YESCARTA 0.4 - 2 x 10⁸ cells for infusion

Introduction

Package Leaflet: Information for the Patient

Yescarta0.4 – 2x108cellssuspension for infusion

axicabtagene ciloleucel (viable CAR+ T cells)

This medicine is subject to additional monitoring, which will help to quickly identify new safety information. You can contribute 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 start using this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• Your doctor will give you a patient information card. Read it carefully and follow the instructions.
• Always show the patient information card to the doctor or nurse who treats you or if you go to the hospital.
• If you have any further questions, ask your doctor or nurse.
• If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the package leaflet

1. What is Yescarta and what is it used for
2. What you need to know before you are given Yescarta
3. How Yescarta is given
4. Possible side effects
5. Storage of Yescarta
6. Contents of the pack and other information

1. What is Yescarta and what is it used for

Yescarta is a gene therapy medicine used to treat adult patients with aggressive diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) that affects the lymph tissue (part of the immune system), which in turn affects a type of white blood cell called B cells and other organs in the body. The excessive accumulation of these abnormal white blood cells in tissues is the cause of the symptoms you may have. It is used to treat these diseases when other available medicines are no longer effective for your treatment.

The medicine is prepared specifically for you, as a single administration of your own modified white blood cells.

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

Do not use Yescarta:

• if you are allergic to axicabtagene ciloleucel or to any of the other ingredients of this medicine (listed in section 6).
• if you cannot receive a treatment called lymphodepleting chemotherapy, which reduces the number of white blood cells in the blood (see also section 3, How Yescarta is given)

Warnings and precautions

Yescarta is prepared from your own white blood cells and should only be given to you (autologous use).

Before you are given Yescarta, tell your doctor if:

• you have problems with your nervous system (such as seizures, stroke, or memory loss).
• you have kidney problems.
• you have a low number of blood cells (blood counts).
• you have had a hematopoietic stem cell transplant in the last 4 months.
• you have any lung, heart, or blood pressure problems (low or high).
• 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 bloody stools.
• you notice that your cancer symptoms are getting worse. If you have lymphoma, these may include fever, feeling weak, night sweats, sudden weight loss.
• you have an infection. The infection will be treated before you are given Yescarta.
• you have had hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

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

Tests and checks

Before you are given Yescarta, your doctor:

• will examine your lungs and heart and check your blood pressure.
• will look for signs of infection; any infection will be treated before you are given Yescarta.
• will check if your cancer is getting worse.
• will look for signs of graft-versus-host disease that may occur after a transplant.
• will check your uric acid and the number of cancer cells in your blood. This will show if you are likely to develop a complication called tumor lysis syndrome. You may be given medicines to help prevent this complication.
• will check if you have hepatitis B, hepatitis C, or HIV infection.
• will check if you have been vaccinated in the last 6 weeks or if you are planning to have a vaccine in the next few months.

After you are given Yescarta

If you notice any of the following symptoms, tell your doctor or nurse immediately:

• Chills, extreme tiredness, weakness, dizziness, headache, cough, difficulty breathing, or rapid heart rate; these may be symptoms of a complication called cytokine release syndrome. Take your temperature twice a day for 3 to 4 weeks after treatment with Yescarta. If your temperature is high, contact your doctor immediately.
• Seizures, tremors, or difficulty speaking or slurred speech, loss of consciousness or reduced levels of consciousness, confusion, and disorientation, loss of balance or coordination.
• Fever, which may be a sign of infection.
• Extreme tiredness, weakness, and difficulty breathing, which may be symptoms of low red blood cell counts.
• Bleeding or bruising easily, which may be symptoms of low platelet counts.
• Blurred vision, loss of vision, or double vision, difficulty speaking, weakness, or clumsiness of an arm or leg, a change in the way you walk, or balance problems, changes in personality, changes in thinking, memory, and orientation leading to confusion. These may be symptoms of a serious and potentially life-threatening brain disease called progressive multifocal leukoencephalopathy (PML). These symptoms may start several months after finishing treatment and usually develop slowly and gradually over weeks or months. It is important that your family or caregivers are aware of these symptoms.

Your doctor will check your blood counts frequently, as the number of blood cells and other components of the blood may decrease.

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

If you are in any of these situations (or if you are not sure), tell your doctor or nurse before you are given Yescarta. Your doctor may need to provide you with special medical care during treatment with Yescarta.

Sometimes, it may not be possible to give you Yescarta. For example:

• if the administration of the Yescarta infusion is delayed more than 2 weeks after you received preparatory chemotherapy, you may need to receive additional preparatory chemotherapy.

Children and adolescents

Yescarta should not be given to children and adolescents under 18 years of age.

Other medicines and Yescarta

Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines.

Before you are given Yescarta, tell your doctor or nurse if you are taking any medicine that weakens the immune system, such as corticosteroids, as these medicines may interfere with the effect of Yescarta.

You should not be given certain vaccines called live vaccines, in particular:

• During the 6 weeks before you receive the short course of chemotherapy (called lymphodepleting chemotherapy) to prepare your body for Yescarta cells.
• During treatment with Yescarta.
• After treatment while your immune system is recovering.

Ask your doctor if you need any vaccine.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, tell your doctor before you are given this medicine. This is because the effects of Yescarta on pregnant or breastfeeding women are not known, and it may harm the fetus or baby.

• If you are pregnant or think you may be pregnant after treatment with Yescarta, tell your doctor immediately.
• A pregnancy test will be performed before you start treatment. Yescarta should only be given if the results show that you are not pregnant.

Talk to your doctor about pregnancy if you received Yescarta.

Driving and using machines

Some people may feel tired, dizzy, or experience tremors after receiving Yescarta. If this happens to you, do not drive or use heavy machinery for at least 8 weeks after the infusion or until your doctor confirms that you have fully recovered.

Yescarta contains sodium, dimethyl sulfoxide (DMSO), and residual gentamicin

This medicine contains 300 mg of sodium (main component of cooking/table salt) in each infusion bag. This is equivalent to 15% of the maximum recommended daily intake of sodium for an adult.

This medicine contains DMSO and residual gentamicin, which may cause severe allergic reactions.

3. How Yescarta is given

Yescarta will always be given to you by a healthcare professional. It is given by drip (infusion) into a vein (intravenously).

• Since Yescarta is prepared from your own white blood cells, your cells will be collected to prepare your medicine. Your doctor will take some of your blood with a catheter placed in your vein (a procedure called leukapheresis). Some white blood cells will be separated from the blood, and the rest of the blood will be returned to the vein. This may take 3 to 6 hours and may need to be repeated.
• Your white blood cells will be frozen and sent to prepare Yescarta. It usually takes 3 to 4 weeks to receive your Yescarta treatment, but the time may vary.

Other medicines given before Yescarta treatment

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

• Paracetamol.
• An antihistamine such as diphenhydramine.

Before you receive Yescarta, you will be given other medicines, such as preparatory chemotherapy, so that the modified white blood cells in Yescarta can multiply in your body once you are given the medicine.

Your doctor or nurse will carefully check that the medicine to be given to you belongs to you.

How Yescarta is given to you

Yescarta will always be given to you by a doctor in a qualified medical center.

• Yescarta is given as a single dose.
• Your doctor or nurse will give you a single infusion of Yescarta through a catheter placed in a vein (intravenous infusion) over about 30 minutes.

You should only receive the Yescarta infusion in a qualified medical center and be discharged when your doctor considers that you are well enough to go home.

Your doctor may perform blood tests to detect possible side effects.

After you are given Yescarta

• Plan to stay near the hospital where you were treated for at least 4 weeks after you receive Yescarta. Your doctor will recommend that you return to the hospital daily for at least 10 days and consider whether you need to stay in the hospital for the first 10 days after the infusion. This is so that your doctor can check if your treatment is working and help you if you have any side effects.

If you miss an appointment

Contact your doctor or the qualified medical center as soon as possible to make another appointment.

4. Possible side effects

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

Serious side effects

Yescarta may cause side effects related to the immune system or the nervous system. Yescarta may also increase the risk of getting an infection. These side effects can be serious or life-threatening and may cause death.

Tell your doctor immediately if you have any of the following side effects after receiving Yescarta, as you may need urgent medical treatment:

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

• Fever, chills, low blood pressure that can lead to symptoms such as dizziness or fainting, rapid heart rate, irregular heart rate (arrhythmia), low oxygen levels in the blood that can cause shortness of breath or difficulty breathing. These may be signs of a serious condition called cytokine release syndrome.
• Loss of consciousness or reduced levels of consciousness, confusion, or disorganized thinking, memory loss, difficulty speaking or slurred speech, difficulty understanding speech due to changes in brain function (encephalopathy). Other signs of involuntary tremors (tremors), sudden confusion with agitation, disorientation, hallucinations, or irritability (delirium), lack of energy or strength, muscle weakness, difficulty moving (motor dysfunction).
• Feeling hot, fever, chills, or shivering, which may be signs of infection (including bacterial or viral infection). Infections can be due to an abnormally low number of white blood cells or low levels of antibodies called "immunoglobulins" in the blood, which help fight infections.

Other serious side effects that require immediate medical attention are:

Common (may affect up to 1 in 10 people)

• Seizures (including prolonged and potentially life-threatening seizures).
• Sudden and unexpected stop of the heart (cardiac arrest) or heart failure.
• Blood clots: symptoms may include chest pain or upper back pain, difficulty breathing, coughing up blood, or colic-like pain, swelling in one leg, hot and darkened skin around the painful area.
• Difficulty breathing on your own (respiratory failure).
• Kidney failure that causes your body to retain fluids.
• Fluid buildup in the lungs (pulmonary edema) that can cause difficulty breathing.

Uncommon (may affect up to 1 in 100 people)

• Inflammation and swelling of the spinal cord that can cause partial or total paralysis of the limbs and trunk.

If you notice any of the above side effects, tell your doctor immediately. Do not try to treat your symptoms with other medicines without talking to your doctor.

Reporting side effects

If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Yescarta

This information is intended only for healthcare professionals.

Do not use this medicine after the expiry date which is stated on the label of the container and the infusion bag.

It should be stored frozen in the vapor phase of liquid nitrogen ≤ -150 ºC until the time of thawing for use.

Do not re-freeze.

6. Container Contents and Additional Information

Yescarta Composition

• The active substance is axicabtagene ciloleucel. Each patient-specific individual infusion bag contains a dispersion of anti-CD19 CAR T cells in approximately 68 ml, for a target dose of 2 x 10^6 viable anti-CD19 CAR-positive T cells/kg.

• The other components (excipients) are: Cryostor CS10 (contains DMSO), sodium chloride, human albumin. See section 2 "Yescarta contains sodium, dimethyl sulfoxide (DMSO), and residual gentamicin"

This medicinal product contains genetically modified human blood cells.

Appearance and Container Contents of the Product

Yescarta is a clear to opaque, white to red dispersion for infusion, supplied in a single patient-specific infusion bag contained in a metal container. One infusion bag contains approximately 68 ml of cell dispersion.

Marketing Authorisation Holder and Manufacturer

Kite Pharma EU B.V.

Tufsteen 1

2132 NT Hoofddorp

Netherlands

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu. There are also links to other websites on rare diseases and treatments.

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This information is intended for healthcare professionals only:

It is essential to read the entire content related to this procedure before administering Yescarta.

Precautions to be taken before handling or administering the medicinal product

In the administration centre, Yescarta should be transported in closed, breakage-proof, and leak-proof containers.

This medicinal product contains human blood cells. Healthcare professionals handling Yescarta will take necessary precautions (wear gloves and goggles) to avoid possible transmission of infectious diseases.

Work surfaces and materials that may have come into contact with Yescarta should be decontaminated with a suitable disinfectant.

Preparation before administration

• Check that the patient's identification (ID) matches the patient identifiers on the Yescarta container.
• Do not remove the Yescarta bag from the metal container if the patient-specific label information does not match the patient to be treated.
• Once the patient's ID is confirmed, remove the Yescarta bag from the metal container.
• Check that the patient information on the metal container label matches the label on the infusion bag.
• Inspect the product bag for integrity of the container before thawing. If the bag is damaged, follow local guidelines for the treatment of human origin material waste (or contact Kite immediately).

Thawing

• Place the infusion bag in a secondary bag.
• Thaw Yescarta at a temperature of approximately 37 °C, by warming in a water bath or by dry thawing, until no ice is visible in the infusion bag. Gently mix the contents of the bag to eliminate cellular aggregates. If cellular aggregates are still visible, continue to gently mix the contents of the bag. Small cellular aggregates should be eliminated with gentle manual mixing. Yescarta should not be washed, centrifuged, and/or resuspended in a new medium before infusion. Thawing takes approximately 3 to 5 minutes.
• Once thawed, Yescarta is stable at room temperature (between 20 °C and 25 °C) for up to 3 hours. However, the infusion of Yescarta should be started within 30 minutes of complete thawing.

Administration

• DO NOT use a leucodepletion filter.
• The medicinal product should be administered in a qualified medical centre by one or more physicians with experience in the treatment of malignant haematological neoplasias and who have received training on the administration and treatment of patients treated with Yescarta.
• Ensure that at least 1 dose of tocilizumab per patient and an emergency kit are available before infusion and during the recovery period. Hospitals should have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case that tocilizumab is not available due to a shortage listed in the European Medicines Agency's shortage catalogue, ensure that other adequate alternative measures are available in the centre to treat CRS instead of tocilizumab.
• Check that the patient's identity matches the patient identifiers on the infusion bag.
• Yescarta is intended for autologous use only.
• Yescarta should be administered as an intravenous infusion using latex-free intravenous lines without a leucodepletion filter over a period of 30 minutes, either by gravity or using a peristaltic pump.
• During the infusion of Yescarta, gently agitate the bag to prevent cellular aggregates. The entire contents of the infusion bag should be administered.
• Prior to infusion, a sodium chloride 9 mg/ml (0.9%) solution (0.154 mmol of sodium per ml) should be used to prime the lines, as well as to flush them after infusion.
• After the total volume of Yescarta has been infused, the infusion bag should be flushed with 10 to 30 ml of a sodium chloride 9 mg/ml (0.9%) solution for injection by reverse priming to ensure the infusion of as many cells as possible to the patient.

Measures to be taken in case of accidental exposure

In case of accidental exposure, follow local guidelines for the treatment of human origin material. Decontaminate work surfaces and materials that may have come into contact with Yescarta with a suitable disinfectant.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all materials that have come into contact with Yescarta (solid and liquid waste) should be treated and disposed of as potentially infectious waste according to local guidelines for the treatment of human origin material waste.