturers responsible for batch release 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

CELLFORCURE 

ZA de Courtabœuf 

11 avenue des Tropiques 

91940 Les Ulis 

France 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 



28 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of 

Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 

and any subsequent updates published on the European medicines web-portal. 

 

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 

6 months following authorisation. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 

marketing authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 Additional risk minimisation measures 
 

Key elements: 

 

Availability of tocilizumab and site qualification 

 

To minimise the risks associated with KYMRIAH treatment, the MAH must ensure that hospitals and 

their associated centres that dispense KYMRIAH are specially qualified in accordance with the agreed 

control distribution programme. 

 

The MAH must ensure on-site, immediate access to tocilizumab for each patient as CRS management 

medication prior to treating patients. Hospitals should have access to additional doses of tocilizumab 

within 8 hours. 

 

KYMRIAH will only be supplied to hospitals and associated centres that are qualified and only if the 

healthcare professionals involved in the treatment of a patient have completed the educational 

programme. 

 

  



29 

Educational programme 

 

Prior to the launch of KYMRIAH in each Member State, the MAH must agree about the content and 

format of the educational materials with the National Competent Authority. 

 

HCP educational programme 

 

The MAH shall ensure that in each Member State where KYMRIAH is marketed, all HCPs who are 

expected to prescribe, dispense annd administer KYMRIAH shall be provided with a guidance 

document to: 

- facilitate identification of CRS and serious neurological adverse reactions 
- facilitate management of the CRS and serious neurological adverse reactions 
- ensure adequate monitoring of CRS and serious neurological adverse reactions 
- facilitate provision of all relevant information to patients 
- ensure that adverse reactions are adequately and appropriately reported 
- ensure that detailed instructions about the thawing procedure are provided 
- before treating a patient, ensure that tocilizumab for each patient are available on site 
 

Patient educational programme 

 

To inform and explain to patients: 

- the risks of CRS and serious neurological adverse reactions associated with KYMRIAH 
- the need to report the symptoms to their treating doctor immediately 
- the need to remain in the proximity of the location where KYMRIAH was received for at least 

4 weeks following KYMRIAH infusion 

- the need to carry the patient alert card at all times 
 



30 

 Obligation to conduct post-authorisation measures 
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Description Due date 

Non-interventional post-authorisation safety study (PASS): In order 

to further characterise the safety – including long-term safety – of 

Kymriah, the applicant should conduct and submit a study based on 

data from a disease registry in ALL and DLBCL patients. 

Update reports: 

Annual safety reports and 

5-yearly interim reports 

 

Final report of study results: 

December 2038 

Post-authorisation efficacy study (PAES): In order to further 

evaluate the efficacy and safety of Kymriah in ALL patients below 

the age of 3 years, the applicant should conduct and submit a study 

based on data from a disease registry in ALL patients. 

Update reports: 

Included as part of the 

annual reports of the 

non-interventional PASS 

 

Final report: December 

2023 

Post-authorisation efficacy study (PAES): In order to further 

evaluate the efficacy of Kymriah in patients with relapsed/refractory 

DLBCL, the applicant should conduct and submit a prospective, 

observational study in patients with r/r DLBCL based on data from 

registry with efficacy outcome measures in line with study C2201, 

including details of the manufacturing turnaround time (i.e. time 

from last relapse or confirmed refractory status, time from decision 

to treat, and time from leukapheresis to infusion). 

June 2022 

Post-authorisation efficacy study (PAES): In order to further 

characterise the long-term efficacy and safety of Kymriah in 

relapsed/refractory DLBCL, the applicant should submit the 

24 months follow-up of all infused patients from study C2201. In 

addition the applicant should submit the final CSR including 5 years 

of follow-up. 

Updated report: 

November 2020 

 

Final CSR: August 2023 

Post-authorisation efficacy study (PAES): In order to further 

characterise the long-term efficacy and safety of Kymriah in 

relapsed/refractory DLBCL, the applicant should submit the results 

of study CCTL019H2301 – open-label, Phase III study of Kymriah 

versus standard of care in adult patients with relapsed or refractory 

aggressive B-cell non-Hodgkin lymphoma. 

June 2022 

 

  



31 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



32 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



33 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

INFUSION BAG LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kymriah 1.2 x 106 – 6 x 108 cells dispersion for infusion 

tisagenlecleucel (CAR+ viable T cells) 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Autologous human T cells genetically modified ex vivo using a lentiviral vector encoding an 

anti-CD19 chimeric antigen receptor (CAR). 

Contains 1.2 x 106 to 6 x 108 CAR+ viable T cells. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains: glucose, sodium chloride, human albumin solution, dextran 40 for injection, 

dimethylsulfoxide, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, 

sodium-N-acetyltryptophanate, sodium caprylate, aluminium, water for injections. See leaflet for 

further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersion for infusion 

10 mL - 50 mL per bag. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Intravenous use 

Do not use leukocyte depleting filter. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

For autologous use only. 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



34 

9. SPECIAL STORAGE CONDITIONS 

 

Store and transport below -120°C; do not thaw the product until use. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Contains genetically-modified cells. 

Dispose of as per local guideline on handling of biological waste. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1297/001 10 – 50 ml 

 

 

13. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

Name: 

Date of birth: {DD MMM YYYY} 

Aph ID/DIN: 

Batch: 

Bag x 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

Not applicable 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

Not applicable  



35 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



36 

Package leaflet: Information for the patient or carer 
 

Kymriah 1.2 x 106 – 6 x 108 cells dispersion for infusion 

tisagenlecleucel (CAR+ viable T cells) 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you (or your child) are given this medicine because it 

contains important information. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 

- Your doctor will give you a Patient Alert Card. Read it carefully and follow the instructions on 
it. 

- Always show the Patient Alert Card to the doctor or nurse when you see them or if you go to 
hospital. 

- The information in this leaflet is for you or your child – but in the leaflet it will just say “you”. 
 

What is in this leaflet 
1. What Kymriah is and what it is used for 

2. What you need to know before you are given Kymriah 

3. How Kymriah is given 

4. Possible side effects 

5. How to store Kymriah 

6. Contents of the pack and other information 

 

 

1. What Kymriah is and what it is used for 

 

What Kymriah is 

Kymriah, also known as tisagenlecleucel, is made from some of your own white blood cells called T 

cells. T cells are important for your immune system (the body’s defences) to work properly. 

 

How does Kymriah work? 

The T cells are taken from your blood and a new gene is put into the T cells so that they can target the 

cancer cells in your body. When Kymriah is infused into your blood, the modified T cells will find and 

kill the cancer cells. 

 

What Kymriah is used for 

Kymriah is used to treat: 

 B-cell acute lymphoblastic leukaemia (B-cell ALL) - a form of cancer that affects some other 
types of white blood cells. The medicine can be used in children and young adults up to and 

including 25 years of age with this cancer. 

 Diffuse large B-cell lymphoma (DLBCL) - another form of cancer that affects some types of 
white blood cells, mostly in the lymph nodes. The medicine can be used in adults (18 years of 

age or older) with this cancer. 

 

If you have any questions about how Kymriah works or why this medicine has been prescribed for 

you, ask your doctor. 

 

 



37 

2. What you need to know before you are given Kymriah 

 

You should not be given Kymriah: 

 if you are allergic to any of the ingredients of this medicine (listed in section 6). If you think 
you may be allergic, ask your doctor for advice. 

 

Warnings and precautions 

Kymriah is made from your own white blood cells and should only be given to you. 

 

Before you are given Kymriah you should tell your doctor if: 

 You have had a stem cell transplant in the last 4 months. Your doctor will check if you have 
signs or symptoms of graft-versus-host disease. This happens when transplanted cells attack 

your body, causing symptoms such as rash, nausea, vomiting, diarrhoea and bloody stools. 

 You have any lung, heart or blood pressure (low or raised) problems. 

 You notice the symptoms of your cancer are getting worse. If you have leukaemia this might 
include fever, feeling weak, bleeding gums, bruising. If you have lymphoma, this might include 

unexplained fever, feeling weak, night sweats, sudden weight loss. 

 You have an infection. The infection will be treated before the Kymriah infusion. 

 You have had hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection. 

 You are pregnant, think you may be pregnant, or plan to become pregnant (see sections 
“Pregnancy and breast-feeding” and “Contraception for women and men” below). 

 You had a vaccination in the previous 6 weeks or are planning to have one in the next few 
months. 

If any of the above apply to you (or you are not sure), talk to your doctor before being given Kymriah. 

 

Test and checks 

Before you are given Kymriah your doctor will: 

 Check your lungs, heart and blood pressure. 

 Look for signs of infection; any infection will be treated before you are given Kymriah. 

 Check if your lymphoma or leukaemia is getting worse. 

 Look for signs of graft-versus-host disease that can happen after a transplant. 

 Check your blood for uric acid and for how many cancer cells there are in your blood. This will 
show if you are likely to develop a condition called tumour lysis syndrome. You may be given 

medicines to help prevent the condition. 

 Check for hepatitis B, hepatitis C or HIV infection. 
 

After you have been given Kymriah 

Tell your doctor or nurse immediately if you have any of the following: 

 Fever, which may be a symptom of an infection. Your doctor will regularly check your blood 
counts as the number of blood cells and other blood components may decrease. 

 Take your temperature twice a day for 3-4 weeks after treatment with Kymriah. If your 
temperature is high, see your doctor immediately. 

 Extreme tiredness, weakness and shortness of breath, which may be symptoms of a lack of red 
blood cells. 

 Bleeding or bruising more easily, which may be symptoms of low levels of cells in the blood 
known as platelets. 

 

There may be an effect on the results of some types of HIV test – ask your doctor about this. 

 

Your doctor will regularly monitor your blood counts after you receive Kymriah as you may 

experience a reduction in the number of blood cells and other blood components. 

 

Do not donate blood, organs, tissues or cells. 

 



38 

Children and adolescents 

 No formal studies have been performed in paediatric patients below 3 years of age in B-cell 
ALL. 

 Kymriah should not be used in children and adolescents below 18 years of age to treat DLBCL. 
This is because Kymriah has not been studied in this age group. 

 

Other medicines and Kymriah 
Tell your doctor if you are taking, have recently taken or might take any other medicines, including 

medicines obtained without a prescription. This is because other medicines can affect the way 

Kymriah works. 

 

In particular, you must not be given certain vaccines called live vaccines: 

 in the 6 weeks before you are given the short course of chemotherapy (called lymphodepleting 
chemotherapy) to prepare your body for the Kymriah cells. 

 during Kymriah treatment. 

 after treatment while the immune system is recovering. 
Talk to your doctor if you need to have any vaccinations. 

 

Before you are given Kymriah tell your doctor or nurse if you are taking any medicines that weaken 

your immune system such as corticosteroids, since these medicines may interfere with the effect of 

Kymriah. 

 

Pregnancy and breast-feeding 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before being given this medicine. This is because the effects of Kymriah in 

pregnant or breast-feeding women are not known, and it may harm your unborn baby or your 

newborn/infant. 

 If you become pregnant or think you may be pregnant after treatment with Kymriah, talk your 
doctor immediately. 

 You will be given a pregnancy test before treatment starts. Kymriah should only be given if the 
result shows you are not pregnant. 

 

Contraception for women and men 

Discuss pregnancy with your doctor if you have received Kymriah. 

 

Driving and using machines 
Do not drive, use machines, or take part in activities that need you to be alert for. Kymriah can cause 

problems such as altered or decreased consciousness, confusion and seizures (fits) in the 8 weeks 

following infusion. 

 

Kymriah contains sodium, dimethylsulfoxide (DMSO) and dextran 40. 

This medicine contains 24.3 to 121.5 mg sodium per dose. This is equivalent to 1 to 6% of the 

recommended maximum daily dietary intake of 2 g sodium for an adult. If you have not been 

previously exposed to dextran or DMSO you should be observed closely during the first minutes of the 

infusion period. 

 

 

  



39 

3. How Kymriah is given 

 

Kymriah will always be given to you by a doctor in a qualified treatment centre. 

 

Kymriah contains human blood cells. Your doctor handling Kymriah will therefore take appropriate 

precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases. 

 

Giving blood to make Kymriah 

Kymriah is made from your own white blood cells. 

 Your doctor will take some of your blood using a catheter placed in your vein (a procedure 
called leukapheresis). Some of your white blood cells are separated from your blood and the rest 

of your blood is returned to your vein. This can take 3 to 6 hours and may need to be repeated. 

 Your white blood cells are frozen and sent away to make Kymriah. It usually takes about 3 to 
4 weeks to make Kymriah but the time may vary. 

 Kymriah is a treatment that is manufactured specifically for you. There are situations where 
Kymriah cannot be successfully manufactured and be given to you. In some cases, a second 

manufacturing of Kymriah may be attempted. 

Before you are given Kymriah, your doctor may give you a type of treatment called lymphodepleting 

chemotherapy for a few days to prepare your body. 

 

Cancer treatment while Kymriah is being made 

During the period while Kymriah is being made, your lymphoma or leukaemia may get worse and 

your doctor may decide to use an additional treatment (a type of chemotherapy known as “bridging 

therapy”) to stabilise your cancer by stopping new cancer cells from developing. This treatment may 

lead to side effects and these may be severe or life-threatening. Your doctor will inform you of the 

potential side effects of this treatment. 

 

Medicines given immediately before Kymriah treatment 

During the 30 to 60 minutes before you are given Kymriah you may be given other medicines. This is 

to help prevent infusion reactions and fever. These other medicines may include: 

 Paracetamol 

 An antihistamine such as diphenhydramine. 
 

How you are given Kymriah 

 Your doctor will check that the individual patient identifiers on the Kymriah infusion bag match 
up to you. 

 Your doctor will give you Kymriah by infusion, which means it will be given as a drip through 
a tube in your vein. This usually takes less than 1 hour. 

 Kymriah is a one-time treatment. 
 

After you are given Kymriah 

 Plan to stay within 2 hours’ travel from the hospital where you were treated for at least 4 weeks 
after you have been given Kymriah. Your doctor will recommend that you return to the hospital 

daily for at least 10 days and will consider whether you need to stay at the hospital as an 

in-patient for the first 10 days after infusion. This is so your doctor can check if your treatment 

is working and help you if you have any side effects. 

 

If you miss an appointment, call your doctor or the hospital as soon as possible to reschedule. 

 

 

  



40 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Tell your doctor immediately if you get any of the following side effects after the Kymriah infusion. 

They usually happen in the first 8 weeks after the infusion, but can also develop later: 

 

Very common: may affect more than 1 in 10 people 

 high fever and chills. These may be symptoms of a serious condition called cytokine release 
syndrome which may be life-threatening or fatal. Other symptoms of cytokine release syndrome 

are difficulty breathing, nausea, vomiting, diarrhoea, loss of appetite, fatigue, muscle pain, joint 

pain, swelling, low blood pressure, headache, heart, lung and kidney failure and liver injury. 

These symptoms almost always occur within the first 10 days after infusion. 

 problems such as altered thinking or decreased consciousness, loss of contact with reality, 
confusion, agitation, seizures, difficulty speaking and understanding speech, difficulty walking. 

 feeling warm, fever, chills or shivering, sore throat or mouth ulcers may be signs of an 
infection. Some infections may be life-threatening or fatal. 

 

Common: may affect up to 1 in 10 people 

 Rapid breakdown of tumour cells causing release of their contents into the bloodstream. This 
can interfere with the workings of various body organs, especially the kidneys, heart and 

nervous system (tumour lysis syndrome). 

 

Other possible side effects 

Other side effects are listed below. If these side effects become severe or serious, tell your doctor 

immediately. 

 

Very common: may affect more than 1 in 10 people 

 Pale skin, weakness, breathlessness due to low number of red blood cells or low haemoglobin 

 Excessive or prolonged bleeding or bruising due to low number of platelets 

 Fever with dangerously low white blood cell count 

 Increased risk of infection due to abnormally low number of white blood cells 

 Frequent and persistent infections due to decreased antibodies in your blood 

 Weakness, abnormal heart rhythms, muscle spasms/cramping due to abnormal low level of 
blood salts including phosphorus, calcium, potassium, magnesium 

 High levels of liver enzymes or creatinine in the blood that show that your liver or kidneys are 
not working normally 

 Anxiety, irritability 

 Fast or irregular heart beat 

 Raised blood pressure 

 Shortness of breath, laboured breathing, rapid breathing, fluid in the lungs 

 Cough 

 Abdominal pain, constipation 

 Skin rash 

 Difficulty sleeping 

 Swollen ankles, limbs and face 
 

  



41 

Common: may affect up to 1 in 10 people 

 Fever, malaise, enlarged liver, yellow colour of your skin and eyes, low blood cell counts due to 
severe immune activation 

 Dizziness or fainting, flushing, rash, itching, fever, shortness of breath or vomiting, abdominal 
pain, diarrhoea due to infusion related reaction 

 Rash, nausea, vomiting, diarrhoea including bloody stools (possible symptoms of graft-versus-
host disease which is when transplanted cells attack your cells) 

 Pain in the joints due to high level of uric acid 

 Abnormal blood test results (high level of: phosphorus, potassium, calcium, magnesium and 
sodium, an enzyme called alkaline phosphatase to help detect liver disease, fibrin d-dimer, 

serum ferritin; low level of: blood protein called albumin, sodium) 

 Convulsion, fits (seizures) 

 Involuntary or uncontrollable movements 

 Tingling or numbness, difficulty moving because of nerve damage 

 Decreased vision 

 Thirst 

 Weight loss 

 Nerve pain 

 Breathlessness, difficulty breathing when lying down, swelling of the feet or legs (possible 
symptoms of heart failure), stopped heart beat 

 Swelling and pain due to blood clots 

 Swelling due to fluids leaking from blood vessels into the surrounding tissue 

 Bloating and discomfort (abdominal distension),due to an accumulation of fluid in the abdomen 

 Dry mouth, sore mouth, bleeding in the mouth, inflammation in the gums 

 Yellow skin and eyes due to abnormally high levels of bilirubin in the blood 

 Itching 

 Excessive sweating, night sweats 

 Bone and back pain 

 Flu-like illness 

 Failure of multiple organs 
 

Uncommon: may affect up to 1 in 100 people 

 Weakness or paralysis of limbs or face, difficulty speaking (possible symptoms of stroke as a 
result of reduced blood supply) 

 Warm or rapidly reddening skin 

 Cough that produces phlegm or sometimes blood, fever, shortness of breath or difficulty 
breathing 

 

Reporting of side effects 

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 

leaflet. You can also report side effects directly via the national reporting system listed in Appendix 
V. By reporting side effects, you can help provide more information on the safety of this medicine. 

 

 

  



42 

5. How to store Kymriah 

 

The following information is intended for doctors only. 
 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the infusion bag label after EXP. The 

expiry date refers to the last day of that month. 

 

Store and transport below -120°C. Do not thaw the product until it is ready to be used. 

 

Do not use this medicine if the infusion bag is damaged or leaking. 

 

This medicine contains genetically-modified blood cells. Local guidelines on handling of biological 

waste should be followed for unused medicine or waste material. 

 

 

6. Contents of the pack and other information 

 

What Kymriah contains 

 The active substance of Kymriah is called tisagenlecleucel. Each infusion bag of Kmyriah 
contains tisagenlecleucel cell dispersion at a batch-dependent concentration of autologous T 

cells genetically modified to express an anti-CD19 chimeric antigen receptor (CAR-positive 

viable T cells). 1 or more bags contain a total of 1.2 x 106 – 6 x 108 CAR+ viable T cells. 

 The other ingredients are glucose, sodium chloride, human albumin solution, dextran 40 for 
injection, dimethylsulfoxide, sodium gluconate, sodium acetate, potassium chloride, magnesium 

chloride, sodium-N-acetyltryptophanate, sodium caprylate, aluminium, and water for injections. 

See section 2, “Kymriah contains sodium, dimethylsulfoxide (DMSO) and dextran 40”. 

 

What Kymriah looks like and contents of the pack 
Kymriah is a cell dispersion for infusion. It is supplied as an infusion bag containing a cloudy to clear, 

colourless to slightly yellow dispersion of cells. Each bag contains 10 mL to 50 mL of dispersion. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 

 

CELLFORCURE 

ZA de Courtabœuf 

11 avenue des Tropiques 

91940 Les Ulis 

France 

 



43 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 88 04 52 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 
Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 
Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 
Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 
Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



44 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 
 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 



45 

The following information is intended for healthcare professionals only: 

 

Preparation of the infusion bag 

The timing of thaw of Kymriah and of infusion should be coordinated. Confirm the infusion time in 

advance and adjust the start time for thaw so that Kymriah is available for infusion when the recipient 

is ready. Once Kymriah has been thawed and is at room temperature (20°C-25°C), it should be infused 

within 30 minutes to maintain maximum product viability, including any interruption during the 

infusion. 

 

The infusion bag should be placed inside a second, sterile bag during thawing to protect ports from 

contamination and avoid spills in the unlikely event of the bag leaking. Kymriah should be thawed at 

37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. The 

bag should be removed immediately from the thawing device and kept at room temperature 

(20°C-25°C) until infusion. If more than one infusion bag has been received for the treatment dose 

(refer to the batch certificate for number of bags constituting one dose), the next bag should only be 

thawed after the contents of the preceding bag have been infused. 

 

Kymriah should not be manipulated. For example, Kymriah should not be washed (spun down and 

resuspended in new media) prior to infusion. 

 

The infusion bag(s) should be examined for any breaks or cracks prior to thawing. If the infusion bag 

appears to have been damaged or to be leaking, it should not be infused and should be disposed of 

according to local guidelines on handling of biological waste. 

 

Administration 

Kymriah intravenous infusion should be administered by a healthcare professional experienced with 

immunosuppressed patients and prepared to manage anaphylaxis. Ensure that one dose of tocilizumab 

per patient and emergency equipment are available prior to infusion and during the recovery period. 

Hospitals should have access to additional doses of tocilizumab within 8 hours. 

 

The patient’s identity should be matched with the patient identifiers on the infusion bag. Kymriah is 

for autologous use only. Kymriah should be administered as an intravenous infusion using latex-free 

intravenous tubing without a leukocyte depleting filter, at approximately 10 to 20 mL per minute by 

gravity flow. All contents of the infusion bags should be infused. Sterile sodium chloride 9 mg/mL 

(0.9%) solution for injection should be used to prime the tubing prior to infusion as well as rinse it 

afterwards. When the full volume of Kymriah has been infused, the infusion bag should be rinsed with 

10 to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection by back priming to ensure as 

many cells as possible are infused into the patient. 

 

Precautions to be taken before handling or administering Kymriah 

Kymriah contains genetically-modified human blood cells. Local guidelines on handling of biological 

waste should be followed for disposal. 

 

All material that has been in contact with Kymriah (solid and liquid waste) should be handled and 

disposed of as potentially infectious waste in accordance with local guidelines on handling of 

biological waste. 

 

Kymriah should be transported within the facility in closed, break-proof, leak-proof containers. 

 

Kymriah is prepared from autologous blood of the patient collected by leukapheresis. Patient 

leukapheresis material and Kymriah may carry a risk of transmitting infectious viruses to healthcare 

professionals handling the product. Accordingly, healthcare professionals should employ appropriate 

precautions (wearing gloves and glasses) when handling leukapheresis material or Kymriah to avoid 

potential transmission of infectious diseases. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET