Yescarta

Italy
Brand name Yescarta
Form solution for infusion
Active substance / Dosage
AXICABTAGENE CILOLEUCEL
Prescription type Restricted prescription – hospital or equivalent facility use only
ATC code
L01XL03
Registration number 046995
Manufacturer KITE PHARMA EU B.V.
Yescarta solution for infusion

Table of Contents

Package leaflet: Information for the patient

Yescarta 0.4 – 2 × 10^6 cells infusion dispersion

axicabtagene ciloleucel (viable CAR-positive T cells)
Medicinal product subject to additional monitoring. This will allow rapid identification of new
safety information. You can help by reporting any side effects you experience while taking
this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before you are given this medicine because it contains
important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any questions, ask your doctor or nurse.
  • Your doctor will provide you with a patient alert card. Read it carefully and follow the instructions contained therein.
  • Always show your patient alert card to your doctor or nurse during visits or if you go to hospital.
  • If you experience any side effect, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet

  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 medicinal product used to treat adults with aggressive lymphoma, such as diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL), which affect the lymphatic tissue (part of the immune system) and other organs in the body, involving a type of white blood cells known as B-lymphocytes. The symptoms it may cause are due to the accumulation of excessive amounts of these abnormal white blood cells in tissues.
This medicine is specially prepared for you and consists of a single administration of your own modified white blood cells.
How Yescarta works
White blood cells are collected from your blood and genetically modified so that they target cancer cells present in the body. When Yescarta is infused into the bloodstream, the modified white blood cells destroy the cancer cells.

2. What you should know before being given Yescarta

Do not receive 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 the treatment known as lymphodepleting chemotherapy, which reduces the number of white blood cells in the blood (see also section 3, How Yescarta is administered).

Warnings and precautions
Yescarta is made from your own white blood cells and must be administered only to you (autologous use).
Patients treated with Yescarta may develop new types of cancer. Cases have been reported of patients who, after treatment with Yescarta or similar medicines, developed a cancer originating from blood cells. Contact your doctor if you develop new swelling of the glands (lymph nodes) or skin changes such as new lumps or rashes.
Before receiving Yescarta, inform your doctor if any of the following apply to you:

  • you have problems with your nervous system (such as seizures, stroke, or memory loss).
  • you have kidney problems.
  • you have low levels of blood cells (blood counts).
  • you have had a stem cell transplant within the last 4 months.
  • you have lung, heart, or blood pressure problems (high or low).
  • you have signs or symptoms of graft-versus-host disease. This condition occurs when transplanted cells attack the recipient’s body, causing symptoms such as rash, nausea, vomiting, diarrhoea, and blood in the stool.
  • you notice a worsening of tumour symptoms. If you have lymphoma, these may include fever, feeling weak, night sweats, and sudden weight loss.
  • you have an infection. The infection will be treated before Yescarta infusion.
  • you have had infections with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV).

If any of the above situations apply to you (or if you are not completely sure), speak with your doctor before receiving Yescarta. Your doctor may need to monitor you more closely during treatment with Yescarta.
Tests and checks
Before receiving Yescarta, your doctor will perform the following checks:

  • examination of your lungs, heart, kidneys, and blood pressure.
  • tests to detect signs of infection or inflammation, and decide whether you need treatment before Yescarta infusion.
  • tests to detect worsening of the tumour.
  • examination for signs of graft-versus-host disease, which may occur after a transplant. This condition occurs when transplanted cells attack the recipient’s body, causing symptoms such as rash, nausea, vomiting, diarrhoea, and bloody stools.
  • blood tests to check for uric acid levels and to count how many tumour cells are circulating. This helps determine whether you are likely to develop a condition called tumour lysis syndrome. You may be given medicines to help prevent this condition.
  • tests for infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV).
  • check whether you received a vaccination within the previous 6 weeks or plan to receive one in the coming months.
  • check whether you previously received a treatment targeting a protein called CD19.

In some cases, it may not be possible to proceed with the planned Yescarta treatment. If the Yescarta infusion is delayed by more than 2 weeks from the time you received lymphodepleting chemotherapy, you may need to undergo chemotherapy again (see section 3, How Yescarta is administered).
After receiving Yescarta infusion
Contact your doctor or nurse immediately or go to the emergency room if you experience any of the following:

  • Chills, extreme tiredness, weakness, dizziness, headache, cough, shortness of breath, or rapid heartbeat, which could be symptoms of a condition called cytokine release syndrome. Measure your body temperature twice daily for 3–4 weeks after Yescarta treatment. If your temperature is high, go to the doctor immediately.
  • Seizures, tremors, difficulty speaking or slurred speech, loss of consciousness or reduced level of consciousness, confusion and disorientation, loss of balance or coordination.
  • Fever (e.g. temperature above 38°C), which could be a sign of infection.
  • Extreme tiredness, weakness, and shortness of breath, which could be symptoms of a shortage of red blood cells.
  • You bleed or bruise more easily, which could be a sign of low levels of blood cells called platelets.
  • Blurred vision, loss of vision, double vision, difficulty speaking, weakness or lack of coordination in one arm or leg, changes in the way you walk or problems with balance, personality changes, or changes in thinking, memory, and orientation leading to confusion. All of these could be symptoms of a serious and potentially fatal brain disease known as progressive multifocal leukoencephalopathy. These symptoms may begin several months after treatment ends and usually develop slowly and gradually over weeks or months. It is important that your family members or caregivers are also aware of these symptoms, as they may notice signs you do not.

If any of the above situations apply to you (or if you are not completely sure), contact your doctor or nurse.
Your doctor will regularly perform blood counts, as the number of red blood cells and other blood components may decrease.
You may be asked to be enrolled in a registry for at least 15 years to better understand the long-term effects of Yescarta.
Do not donate blood, organs, tissues, or cells for transplantation.
Children and adolescents
Yescarta must not be used in children and adolescents under 18 years of age, as Yescarta has not been studied in this age group.
Other medicines and Yescarta
Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Before receiving Yescarta, inform your doctor or nurse if you are taking medicines that weaken the immune system, such as corticosteroids, as these medicines may interfere with the effect of Yescarta.
In particular, certain vaccines known as live vaccines must not be given:

  • within the 6 weeks before receiving the short course of chemotherapy (called lymphodepleting chemotherapy) to prepare your body to receive Yescarta cells;
  • during treatment with Yescarta;
  • after treatment, while your immune system is recovering.

Talk to your doctor if you need vaccinations.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, plan to become pregnant, or are breastfeeding, ask your doctor for advice before this medicine is administered. The effects of Yescarta in pregnant women or those who are breastfeeding are unknown and could harm the unborn baby or breastfed infant.

  • If you are pregnant, or suspect pregnancy after Yescarta treatment, tell your doctor immediately.
  • You will need to have a pregnancy test before starting treatment. Yescarta may be administered only if test results show that you are not pregnant.

Discuss with your doctor the possibility of becoming pregnant after receiving Yescarta infusion.
Driving and using machines
Some people may experience tiredness, dizziness, or tremors after receiving Yescarta. For this reason, do not drive and do not operate heavy machinery for at least 8 weeks after infusion, or until your doctor determines that your recovery is complete.
Yescarta contains sodium, dimethyl sulfoxide (DMSO), and residual gentamicin
This medicine contains 300 mg of sodium (the main component of table salt) in each infusion bag. This is equivalent to 15% of the maximum daily dietary intake recommended for an adult.
This medicine contains DMSO and residual gentamicin, which may cause severe allergic reactions.

3. How Yescarta is administered

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

  • Since Yescarta is manufactured using your white blood cells, your cells will first be collected to prepare the medicine. Your doctor will collect some of your blood using a catheter inserted into a vein (a procedure called leukapheresis). Some of your white blood cells are separated from the blood, and the rest of the blood is returned to your vein. This procedure may take from 3 to 6 hours and might need to be repeated.
  • The collected white blood cells will be sent for manufacturing of Yescarta. It usually takes about 3–4 weeks before you receive Yescarta, but the timing may vary.

Other medicines administered before treatment with Yescarta
From 30 to 60 minutes before administration of Yescarta, you may be given other medicines to help prevent infusion reactions and fever. These medicines may include:

  • paracetamol;
  • an antihistamine such as diphenhydramine.

Before receiving Yescarta, you will be given additional medicines, for example, you will undergo lymphodepleting chemotherapy, which will allow the modified white blood cells in Yescarta to multiply in your body once the medicine is administered.
Your doctor or nurse will carefully verify that the medicine you receive is the one prepared specifically for you.
How Yescarta is administered
Yescarta will always be administered by a physician at a qualified clinical center.

  • Yescarta is administered as a single dose.
  • Your doctor or nurse will give you Yescarta as a single infusion through a catheter inserted into a vein (intravenous infusion). The infusion will last approximately 30 minutes.
  • Yescarta is the genetically modified version of your own white blood cells. Therefore, the healthcare professional handling the treatment will take appropriate precautions (such as wearing gloves and protective eyewear) to avoid potential transmission of infectious diseases and will follow local guidelines for handling waste materials of human origin to clean or dispose of all materials that have come into contact with Yescarta.

You will receive the Yescarta infusion at a qualified treatment center and will be discharged only when your doctor determines that it is safe for you to go home.
Your doctor may perform blood tests to monitor for possible adverse effects.
After administration of Yescarta

  • You must remain near a hospital, as discussed with your doctor, for at least 4 weeks after receiving Yescarta. Your doctor will advise you to go to the hospital daily for at least 7 days and will assess whether hospitalization is necessary during the first 7 days after infusion. This allows your doctor to monitor whether the treatment is working and to assist you promptly if any adverse effects occur.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
Yescarta can cause side effects affecting the immune system or the nervous system.
In addition, Yescarta can increase the risk of developing an infection. These side effects can be serious, potentially life-threatening, or may lead to death.
Inform your doctor immediately if you experience any of the following side 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 which may cause symptoms such as dizziness or feeling lightheaded, rapid heartbeat, irregular heartbeat (arrhythmia), low oxygen levels in the blood which may cause shortness of breath or difficulty breathing. These could be signs of a serious condition called cytokine release syndrome.
  • Loss of consciousness or reduced 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 trembling (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 shaking, which may be signs of infection (including bacterial or viral infection). Infections may 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 requiring immediate medical attention include:
Common (may affect up to 1 in 10 people)

  • Seizures (including seizures that may be prolonged and potentially life-threatening).
  • Sudden and unexpected stopping of the heartbeat (cardiac arrest) or heart failure.
  • Blood clots: symptoms may include chest or upper back pain, difficulty breathing, coughing up blood or cramping pain, swelling in one leg, warm and discolored skin around the painful area.
  • Inability to breathe independently (respiratory failure).
  • Kidney failure, during which the body retains fluids.
  • Fluid accumulation in the lungs (pulmonary edema), which may cause difficulty breathing.

Uncommon (may affect up to 1 in 100 people)

  • Severe systemic inflammation, whose symptoms may include fever, rash, enlarged liver, spleen and lymph nodes.
  • Failure of at least two organs (e.g. liver, lungs and kidneys) requiring treatment and/or medical procedures to restore normal organ function.

Other possible side effects
The following side effects have been observed with Yescarta:
Very common (may affect more than 1 in 10 people)

  • Decreased number of red blood cells (cells that carry oxygen): symptoms may include extreme tiredness and loss of energy.
  • Low number of cells contributing to blood clotting (thrombocytopenia): symptoms may include excessive or prolonged bleeding (hemorrhage) and bruising.
  • Low levels of sodium or phosphate detected by blood tests.
  • Elevated levels of uric acid or sugar (glucose) detected by blood tests.
  • Reduced appetite.
  • Difficulty sleeping.
  • Headache.
  • Dizziness.
  • Rapid heartbeat.
  • Irregular heartbeat (arrhythmia).
  • Low blood pressure.
  • High blood pressure.
  • Cough.
  • Nausea, constipation, diarrhea, abdominal pain, vomiting.
  • Increased liver enzymes detected by blood tests.
  • Rash or skin problems.
  • Muscle and joint pain, back pain.
  • Fluid accumulation in tissues (edema), which may cause swelling, weight gain, and reduced urine production.
  • Extreme tiredness.

Common (may affect up to 1 in 10 people)

  • Fungal infection.
  • Impaired ability of the blood to form clots (coagulopathy): symptoms may include excessive or prolonged bleeding (hemorrhage) and bruising.
  • Hypersensitivity: symptoms may include rash, hives, itching, swelling, and anaphylaxis.
  • Low levels of albumin, potassium or calcium detected by blood tests.
  • Dehydration.
  • Weight loss.
  • Anxiety.
  • Mood disorders.
  • Loss of control over body movements.
  • Weakness or inability to move one side of the body, resulting in difficulty performing daily activities such as eating or dressing.
  • Loss of facial muscle movements.
  • Pain in hands or feet.
  • Muscle spasms.
  • Vision changes, making it difficult to see things (impaired vision).
  • Low oxygen levels in the blood.
  • Fluid around the lungs (pleural effusion).
  • Shortness of breath, difficulty breathing.
  • Nasal inflammation.
  • Dry mouth, difficulty swallowing.
  • Elevated bilirubin levels detected by blood tests.
  • Infusion-related reactions: symptoms may include dizziness or fainting, flushing, rash, itching, fever, shortness of breath or vomiting, abdominal pain and diarrhea.
  • Pain.

Uncommon (may affect up to 1 in 100 people)

  • Paralysis of all four limbs.
  • Swelling of the spinal cord which may cause partial or complete paralysis of limbs and trunk.
  • Difficulty understanding numbers.
  • Weakness in legs or arms.
  • Breakdown of muscle tissue causing the release of muscle fibers into the blood.
  • A new type of cancer originating from a type of white blood cells called T cells (malignant secondary neoplasm of T-cell origin).

Inform your doctor immediately if you experience any of the side effects listed above.
Do not attempt to treat symptoms on your own by taking other medicines.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Yescarta

The following information is intended for healthcare professionals only.
Do not use this medicinal product after the expiry date stated on the container label and on the infusion bag after "Exp.".
Store frozen in the vapour phase of liquid nitrogen at a temperature below ≤ -150 °C until thawing.
Do not refreeze.

6. Package contents and other information

What Yescarta contains

  • 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 × 106 viable anti-CD19 CAR T cells/kg.
  • The other ingredients (excipients) are: Cryostor CS10 (contains DMSO), sodium chloride, human albumin. See section 2 “Yescarta contains sodium, dimethyl sulfoxide (DMSO) and residual gentamicin”.

The following information is intended exclusively for healthcare professionals:

It is important that you read the entire content of this procedure before administering Yescarta.
Precautions to be taken before handling or administration of the medicinal product
Yescarta must be transported within the facility in closed, unbreakable, and airtight containers.
This medicinal product contains human blood cells. Healthcare professionals handling Yescarta must take appropriate precautions (wear gloves and eye protection) to avoid potential transmission of infectious diseases.
Work surfaces and materials that may have come into contact with Yescarta must be decontaminated according to local guidelines for handling waste from human materials.

Preparation prior to administration

  • Verify that the patient's identity matches the patient identifiers on the Yescarta metal container label.
  • The Yescarta infusion bag must not be removed from the metal container if the patient-specific information on the label does not correspond to the intended patient.
  • After confirming the patient's identity, remove the Yescarta infusion bag from the metal container.
  • Check that the patient information on the metal container label matches the information on the infusion bag label.
  • Visually inspect the infusion bag for any damage to container integrity before thawing. If the infusion bag is damaged, follow local guidelines for disposal of human material waste (or contact the Marketing Authorisation Holder, Kite, immediately).

Thawing

  • Place the infusion bag into a secondary bag.
  • Thaw Yescarta at approximately 37 °C using a water bath or a dry thawing method until all visible ice has disappeared from the infusion bag. Gently mix the contents of the infusion bag to disperse any cellular aggregates. If cellular aggregates are still visible, continue gently mixing the contents. Small aggregates of cellular material should disperse when the bag contents are gently agitated manually. Yescarta must not be washed, centrifuged, and/or resuspended in another fluid prior to infusion. Thawing should take approximately 3–5 minutes.
  • Once thawed, Yescarta is stable at room temperature (between 20 °C and 25 °C) for up to 3 hours. However, infusion of Yescarta must begin within 30 minutes after completion of thawing.

Administration

  • DO NOT use a leukocyte-depleting filter.
  • The medicinal product must be administered in a qualified clinical center by physicians experienced in the treatment of hematological malignancies and trained in the administration and management of patients treated with Yescarta.
  • Ensure that emergency equipment and at least one dose of tocilizumab are available for each patient prior to infusion and during the recovery period. Hospitals must have access to an additional dose of tocilizumab within 8 hours of administration of each preceding dose. In the exceptional case where tocilizumab is unavailable due to a shortage listed in the European Medicines Agency’s list of critically endangered medicines,

adequate alternative measures to tocilizumab for the treatment of CRS must be available prior to infusion.

  • The patient’s identity must match the patient identifiers on the infusion bag.
  • Yescarta is for autologous use only.
  • Yescarta must be administered via intravenous infusion through a latex-free intravenous line without a leukocyte-depleting filter, either by gravity within 30 minutes or via a peristaltic pump.
  • Gently agitate the infusion bag during Yescarta infusion to prevent the formation of cellular aggregates. The entire contents of the infusion bags must be infused.
  • Flush the infusion lines with sterile 0.9% sodium chloride solution 9 mg/mL (0.9%) (0.154 mmol sodium per mL) before and after the infusion. After completion of the infusion of the entire volume of Yescarta, flush the infusion bag with 10–30 mL of sterile 0.9% sodium chloride solution using the “back priming” technique to ensure that the maximum number of cells possible is infused into the patient.

Measures to be taken in case of accidental exposure
In case of accidental exposure, follow local guidelines for handling human material, which may include washing contaminated skin and removing contaminated clothing. Work surfaces and materials that may have come into contact with Yescarta must be decontaminated using an appropriate disinfectant.

Precautions for disposal of the medicinal product
Unused medicinal product and all materials that have come into contact with Yescarta (solid and liquid waste) must be handled and disposed of as potentially infectious waste in accordance with local guidelines for handling human material.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS OF THE
MARKETING AUTHORISATION(S)
Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for axicabtagene ciloleucel, the scientific conclusions of the PRAC are as follows:
In light of available data on hemorrhage from clinical trials, literature, and spontaneous reports, including in some cases a close temporal relationship and considering a plausible mechanism of action, the PRAC considers that a causal relationship between axicabtagene ciloleucel and hemorrhage is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing axicabtagene ciloleucel should be amended accordingly.
In light of available data on secondary myeloid origin tumors from clinical trials, literature, registry-based studies, and spontaneous reports, including a high proportion of fatal cases, the PRAC considers that a warning on secondary myeloid origin tumors should be included in the product information for medicinal products containing axicabtagene ciloleucel.
In light of available data on secondary malignant T-cell neoplasms from spontaneous reports, the PRAC concluded that the frequency reported in the product information for medicinal products containing axicabtagene ciloleucel should be updated.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and rationale of the recommendation.

Reasons for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions for axicabtagene ciloleucel, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing axicabtagene ciloleucel remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).