Label: information for the patient or caregiver

Kymriah 1,2×106a 6,0×108cells for infusion

tisagenlecleucel(viable T-cellsT-CAR+)

This medicine is subject to additional monitoring, which will expedite the detection of new information about its safety. You may contribute by reporting any adverse effects you experience. The final part of section4 includes information on how to report these adverse effects.

Read this label carefully before starting to administer this medicine to you (or your child), because it contains important information.

• Keep this label, as you may need to refer to it again.

• If you have any doubts, consult your doctor.

• Your doctor will provide you with a patient information leaflet. Read it carefully and follow their instructions.
• Always show the patient information leaflet to your doctor or nurse when you see them or visit a hospital.
• If you experience adverse effects, consult your doctor, even if they are not listed in this label. See section4.
• The information in this label is for you or your child – but in the label, it will only refer to you.

1.What Kymriah is and how it is used

2.What you need to know before starting to receiveKymriah

3.How Kymriah is administered

4.Possible adverse effects

5.Storage of Kymriah

6.Contents of the package and additional information

What isKymriah

Kymriah, also known as tisagenlecleucel, is made from your own white blood cells, called T lymphocytes (T cells). The T cells are necessary for your immune system (your body's defenses) to function correctly.

How it worksKymriah

The T cells are taken from your blood and a new gene is added to the T cells that allows them to target cancer cells in your body.When you receive Kymriah and it enters your blood, the modified T cells will recognize the cancer cells and destroy them.

What is it used forKymriah

Kymriah is used to treat:

• Acute Lymphoblastic Leukemia (ALL) of B cells– a type of cancer that affects different white blood cells. The medication may be used in children and young adults up to 25 years of age, inclusive, with this disease when they did not respond to previous treatments, have relapsed two or more times, or have relapsed after a bone marrow transplant.
• Diffuse Large B-Cell Lymphoma (DLBCL)– a type of cancer that affects different white blood cells, mainly in the lymph nodes. The medication may be used in adults (18 years of age or older) with this disease when it has relapsed or does not respond to two or more previous treatments.
• Follicular Lymphoma (FL)– a type of cancer that affects different white blood cells, called lymphocytes, mainly in the lymph nodes. The medication may be used in adults (18 years of age or older) with this disease when it has relapsed or does not respond to two or more previous treatments.

If you have any questions about how Kymriah works or why you have been prescribed this medication, ask your doctor.

You should not receive Kymriah

• if you are allergic to any of the components of this medication (listed in section6).If you think you may be allergic, ask your doctor
• if you cannot receive lymphocyte-reducing chemotherapy, which reduces the number of white blood cells in your blood

Warnings and precautions

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

Patients treated with Kymriah may develop new types of cancer. Cases of patients developing cancer, starting with a type of white blood cells called T lymphocytes, have been reported after treatment with Kymriah and similar medications. Consult your doctor if you experience any new lymph node inflammation or skin changes, such as new rashes or lumps.

You will be asked to enroll in a registry for at least 15years to better understand the long-term effects of Kymriah.

Before Kymriah is administered, you must tell your doctor if:

• You have received a hematopoietic stem cell transplant in the last 4months. Your doctor will check for signs or symptoms of graft-versus-host disease. This occurs when the transplanted cells attack your body, causing symptoms such as rash, nausea, vomiting, diarrhea, and blood in stool.
• You have lung, heart, or blood pressure problems (high or low).
• Your cancer symptoms worsen. If you have leukemia, this would be fever, feeling weak, bleeding gums, bruises. If you have lymphoma, this would be unexplained fever, night sweats, sudden weight loss.
• You have an infection. You must treat the infection before Kymriah infusion.
• You have hepatitisB, hepatitisC, or human immunodeficiency virus (HIV) infection.
• You are pregnant, think you may be pregnant, or plan to become pregnant (see the sections “Pregnancy and breastfeeding” and “Contraception for women and men” below).
• You were vaccinated in the last 6weeks or plan to be vaccinated in the coming months.

If any of the above applies (or you are unsure), talk to your doctor before Kymriah is administered.

Tests and examinations

Before Kymriah administration, your doctor will:

• Examine your lungs, heart, and blood pressure.
• Look for signs of infection; any infection must be treated before Kymriah is administered.
• Check if your lymphoma or leukemia has worsened.
• Look for signs of graft-versus-host disease that may appear after a transplant.
• Check your blood uric acid and cancer cells in your blood. This will indicate if you may develop a condition called tumor lysis syndrome. You may be given medications to prevent this condition.
• Check if you have hepatitisB, hepatitisC, or HIV infection.

After Kymriah administration

Inform your doctor or nurse immediately if you experience any of the following symptoms:

• Fever, which could be a sign of an infection. Your doctor will regularly check your blood count as it may decrease the number of blood cells and other blood components.
• Take your temperature twice a day for 3‑4weeks after Kymriah administration. If your temperature rises, go to your doctor immediately.
• Extreme fatigue, weakness, and shortness of breath, which could be a sign of low red blood cell count.
• Frequent bleeding or bruising, which could be a sign of low blood cell counts, such as platelets.

You may experience an effect on the results of some types of HIV tests – ask your doctor about this.

After receiving Kymriah, your doctor will regularly check your blood count as you may experience a decrease in the number of blood cells and other blood components.

You should not donate blood, organs, tissues, or cells.

Children and adolescents

• There is very little experience with Kymriah in pediatric patients under 3years of age.
• Kymriah is not recommended for children or adolescents under 18years for the treatment of B-cell lymphoma. This is because there is very little experience in the treatment of non-Hodgkin lymphoma in this age group..
• Kymriah should not be used in children or adolescents under 18years for the treatment of leukemia. This is because Kymriah has not been studied in this age group.

Other medications and Kymriah

Inform your doctor if you are taking, have taken recently, or may need to take any other medication, including over-the-counter medications. This is because other medications may affect how Kymriah works.

Particularly, do not receive certain live vaccines:

• 6weeks before a short cycle of chemotherapy (called lymphocyte-reducing chemotherapy), which prepares your body for Kymriah cells.
• during your Kymriah treatment.
• after your treatment until your immune system has recovered.

Talk to your doctor if you need to be vaccinated.

Before Kymriah is administered, inform your doctor or nurse if you are taking other medications that may weaken your immune system, such as corticosteroids, as these medications may interfere with Kymriah's effect.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before receiving this medication. This is because the effect of Kymriah on pregnant or breastfeeding women is unknown and may be harmful to the fetus/baby.

• If you become pregnant or plan to become pregnant after treatment with Kymriah, talk to your doctor immediately.
• Before starting treatment, a pregnancy test will be performed. Kymriah can only be administered if the test shows you are not pregnant.

Contraception for women and men

You should discuss pregnancy with the doctor who treated you after receiving Kymriah.

Driving and using machines

Some people may feel confused, have problems such as altered or decreased consciousness, confusion, or seizures (fits) after receiving Kymriah. Therefore, do not drive, use machines, or participate in activities that require you to be alert for 8weeks after infusion.

Kymriah containssodium, dimethyl sulfoxide (DMSO), dextran40, and potassium

This medication contains 24.3mg to 121.5mg of sodium (main component of table salt/food seasoning) per dose. This is equivalent to 1 to 6% of the maximum daily recommended sodium intake for an adult.

This medication contains dextran40 and DMSO (substances used to preserve frozen cells), which may cause allergic reactions. You will be under observation during infusion.

This medication contains potassium, less than 1mmol (39mg) per dose; this is essentially potassium-free.

Kymriah will always be administered by your doctor in a qualified treatment center.

Extracting blood to make Kymriah

Kymriah is made from your own white blood cells.

• Your doctor will extract blood using a catheter placed in your vein (a procedure called leucaféresis). Some white blood cells will be taken from your blood and the rest will be returned to you through a vein. This may take 3 to 6 hours and may need to be repeated.
• Your white blood cells will be frozen and sent to make Kymriah for you. The manufacturing of Kymriah usually takes 3 to 4 weeks, but may vary.
• Kymriah is a medication made specifically for you.

• Before Kymriah is administered to you, your doctor may administer a type of treatment called lymphocyte-reducing chemotherapy for a few days to prepare your body.

Treatment for cancer while Kymriah is being made

During the time Kymriah is being made, your leukemia or lymphoma may worsen and your doctor may decide to use an additional treatment (called a "bridge treatment") to stabilize the cancer and prevent cancer cells from multiplying. This treatmentmay cause you severe side effects that could be life-threatening. Your doctor will inform you of the possible side effects of this treatment.

Other medications administered just before Kymriah treatment

30 to 60 minutes before Kymriah is administered to you, you will be given other medications. This is to help prevent infusion reactions and fever. These other medications may be:

• Paracetamol
• An antihistamine such as diphenhydramine.

How Kymriah is administered

• Your doctor will check that the patient identification data on the Kymriah infusion bag matches you.
• Your doctor will administer Kymriah by infusion, which means they will put a drip through a tube placed in a vein. This usually takes less than 1 hour. During the infusion, your doctor will check if you have breathing problems or dizziness (possible symptoms of an allergic reaction).
• Kymriah is a single-dose treatment.

After Kymriah administration

• Plan to stay near the hospital (no more than 2 hours of travel time) where you were treated for at least 4 weeks after Kymriah was administered to you. Your doctor will recommend that you visit the hospital every day at least until the 10th day and will assess the need for you to be hospitalized for the first 10 days after the infusion. This is to allow your doctor to check that your treatment is working and to help you if you have any side effects.

Missing an appointment

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor immediatelyif you experience any of the following side effects after receiving the Kymriah infusion. They usually appear within 8weeks after the infusion, but can also appear later:

Very common: can affect more than 1 in 10people

• High fever and chills can be symptoms of a serious disease called cytokine release syndrome that can be life-threatening or fatal. Other symptoms of cytokine release syndrome are difficulty breathing, nausea, vomiting, diarrhea, 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 usually appear within the first14days after the infusion
• Problems such as altered thinking or decreased consciousness, loss of contact with reality, confusion, agitation, seizures, difficulty speaking and understanding, difficulty walking. These could be symptoms of a disease called immune effector cell-associated neurotoxicity syndrome (ICANS, in English).
• Sensation of heat, fever, chills, or tremors, sore throat, or mouth sores, could be signs of an infection. Some infections can be life-threatening or fatal.

Common: can affect up to 1 in 10people

• Rapid destruction of tumor cells that causes the release of their contents into the bloodstream. This can interfere with the functioning of several organs in the body, especially the kidneys, heart, and nervous system (tumor lysis syndrome)

Other possible side effects

The following are other possible side effects. If these side effects become severe or serious, inform your doctor immediately.

Very common(can affect more than 1 in 10people)

• Pallor, weakness, difficulty breathing due to low red blood cell count or low hemoglobin
• Bleeding or bruising that is excessive or prolonged due to low platelet count
• Fever with very low white blood cell count
• Increased risk of infections due to very low white blood cell count
• Frequent and persistent infections due to low levels of antibodies in the blood
• Weakness, abnormal heart rhythm, due to abnormally low levels of phosphate, potassium in the blood
• Abnormally high levels of liver enzymes or creatinine in the blood that show that the liver or kidneys are not functioning correctly
• High blood pressure
• Labored breathing, difficulty breathing, rapid breathing
• Cough
• Abdominal pain, constipation
• Back pain, bone pain
• Rash
• Swollen ankles, swelling of the extremities and face

Common(can affect up to 1 in 10people)

• Fever, discomfort, liver enlargement, yellow skin and eyes, low blood cell count due to severe immune activation
• Dizziness or fainting, redness, rash, fever, shortness of breath or vomiting, abdominal pain, diarrhea due to a reaction to the infusion
• Rash, nausea, vomiting, diarrhea including bloody stools (possible symptoms of graft-versus-host disease that occurs when transplanted cells attack the recipient's cells)
• Joint pain due to high levels of uric acid
• Abnormal blood test results (elevated levels of: phosphate, potassium, calcium, and sodium, d-dimer of fibrin, serum ferritin; low levels of a blood protein called albumin, sodium, magnesium)
• Seizures, attacks (epileptic seizures)
• Muscle spasms/cramps due to abnormally low levels of calcium salts
• Involuntary movements
• Involuntary body jerks, difficulty writing, difficulty expressing thoughts verbally, attention problems, drowsiness
• Numbness or tingling, difficulty moving due to nerve damage
• Decreased vision
• Thirst, low urine production, dark urine, dry skin, and redness, irritability (possible symptoms of high blood sugar)
• Weight loss
• Nerve pain
• Anxiety, irritability
• Severe confusion
• Difficulty sleeping
• Shortness of breath, difficulty breathing when lying down, swelling of feet and legs (possible symptoms of heart failure), rapid and irregular heartbeat, heart stoppage
• Swelling and pain due to blood clots
• Swelling due to bleeding of blood vessels into adjacent tissues
• Swelling and discomfort (abdominal distension) due to accumulation of fluid in the abdomen
• Dry mouth, mouth pain, bleeding gums
• Yellow skin and eyesdue to abnormally high levels of bilirubin
• Itching
• Excessive sweating, night sweats
• Flu-like symptoms
• Multi-organ failure
• Liquid in the lungs
• Stuffy nose
• Bleeding disorder (coagulopathy, increased international normalized ratio, prolonged prothrombin time, decreased fibrinogen, prolonged activated partial thromboplastin time)

Uncommon(can affect up to 1 in 100people)

• Abnormal blood test results (elevated levels of magnesium)
• Weakness or paralysis of the limbs or face, difficulty speaking (possible symptoms of a stroke due to decreased blood flow)
• Heat and redness of the skin
• Cough that produces mucus or sometimes with blood, fever, shortness of breath or difficulty breathing.
• Difficulty controlling movements

Rare(can affect up to 1 in 10,000people)

• A new type of cancer that begins in a type of white blood cells called T cells (secondary neoplasm of origin from T cells)

Unknown(cannot be estimated from available data)

• Difficulty breathing or dizziness (possible symptoms of an allergic reaction)
• Weakness or numbness of arms and legs, worsening or loss of vision, having fixed and irrational thoughts that are not shared by others, headache, deterioration of memory or thought, unusual behavior

Reporting of side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through thenational reporting system included in theAppendix V. By reporting side effects, you can contribute to providing more information about the safety of this medicine.

This information is intended for healthcare professionals only.

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

Do not use this medication after the expiration date that appears on the infusion bag label after EXP.

Store and transport at ≤ –120 °C. Do not thaw the product until it is to be used.

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

Composition of Kymriah

• The active ingredient is tisagenlecleucel. Each infusion bag of Kymriah contains a dispersion of genetically modified tisagenlecleucel cells to express a chimeric anti-CD19 antigen receptor (viable CD19+ T cells) at a concentration dependent on the batch of autologous T cells.1 or more bags contain a total of 1.2 × 10^6 to 6 × 10^8 viable T-CAR+ cells.
• The other components are glucose, sodium chloride, human albumin solution, dextran 40 for injectables, dimethyl sulfoxide, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, N-acetyl tryptophanate sodium, caprilate sodium, aluminum, water for injectable preparations. See section 2, “Kymriah contains sodium, dimethyl sulfoxide (DMSO), dextran 40 and sodium”.

This medicine contains human-derived cells.

Appearance of Kymriah and contents of the packaging

Kymriah is a cell suspension for infusion. It is supplied in infusion bags containing a cell suspension, colorless slightly yellowish turbid to clear. Each bag contains 10 to 50 ml of suspension.

Marketing Authorization Holder

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Responsible for manufacturing

Novartis Pharma GmbH

Roonstrasse 25

90429 Nuremberg

Germany

Novartis Pharma GmbH

Sophie-Germain-Strasse 10

90443 Nürnberg

Germany

For more information about this medicine, please contact the local representative of the marketing authorization holder:

Last review date of this leaflet 11/2024

Other sources of information

The detailed information about this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu

This information is intended solely for healthcare professionals:

Precautions to be taken before handling or administering the medicine

Kymriah must be transported within the installation in closed, break-resistant, and leak-proof containers.

This medicine contains human-derived cells. Healthcare professionals handling Kymriah must take the necessary precautions (wear gloves and eye protection) to avoid the possible transmission of infectious diseases.

Preparation prior to administration

Before administration, it must be confirmed that the patient's identification data match the information provided for that patient only in the infusion bags of Kymriah and the accompanying documentation.It must also be confirmed that the total number of infusion bags to be administered matches the information specific to the patient provided in the specific batch documentation accompanying the medicine.

The time of thawing and infusion of Kymriah must be coordinated.The thawing time must be confirmed in advance and adjusted so that Kymriah is available when the recipient is ready.Once Kymriah has thawed and is at room temperature (20 °C - 25 °C), it must be administered within 30 minutes to maintain the maximum viability of the product, including any interruptions that may occur during infusion.

Inspection and thawing of the infusion bags

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

The infusion bag must be placed inside a sterile outer bag during thawing to protect the connections from contamination and, in the unlikely event of a leak, prevent spills.Kymriah must be thawed at 37 °C using a warm bath or a dry method until no ice is visible in the infusion bag.After complete thawing, the infusion bag must be removed from the thawing device and stored at room temperature (20 °C - 25 °C) until infusion.If more than one infusion bag has been received for treatment (see batch certificate for the number of bags that constitute a dose), the next infusion bag must only be thawed after the contents of the previous infusion bag have been infused.

Kymriah must not be manipulated. That is, Kymriah cannot be washed (centrifuged or resuspended in new media) before infusion.

The infusion bags must be inspected for cracks or tears.If the infusion bag appears to have been damaged or shows leaks, it must not be infused and must be disposed of in accordance with local procedures for the handling of biological waste.

Administration

Kymriah must be administered by an experienced healthcare professional in immunocompromised patients and prepared to manage anaphylaxis.In the event of cytokine release syndrome (CRS), ensure that at least one dose of tocilizumab and an emergency response team are available before infusion.The treatment center must have access to additional doses of tocilizumab within 8 hours.In the exceptional case where tocilizumab is not available due to a shortage listed on the European Medicines Agency's shortage list, ensure that the center has available alternative measures for the treatment of cytokine release syndrome.

The patient's identity must match the patient identification data on the infusion bag.Kymriah is intended exclusively for autologous use and must not be administered to any other patients under any circumstances.

Kymriah must be administered as an intravenous infusion using non-latex intravenous tubes, without a leukoreduction filter, at a flow rate of approximately 10 to 20 ml per minute by gravity.The entire contents of the infusion bag must be infused.A 0.9% sodium chloride solution must be used to prime the tube before infusion and to flush it afterwards.After infusing all the contents of Kymriah, the infusion bag must be flushed with 10 to 30 ml of 0.9% sodium chloride solution to ensure that all possible cells are infused to the patient.

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

Measures to be taken in case of accidental exposure

In the event of accidental exposure, the local guidelines for handling human-derived materials must be followed.The work surfaces and materials that may have come into contact with Kymriah must be decontaminated with an appropriate disinfectant.

Precautions to be taken in the disposal of the medicine

The unused medicine 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.