Ixed

PACKAGE LEAFLET: INFORMATION FOR THE USER

IXED

500 IU/10 ml powder and solvent for solution for infusion
IXED
1000 IU/10 ml powder and solvent for solution for infusion
Coagulation Factor IX of human plasma
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 side effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What IXED is and what it is used for

IXED is a solution of coagulation factor IX derived from human plasma. Factor IX is a protein with antihemorrhagic activity.
IXED 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 IXED

Do not use IXED

• 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 IXED. As with any intravenous protein product, allergic-type hypersensitivity reactions may occur. IXED contains traces of other human proteins besides factor IX. If during administration of the product you notice any of the symptoms listed below, you must stop administration immediately and contact your doctor, as these symptoms may be the first signs of an allergic reaction. The symptoms that may occur are:
• urticaria,
• generalized urticaria,
• 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 IXED may increase these risks.
If a central venous access device (CVC) is required for IXED injection, your doctor must consider the risk of complications including local infections, spread of bacteria into the bloodstream (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 a correlation between the presence of antibodies that neutralize factor IX (inhibitors) and allergic reactions. Therefore, in patients experiencing allergic reactions, the presence of an inhibitor should be considered. 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, in accordance with 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 suffer from 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 (liver disorders), in the post-operative period, in newborns, or in patients at risk of thrombotic events or disseminated intravascular coagulation (DIC), clinical monitoring should be carried out through appropriate biological tests to detect early signs of thrombotic and consumptive coagulopathies.
In each of these situations, the benefit of treatment with IXED must be weighed against the risk of such complications.

Viral safety of IXED
When medicines are prepared from human blood or plasma, specific measures are taken 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.

Manufacturers of these medicines also incorporate into the processing of blood and plasma certain steps 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 excluded. This applies also to emerging or unknown viruses or other types of infectious agents.
The measures adopted are considered effective against 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.
Infection with parvovirus B19 can be serious during pregnancy (fetal infection) and in individuals with weakened immune systems or with 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 trade name and batch number of the product each time you receive a dose of IXED, in order to maintain traceability of the batch used.

Children and adolescents
There are insufficient data to recommend the use of IXED 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 IXED
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.
IXED must not be mixed with other medicines.

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

Driving and using machines
IXED does not affect or affects negligibly the ability to drive or use machines.

IXED 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 cell count, 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 IXED

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 IXED exactly as instructed in the section “Instructions for correct use”.
Only use the infusion devices provided 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 in doubt, consult your doctor.
Treatment should begin under the supervision of a physician experienced in the management of hemophilia.
Your doctor will determine the appropriate dose and duration of treatment based on the severity of your 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.
Bleeding prophylaxis
For long-term prophylaxis (prevention) of bleeding in patients with severe hemophilia B, the usual dose is 20 to 40 IU of factor IX per kg of body weight, administered every 3–4 days. In some cases, particularly in younger patients, shorter intervals or higher doses may be required.
Use in children and adolescents
The safety and efficacy of IXED in children under 6 years of age have not yet been established.
Method of administration
For intravenous use.
This product must be administered intravenously, either 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 the individual patient.
Instructions for correct use
Reconstitution of the powder with 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 cover; take care not to touch the inside (fig. A);
6. Do not remove the device from its packaging;
7. Turn the device package upside down and insert the plastic spike through the stopper of the solvent vial 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 off 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 stopper of the powder vial; 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, as incomplete dissolution may result in loss of product activity.

Administration of the solution
The reconstituted medicine should be inspected visually before administration for 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 above the device, and slowly draw the concentrate into the syringe by pulling back the plunger (fig. H);
3. Detach 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, their 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.
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.
If you use more IXED than you should
No symptoms of overdose have been reported with human plasma coagulation factor IX.
In case of accidental ingestion or administration of an excessive dose of IXED, contact your doctor immediately or go to the nearest hospital.
If you have any doubts about the use of IXED, consult your doctor (or pharmacist).

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Adverse reactions known to be associated with administration of human factor IX concentrates may also occur with IXED.
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), skin rash all over the body (generalized urticaria), headache (cephalaea), low blood pressure (hypotension), restlessness, rapid heartbeat (tachycardia), feeling of chest tightness (sensation of chest oppression), wheezing; drowsiness (lethargy), tingling or altered sensation in limbs or other body parts (paresthesia); nausea, vomiting; up to angioedema (rapid swelling of skin and mucous membranes). In some cases, these reactions have progressed to severe anaphylaxis (including anaphylactic shock) and 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 urine leading to reduced normal blood levels of these proteins) has been reported following attempts at immunological tolerance induction in patients with hemophilia B who have factor IX inhibitors and a history of allergic reactions.
• Fever (pyrexia) has also been observed.
• Patients with hemophilia B may develop neutralizing antibodies against factor IX (inhibitors). The presence of these inhibitors is manifested by 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). Use of highly purified factor IX is rarely associated with such adverse reactions.

Additional side effects in children and adolescents
Specific data for 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 system at 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 safety information regarding transmissible agents, see section 2, “What you need to know before using IXED”.

5. How to store IXED

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date 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 a 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 medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

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

Each vial contains nominally 500 IU or 1,000 IU of human coagulation factor IX.
IXED 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.
Produced from plasma of human donors.
The activity (IU) is determined using the one-stage clotting method of the European Pharmacopoeia.
The specific activity of IXED is about 100 IU/mg of protein.
Other components are sodium chloride, sodium citrate, glycine, sodium heparin, concentrated human antithrombin III, and water for injections.
The powder vial contains human plasma coagulation factor IX, sodium chloride, sodium citrate, glycine, sodium heparin, and concentrated human antithrombin III.
The solvent vial contains water for injections.

Description of the appearance of IXED and contents of the pack
Powder and solvent for solution for infusion.
IXED 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 IXED pack contains one vial of powder, one vial of solvent for preparing the solution to be administered, and a sterile, pyrogen-free, single-use set consisting of a reconstitution device, an injection syringe, and a butterfly needle with a PVC tubing.

Pack sizes
IXED 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.
IXED 1000 IU/10 mL powder and solvent for solution for infusion.
Contains: 1 vial of 1000 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 patient's clinical condition.
The number of factor IX units 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 milliliter of normal human plasma.

On-demand treatment
The calculation of the required factor IX dose 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) × desired increase in factor IX (%) (IU/dL) × (reciprocal of observed recovery)
The amount to be administered and the frequency of infusions should 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 should 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:

| Bleeding Grade / Surgical Procedure | Required Factor IX Level (%)(IU/dL) | Dosing Frequency (hours) / Duration of Therapy (days) | |----------------------------------------|----------------------------------------|----------------------------------------------------------| | Bleeding | | | | Early hemarthrosis, muscle bleeding or oral bleeding indicated by pain | 20 – 40 | Repeat every 24 hours. At least 1 day, until the bleeding episode is resolved or healing is achieved. | | Extensive hemarthrosis, muscle bleeding or severe hematoma | 30 – 60 | Repeat infusion every 24 hours for 3–4 days or more, until pain and severe disability have subsided. | | Life-threatening bleeding | 60 – 100 | Repeat infusion every 8–24 hours until symptoms resolve. | | Surgery | | | | Minor surgery, including dental extractions | 30 – 60 | Every 24 hours, at least 1 day, until healing is achieved. | | Major surgery | 80 – 100 | Repeat infusion every 8–24 hours (pre- and post-operatively) 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, particularly in younger patients, shorter treatment intervals or higher doses may be required.

Paediatric population
The safety and efficacy of IXED in children under 6 years of age have not yet been established.

Monitoring of treatment
Appropriate monitoring of factor IX levels is required during treatment to adjust the dose and frequency of infusions. Responses to factor IX may vary among individual patients, with differing levels of in vivo recovery and different half-lives. Dosing 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 assay 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 test. This is particularly important when changing laboratory and/or reagents used in the assay.

Special warnings and precautions for use
Inhibitors
Patients receiving repeated treatments with human plasma coagulation factor IX products should be monitored for the development of neutralizing antibodies (inhibitors), which should be quantified in Bethesda Units (BU) using appropriate biological assays.

Published literature reports indicate a correlation between the presence of factor IX inhibitors and allergic reactions. Therefore, in patients experiencing 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 is available.