Aimafix

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AYMAFIX

Composition:

Active substance: human blood coagulation factor IX;

1 vial of powder contains 500 IU or 1000 IU of human blood coagulation factor IX;

Excipients: sodium chloride, sodium citrate, glycine, sodium heparin, antithrombin III;

the vial of solvent contains 10 ml of water for injections.

The reconstituted solution contains human blood coagulation factor IX at a concentration of 50 IU/ml (500 IU/10 ml) or 100 IU/ml (1000 IU/10 ml).

The specific activity of AYMAFIX is approximately 100 IU/mg protein.

Activity (IU) is determined by the coagulation method of the European Pharmacopoeia.

Total protein content does not exceed 8 mg/vial or 16 mg/vial.

Pharmaceutical form. Powder and solvent for solution for infusion.

Main physicochemical characteristics:
Powder: white or pale yellow hygroscopic powder or brittle mass;
Solvent: clear, colorless liquid.

Pharmacotherapeutic group. Antihemorrhagic agents, blood coagulation factor IX.

ATC code B02B D04.

Pharmacological Properties.

Pharmacodynamics.

Factor IX is a single-chain glycoprotein with a molecular weight of approximately 68,000 daltons. It is synthesized in the liver and is a vitamin K-dependent coagulation factor. Factor IX is activated by factor XIa via the intrinsic coagulation pathway and by the factor VII/tissue factor complex via the extrinsic coagulation pathway. Activated factor IX, in complex with activated factor VIII, activates factor X. Activated factor X then converts prothrombin into thrombin. Thrombin subsequently converts fibrinogen into fibrin, leading to clot formation.

Hemophilia B is an X-linked inherited coagulation disorder caused by reduced levels of factor IX, resulting in severe bleeding into joints, muscles, or internal organs, occurring either spontaneously or following trauma or surgical procedures. Replacement therapy increases factor IX levels, thereby temporarily correcting the deficiency and reducing the tendency to bleed.

Children

Although specific data on use in children are limited, published study results have not demonstrated significant differences in efficacy and safety between adults and children with the same condition.

Pharmacokinetics.

Administration of human coagulation factor IX concentrate to patients with hemophilia B restores 30–60% of factor IX plasma activity. The plasma half-life of factor IX ranges from 16 to 30 hours, with an average of 24 hours.

Children

Although specific data on use in children are limited, published study results have not demonstrated significant differences in efficacy and safety between adults and children with the same condition.

Preclinical Safety Data

Human coagulation factor IX is a natural component of human plasma and acts similarly to endogenous factor IX.

Single-dose toxicity studies are not considered relevant because high doses cause hypervolemia.

Repeated-dose (multiple-dose) toxicity studies in animals are not feasible due to interference from antibodies formed against the heterologous protein.

Even doses significantly exceeding the recommended human dose per kg of body weight do not demonstrate any toxic effects in experimental animals.

Given the clinical experience with human coagulation factor IX, which has not shown evidence of carcinogenic or mutagenic effects, experimental studies, particularly those involving heterologous species, are not considered necessary.

Clinical characteristics.

Indications.

Treatment and prevention of bleeding in patients with hemophilia B (congenital factor IX deficiency).

The drug may be used for treatment of acquired factor IX deficiency.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

There have been no reports of interactions between human coagulation factor IX products and other medicinal products.

Children

Specific data in children are lacking.

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products, it is recommended to record the name and batch number of the AYMAFIX product each time it is administered to a patient.

Hypersensitivity

Hypersensitivity reactions may occur during administration of AYMAFIX.

In addition to factor IX, the product contains traces of other human proteins. Patients should be advised to discontinue infusion immediately and contact their physician if symptoms of hypersensitivity occur. Patients should be informed about early signs of hypersensitivity reactions, including rash, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. In case of shock, current medical standards for shock management should be followed.

Important information on excipients of AYMAFIX

This medicinal product contains up to 41 mg of sodium per vial (10 mL), which corresponds to 2.05% of the WHO recommended maximum daily intake of sodium for adults (2 g).

This medicinal product contains up to 10 IU/mL of heparin. Heparin may cause allergic reactions and a decrease in red blood cell count, which may affect the blood coagulation system. Patients with a history of heparin-induced allergic reactions should avoid using heparin-containing products.

Inhibitors

Patients receiving repeated treatment with factor IX coagulation factor products should be monitored for the development of neutralizing antibodies (inhibitors), which are quantified in Bethesda Units (BU) using appropriate biological assays.

There have been reports of an association between the development of factor IX inhibitors and allergic reactions. Therefore, patients experiencing allergic reactions should be tested for the presence of inhibitors. It should be noted that patients with factor IX inhibitors have an increased risk of developing anaphylaxis upon repeated administration of factor IX.

Due to the potential risk of allergic reactions with factor IX concentrates, initial administrations of factor IX should be performed under physician supervision and medical monitoring to ensure appropriate medical intervention in case of allergic reactions.

Thromboembolism

Due to the potential risk of thrombotic complications associated with administration of this product, clinical monitoring should be initiated in patients with liver disease, postoperative patients, and patients at risk of thrombotic events or disseminated intravascular coagulation (DIC). This monitoring should include appropriate biological tests to detect early signs of thrombosis and consumption coagulopathy. In each of these cases, the benefits of treatment with AYMAFIX should be carefully weighed against the risks of these complications.

Cardiovascular events

In patients with existing cardiovascular risk factors, replacement therapy with factor IX may increase this risk.

Catheter-related complications

If central venous access is required, the risk of device-related complications should be considered, including local infections, bacteremia, and catheter site thrombosis.

Viral safety

Standard measures to prevent infections from medicinal products derived from human blood or plasma include donor selection, screening of individual plasma units and plasma pools for specific infectious markers, and implementation of effective viral inactivation/removal steps during manufacturing.

Nevertheless, it is not possible to completely exclude the risk of transmission of infectious agents when administering medicinal products derived from human blood or plasma. This also applies to unknown or emerging viruses and other pathogens.

The measures implemented are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as against non-enveloped viruses such as hepatitis A virus (HAV). However, the effectiveness of these measures may be limited against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious in pregnant women (fetal infection) and in immunocompromised patients or those with increased erythropoiesis (e.g., hemolytic anemia).

Appropriate vaccination (against hepatitis A and B) should be considered for patients receiving regular treatment with human coagulation factor IX products.

It is strongly recommended to record the name and batch number of AYMAFIX each time the product is administered to a patient to ensure traceability between the patient's condition and the specific product batch.

Children

There are insufficient data to recommend the use of AYMAFIX in children under 6 years of age. The special warnings and precautions specified in this section apply to both adults and children.

Use during pregnancy or breastfeeding

Animal studies on the effects of factor IX on reproductive function have not been conducted. Due to the low prevalence of hemophilia B in women, there is no clinical experience with the use of factor IX during pregnancy or breastfeeding. Therefore, factor IX should be used during pregnancy and breastfeeding only if clearly indicated.

Ability to affect reaction speed when driving or operating machinery

The effect of AYMAFIX on the ability to drive or operate machinery is absent or negligible.

Method of Administration and Dosage

Treatment should be initiated under the supervision of a physician experienced in the management of hemophilia.

Patients who have not previously received treatment

The safety and efficacy of AYMAFIX in patients who have never received prior treatment have not yet been established.

Monitoring of treatment

During the course of treatment, appropriate monitoring of factor IX levels is recommended to guide dosing and the frequency of repeat infusions. Individual patients may respond differently to factor IX, demonstrating variable half-lives and recovery times.

The dose calculated based on body weight may require adjustment in patients with low or high body weight. Particularly during extensive surgical procedures, precise monitoring of replacement therapy using coagulation blood tests (factor IX activity in plasma) is mandatory and essential.

When using a one-stage clotting assay in vitro based on activated partial thromboplastin time (aPTT) to determine factor IX activity in patient plasma samples, the results may significantly depend on both the type of aPTT reagent and the reference standard used in the assay. This is particularly important when changing laboratories and/or reagents used for testing.

Dosage

The dosage and duration of replacement therapy depend on the severity of factor IX deficiency, the location and intensity of bleeding, and the patient's clinical condition.

The amount of factor IX administered is expressed in International Units (IU) according to the current WHO standard for factor IX preparations. Factor IX activity in plasma is expressed as a percentage (relative to normal human plasma) or in International Units (relative to the international standard for blood coagulation factor IX).

One International Unit (IU) of factor IX activity corresponds to the amount of factor IX present in 1 mL of normal human plasma.

On-demand treatment

The calculation of the required factor IX dosage is based on empirically derived data. 1 International Unit (IU) of factor IX per 1 kg of body weight raises plasma factor IX activity by 0.8% of normal activity. The required dosage can be determined using the following formula:

Required number of units = body weight (kg) × desired increase in factor IX (%) (IU/dL) × (reciprocal of the incremental recovery typically observed after factor infusion)

The amount of product to be administered and the frequency of administration should always be guided by the clinical response in each individual case. In the situations listed below, factor IX activity should not fall below the specified plasma activity level (% of normal) during the appropriate period. Table 1 can be used as a guideline for dosing in bleeding episodes and surgical procedures.

Table 1

Prevention

For long-term prevention of bleeding episodes in patients with severe haemophilia B, doses of 20 to 40 IU of factor IX per kg of body weight are usually administered every 3 to 4 days.

In individual cases, especially in younger patients, shorter intervals between administrations or higher doses may be required.

Route of administration

Administered intravenously by injection or slow infusion.

It is recommended not to exceed 100 IU/kg body weight per day.

The infusion rate should be determined individually for each patient.

Reconstitution of powder with solvent

1. Bring the vial with powder and the vial with solvent to room temperature.
2. Maintain room temperature throughout the entire reconstitution (dissolving) process (maximum 10 minutes).
3. Remove the protective caps from both the vial with powder and the vial with solvent.
4. Disinfect the stopper surfaces of both vials with ethyl alcohol.
5. Open the device package as shown in Fig. A, without touching the inside of the package (Fig. A).
6. Do not remove the device from the package.
7. Turn the package with the device upside down and pierce the solvent vial stopper with the plastic spike of the device so that the blue part of the device connects to the solvent vial (Fig. B).
8. Holding the edge of the device package, remove the package without touching the device itself (Fig. C).
9. Ensure the powder vial is placed on a stable surface; turn the solvent vial with the attached device upside down so that the solvent vial is above the device; press the transparent adapter on the powder vial stopper to allow the plastic spike to pierce the powder vial stopper; the solvent will automatically begin to flow into the powder vial (Fig. D).
10. After the transfer of solvent, unscrew the blue part of the system to which the solvent vial is attached, and discard it (Fig. E).
11. Gently shake the vial until the powder is completely dissolved (Fig. F). Do not shake vigorously to avoid foaming.

Ensure that the powder is completely dissolved; otherwise, the preparation will be less effective.

Administration of the solution

Before administration, the solution should be visually inspected for the presence of particles or discoloration. The solution should be clear or slightly opalescent. Do not use the solution if it is cloudy or contains precipitate.

1. Draw air into the syringe by pulling back the plunger; attach the syringe to the device and inject the air from the syringe into the vial containing the reconstituted solution (Fig. E).
2. While holding the plunger, invert the system so that the vial with the reconstituted solution is positioned above the device. Slowly pull back the plunger to draw the concentrate into the syringe (Fig. F).
3. Detach the syringe by rotating it counterclockwise.
4. Visually inspect the solution in the syringe, which should be clear or slightly opalescent and free from particles.
5. Attach a butterfly needle to the syringe and administer the preparation intravenously by infusion or slow injection.

After opening, the contents of the vial must be used immediately.

The reconstituted solution drawn into a syringe must be used immediately.

The contents of the vial are intended for single use only.

The use of the medicinal product after the expiry date stated on the packaging is prohibited.

Any unused medicinal product or waste material remaining after use must be disposed of in accordance with local requirements.

Children.

The safety and efficacy of AYMAFIX in children under 6 years of age have not been established.

Overdose.

There have been no reports of symptoms related to overdosage with human coagulation factor IX.

Adverse reactions.

Summary of safety profile

Hypersensitivity or allergic reactions (including angioneurotic edema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, rash, hypotension, lethargy, nausea, restlessness, tachycardia, chest tightness, tingling, vomiting, and wheezing) are uncommon and in some cases may progress to severe anaphylaxis (including shock). In some cases, these reactions progressed to severe anaphylaxis and were observed in close temporal association with the development of inhibitors to factor IX (see also section "Special precautions").

Nephrotic syndrome has been reported during attempts to induce immune tolerance in patients with hemophilia B who have factor IX inhibitors and a history of allergic reactions.

In patients with hemophilia B, neutralizing antibodies (inhibitors) to factor IX may develop. The appearance of such inhibitors will manifest as a suboptimal clinical response. In such cases, referral to a specialized hemophilia center is recommended.

Following administration of factor IX products, there is a potential risk of thromboembolic complications, with the risk being higher when using low-purity factor IX products. Myocardial infarction, disseminated intravascular coagulation, venous thrombosis, and pulmonary embolism have been reported with the use of low-purity factor IX products. The use of high-purity factor IX products rarely leads to such adverse effects.

For safety information regarding transmission of infectious agents, see section "Special precautions".

List of adverse reactions in tabular form

Adverse effects that may occur during administration of human blood coagulation factor IX are presented in Table 2 according to MedDRA [Medical Dictionary for Regulatory Activities] system organ class and preferred terms.

Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Confirmed data on the frequency of adverse reactions from clinical trials are lacking.

The data listed below are based on the safety profile of factor IX products and have been partially observed during the post-marketing period; since post-marketing adverse reaction reports are voluntary and come from a population of unknown size, it is not possible to reliably estimate their frequency.

Table 2

* These reactions to factor IX products have also been observed in the post-marketing period.

If there is no correspondence between the description of an adverse reaction and the MedDRA preferred term, the latter is indicated in parentheses.

Paediatric population

Specific data in children are not available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Diluent (water for injections): 5 years.

After reconstitution, the product should be used immediately.

Storage conditions

Store in a refrigerator (at 2 to 8 °C). Do not freeze.

Store in the original packaging to protect from light, in a place inaccessible to children.

Incompatibilities

Due to lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Only the provided injection/infusion set should be used, as treatment may be ineffective due to adsorption of human coagulation factor IX onto the internal surfaces of other administration devices.

Packaging

500 IU or 1000 IU per vial in a set with 10 ml of diluent (water for injections) in a vial and a reconstitution and administration kit, packed in a cardboard box.

Prescription status

Prescription only.

Manufacturer

KEDRION S.P.A.

Manufacturer's location and address of the site of operation

VIA PROVINCIALE (loc. BOLOGNANA) - 55027 GALLICANO (LU), ITALY