Patient Information Leaflet

Kymriah 1.2 × 10^6 – 6 × 10^6 cells dispersion for infusion

tisagenlecleucel (CAR+ viable T cells)
Medicinal product subject to additional monitoring. This will allow rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before you (or your child) are given this medicine as it contains important information.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor.
Your doctor will provide you with a patient alert card. Read it carefully and follow the instructions contained therein.
Always show your patient alert card to your doctor or nurse during visits or if you go to hospital.
If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.
The information in this leaflet is intended for you or your child – but the text will simply refer to “you”.

Contents of this leaflet

What Kymriah is and what it is used for
What you need to know before receiving Kymriah
How Kymriah is administered
Possible side effects
How to store Kymriah
Contents of the pack and other information

1. What Kymriah is and what it is used for

What is Kymriah
Kymriah, also known as tisagenlecleucel, is made from some of your white blood cells called
T cells. T cells are important for the proper functioning of your immune system (the body’s
defences).
How Kymriah works
Your T cells are taken from your blood, and a new gene is inserted into these T cells so that
they can attack cancer cells in your body. When Kymriah is infused into your bloodstream, the modified T cells find the cancer cells and destroy them.
What Kymriah is used for
Kymriah is used to treat:

B-cell acute lymphoblastic leukaemia (B-ALL) – a type of cancer affecting certain 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 when it has not responded to prior treatment, has relapsed two or more times, or has relapsed after a stem cell transplant.
Diffuse large B-cell lymphoma (DLBCL) – a type of cancer affecting certain types of white blood cells, mainly in the lymph nodes. The medicine can be used in adults (18 years of age and older) with this cancer when it has relapsed or did not respond after two or more prior treatments.
Follicular lymphoma (FL) – a type of cancer affecting certain white blood cells called lymphocytes, mainly in the lymph nodes. The medicine can be used in adults (18 years of age and older) with this cancer when it has relapsed or did not respond after two or more prior treatments.

If you have any questions about how Kymriah works or why this medicine has been prescribed for you,
please consult your doctor.

2. What you should know before receiving Kymriah

Do not receive Kymriah:

if you are allergic to any of the ingredients of this medicine (listed in section 6). If you think you may be allergic, consult your doctor.
if you cannot receive a treatment called lymphodepleting chemotherapy, which reduces the number of white blood cells in the blood.

Warnings and precautions
Kymriah is made from your white blood cells and must be given only to you.
Patients treated with Kymriah may develop new types of cancer. Cases have been reported of
patients who, after treatment with Kymriah or similar medicines, developed a cancer originating from a type of white blood cells called T cells. Contact your doctor if you develop new swelling of the glands (lymph nodes) or skin changes, such as new lumps or rashes.
You will be asked to enrol in a registry for at least 15 years to better understand the long-term effects of Kymriah.
Before Kymriah is administered to you, inform your doctor if:

You have had a stem cell transplant within the last 4 months. Your doctor will check for signs or symptoms of graft-versus-host disease. This occurs when transplanted cells attack your body, causing symptoms such as rashes, nausea, vomiting, diarrhoea, and blood in the stool.
You have lung, heart, or blood pressure problems (low or high).
You notice that your tumour symptoms are worsening. If you have leukaemia, this may include fever, feeling weak, bleeding gums, bruising. If you have lymphoma, this may include unexplained fever, feeling weak, night sweats, sudden weight loss.
You have an infection. The infection will be treated before Kymriah infusion.
You have had infections with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV).
You are pregnant, think you may be pregnant, or are planning pregnancy (see the sections “Pregnancy and breastfeeding” and “Contraception for women and men” below).
You have been vaccinated within the past 6 weeks or will be vaccinated in the coming months. If you are in any of the above situations (or are unsure), contact your doctor before Kymriah is administered to you.

Tests and monitoring
Before Kymriah is administered to you, your doctor will:

Check your lungs, heart, and blood pressure.
Look for signs of infection; any infection will be treated before Kymriah is given to you.
Check whether the lymphoma or leukaemia is worsening.
Look for signs of graft-versus-host disease, which may occur after a transplant.
Measure the level of uric acid in your blood and the number of tumour cells present in your blood. This will indicate the likelihood of developing a condition called tumour lysis syndrome. You may be given medicines to help prevent this condition.
Perform tests for infection with hepatitis B virus, hepatitis C virus, or HIV.

After Kymriah has been administered to you
Inform your doctor or nurse immediately if you experience any of the following:

Fever, which may be a sign of infection. Your doctor will regularly monitor your blood counts, as the number of blood cells and other blood components may decrease.
Check your temperature twice daily for 3–4 weeks after receiving Kymriah. If your temperature is high, contact your doctor immediately.
Changes or decreased level of consciousness, delirium, anxiety, dizziness, tremors, headache, confusion, agitation, seizures, difficulty speaking or understanding, and/or loss of balance. These usually occur within the first 8 weeks after infusion but may occur later. These may be symptoms of a condition called immune effector cell-associated neurotoxicity syndrome (ICANS).
Extreme fatigue, weakness, and shortness of breath, which may be symptoms of a lack of red blood cells.
Bleeding or easy bruising, which may be symptoms of low levels of blood cells known as platelets.

Some types of HIV tests may be affected – please consult your doctor.
After receiving Kymriah, your doctor will regularly monitor your blood count, as a reduction in blood cells and other blood components may occur.
Do not donate blood, organs, tissues, or cells.
Children and adolescents

Experience with Kymriah in paediatric patients under 3 years of age is limited.
The use of Kymriah is not recommended in children and adolescents under 18 years of age for the treatment of DLBCL. This is because experience in treating non-Hodgkin lymphoma in this age group is limited.
Kymriah must not be used in children and adolescents under 18 years of age for the treatment of FL. This is because Kymriah has not been studied in this age group.

Other medicines and Kymriah
Inform your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription. This is because other medicines may affect how Kymriah works.
In particular, certain vaccines called live vaccines must not be given:

within the 6 weeks before receiving the short course of chemotherapy (called lymphodepleting chemotherapy) to prepare your body for Kymriah cells.
during treatment with Kymriah.
after treatment while your immune system is recovering. Contact your doctor if you need any vaccinations.

Before Kymriah is administered to you, inform your doctor or nurse if you are taking medicines that weaken the immune system, such as corticosteroids, as these medicines may interfere with the effect of Kymriah.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor before receiving this medicine. This is because the effects of Kymriah in pregnant or breastfeeding women are unknown, and it may harm the unborn child or the breastfed infant.

If you become pregnant or suspect pregnancy during treatment with Kymriah, contact your doctor immediately.
A pregnancy test will be performed before starting treatment. Kymriah should only be administered if the result shows that you are not pregnant.

Contraception for women and men
If you have received Kymriah, discuss the possibility of pregnancy with your doctor.
Driving and using machines
Some people may feel confused or experience problems such as altered or decreased level of consciousness, confusion, and seizures (fits) after receiving Kymriah. Therefore, do not drive, operate machinery, or engage in activities requiring alertness during the 8 weeks following infusion.
Kymriah contains sodium, dimethyl sulfoxide (DMSO), dextran 40, and potassium
This medicine contains 24.3 to 121.5 mg of sodium (a main component of table salt) per dose. This corresponds to 1–6% of the maximum daily recommended dietary intake of sodium for an adult.
This medicine contains dextran 40 and DMSO (substances used to preserve frozen cells), which may occasionally cause difficulty breathing and/or dizziness (possible symptoms of severe allergic or hypersensitivity reactions). You must be closely observed during the infusion period.
This medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e., essentially ‘potassium-free’.

3. How Kymriah is administered

Kymriah will always be administered by a physician at a qualified clinical center for treatment.
Providing blood to produce Kymriah
Kymriah is made from your own white blood cells.

Your doctor will collect your blood using a catheter placed in a vein (a procedure called leukapheresis). Some of your white blood cells will be separated from the blood, and the rest of the blood will be returned into the vein. This procedure may take from 3 to 6 hours and may need to be repeated.
Your white blood cells will be frozen and sent for the production of Kymriah. It usually takes 3 to 4 weeks to produce Kymriah, but the time may vary.
Kymriah is a treatment specifically manufactured for you.
Before administering Kymriah, your doctor may treat you with a type of chemotherapy called lymphodepleting chemotherapy for several days to prepare your body.

Treatment of the tumour during the production of Kymriah
During the time Kymriah is being produced, your lymphoma or leukaemia may worsen, and your
doctor may decide to use an additional treatment (known as “bridging therapy”) to
stabilize the tumour and prevent the development of new tumour cells. This treatment may
cause side effects, which can be serious or life-threatening. Your doctor will inform you about the potential adverse effects of this treatment.
Other medicines given shortly before Kymriah treatment
Within 30–60 minutes before your Kymriah infusion, you may be given other medicines.
These are intended to help prevent infusion reactions and fever. These other medicines
may include:

Paracetamol
An antihistamine such as diphenhydramine.

How Kymriah is administered

Your doctor will check that the patient identifiers on the Kymriah infusion bag match your own.
Your doctor will administer Kymriah by infusion, meaning it will be given as an intravenous drip through a cannula placed in a vein. This usually takes less than 1 hour. During the infusion, your doctor will monitor you for difficulty breathing or dizziness (possible symptoms of an allergic reaction).
Kymriah treatment is intended to be given only once.

After Kymriah administration

For at least 4 weeks after receiving Kymriah, you should remain within a 2-hour travel distance from the hospital where you were treated. During the first week after treatment, your doctor may recommend that you return to the hospital 2 or 3 times, or more frequently. This allows your doctor to monitor whether the treatment is working and to assist you if you experience any adverse effects.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Contact your doctor immediately if you experience any of the following side effects after
receiving Kymriah infusion. These usually occur within the first 8 weeks after infusion, but
may 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 can be life-threatening or fatal. Other symptoms of cytokine release syndrome include difficulty breathing, nausea, vomiting, diarrhoea, loss of appetite, fatigue, muscle pain, joint pain, swelling, low blood pressure, rapid heartbeat, headache, heart, lung and kidney failure, and liver damage. These symptoms almost always occur within the first 14 days after treatment with Kymriah, but in some patients they may develop later.
Problems such as altered thinking or reduced level of consciousness, loss of contact with reality, confusion, agitation, seizures, difficulty speaking and understanding speech, difficulty walking. These may be symptoms of a condition called immune effector cell-associated neurotoxicity syndrome (ICANS). These symptoms mainly occur within the first 8 weeks after treatment with Kymriah, but in some patients they may develop later.
Feeling of warmth, fever, chills or shaking, 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 leading to the release of their contents into the bloodstream. This can interfere with the normal function of various organs in the body, particularly 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 intense,
contact your doctor immediately.
Very common (may affect more than 1 in 10 people)

Pale skin, weakness, shortness of breath due to a low number of red blood cells or low haemoglobin
Excessive or prolonged bleeding or bruising due to a low number of platelets
Fever with a dangerously low white blood cell count
Increased risk of infection due to abnormally low white blood cell count
Frequent and persistent infections due to reduced antibodies in the blood
Weakness, abnormal heart rhythms, due to abnormally low levels of blood salts including phosphate, potassium
High levels of liver enzymes or creatinine in the blood indicating that liver and kidneys are not functioning normally
Increased blood pressure
Shortness of breath, laboured breathing, rapid breathing
Cough
Abdominal pain, constipation
Bone and back pain
Rash
Swelling of ankles, limbs and face

Common (may affect up to 1 in 10 people)

Fever, malaise, enlarged liver, yellowing of the 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 reactions
Rash, nausea, vomiting, diarrhoea including bloody stools (possible symptoms of graft-versus-host disease, which occurs when transplanted cells attack your own cells)
Joint pain due to high levels of uric acid
Abnormal blood test results (high levels of: phosphate, potassium, calcium and sodium, fibrin D-dimer, serum ferritin; low levels of: a blood protein called albumin, sodium, magnesium)
Seizures, fits (convulsions)
Muscle spasms/cramps due to abnormally low levels of blood salts including calcium
Involuntary or uncontrollable movements
Involuntary tremors of the body, difficulty writing, difficulty expressing thoughts verbally, attention disturbance, drowsiness
Tingling or numbness, difficulty moving due to nerve damage
Reduced vision
Thirst, low urine output, dark urine, dry red skin, irritability (possible symptoms of high blood sugar levels)
Weight loss
Nerve pain
Anxiety, irritability
Severe confusion
Difficulty sleeping
Shortness of breath, difficulty breathing when lying down, swelling of feet or legs (possible symptoms of heart failure), rapid or irregular heartbeat, stopped heartbeat
Swelling and pain due to blood clots
Swelling due to leakage of fluid from blood vessels into surrounding tissue
Swelling and discomfort (abdominal distension) due to fluid accumulation in the abdomen
Dry mouth, mouth ulcers, bleeding in the mouth
Yellowing of the skin and eyes due to abnormally high levels of bilirubin in the blood
Itching
Excessive sweating, night sweats
Flu-like illness
Multi-organ failure
Fluid in the lungs
Stuffy nose
Blood clotting disorders (coagulopathy, increased international normalized ratio, prolonged prothrombin time, decreased blood fibrinogen, prolonged activated partial thromboplastin time)

Uncommon (may affect up to 1 in 100 people)

Abnormal blood test results (high levels of magnesium)
Weakness or paralysis of limbs or face, difficulty speaking (possible symptoms of stroke due to reduced blood flow)
Skin that feels hot or rapidly reddens
Cough with phlegm or sometimes blood, fever, shortness of breath or difficulty breathing
Difficulty controlling movement

Rare (may affect up to 1 in 1,000 people)

A new type of cancer originating from a type of white blood cells called T cells (malignant secondary neoplasm of T-cell origin)

Not known (frequency cannot be estimated from the available data)

Difficulty breathing or dizziness (possible symptoms of an allergic reaction)
Weakness or numbness in arms or legs, worsening or loss of vision, fixed and irrational thoughts not shared by others, headache, altered memory or thinking, unusual behaviour

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor.
You may also report side effects directly via the national reporting system listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Kymriah

The following information is intended for physicians only.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the infusion bag label after EXP.
Store and transport at ≤ -120°C. Do not thaw the product until it is ready for use.
Do not use this medicine if the infusion bag is damaged or leaking.

6. Package contents and other information

What Kymriah contains

The active substance is tisagenlecleucel. Each Kymriah infusion bag contains a cellular dispersion of tisagenlecleucel at a batch-dependent concentration of genetically modified autologous T cells expressing a chimeric antigen receptor against CD19 (viable CAR-positive T cells). 1 or more bags contain a total of 1.2 × 10⁶ to 6 × 10⁸ viable CAR+ T cells.
The other components are glucose, sodium chloride, human albumin solution, dextran 40 for injectable preparations, dimethyl sulfoxide (DMSO), sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, sodium N-acetyltryptophanate, sodium caprylate, aluminium, and water for injectable preparations. See section 2, “Kymriah contains sodium, dimethyl sulfoxide (DMSO), dextran 40 and potassium”.

This medicinal product contains cells of human origin.
Description of the appearance of Kymriah and contents of the pack
Kymriah is a cellular dispersion for infusion. It is supplied in an infusion bag containing a dispersion ranging from cloudy to clear, colourless to slightly yellow. Each bag contains 10 mL to 50 mL of dispersion.
Marketing Authorization Holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland
Manufacturer
Novartis Pharma GmbH
Roonstrasse 25
90429 Nuremberg
Germany
Novartis Pharma GmbH
Sophie-Germain-Strasse 10
90443 Nuremberg
Germany
For further information on this medicinal product, please contact the local representative of the Marketing Authorization Holder:
België/Belgique/Belgien Lietuva
Novartis Pharma N.V. SIA Novartis Baltics Lietuvos filialas
Tél/Tel: +32 2 246 16 11 Tel: +370 5 269 16 50
България Luxembourg/Luxemburg
Novartis Bulgaria EOOD Novartis Pharma N.V.
Тел: +359 2 489 98 28 Tél/Tel: +32 2 246 16 11
Česká republika Magyarország
Novartis s.r.o. Novartis Hungária Kft.
Tel: +420 225 775 111 Tel.: +36 1 457 65 00
Danmark Malta
Novartis Healthcare A/S Novartis Pharma Services Inc.
Tlf.: +45 39 16 84 00 Tel: +356 2122 2872
Deutschland Nederland
Novartis Pharma GmbH Novartis Pharma B.V.
Tel: +49 911 273 0 Tel: +31 88 04 52 111
Eesti Norge
SIA Novartis Baltics Eesti filiaal Novartis Norge AS
Tel: +372 66 30 810 Tlf: +47 23 05 20 00
Ελλάδα Österreich
Novartis (Hellas) A.E.B.E. Novartis Pharma GmbH
Τηλ: +30 210 281 17 12 Tel: +43 1 86 6570
España Polska
Novartis Farmacéutica, S.A. Novartis Poland Sp. z o.o.
Tel: +34 93 306 42 00 Tel.: +48 22 375 4888
France Portugal
Novartis Pharma S.A.S. Novartis Farma - Produtos Farmacêuticos, S.A.
Tél: +33 1 55 47 66 00 Tel: +351 21 000 8600
Hrvatska România
Novartis Hrvatska d.o.o. Novartis Pharma Services Romania SRL
Tel. +385 1 6274 220 Tel: +40 21 31299 01
Ireland Slovenija
Novartis Ireland Limited Novartis Pharma Services Inc.
Tel: +353 1 260 12 55 Tel: +386 1 300 75 50
Ísland Slovenská republika
Vistor hf. Novartis Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 2 5542 5439
Italia Suomi/Finland
Novartis Farma S.p.A. Novartis Finland Oy
Tel: +39 02 96 54 1 Puh/Tel: +358 (0)10 6133 200
Κύπρος Sverige
Novartis Pharma Services Inc. Novartis Sverige AB
Τηλ: +357 22 690 690 Tel: +46 8 732 32 00
Latvija
SIA Novartis Baltics
Tel: +371 67 887 070
Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website, https://www.ema.europa.eu/

The following information is intended exclusively for healthcare professionals:

Precautions to be taken before handling or administration of the
medicinal product
Kymriah must be transported within the facility in closed, non-breakable and hermetically sealed containers.
This medicinal product contains human blood cells. Healthcare professionals handling Kymriah must take appropriate precautions (wear gloves and protective eyewear) to avoid potential transmission of infectious diseases.
Preparation prior to administration
Prior to administration, it is necessary to verify that the patient's identity matches the unique patient information on the Kymriah infusion bags and accompanying documentation. Also verify the total number of infusion bags to be administered against the patient-specific information on the lot-specific documentation accompanying the medicinal product.
The thawing and infusion times of Kymriah must be coordinated. The infusion start time must be confirmed in advance and scheduled appropriately to allow for thawing so that Kymriah is available for infusion when the patient is ready. Once thawed and at room temperature (20°C–25°C), Kymriah must be infused within 30 minutes to maintain maximum product viability, including any interruptions during infusion.
Inspection and thawing of the infusion bag(s)
Do not thaw the product until it is ready for use.
During thawing, the infusion bag must be placed inside a second sterile bag to protect the infusion ports from contamination and to prevent leakage in the unlikely event that the bag leaks. Kymriah must be thawed at 37°C using a water bath or a dry thawing method until no visible ice remains in the infusion bag. The bag must 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 lot certificate for the number of bags constituting a dose), the next bag should only be thawed after the contents of the previous bag have been infused.
Kymriah must not be manipulated. For example, Kymriah must not be washed (centrifuged and resuspended in a new solution) prior to infusion.
The infusion bag(s) must be inspected for any tears or cracks before thawing. If the infusion bag appears damaged or leaking, it must not be used for infusion and must be disposed of according to local guidelines for the management of biological waste.
Administration
Intravenous infusion of Kymriah must be administered by a healthcare professional experienced in managing immunosuppressed patients and prepared to manage anaphylaxis. In the event of cytokine release syndrome (CRS), ensure that at least one dose of tocilizumab per patient and emergency equipment are available prior to infusion. Hospitals must have access to additional doses of tocilizumab within 8 hours. In the exceptional case where tocilizumab is unavailable due to a shortage listed in the European Medicines Agency’s catalogue of shortages, ensure that adequate alternative on-site measures are available for the treatment of cytokine release syndrome.
The patient’s identity must match the patient identifiers on the infusion bag. Kymriah is intended exclusively for autologous use and must under no circumstances be administered to other patients.
Kymriah must be administered as an intravenous infusion using a latex-free, leucocyte-depleting filter-free intravenous line at a flow rate of approximately 10–20 mL/minute by gravity. The entire contents of each infusion bag must be infused. A 9 mg/mL (0.9%) sodium chloride injectable solution must be used to prime the infusion line before infusion and to flush the line after infusion. Once the entire volume of Kymriah has been infused, the infusion bag must be flushed with 10–30 mL of 9 mg/mL (0.9%) sodium chloride injectable solution by back-flushing to ensure that the maximum possible number of cells are infused into the patient.
If the volume of Kymriah to be administered is ≤20 mL, rapid intravenous bolus injection may be used as an alternative administration method.
Measures to be taken in case of accidental exposure
In case of accidental exposure, follow local guidelines for handling human-derived materials. Work surfaces and materials that may have come into contact with Kymriah must be decontaminated with an appropriate disinfectant.
Precautions to be taken for disposal of the medicinal product
Unused medicinal product and all materials that have come into contact with Kymriah (solid and liquid waste) must be handled and disposed of as potentially infectious waste in accordance with local guidelines for handling human-derived materials.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION OF THE TERMS OF THE
MARKETING AUTHORISATIONS

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for tisagenlecleucel, the scientific conclusions of the PRAC are as follows:
In light of available data indicating a higher frequency of immune effector cell-associated neurotoxicity syndrome (ICANS) from literature and spontaneous reports, and considering a plausible mechanism of action, the PRAC considers a causal relationship between tisagenlecleucel and ICANS. The PRAC concluded that the product information for medicinal products containing tisagenlecleucel should therefore be amended.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and rationale of the recommendation.

Grounds for the variation of the terms of the marketing authorisations
Based on the scientific conclusions on tisagenlecleucel, the CHMP considers that the benefit-risk balance of medicinal products containing tisagenlecleucel remains favourable, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisations.