Zynteglo - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

Package leaflet: Information for the patient or carer Zynteglo 1.2–20 × 10 6 cells/mL dispersion for infusion betibeglogene autotemcel

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

You will be given a Patient Alert Card which contains important safety information that you need to know about your treatment with Zynteglo. You should carry the Patient Alert Card with you at all times and show it to your doctor or nurse when you see them or if you are admitted to the hospital. – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor or nurse.

• – If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

• – Read the Patient Alert Card carefully and follow the instructions on it.

What is in this leaflet

• 1. What Zynteglo is and what it is used for

• 2. What you need to know before you are given Zynteglo

• 3. How Zynteglo is given

• 4. Possible side effects

• 5. How to store Zynteglo

• 6. Contents of the pack and other information

1. What Zynteglo is and what it is used for

Zynteglo is used to treat a serious genetic disease called transfusion-dependent beta-thalassaemia (TDT), which includes the disease commonly known as beta-thalassaemia major, in people 12 years and older. People with this condition cannot make enough haemoglobin, a protein in the blood that carries oxygen. More specifically, people with TDT do not make enough of a part of the haemoglobin called beta-globin, due to a gene defect. Because of this defect, people with TDT are anaemic and need frequent blood transfusions to survive.

Zynteglo is a type of medicine called gene therapy. It is made specifically for each patient, using the patient’s own (also called autologous) blood stem cells. Zynteglo works by adding functional copies of the beta-globin gene into these cells, so that the patient can make enough beta-globin to increase total haemoglobin, improve anaemia, and carry more oxygen around their body. This reduces or eliminates the need for blood transfusions.

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

You must not be given Zynteglo if you :

• – are allergic to any of the ingredients of this medicine (listed in section 6)

• – are pregnant or breast-feeding

• – have previously received gene therapy of your blood stem cells

• – are allergic to any of the ingredients in the medicines you will be given for mobilisation and chemotherapy (see section 3).

Warnings and precautions

Talk to your doctor before you are given Zynteglo.

Before treatment with Zynteglo, you will be given medicines known as mobilisation medicine and chemotherapy medicine (see sections 3 and 4 for more information on these medicines, including possible side effects).

Before treatment with Zynteglo, your doctor will perform tests to make sure your heart and liver are functioning properly so you can be treated safely with Zynteglo.

Zynteglo is made specifically for you, using your own blood stem cells.

After you have been treated with Zynteglo, you will not be able to donate blood, organs, or tissues in the future. This is because Zynteglo is a gene therapy medicine.

Adding a new gene into the DNA of your blood stem cells could theoretically cause myelodysplasia, leukaemia, or lymphoma, although no patients have developed myelodysplasia, leukaemia, or lymphoma in clinical trials with Zynteglo. After treatment with Zynteglo, you will be asked to enrol in a registry for at least 15 years in order to better understand the long-term effects of Zynteglo. During the long-term follow-up, your doctor will monitor you for any signs of myelodysplasia, leukaemia, or lymphoma at least once a year.

Zynteglo is prepared using parts of the human immunodeficiency virus (HIV), which have been altered so that they cannot cause HIV infection. The modified virus is used to insert a functional beta-globin gene into your blood stem cells. Although this medicine will not give you HIV infection, having Zynteglo in your blood may cause a false positive HIV test result with some commercial tests that recognise a piece of HIV used to make Zynteglo. If you test positive for HIV following treatment, please contact your doctor or nurse.

Before receiving Zynteglo you will be given chemotherapy in order to remove your existing bone marrow. If Zynteglo cannot be administered after chemotherapy or if the modified stem cells do not take hold (engraft) in your body, the doctor may give you an infusion of your own original blood stem cells that were collected and stored before the treatment started (see also section 3, How Zynteglo is given).

After you receive Zynteglo, you may have a low number of platelets in your blood. This means that your blood may not be able to clot as well as normal and you may be prone to bleeding. You must get medical attention if you:

• bump your head or have a head injury
• have symptoms that could be from internal bleeding, such as unusual stomach or back pain, or severe headache
• have abnormal bruising or bleeding (such as bruising without injury, blood in your urine, stool, vomit, or cough up blood).

Your doctor will tell you when your platelet count has recovered to normal levels.

Other medicines and Zynteglo

Tell your doctor if you are taking, have recently taken or might take any other medicines.

You should not take hydroxyurea (a medicine for blood disorders) or any medicines for HIV infection from at least one month before you undergo mobilisation until at least 7 days after Zynteglo infusion (see also section 3, How Zynteglo is given).

You should stop taking medicines to remove iron from your body (so-called chelating agents: deferoxamine, deferiprone and/or deferasirox) 7 days before you start the chemotherapy before the infusion of Zynteglo (see section 3, How Zynteglo is given). Your doctor will advise you if and when you should start taking these medicines after Zynteglo infusion.

Talk to your doctor if you need to have any vaccinations.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, tell your doctor before you are given this medicine.

If you are a woman, you will be given a pregnancy test before starting mobilisation, before you are given chemotherapy, and before Zynteglo treatment in order to confirm that you are not pregnant.

Women who could become pregnant and men capable of fathering a child must start using a reliable method of contraception from before their blood stem cells are collected and continue until at least 6 months after receiving Zynteglo. Reliable methods of contraception include intra-uterine device or a combination of oral contraceptive (also know as the pill) and condoms.

The added gene from Zynteglo will not be passed on to your children. Your children are still at risk of inheriting your original beta-globin gene.

You should not be given Zynteglo if you are breast-feeding. It is not known whether the ingredients of Zynteglo can pass into breast milk.

It may no longer be possible for you to become pregnant or father a child after receiving chemotherapy medicine. If you are concerned about having children, you should discuss this with your doctor before treatment. Options may include providing reproductive material for storage in a tissue bank to use at a later time. For men, this may be sperm or testicular tissue. For women, this may be eggs (oocytes) or ovarian tissue.

Driving and using machines

Zynteglo has no influence on the ability to drive or use machines. However, the mobilisation and chemotherapy medicines may cause dizziness and fatigue. Avoid driving or using machines if you feel dizzy, tired or unwell.

Sodium content

This medicine contains 391–1564 mg sodium (main component of cooking/table salt) in each dose.

This is equivalent to 20–78% of the recommended maximum daily dietary intake of sodium for an adult.

• 3. How Zynteglo is given

Zynteglo is given by a drip (infusion) into a vein. It can only be given in a specialised hospital by doctors who are experienced in treating patients with TDT, administering bone marrow transplants, and using gene therapy medicines.

Zynteglo can only be made if enough of the right kind of blood stem cells can be collected from your blood (CD34+ blood stem cells). Approximately 2 months before treatment with Zynteglo, you will be given a mobilisation medicine that will move your blood stem cells from your bone marrow into your blood stream. The blood stem cells can then be collected by a machine that separates blood components (apheresis machine). It may take more than 1 day to collect enough blood stem cells to make Zynteglo and to store as replacement cells if Zynteglo cannot be given or does not work.

Time	What happens	Why
Approximately 2 months before Zynteglo infusion	Mobilisation medicine is given	To move the blood stem cells from your bone marrow into your blood stream.
Approximately 2 months before Zynteglo infusion	Blood stem cells are collected	To make Zynteglo and to serve as replacement cells if needed.
At least 6 days before Zynteglo infusion	A chemotherapy medicine is given for 4 days in a hospital	To prepare your bone marrow for treatment with Zynteglo.

Time	What happens	Why
Start of Zynteglo treatment	Zynteglo is given by a drip (infusion) into a vein. This will take place in a hospital and will take less than 30 minutes for each infUsion bag. The number of bags will vary by patient.	To add blood stem cells containing functional copies of the beta-globin into your bone marrow.
After Zynteglo infusion	You will remain in the hospital for approximately 3–6 weeks	To recover and be monitored until your doctor is satisfied that it is safe for you to leave the hospital.

4. Possible side effects

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

Some side effects observed in clinical studies with Zynteglo are related to mobilisation and blood stem cell collection or to the chemotherapy medicine used to prepare your bone marrow for treatment with Zynteglo.

You should discuss possible side effects due to the mobilisation medicines and chemotherapy medicine with your doctor. You should also read the package leaflets for these medicines.

Mobilisation and blood stem cell collection

Most of these side effects occur during or within a few days after mobilisation and blood stem cell collection but can occur later. Tell your doctor immediately if side effects become severe or serious.

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

• a low level of blood platelets, which may reduce the ability of blood to clot
• bone pain
• numbness and pain in hands and feet
• feeling sick (nausea)
• headache
• low blood calcium level

Common side effects (may affect up to 1 in 10 people)

• bleeding
• low oxygen level in blood
• low blood pressure
• abdominal pain
• back pain
• bone or muscle pain
• chest pain or discomfort
• other pain
• agitation
• abnormal blood test results (decrease in magnesium and potassium, too much citrate, or increase in white blood cells)
• abnormal heart rhythm
• bruising, bleeding or pain from catheter or injection site
• injection site reaction
• bruising
• dizziness, tiredness
• head discomfort
• excessive sweating
• flu like illness
• lip swelling
• tingling or numbness of the hands, feet, or mouth
• fever
• rash
• enlarged spleen which may result in pain in your upper left belly or left shoulder
• vomiting

Chemotherapy medicine

Tell your doctor immediately if you get any of the following side effects after receiving chemotherapy medicine. They usually happen within the first few days and several weeks after receiving chemotherapy medicine, but can also develop much later.

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

• Pain in the right upper abdomen under the ribs, yellowing of eyes or skin, rapid weight gain, swelling of arms, legs and abdomen, and trouble breathing. These may be signs of a serious liver condition called veno-occlusive disease.
• Prolonged bleeding or bleeding without injury such as nosebleeds, bleeding from gums, or vaginal bleeding.

Other possible side effects

Tell your doctor immediately if side effects become severe or serious.

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

• low level of red and white blood cells, sometimes with a fever
• increase of certain enzymes in the blood which may indicate a problem with your liver
• a low level of blood platelets, which may reduce the ability of blood to clot
• unusual hair loss or thinning
• stomach pain, constipation, diarrhoea
• feeling sick (nausea), being sick (vomiting)
• fever
• soreness of the mouth
• inflammation of the throat
• dark patches on skin
• soreness of the rectum area
• trouble sleeping
• decreased appetite
• headache
• tiredness
• itchy skin
• soreness and swelling of the digestive tract lining which runs from the mouth to the anus

Common side effects (may affect up to 1 in 10 people)

• life-threatening inflammatory response to an infection along with low white blood cell count
• heart failure
• infections which may make you feel warm, chilly, or sweaty
• mass in the lungs
• enlarged abdomen
• enlarged liver
• difficulty breathing
• abdominal pain
• bleeding or bruising
• blood in urine
• yellowing of eyes or skin
• small tear in tissue that lines the anus
• dizziness, or sensation of feeling off balance or like the room is spinning
• memory problems
• anxiety
• positive test for Aspergillus (lung disease caused by fungus)
• changes and abnormalities in heart rhythm
• pain, including in back, bone, skin, limbs, anus, or muscles
• vaginal yeast infection
• heartburn
• inflammation of the gallbladder
• gallstones
• cough
• abnormal sense of taste or loss of taste
• difficulty swallowing
• swelling of the face
• feeling cold
• excess water in the body
• inflammation or infection of hair follicles
• decrease in speed of air leaving your lungs
• stomach discomfort with nausea and vomiting
• inflammation in the digestive tract
• gum disease
• piles (haemorrhoids)
• hiccups
• low blood pressure
• low body temperature
• low oxygen level in blood
• pain in mouth, throat or larynx (voice box)
• lack of energy
• irregular menstruation
• loss of function or decreased function of your ovaries or testes
• premature menopause
• spots on skin from bleeding under the skin
• skin that is discoloured, blotchy, or darker or lighter than normal
• fluid in or around the lung
• hot flush
• increased frequency of urination
• dry, itchy skin
• dry lips
• rash sometimes with lesions or pus
• inflamed skin lesions
• skin abrasion/scrape
• sweat gland disorder
• transfusion reaction
• weight decreased
• abnormal liver tests
• increased concentration of haemoglobin in cells
• changes in magnesium, calcium, potassium, phosphate, albumin, protein, sodium in blood
• increase in blood test for inflammation
• excess acid in the body not removed by the kidneys
• increase or decrease in white blood cells
• low number of immature (not fully developed) red blood cells
• increase in female hormones
• decreased testosterone

Zynteglo

Most side effects occur during or within a few days after treatment with Zynteglo but can occur later. Tell your doctor immediately if side effects become severe or serious.

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

• stomach pain

Common side effects (may affect up to 1 in 10 people)

• low level of blood platelets, which may reduce the ability of blood to clot
• low level of white blood cells
• shortness of breath
• chest pain not due to a heart problem
• flushing (redness and warmth of skin)
• pain in legs

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via 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. How to store Zynteglo

This information is intended for doctors only.

As this medicine will be given by a qualified doctor, they are responsible for the correct storage of the medicine before and during its use, as well as for its correct disposal.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the outer container label(s) and infusion bag label(s).

Store at ← 140°C for up to a year. Do not thaw the product until it is ready to be used. Once thawed store at room temperature (20°C-25°C) and use within 4 hours.

This medicine contains genetically-modified cells. Unused medicine must be disposed of in compliance with the local guidelines on handling human-derived material.

6. Contents of the pack and other information

What Zynteglo contains

• – The active substance of Zynteglo consists of your own blood stem cells that contain functional copies of the beta-globin gene that can be measured in your blood. The concentration is 1.2–20 × 106 CD34+ cells (blood stem cells) per millilitre.

• – The other ingredients are a solution used to preserve frozen cells and sodium chloride. See section

What Zynteglo looks like and contents of the pack

Zynteglo is a clear to slightly cloudy, colourless to yellow or pink dispersion of cells that is supplied in one or more clear infusion bags, each packed in a transparent pouch inside a closed metal container.

Your name and date of birth, as well as coded information identifying you as the patient, are printed onto each infusion bag and each metal container.

Marketing Authorisation Holder and Manufacturer

bluebird bio (Netherlands) B.V.

Stadsplateau 7

WTC Utrecht

3521AZ Utrecht

The Netherlands

Tel: +31 (0) 303 100 450

Manufacturer

Minaris Regenerative Medicine GmbH

Haidgraben 5

85521 Ottobrunn

Germany

This leaflet was last revised in < {MM/YYYY }>

This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine.

The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary.

Detailed information on this medicine is available on the European Medicines Agency web site: <, and on the website of {name of MS Agency (link)}>.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

The following information is intended for healthcare professionals only:

Zynteglo is shipped from the manufacturing facility to the infusion centre storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal cassette contains one infusion bag with Zynteglo. A patient may have multiple infusion bags. The infusion bag(s) must be kept inside the metal cassette(s) until ready to thaw and use.

Confirm that Zynteglo is printed on the infusion bag(s). Confirm that patient identity matches the unique patient information located on the infusion bag(s) and metal cassette(s) prior to infusion. Account for all infusion bags and confirm each infusion bag of Zynteglo is within the expiry date using the accompanying Lot Information Sheet.

Inspect each infusion bag for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow the local guidelines on handling human-derived material and contact bluebird bio immediately.

Zynteglo is intended solely for autologous use.

After carefully removing the outer metal container, thaw each infusion bag at 37°C in a water bath or dry bath for approximately 2–4 minutes. Do not overthaw the medicinal product. Do not leave the medicinal product unattended and do not submerge the infusion ports if thawed in a water bath. After thaw, mix the medicinal product gently by massaging the infusion bag until all of the contents are uniform. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port. Access the infusion bag and infuse per the administration site’s standard procedures for administration of cell therapy products. Do not use an in-line blood filter or an infusion pump. Do not sample, alter, or irradiate the medicinal product.

Administer each infusion bag via intravenous infusion over a period of less than 30 minutes. If more than one infusion bag is provided, administer each infusion bag completely before proceeding to thaw and infuse the next bag.

Zynteglo must not be re-frozen. Infuse as soon as possible and no more than 4 hours after thawing.

Flush all Zynteglo remaining in the infusion bag and any associated tubing with at least 50 mL of 0.9% sodium chloride solution to ensure as many cells as possible are infused into the patient.

This medicinal product contains genetically-modified cells. Local guidelines on handling and waste of human-derived material applicable for such products should be followed.

Healthcare professionals handling Zynteglo should take standard precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.

Work surfaces and material which have potentially been in contact with Zynteglo must be decontaminated with a viricidal disinfectant according to the manufacturer's in­structions.

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