CARVYKTI 3.2 × 10⁶ - 1 × 10⁸ CELLS FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

CARVYKTI 3.2 × 106– 1.0 × 108cells, dispersion for infusion

ciltacabtagene autoleucel (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 leaflet includes 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.
• 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.
• Your doctor or nurse will give you a patient information card that contains important safety information about treatment with CARVYKTI. Read it carefully and follow the instructions.
• Carry the patient information card with you at all times and show it to any doctor or nurse who treats you or if you go to the hospital.

Contents of the pack

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

1. What is CARVYKTI and what is it used for

• CARVYKTI is a type of medicine called “gene-modified cellular therapy”, which has been specially made for you from your own white blood cells, called T lymphocytes.
• CARVYKTI is used to treat adult patients with a type of bone marrow cancer called multiple myeloma. It is given when at least three other types of treatment have not worked.

How CARVYKTI works

• The white blood cells taken from your blood are modified in the laboratory to introduce a gene that allows them to produce a protein called chimeric antigen receptor (CAR).
• The CAR can bind to a specific protein on the surface of myeloma cells, allowing your white blood cells to recognize and attack the myeloma cells.

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

You must not be given CARVYKTI

• if you are allergic to any of the components of this medicine (listed in section 6).
• if you are allergic to any of the components of the medicines that you will be given to reduce the number of white blood cells in your blood (lymphodepletion treatment) before treatment with CARVYKTI (see also section 3, How CARVYKTI is given).

If you think you may be allergic, talk to your doctor.

Warnings and precautions

Tell your doctor before you are given CARVYKTI if you have:

• Current or past problems with your nervous system, such as seizures, strokes, new or worsening memory loss.
• Any lung, heart, or blood pressure problems (low or high).
• Liver or kidney problems.
• Signs or symptoms of graft-versus-host disease. This disease occurs when the transplanted cells attack your body, causing symptoms such as skin rash, nausea, vomiting, diarrhea, and bloody stools.

If you are in any of these situations (or are unsure), talk to your doctor before you are given CARVYKTI.

Tests and examinations

Before you are given CARVYKTI, your doctor:

• will check your blood cell counts
• will assess your lungs, heart, and blood pressure
• will look for signs of infection: infection will be treated before CARVYKTI is given
• will check if your cancer is getting worse
• will check if you have a hepatitis B, hepatitis C, or HIV infection
• will check if you have been vaccinated in the last 6 weeks or plan to be vaccinated in the coming months.

After treatment with CARVYKTI, your doctor:

• will regularly check your blood, as the number of blood cells and other blood components may decrease.

Tell your doctor right away if you have a fever, chills, or any signs or symptoms of an infection, if you feel tired, or if you have bruising or bleeding.

Be aware of possible serious side effects

There are serious side effects that you should tell your doctor or nurse about right away, which may require immediate medical attention. See section 4, “Serious side effects”.

Children and adolescents

CARVYKTI must not be used in children and adolescents under 18 years of age, as the medicine has not been studied in this age group and it is not known if it is safe and effective.

Other medicines and CARVYKTI

Before you are given CARVYKTI, tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines, especially:

• medicines that weaken your immune system, such as corticosteroids.

These medicines may interfere with the effect of CARVYKTI.

Vaccines and CARVYKTI

You must not be vaccinated with certain vaccines, called live vaccines:

• In the 6 weeks before you are given the short chemotherapy cycle (called lymphodepletion chemotherapy) to prepare your body for the CARVYKTI cells.
• After treatment with CARVYKTI, while your immune system is recovering.

Ask your doctor if you need to be vaccinated.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, talk to your doctor before you are given this medicine.

• This is because the effects of CARVYKTI on pregnant or breastfeeding women are not known.
• CARVYKTI may harm the unborn child or baby.

If you are pregnant or think you may be pregnant after treatment with CARVYKTI, talk to your doctor right away.

A pregnancy test must be done before you start treatment. CARVYKTI will only be given if the test shows you are not pregnant.

If you have been treated with CARVYKTI, you should discuss any future plans for pregnancy with your doctor.

Driving and using tools or machines

CARVYKTI may greatly affect your ability to drive or use tools or machines, as some side effects may make you:

• feel tired
• have problems with balance and coordination
• feel confused, weak, or dizzy.

Do not drive or use tools or machines until at least 8 weeks after you have been given CARVYKTI, or if these symptoms come back.

CARVYKTI contains dimethyl sulfoxide (DMSO) and kanamycin

This medicine contains DMSO (a substance used to preserve frozen cells) and may contain traces of kanamycin (an aminoglycoside antibiotic), which may cause allergic reactions in some cases. Your doctor will monitor you for signs of a possible allergic reaction.

3. How CARVYKTI is given

CARVYKTI will be given to you by a healthcare professional, always in a qualified center.

Preparation of CARVYKTI from your own blood cells

CARVYKTI is made from your own white blood cells. To prepare your medicine, some of your blood cells will be taken.

• Your doctor will take some of your blood with a catheter (line) that is put into a vein.
• Some of the white blood cells are separated from the blood; the rest of the blood is returned to the vein. This process is called “leukapheresis”.
• This process can take 3 to 6 hours and may need to be repeated.
• Your white blood cells will be sent to the manufacturing site, where they are modified to produce CARVYKTI. This process takes about 4 weeks.
• While CARVYKTI is being made, you may be given other medicines to treat your multiple myeloma. This is to prevent it from getting worse.

Medicines given before treatment with CARVYKTI

A few days before, you will be given a treatment called “lymphodepletion treatment” to prepare your body for CARVYKTI. This treatment reduces the number of white blood cells in your blood, so that the genetically modified white blood cells of CARVYKTI can grow in number when they are returned to your body.

You may be given other medicines 30 to 60 minutes before. These may include:

• antihistamines in case of an allergic reaction, such as diphenhydramine
• medicines for fever, such as paracetamol.

Your doctor or nurse will carefully check that the treatment with CARVYKTI is from your own white blood cells.

How CARVYKTI is given to you

CARVYKTI is a one-time treatment and will not be given to you again.

• Your doctor or nurse will give you CARVYKTI through a drip into a vein. This is called “intravenous infusion” and usually takes less than 60 minutes.

CARVYKTI is the genetically modified version of your white blood cells.

• The healthcare professional handling CARVYKTI will take the necessary precautions to avoid the possibility of transmitting infectious diseases.
• They will also follow local guidelines for cleaning or disposing of any materials that have come into contact with CARVYKTI.

After you are given CARVYKTI

• After you are given CARVYKTI, you must stay near the hospital where you received the treatment for at least 4 weeks.

• After you are given CARVYKTI, you will need to go back to the hospital every day for at least 14 days. This is so your doctor can check if the treatment is working and treat you if you have any side effects. If you have serious side effects, you may need to stay in the hospital until they are under control and you can be safely discharged.
• If you miss an appointment, call your doctor or the qualified center as soon as possible to make another appointment.

• To monitor your health and understand the long-term effects of CARVYKTI, you will be asked to register in a registry for at least 15 years.
• The presence of CARVYKTI in your blood may cause some commercial HIV tests to give a false positive result, even if you are HIV negative.
• Do not donate blood, organs, tissues, or cells for transplants after treatment with CARVYKTI.

4. Possible side effects

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

CARVYKTI may cause side effects that can be serious or even life-threatening.

Serious side effects

Get medical help right away if you have any of the following serious side effects that can be serious or even life-threatening.

• A serious immune reaction called “cytokine release syndrome (CRS)”, some of the signs of which are:

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

• chills, fever (38°C or higher),
• fast heart rate, difficulty breathing,
• low blood pressure, which can make you feel dizzy or faint.

• Effects on the nervous system, symptoms that can occur days or weeks after the infusion and can initially be subtle. Some of these symptoms can be signs of a serious immune reaction called “immune effector cell-associated neurotoxicity syndrome” (ICANS) or can be signs and symptoms of parkinsonism:

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

• feeling confused,
• reduced alertness, disorientation, anxiety, memory loss,
• difficulty speaking or slurred speech,
• slower movements, changes in handwriting

Common(may affect up to 1 in 10 people):

• loss of coordination that affects movement and balance,
• difficulty reading, writing, and understanding words,
• changes in personality, which can include being less talkative, feeling uninterested in activities, and reduced facial expression.

• CARVYKTI may increase the risk of life-threatening infections that can cause death.

If you notice any of the above side effects, get medical help right away.

Other side effects

The following are other side effects. If you have any of these side effects, tell your doctor or nurse.

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

• nose, sinus, or throat infection (cold)
• bacterial infection
• cough, shortness of breath
• headache
• pain, including muscle and joint pain
• stomach pain
• swelling caused by fluid build-up in the body
• feeling extremely tired
• nausea (feeling sick), reduced appetite, constipation, vomiting, diarrhea
• problems with movement, including muscle spasms, muscle tension
• nerve damage that can cause tingling, numbness, pain, or loss of pain sensation
• low levels of antibodies called immunoglobulins in the blood, which can cause infections
• abnormal blood test results that indicate:

• a low number of white blood cells (including neutrophils and lymphocytes) which can occur with infection and fever
• low levels of “platelets” (cells that help blood clot) and red blood cells
• low levels of calcium, sodium, potassium, magnesium, phosphate in the blood
• low levels of “albumin”, a type of protein in the blood
• low levels of “fibrinogen”, a type of protein in the blood, which can make it harder for blood to clot
• high levels of a protein called “ferritin” in the blood
• high levels of enzymes called “alkaline phosphatase”, “lactate dehydrogenase”, “gamma-glutamyltransferase”, and “transaminases” in the blood

• low oxygen levels in the blood, which can cause difficulty breathing, cough, headache, and confusion
• high blood pressure

Common(may affect up to 1 in 10 people):

• abnormal heart rhythm
• bleeding, which can be serious, called “hemorrhage”
• kidney failure
• pneumonia (lung infection)
• viral infection
• fungal infection
• serious infection throughout the body (sepsis)
• serious immune reaction that affects blood cells: can cause an increase in the size of the liver and spleen, called “hemophagocytic lymphohistiocytosis”.
• muscle tremors
• difficulty sleeping
• mild muscle weakness caused by nerve damage
• tingling, numbness, and pain in hands and feet, difficulty walking, weakness in leg and/or arm, and difficulty breathing
• facial numbness, difficulty moving facial and eye muscles
• high levels of “bilirubin” in the blood
• blood clots
• skin rash
• high levels of a protein called “C-reactive protein” in the blood, which can indicate infection or inflammation
• severe confusion
• a type of infection caused by the herpes virus, called “cytomegalovirus”

If you have any of these side effects, tell your doctor or nurse. Do not try to treat your symptoms with other medicines on your own.

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 CARVYKTI

The following information is intended only for healthcare professionals.

Do not use this medicine after the expiry date which is stated on the carton and on the infusion bag after “EXP”.

Store frozen in liquid nitrogen vapor phase (≤ -120°C) until it is needed for use.

Do not refreeze.

6. Container Content and Additional Information

Composition of CARVYKTI

The active substance is ciltacabtagene autoleucel.

Each CARVYKTI infusion bag contains a cellular dispersion of ciltacabtagene autoleucel that contains 3.2 × 10^6 to 1.0 × 10^8 viable CAR-positive T cells suspended in a cryopreservation solution.

An infusion bag contains 30 ml or 70 ml of infusion dispersion.

The other components are a solution (Cryostor CS5) used to preserve frozen cells (see section 2, CARVYKTI contains DMSO and kanamycin).

This medicinal product contains genetically modified human cells.

Appearance and Container Content of the Product

CARVYKTI is a colorless to white cellular dispersion for infusion, including shades of white, yellow, and pink, of 30 ml or 70 ml, supplied in a 50 ml or 250 ml infusion bag, respectively, individually packaged in an aluminum cryogenic container.

Marketing Authorization Holder

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

Manufacturer

Janssen Biologics B.V.

Einsteinweg 101

2333 CB Leiden

Netherlands

For further information on this medicinal product, please contact the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet: MM/YYYY.

This medicinal product has been authorized with a "conditional approval".

This type of approval means that more information on this medicinal product is expected.

The European Medicines Agency will review the new information on this medicinal product at least once a year, and this leaflet will be updated as necessary.

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu

This information is intended solely for healthcare professionals:

CARVYKTI should not be irradiated, as irradiation could inactivate the medicinal product.

Precautions to be taken before handling or administering the medicinal product

CARVYKTI should be transported within the center in closed, breakage-proof, and leak-proof containers.

This medicinal product contains human blood cells. Healthcare professionals handling CARVYKTI should take appropriate precautions (wear gloves, protective clothing, and eye protection) to avoid the possible transmission of infectious diseases.

CARVYKTI should remain at ≤ -120 °C at all times until the contents of the bag are thawed for infusion.

Preparation before Administration

The time of thawing and infusion of CARVYKTI should be coordinated; the infusion time should be confirmed in advance, and the start time of thawing should be adjusted so that CARVYKTI is available for infusion when the patient is ready. Once thawed, the medicinal product should be administered immediately, and the infusion should be completed within 2.5 hours.

• Before preparing CARVYKTI, the patient's identity should be confirmed by comparing the patient identifiers on the CARVYKTI cryogenic container and the batch information sheet. The CARVYKTI infusion bag should not be removed from the cryogenic container if the patient-specific information on the label does not match the intended patient.
• Once the patient's identity has been confirmed, the CARVYKTI infusion bag should be removed from the cryogenic container.
• The infusion bag should be inspected for any damage to the container integrity, such as breaks or cracks, both before and after thawing. Do not administer the product if the bag is damaged, and contact Janssen-Cilag International NV.

Thawing

• Before thawing, the infusion bag should be placed inside a sealed plastic bag.
• CARVYKTI should be thawed at 37 °C ± 2 °C using a water bath or a dry thawing device until no ice is visible in the infusion bag. The total time from the start of thawing to completion should not exceed 15 minutes.
• The infusion bag should be removed from the sealed plastic bag and dried with a cloth. The contents of the infusion bag should be gently mixed to disperse any aggregated cellular material. If aggregated cells are observed, continue to gently mix the contents of the bag. Small aggregations of cellular material should be manually dispersed gently. CARVYKTI should not be pre-filtered into a different container, washed, centrifuged, and/or resuspended in new media before infusion.
• Once thawed, the medicinal product should not be refrozen or refrigerated.

Administration

• CARVYKTI is for autologous use only.
• Before infusion and during the recovery period, ensure that tocilizumab and emergency equipment are available. In the exceptional case where tocilizumab is not available due to a shortage listed on the European Medicines Agency's shortage list, ensure that the center has adequate alternative measures for the treatment of CRS instead of tocilizumab.
• Confirm the patient's identity with the patient identifiers on the CARVYKTI infusion bag and the batch information sheet. Do not infuse CARVYKTI if the patient-specific information on the label does not match the intended patient.
• Once thawed, the entire contents of the CARVYKTI bag should be administered via intravenous infusion within 2.5 hours at room temperature (20 °C to 25 °C), using infusion equipment with an in-line filter. The infusion usually takes less than 60 minutes.
• DO NOT use a leucodepletion filter.
• Gently mix the contents of the bag during the infusion of CARVYKTI to disperse any aggregated cells.
• After the entire contents of the product bag have been infused, flush the administration line, including the in-line filter, with a 9 mg/ml (0.9%) sodium chloride injection solution to ensure that all of the medicinal product is administered.

Precautions to be taken for the disposal of the medicinal product

Handling and disposal of unused medicinal product and all materials that have come into contact with CARVYKTI (solid and liquid waste) should be done as if they were potentially infectious and in accordance with local regulations for handling human-derived material.

Measures to be taken in case of accidental exposure

In case of accidental exposure, follow local regulations for handling human-derived material. Work surfaces and materials that may have come into contact with CARVYKTI should be decontaminated with a suitable disinfectant.