Kymriah 1.2 x 10e6 - 6.0 x 10e8 cells dispersion for infusion

Package leaflet: Information for the patient or caregiver

Introduction

Package leaflet: information for the patient or caregiver

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

tisagenlecleucel (CAR-T cells)

This medicinal product is subject to additional monitoring, which will allow quicker identification of new safety information. You can help by reporting any side effects you may experience. The end of section 4 includes information on how to report these side effects.

Read this entire leaflet carefully before you (or your child) start receiving this medicine, because it contains important information.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor.
• Your doctor will give you a patient information card. Read it carefully and follow its 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 any side effects, consult your doctor, even if they are side effects not listed in this leaflet. See section 4.
• The information in this leaflet is intended for you or your child – however, in the leaflet you will be referred to simply as “you”.

Contents of this leaflet

1. What Kymriah is and what it is used for
2. What you need to know before receiving Kymriah
3. How Kymriah is administered
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 manufactured using your own white blood cells called T-lymphocytes. T-lymphocytes are necessary for the immune system (the body's defenses) to function properly.

How Kymriah works

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

What Kymriah is used for

Kymriah is used to treat:

• B-cell acute lymphoblastic leukemia (B-cell ALL) – a type of cancer affecting certain white blood cells. The medicine may be used in children and young adults up to and including 25 years of age with this disease when they have not responded to prior 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 affecting certain white blood cells, primarily in the lymph nodes. The medicine may be used in adults (18 years of age or older) with this disease when it has relapsed or has not responded to two or more prior treatments.
• Follicular lymphoma (FL) – a type of cancer affecting certain white blood cells called lymphocytes, primarily in the lymph nodes. The medicine may be used in adults (18 years of age or older) with this disease when it has relapsed or has not responded to two or more prior treatments.

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

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

Do not receive Kymriah

• if you are allergic to any of the components of this medicine (listed in section 6). If you think you might be allergic, consult your doctor
• if you cannot receive lymphodepleting 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 given 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 register 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 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 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 worsening. If you have leukemia, this would include fever, feeling weak, bleeding gums, or bruising. If you have lymphoma, this would include unexplained fever, night sweats, or sudden weight loss.
• You have an infection. Any infection must be treated before the Kymriah infusion.
• You have had hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
• You are pregnant, think you might be pregnant, or plan to become pregnant (see sections “Pregnancy and breastfeeding” and “Contraception for women and men” below).
• You were vaccinated within the previous 6 weeks or plan to be vaccinated in the coming months.

If any of the above apply to you (or you are unsure), speak with your doctor before receiving Kymriah.

Tests and examinations

Before receiving Kymriah, your doctor will:

• Examine your lungs, heart, and blood pressure.
• Look for signs of infection; any infection must be treated before you receive Kymriah.
• Check whether your lymphoma or leukemia has worsened.
• Look for signs of graft-versus-host disease that may occur after a transplant.
• Check your blood uric acid levels and the number of cancer cells in your blood. This will indicate whether you might develop a condition called tumor lysis syndrome. You may be given medications to prevent this condition.
• Check whether you have hepatitis B, hepatitis C, or HIV infection.

After receiving Kymriah

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

• Fever, which could 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.
• Take your temperature twice daily for 3–4 weeks after receiving Kymriah. If your temperature rises, contact your doctor immediately.
• Changes or reduction in 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 also 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 could be signs of low red blood cells.
• Frequent bleeding or bruising, which could be symptoms of low levels of blood cells such as platelets.

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

After receiving Kymriah, your doctor will monitor your blood counts regularly, as 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 or adolescents under 18 years of age for the treatment of DLBCL. This is due to very limited experience in treating non-Hodgkin lymphoma in this age group.
• Kymriah should not be used in children or 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 need to take any other medicines, including over-the-counter medicines. This is because other medicines may affect how Kymriah works.

In particular, you should not receive certain vaccines known as live vaccines:

• 6 weeks before you receive a short course of chemotherapy (called lymphodepleting chemotherapy), which prepares your body for 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, inform your doctor or nurse if you are taking other medicines that may weaken your immune system, such as corticosteroids, as these medicines could interfere with the effect of Kymriah.

Pregnancy and breastfeeding

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

• If you become pregnant or wish to become pregnant after treatment with Kymriah, speak with your doctor immediately.
• Before starting treatment, you will have a pregnancy test. Kymriah will only be administered if the result shows you are not pregnant.

Contraception for women and men

If you have received Kymriah, you should discuss pregnancy with your treating doctor.

Driving and using machines

Some people may feel confused or experience problems such as altered or reduced consciousness, confusion, or seizures (fits) after receiving Kymriah. Therefore, do not drive, operate machinery, or participate in activities requiring alertness within 8 weeks after the infusion.

Kymriah contains sodium, dimethyl sulfoxide (DMSO), dextran 40, and potassium

This medicine contains between 24.3 mg and 121.5 mg of sodium (the main component of table/cooking salt) per dose. This corresponds to 1% to 6% of the maximum recommended daily intake of sodium for an adult.

This medicine contains dextran 40 and DMSO (substances used to preserve frozen cells), which may sometimes cause difficulty breathing and/or dizziness (possible symptoms of serious allergic or hypersensitivity reactions). You will be under observation during the infusion.

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

3. How Kymriah is administered

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

Blood collection to make Kymriah

Kymriah is manufactured using your own white blood cells.

• Your doctor will collect your blood using a catheter placed into your vein (a procedure called leukapheresis). Some of your white blood cells will be removed from your blood, and the rest will be returned to you through the vein. This may take from 3 to 6 hours and may need to be repeated.

• Your white blood cells will be frozen and sent for the manufacturing of Kymriah. The production of Kymriah usually takes about 3 to 4 weeks, but this may vary.

• Kymriah is a medicine specifically manufactured for you.

• Before you receive Kymriah, your doctor may administer a type of treatment called lymphodepleting chemotherapy for several 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 an additional treatment (called "bridging therapy") to stabilize the cancer and prevent cancer cells from multiplying. This treatment may cause adverse effects that could be serious or life-threatening. Your doctor will inform you about the possible adverse effects of this treatment.

Other medicines administered shortly before Kymriah treatment

From 30 to 60 minutes before you receive Kymriah, you will 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 verify that the patient identification information on the Kymriah infusion bag matches your details.
• Your doctor will administer Kymriah by infusion, meaning that you will receive it through an intravenous line. This usually takes less than 1 hour. During the infusion, your doctor will monitor you for breathing problems or dizziness (possible signs of an allergic reaction).
• Kymriah is a single-dose treatment.

After Kymriah administration

• Plan to stay near the hospital (within no more than a 2-hour travel distance) where you were treated for at least 4 weeks after receiving Kymriah. During the first week after treatment, your doctor may recommend that you return to the hospital 2 to 3 times, or more frequently. This is so your doctor can monitor whether your treatment is working and assist you if you experience any adverse effects.

If you miss an appointment

If you miss an appointment, contact 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 everyone experiences them.

Tell your doctor immediately if you experience any of the following adverse effects after receiving the Kymriah infusion. These usually occur within 8 weeks after the infusion, but may also appear later:

Very common: may affect more than 1 in 10 people

• High fever and chills, which may be symptoms of a serious condition called cytokine release syndrome (CRS), which can be life-threatening or fatal. Other symptoms of cytokine release syndrome include 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 occur within the first 14 days after treatment with Kymriah, but in some patients they may develop later.
• Problems such as altered thinking or decreased consciousness, loss of contact with reality, confusion, agitation, seizures, difficulty speaking and understanding speech, difficulty walking. These could be symptoms of a condition called immune effector cell-associated neurotoxicity syndrome (ICANS). These symptoms mainly occur during the first 8 weeks after treatment with Kymriah, but may also appear later in some patients.
• Feeling of warmth, fever, chills or shaking, sore throat or mouth sores, which could 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 tumor cells leading to the release of their contents into the bloodstream. This can interfere with the function of several organs in the body, especially the kidneys, heart, and nervous system (tumor lysis syndrome).

Other possible adverse effects

Listed below are other possible adverse effects. If these adverse effects become severe or intense, inform your doctor immediately.

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

• Paleness, weakness, difficulty breathing due to low red blood cell count or low hemoglobin levels
• Excessive or prolonged bleeding or bruising due to low platelet count
• Fever with very low white blood cell counts
• Increased risk of infections due to very low white blood cell count
• Frequent and persistent infections due to reduced levels of antibodies in the blood
• Weakness, irregular heartbeat due to abnormally low levels of phosphate and potassium salts in the blood
• Elevated levels of liver enzymes or creatinine in the blood, indicating impaired liver or kidney function
• High blood pressure
• Shortness of breath, difficulty breathing, rapid breathing
• Cough
• Abdominal pain, constipation
• Bone and back pain
• Skin rash
• Swollen ankles, swelling of 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, redness, 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, which occurs when transplanted cells attack your own cells)
• Joint pain due to elevated uric acid levels
• Abnormal blood test results (elevated levels of: phosphate, potassium, calcium, and sodium, D-dimer, serum ferritin; low levels of a blood protein called albumin, sodium, magnesium)
• Seizures, fits (epileptic seizures)
• Muscle spasms/cramps due to abnormally low calcium levels
• Involuntary, uncontrollable movements
• Involuntary body jerks, difficulty writing, difficulty expressing thoughts verbally, attention problems, drowsiness
• Tingling or numbness, difficulty moving due to nerve damage
• Decreased vision
• Thirst, low urine output, dark urine, dry and flushed skin, irritability (possible symptoms of high blood sugar levels)
• Weight loss
• Nerve pain
• Anxiety, irritability
• Severe confusion
• Difficulty sleeping
• Shortness of breath, breathing difficulty 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 from blood vessels into surrounding 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 bilirubin levels
• Itching
• Excessive sweating, night sweats
• Flu-like symptoms
• Multi-organ failure
• Fluid in the lungs
• Nasal congestion
• Blood clotting disorder (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 (elevated magnesium levels)
• Weakness or paralysis of limbs or face, difficulty speaking (possible symptoms of stroke due to reduced blood flow)
• Warmth and redness of the skin
• Cough producing phlegm or sometimes 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 starting in a type of white blood cells called T lymphocytes (secondary T-cell origin neoplasm)

Frequency not known (cannot be estimated from available data)

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

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system detailed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of 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 following EXP.

Store and transport at ≤ –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 leaks.

6. Contents of the pack and other information

Composition of Kymriah

• The active substance is tisagenlecleucel. Each Kymriah infusion bag contains a dispersion of genetically modified tisagenlecleucel cells designed to express an anti-CD19 chimeric antigen receptor (viable CAR-positive T cells) at a batch-dependent concentration of autologous T lymphocytes. One or more bags contain a total of 1.2 × 10⁶ – 6 × 10⁸ viable CAR+ T cells.
• The other components are glucose, sodium chloride, human albumin solution, dextran 40 for injectable preparations, dimethylsulfoxide (DMSO), sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, sodium N-acetyl tryptophanate, sodium caprylate, aluminium, water for injectable preparations. See section 2, "Kymriah contains sodium, dimethylsulfoxide (DMSO), dextran 40 and sodium".

This medicinal product contains cells of human origin.

Appearance of Kymriah and contents of the pack

Kymriah is a cell dispersion for infusion. It is supplied in infusion bags containing a cell dispersion, slightly yellowish and colourless, ranging from cloudy to clear in appearance. 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
Sophie-Germain-Strasse 10
90443 Nuremberg
Germany

Further information on this medicinal product is available upon request by contacting the local representative of the Marketing Authorisation Holder:

Date of the most recent review of this summary

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 for healthcare professionals only:

Precautions to be taken before handling or administering the medicine

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

This medicine contains human blood cells. Healthcare professionals handling Kymriah must take appropriate precautions (wear gloves and eye protection) to prevent potential transmission of infectious diseases.

Preparation prior to administration

Prior to administration, the patient's identification details must be confirmed to match the information specified for that patient only on the Kymriah infusion bags and accompanying documentation. The total number of infusion bags to be administered must also be verified by cross-checking with the patient-specific information provided in the batch-specific documentation accompanying the medicine.

The timing of thawing and infusion of Kymriah must be coordinated. The infusion time should be confirmed in advance and thawing adjusted accordingly, 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 must 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 ready to be used.

The infusion bag must be placed inside a second sterile bag during thawing to protect the connections from contamination and, in the unlikely event of leakage, to prevent spills. Kymriah must be thawed at 37 °C using a water bath or a dry thawing method until no ice is visible in the infusion bag. After complete thawing, the bag must 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 (refer to the batch 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. That is, Kymriah must not be washed (centrifuged or resuspended in new media) prior to infusion.

The infusion bag(s) must be inspected for tears or cracks. If the infusion bag appears damaged or shows signs of leakage, it must not be infused and must be discarded according to local procedures for the handling of biological waste.

Administration

Kymriah intravenous infusion must be administered by a healthcare professional experienced in managing immunocompromised patients and prepared to manage anaphylaxis. In the event of cytokine release syndrome (CRS), ensure that at least one dose of tocilizumab and emergency resuscitation equipment are available prior to infusion. The treatment center must have access to additional doses of tocilizumab within 8 hours. In the exceptional case where tocilizumab is unavailable due to a shortage listed on the European Medicines Agency's shortage list, ensure that appropriate alternative measures for the treatment of cytokine release syndrome are available at the center.

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

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

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

Measures to be taken in case of accidental exposure

In the event of accidental exposure, local guidelines for handling materials of human origin must be followed. 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 medicine

Any 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 materials of human origin.