ZOLGENSMA

Package leaflet: Information for the user

Zolgensma 2 × 10 vector genomes/mL solution for infusion

onasemnogene abeparvovec
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 notice in the child while using this medicine. See the end of section 4 for information on how to report adverse reactions.
Please read this leaflet carefully before this medicine is given to the child,
as it contains important information.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your child’s doctor or nurse.
• If the child experiences any side effects, including those not listed in this leaflet, tell your child’s doctor or nurse. See section 4.

Contents of this leaflet

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

1. What Zolgensma is and what it is used for

What Zolgensma is
Zolgensma is a type of medicine called a "gene therapy". It contains the active substance
onasemnogene abeparvovec, which contains human genetic material.
What Zolgensma is used for
Zolgensma is used to treat "spinal muscular atrophy" (SMA), a rare, serious inherited disease.
How Zolgensma works
SMA occurs when a gene needed to produce a vital protein known as "survival motor neuron" (SMN) protein is missing or abnormal. The lack of SMN protein leads to the death of nerves that control muscles (motor neurons). This causes muscle weakness and wasting, resulting in loss of movement.
The medicine works by delivering a fully functional copy of the SMN gene, which then helps the body produce sufficient amounts of SMN protein. The gene is delivered into the cells where it is needed, using a modified virus that does not cause disease in humans.

2. What you should know before Zolgensma is administered to the child

DO NOT use Zolgensma

• if the child is allergic to onasemnogene abeparvovec or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
The child’s doctor will check for the presence of antibodies before treatment, which will help determine whether this medicine is suitable for the child.
Infusion-related reactions and severe allergic reactions
Undesirable effects related to infusion and severe allergic reactions may occur during and/or immediately after administration of Zolgensma to the child. Possible signs to watch for include itchy rash, pallor, vomiting, swelling of the face, lips, mouth or throat (which may cause difficulty swallowing or breathing), and/or changes in heart rate and blood pressure. Immediately inform the child’s doctor or nurse if you notice the child developing these or any other new signs or symptoms during and/or immediately after treatment with Zolgensma. Before the child is discharged, the doctor will provide information on what to do if the child develops new side effects or if side effects reoccur after leaving the healthcare facility.
Liver problems
Talk to the child’s doctor or nurse before administering this medicine if the child has had liver problems. This medicine may cause an increase in liver enzymes (proteins found in the body) or liver damage. Liver injury can lead to serious outcomes, including liver failure and death. After the child has received this medicine, you will need to monitor for signs including vomiting, jaundice (yellowing of the skin or whites of the eyes), or reduced alertness (see section 4 for more information). Immediately inform the child’s doctor if you notice the child developing symptoms indicating liver damage.
The child will have blood tests to check liver function before starting treatment with Zolgensma. The child will also have regular blood tests for at least 3 months after treatment to monitor for any increases in liver enzymes.
Infection
An infection (e.g., cold, flu, or bronchiolitis) before or after treatment with Zolgensma may lead to more serious complications. Caregivers and close contacts should follow infection prevention practices (e.g., hand hygiene, cough/sneeze etiquette, limiting potential exposures). Be vigilant for signs of infection such as cough, wheezing, sneezing, runny nose, sore throat, or fever. Immediately inform the child’s doctor if you notice the child developing any symptoms indicating infection before or after treatment with Zolgensma.
Regular blood tests
This medicine may lower the platelet count in the blood (thrombocytopenia). Be alert for possible signs of low platelet count after the child receives Zolgensma, such as bruising or abnormal bleeding (see section 4 for more information). Most reported cases of low platelet count occurred within the first three weeks after administration of Zolgensma to the child.
Before starting treatment with Zolgensma, the child will undergo blood tests to check blood cell counts (including red blood cells and platelets), as well as troponin I levels in the body. The child will also have a blood test to check creatinine levels, which is an indicator of kidney function. The child will also have regular blood tests for a certain period after treatment to monitor for any changes in platelet levels.
Increased troponin I levels (a heart protein)
Zolgensma may increase levels of a heart protein called troponin I. This can be detected through laboratory tests performed by the child’s doctor as needed.
Abnormal blood clotting in small blood vessels (thrombotic microangiopathy)
Cases of thrombotic microangiopathy have been reported, generally within the first two weeks after treatment with Zolgensma. Thrombotic microangiopathy is associated with a decrease in red blood cells and clotting cells (platelets) and may be fatal. These blood clots could damage the child’s kidneys. The child’s doctor may wish to perform blood tests (platelet count) and monitor blood pressure. Possible signs to watch for after Zolgensma administration include easy bruising, seizures (fits), or decreased urine output (see section 4 for further information). Seek urgent medical help if the child develops any of these signs.
Donation of blood, organs, tissues, and cells
After the child has been treated with Zolgensma, they will no longer be able to donate blood, organs, tissues, or cells for transplantation. This is because Zolgensma is a gene therapy product.
Other medicines and Zolgensma
Inform the child’s doctor or nurse if the child is taking, has recently taken, or might take any other medicines.
Prednisolone
During treatment with Zolgensma, the child will also receive a corticosteroid medicine such as prednisolone for approximately 2 months or longer (see also section 3). The corticosteroid medicine will help manage any increase in liver enzymes that the child may experience after receiving Zolgensma.
Vaccinations
Because corticosteroids may affect the body’s immune (defence) system, the child’s doctor may decide to postpone certain vaccinations during the period when the child is receiving corticosteroid treatment. If you have any doubts, consult the child’s doctor or nurse.
Zolgensma contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per mL, equivalent to 0.23% of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium.
Each 5.5 mL vial contains 25.3 mg of sodium and each 8.3 mL vial contains 38.2 mg of sodium.
Additional information for parents/caregivers
Advanced SMA
Zolgensma can save vital motor neurons but cannot restore dead ones. Children with less severe SMA symptoms (such as absent reflexes or reduced muscle tone) may have enough surviving motor neurons to benefit significantly from treatment with Zolgensma. Zolgensma may be less effective in children with severe muscle weakness or paralysis, breathing difficulties, inability to swallow, or significant malformations (such as heart defects), including patients with SMA type 0, as there may be limited potential for improvement with Zolgensma treatment. The child’s doctor will decide whether to administer this medicine to the child.
Risk of tumors due to potential integration into DNA
There is a possibility that therapies such as Zolgensma may integrate into the DNA of human cells. As a result, Zolgensma could contribute to the risk of tumors due to the nature of the medicine. Discuss this with the child’s doctor. In case of tumor development, the child’s doctor may take a sample for further evaluation.
Hygiene precautions
The active substance in Zolgensma may be temporarily excreted in the child’s bodily waste; this is known as “shedding.” Parents and caregivers should maintain good hand hygiene for up to 1 month after the child receives Zolgensma. Wear protective gloves when in direct contact with the child’s bodily fluids or waste, and then thoroughly wash hands with soap and running warm water or use an alcohol-based hand sanitizer. Use a double bag for disposal of soiled diapers and other waste. Disposable diapers may be disposed of in household waste.
You should continue to follow these instructions for at least 1 month after the child has been treated with Zolgensma. If you have any doubts, consult the child’s doctor or nurse.

3. How Zolgensma is administered

Zolgensma will be administered by a doctor or a nurse trained to manage the disease.
The doctor will determine the amount of Zolgensma the child will receive based on the child's body weight.
Zolgensma is given as a single intravenous (into a vein) infusion (drip) lasting for more than
1 hour approximately.
Zolgensma will be administered to the child ONLY ONCE.
The child will also receive prednisolone (or another corticosteroid) orally, starting 24 hours
before administration of Zolgensma. The dose of corticosteroid will also depend on the child's weight.
The child's doctor will determine the total dose to be administered.
The child will receive corticosteroid treatment daily for approximately 2 months after the Zolgensma dose, or until liver enzymes decrease to an acceptable level. The doctor will gradually reduce the corticosteroid dose until administration can be completely stopped.
If you have any doubts, consult the child's doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Seek urgent medical assistance if the child develops any of the following serious side effects:
Common (may affect up to 1 in 10 people)

• bruising or bleeding lasting longer than usual after injury – these could be signs of low platelet count.

Uncommon (may affect up to 1 in 100 people)

• vomiting, jaundice (yellowing of the skin or whites of the eyes), or reduced alertness – these could be signs of liver damage (including liver failure);
• tendency to bruise easily, seizures (fits), decreased urine production – these could be signs of thrombotic microangiopathy;
• infusion-related reactions (see section 2, “Warnings and precautions”).

Rare (may affect up to 1 in 1,000 people)

• severe allergic reactions (see section 2, “Warnings and precautions”).

If the child develops any other side effect, consult the child’s doctor or nurse. These side effects may include:
Very common (may affect more than 1 in 10 people):

• increased liver enzymes observed in blood tests.

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

• vomiting;
• fever;
• increased troponin I (a heart protein) observed in blood tests.

Reporting of side effects
If the child experiences any side effect, including those not listed in this leaflet, consult the child’s doctor or nurse. You may also report side effects directly through 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 Zolgensma

Keep this medicine out of the sight and reach of children.
The following information is intended for healthcare operators who will prepare and administer the
medicine.
Do not use this medicine after the expiry date stated on the vial label and on the carton after “Scad/EXP”. The expiry date refers to the last day of that month.
The vials will be transported in a freezer (at a temperature equal to or below -60 °C).
Upon receipt, the vials must be immediately stored in a refrigerator at 2 °C – 8 °C and kept in the original carton. Treatment with Zolgensma must be initiated within 14 days of receiving the vials.
This medicine contains genetically modified organisms. Unused medicine or waste must be disposed of in accordance with local guidelines for the management of biological waste. Since this medicine will be administered by a physician, the physician is responsible for the proper disposal of the product. This will help protect the environment.

6. Package contents and other information

What Zolgensma contains
* The active substance is onasemnogene abeparvovec. Each vial contains onasemnogene abeparvovec at a nominal concentration of 2 × 10 vector genomes/mL.
* The other components are tromethamine, magnesium chloride, sodium chloride, poloxamer 188, hydrochloric acid (for pH adjustment), and water for injections.

Description of the appearance of Zolgensma and package contents
Zolgensma is an infusion solution that is transparent to slightly opalescent and colourless to pale white.
Zolgensma may be supplied in vials with a nominal fill volume of 5.5 mL or 8.3 mL. Each vial is for single use only.
Each carton will contain between 2 and 14 vials.

Marketing Authorisation Holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland

Manufacturer
Novartis Pharmaceutical Manufacturing GmbH
Biochemiestraße 10
6336 Langkampfen
Austria
Novartis Pharma GmbH
Roonstrasse 25
90429 Nuremberg
Germany
Novartis Pharma GmbH
Sophie-Germain-Strasse 10
90443 Nuremberg
Germany

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

België/Belgique/Belgien Lietuva
Novartis Pharma N.V. SIA Novartis Baltics Lietuvos filialas
Tél/Tel: +32 2 246 16 11 Tel: +370 5 269 16 50

България Luxembourg/Luxemburg
Novartis Bulgaria EOOD Novartis Pharma N.V.
Тел: +359 2 489 98 28 Tél/Tel: +32 2 246 16 11

Česká republika Magyarország
Novartis s.r.o. Novartis Hungária Kft.
Tel: +420 225 775 111 Tel.: +36 1 457 65 00

Danmark Malta
Novartis Healthcare A/S Novartis Pharma Services Inc.
Tlf.: +45 39 16 84 00 Tel: +356 2122 2872

Deutschland Nederland
Novartis Pharma GmbH Novartis Pharma B.V.
Tel: +49 911 273 0 Tel: +31 88 04 52 111

Eesti Norge
SIA Novartis Baltics Eesti filiaal Novartis Norge AS
Tel: +372 66 30 810 Tlf: +47 23 05 20 00

Ελλάδα Österreich
Novartis (Hellas) A.E.B.E. Novartis Pharma GmbH
Τηλ: +30 210 281 17 12 Tel: +43 1 86 6570

España Polska
Novartis Farmacéutica, S.A. Novartis Poland Sp. z o.o.
Tel: +34 93 306 42 00 Tel.: +48 22 375 4888

France Portugal
Novartis Pharma S.A.S. Novartis Farma - Produtos Farmacêuticos, S.A.
Tél: +33 1 55 47 66 00 Tel: +351 21 000 8600

Hrvatska România
Novartis Hrvatska d.o.o. Novartis Pharma Services Romania SRL
Tel. +385 1 6274 220 Tel: +40 21 31299 01

Ireland Slovenija
Novartis Ireland Limited Novartis Pharma Services Inc.
Tel: +353 1 260 12 55 Tel: +386 1 300 75 50

Ísland Slovenská republika
Vistor hf. Novartis Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 2 5542 5439

Italia Suomi/Finland
Novartis Farma S.p.A. Novartis Finland Oy
Tel: +39 02 96 54 1 Puh/Tel: +358 (0)10 6133 200

Κύπρος Sverige
Novartis Pharma Services Inc. Novartis Sverige AB
Τηλ: +357 22 690 690 Tel: +46 8 732 32 00

Latvija
SIA Novartis Baltics
Tel: +371 67 887 070

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. In addition, links to other websites on rare diseases and their therapeutic treatments are provided.

The following information is intended exclusively for healthcare professionals:

Important: Before using the medicinal product, consult the Summary of Product Characteristics (SmPC).
Each vial is for single use only.
This medicinal product contains genetically modified organisms. Observe local guidelines for the management of biological waste.

Handling

• Zolgensma must be handled under aseptic conditions and in a sterile environment.
• Personal protective equipment (including gloves, safety goggles, and laboratory coat with sleeves) must be worn during handling or administration of Zolgensma. Personnel with cuts or abrasions on the skin should not handle Zolgensma.
• Any spills of Zolgensma should be absorbed with absorbent gauze and the area disinfected with a bleach-based solution, followed by alcohol-soaked swabs. All materials used for cleanup must be placed in double bags and disposed of in accordance with local guidelines for biological waste management.
• All materials potentially in contact with Zolgensma (e.g., vial, materials used for injection, including sterile drapes and needles) must be disposed of in accordance with local guidelines for biological waste management.

Accidental exposure
Avoid accidental exposure to Zolgensma.
In case of accidental skin exposure, the affected area should be thoroughly washed with soap and water for at least 15 minutes. In case of accidental eye exposure, the affected area should be thoroughly rinsed with water for at least 15 minutes.

Storage
Vials will be transported in a freezer (at a temperature ≤ -60 °C). Upon receipt, vials must be immediately stored in a refrigerator at 2 °C – 8 °C, and kept in the original carton. Treatment with Zolgensma must be initiated within 14 days of receiving the vials. The date of receipt must be recorded on the original carton before storing the product in the refrigerator.

Preparation
Vials must be thawed before use:

• For packages containing up to 9 vials – thaw for approximately 12 hours in a refrigerator (2–8 °C) or for 4 hours at room temperature (20–25 °C);
• For packages containing up to 14 vials – thaw for approximately 16 hours in a refrigerator (2–8 °C) or for 6 hours at room temperature (20–25 °C).

Do not use Zolgensma unless it has been thawed.
Once thawed, Zolgensma must not be re-frozen.
After thawing, gently rotate Zolgensma. DO NOT shake.
Do not use this medicinal product if particulate matter or discoloration is observed after thawing of the frozen product and before administration.
After thawing, Zolgensma should be administered as soon as possible.

Administration
Zolgensma must be administered only ONCE to patients.
The dose of Zolgensma and the exact number of vials required for each patient are calculated based on the patient’s body weight (see SmPC, sections 4.2 and 6.5).
To administer Zolgensma, draw up the entire dose volume into a syringe. After drawing up the dose volume into the syringe, administration must be completed within 8 hours. Remove any air from the syringe before administering the intravenous infusion via a venous catheter. Insertion of a secondary catheter (“backup”) is recommended in case of occlusion of the primary catheter.
Zolgensma must be administered using a syringe pump as a single, slow intravenous infusion over approximately 60 minutes. It must be administered only by intravenous infusion. Do not administer as a bolus or by rapid intravenous injection. After completion of the infusion, the line must be flushed with an injectable solution of 0.9% sodium chloride (0.9% NaCl).

Disposal
Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local guidelines for biological waste management.
Transient dissemination of Zolgensma may occur, primarily via bodily waste. Caregivers and family members of patients should be informed about the following instructions for proper handling of patient fluids and waste:

• Good hand hygiene is required (wearing protective gloves and then thoroughly washing hands with soap and running warm water, or using an alcohol-based hand cleanser) in case of direct contact with patient bodily fluids and waste for at least 1 month after treatment with Zolgensma;
• Disposable diapers should be sealed in double plastic bags and may be disposed of in household waste.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for onasemnogene abeparvovec, the scientific conclusions of the PRAC are as follows:
In light of available data on “infusion-related reactions, including anaphylactic reactions” and “cardiac adverse events” from clinical studies, literature, and spontaneous reports, the PRAC concluded that the product information for the medicinal product containing onasemnogene abeparvovec should be updated accordingly.
Having reviewed the PRAC recommendations, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.

Reasons for the variation of the terms of the marketing authorisation
Based on the scientific conclusions regarding onasemnogene abeparvovec, the CHMP considers that the benefit-risk balance of the medicinal product containing onasemnogene abeparvovec remains unchanged, subject to the proposed updates to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.