ROCTAVIAN 2 × 10E13 GENE VECTORS/ML SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

ROCTAVIAN 2 × 1013genome copies of vector/ml solution for infusion

valoctocogene roxaparvovec

This medicinal product is subject to additional monitoring, which will allow for quicker identification of new safety information. You can help by reporting any side effects you may have. The last section of section 4 will tell you how to report side effects.

Read all of this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
• Your doctor will give you a Patient Card. Read it carefully and follow the instructions on it.

Contents of the pack

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

1. What is ROCTAVIAN and what is it used for

What is ROCTAVIAN

ROCTAVIAN is a gene therapy medicine that contains the active substance valoctocogene roxaparvovec. A gene therapy medicine works by releasing a gene into the body to correct a genetic defect.

What ROCTAVIAN is used for

This medicine is used to treat severe haemophilia A in adults who do not have or have not had inhibitors of factor VIII and who do not have antibodies against the AAV5 virus vector.

Haemophilia A is a disease where people inherit a faulty version of the gene needed to produce factor VIII, a protein necessary for blood to clot and bleeding to stop. People with haemophilia A cannot produce factor VIII and are prone to internal or external bleeding episodes.

How ROCTAVIAN works

The active substance in ROCTAVIAN is made up of a virus that does not cause disease in humans. This virus has been modified so that it cannot spread in the body, but it can release a functional copy of the factor VIII gene into liver cells. This allows liver cells to produce the factor VIII protein and increases the levels of functional factor VIII in the blood. This helps the blood to clot better and prevents or reduces bleeding episodes.

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

ROCTAVIAN will not be given to you

• if you are allergic to valoctocogene roxaparvovec or any of the other ingredients of this medicine (listed in section 6).
• if you have an active or chronic (long-term) infection that is not controlled with the medicines you are taking, or if you have liver scarring (significant hepatic fibrosis or cirrhosis), as this may affect your body's initial response to ROCTAVIAN.
• if you have antibodies against the type of virus used to make this medicine. Your doctor will test you for this before giving you ROCTAVIAN.

If any of the above applies to you, or if you are not sure, talk to your doctor before receiving ROCTAVIAN.

Warnings and precautions

Importance of liver health

• The liver is the organ that produces factor VIII after treatment with ROCTAVIAN. You should take care of your liver health so that it works as well as possible and can produce factor VIII and continue to produce it regularly.
• Talk to your doctor about what you can do to improve and maintain your liver health (see also, above ROCTAVIAN will not be given to youand at the end of this section Other medicines and ROCTAVIANand ROCTAVIAN with alcohol).
• Your doctor may advise against treatment with ROCTAVIAN if you have a liver disease that may prevent ROCTAVIAN from working correctly.

Possibility of needing an additional medicine

• You may need to take another medicine (corticosteroids) for a long time (2 months or more) after receiving ROCTAVIAN to treat liver problems seen in tests. Corticosteroids can cause side effects while you are taking them. Your doctor may advise against receiving or delaying treatment with ROCTAVIAN if you cannot safely take corticosteroids. Your doctor may also tell you what steps to follow for safe use or give you an alternative medicine. See also section 3.

Side effects during or soon after infusion of ROCTAVIAN

• Infusion-related side effects can occur during or soon after the infusion of ROCTAVIAN. The symptoms of these side effects are listed in section 4. Possible side effects. If you experience these or any other symptoms during or soon after the infusion, tell your doctor or nurse immediately. Depending on the symptoms, the infusion may be given more slowly or temporarily stopped, or you may be given medicines to treat the symptoms. Before you are discharged, your doctor will give you information on what to do if you experience new or recurring side effects once you have left the hospital.

Possibility of unwanted blood clots forming due to increased factor VIII levels

• After treatment with ROCTAVIAN, it is possible that your factor VIII level may increase. In some patients, it may increase to levels above the normal range for some time.

Factor VIII is the protein needed for stable blood clot formation. Depending on your individual risk factors, an increase in factor VIII level may increase the risk of unwanted blood clots (called "thrombosis" in both veins and arteries). Talk to your doctor about your general risk factors for unwanted clots and cardiovascular disease, as well as what to do about them. Also, ask your doctor how to recognize the symptoms of unwanted clots and what to do if you think you may have one.

Avoiding blood donations and donations for transplants

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

Immunocompromised patients or patients receiving immunosuppressive treatment

• If you are immunocompromised (when your immune system's ability to fight infections is reduced) or are receiving immunosuppressive treatment, contact your doctor before starting treatment with ROCTAVIAN. You may need closer monitoring if your immune system is not working properly, and to ensure that you can receive treatment or other medicines such as corticosteroids, or if you need to change your existing medicines.

Receiving a second gene therapy in the future

• After receiving ROCTAVIAN, your immune system will produce antibodies against the AAV vector capsule. It is not yet known if treatment with ROCTAVIAN can be repeated and, if so, under what conditions. It is also not yet known if the use of a different gene therapy is possible and, if so, under what conditions.

Use of other treatments for haemophilia

• After using ROCTAVIAN, talk to your doctor about whether you should stop other haemophilia treatments and develop a treatment plan for what to do in case of surgery, trauma, bleeding, or procedures that may increase the risk of bleeding. It is essential to continue with monitoring and medical visits to determine if you need other treatments to control haemophilia.

Monitoring tests

Before treatment with ROCTAVIAN, your doctor will perform tests to assess your liver health.

After treatment with ROCTAVIAN, you will have blood tests to check:

• when your liver starts producing factor VIII, to know when you can stop your usual factor VIII treatment,
• how much factor VIII your liver is producing continuously,
• how your liver cells are reacting to treatment with ROCTAVIAN, and
• if you have developed inhibitors (neutralizing antibodies) of factor VIII.

The frequency of these tests will vary depending on how you respond to ROCTAVIAN. In general, during the first 26 weeks after treatment, you will have a blood test every week, and then every 2 to 4 weeks until the end of the first year. After the first year, blood tests will be done less frequently as indicated by your doctor. It is essential that you discuss the planning for these blood tests with your doctor so that you can have them done as needed.

Since not all patients will respond to ROCTAVIAN, and the reasons are not established, your doctor will not be able to anticipate if you will have a complete response to treatment. There is a possibility that you may not benefit from ROCTAVIAN and, at the same time, be exposed to long-term risks.

If you respond to treatment, the duration of the treatment is not known. A positive treatment effect has been reported for up to five years in some patients.

It is not expected to re-administer the medicine in patients who do not respond to treatment or who have lost response.

Long-term follow-up tests may be necessary to verify the continued safety and efficacy of the response to ROCTAVIAN.

Risk of tumours possibly associated with ROCTAVIAN

• ROCTAVIAN can be inserted into the DNA of liver cells, and there is a possibility that it can also be inserted into the DNA of other cells in the body. As a result, ROCTAVIAN may contribute to a risk of cancer. Although clinical trials do not show evidence of this so far, it is still possible due to the nature of the medicine. You should discuss this with your doctor. After treatment with ROCTAVIAN, you will be advised to enroll in a registry to help study the long-term safety of the treatment for 15 years, how well it continues to work, and any side effects that may be related to the treatment. If cancer occurs, your doctor will take a sample for further evaluation.

Children and adolescents

ROCTAVIAN should only be used in adults. The use of ROCTAVIAN in children and adolescents has not yet been tested.

Other medicines and ROCTAVIAN

Before and after treatment with ROCTAVIAN, tell your doctor if you are using, have recently used, or may need to use any other medicines, including herbal products or nutritional supplements. The purpose of this is to ensure that, as far as possible, you do not take anything that may harm your liver or affect your response to corticosteroids or ROCTAVIAN (such as isotretinoin, a medicine used to treat acne) or some medicines for treating HIV (see the previous section on Immunocompromised patients or patients receiving immunosuppressive treatment). This is especially important during the first year after treatment with ROCTAVIAN (see also Warnings and precautions).

Since corticosteroids can harm your body's immune system (defences), your doctor will adjust your vaccination schedule and advise you not to receive certain vaccinations while you are taking corticosteroids. If in doubt, consult your doctor.

ROCTAVIAN with alcohol

Alcohol consumption may affect the liver's ability to produce factor VIII after treatment with ROCTAVIAN. You should avoid consuming alcohol for at least one year after treatment. Talk to your doctor about what amount of alcohol may be acceptable after the first year in your case (see also Warnings and precautions).

Pregnancy, breastfeeding, and fertility

ROCTAVIAN should not be used in women who may become pregnant. It is not yet known if ROCTAVIAN can be used in these patients safely, as the effects of ROCTAVIAN on pregnancy and the fetus are not known. It is also not known if ROCTAVIAN passes into breast milk.

There is no information on the effect of ROCTAVIAN on fertility in men or women.

Use contraceptive methods and avoid pregnancy for some time

• After the male patient has been treated with ROCTAVIAN, the patient and any partner should avoid pregnancy for 6months. You should use effective contraceptive methods (e.g., double barrier contraceptive methods, such as condoms or a diaphragm). This is to avoid the theoretical risk that the factor VIII gene from ROCTAVIAN treatment may be passed on to the child with unknown consequences. For the same reason, male patients should not donate semen for 6 months. Consult your doctor about suitable contraceptive methods.

Driving and using machines

After infusion of ROCTAVIAN, temporary dizziness (feeling of fainting), dizziness, fatigue, and headaches have been reported. If this happens to you, act with caution until you are sure that ROCTAVIAN does not negatively affect your ability to drive or use machines. Talk to your doctor about this.

ROCTAVIAN contains sodium

This medicine contains 29 mg of sodium (the main component of table/cooking salt) in each vial. This is equivalent to 1.5% of the maximum recommended daily intake of sodium for an adult. The amount of sodium you will receive with the treatment depends on the number of ROCTAVIAN vials used for the infusion.

3. How ROCTAVIAN will be given

ROCTAVIAN will be given to you by a doctor who is specialized in the treatment of your disease.

Your doctor will prepare the correct dose for you, based on your body weight.

Treatment with ROCTAVIAN consists of a single infusion (drip) into a vein. The infusion may take several hours to complete.

The infusion will be given to you in a hospital. You will be monitored during and after the infusion to detect any possible side effects.

When it is considered that you no longer need to be monitored, you can go home (usually on the same day).

Possibility of needing an additional medicine

You may need to take another medicine (corticosteroids) for some time after treatment with ROCTAVIAN (e.g., 2 months or more) to improve the response to therapy. It is essential that you take this additional medicine as instructed. If you are prescribed another medicine, read the package leaflet and talk to your doctor about possible side effects and, if necessary, the need for monitoring.

If you are given too much ROCTAVIAN

Since this medicine is given in a hospital and the dose is prepared and supervised by the medical team, it is unlikely that you will be given too much. If you are given too much ROCTAVIAN, you may have higher factor VIII levels than necessary, which may theoretically increase the risk of unwanted blood clots. If this happens, your doctor will give you the necessary treatment.

If you have any further questions on the use of this medicine, ask your doctor.

4. Possible Adverse Effects

Like all medicines, this medicine may cause adverse effects, although not all people suffer from them.

Adverse effects related to perfusion may occur during or shortly after perfusion (frequent; may affect up to 1 in 10 people). Inform your doctor or nurse immediatelyif you experience any of the symptoms listed below or any other symptom during or shortly after perfusion:

• Hives or other rashes, itching
• Difficulty breathing, sneezing, coughing, runny nose, tearful eyes, tingling in the throat
• Nausea (feeling of sickness), diarrhea
• High or low blood pressure, rapid heartbeat, dizziness (feeling of fainting)
• Muscle pain, back pain
• Fever, chills, shivering

You may experience one of these symptoms or a combination of them. Depending on the symptoms, it is possible that the perfusion will be administered more slowly or temporarily interrupted, or that you will be given medications to treat the symptoms. Before discharge, your doctor will provide you with information on what to do in case you experience a new or recurrent adverse effect once you have left the healthcare facility.

There have been reports of increased levels of liver proteins after ROCTAVIAN perfusion. In some cases, these increases were accompanied by a decrease in factor VIII levels. The increase in liver protein levels observed in blood tests may be the reason for starting treatment with a corticosteroid.

ROCTAVIAN may cause the following adverse effects. Some of these adverse effects may occur during or shortly after perfusion.

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

• Increased levels of liver enzymes observed in blood tests
• Nausea (feeling of sickness)
• Headache
• High levels of factor VIII
• Fatigue
• Diarrhea
• Abdominal pain (abdomen)
• Vomiting
• Increased levels of creatine phosphokinase (CPK) (an enzyme released into the blood when there is muscle damage) observed in blood tests

Common (may affect up to 1 in 10 people)

• Rash (hives or other types of rash)
• Heartburn (dyspepsia)
• Muscle pain
• Flu-like symptoms
• Dizziness
• Itching
• High blood pressure
• Allergic reaction

Uncommon (may affect up to 1 in 100 people)

• Dizziness (feeling of fainting)
• Difficulty breathing

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or nurse, even if it is an adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of ROCTAVIAN

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

Do not use this medicine after the expiration date that appears on the box and vial after "EXP". The expiration date is the last day of the month indicated.

The storage of ROCTAVIAN, in the healthcare facility, is the responsibility of healthcare professionals. It must be stored in a vertical position and in the original box (to protect it from light).

It must be stored and transported frozen at -60 °C or lower. Once thawed, it must be used within 10 hours at 25 °C (this period includes the time the solution remains in the vial and syringe and the infusion time) or discarded. If necessary, intact vials (i.e., vials whose stopper has not been pierced) that have been thawed can be stored refrigerated (2 to 8 °C) for a maximum period of 3 days, in a vertical position and protected from light (e.g., in the original box).

ROCTAVIAN should not be used if, after thawing, the solution is not transparent, colorless, or pale yellow.

6. Package Contents and Additional Information

Composition of ROCTAVIAN

• The active substance is valoctocogene roxaparvovec.
• The other components are: disodium phosphate dodecahydrate (E 339), mannitol (E 421), poloxamer 188, sodium chloride, sodium dihydrogen phosphate dihydrate (E 339), and water for injectable preparations.

In the final part of section 2 ROCTAVIAN contains sodium, information is provided regarding the total sodium content.

This medicine contains genetically modified organisms (GMOs).

Appearance of ROCTAVIAN and Package Contents

Once thawed, ROCTAVIAN is a clear solution for infusion, colorless or pale yellow. It is supplied in a vial.

Package size: 1 vial of 8 ml

Marketing Authorization Holder and Manufacturer

BioMarin International Ltd.

Shanbally, Ringaskiddy

County Cork

P43 R298

Ireland

Date of Last Revision of this Leaflet

This medicine has been authorized with a "conditional approval". This type of approval means that more information is expected to be obtained about this medicine.

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

Other Sources of Information

Detailed information about this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. There are also links to other websites about rare diseases and orphan medicines.

This information is intended only for healthcare professionals:

Important: Consult the Summary of Product Characteristics (SPC) or Package Leaflet before administering ROCTAVIAN.

Precautions must be taken before handling or administering the medicine.

Each vial is for single use.

This medicine contains genetically modified organisms (GMOs).

During preparation, administration, and disposal, it is necessary to use personal protective equipment (gown, glasses, mask, and gloves) when handling the valoctocogene roxaparvovec solution and materials that have come into contact with the solution (solid and liquid waste).

ROCTAVIAN should not be exposed to light emitted by a UV disinfection lamp. ROCTAVIAN must be prepared using an aseptic technique.

During the assembly of the infusion system, it is necessary to ensure that the surface of the components that will come into contact with the ROCTAVIAN solution is made of one of the compatible materials listed in the SPC.

Compatible Materials for Infusion System Components

a In case of using extension tubes, their length should not exceed approximately 100 cm.

ROCTAVIAN must be infused using a syringe pump at a controlled flow rate.

The following syringes should be prepared:

• Syringes filled with ROCTAVIAN (the number of syringes will vary depending on the patient's dose volume).
• A syringe with sodium chloride 9 mg/ml (0.9%) injectable solution to flush the infusion line once the ROCTAVIAN infusion is complete.

The infusion requires integrated filters with low protein binding and high volume, with a pore size of 0.22 microns and a maximum operating pressure suitable for the syringe pump or pump configuration. It is necessary to ensure the availability of a sufficient number of replacement filters, determined by the filter specification regarding the maximum volume of filtered liquid.

Thawing and Inspection

• ROCTAVIAN must be thawed at room temperature. Do not thaw the vials in any other way, such as by heating them. The thawing time is approximately 2 hours.
• Keep each vial in the original box until it is ready to be thawed. ROCTAVIAN is sensitive to light.
• Remove the required number of vials from their respective boxes.
• Inspect the vials for any damage to the vial or cap. Do not use vials that are damaged.
• Place the vials in a vertical position. For optimal thawing, spread them out evenly or place them on grids maintained at room temperature.
• Visually confirm that all vials have been thawed. There should be no visible ice. Gently invert each vial 5 times to mix its contents. It is important to minimize foam formation as much as possible. Let the solution settle for approximately 5 minutes before proceeding.
• Then, visually inspect the completely thawed vials. Do not use vials whose solution is not transparent, not colorless or pale yellow, or contains visible particles.

For microbiological safety reasons, keep the thawed solution in the vials until it is ready to be extracted into the infusion syringes.

Deadline for Final Preparation and Administration

Once thawed, the infusion of the solution must be completed within the in-use stability limit of 10 hours at 25 °C. The infusion time varies depending on the volume to be infused, the infusion rate, and the patient's response; this time may be, for example, 2 to 5 hours or longer in case the patient weighs 100 kg.

Extraction into Syringes

Using sharp 18 to 21 gauge needles, slowly extract the total calculated dose volume of ROCTAVIAN from the vials into the syringes.

Adding the Integrated Filter and Purging the Infusion System

• Insert the integrated filter near the infusion site.
• Purge the tube and filter with ROCTAVIAN.
• In case a filter replacement is needed during infusion, use sodium chloride 9 mg/ml (0.9%) injectable solution for purging and flushing.

Administration

• Do not administer this medicine before the solution has reached room temperature.
• Infuse the solution through a suitable peripheral vein, using an infusion catheter and a programmable syringe pump.
• Start the infusion at a rate of 1 ml/min. If the patient tolerates this rate, it can be increased by 1 ml/min every 30 minutes up to a maximum rate of 4 ml/min. In case of a perfusion-related reaction, if clinically indicated, decrease the rate or stop the infusion and, if necessary, administer other medications such as systemic antihistamines, corticosteroids, or intravenous fluids to control the perfusion reaction or before resuming the infusion. To resume the infusion, start with a rate of 1 ml/min and consider maintaining it at a level that the patient has previously tolerated for the remainder of the infusion.
• To ensure that the patient receives the full dose, once the volume of the last ROCTAVIAN syringe has been infused, infuse a sufficient volume of sodium chloride 9 mg/ml (0.9%) injectable solution through the same tube and filter and at the same infusion rate.
• Maintain venous access during the post-infusion observation period.

Measures to be Taken in Case of Accidental Exposure

All spills of valoctocogene roxaparvovec must be cleaned up with absorbent pads, and the spill area must be disinfected with a bleach solution and alcohol wipes.

Precautions to be Taken for the Disposal of the Medicine

The unused medicine and waste that has come into contact with ROCTAVIAN (solid and liquid waste) must be disposed of in accordance with local guidelines for pharmaceutical waste.