Tecartus: detailed information

Package leaflet: Information for the patient

Tecartus, 0.4 – 2 × 10 cells, dispersion for infusion

brexucabtagene autoleucel (viable CAR T cells)
This medicinal product is subject to additional monitoring. This will allow for 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.
Your doctor will provide you with a patient alert card. Please 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 have any questions, ask your doctor or nurse.
If you experience any side effects, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet

What Tecartus is and what it is used for
What you need to know before you are given Tecartus
How Tecartus is administered
Possible side effects
How to store Tecartus
Contents of the pack and other information

1. What Tecartus is and what it is used for

Tecartus is a gene therapy used to treat mantle cell lymphoma and B-cell acute lymphoblastic leukaemia in adults. It is used when other available treatments have failed (relapsed or refractory disease). The medicine is specially manufactured for you from your own white blood cells, which have been modified, and is known as brexucabtagene autoleucel.
Mantle cell lymphoma and B-cell acute lymphoblastic leukaemia are types of cancers that affect part of the immune system (the body's defences), involving a type of white blood cell known as B-lymphocytes. In both mantle cell lymphoma and B-cell acute lymphoblastic leukaemia, B-lymphocytes multiply uncontrollably and accumulate in the lymphatic tissue, bone marrow or blood.
How Tecartus works
White blood cells are collected from your blood and genetically modified so that they can target cancer cells in the body. When Tecartus is infused into the bloodstream, the modified white blood cells destroy the cancer cells.

2. What you should know before receiving Tecartus

Do not receive Tecartus

if you are allergic to any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, consult your doctor;
if you cannot receive the medicine used to reduce the number of white blood cells in the blood ( lymphodepleting chemotherapy ) (see also section 3, How Tecartus is administered).

Warnings and precautions
Tecartus is manufactured using your own white blood cells and must be administered only to you ( autologous use ).
Patients treated with Tecartus may develop new types of cancer. Cases have been reported in patients who, after treatment with similar medicines, developed a cancer originating from a type of white blood cells called T cells. Contact your doctor if you develop new swelling of the glands (lymph nodes) or skin changes such as new nodules or rashes.
Tests and monitoring
Before receiving Tecartus, your doctor will perform the following checks:

assessment of lungs, heart, kidneys, and blood pressure
tests to detect signs of infection or inflammation, and to determine whether these need to be treated before Tecartus infusion
tests to detect any worsening of the tumor
assessment for signs of graft-versus-host disease, which may occur after transplantation. This condition arises when transplanted cells attack the recipient’s body, causing symptoms such as rash, nausea, vomiting, diarrhea, and blood in the stool
blood tests to check for uric acid levels and to count the number of circulating tumor cells. This helps determine whether you are at risk of developing a condition called tumor lysis syndrome. You may be given medications to help prevent this condition
tests for hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV) infection
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 the protein called CD19.

In some cases, treatment with Tecartus may not be possible. If the Tecartus infusion is delayed by more than 2 weeks from the time you received lymphodepleting chemotherapy, you may need to undergo lymphodepleting chemotherapy again (see section 3, How Tecartus is administered).
After receiving Tecartus 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, rapid or irregular heartbeat, severe nausea, vomiting, or diarrhea, which could be symptoms of a condition called cytokine release syndrome. Measure your body temperature twice daily for 3–4 weeks after treatment with Tecartus. If your temperature is high, contact your 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 low red blood cell count
bleeding or easy bruising, which could be a sign of low levels of blood cells called platelets.

If you experience any of the above conditions (or are unsure), contact your doctor or nurse.
Your doctor will regularly monitor your blood cell counts, as the number of red blood cells and other blood components may decrease.
You may be asked to enroll in a registry for at least 15 years to better understand the long-term effects of Tecartus.
Do not donate blood, organs, tissues, or cells for transplantation.
Children, adolescents, and young adults
Tecartus must not be used in children and adolescents under 18 years of age or in young adults under 26 years of age.
Other medicines and Tecartus
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Before receiving Tecartus, inform your doctor or nurse if you are taking medicines that weaken the immune system, such as corticosteroids, as these may interfere with the effect of Tecartus.
In particular, certain vaccines known as live vaccines must not be given:

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

Talk to your doctor if you need vaccinations.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor before receiving this medicine. The effects of Tecartus in pregnant or breastfeeding women are unknown and could harm the fetus or breastfed infant.

If you are pregnant or suspect you are pregnant after treatment with Tecartus, inform your doctor immediately.
You will need to undergo a pregnancy test before starting treatment. Tecartus may only be administered if test results confirm you are not pregnant.

Discuss with your doctor the possibility of pregnancy after receiving Tecartus.
Driving and using machines
Tecartus may cause problems such as altered mental status or reduced level of consciousness, confusion, and seizures within 8 weeks after administration.
Avoid driving, operating machinery, or engaging in activities requiring high levels of alertness for at least 8 weeks after treatment with Tecartus, or until your doctor confirms you have fully recovered.
Tecartus contains sodium, dimethyl sulfoxide (DMSO), and gentamicin
This medicine contains 300 mg of sodium (a main component of table salt) per infusion bag. This corresponds to 15% of the maximum daily dietary intake recommended for an adult. It also contains DMSO and gentamicin, which may cause severe hypersensitivity reactions.

3. How Tecartus is administered

Tecartus will always be administered to you by a healthcare professional.

Since Tecartus is manufactured using your own 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 may need to be repeated.
The white blood cells will be sent to a manufacturing center for the production of Tecartus. It usually takes about 2–3 weeks for Tecartus to be ready, but the timing may vary.

Medicines administered before treatment with Tecartus
A few days before receiving Tecartus, you will undergo lymphodepleting chemotherapy, which will allow the modified white blood cells in Tecartus to multiply in your body once the medicine is administered.
From 30 to 60 minutes before the administration of Tecartus, you may be given additional medicines to prevent infusion reactions and fever. These medicines may include:

paracetamol;
an antihistamine such as diphenhydramine.

How Tecartus will be administered to you
Tecartus will always be administered in a clinical center.

Tecartus is given as a single dose.
Your doctor or nurse will administer Tecartus to you as a single infusion through a catheter inserted into a vein ( intravenous infusion ) over approximately 30 minutes.
Tecartus is the genetically modified version of your white blood cells. Therefore, the healthcare professional handling the treatment will take appropriate precautions (wearing gloves and eye protection) to avoid potential transmission of infectious diseases and will follow local guidelines for handling waste of human origin materials when cleaning or disposing of all materials that have come into contact with Tecartus.

After you have received Tecartus

You must remain near a hospital, as discussed with your doctor, for at least 4 weeks after receiving Tecartus. Your doctor will advise you to go to the hospital daily for at least 7 days or to remain hospitalized for the first 7 days after treatment with Tecartus. This allows your doctor to monitor whether the treatment is working and to assist you if any side effects occur.

If you are unable to attend an appointment, contact your doctor or treatment center as soon as possible to schedule a new appointment date.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Do not try to treat side effects on your own.
Tecartus may cause side effects, some of which can be serious or potentially fatal. Contact your doctor
immediately if you experience any of the following side effects after Tecartus infusion.

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

Fever, chills, low blood pressure, which may cause symptoms such as dizziness, feeling faint, fluid in the lungs. These symptoms can be severe and may even lead to death (all are symptoms of a condition called cytokine release syndrome).
Loss of consciousness or reduced level of consciousness, confusion or memory loss due to brain function disturbances, difficulty speaking or slurred speech, involuntary tremor, sudden confusion with agitation, disorientation, hallucinations or irritability (delirium).
Fever, chills, which may be signs of infection.

Other serious side effects requiring immediate medical treatment include:
Common (may affect up to 1 in 10 people)

Seizures (including epileptic seizures, or a series of seizures lasting longer than 5 minutes).

Other possible side effects
The following side effects may also occur. If any of these become severe or serious, contact your doctor immediately.
Very common (may affect more than 1 in 10 people)

Abnormally low white blood cell count, which may increase the risk of infection.
Low number of cells that help blood clot (thrombocytopenia): symptoms may include excessive or prolonged bleeding or bruising.
High blood pressure.
Decreased number of red blood cells (cells that carry oxygen in the blood): symptoms may include extreme tiredness and loss of energy.
Extreme tiredness.
Fast or slow heartbeat.
Reduced oxygen supply to body tissues: symptoms may include changes in skin color, confusion, and rapid breathing.
Shortness of breath, cough.
Excessive bleeding.
Nausea, constipation, diarrhoea, abdominal pain, vomiting.
Muscle, joint, and bone pain, limb pain.
Lack of energy or strength, muscle weakness, difficulty moving, muscle spasm.
Headache.
Kidney problems causing fluid retention by the body, fluid accumulation in tissues (edema), which may lead to weight gain and difficulty breathing.
Elevated levels of uric acid and sugar (glucose), detected through blood tests.
Decreased levels of sodium, magnesium, phosphate, potassium, or calcium, detected through blood tests.
Reduced appetite, painful mouth.
Difficulty sleeping, anxiety.
Swelling of limbs, fluid around the lungs (pleural effusion).
Rash or skin problems.
Lowered levels of immunoglobulins, detected through blood tests, which could lead to infections.
Increased liver enzymes, detected through blood tests.
Nerve pain.

Common (may affect up to 1 in 10 people)

Low levels of albumin, detected through blood tests.
Elevated bilirubin levels, detected through blood tests.
Irregular heartbeat (arrhythmia).
Inability to control body movements.
Dry mouth, dehydration, difficulty swallowing.
Decreased urine production (due to the previously mentioned kidney problems).
Shortness of breath (respiratory failure).
Breathing difficulties making it hard to speak a full sentence, cough due to fluid in the lungs.
Increased pressure inside the skull.
Blood clots: symptoms may include chest or upper back pain, difficulty breathing, coughing up blood, or painful cramps, swelling in one leg, warm and discolored skin around the painful area.
Impaired blood clotting (coagulopathy): symptoms may include excessive or prolonged bleeding or bruising.
Vision changes, making it difficult to see things.
Infusion-related reactions: symptoms include dizziness or fainting, flushing, rash, itching, fever, shortness of breath or vomiting, abdominal pain and diarrhoea.
Hypersensitivity: symptoms may include rash, hives, itching, swelling, and anaphylaxis.

For similar medicines, a new type of cancer originating in a type of white blood cells called T cells (malignant secondary neoplasm of T-cell origin) has been reported.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, speak to your doctor or nurse. You can also report side effects directly through the national reporting system listed in Annex V. Reporting side effects helps provide more information on the safety of this medicine.

5. How to store Tecartus

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 gaseous phase of liquid nitrogen at a temperature ≤ −150 °C until thawing.
Tecartus may be stored once at -80 °C (±10 °C) for a maximum of 90 days. The product stored at -80 °C (±10 °C) must be used within 90 days or by the expiry date, whichever comes first. After these dates have been exceeded, the product must be discarded.
Do not refreeze.

6. Package contents and other information

What Tecartus contains
The active substance is brexucabtagene autoleucel (infusion dispersion containing 0.4 – 2 × 10 cells).
Each single patient-specific infusion bag contains a dispersion of viable anti-CD19 CAR-positive T cells, approximately 68 mL, for a target dose of 2 × 10 viable anti-CD19 CAR-positive T cells/kg in patients with mantle cell lymphoma and a target dose of 1 × 10 viable anti-CD19 CAR-positive T cells/kg in patients with B-cell acute lymphoblastic leukemia.
The other components (excipients) are: Cryostor CS10 (contains DMSO), sodium chloride, human albumin. See section 2 “Tecartus contains sodium, dimethyl sulfoxide (DMSO), and residual gentamicin”.
This medicinal product contains genetically modified human blood cells.

Description of the appearance of Tecartus and contents of the pack
Tecartus is an infusion dispersion, ranging from clear to opaque, in color from white to red, supplied in a single infusion bag packed within a metal container. A single infusion bag contains approximately 68 mL of cellular dispersion.

Marketing Authorization Holder
Kite Pharma EU B.V.
Tufsteen 1
2132 NT Hoofddorp
The Netherlands

Manufacturer
Kite Pharma EU B.V.
Tufsteen 1
2132 NT Hoofddorp
The Netherlands

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

Belgium/Belgium/Belgium Lithuania
Gilead Sciences Belgium SRL-BV Gilead Sciences Poland Sp. z o.o.
Tel: + 32 (0) 24 01 35 50 Tel: + 48 22 262 8702

Bulgaria Luxembourg/Luxembourg
Gilead Sciences Ireland UC Gilead Sciences Belgium SRL-BV
Tel: + 353 (0) 1 686 1888 Tel: + 32 (0) 24 01 35 50

Czech Republic Hungary
Gilead Sciences s.r.o. Gilead Sciences Ireland UC
Tel: + 420 910 871 986 Tel: + 353 (0) 1 686 1888

Denmark Malta
Gilead Sciences Sweden AB Gilead Sciences Ireland UC
Tlf: + 46 (0) 8 5057 1849 Tel: + 353 (0) 1 686 1888

Germany Netherlands
Gilead Sciences GmbH Gilead Sciences Netherlands B.V.
Tel: + 49 (0) 89 899890-0 Tel: + 31 (0) 20 718 36 98

Estonia Norway
Gilead Sciences Poland Sp. z o.o. Gilead Sciences Sweden AB
Tel: + 48 22 262 8702 Tlf: + 46 (0) 8 5057 1849

Greece Austria
Gilead Sciences Hellas MEPE Gilead Sciences GesmbH
Tel: + 30 210 8930 100 Tel: + 43 1 260 830

Spain Poland
Gilead Sciences, S.L. Gilead Sciences Poland Sp. z o.o.
Tel: + 34 91 378 98 30 Tel: + 48 22 262 8702

France Portugal
Gilead Sciences Gilead Sciences, Lda.
Tel: + 33 (0) 1 46 09 41 00 Tel: + 351 21 7928790

Croatia Romania
Gilead Sciences Ireland UC Gilead Sciences Ireland UC
Tel: + 353 (0) 1 686 1888 Tel: + 353 (0) 1 686 1888

Ireland Slovenia
Gilead Sciences Ireland UC Gilead Sciences Ireland UC
Tel: + 353 (0) 214 825 999 Tel: + 353 (0) 1 686 1888

Iceland Slovakia
Gilead Sciences Sweden AB Gilead Sciences Slovakia s.r.o.
Sími: + 46 (0) 8 5057 1849 Tel: + 421 232 121 210

Italy Finland
Gilead Sciences S.r.l. Gilead Sciences Sweden AB
Tel: + 39 02 439201 Puh/Tel: + 46 (0) 8 5057 1849

Cyprus Sweden
Gilead Sciences Hellas MEPE Gilead Sciences Sweden AB
Tel: + 30 210 8930 100 Tel: + 46 (0) 8 5057 1849

Latvia United Kingdom (Northern Ireland)
Gilead Sciences Poland Sp. z o.o. Gilead Sciences Ireland UC
Tel: + 48 22 262 8702 Tel: + 44 (0) 8000 113700

This medicinal product has been granted a conditional marketing authorization.
This means that additional data will be required in the future for this medicinal product.
The European Medicines Agency will review new information on this medicinal product at least annually, and this package leaflet will be updated as necessary.

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu. Links to other websites on rare diseases and their treatments are also provided.
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The following information is intended exclusively for healthcare professionals:

It is important that you read the entire content of the procedure before administering Tecartus.
Precautions to be taken before handling or administering the medicinal product
Tecartus must be transported within the facility in closed, non-breakable, and airtight containers.
This medicinal product contains human blood cells. Healthcare professionals handling Tecartus 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 Tecartus must be decontaminated according to local guidelines for the handling of waste from human materials.
Preparation prior to administration

Verify that the patient’s identity matches the patient identifiers listed on the Tecartus metal container.
The infusion bag containing the Tecartus product must not be removed from the metal container if the patient-specific information on the label does not match the intended patient.
Once the patient’s identity has been confirmed, remove the infusion bag from the metal container.
Check that the patient information on the label of the metal container 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 the handling of waste from human materials (or contact Kite immediately).

Thawing

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

DO NOT use a leukocyte-depletion filter.
Administration

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 Tecartus.
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 and associated centers 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 short-supplied 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.
Tecartus is for autologous use only.
Tecartus must be administered via intravenous infusion through a latex-free intravenous line without a leukocyte-depletion filter, either by gravity over 30 minutes or by a peristaltic pump.
Gently agitate the infusion bag during infusion to avoid formation of cellular aggregates. The entire contents of the infusion bag 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 infusion. After completion of the entire Tecartus volume infusion, flush the infusion bag with 10–30 mL of sterile 0.9% sodium chloride solution 9 mg/mL (0.9%) using the “back priming” technique to ensure that the maximum number of cells possible is infused into the patient.

Precautions for disposal of the medicinal product
Unused medicinal product and waste materials that have come into contact with Tecartus (solid and liquid waste) must be handled and disposed of as potentially infectious waste according to local guidelines for the handling of human materials.
Accidental exposure
In the event of accidental exposure, follow local guidelines for the handling of human materials, which may include washing contaminated skin and removing contaminated clothing. Work surfaces and materials that may have come into contact with Tecartus must be decontaminated using an appropriate disinfectant.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION(S)
Scientific conclusions
Taking into account the assessment of the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for brexucabtagene autoleucel, the PRAC’s scientific conclusions are as follows:
In light of available data on status epilepticus from clinical trials and spontaneous reports, in some cases including a close temporal relationship, and in light of a plausible mechanism of action, the PRAC considers that a causal relationship between brexucabtagene autoleucel and status epilepticus is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing brexucabtagene autoleucel should be amended accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.
Grounds for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions for brexucabtagene autoleucel, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing brexucabtagene autoleucel remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation(s).