Factor IX Grifols is indicated in the treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency). 

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia. 

Posology

The dosage and duration of treatment 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 is related to the current World Health Organization (WHO) standard of 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 and 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. 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 body weight raises the plasma factor IX activity by 1.3 ± 0.3 % 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 0.8

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. Factor IX products rarely require to be administered more than once daily.  

In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal plasma or IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.  

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. 

There are insufficient data from clinical trials to recommend the use of Factor IX Grifols in children less than 6 years of age. 

Patients should be monitored for the development of factor IX inhibitors. If the expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor IX inhibitor is present. In patients with high levels of inhibitor, factor IX therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia. See also section 4.4.

Method of administration

Dissolve the preparation as described in section 6.6. The product should be administered slowly, especially the first dose (approximately 3 ml/min), via the intravenous route. 

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor IX. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, they should be advised to discontinue use of the product immediately and contact their physician. 

In case of shock, the current medical standards for shock-treatment should be observed. 

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). 

It is recommended proper vaccination (hepatitis A and B) for patients who regularly/repeatedly receive human plasma-derived products (for example, factor IX concentrates). 

After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralizing 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 factor IX inhibitors. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis when having treatment with factor IX. 

Because of the risk of allergic reactions with factor IX concentrates, the initial administrations of factor IX should, according to the treating physician’s judgment, be performed under medical observation where proper medical care for allergic reactions could be provided. 

Since the use of factor IX complex concentrates has been associated with the development of thromboembolic complications, the risk being higher in low purity preparations, the use of factor IXcontaining products may be potentially hazardous in patients with signs of fibrinolyis or in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Factor IX Grifols should be weighed against the risk of these complications. 

In order to maintain the traceability of the product and to patients benefit, it is recommended that the name and lot number of the product are recorded in order to maintain a link between the patient and the lot of the product.  

Special warnings about excipients: This medicinal product contains 4.14 mg of sodium per ml. This should be taken into account by patients on a controlled sodium diet who receive high doses of Factor IX Grifols. 

No interactions of human coagulation factor IX products with other medicinal products are known.

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

The influence of Factor IX Grifols on the ability to drive and use machines is null or negligible. 

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently in patients treated with factor IX-containing products. 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 section 4.4).

Factor IX Grifols experience in the treatment of previously untreated patients is limited. 

Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.

On rare occasions, fever has been observed.

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. 

There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX 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 side effects.

For safety with respect to transmissible agents see section 4.4.

To report any side effect(s):

• Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

• Other GCC States:

Please contact the relevant competent authority.

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

Pharmacotherapeutic Group: Antihaemorrhagics: 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 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 level of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

There are insufficient data from clinical trials in children less than 6 years of age.

According to data of the clinical trial performed with Factor IX Grifols in 25 patients, the recovery was 1.3 ± 0.3 IU/dl:IU/kg and the terminal half-life 26.7 ± 3.8 h (19.3 - 34.5) using a noncompartimental model. The mean residence time values were 32.2 ± 4.9 h (24.7 - 43.1), clearance 3.6 ± 0.9 ml/min/kg (1.9 – 6.1) and area under the curve  18.5 ± 4.9 IU x h/ml (10.7 – 30.2). These pharmacokinetic results were obtained after an infusion of 65 - 75 UI/kg.

Human plasma coagulation factor IX (which constitutes Factor IX Grifols) is a normal constituent of the human plasma and acts like the endogenous factor IX.

Single dose toxicity testing in rats and mice set a safety margin higher than 20. 

Repeated dose toxicity testing in animals is impractical due to interference with developing antibodies to heterologous proteins.

Thrombogenicity tests in rabbits and rats failed to show any evidence of thrombogenicity at doses of 200 - 300 IU/kg body weight.

Factor IX Grifols must not be mixed with other medicinal products. 

Only the provided infusion set 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 (2ºC to 8ºC). 

Keep the container in the outer carton in order to protect from light.

When its ambulatory administration is suitable, the product may be kept at room temperature (do not store above 25 ºC) during a single period of maximum 3 months.

The product must not be refrigerated again after being kept at room temperature. 

Factor IX Grifols is a highly purified lyophilised factor IX concentrate that is supplied in single vials containing nominally 250 IU, 500 IU, 1000 IU or 1500 IU. The product is supplied in Type II glass vials closed with bromo-butyl rubber stoppers, aluminium crimp seal and plastic cap.

Each vial of Factor IX Grifols of the presentations of 250 IU/5 ml, 500 IU/10 ml and 1000 IU/20 ml is supplied with a prefilled syringe with solvent containing 5 ml, 10 ml or 20 ml of water for injections, along with the accessories for reconstitution and administration (vial adaptor, filter, 2 alcohol swabs and butterfly needle). 

Each vial of Factor IX Grifols of the presentation of 1500 IU/30 ml is supplied with a solvent vial containing 30 ml of water for injections, along with the accessories for reconstitution and administration (double-ended needle, filter, 2 alcohol swabs, butterfly needle and syringe with needle). 

Not all pack sizes may be marketed.

Pack size: 1 lyophilised vial, 1 syringe pre-filled/vial with solvent and accessories.

For reconstitution and administration of Factor IX Grifols, presentations of 250 IU/5 ml, 500 IU/10 ml and 1000 IU/20 ml, where the solvent is supplied in prefilled syringes, the preparation of the solution is as follows: 

1. Warm the vial and solvent syringe but not above 37 ºC.
2. Attach plunger to syringe containing solvent.
3. Remove filter from packaging. Remove cap from solvent syringe tip and attach to the filter. 
4. Remove vial adaptor from packaging and attach to syringe and filter. 
5. Remove cap from vial and wipe stopper with alcohol swab provided.
6. Pierce vial stopper with adaptor needle. 
7. Transfer all solvent from syringe to vial. 
8. Gently swirl vial avoiding foam until all product is dissolved. Do not shake. 
9. Separate the syringe/filter from vial/adaptor. Pull back the plunger to draw a volume of air similar to the total volume of solution. Rejoin the syringe/filter to vial/adaptor. 
10. Invert vial and aspirate solution into the syringe. 
11. Separate syringe and administer the solution slowly intravenously using the butterfly needle provided at a rate of 3 ml/min. 

For reconstitution and administration of Factor IX Grifols, presentation of 1500 IU/30 ml, where the solvent is supplied in vials, the preparation of the solution is as follows: 

1. Warm the vials but not above 37 ºC.
2. Remove cap from solvent vial and wipe stopper with alcohol swab provided.
3. Remove the double-ended needle from package. Separate one of the caps that protect the points and pierce the solvent vial cap. 
4. Remove the lyophilised product vial and wipe the stopper with the alcohol swab. 
5. Remove cap from the other point of the needle. 
6. Turn the vial upside down and pierce the vial of the lyophilisate, assuring that all solvent is transferred and avoiding vacuum loss. 
7. Separate the solvent flask with the double-ended needle.  Gently swirl the vial avoiding foam until all product is dissolved. Do not shake. 
8. Remove filter from blister and insert in the syringe, reload the syringe with air enough for the total volume of the solution. Insert the needle in the filter and pierce the vial of the reconstituted product. Inject the preload air in the syringe, through the filter, to immediately after turn the vial upside down and vacuum the syringe contents. 
9. Remove the filter-needle packaging and administer slowly intravenously using the butterfly needle provided at a rate of 3 ml/min.

Any unused product or waste material should be disposed of in accordance with local requirements.

The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.

Reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.