Skysona - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

Package leaflet: Information for the patient or carer

Skysona 2–30 × 106 cells/mL dispersion for infusion elivaldogene autotemcel (autologous CD34+ cells encoding ABCD1 gene)

▼ 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 or your child may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you/your child is given 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 the doctor or nurse.

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

• – The doctor or nurse will give you a Patient Alert Card which contains important safety information about the treatment with Skysona. Read it carefully and follow the instructions on it.

• – Carry the Patient Alert Card with you at all times and always show it to any doctor or nurse who sees you or if you go to the hospital.

What is in this leaflet

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

• 2. What you need to know before you or your child is given Skysona

• 3. How Skysona is made and given

• 4. Possible side effects

• 5. How to store Skysona

• 6. Contents of the pack and other information

1. What Skysona is and what it is used for

Skysona is used to treat a serious genetic disease called cerebral adrenoleukodys­trophy (CALD) in children and adolescents younger than 18 years old.

People with CALD have an alteration in the gene that makes a protein called adrenoleukodys­trophy protein (ALDP). People with CALD either cannot make this protein or have a protein that does not work well. This leads to the build-up of very long chain fatty acids in the body, particularly in the brain. These fatty acids cause severe damage to brain cells. If untreated, this damage will lead to problems with vision, hearing, talking, walking and/or thinking, and will likely lead to death.

Skysona is a type of medicine called gene therapy. It is made specifically for each patient, using the patient’s own blood stem cells.

Cells called stem cells are collected from the patient’s blood. They are then modified in a laboratory to insert a working gene for making ALDP. When you/your child is given Skysona, which is made up of these modified cells, the cells will start making ALDP, which will then break down the very long chain fatty acids. This is expected to slow down the progression of the disease.

Skysona is given by a drip (infusion) into a vein (intravenously). For more information on what happens before and during treatment, see section 3, How Skysona is made and given.

2. What you need to know before you or your child is given Skysona

You or your child must not be given Skysona if you or your child:

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

• – are allergic to any of the ingredients in the medicines your child will be given before treatment with

Skysona (see section 3).

Warnings and precautions

• Information about cell-based medicinal products, like Skysona, must be kept for 30 years at the hospital. The information kept about you or your child will be your name and the batch number of Skysona received.
• Skysona is made from your or your child’s own stem cells and should only be given to you or your child.
• An ingredient of Skysona called dimethyl sulfoxide (DMSO) may cause an allergic reaction, so the doctor or nurse should watch closely during and following the infusion for any signs or symptoms of a reaction.

Before the treatment with Skysona the doctor will

• check the kidneys and liver;
• check for human immunodeficiency virus (HIV);
• discuss possible impacts of the conditioning medicine on fertility (see below under “Fertility in men and women”);
• prepare for stem cells to be taken (mobilisation) and then clear the cells from your child’s bone marrow ready for Skysona to be given (conditioning). For more information on this, including possible side effects of the medicines used, see sections 3 and 4.

After the treatment with Skysona

• Blood counts may remain low for more than 2 months after conditioning and treatment with Skysona. During that time, there may be a risk for bleeding and infection. The doctor will monitor this using blood tests and will tell you when blood counts have returned to safe levels.
• If you require a blood transfusion within the first 3 months after having received Skysona, blood products should be irradiated. This will reduce the white blood cells, called lymphocytes, and minimise the risk of a reaction to the transfusion.
• After treatment with Skysona, you will not be able to donate blood, organs, tissues or cells. This is because Skysona is a gene therapy medicine.
• Adding a new gene into the stem cells could theoretically cause blood cancers (myelodysplasia, leukaemia, and lymphoma). After the treatment, the doctor will monitor you at least every year, which will include a blood test, for at least 15 years and the doctor will check for any signs of cancer of the blood. Contact the doctor if you have fever, you are more tired than usual, are losing weight without trying, or if you have frequent nosebleeds, bleeding, or bruising.
• Skysona is prepared using parts of HIV, which have been altered so that they cannot cause HIV infection. The virus is used to insert a working gene into your child’s blood stem cells.
• Although this medicine will not give an HIV infection, having Skysona in the blood may cause a false positive HIV test result because some HIV tests recognise a piece of HIV that is used to make Skysona. If the patient tests positive for HIV following treatment, please contact the doctor or nurse.

When Skysona treatment cannot be completed or fails

Before receiving Skysona you or your child will be given conditioning medicine in order to remove cells from the existing bone marrow.

If Skysona cannot be given after having the conditioning medicine or if the modified stem cells do not take hold (engraft) in the 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 Skysona is made and given). If you or your child get your original cells back, you or your child will not have any treatment benefit.

Other medicines and Skysona

Tell your doctor if you or your child is taking, has recently taken or might take any other medicines.

Your child should not take any medicines for HIV infection from at least one month before having the mobilisation medicines (see also section 3, How Skysona is made and given). If such medicines are needed, the procedure will be postponed.

It is not recommended that live vaccines be given within 6 weeks before receiving the conditioning medicine to prepare for Skysona treatment, nor after treatment while the immune system (the body’s defence system) is recovering. Talk to the doctor if there is a need to have any vaccinations.

Contraception, pregnancy, breast-feeding and fertility

Contraception in men and women

Women who could become pregnant and men capable of fathering a child must start using an effective method of contraception from before the blood stem cells are collected and continue until at least 6 months after receiving Skysona. Effective methods of contraception include intra-uterine device or a combination of oral contraceptive (also known as the pill) and condoms. Also read the package leaflet for the conditioning medicine for information regarding contraception.

Pregnancy

Skysona must not be given during pregnancy because of the conditioning medicine.

Women who could become pregnant will be given a pregnancy test before starting mobilisation, before given conditioning medicine, and before Skysona treatment in order to confirm that she is not pregnant. If a woman becomes pregnant after treatment with Skysona, she should contact her treating physician.

The added gene from Skysona will not be passed on to the foetus in case of a pregnancy and the unborn child is still at risk of inheriting the original ABCD1 gene, which, when absent or does not work, causes adrenoleukodys­trophy.

Breast-feeding

Skysona must not be given when breast-feeding. It is not known whether the ingredients of Skysona can pass into breast milk.

Fertility in men and women

It may no longer be possible to become pregnant or father a child after receiving conditioning medicine. If you are concerned, you should discuss this with the doctor before treatment.

Driving and using machines

Skysona has no effect on the ability to drive or use machines. However, the mobilisation and conditioning medicines may cause dizziness and tiredness. You or your child should avoid activities requiring balance (for example, cycling or skateboarding) and driving or using machines if you or your child feel dizzy, tired, or unwell.

Skysona contains sodium

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 Skysona is made and given

About 2 months before treatment with Skysona, you or your child will be given medicines that will move blood stem cells from the bone marrow into the blood stream (mobilisation). The blood stem cells can then be collected by a machine that separates blood components (apheresis machine). It may take more than 1 session to collect enough blood stem cells both to make Skysona and to store as replacement cells if Skysona cannot be given or does not work.

How you or your child is given Skysona

Skysona is given by a drip (infusion) into a vein, this is often through a central venous catheter. It can only be given in a specialised hospital by doctors who are experienced in treating patients with CALD, transplanting bone marrow, and using gene therapy medicines. Skysona is a one-time treatment. It will not be given again. If Skysona does not work, you will come back to the treatment center and you will receive a transfusion of your original replacement stem cells. These cells do not contain the medicine and therefore your CALD will not be treated.

When	What is done	Why
About 2 months before Skysona infusion	Mobilisation medicine is given	To move the blood stem cells from your child’s bone marrow into the blood stream.
About 2 months before Skysona infusion	Blood stem cells are collected	To make Skysona and to store some stem cells as replacement cells, if needed.
At least 6 days before Skysona infusion	Conditioning medicine is given in a hospital	To prepare the bone marrow for treatment by destroying cells in the bone marrow so they can be replaced with the modified cells in Skysona.
Start of Skysona treatment	Skysona is given by a drip (infusion) into a vein. This will be in a hospital and will take less than 60 minutes for each	To add blood stem cells containing the ALDP gene into the bone marrow.

	infusion bag. The number of bags will vary by patient.
After Skysona infusion	You or your child will likely remain in the hospital for about 3–6 weeks	To recover and be monitored until the doctor is satisfied that it is safe 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 are related to the mobilisation medicine and blood stem cell collection or to the conditioning medicine used to prepare the bone marrow for treatment with Skysona. You should discuss possible side effects due to the mobilisation medicines and conditioning medicine with the doctor. You should also read the package leaflets for these medicines.

Tell the doctor or nurse immediately if you or your child is having any side effects after receiving the treatment. The side-effects below usually happen within the first few days and several weeks after receiving treatment but can also develop much later.

Mobilisation and blood stem cell collection

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

• low level of potassium seen in a blood test

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

• low level of blood platelets, which may lead to bleeding
• low level of red blood cells which may lead to fatigue
• low level of magnesium seen in a blood test
• headache
• high blood pressure
• feeling sick (nausea), being sick (vomiting)
• tingling sensation in the mouth
• itchy skin
• pain in bones, arms and legs

Conditioning Medicine

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

• low level of white blood cells, sometimes with fever, which may lead to an infection
• low level of red blood cells which may lead to fatigue
• low level of blood platelets, which may lead to bleeding
• fever
• soreness of the mouth
• nosebleeds
• blood tests showing decrease in magnesium, potassium, or phosphate, increase of liver enzymes
• headache
• decreased appetite
• stomach pain, constipation, diarrhoea
• feeling sick (nausea), being sick (vomiting)
• unusual hair loss or thinning
• dark patches on skin
• high blood pressure

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

• various kinds of infections in different parts of the body that may be caused by viruses, bacteria, or fungi. These may include an infection of the bloodstream or venous catheter infections, infection of the gastrointestinal system, ear infection, thrush, anal yeast infection, respiratory infection. These may cause symptoms such as feeling hot (feverish), chilly or sweaty, cough, diarrhoea, and vomiting.
• impaired function of the adrenal glands which may result in dangerously low blood pressure
• low level of oxygen in the blood measured by a monitor
• high level of antidiuretic hormone which leads to water retention in the body
• inflammation of the digestive tract lining (which runs from the mouth to the anus), small tear in tissue that lines the anus (anal fissure), inflammation or itching of anus
• blood in stool, spots on the skin from bleeding under the skin, bleeding in eye, increase in time to clot your blood
• stomach irritation
• urinary incontinence, blood in urine, discomfort when passing urine, urinary tract pain
• sore throat, pain in the mouth, rectum, penis, lymph nodes
• slow or fast heart rate
• fast breathing
• excessive sweating
• blood test showing decrease in antibodies
• blood tests showing decrease in sodium, blood test showing increase in alkaline phosphatase, lactate dehydrogenase
• low blood sugar
• cough
• runny nose
• decrease in skin sensation in legs
• dry, peeling or itchy skin, rash, diaper rash, sore on the scrotum
• involuntary movement (tremor)
• decrease in reflexes
• allergic reaction to platelet transfusion
• dislike of swallowing medication
• swelling in face or body (oedema)
• tiredness, trouble sleeping
• weight increased or decreased

Skysona

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

• low level of white blood cells, which may lead to an infection
• low level of red blood cells which may lead to fatigue
• low level of blood platelets, which may lead to bleeding
• viral infection in bladder. This may cause symptoms such as feeling hot (feverish), chilly or sweaty, blood in urine, pain in lower stomach, and in small children also vomiting.
• vomiting

Reporting of side effects

If you or your child experience any side effects, talk to the 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 By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Skysona

This information is intended for healthcare professionals only. This information is shared for the patient’s awa­reness only.

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 and infusion bag.

Store at or below –140 °C for up to six months.

Keep infusion bag(s) in the metal cassette(s).

Do not re-freeze after thawing.

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.

6. Contents of the pack and other information

What Skysona contains

• The active substance of Skysona consists of your child’s own blood stem cells that contains functional copies of the ALDP gene. The concentration per bag is 2–30 × 106 blood stem cells per millilitre.
• The other ingredient is a solution used to preserve frozen cells (see section 2, Skysona contains sodium).

This medicine contains genetically modified human blood cells.

What Skysona looks like and contents of the pack

Skysona is a colourless to white to red dispersion of cells including shades of white or pink, light yellow, and orange. The medicine is supplied in one or more clear infusion bags, each packed in a transparent pouch inside a closed metal container. Skysona may be packaged in one or more 20 mL bags, depending on the total number of cells present. One or more bags may be given to obtain the full dose.

The patient’s name and date of birth, as well as coded information identifying you or your child 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

Manufacturer

Minaris Regenerative Medicine GmbH

Haidgraben 5

85521 Ottobrunn

Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Deutschland

bluebird bio (Germany) GmbH

Tel: +49 (0) 893 803 7456 (0800 181 0702)

EXXáSa, Kúnpog

Bluebird Bio Greece Single Member L.L.C. +30 21 0300 5938

France

bluebird bio (France) SAS

Tél: +33 (0)1 85 14 97 89 (0800 914 510)

Belgie/Belgiqu­e/Belgien, Et.nrapun, Česká republika, Danmark, Eesti, España, Hrvatska, Ireland, Ísland, Latvija, Lietuva, Luxembourg/Lu­xemburg, Magyarország, Malta, Norge, United Kingdom (Northern Ireland), Österreich, Polska, Portugal, Romania, Slovenija, Slovenská republika, Suomi/Finland, Sverige bluebird bio (Netherlands) B.V.

Tél/Tel/Ten/T­lf/TnVSími/Puh:

+31 (0) 303 100 450

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

Detailed information on this medicine is available on the European Medicines Agency web site:.

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

The following information is intended for healthcare professionals only:

Precautions to be taken before handling or administering the medicinal product

• This medicinal product contains genetically modified human blood cells. Healthcare professionals handling Skysona should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.
• Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at < –140 °C until ready for thaw and administration.

Preparation for infusion

• Skysona 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 Skysona. A patient may have multiple infusion bags.
• Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from the metal cassette.
• Confirm that Skysona is printed on the infusion bag(s).
• Confirm that patient identity matches the unique patient identification information located on the Skysona infusion bag(s) and on the Lot Information Sheet. Skysona is intended solely for autologous use. Do not infuse Skysona if the information on the patient-specific label on the infusion bag does not match the intended patient.
• Ensure that you have the correct number of infusion bags and confirm each infusion bag is within the expiry date using the accompanying Lot Information Sheet.
• Each infusion bag should be inspected for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow the local guidelines for handling of waste of human-derived material and contact bluebird bio immediately.

Thawing

• If more than one infusion bag is provided, thaw and administer each infusion bag completely before proceeding to thaw the next infusion bag.
• Do not sample, alter, irradiate, or refreeze the medicinal product.
• Thaw Skysona at 37 °C in a water bath or dry bath. Thawing of each infusion bag takes

approximately 2 to 4 minutes. Do not over thaw the medicinal product. Do not leave the medicinal product unattended and do not submerge the infusion ports in a water bath.

• After thaw, mix the medicinal product gently by massaging the infusion bag until all of the contents are uniform.

Administration

• Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port.
• Access the medicinal product 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.
• Infuse Skysona as soon as possible and store for no more than 4 hours at room temperature (20 °C – 25 °C) after thawing.
• Administer each infusion bag of Skysona via intravenous infusion over a period of less than

• 60 minutes.

• Flush all Skysona remaining in the infusion bag and any associated tubing with at least 50 mL of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure as many cells as possible are infused into the patient.