KYMRIAH 1.2 x 10^6 - 6.0 x 10^8 cells dispersion for infusion

Introduction

Package Leaflet: Information for the Patient or Caregiver

Kymriah®1,2× 106to 6.0× 108cell dispersion for infusion

tisagenlecleucel (viable T-CAR+ lymphocytes)

This medicinal product is subject to additional monitoring, which will allow for quicker identification of new safety information. You can help by reporting any side effects you may have. The last section of the package leaflet contains information on how to report side effects.

Read all of this leaflet carefully before you (or your child) start receiving 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.

• Your doctor will give you a patient information card. Read it carefully and follow the instructions.
• Always show the patient information card to your doctor or nurse when you see them or if you go to a hospital.
• If you experience side effects, consult your doctor, even if they are not listed in this leaflet. See section 4.
• The information in this leaflet is for you (or your child) – but in the leaflet, only “you” will be referred to.

Contents of the package leaflet

1. What is Kymriah and what is it used for
2. What you need to know before you start receiving Kymriah
3. How Kymriah is administered
4. Possible side effects
5. Storage of Kymriah
6. Contents of the pack and further information

1. What is Kymriah and what is it used for

What isKymriah

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

HowKymriahworks

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

WhatKymriahis used for

Kymriah is used to treat:

• B-cell acute lymphoblastic leukaemia (B-ALL)– a type of cancer that affects different white blood cells. The medicine can be used in children and young adults up to 25 years of age, inclusive, with this disease when they have not responded 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 medicine can be used in adults (18 years of age or older) with this disease when it has relapsed or not responded 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 medicine can be used in adults (18 years of age or older) with this disease when it has relapsed or not responded to two or more previous treatments.

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

2. What you need to know before you start receiving Kymriah

You must not receive Kymriah

• if you are allergic to any of the components of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice
• if you cannot receive lymphocyte-depleting 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 have been reported of patients developing cancer, starting from a type of white blood cell called T lymphocytes, after treatment with Kymriah and similar medicines. Consult your doctor if you experience any new swelling of the glands (lymph nodes) or changes in the skin, such as new rashes or lumps.

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

Before you are given Kymriah, you must tell your doctor if:

• You have received a hematopoietic stem cell transplant in the last 4 months. Your doctor will check if you have 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 the stool.
• You have lung, heart, or blood pressure problems (low or high).
• You notice that your cancer symptoms are getting worse. If you have leukemia, this would be fever, feeling weak, bleeding gums, bruising. If you have lymphoma, this would be unexplained fever, night sweats, sudden weight loss.
• You have an infection. The infection must be treated before Kymriah is infused.
• 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 the sections “Pregnancy and breast-feeding” and “Contraception for women and men” below).
• You have been vaccinated in the last 6 weeks or plan to be vaccinated in the coming months.

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

Tests and examinations

Before Kymriah is administered, 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.
• Check 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 are likely to develop a condition called tumor lysis syndrome. You may be given medicines to prevent this condition.
• Check if you have a hepatitis B, hepatitis C, or HIV infection.

After Kymriah is administered

Tell 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 3-4 weeks after Kymriah is administered. If your temperature rises, go to the doctor immediately.
• Altered or decreased consciousness, delirium, anxiety, dizziness, tremors, headache, confusion, agitation, seizures, difficulty speaking and understanding, and/or loss of balance. This usually occurs during the first 8 weeks after infusion, but can also occur later. These can be symptoms of a condition called immune effector cell-associated neurotoxicity syndrome (ICANS).
• Extreme fatigue, weakness, and shortness of breath, which could be a sign of a lack of red blood cells.
• Frequent bleeding or bruising, which could be a sign of low levels of blood cells such as platelets.

There may be 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 because you may experience a decrease in the number of blood cells and other blood components.

Do not donate blood, organs, tissues, or cells.

Children and adolescents

• There is very limited experience with Kymriah in pediatric patients under 3 years of age.
• Kymriah is not recommended for children and adolescents under 18 years of age for the treatment of DLBCL. This is because there is very limited experience in the treatment of non-Hodgkin lymphoma in this age group.
• 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

Tell 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, you must not be given certain live vaccines:

• 6 weeks before you are given a short course of chemotherapy (called lymphodepleting chemotherapy), which prepares your body for the Kymriah cells.
• during your treatment with Kymriah.
• after your treatment until your immune system has recovered.

Talk to your doctor if you need to be vaccinated.

Before you are given Kymriah, tell your doctor or nurse if you are taking other medicines that may weaken your immune system, such as corticosteroids, as 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 plan to become pregnant, consult your doctor before you are given this medicine. This is because the effects of Kymriah on pregnant or breast-feeding women are not known and may be harmful to the fetus/baby.

• If you become pregnant or want to become pregnant after treatment with Kymriah, talk to your doctor immediately.
• Before you start treatment, you will have a pregnancy test. Kymriah can only be administered if the result shows that you are not pregnant.

Contraception for women and men

If you have received Kymriah, you must talk to the doctor who treated you about pregnancies.

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 take part in activities that require you to be alert for 8 weeks after infusion.

Kymriahcontainssodium, dimethyl sulfoxide (DMSO), dextran40, and potassium

This medicine contains from 24.3 mg to 121.5 mg of sodium (the main component of table salt/kitchen salt) per dose. This is equivalent to 1 to 6% of the maximum daily recommended 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 will be monitored during the infusion.

This medicine contains potassium, less than 1 mmol (39 mg) per dose, which is essentially potassium-free.

3. How Kymriah is administered

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

Collecting blood to make Kymriah

Kymriah is made from your own white blood cells.

• Your doctor will take blood from you using a catheter that is placed in your vein (a procedure called leukapheresis). Some of your 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 are frozen and sent to manufacture Kymriah. The manufacture of Kymriah usually takes about 3 to 4 weeks, but may vary.
• Kymriah is a medicine that is specifically made for you.

• 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 manufactured

During the time Kymriah is being manufactured, your leukemia or lymphoma may worsen, and your doctor may decide to use additional treatment (called “bridging treatment”) to stabilize the cancer and prevent the cancer cells from multiplying. This treatment may cause side effects that can be serious or life-threatening. Your doctor will inform you of the possible side effects of this treatment.

Other medicines given just before treatment with Kymriah

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

• Paracetamol
• An antihistamine such as diphenhydramine.

How Kymriah is administered

• Your doctor will check that the patient identification on the Kymriah infusion bag matches you.
• Your doctor will give you Kymriah by infusion, which means you will have 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 problems breathing or feel dizzy (possible symptoms of an allergic reaction).
• Kymriah is a single-dose treatment.

After Kymriah is administered

• Plan to stay near the hospital (within 2 hours of travel) where you were treated for at least 4 weeks after you were given Kymriah. During the first week after treatment, your doctor may recommend that you return to the hospital 2 to 3 times, or more often. This is so your doctor can check that your treatment is working and can help you if you have any side effects.

If you miss an appointment

If you miss an appointment, call your doctor or treatment center as soon as possible to schedule another appointment.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Report immediately to your doctorif you have any of the following adverse effects after you have been administered the Kymriah infusion. They usually appear within 8 weeks after infusion, but they can also appear later:

Very frequent: may affect more than 1 in 10 people

• High fever and chills may 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 almost always appear in the first 14 days after treatment with Kymriah, but in some patients, they can also develop later.
• Problems such as changes in 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). These symptoms appear mainly during the first 8 weeks after treatment with Kymriah, but in some patients, they can also appear later.
• A feeling of heat, fever, chills, or tremors, sore throat, or sores in the mouth, could be signs of an infection. Some infections can be life-threatening or fatal.

Frequent: may affect up to 1 in 10 people

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

Other possible adverse effects

The following are other possible adverse effects. If these adverse effects become intense or severe, report them immediately to your doctor.

Very frequent(may affect more than 1 in 10 people)

• Pallor, weakness, difficulty breathing due to low red blood cell count or low hemoglobin
• Excessive or prolonged bleeding or bruising 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 decreased antibodies in the blood
• Weakness, abnormal heart rhythm, due to abnormally low levels of phosphorus, potassium in the blood
• High levels of liver enzymes or creatinine in the blood that show that the liver or kidneys are not functioning properly
• High blood pressure
• Shortness of breath, difficulty breathing, rapid breathing
• Cough
• Abdominal pain, constipation
• Pain in bones and back
• Rash
• Swollen ankles, swelling of limbs and face

Frequent(may affect up to 1 in 10 people)

• Fever, discomfort, liver enlargement, yellowing of the skin and eyes, low blood cell count due to severe immune activation
• Dizziness or fainting, flushing, rash, itching, fever, shortness of breath or vomiting, abdominal pain, diarrhea due to an infusion reaction
• Rash, nausea, vomiting, diarrhea including bloody stools (possible symptoms of graft-versus-host disease that occurs when transplanted cells attack the patient's cells)
• Joint pain due to high levels of uric acid
• Abnormal blood test results (high levels of: phosphorus, 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 shakes, 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 and reddened 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 and legs (possible symptoms of heart failure), rapid and irregular heartbeat, cardiac arrest
• Swelling and pain due to blood clots
• Swelling due to leakage of blood vessels into adjacent tissues
• Swelling and discomfort (abdominal distension) due to fluid accumulation in the abdomen
• Dry mouth, mouth pain, oral bleeding
• Yellowing of the skin and eyes due to abnormally high levels of bilirubin
• Itching
• Excessive sweating, night sweats
• Flu-like symptoms
• Multi-organ failure
• Fluid in the lungs
• Nasal congestion
• Blood coagulation defect (coagulopathy, increased international normalized ratio, prolonged prothrombin time, decreased 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 a stroke due to decreased blood flow)
• Heat and redness of the skin
• Cough producing phlegm or sometimes with blood, fever, shortness of breath or difficulty breathing.
• Difficulty controlling movements

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

• A new type of cancer that starts in a type of white blood cell called T lymphocytes (secondary neoplasia of T-cell origin)

Frequency not known(cannot be estimated from the 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 adverse effects

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

5. Storage of Kymriah

The following information is intended only for healthcare professionals.

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

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

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

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

6. Package contents and additional information

Kymriah composition

• The active ingredient is tisagenlecleucel. Each Kymriah infusion bag contains a dispersion of genetically modified tisagenlecleucel cells to express a chimeric antigen receptor anti-CD19 (viable CAR-positive T lymphocytes) at a concentration dependent on the batch of autologous T lymphocytes. 1 or more bags contain a total of 1.2 × 10^6 – 6 × 10^8 viable CAR-positive T lymphocytes.
• 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, sodium caprylate, aluminum, water for injectable preparations. See section 2, "Kymriah contains sodium, dimethyl sulfoxide (DMSO), dextran 40, and sodium".

This medicine contains cells of human origin.

Appearance of Kymriah and package contents

Kymriah is a cell dispersion for infusion. It is supplied in infusion bags containing a cell dispersion, colorless to slightly yellowish in appearance, and turbid to clear. 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 Nürnberg

Germany

You can obtain more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of last revision of this prospectus

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website: https://www.ema.europa.eu

This information is intended only for healthcare professionals:

Precautions to be taken before handling or administering the medicine

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

This medicine contains human blood cells. Healthcare professionals who handle Kymriah should take appropriate precautions (wear gloves and eye protection) to avoid possible transmission of infectious diseases.

Preparation before administration

Before administration, it should be confirmed that the patient's identification data match the information on the Kymriah infusion bag and the accompanying documentation. The total number of infusion bags to be administered should also be confirmed by checking the patient-specific information on the batch-specific documentation that accompanies the medicine.

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

Inspection and thawing of infusion bags

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

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

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

The infusion bag(s) should be inspected for breaks or cracks. If the infusion bag appears to be damaged or has leaks, it should not be infused and should be eliminated according to local procedures for handling biological waste.

Administration

Kymriah intravenous infusion should be administered by an experienced healthcare professional in immunosuppressed patients and prepared to manage anaphylaxis. In case of cytokine release syndrome (CRS), ensure that at least one dose of tocilizumab and an emergency care team are available before infusion. The treatment center should have access to additional doses of tocilizumab within 8 hours. In the exceptional case that tocilizumab is not available due to a shortage that appears on the European Medicines Agency's list of shortages, ensure that the center has adequate alternative measures available 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 should not be administered under any circumstances to other patients.

Kymriah should be administered as an intravenous infusion using latex-free intravenous tubing, without a leukocyte-reducing filter, at approximately 10 to 20 ml per minute by gravity flow. The entire contents of the infusion bag(s) should be infused. A 9 mg/ml (0.9%) sodium chloride solution for injectables should be used to prime the tubing before infusion and to flush it afterward. When the entire contents of Kymriah have been infused, the infusion bag should be flushed with 10 to 30 ml of 9 mg/ml (0.9%) sodium chloride solution for injectables to ensure that all possible cells are infused into the patient.

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

Measures to be taken in case of accidental exposure

In case of accidental exposure, local guidelines for handling human-derived materials should be followed. Work surfaces and materials that may have come into contact with Kymriah should be decontaminated with a suitable disinfectant.

Precautions to be taken when disposing of the medicine

The unused medicine and all materials that have come into contact with Kymriah (solid and liquid waste) should be handled and disposed of as potentially infectious biological waste in accordance with local guidelines for handling human-derived materials.