Alprolix

Package leaflet: Information for the user

ALPROLIX 250 IU powder and solvent for solution for injection, 500 IU powder and solvent for solution for injection, 1000 IU powder and solvent for solution for injection, 2000 IU powder and solvent for solution for injection, 3000 IU powder and solvent for solution for injection

eftrenonacog alfa (recombinant coagulation factor IX fused with Fc protein)
Please read this leaflet carefully before using this medicine because it contains important
information for you.
­ Keep this leaflet. You may need to read it again.
­ If you have any questions, ask your doctor, pharmacist, or nurse.
­ This medicine has been prescribed for you only. Do not give it to others, even if their symptoms
are the same as yours, because it could be harmful.
­ If you experience any side effect, including those not listed in this leaflet, talk to your doctor,
pharmacist, or nurse. See section 4.
Contents of this leaflet

1. What ALPROLIX is and what it is used for
2. What you need to know before using ALPROLIX
3. How to use ALPROLIX
4. Possible side effects
5. How to store ALPROLIX
6. Contents of the pack and other information
7. Instructions for preparation and administration

1. What ALPROLIX is and what it is used for

ALPROLIX contains the active substance eftrenonacog alfa, a fusion protein consisting of recombinant coagulation factor IX and Fc. Factor IX is a natural protein produced by the body that is essential for blood clot formation and for stopping bleeding.
ALPROLIX is a medicine used for the treatment and prevention of bleeding episodes in patients of all age groups with haemophilia B (an inherited bleeding disorder caused by factor IX deficiency).
ALPROLIX is produced using recombinant technology without the addition of any human or animal-derived components during the manufacturing process.
How ALPROLIX works
In patients with haemophilia B, factor IX is either missing or does not function properly. This medicine works by replacing the missing or deficient factor IX. ALPROLIX increases factor IX levels in the blood and temporarily corrects the tendency to bleed. The Fc fusion protein present in this medicine prolongs the duration of action of the medicine.

2. What you need to know before using ALPROLIX

Do not use ALPROLIX

• if you are allergic to eftrenonacog alfa or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using ALPROLIX.

• There is a small possibility that you may develop an anaphylactic reaction (a severe and sudden allergic reaction) to ALPROLIX. Signs of an allergic reaction may include generalized itching, hives, chest tightness, difficulty breathing, and low blood pressure. If any of these symptoms occur, stop the injection immediately and contact your doctor. Because of the risk of allergic reactions to factor IX, the first infusions of factor IX should be administered under medical supervision in a facility equipped to provide necessary medical care in case of an allergic reaction.
• Contact your doctor if you feel that bleeding is not adequately controlled with your current dose, as there may be several reasons—for example, the development of antibodies (also called inhibitors) directed against factor IX is a known complication that may occur during treatment for hemophilia B. In the presence of these antibodies, treatment may not work as intended. Your doctor will investigate this possibility. Do not increase the total dose of ALPROLIX to control bleeding without consulting your doctor.

Patients who have a factor IX inhibitor may be at increased risk of anaphylaxis during future treatment with factor IX. Therefore, if you experience allergic reactions such as those described above, the presence of an inhibitor should be investigated.
Medicines containing factor IX may increase the risk of inappropriate blood clots in the body, particularly if you have risk factors for developing blood clots. Symptoms of a possible inappropriate blood clot may include pain and/or excessive tenderness along a vein, unexpected swelling in an arm or leg, or sudden onset of shortness of breath or difficulty breathing.
Cardiovascular events
If you have been diagnosed with heart disease or are at risk of heart disease, exercise particular caution when using factor IX and consult your doctor.
Catheter-related complications
If a central venous access device (CVAD) is required, the risk of CVAD-related complications should be considered, including local infections, presence of bacteria in the blood, and blood clots at the catheter site.
Documentation
It is strongly recommended to record the name and batch number of the medicine each time you receive ALPROLIX.
Other medicines and ALPROLIX
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
ALPROLIX does not affect the ability to drive or operate machinery.
ALPROLIX contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e., essentially “sodium-free”. In case of treatment with multiple vials, the total sodium content should be taken into consideration.

3. How to use ALPROLIX

Treatment with ALPROLIX will be initiated by a physician experienced in the management of patients with haemophilia. Use this medicine exactly as prescribed by your doctor (see section 7). If you have any doubts, consult your doctor, pharmacist, or nurse.
ALPROLIX is administered by intravenous injection. You or another person may administer it after proper training. Your doctor will determine the dose (in International Units or “IU”) you should receive. The dose depends on your individual need for factor IX replacement therapy and varies according to whether it is used for prevention or treatment of bleeding episodes. Contact your doctor if you feel that your bleeding episodes are not adequately controlled with your current dose.
How often you need to receive ALPROLIX depends on how the medicine works in your specific case. Your doctor will perform appropriate laboratory tests to monitor that factor IX levels in your blood are adequate.
Treatment of bleeding episodes
The dose of ALPROLIX is calculated based on body weight and the required factor IX levels. These factor IX levels depend on the severity and location of the bleeding.
Prevention of bleeding episodes
If you are using ALPROLIX to prevent bleeding episodes, your doctor will determine the dose you should receive.
The usual dose of ALPROLIX is 50 IU per kg of body weight administered once weekly, or 100 IU per kg of body weight administered every 10 days. Your doctor may adjust the dose or dosing interval. In some cases, particularly in younger patients, shorter dosing intervals or higher doses may be required.
Use in children and adolescents
ALPROLIX can be used in children and adolescents of any age. In children under 12 years of age, higher doses or more frequent administration may be needed, and the usual dose ranges between 50 and 60 IU per kg of body weight administered every 7 days.
If you use more ALPROLIX than you should
Inform your doctor as soon as possible. Always use ALPROLIX exactly as prescribed by your doctor. If you have any doubts, consult your doctor, pharmacist, or nurse.
If you forget to use ALPROLIX
Do not take a double dose to make up for the missed dose. Take the missed dose as soon as you remember, then continue with your regular dosing schedule. If you have any doubts, consult your doctor, pharmacist, or nurse.
If you stop using ALPROLIX
Do not stop treatment with ALPROLIX without consulting your doctor. If you stop treatment with ALPROLIX, you may no longer be protected against bleeding episodes, or an ongoing bleed may not stop.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If severe allergic reactions (anaphylactic reactions) occur suddenly, administration must be stopped immediately. You must contact your doctor immediately if you experience any of the following symptoms of an allergic reaction: swelling of the face, rash, generalized itching, hives, tightness in the chest, difficulty breathing, burning and stinging at the injection site, chills, flushing, headache, general feeling of malaise, nausea, restlessness, rapid heartbeat, and low blood pressure.
In previously untreated children with factor IX-based medicines, inhibitors may commonly occur (up to 1 in 10 patients) (see section 2). In such cases, the medicine may no longer work as expected and the child may experience persistent bleeding. If this happens, contact your doctor immediately.
The following side effects may occur with this medicine:
Common side effects (may affect up to 1 in 10 people): headache, numbness or tingling around the mouth, flank pain with blood in the urine (obstructive uropathy), and redness at the injection site.
Previously untreated children with factor IX-based medicines: factor IX inhibitors, hypersensitivity.
Uncommon side effects (may affect up to 1 in 100 people): dizziness, altered taste sensation, bad breath, feeling of fatigue, pain at injection site, rapid heartbeat, blood in the urine (haematuria), flank pain (renal colic), low blood pressure, and reduced appetite.
Side effects with unknown frequency (frequency cannot be estimated from the available data): sudden severe allergic reaction and life-threatening allergic reaction (anaphylactic shock).
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via 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 ALPROLIX

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 carton and on the label of the
vial after “Exp.” The expiry date refers to the last day of that month. Do not use
this medicine if it has been stored at room temperature for more than 6 months.
Store in a refrigerator (2 °C – 8 °C). Do not freeze. Keep in the original packaging to
protect the medicine from light.
Alternatively, ALPROLIX may be stored at room temperature (up to 30 °C) for a single period not exceeding 6 months.
Record on the carton the date when ALPROLIX was removed from the refrigerator and stored at room temperature. Once stored at room temperature, the medicine must not be returned to the refrigerator.
After reconstitution, ALPROLIX should be used immediately. If you cannot use the solution immediately after reconstitution, use it within 6 hours if stored at room temperature. Do not store the solution in the refrigerator after reconstitution. Protect the solution from direct sunlight.
The reconstituted solution should be clear to slightly opalescent and colourless. Do not use this medicine if you notice that the solution is cloudy or contains particles.
This medicine is for single use only.
Dispose of unused solution properly. Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What ALPROLIX contains
Powder:

• The active substance is eftrenonacog alfa (a recombinant coagulation factor IX fused with Fc). Each vial of ALPROLIX nominally contains 250, 500, 1,000, 2,000 or 3,000 IU of eftrenonacog alfa.
• The other components are sucrose, histidine, mannitol, polysorbate 20, sodium hydroxide and hydrochloric acid. If you are on a low-sodium diet, see section 2.

Solvent:
5 mL of sodium chloride and water for injections.
Description of the appearance of ALPROLIX and package contents
ALPROLIX is supplied as a powder and solvent for solution for injection. The powder is a white to off-white powder or cake. The solvent provided for solution preparation is a clear, colourless solution. After reconstitution, the solution is clear to slightly opalescent and colourless.
Each package of ALPROLIX contains 1 vial of powder, 5 mL solvent in a pre-filled syringe, 1 plunger, 1 vial adapter, 1 infusion set, 2 alcohol swabs, 2 adhesive bandages and 1 gauze pad.
Marketing Authorisation Holder and Manufacturer
Swedish Orphan Biovitrum AB (publ)
SE-112 76 Stockholm
Sweden
Tel.: +46 8 697 20 00
More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.
For section 7. Instructions for preparation and administration, turn over the leaflet.

7. Instructions for Preparation and Administration

The procedure below describes the preparation and administration of ALPROLIX.
ALPROLIX is administered by intravenous (i.v.) injection after dissolving the powder contained in the vial with the solvent provided in the pre-filled syringe. The ALPROLIX pack contains:

ALPROLIX must not be mixed with other injectable or infusion solutions.
Wash hands before opening the pack.
Preparation:

1. Check the name and dosage shown on the packaging and ensure that it contains the correct medicine. Check the expiry date on the ALPROLIX carton. Do not use if the medicine is expired.
2. If ALPROLIX has been stored in the refrigerator, allow the ALPROLIX vial (A) and the syringe with solvent (B) to reach room temperature before use. Do not use external heat sources.
3. Place the vial on a clean, flat surface.

Remove the plastic flip-off cap from the vial.

4. Clean the top of the vial with one of the

alcohol-impregnated swabs (F) provided in the pack and let it air dry. Once cleaned, do not touch the top of the vial or allow it to come into contact with other objects.

5. Open the paper protective cover of the transparent plastic vial adapter (D). Do not remove the adapter from its protective seal. Do not touch the inside of the vial adapter packaging.
6. Place the vial on a flat surface.

Grasp the vial adapter with its protective seal and position it perpendicularly over the vial. Press firmly downward until the adapter clicks into place on top of the vial, with the tip piercing the vial stopper.

7. Insert the plunger into the syringe (C). Firmly

rotate the plunger clockwise until it is securely locked into the syringe.

8. Break the white tamper-evident cap of the solvent-filled syringe by bending the cap at the perforated area until it breaks. Set aside the cap on a flat surface with the top side facing down. Do not touch the inside of the cap or the tip of the syringe.

9. Remove the protective seal from the vial

adapter and discard it.

10. To connect the solvent-filled syringe to the

vial adapter, insert the syringe tip into the adapter. Press firmly and rotate the syringe clockwise until securely attached.

11. Slowly push the plunger to inject all the solvent into

the ALPROLIX vial.

12. With the syringe still attached to the adapter and

continuing to press the plunger, gently rotate the vial until the powder is completely dissolved.
Do not shake.

13. The final solution must be visually inspected before administration. The solution should be from clear to slightly milky (opalescent) and colourless. Do not use the solution if it is cloudy or contains visible particles.
14. Invert the vial, continuing to press the syringe

plunger fully down. Slowly pull back the plunger to draw all the solution into the syringe through the vial adapter.
Note: If more than one ALPROLIX vial is used for injection, each vial must be prepared separately according to instructions (steps 1–13), and the solvent-filled syringe must be removed, leaving the vial adapter in place. To draw the contents from individual vials after preparation, a single large syringe with a luer-lock (screw) tip may be used.

15. Disconnect the syringe from the vial adapter by gently

pulling the vial and rotating it counterclockwise.

16. Discard the vial and adapter.

Note: If the solution is not used immediately, the syringe must be carefully recapped with its cap. Do not touch the syringe tip or the inside of the cap. After preparation, ALPROLIX may be stored at room temperature prior to administration for up to 6 hours. After this time, ALPROLIX must be discarded. Protect from direct sunlight.
Administration (intravenous injection):
ALPROLIX must be administered using the infusion set (E) provided in the pack.

1. Open the infusion set packaging and remove the cap

from the end of the tubing. Attach the syringe containing the prepared ALPROLIX solution to the end of the infusion set tubing by rotating clockwise.

2. If necessary, apply a tourniquet and clean the injection site by thoroughly wiping the skin with the other alcohol-impregnated swab included in the pack.

3. Remove any air present in the infusion set tubing by slowly pushing the plunger until the solution reaches the needle of the infusion set. Do not expel solution through the needle. Remove the transparent plastic protective cap from the needle.
4. Insert the infusion set needle into a vein, as instructed by the physician or nurse, and remove the tourniquet. If desired, one of the adhesive bandages (G) provided in the pack may be used to secure the plastic wings of the needle at the injection site. The prepared medicine should be administered by intravenous injection over several minutes. For greater comfort, the physician may adjust the recommended injection rate.
5. After completing the injection and removing the needle, cover

the needle with the protective cap, closing it until it clicks.

6. Safely dispose of the used needle, any remaining solution, the syringe, and the empty vial in a dedicated medical waste container, as these materials may pose harm to others if not properly disposed of. Do not reuse any used materials.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION(S)
Scientific Conclusions
Taking into account the assessment of the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for eftrenonacog alfa, the scientific conclusions of the PRAC are as follows:
Based on available data on risks from spontaneous reports, with in most cases a close temporal relationship, a positive response to withdrawal of treatment (de-challenge) and/or re-administration (re-challenge), and considering a plausible mechanism of action, the PRAC considers that there is a causal relationship between eftrenonacog alfa and anaphylactic shock. Currently, the product characteristics summary lists only “anaphylactic reaction”. Since “anaphylactic shock” is more severe than an anaphylactic reaction, it should be listed separately.
The PRAC considers that the product information for medicinal products containing eftrenonacog alfa should be amended accordingly.
Summary of Product Characteristics

• Section 4.8

The following adverse reaction must be added to the System Organ Class (SOC) “Immune system disorders” with frequency “not known”: Anaphylactic shock.
Patient Information Leaflet

• Section 4 Possible side effects

Side effects with not known frequency (frequency cannot be estimated from the available data): severe sudden allergic reaction and life-threatening allergic reaction (anaphylactic shock).
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and the grounds for the recommendation.
Reasons for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions on eftrenonacog alfa, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing eftrenonacog alfa remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).