Prospect: information for the user

Hemgenix 1 x 1013copies of the genome/ml concentrated for perfusion solution

etranacogén dezaparvovec

This medicine is subject to additional monitoring, which will expedite the detection of new information about its safety. You can contribute by reporting any adverse effects you may experience. The final part of section 4 includes information on how to report these adverse effects.

Read this prospect thoroughly before starting to use this medicine, because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any further questions, consult your doctor or nurse.
• If you experience adverse effects, consult your doctor or nurse, even if they are possible adverse effects not listed in this prospect. See section 4.
• Your doctor will give you a patient information leaflet. Read it thoroughly and follow the instructions it contains.

What is Hemgenix and what is it used for

Hemgenix is a gene therapy product that contains the active ingredient etranacog ala dezaparvovec. A gene therapy product works by introducing a gene into the body to correct a genetic defect.

Hemgenix is used for the treatment of severe and moderately severe hemophilia B (congenital factor IX deficiency) in adults who do not present, or have not presented, inhibitors (neutralizing antibodies) against factor IX protein.

People with hemophilia B are born with an altered form of a gene necessary to produce factor IX, an essential protein for blood to clot and stop any bleeding. People with hemophilia B have insufficient levels of factor IX and are prone to experiencing internal or external hemorrhagic episodes.

How Hemgenix works

The active ingredient of Hemgenix is based on a virus that does not cause diseases in humans. This virus has been modified to not spread through the body, but to deliver a copy of the factor IX gene to liver cells. This allows the liver to produce the factor IX protein and increase factor IX levels in the blood. This helps blood to clot normally and prevents, or reduces, hemorrhagic episodes.

You should not receive Hemgenix

• If you are allergic to etranacogén dezaparvovec or any of the other components of this medication (listed in section 6).

• If you have an active infection, whether it is an acute (short-term) or chronic (long-term) infection, that cannot be controlled with medication.

• If your liver does not function correctly due to advanced liver fibrosis (scarring and thickening of tissue) or cirrhosis (scarring caused by prolonged liver damage).

If any of the above situations apply to you, or if you are unsure about any of the above situations, consult your doctor before receiving Hemgenix.

Warnings and precautions

Before receiving treatment with Hemgenix

Your doctor will perform several testsbeforeadministeringthe treatment with Hemgenix.

Blood tests for antibody detection

Before receiving treatment with Hemgenix, your doctor will perform blood tests to check for the presence of certain antibodies (proteins), including:

• Blood tests to check for antibodies in the blood directed against human factor IX protein (factor IX inhibitors).

If you test positive for these antibodies, another test will be performed approximately 2 weeks later. If the results of both tests are positive, treatment with Hemgenix will not be initiated.

• A blood test may also be performed to check the amount of antibodies in your blood directed against the type of virus used to manufacture Hemgenix.

Liver health

When deciding whether this medication is suitable for you, your doctor will check your liver health before starting treatment with Hemgenix and will perform the following:

• Blood tests to check the level of liver enzymes in the blood.
• Ultrasound of the liver.
• Elastography tests to check for scarring or thickening of the liver.

During or shortly after the infusion of Hemgenix

Your doctor will monitorduring, or shortly afterthe infusion of Hemgenix.

Infusion-related reactions

During or shortly after the administration of the infusion (catheter) of Hemgenix, infusion-related reactions may occur. Your doctor will monitor you during the infusion of Hemgenix and for at least 3 hours after Hemgenix is administered.

• The symptoms of these adverse reactions are listed in section 4 "Possible adverse reactions". Inform your doctor or nurseimmediatelyif you experience these or other symptoms during or shortly after the infusion.

• Depending on your symptoms, your infusion may be slowed down or stopped. If the infusion is stopped, it may be resumed at a slower rate when the infusion reaction is resolved. Your doctor may also evaluate whether you should receive corticosteroids (e.g., prednisolone or prednisone) to help control the infusion reaction.

After treatment with Hemgenix

Afterthe treatment with Hemgenix, your doctor will continue to monitor your health. It isimportantthat you discuss the scheduling of these blood tests with your doctor so that they can be performed as needed.

Liver enzymes

Hemgenix will trigger a response within your immune system that could cause an increase in the blood level of certain liver enzymes, called transaminases (transaminitis). Your doctor will monitor your liver enzyme levels periodically to ensure that the medication is working as it should:

• During the first 3 months after Hemgenix is administered, blood tests will be performed at least once a week to check your liver enzyme levels.

• If you experience an increase in liver enzymes, it may be necessary to perform blood tests more frequently to check your liver enzyme levels until they return to normal. You may also need to take another medication (corticosteroids) to control these adverse effects.

• Your doctor may also perform additional tests to rule out other causes of increased liver enzymes, if necessary, after consulting with a specialist in liver diseases.

• Your doctor will repeat liver enzyme tests every 3 months from month 4 to 1 year after Hemgenix is administered to continue monitoring your liver health. In the second year after receiving Hemgenix, your doctor will check your liver enzyme levels semiannually. After the second year, your doctor will check your liver enzyme levels annually for at least 5 years after Hemgenix is administered.

Factor IX levels

Your doctor will periodically check your factor IX levels to determine if treatment with Hemgenix has been effective.

• At least during the first 3 months after receiving Hemgenix, blood tests will be performed at least once a week to check your factor IX levels.

• Your doctor will repeat these tests every 3 months from month 4 to 1 year after Hemgenix is administered to continue monitoring your factor IX levels. In the second year after receiving Hemgenix, your doctor will check your factor IX levels semiannually. After that, your doctor will check your factor IX levels annually for at least 5 years after Hemgenix is administered.

• If you experience an increase in liver enzymes or need to take another medication (e.g., corticosteroids), blood tests will be performed more frequently to check your factor IX levels until your liver enzyme levels return to normal or until you stop taking the additional medication.

Use of other treatments for hemophilia

After using Hemgenix, discuss with your doctor whether you should discontinue other treatments you are receiving for hemophilia, or when you should do so, and develop a treatment plan to know what to do in case of surgery, trauma, bleeding, or any procedure that may increase the risk of bleeding. It is very important to continue monitoring and visiting your doctor to determine if you need to receive other treatments to treat hemophilia.

Abnormal blood coagulation (thromboembolic events)

After treatment with Hemgenix, your factor IX level may increase. In some patients, it may increase to levels above normal for a period of time.

• Unusually high factor IX levels may cause your blood to clot abnormally, increasing the risk of forming clots, such as in the lungs (pulmonary embolism) or in a blood vessel in the leg (deep vein thrombosis or arterial thrombosis). This theoretical risk is low due to your congenital deficiency in the coagulation cascade compared to healthy individuals.

• You may be at risk of abnormal blood coagulation if you have pre-existing cardiovascular problems (e.g., cardiovascular disease, arterial stiffness, high blood pressure, or if you are diabetic or over 50 years old).

• Your doctor will periodically check your blood to detect any possible abnormalities in factor IX levels, particularly if you continue to receive your routine prophylaxis with factor IX (factor IX substitution therapy) after Hemgenix administration (see also section 3 "How to use Hemgenix").

• Consult your doctor immediately if you observe signs of abnormal blood coagulation, such as sudden chest pain, shortness of breath, sudden muscle weakness, numbness and/or loss of balance, decreased alertness, difficulty speaking, or swelling of one or both legs.

Avoid blood and organ donations

The active principle of Hemgenix may be temporarily excreted through the blood, semen, breast milk, or body waste, a process called excretion (see also section 2 "Pregnancy, lactation, and fertility").

To ensure that other people without hemophilia B are not exposed to the Hemgenix DNA through the excretion process that occurs in your body and/or semen, you will not be able to donate blood, semen, or organs, tissues, or cells for transplantation after being treated with Hemgenix.

Immunocompromised patients or patients with HIV or other infections

If you experience problems with your immune system (you are immunocompromised), are undergoing or will undergo immunosuppressive treatment, or have a new or recent HIV infection, your doctor will decide when you can receive Hemgenix.

Neutralizing antibodies against factor IX proteins (factor IX inhibitors)

Neutralizing antibodies against factor IX proteins may prevent Hemgenix from working correctly. Your doctor may perform blood tests to check for the presence of these antibodies if bleeding is not controlled or recurs after Hemgenix administration (see also section 3 "How to use Hemgenix").

Receiving gene therapy in the future

After receiving Hemgenix, your immune system will produce antibodies against the AAV vector envelope. It is still unknown whether Hemgenix treatment can be repeated, under what conditions, or whether another gene therapy can be used in the future, under what conditions.

Potential risk of malignancy associated with Hemgenix

• Hemgenix will be inserted into liver cells and may be inserted into the DNA of liver cells or other cells in the body. Therefore, Hemgenix may contribute to an increased risk of cancer, such as liver cancer (hepatocellular carcinoma). Although there is currently no evidence of this in clinical studies, this remains possible due to the nature of the medication. Therefore, you should discuss this with your doctor.

• If you are a patient with pre-existing risk factors for hepatocellular carcinoma (e.g., have liver fibrosis, hepatitis B, hepatitis C, or fatty liver disease), your doctor will periodically evaluate your long-term liver health for at least 5 years after Hemgenix administration and perform the following tests:

• Annual liver ultrasound and
• Annual blood tests to check for an increase in the alpha-fetoprotein.

• After treatment with Hemgenix, it is planned to include you in a follow-up study to help study the long-term safety of the treatment (15 years), its efficacy, and any adverse effects that may be related to the treatment. In the event of cancer, your doctor may take a sample of your cancer (biopsy) to check if Hemgenix has been inserted into the cellular DNA.

Children and adolescents

Hemgenix has not been studied in children or adolescents under 18 years of age.

Other medications and Hemgenix

Inform your doctor or nurse if you are taking, have recently taken, or may need to take any other medication.

If you are taking medications that are known to damage the liver (hepatotoxic medications), your doctor may decide that you need to discontinue this medication to receive Hemgenix.

Pregnancy, lactation, and fertility

There are no data on the use of Hemgenix in women with hemophilia B.

If you are pregnant, breastfeeding, believe you may be pregnant, or plan to become pregnant, consult your doctor before using Hemgenix.

• Treatment with Hemgenix is not recommended for women who may become pregnant.

It is still unknown whether Hemgenix can be used safely in these patients, as the effects on pregnancy and the fetus are unknown.

• Hemgenix should not be used during pregnancy. The effects of this medication on the fetus are unknown.

• Hemgenix should not be used during breastfeeding. It is unknown whether this medication is excreted in breast milk. The risk in newborns/babies cannot be ruled out.

Use of contraceptive methods to prevent pregnancy in the partner during a period of time

After a male patient has been treated with Hemgenix, the patient and his female partner should avoid pregnancy for 12 months. You should use effective contraceptive methods (e.g., double barrier methods such as condoms and diaphragms). You should do this to avoid the theoretical risk that the factor IX gene from the Hemgenix treatment in the father may be transmitted to his child, with unknown consequences. For the same reason, male patients should not donate semen. Consult your doctor about which contraceptive methods are suitable.

Driving and operating machinery

The influence of Hemgenix on your ability to drive and operate machinery is small. Dizziness, fatigue, and temporary headaches have occurred shortly after the infusion of Hemgenix. If this is your case, you should proceed with caution until you are sure that Hemgenix does not negatively affect your ability to drive or operate machinery. Discuss this with your doctor.

Hemgenix contains sodium and potassium

• The medication contains 35.2 mg of sodium (main component of table salt/for cooking) in each vial. This is equivalent to 1.8% of the maximum daily recommended intake for an adult.

• This medication contains less than 39 mg (1 mmol) of potassium per vial; therefore, it is considered essentially "potassium-free".

Hemgenix will be administered in a hospital setting under the supervision of a doctor with experience and training in treating your disease, hemophilia B.

Hemgenix will be administeredoncevia a single slow infusion (IV) in a vein. The infusion typically takes between 1 and 2 hours to complete.

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

Discontinuation of exogenous factor IX treatment

• It may take several weeks to notice an improvement in bleeding control after the Hemgenix infusion, and you may need to continue your substitution treatment, with exogenous factor IX, during the first weeks after the Hemgenix infusion.

• Your doctor will monitor your factor IX activity levels in your blood, that is, once a week for at least the first 3 months, and at regular intervals thereafter, and will decide whether you should receive, reduce, or discontinue your exogenous factor IX treatment and when (see section 2).

If you have any other questions about the use of this medication, ask your doctor.

Like all medications, this medication may produce adverse effects, although not all people will experience them.

The following adverse effects were observed in clinical studies with Hemgenix.

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

• Headache
• Increased levels of liver enzymes in the blood (elevated alanine aminotransferase)
• Increased levels of liver enzymes in the blood (elevated aspartate aminotransferase)
• Pharyngitis-like syndrome
• Increased levels of C-reactive protein, an inflammation marker
• Perfusion-related reaction (allergic reactions [hypersensitivity], reaction at the perfusion site, dizziness, eye itching [pruritus], skin redness [flushing], upper abdominal pain, skin rash with itching [urticaria], chest discomfort, and fever)

Common(may affect up to 1 in 10 patients)

• Dizziness
• Unpleasant sensation (nausea)
• Fatigue
• General feeling of discomfort
• Increased levels of bilirubin in the blood, a yellowish substance formed during the breakdown of red blood cells
• Increased blood levels of creatine phosphokinase, an enzyme (protein) mainly found in the heart, brain, and skeletal muscle

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not listed in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use:www.notificaram.es.Reporting adverse effects can help provide more information on the safety of this medication.

This information is intended solely for physicians.

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

Do not use this medication after the expiration date that appears on the vial label and on the box after EXP.

Store in refrigerator (between 2 °C and 8 °C). Do not freeze.

Store vials in the original packaging to protect them from light.

Dilute before use.

Once diluted with the 9 mg/ml (0.9 %) sodium chloride injection solution, Hemgenix can be stored at a temperature of between 15 °C and 25 °C, in the infusion bag, protected from light, for a maximum of 24 hours after the dose preparation.

Do not use this medication if you observe particles, turbidity, or discoloration.

Composition of Hemgenix

• The active ingredient is etranacog alfa dezaparvovec. Each milliliter of etranacog alfa dezaparvovec contains 1 x 10¹³ copies of the gene (cg)/ml.

• The other components (excipients) are sucrose, polisorbate 20, potassium chloride, dihydrogen phosphate potassium, sodium chloride, sodium hydrogen phosphate, hydrochloric acid (for pH adjustment) and water for injection (see also section 2 "Hemgenix contains sodium and potassium").

This medicine contains genetically modified organisms.

Appearance of Hemgenix and contents of the package

Hemgenix is a sterile concentrate for solution for infusion (concentrate).

Hemgenix is a transparent and colorless solution.

Hemgenix is supplied in a vial containing 10 ml of etranacog alfa dezaparvovec.

The total number of vials in a package corresponds to the required dose for each patient, based on their body weight, and is indicated on the package.

Holder of the marketing authorization and responsible for manufacturing

CSL Behring GmbH

Emil-von-Behring-Strasse 76

D-35041 Marburg

Germany

For more information about this medicine, please contact the local representative of the marketing authorization holder:

Last update of this leaflet: 12/2024

This medicine has been authorized under 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

More detailed information about this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu,and on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS)(http://www.aemps.gob.es/).

This leaflet is also available in all languages of the European Union/European Economic Area on the website of the European Medicines Agency.

---------------------------------------------------------------------------------------------------------------------------------------------------------

This information is intended only for healthcare professionals:

Important:see the full product information before using it.

Precautions to be taken before handling or administering the medicine

This medicine contains genetically modified organisms (GMOs).

During the preparation and administration of etranacog alfa dezaparvovec, personal protective equipment (PPE) such as gloves, safety glasses, protective clothing, and masks should be used.

Preparation of etranacog alfa dezaparvovec before administration

1. Use aseptic techniques during the preparation and administration of etranacog alfa dezaparvovec.
2. Use the etranacog alfa dezaparvovec vial(s) only once (single-use vial(s)).
3. Verify the required dose of etranacog alfa dezaparvovec based on the patient's body weight. The total number of vials in each finished package corresponds to the required doses for each patient based on their body weight.
4. Etranacog alfa dezaparvovec must be diluted with a 9 mg/ml (0.9 %) sodium chloride solution before administration.

• Extract the calculated dose volume from the Hemgenix vial(s) from the 500 ml infusion bags containing a 9 mg/ml (0.9 %) sodium chloride solution.

The volume to be extracted will vary depending on the patient's body weight.

• For patients <120>kg, extract the corresponding volume of 9 mg/ml (0.9 %) sodium chloride solution from a 500 ml infusion bag.
• For patients ≥ 120 kg, extract half the volume of 9 mg/ml (0.9 %) sodium chloride solution from two 500 ml infusion bags.

• Subsequently, add the required dose of Hemgenix to the infusion bag(s) to make the total volume of each infusion bag 500 ml.

1. Add the dose of Hemgenix directly to the 9 mg/ml (0.9 %) sodium chloride solution. Do not add the dose of Hemgenix to the air in the infusion bag during dilution.
2. Gently rotate the infusion bag(s) at least 3 times to mix the solution and ensure uniform distribution of the diluted product.
3. To prevent foam formation:

• Do not agitate the etranacog alfa dezaparvovec vial(s) or the prepared infusion bag(s).
• Do not use filter needles during the preparation of etranacog alfa dezaparvovec.

1. To reduce the risk of spillage and/or aerosol formation, the infusion bag(s) must be connected to a pre-loaded infusion tube with a 9 mg/ml (0.9 %) sodium chloride solution.
2. The pre-loaded infusion tube with the 9 mg/ml (0.9 %) sodium chloride solution must be connected to the main intravenous line also primed with a 9 mg/ml (0.9 %) sodium chloride solution before use.
3. Only use the 9 mg/ml (0.9 %) sodium chloride solution, as the stability of etranacog alfa dezaparvovec has not been determined with other solutions and diluents.
4. Do not infuse the diluted etranacog alfa dezaparvovec solution in the same intravenous line with any other product.
5. Do not use a central line.

Administration

1. The diluted etranacog alfa dezaparvovec solution must be visually inspected before administration. The diluted solution must be transparent and colorless. If particles, turbidity, or discoloration are observed in the infusion bag, do not use etranacog alfa dezaparvovec.
2. After dilution, use the product as soon as possible.Do notexceed the storage time of the diluted product beyond the time specified in section 6.3 of the product information.
3. Use an integrated filter (in-line) with a pore size of 0.2 µm made of polyethersulfone (PES).
4. The diluted etranacog alfa dezaparvovec solution must be administered in a peripheral vein through a separate intravenous line using a peripheral venous catheter.
5. The etranacog alfa dezaparvovec solution must be infused at the strictly specified infusion rates as provided in section 4.2 of the product information. Administration must be completed within ≤ 24 hours after preparation of the dose (see section 4.2 of the product information).
6. After infusing the entire contents of the infusion bag, the infusion line must be flushed at the same infusion rate with a 9 mg/ml (0.9 %) sodium chloride solution to ensure that all the etranacog alfa dezaparvovec is administered.

Measures to be taken in case of accidental exposure

In case of accidental exposure, follow local guidelines on pharmaceutical waste.

• In case of accidental exposure to the eyes, wash them immediately with water for at least 15 minutes. Do not use an alcoholic solution.
• In case of accidental exposure to a needlestick, encourage bleeding from the wound and thoroughly wash the injection site with water and soap.
• In case of accidental exposure to the skin, thoroughly clean the affected area with water and soap for at least 15 minutes. Do not use an alcoholic solution.
• In case of accidental inhalation, move the person to the outdoors.
• In case of accidental oral exposure, thoroughly rinse the mouth with water.
• Seek medical attention in all cases.

The work surfaces and materials that may have come into contact with etranacog alfa dezaparvovec must be decontaminated with an appropriate viricidal disinfectant (e.g., a disinfectant releasing chlorine as hypochlorite containing available chlorine at 0.1 % [1000 ppm]) after use.

Precautions to be taken for disposing of the medicine

The unused medicine and disposable materials that may have come into contact with Hemgenix (solid and liquid waste) must be disposed of in accordance with local guidelines on pharmaceutical waste. However, the risk of adverse effects on human health following accidental exposure to Hemgenix and environmental risks are considered negligible. Caregivers should receive guidance on how to correctly handle the waste generated by contaminated medical components during the use of Hemgenix.

The work surfaces and materials that may have come into contact with etranacog alfa dezaparvovec must be decontaminated with an appropriate viricidal disinfectant (e.g., a disinfectant releasing chlorine as hypochlorite containing available chlorine at 0.1 % [1000 ppm]) after use and sterilized in an autoclave, if possible.