Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
This product may be used in the management of acquired factor IX deficiency.

Treatment should be carried out under the supervision of a physician experienced in the treatment of haemophilia.
Previously untreated patients
The safety and efficacy of AIMAFIX in previously untreated patients have not yet been established. No data are available.
Treatment monitoring
During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of infusions. Factor IX responses may vary in individual patients, reaching different levels of in vivo recovery and showing a different half-life.
Dose based on bodyweight may require adjustment in underweight or overweight patients. In particular, in the case of major surgeries, it is essential to carefully monitor the substitution therapy by coagulation analysis (plasma factor IX activity).
When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor IX activity in patients’ blood samples, plasma factor IX activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. This is important particularly when changing the laboratory and/or reagents used in the assay.

Posology
Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient’s clinical condition.
The number of units of factor IX administered is expressed in International Units (IU), which are related 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 factor IX in plasma).
One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.

On demand treatment
The calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) of factor IX per kg of body weight raises the plasma factor IX activity by 0.8% of normal activity. The required dosage is determined using the following formula:
Required units = body weight (kg) x desired factor IX rise (%) (IU/dl) x (reciprocal of observed recovery)
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

Haemorrhage

- Early haemarthrosis, muscle bleeding or oral bleeding
20 – 40
Repeat every 24 hours. For at least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.

- More extensive haemarthrosis, muscle bleeding or haematoma
30 – 60
Repeat infusion every 24 hours for 3 – 4 days or more, until pain and acute disability are resolved.

- Life-threatening haemorrhages
60 – 100
Repeat infusion every 8 - 24 hours until threat is resolved.

Surgery

Minor surgery

- Including tooth extraction
30 – 60
Every 24 hours, at least 1 day, until healing is achieved.

Major surgery
80 – 100
(pre-and post-operative)
Repeat infusion every 8-24 hours until adequate wound healing; then therapy for at least another 7 days to maintain a factor IX activity of 30% to 60% (IU/dl)

- Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kg of body weight at intervals of 3 to 4 days.
In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.
Paediatric population
The safety and efficacy of AIMAFIX in children less than 6 years of age have not yet been established.

- Method of administration
Intravenous use
For instruction on reconstitution of the medicinal product before administration, see section 6.6.
The product should be administered via the intravenous route, by injection or slow infusion.
It is recommended not to administer more than 100 IU/kg of body weight pro die.
The infusion rate should be evaluated for each patient.

- Traceability
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
- Hypersensitivity
Allergic type hypersensitivity reactions are possible with AIMAFIX.
The product contains traces of human proteins other than factor IX. Patients should be advised to immediately stop the product administration and to contact their doctor if symptoms of hypersensitivity appear. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. In case of shock, the current medical standards for shock – treatment should be observed.
- Important information on ingredients of AIMAFIX
This medicinal product contains up to 41 mg sodium per vial of 10 ml, equivalent to 2.05 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicine contains up to 10 IU/ml heparin. Heparin may cause allergic reactions and reduced red blood cell counts which may affect the blood clotting system. Patients with a history of heparin-induced allergic reactions should avoid the use of heparin-containing medicines.
- Inhibitors
After repeated treatment with human plasma coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing.
There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge to factor IX.
Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IX, according to the treating physician’s judgement, should be performed under medical observation where proper medical care for allergic reactions could be provided.
- Thromboembolism
Because of the potential risk of the thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy must be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with AIMAFIX must be weighed against the risk of these complications.
- Cardiovascular events
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
- Catheter-related complications
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.

- Viral safety

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses.
Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV and for the non-enveloped virus HAV. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular receipt of human plasma coagulation factor IX.
It is strongly recommended that every time that AIMAFIX is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

- Paediatric population
There are not enough data to recommend the use of AIMAFIX in children under 6 years of age. The special warnings and precautions for use listed in this section apply to both adult and paediatric populations.

No interaction of human plasma coagulation factor IX products with other medicinal products has been reported.
Paediatric population
No specific data are available for the paediatric population.

Animal reproduction studies have not been conducted with factor IX. Because of the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available. Therefore factor IX should be used during pregnancy and lactation only if clearly indicated.

AIMAFIX has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently and may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4).
Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) the factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, is recommended that a specialised haemophilia centre be contacted.
There is a potential risk of thromboembolic events following the administration of factor IX products, with a higher risk for low purify preparations. The use of low purify factor IX based products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such adverse reactions.
For safety information with respect to transmissible agents, see section 4.4.
Tabulated list of adverse reactions
The table below has been drawn up according to the MedDRA system organ classification (SOC and Preferred Term Level [PT]).
Frequencies have been evaluated according to the following convention: 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), not known (cannot be estimated from the available data).
There are no robust data on the frequency of adverse reaction from clinical trials.

The following data are based on the safety profile of Factor IX products and partially observed in post-marketing; since the post-marketing reporting of adverse reactions is voluntary and on a population of unknown size, it is not possible to estimate the frequency of these reactions.

- Blood and lymphatic system disorders
Disseminated intravascular coagulation

- Immune system disorders
Hypersensitivity or allergic reactions (Hypersensitivity),
Anaphylactic reaction*
Not known
Anaphylactic shock

- Psychiatric disorders
Restlessness

- Nervous system disorders
Headache
Lethargy
Paresthesia

- Cardiac disorders
Tachycardia
Myocardial infarction

- Vascular disorders
Flushing
Hypotension
Thromboembolic events (embolism)
Venous thrombosis

- Respiratory, thoracic and mediastinal disorders
Wheezing
Pulmonary embolism (Pulmonary embolism and pulmonary infarction)

- Gastrointestinal disorders
Nausea
Vomiting

- Skin and subcutaneous tissue disorders
Angioedema
Generalised urticaria
Hives (urticaria)

- Renal and urinary disorders
Nephrotic syndrome

- General disorders and administration site conditions
Burning sensation at the infusion site (burning sensation)
Stinging at the infusion site (infusion site pain)
Chills
Tightness of the chest (chest discomfort)
Pyrexia

- Diagnostic exams
Development of factor IX inhibitors (Inhibitory antibodies)

- Paediatric population
No specific data are available for the paediatric population.
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 are asked to report any suspected adverse reactions via the national reporting system.
To Report any side effect:
Kingdom of Saudi Arabia
National Pharmacovigilance & Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Ext’s 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
For other GCC countries: report side effects via the national reporting system.

No symptoms of overdose with human coagulation factor IX have been reported.

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor IX. ATC code: B02BD04.
Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 dalton. It is a vitamin-K dependent coagulation factor and it is synthesized in the liver. Factor IX is activated by a factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed.
Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Paediatric population
Although there are no specific data for the paediatric population, the published data on the efficacy and safety studies have not shown significant differences between adults and children suffering from the same disease.

Infusion of human plasma coagulation factor IX concentrate into patients with hemophilia B results in recoveries of 30% - 60% of the plasma factor IX activity.
The plasma half-life of factor IX ranges from 16 - 30 hours, with an average of 24 hours.
Paediatric population
Although there are no specific data for the paediatric population, the published data on the efficacy and safety studies have not shown significant differences between adults and children suffering from the same disease.

Human plasma coagulation factor IX is a normal constituent of the human plasma and acts like the endogenous factor IX.
Single dose toxicity testing is of no relevance since higher doses result in overloading.
Repeated dose toxicity testing in animals is impracticable due to interference with developing antibodies to heterologous protein.
Even doses which are largely higher than those recommended in man per Kg of body weight do not show any toxic effects in experimental animals.
Since clinical experience provides no indication for tumorigenic and mutagenic effects of human plasma coagulation factor IX, experimental studies, particularly in heterologous species, are not considered mandatory.

Vial of powder
Sodium chloride
Sodium citrate
Glycine
Heparin sodium
Human Antithrombin III concentrate
Vial of solvent
Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Only the provided injection/infusion sets should be used because treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some infusion equipment.

Store in a refrigerator (+2°C / +8°C) . Do not freeze.
Keep the vial in the outer carton, in order to protect from light.

One neutral type I glass vial with type I elastomer stopper containing the powder; one neutral type I glass vial with type I elastomer stopper containing the solvent; a non pyrogenic, sterile set for reconstitution and administration consisting of injection syringe, perforating double needle, butterfly needle, filter needle, medicated plaster .
AIMAFIX 500 IU/10 ml powder and solvent for solution for infusion. One vial of powder + one vial of solvent + set for reconstitution and administration.

Instructions for use
Reconstitution of the powder with the solvent:
1. heat the solvent in a water bath at a temperature of not more than +37°C;
2. remove the protection stoppers overseal cap from the powder and solvent vials;
3. clean the stopper surfaces of the two vials with alcohol;
4. insert the double needle into solvent vial, from the undulated side;
5. remove the needle hood on the other side of the double needle;
taking care not to touch the second needle;
6. up-turn the solvent vial with the double needle and insert the second needle into the powder vial; during the perforation of the stopper of the vial containing the powder, the needle top in the solvent vial should be in contact with the liquid and not with the air;
the formation of foam is avoided by ensuring that the solvent flows slowly down the sides of the vial;
7. shake gently until completely solubilized;
8. remove the solvent vial with the double needle;
9. apply the filter needle to the syringe and draw the reconstituted concentrate;
10. replace the filter needle with the butterfly needle and inject or infuse intravenously.

Reconstitution time less than 3 min.
The solution should be clear or slightly opalescent.
The product may show a few small flakes or particles after reconstitution.

The products should be inspected visually prior to administration. Do not use solutions that are cloudy or have deposits.
Reconstituted product should be inspected visually for particulate and discoloration prior to administration.
After reconstitution the product should be used immediately.
The reconstituted solution transferred into the syringe should be used immediately.
The content of the vial should be used in a single administration.
Do not use after the expiry date stated on the label.
Any unused product or waste material should be disposed of in accordance with local requirements.