Aimafix

PACKAGE LEAFLET: INFORMATION FOR THE USER

AIMAFIX

500 IU/10 ml powder and solvent for solution for infusion
AIMAFIX
1000 IU/10 ml powder and solvent for solution for infusion
Human plasma coagulation factor IX
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 or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What AIMAFIX is and what it is used for

AIMAFIX is a solution of coagulation factor IX derived from human plasma. Factor IX is a protein with antihemorrhagic activity.
AIMAFIX is used in the following treatments:

• in the treatment and prophylaxis (prevention) of bleeding episodes in patients with haemophilia B (congenital factor IX deficiency).
• in the treatment of acquired factor IX deficiency.

2. What you should know before using AIMAFIX

Do not use AIMAFIX

• if you are allergic to factor IX or to any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor or pharmacist before using AIMAFIX. As with any intravenous protein product, allergic-type hypersensitivity reactions may occur. AIMAFIX contains traces of other human proteins besides factor IX. If during administration of the product you notice any of the following symptoms, you must immediately stop the infusion and contact your doctor, as these symptoms may be the first signs of an allergic reaction. The symptoms that may occur are:
• hives,
• generalized hives,
• chest tightness,
• wheezing,
• hypotension (low blood pressure),
• anaphylaxis. In case of shock, your doctor will follow standard medical treatment for shock.

If you have cardiovascular risk factors, taking AIMAFIX may increase these risks.
If a central venous access device (CVC) is required for the injection of AIMAFIX, your doctor must consider the risk of complications including local infections, bloodstream infection (bacteremia), or formation of a blood clot in the blood vessel (thrombosis) at the site where the catheter is inserted.
If you have a history of allergic reactions caused by heparin, you should avoid using medicines containing heparin.
After repeated treatments with human coagulation factor IX, patients should be monitored for the development of neutralizing antibodies (inhibitors). There are reports in the literature showing an association between the presence of antibodies neutralizing factor IX (inhibitors) and allergic reactions. Therefore, allergic reactions should prompt consideration of the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may have an increased risk of anaphylaxis (severe and rapid allergic reaction) upon subsequent exposure to factor IX.
Due to the risk of allergic reactions with factor IX products, the first administration of factor IX should be performed, according to the opinion of the treating physician, under medical supervision and in a setting where appropriate medical intervention for allergic reactions can be provided.

Thromboembolism
Inform your doctor if you have liver or heart disease or if you have recently undergone major surgery. Because of the potential risk of thrombotic complications, when administering this medicine to patients with pre-existing risk factors such as liver disease, those in the post-operative period, neonates, or patients at risk of thrombotic events or disseminated intravascular coagulation (DIC), clinical monitoring through appropriate biological tests should be carried out to detect early signs of thrombotic coagulopathies and consumption coagulopathy.
In each of these situations, the benefit of treatment with AIMAFIX must be weighed against the risk of such complications.

Viral safety of AIMAFIX
When medicines are prepared from human blood or plasma, specific measures are implemented to prevent transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure that potentially infected donors are excluded,
• testing of each donation and plasma pool to detect possible presence of viruses. In addition, manufacturers incorporate steps in the processing of blood and plasma that are capable of inactivating or removing viruses. Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to emerging or unknown viruses or other types of infectious agents. The measures adopted are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and the non-enveloped hepatitis A virus (HAV). The measures adopted may have limited effect against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection can be severe during pregnancy (fetal infection) and in individuals with weakened immune systems or certain types of anemia (e.g., sickle cell anemia or hemolytic anemia). Your doctor may advise you to consider vaccination against hepatitis A and B if you regularly receive human coagulation factor IX. It is strongly recommended to record the brand name and batch number of the product each time you receive a dose of AIMAFIX, in order to maintain traceability of the batch used.

Children and adolescents
There are insufficient data to recommend the use of AIMAFIX in children under 6 years of age. The warnings and precautions listed in this section apply to both adult and pediatric populations.

Other medicines and AIMAFIX
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No interactions between human coagulation factor IX products and other medicines are known.
AIMAFIX must not be mixed with other medicines.

Pregnancy, breast-feeding and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breast-feeding, consult your doctor or pharmacist before using this medicine.
Animal reproductive studies have not been conducted with factor IX.
Due to the rarity of hemophilia B in women, data on the use of factor IX during pregnancy and breast-feeding are not available. Therefore, factor IX should be used during pregnancy and breast-feeding only if clearly indicated.

Driving and using machines
AIMAFIX does not affect or has negligible influence on the ability to drive vehicles or operate machinery.

AIMAFIX contains sodium and heparin
This medicine contains up to a maximum of 41 mg of sodium (a main component of table salt) per 10 ml vial.
This corresponds to 2.05% of the maximum daily recommended dietary intake for an adult.
This medicine contains heparin. Heparin may cause allergic reactions and a reduction in blood cells, which may impair blood clotting. If you have previously experienced allergic reactions caused by heparin, do not take medicines containing heparin.

3. How to use AIMAFIX

Use this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist.
If you are administering the product yourself, always use AIMAFIX exactly as instructed in the section “Instructions for correct use”.
Only use the infusion devices supplied in the package, as treatment may be ineffective due to adsorption of human plasma coagulation factor IX onto the internal surfaces of certain infusion devices.
If you have any doubts, consult your doctor.
Treatment should begin under the supervision of a physician experienced in the management of haemophilia.
Your doctor will determine the appropriate dose and duration of treatment based on the severity of factor IX deficiency, the site and extent of bleeding, and your clinical condition.
The dose and frequency of administration should always be guided by clinical efficacy in the individual case.
During treatment, appropriate monitoring of factor IX levels is required to adjust the dose and frequency of infusions.
In particular, during major surgical procedures, replacement therapy with factor IX must be carefully monitored through coagulation tests (plasma factor IX activity).
Individual patient responses to factor IX may vary, resulting in different in vivo recovery levels and differing half-lives.
Dose calculations based on body weight may require adjustment in underweight or overweight patients.
Further information regarding dosage and duration of therapy is provided at the end of this leaflet in the section intended for physicians or healthcare professionals.

Prophylaxis of bleeding
For long-term prophylaxis (prevention) of bleeding in patients with severe haemophilia B, the usual dose is 20 to 40 IU of factor IX per kg body weight, administered every 3–4 days. In some cases, particularly in younger patients, shorter dosing intervals or higher doses may be required.

Use in children and adolescents
The safety and efficacy of AIMAFIX in children under 6 years of age have not yet been established.

Method of administration
For intravenous use.
This product must be administered intravenously by slow injection or infusion.
It is recommended not to administer doses exceeding 100 IU/kg body weight per day.
The infusion rate should be adjusted according to each individual patient.

Instructions for correct use
Reconstitution of the powder with the solvent:

1. Bring the vial of powder and the solvent vial to room temperature;
2. Maintain this temperature throughout the entire reconstitution process (within a maximum of 10 minutes);
3. Remove the protective caps from the powder and solvent vials;
4. Clean the stoppers of both vials with alcohol;
5. Open the device package by removing the top part; take care not to touch the inside (fig. A);
6. Do not remove the device from its packaging;
7. Invert the device package and insert the plastic spike through the solvent vial stopper so that the blue part of the device is connected to the solvent vial (fig. B);
8. Grasp the edge of the device package and pull it away to release the device without touching it (fig. C);
9. Ensure the vial containing the powder is securely placed on a stable surface. Invert the system so that the solvent vial is positioned above the device; press the transparent/white adapter onto the stopper of the powder vial so that the plastic spike pierces the powder vial stopper; the solvent will be automatically drawn into the powder vial (fig. D);
10. After solvent transfer, unscrew the blue part of the transfer system with the attached solvent vial and remove it (fig. E);
11. Gently rotate the vial until the powder is completely dissolved. Do not shake vigorously to avoid foaming (fig. F).

Check that the powder is completely dissolved; otherwise, there may be a loss of product activity.

Administration of the solution
The reconstituted medicine should be inspected visually before administration for the presence of particles or discoloration. The solution should be clear or slightly opalescent. Do not use cloudy solutions or those containing deposits.

1. Draw air into the syringe by pulling back the plunger, attach the syringe to the device, and inject the air into the vial containing the reconstituted solution (fig. G);
2. While holding the plunger steady, invert the system so that the vial with the reconstituted solution is positioned above the device, and slowly draw the concentrate into the syringe by pulling back the plunger (fig. H);
3. Disconnect the syringe by rotating it counterclockwise;
4. Visually inspect the solution in the syringe, which should appear clear or slightly opalescent and free of particles;
5. Attach the butterfly needle to the syringe and administer the solution slowly by intravenous infusion or injection.

Once the vials have been opened, the contents must be used immediately.
The reconstituted solution transferred into the syringe must be administered immediately.
The contents of the vial should be used for a single administration only.
Do not use after the expiry date stated on the label.
Any unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.

If you use more AIMAFIX than you should
No symptoms of overdose with human plasma coagulation factor IX have been reported.
In case of accidental ingestion or administration of an excessive dose of AIMAFIX, contact your doctor immediately or go to the nearest hospital.
If you have any doubts about the use of AIMAFIX, consult your doctor (or pharmacist).

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Adverse reactions known to be associated with administration of human factor IX concentrates may also occur with AIMAFIX.
If you experience any of these side effects, contact your doctor immediately or go to the nearest hospital:

• Allergic reactions (hypersensitivity) which may present as burning sensation and sharp pain at the infusion site, chills, flushing, hives (urticaria), rash all over the body (generalized urticaria), headache (cephalalgia), drop in blood pressure (hypotension), restlessness, rapid heartbeat (tachycardia), tightness in the chest (chest tightness), wheezing, drowsiness (lethargy), tingling or altered sensation in limbs or other body parts (paresthesia), nausea, vomiting, up to angioedema (rapid swelling of the skin and mucous membranes). In some cases, these reactions have progressed to severe anaphylaxis (including anaphylactic shock) and have occurred in close temporal association with the development of factor IX inhibitors (positive for anti-factor IX antibodies).
• Nephrotic syndrome (a condition of severe kidney dysfunction characterized by loss of proteins in the urine leading to decreased normal blood protein levels) has been reported following attempts of immune tolerance induction in patients with hemophilia B who have factor IX inhibitors and a history of allergic reactions.
• Pyrexia has also been observed.
• Patients with hemophilia B may develop neutralizing antibodies to factor IX (inhibitors). The presence of these inhibitors manifests as inadequate clinical response. In such cases, it is advisable to contact a specialized hemophilia center.
• There is a potential risk of thromboembolic events (abnormal formation of blood clots) following administration of factor IX-containing products, with a higher risk associated with poorly purified preparations. Use of low-purity factor IX products has been linked to cases of myocardial infarction, disseminated intravascular coagulation (widespread clotting in blood vessels), venous thrombosis (blood clots in veins), and pulmonary embolism (blood clots in the lungs). The use of highly purified factor IX products is rarely associated with such adverse reactions.

Additional side effects in children and adolescents
Specific data in the pediatric population are not available.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

For information on safety regarding transmissible agents, see section 2, "What you need to know before using AIMAFIX".

5. How to store AIMAFIX

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 packaging after “Exp”.
The expiry date refers to the product in its original, unopened packaging, correctly stored.
The expiry date refers to the last day of that month.
Store in the refrigerator ( 2°C - 8°C ). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
Once the infusion container has been opened, its contents must be used immediately.
The contents of the vial must be used for a single administration only.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What AIMAFIX contains
The active substance is human plasma coagulation factor IX.
AIMAFIX is presented as a powder and solvent for solution for infusion.

Each vial contains nominally 500 IU or 1,000 IU of human coagulation factor IX.
AIMAFIX contains approximately 50 IU/ml (500 IU/10 ml) or 100 IU/ml (1,000 IU/10 ml) of human coagulation factor IX after reconstitution.
Product derived from plasma of human donors.
The activity (IU) is determined using the one-stage clotting method of the European Pharmacopoeia.
The specific activity of AIMAFIX is about 100 IU/mg of protein.
The other components are sodium chloride, sodium citrate, glycine, sodium heparin, concentrated human antithrombin III, water for injection.
The powder vial contains coagulation factor IX from human plasma, sodium chloride, sodium citrate, glycine, sodium heparin, concentrated human antithrombin III.
The solvent vial contains water for injection.
Description of the appearance of AIMAFIX and contents of the package
Powder and solvent for solution for infusion.
AIMAFIX is presented as a white or pale yellow powder, hygroscopic powder or friable mass.
Before administration, the dissolved products must be visually inspected for the presence of suspended particles or abnormal discoloration. The solution should be clear or slightly opalescent.
Do not use cloudy solutions or those showing deposits. The AIMAFIX package contains one vial of powder, one vial of solvent used to prepare the solution for administration, and a sterile, pyrogen-free, single-use set consisting of a reconstitution device, an injection syringe, and a butterfly needle with PVC tubing.
Packages
AIMAFIX 500 IU/10 ml powder and solvent for solution for infusion.
Contains: 1 vial of 500 IU powder + 1 vial of 10 ml solvent + reconstitution and administration set.
AIMAFIX 1000 IU/10 ml powder and solvent for solution for infusion.
Contains: 1 vial of 1,000 IU powder + 1 vial of 10 ml solvent + reconstitution and administration set.
Marketing Authorization Holder
Kedrion S.p.A. – Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca).
Manufacturer
Kedrion S.p.A. – 55027 Bolognana, Gallicano (Lucca).

The following information is intended exclusively for physicians or healthcare professionals.
See also section 3.
Dosage:
The dosage and duration of replacement therapy depend on the severity of factor IX deficiency, the site and extent of bleeding, and the clinical condition of the patient.
The number of units of factor IX administered is expressed in International Units (IU), referenced to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for plasma factor IX).
The activity of one International Unit (IU) of factor IX is equivalent to the amount of factor IX contained in one millilitre of normal human plasma.
On-demand treatment
The calculation of the required dose of factor IX is based on the empirical observation that 1 International Unit (IU) of factor IX per kg of body weight increases plasma factor IX activity by 0.8% of normal activity. The required dose is calculated using the following formula:
Required units = body weight (kg) x desired increase in factor IX (%) (IU/dl) x (reciprocal of observed recovery)
The amount to be administered and the frequency of administration must always be guided by clinical efficacy in the individual case.
In the case of the following bleeding events, factor IX activity during the corresponding period must not fall below the indicated plasma activity level (in % of normal). The following table may be used as a reference in bleeding episodes and surgical procedures:

Degree of bleeding/Type of Required factor IX level Dosing frequency (hours)/
surgical procedure (%)(IU/dl) Duration of therapy (days)
Bleeding
Early haemarthrosis, muscle 20 – 40 Repeat every 24 hours. At least 1
bleeding or oral bleeding day, until the bleeding episode is
indicated by pain resolved or healing is achieved.
Haemarthrosis, extensive muscle 30 – 60 Repeat infusion every 24 hours for
bleeding or haematoma 3 – 4 days or more, until severe pain
and disability have subsided.
Life-threatening bleeding 60 – 100 Repeat infusion every 8 - 24 hours
until symptoms resolve.
Surgery
Minor surgery, including 30 – 60 Every 24 hours, at least 1 day, until
dental extractions healing.
Major surgery 80 – 100 Repeat infusion every 8 - 24 hours
(pre- and post-operative) until adequate wound healing; then continue therapy for at least another 7 days to maintain factor IX activity between 30% and 60% (IU/dl).
Prophylaxis
For long-term prophylaxis of bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kg body weight administered at intervals of 3 – 4 days.
In some cases, especially in younger patients, shorter treatment intervals or higher doses may be required.
Paediatric population
The safety and efficacy of AIMAFIX in children under 6 years of age have not yet been established.
Monitoring of treatment
During treatment, appropriate measurement of factor IX levels is required to adjust the dose and frequency of infusions. Responses to factor IX may vary among individual patients, achieving different levels of in vivo recovery and showing different half-lives. Dosing calculated based on body weight may require adjustment and monitoring of factor IX levels in underweight or overweight patients. In particular, during major surgical procedures, careful monitoring of replacement therapy through coagulation assays (plasma factor IX activity) is essential.
When using an in vitro one-stage coagulation test based on activated partial thromboplastin time (aPTT) to determine factor IX activity in patient blood samples, the results of plasma factor IX activity may be significantly influenced by both the type of aPTT reagent and the reference standard used in the assay. This is particularly important when changing laboratory and/or reagents used in the test.
Special warnings and precautions for use
Inhibitors
After repeated treatments with products containing human coagulation factor IX, patients should be monitored for the development of neutralizing antibodies (inhibitors), which should be quantified in Bethesda Units (BU) using appropriate biological assays.
There are reports in the literature showing a correlation between the presence of factor IX inhibitors and allergic reactions. Therefore, in patients who experience allergic reactions, the presence of an inhibitor should be evaluated. It should be noted that patients with factor IX inhibitors may have an increased risk of anaphylaxis upon subsequent exposure to factor IX.
Due to the risk of allergic reactions with factor IX products, initial administration of factor IX should be performed, in accordance with the treating physician's judgment, under medical supervision and in a setting where appropriate medical care for allergic reactions can be provided.