Yescarta 0.4 - 2 x 10^8 cells dispersion for infusion

Package Leaflet: Information for the User

Introduction

Package Leaflet: Information for the Patient

Yescarta 0.4 – 2x10⁸ cells dispersion for infusion

axicabtagene ciloleucel (viable 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. Information on how to report side effects is provided at the end of section 4.

Read the entire leaflet carefully before you start using this medicine, as it contains important information for you.

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

Leaflet Contents

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

1. What Yescarta is and what it is 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), which affect the lymphatic tissue (part of the immune system) and in turn involve a type of white blood cells called B-cells, as well as other organs in the body. The excessive accumulation of these abnormal white blood cells in tissues causes the symptoms that may occur. This medicine is used to treat these diseases when other available treatments are no longer effective.

The medicine is specifically prepared for you as a single infusion 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 any of the other components 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 made from your own white blood cells and should only be given to you (autologous use).

Before you are given Yescarta, you must consult your doctor if you:

• have problems with the nervous system (such as seizures, stroke or memory loss).
• have kidney problems.
• have low blood cell counts (low blood counts).
• have had a haematopoietic progenitor cell transplant within the last 4 months.
• have any lung, heart or blood pressure problems (low or high).
• have signs or symptoms of graft-versus-host disease. This occurs when transplanted cells attack your body, causing symptoms such as rash, nausea, vomiting, diarrhoea and bloody stools.
• notice that your cancer symptoms are worsening. If you have lymphoma, these may include fever, feeling weak, night sweats, sudden weight loss.
• have an infection. Any infection will be treated before Yescarta infusion is given.
• have had hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.

If any of the above apply to you (or you are unsure), consult 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.
• look for signs of infection; any infection will be treated before you are given Yescarta.
• check whether your cancer is worsening.
• look for signs of graft-versus-host disease that may occur after a transplant.
• check your uric acid levels and the number of cancer cells in your blood. This will show whether you are likely to develop a complication called tumour lysis syndrome. You may be given medicines to help prevent this complication.
• check whether you have hepatitis B, hepatitis C or HIV infection.
• check whether you were vaccinated in the last 6 weeks or whether you are planning to receive a vaccine in the coming months.

After you are given Yescarta

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

• Chills, extreme tiredness, weakness, dizziness, headache, cough, difficulty breathing or rapid heartbeat; 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 changes in speech, loss of consciousness or reduced level 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 levels.
• Bleeding or bruising easily, which may be symptoms of low levels of a type of blood cell called platelets.
• Blurred vision, loss of vision or double vision, difficulty speaking, weakness or clumsiness in one arm or leg, a change in the way you walk or balance problems, personality changes, changes in thinking, memory and orientation leading to confusion. All of these may be symptoms of a serious and potentially life-threatening brain disease called progressive multifocal leucoencephalopathy (PML). These symptoms may start several months after treatment ends and usually develop slowly and gradually over weeks or months. It is important that your family members or caregivers watch for these symptoms if you are not aware of them.

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

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

If you are in any of these situations (or if you are unsure), consult 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 Yescarta treatment. For example:

• if the Yescarta infusion is delayed by more than 2 weeks after you have received preparative chemotherapy (called lymphodepleting chemotherapy), you may need to receive additional preparative chemotherapy.

Children and adolescents

Yescarta must 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 need to take any other medicines.

Before you are given Yescarta, inform 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 must not be given certain vaccines called live virus vaccines, particularly:

• 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.

Consult your doctor if you need any vaccination.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, 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 Yescarta in pregnant or breastfeeding women are unknown, and it may harm the unborn baby or breastfed infant.

• If you are pregnant or think you may be pregnant after Yescarta treatment, consult your doctor immediately.
• You will be tested for pregnancy before starting treatment. Yescarta should only be given if test results show that you are not pregnant.

Talk to your doctor about pregnancy if you have 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 operate heavy machinery for at least 8 weeks after the infusion or until your doctor confirms you have fully recovered.

Yescarta contains sodium, dimethylsulfoxide (DMSO) and residual gentamicin

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

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

3. How Yescarta is administered

Yescarta will always be administered by a healthcare professional. It is given as an intravenous infusion (drip) into a vein.

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

Other medicines given before Yescarta treatment

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

• Paracetamol.
• An antihistamine such as diphenhydramine.

Before receiving Yescarta, you will be given other medicines, such as preparative chemotherapy, to allow the modified white blood cells in Yescarta to multiply in your body after you receive the medicine.

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

How Yescarta is administered to you

Yescarta will always be administered by a doctor at a qualified medical center.

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

You should only receive the Yescarta infusion at a qualified medical center and be discharged when your doctor considers it safe for you to return home.

Your doctor may perform blood tests to monitor for possible adverse effects.

After Yescarta is administered

• Plan to stay near the hospital where you were treated for at least 4 weeks after receiving Yescarta. Your doctor will recommend that you return to the hospital daily for at least 10 days and will consider whether you need to remain hospitalized during the first 10 days after the infusion. 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

Contact your doctor or qualified medical 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 will experience them.

Serious adverse effects

Yescarta may cause adverse effects related to the immune system or the nervous system. Yescarta may also increase the risk of developing an infection. These adverse effects can be serious or potentially fatal, and may even result in death.

Immediately inform your doctor if you experience any of the following adverse effects after receiving Yescarta, as you may require urgent medical treatment:

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

• Fever, chills, low blood pressure that may cause symptoms such as dizziness or fainting, rapid heartbeat, irregular heartbeat (arrhythmia), low oxygen levels in the blood that may cause shortness of breath or difficulty breathing. These may be signs of a serious condition called cytokine release syndrome.
• Loss of consciousness or decreased level of consciousness, confusion or disorganized thinking, memory loss, difficulty speaking or slurred speech, difficulty understanding speech due to disturbances in brain function (encephalopathy). Other signs include involuntary shaking (tremor), sudden confusion with agitation, disorientation, hallucinations or irritability (delirium), lack of energy or strength, muscle weakness, difficulty moving (motor dysfunction).
• Feeling of warmth, fever, chills or shivering, which may be signs of infection (including bacterial or viral infection). Infections may result from 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 requiring immediate medical attention are:

Common (may affect up to 1 in 10 people)

• Seizures (convulsions, including convulsions that may be prolonged and potentially fatal).
• Sudden and unexpected stopping of the heart (cardiac arrest) or heart failure.
• Blood clots: symptoms may include chest or upper back pain, difficulty breathing, coughing up blood or colicky pain, swelling in one leg only, warm and discolored skin around the painful area.
• Inability to breathe on your own (respiratory failure).
• Kidney failure causing your body to retain fluids.
• Fluid accumulation in the lungs (pulmonary edema) that may cause difficulty breathing.

Uncommon (may affect up to 1 in 100 people)

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

If you notice any of the adverse effects listed above, inform your doctor immediately. Do not attempt to treat your symptoms with other medicines without consulting your doctor.

Reporting of adverse effects

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

5. Storage of Yescarta

This information is intended for healthcare professionals only.

Do not use this medicinal product after the expiry date stated on the container label and infusion bag.

Store frozen in the vapor phase of liquid nitrogen at ≤ -150 °C until thawing for use.

Do not refreeze.

6. Contents of the package and other information

Composition of Yescarta

• The active substance is axicabtagene ciloleucel. Each single patient-specific infusion bag contains a dispersion of anti-CD19 CAR T cells in approximately 68 mL, for a target dose of 2 x 10⁶ 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, dimethylsulfoxide (DMSO) and residual gentamicin”.

This medicinal product contains genetically modified human blood cells.

Appearance of the product and contents of the pack

Yescarta is an infusion dispersion ranging from transparent to opaque, white to red in colour, supplied in a single infusion bag packaged individually 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

The Netherlands

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

This information is intended for healthcare professionals only:

It is important that you read all information regarding this procedure before administering Yescarta.

Precautions to be taken before handling or administering the medicine

At the administration site, Yescarta must be transported in closed, leak-proof and break-resistant containers.

This medicine contains human blood cells. Healthcare professionals handling Yescarta must take appropriate precautions (wearing gloves and goggles) to prevent possible transmission of infectious diseases.

Work surfaces and materials that may have come into contact with Yescarta must be decontaminated using an appropriate disinfectant.

Preparation prior to administration

• Verify that the patient 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 correspond to the patient to be treated.
• Once patient ID has been confirmed, remove the Yescarta bag from the metal container.
• Check that the patient information on the label of the metal container matches that on the bag label.
• Inspect the product bag to verify container integrity before thawing. If the bag is damaged, follow local guidelines for disposal of human-source materials (or contact Kite immediately).

Thawing

• Place the infusion bag into a secondary bag.
• Thaw Yescarta at approximately 37 °C, using a water bath or dry thawing method, until no visible ice remains in the infusion bag. Gently mix the contents of the bag to eliminate cellular aggregates. If visible cellular aggregates persist, continue gently mixing the bag contents. Small cellular aggregates should be dispersed by gentle manual mixing. Yescarta must not be washed, centrifuged, and/or resuspended in a new medium prior to infusion. Thawing takes approximately 3 to 5 minutes.
• After thawing, Yescarta is stable at room temperature (between 20 °C and 25 °C) for up to 3 hours. However, infusion of Yescarta should be initiated within 30 minutes after complete thawing.

Administration

• DO NOT use a leukocyte-depletion filter.
• The medicine must be administered in a qualified medical center by one or more physicians experienced in the treatment of malignant hematological neoplasms and who have been trained in the administration and management of patients treated with Yescarta.
• Ensure that at least one dose of tocilizumab per patient and emergency equipment are available before infusion and during the recovery period. Hospitals must have access to an additional dose of tocilizumab within 8 hours after each previous dose. In the exceptional case that tocilizumab is unavailable due to a shortage listed in the European Medicines Agency’s shortage catalogue, ensure that alternative appropriate measures to treat CRS are available at the center instead of tocilizumab.
• Verify that the patient identity matches the patient identifiers on the infusion bag.
• Yescarta is intended for autologous use only.
• Yescarta must be administered as an intravenous infusion using latex-free intravenous lines without a leukocyte-depletion filter over a period of 30 minutes, either by gravity or using a peristaltic pump.
• During Yescarta infusion, gently agitate the bag to prevent cellular aggregation. The entire contents of the infusion bag must be administered.
• Prior to infusion, a 9 mg/ml (0.9%) sodium chloride solution (0.154 mmol sodium per ml) must be used to prime the lines and to flush them after infusion.
• After the total volume of Yescarta has been infused, the infusion bag must be flushed with 10 to 30 ml of 9 mg/ml (0.9%) sodium chloride solution for injection using a reverse prime to ensure delivery of the maximum number of cells possible to the patient.

Measures to be taken in case of accidental exposure

In case of accidental exposure, follow local guidelines for handling human-source materials. Work surfaces and materials that may have come into contact with Yescarta must be decontaminated with an appropriate disinfectant.

Precautions for disposal of the medicine

Unused medicine and all materials that have come into contact with Yescarta (solid and liquid waste) must be treated and disposed of as potentially infectious waste according to local guidelines for handling human-source materials.