Breyanzi

Package leaflet: Information for the patient

Breyanzi 1.1-70 × 10 cells/mL / 1.1-70 × 10 cells/mL infusion dispersion

lisocabtagene maraleucel (viable T cells expressing chimeric antigen receptor [CAR])
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 receiving this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• Your doctor will provide you with a patient card. Please read it carefully and follow the instructions contained therein.
• Always show your patient 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

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

1. What Breyanzi is and what it is used for

What Breyanzi is
Breyanzi contains the active substance lisocabtagene maraleucel, a type of treatment known as
"genetically modified cellular therapy".
Breyanzi is manufactured using your own white blood cells. The process involves collecting blood from you, from which white blood cells are extracted and sent to a laboratory where they are genetically modified to produce Breyanzi.

What Breyanzi is used for
Breyanzi is used to treat adults with a type of blood cancer called lymphoma, which affects the lymphatic tissues and causes uncontrolled growth of white blood cells. Breyanzi is used in cases of:

• diffuse large B-cell lymphoma
• high-grade B-cell lymphoma
• primary mediastinal large B-cell lymphoma
• follicular lymphoma
• mantle cell lymphoma.

How Breyanzi works

• The cells in Breyanzi have been genetically modified to recognize lymphoma cells in your body.
• When these cells are reintroduced into the bloodstream, they are able to identify and attack the lymphoma cells.

2. What you should know before receiving Breyanzi

Breyanzi must not be given to you:

• if you are allergic to any of the ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice;
• 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 Breyanzi is given”).

Warnings and precautions
Before you are given Breyanzi, you must inform your doctor if:

• you have heart or lung problems
• you have low blood pressure
• you have an infection or other inflammatory diseases. The infection will be treated before you are given Breyanzi
• you have received a stem cell transplant from another person within the last 4 months – the transplanted cells may attack your body (“graft-versus-host disease”), causing symptoms such as rash, nausea, vomiting, diarrhoea and blood in the stools
• you notice that symptoms of your tumour are worsening. These symptoms include fever, feeling weak, night sweats, sudden weight loss
• you have had an infection with hepatitis B or C or human immunodeficiency virus (HIV)
• you have received a vaccination within the last 6 weeks or are planning to receive one in the coming months. For more information, see the section “Live vaccines” below.

If you fall into any of the above conditions (or if you have any doubts), consult your doctor
before receiving Breyanzi.
Patients treated with Breyanzi may develop new types of cancer. Cases have been reported of
patients who, after treatment with Breyanzi and similar medicines, developed a cancer originating from a type of white blood cells called T cells. Contact your doctor if you experience new swelling of the glands (lymph nodes) or skin changes, such as new nodules or rashes.
Tests and monitoring
Before you are given Breyanzi, your doctor will:

• perform an examination of your lungs, heart and blood pressure
• look for signs of infection; any infections will be treated before you receive Breyanzi
• look for signs of “graft-versus-host disease”, which may develop after a stem cell transplant from another person
• perform a blood test to check your uric acid levels and the number of tumour cells in your blood. This will show whether you are likely to develop a condition called “tumour lysis syndrome”. You may be given medicines to prevent this condition
• check whether your tumour is worsening
• test for infection with hepatitis B and C, and HIV.

After receiving Breyanzi

• If you experience any serious side effects, you must inform your doctor or nurse immediately, as you may need treatment. See section 4 below, “Serious side effects”.

• Your doctor will regularly monitor your blood count, as your blood cell counts may decrease.

• Remain close to the treatment centre where you received Breyanzi for at least 2 weeks. Your doctor may advise you to stay longer to ensure that
  the care you receive after treatment meets your individual needs. See
  sections 3 and 4.

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

You will be asked to enrol in a registry for at least 15 years to help better understand the long-term effects of Breyanzi.
Children and adolescents
Breyanzi must not be given to children and adolescents under 18 years of age.
Other medicines and Breyanzi
Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines, including those not requiring a prescription.
Refer to section 3 for information about medicines that will be given to you before receiving Breyanzi.
Medicines affecting the immune system
Before you are given Breyanzi, inform your doctor or nurse if you are taking medicines that weaken the immune system, such as:

• corticosteroids.

This is because such medicines may reduce the effect of Breyanzi.
Other medicines for treating tumours
Some anticancer medicines may reduce the effect of Breyanzi. Your doctor will assess whether you need other anticancer treatments.
Live vaccines
You must not receive certain vaccines known as live vaccines:

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

Talk to your doctor if you need any vaccinations.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before receiving this medicine or undergoing lymphodepleting chemotherapy. The effects of Breyanzi in pregnant or breastfeeding women are unknown, and this medicine could harm the unborn baby or breastfed newborn.

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

Discuss the need for contraceptive measures with your doctor.
Talk to your doctor about pregnancy if you have received Breyanzi.
Driving and using machines
Avoid driving, operating machinery, or engaging in activities requiring alertness for at least 4 weeks after treatment. Breyanzi may cause drowsiness, reduced attention, confusion, or seizures (convulsions). Depending on your individual condition, your doctor may advise you to wait longer before driving.
Breyanzi contains sodium, potassium and dimethyl sulfoxide (DMSO)
This medicine contains up to 12.5 mg of sodium (the main component of table salt) per vial. This corresponds to 0.6% of the maximum daily recommended dietary intake for an adult. Up to 8 vials of this medicine may be administered per dose, for a total of 100 mg of sodium, or 5% of the maximum daily recommended sodium intake for an adult.
This medicine contains up to 0.2 mmol (or 6.5 mg) of potassium per dose. Your doctor will take this potassium content into account if your kidneys are not functioning properly or if you are on a low-potassium diet.
This medicine also contains DMSO, which may cause severe hypersensitivity reactions.

3. How Breyanzi is administered

Patient card

• Your doctor will give you a patient card. Read it carefully and follow the instructions it contains.
• Always show your patient card to your doctor or nurse during visits or if you go to hospital.

Blood collection to produce Breyanzi from your white blood cells
Breyanzi is made using your own white blood cells.

• Your doctor will collect blood through a tube (catheter) placed into a vein. Some of your white blood cells will be separated from the blood, and the remaining blood will be returned to your body. This procedure is called "leukapheresis" and may take from 3 to 6 hours. You may need to repeat this procedure.
• The separated white blood cells will be sent for the production of Breyanzi.

Other medicines you will receive before Breyanzi

• A few days before receiving Breyanzi, you will undergo a short course of chemotherapy. This is to remove existing white blood cells.
• Shortly before receiving Breyanzi, you will be given paracetamol and an antihistamine. This is to reduce the risk of infusion reactions and fever.

How Breyanzi is administered

• Your doctor will verify that Breyanzi has been manufactured from your own blood by checking that the patient identification details on the medicine label match your personal information.
• Breyanzi is administered as an intravenous infusion (through a drip) via a tube inserted into a vein.
• You will receive infusions of CD8-positive cells, followed immediately by infusions of CD4-positive cells. The infusion time may vary, but will generally be less than 15 minutes for each of the two cell types.

After receiving Breyanzi

• Remain near the treatment center where you received Breyanzi for at least 2 weeks.
• During the first week after treatment, you must return to the treatment center 2 or 3 times so your doctor can monitor whether the treatment is working and assist you if any side effects occur. See sections 2 and 4.

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
Tell your doctor immediately if, after receiving Breyanzi, you experience any of the following side effects:

• fever, chills or tremors, feeling tired, fast or irregular heartbeat, feeling dizzy and shortness of breath – these may be signs of a serious condition called “cytokine release syndrome”
• confusion, reduced alertness (reduced level of consciousness), difficulty speaking or slurred speech, chills (tremors), feeling anxious, dizziness and headache – these may be symptoms of a condition called immune effector cell-associated neurotoxicity syndrome (ICANS) or signs of nervous system problems
• feeling warm, fever, chills or tremors – these may be signs of infection. Infections may be caused by:
  • low levels of white blood cells, which help fight infections, or
  • low levels of antibodies called “immunoglobulins”
• blurred vision, loss of vision or double vision, difficulty speaking, weakness or clumsiness in one arm or leg, change in the way you walk or problems with balance, changes in personality, changes in thinking, memory and orientation leading to confusion. These could all be symptoms of a serious and potentially fatal brain condition known as progressive multifocal leukoencephalopathy (PML). These symptoms may occur several months after treatment has ended 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 symptoms that you do not.
• feeling extremely tired, weakness and shortness of breath – these may be signs of low levels of red blood cells (anaemia)
• increased tendency to bleed or bruise easily – these may be signs of low levels of blood cells called “platelets”.

Tell your doctor immediately if you experience any of the above side effects after receiving Breyanzi, as you may need urgent medical treatment.
Other possible side effects
Very common: may affect more than 1 in 10 people

• difficulty sleeping
• low blood pressure, including signs such as dizziness, fainting or changes in vision
• cough
• feeling unwell or malaise
• diarrhoea or constipation
• stomach ache
• swelling in the ankles, arms, legs and face
• rash.

Common: may affect up to 1 in 10 people

• difficulty with balance or walking
• high blood pressure, which may include signs such as severe headache, sweating or difficulty sleeping
• changes in vision
• changes in taste
• numbness and tingling in feet or hands
• blood clots or problems with blood clotting
• bleeding in the intestine
• less frequent urination
• infusion reactions – such as dizziness, fever and shortness of breath
• low levels of phosphates in the blood
• low levels of oxygen in the blood.

Uncommon: may affect up to 1 in 100 people

• a new type of cancer originating from a type of white blood cells called T cells (malignant secondary neoplasm of T-cell origin)
• rapid breakdown of tumour cells leading to the release of toxic waste products into the bloodstream – one sign may be dark-coloured urine with symptoms such as nausea or pain on one side of the stomach
• severe inflammatory illness – symptoms may include fever, rash, enlargement of the liver, spleen and lymph nodes
• heart weakness, causing shortness of breath and swelling of the ankles
• fluid around the lungs
• stroke or mini-stroke
• seizures or fits (convulsions)
• weakness of facial muscles, vocal cords or weakness throughout the body
• swelling of the brain.

Reporting of side effects
If you get any side effects, including ones 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 Breyanzi

Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the cartons and on the vial label after "Exp./EXP".
Store frozen in vapours of liquid nitrogen (≤ -130 °C).

6. Package contents and other information

What Breyanzi contains

• The active substance is lisocabtagene maraleucel. Each 4.6 mL vial contains a dispersion of viable T cells expressing the CAR receptor (CD8-positive cellular component or CD4-positive cellular component) at a concentration ranging from 1.1 × 10 to 70 × 10 viable T cells expressing the CAR receptor per mL for each cellular component. Up to 4 vials of each cellular component, CD8-positive or CD4-positive, may be provided depending on the concentration of the cryopreserved medicinal product.
• The other components (excipients) are CryoStor CS10 (containing dimethyl sulfoxide or DMSO), sodium chloride, sodium gluconate, sodium acetate trihydrate, potassium chloride, magnesium chloride, human albumin, N-acetyl-DL-tryptophan, caprylic acid, water for injections. See section 2, “Breyanzi contains sodium, potassium and dimethyl sulfoxide (DMSO)”.

This medicinal product contains genetically modified human blood cells.
Description of the appearance of Breyanzi and contents of the pack
Breyanzi is a cellular dispersion for infusion. It is supplied in vials containing a slightly opaque to opaque dispersion, colourless to yellow or yellowish-brown. Each vial contains 4.6 mL of cellular dispersion of the CD8-positive or CD4-positive cellular component.
Marketing Authorisation Holder
Bristol-Myers Squibb Pharma EEIG
Plaza 254
Blanchardstown Corporate Park 2
Dublin 15, D15 T867
Ireland
Manufacturer
Celgene Distribution B.V.
Orteliuslaan 1000
3528 BD Utrecht
The Netherlands
BMS Netherlands Operations B.V.
Francois Aragostraat 2
2342 DK Oegstgeest
The Netherlands
For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Lietuva
N.V. Bristol-Myers Squibb Belgium S.A. Swixx Biopharma UAB
Tél/Tel: + 32 2 352 76 11 Tel: + 370 52 369140
[email protected] [email protected]
България Luxembourg/Luxemburg
Swixx Biopharma EOOD N.V. Bristol-Myers Squibb Belgium S.A.
Teл.: + 359 2 4942 480 Tél/Tel: + 32 2 352 76 11
[email protected] [email protected]
Česká republika Magyarország
Bristol-Myers Squibb spol. s r.o. Bristol-Myers Squibb Kft.
Tel: + 420 221 016 111 Tel.: + 36 1 301 9797
[email protected] [email protected]
Danmark Malta
Bristol-Myers Squibb Denmark A.M. Mangion Ltd
Tlf: + 45 45 93 05 06 Tel: + 356 23976333
[email protected] [email protected]
Deutschland Nederland
Bristol-Myers Squibb GmbH & Co. KGaA Bristol-Myers Squibb B.V.
Tel: 0800 0752002 (+ 49 89 121 42 350) Tel: + 31 (0)30 300 2222
[email protected] [email protected]
Eesti Norge
Swixx Biopharma OÜ Bristol-Myers Squibb Norway AS
Tel: + 372 640 1030 Tlf: + 47 67 55 53 50
[email protected] [email protected]
Ελλάδα Österreich
Bristol-Myers Squibb A.E. Bristol-Myers Squibb GesmbH
Τηλ: + 30 210 6074300 Tel: + 43 1 60 14 30
[email protected] [email protected]
España Polska
Bristol-Myers Squibb, S.A. Bristol-Myers Squibb Polska Sp. z o.o.
Tel: + 34 91 456 53 00 Tel.: + 48 22 2606400
[email protected] [email protected]
France Portugal
Bristol-Myers Squibb SAS Bristol-Myers Squibb Farmacêutica Portuguesa,
Tél: + 33 (0)1 58 83 84 96 S.A.
[email protected] Tel: + 351 21 440 70 00
[email protected]
Hrvatska România
Swixx Biopharma d.o.o. Bristol-Myers Squibb Marketing Services S.R.L.
Tel: + 385 1 2078 500 Tel: + 40 (0)21 272 16 19
[email protected] [email protected]
Ireland Slovenija
Bristol-Myers Squibb Pharmaceuticals uc Swixx Biopharma d.o.o.
Tel: 1 800 749 749 (+ 353 (0)1 483 3625) Tel: + 386 1 2355 100
[email protected] [email protected]
Ísland Slovenská republika
Vistor ehf. Swixx Biopharma s.r.o.
Sími: + 354 535 7000 Tel: + 421 2 20833 600
[email protected] [email protected]
Italia Suomi/Finland
Bristol-Myers Squibb S.r.l. Oy Bristol-Myers Squibb (Finland) Ab
Tel: + 39 06 50 39 61 Puh/Tel: + 358 9 251 21 230
[email protected] [email protected]
Κύπρος Sverige
Bristol-Myers Squibb A.E. Bristol-Myers Squibb Aktiebolag
Τηλ: 800 92666 (+ 30 210 6074300) Tel: + 46 8 704 71 00
[email protected] [email protected]
Latvija
Swixx Biopharma SIA
Tel: + 371 66164750
[email protected]
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 .

The following information is intended exclusively for healthcare professionals:

Precautions to be taken before handling or administration of the
medicinal product
Breyanzi must be transported to the treatment center in closed, leak-proof, and airtight containers.
This medicinal product contains human blood cells. Healthcare professionals handling Breyanzi
must take appropriate precautions (wear gloves, protective clothing, and eye protection)
to prevent potential transmission of infectious diseases.

Preparation prior to administration
Before thawing the vials

• Confirm that the patient’s identity matches the patient identification details on the shipping container.
• Breyanzi consists of viable CAR-expressing T cells formulated as separate CD8+ and CD4+ cellular components; a Release for Infusion Certificate (RfIC) is provided separately for each cellular component. Read the RfIC (provided inside the shipping container) to obtain information on the number of syringes required and the volume of CD8+ and CD4+ cellular components to be administered (syringe labels are provided with the RfIC).
• Confirm the infusion time in advance and adjust the timing of Breyanzi thawing so that it is available for infusion when the patient is ready.

Note: Once the vials containing viable CAR-expressing T cells (CD8+ and CD4+ cellular components) have been removed from frozen storage, thawing must be completed and the cells administered within 2 hours.
Thawing the vials

• Confirm that the patient’s identity matches the patient identification details on the outer box and on the Release for Infusion Certificate (RfIC).
• Remove the box containing the CD8+ cellular component and the box containing the CD4+ cellular component from the outer box.
• Open each inner box and visually inspect the vial(s) for damage. If vials are damaged, contact the company.
• Carefully remove the vials from the boxes, place them on a protective barrier pad, and thaw at room temperature. All vials must be thawed simultaneously. Ensure that CD8+ and CD4+ cellular components remain separated.

Dose preparation

• Depending on the concentration of viable CAR-expressing T cells in each component, more than one vial of each CD8+ and CD4+ cellular component may be required to complete a dose. A separate syringe must be prepared for each vial of CD8+ or CD4+ cellular component received.

Note: The volume to be withdrawn and infused may differ for each component.

• Each 5 mL vial contains a total extractable volume of 4.6 mL of T cells with either CD8+ or CD4+ cellular component. The RfIC for each component specifies the volume (mL) of cells to be withdrawn into each syringe. Use the smallest necessary luer-lock tip syringe (1 mL to 5 mL) to withdraw the specified volume from each vial. A 5 mL syringe must not be used for volumes less than 3 mL.
• Prepare the syringe(s) for the CD8+ cellular component first. Ensure that the patient identification details on the syringe label for the CD8+ cellular component match those on the vial label for the CD8+ cellular component. Affix the CD8+ cellular component syringe labels to the syringe(s) before withdrawing the required volume into the syringe(s).
• Repeat the process for the CD4+ cellular component.

Note: It is important to verify that the volume withdrawn from each cellular component matches the volume specified on the respective Release for Infusion Certificate (RfIC).
Withdrawal of the required volume of cells from each vial into a separate syringe must be performed according to the following instructions:

1. Hold the thawed vial(s) upright and gently invert the vial(s) to mix the cellular product. If clumps are present, continue inverting the vial(s) until clumps have dispersed and cells appear uniformly resuspended.

Vial in upright position  Vial in inverted position

2. Visually inspect the thawed vial(s) for damage or leakage. Do not use if the vial is damaged or if clumps do not disperse; contact the company. The liquid in the vials should be slightly opaque to opaque, colorless to yellow or yellowish-brown.
3. Remove the polyaluminum cover (if present) from the bottom of the vial and wipe the septum with an alcohol-impregnated swab. Allow to air dry before proceeding.

NOTE: The absence of the polyaluminum cover does not affect the sterility of the vial.

4. While holding the vial(s) upright, cut the seal on the tubing located at the top of the vial, just above the filter, to open the air inlet on the vial.

NOTE: Take care to select the correct tubing—i.e., the one with the filter. Cut ONLY the tubing with the filter.

Cut here
Filter

5. Take a 20-gauge needle, 2.5–3.8 cm in length, holding the needle tip opening away from the access septum.
   a. Insert the needle into the septum at a 45°–60° angle to puncture the access septum.
   b. Gradually increase the angle of the needle as it penetrates the vial.
   a b

6. WITHOUT aspirating air into the syringe, slowly withdraw the

target volume (as specified on the Release for Infusion Certificate [RfIC]).

7. Before proceeding, carefully inspect the syringe for any signs of particulate matter. If particulates are observed, contact the company.
8. Verify that the volume of the CD8+/CD4+ cellular component matches the volume specified on the Release for Infusion Certificate (RfIC) for the relevant cellular component.

Once the volume has been verified, place the vial and syringe horizontally and
remove the syringe/needle from the vial.
Carefully detach the needle from the syringe and cap the syringe.

9. Keep the vial in a horizontal position and return it to its box to prevent leakage.
10. Dispose of any unused portions of Breyanzi.

Administration

• DO NOT use a leukocyte-depleting filter.
• Ensure that tocilizumab and emergency equipment are available before and during the infusion period and recovery phase. In the rare event that tocilizumab is unavailable due to a shortage listed in the European Medicines Agency’s list of centrally monitored medicines, ensure that suitable alternative measures to tocilizumab are available on-site for the treatment of CRS.
• Confirm that the patient’s identity matches the patient identification details on the syringe label provided on the respective Release for Infusion Certificate (RfIC).
• After withdrawing Breyanzi components into syringes, administer as promptly as possible. The total time from removal of Breyanzi from frozen storage to administration to the patient must not exceed 2 hours.
• Use intravenous 9 mg/mL (0.9%) sodium chloride injection solution to flush all infusion lines before and after administration of each CD8+ or CD4+ cellular component.
• Administer the CD8+ cellular component first. The entire volume of the CD8+ cellular component is administered intravenously at an infusion rate of approximately 0.5 mL/minute, using the nearest port or Y-site (“piggyback”).
• If more than one syringe is required to deliver a complete dose of the CD8+ cellular component, administer the contents of each syringe consecutively without delay between syringes (unless there is a clinical reason to pause, such as an infusion reaction). After administration of the CD8+ cellular component, flush the line with 9 mg/mL (0.9%) sodium chloride injection solution.
• Administer the CD4+ cellular component immediately after completion of the CD8+ cellular component administration, following the same steps and infusion rate as described for the CD8+ cellular component. After administration of the CD4+ cellular component, flush the line with 9 mg/mL (0.9%) sodium chloride injection solution, using sufficient volume to clear the entire length of the tubing and intravenous catheter. Infusion time will vary and will generally be less than 15 minutes for each component.

Measures to be taken in case of accidental exposure
In the event of accidental exposure, follow local guidelines for handling human-source materials. Work surfaces and materials that may have come into contact with Breyanzi must be decontaminated using an appropriate disinfectant.
Precautions for disposal of Breyanzi
Unused medicinal product and all materials that have come into contact with Breyanzi (solid and liquid waste) must be handled and disposed of as potentially infectious waste in accordance with local guidelines for handling human-source materials.