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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

BETAFACT 50 IU/ml, powder and solvent for solution for injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of BETAFACT 50 IU/ml contains nominally 250 IU, 500 IU or 1000 IU human coagulation factor IX.

After reconstitution of BETAFACT 50 IU/ml with 5, 10 or 20 ml of water for injections, each ml contains approximately 50 IU of human coagulation factor IX (250 IU/5 ml, 500 IU/10 ml, 1000 IU/20 ml).

The potency (IU) is determined using the European Pharmacopoeia one-stage clotting test.

The specific activity of BETAFACT is approximately 110 IU/mg protein.

Produced from the plasma of human donors.

Excipients with known effect: sodium, heparin. See section 4.4.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

4.2 Posology and method of administration

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

Posology

The 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.

For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kilogram 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.

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, demonstrating different half-lives and recoveries.

Previously untreated _patients

Currently available data are described in section 4.8 but no recommendation on a posology can be made.

Paediatric _ population

In a clinical trial, 13 children less than 6 years old have been treated with BETAFACT, for them the dosage is similar to that administered in adults (see also sections 4.4, 5.1 and 5.2). 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. If the inhibitor is present at levels less than 10 Bethesda Units (BU) per ml, administration of additional human coagulation factor IX may neutralise the inhibitor. In patients with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin complex concentrate (aPCC) or activated factor VII (FVIIa) has to be considered. These therapies should be directed by physicians with experience in the care of patients with haemophilia.

Method of administration Intravenous use.

It is recommended that factor IX should not be administered at a flow rate in excess of 4 ml/minute.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, notably to heparin or to its derivatives, including the Low Molecular Weight Heparin (LMWH).

Past history of serious type II heparin-induced thrombocytopenia (HIT).

4.4 Special warnings and precautions for use

Hypersensitivity

Allergic type hypersensitivity reactions are possible with BETAFACT. The product contains traces of human proteins other than factor IX. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician.

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, standard medical treatment for shock should be implemented.

Inhibitors

After repeated treatment with human 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 with factor IX. Because of the risk of allergic reactions with factor IX concentrates products, the initial administrations of human coagulation factor IX should, according to the treating physician’s judgement, be performed under medical observation where proper medical care for allergic reactions could be provided. Thromboembolism

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 disseminated intravascular coagulation (DIC). In each of these situations, the benefit of treatment with BETAFACT should be weighed against the risk of these complications. Transmissible agents

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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). The measures taken may be of limited value against non-enveloped viruses such as hepatitis A virus (HAV) and 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/repeated receipt of human plasma derived factor IX products.

It is strongly recommended that every time that BETAFACT 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 medicinal product. Excipients with known effect

BETAFACT contains sodium. This medicine contains around 2.6 mg of sodium per ml of substance (13 mg or 0.56 mmol per 1 vial BETAFACT 250 IU/5 ml - 26 mg or 1.13 mmol per 1 vial BETAFACT 500 IU/10 ml - 52 mg or 2.26 mmol per 1 vial BETAFACT 1000 IU/20 ml). This should be taken into account by patients following a strict low sodium diet.

This medicine contains heparin and can cause allergic reactions and serious immune type II thrombocytopenia (HIT) and coagulation disorders.

Paediatric population

Clinical results collected in previously untreated patients and children below 6 years are limited but consistent with those of older patients. The listed warnings and precautions apply both to adults and children.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions of human coagulation factor IX products with other medicinal products have been reported.

4.6 Fertility, pregnancy and lactation

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 breast-feeding is not available. Therefore, factor IX should be used during pregnantcy and lactationg only if clearly indicated.

4.7 Effects on ability to drive and use machines

BETAFACT has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile (class effect):

The effects specified in the summary of the safety profile have been described during administration of factors IX products.

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 rarely 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 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) 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 such as BETAFACT is rarely associated with such adverse reactions.

For safety information with respect to transmissible agents, see section 4.4. Tabulated list of adverse reactions

During clinical studies conducted with BETAFACT 50 IU/ml and BETAFACT 100 IU/ml, 17 adverse reactions have been reported in 8/109 (7.3%) patients who received a total of 8054 treatment days.

The most significant reactions are reported in the listing below according to the MedDRA classification (System Organ Class and Preferred Term Level). Most concern ‘immune system disorders’ and ‘general disorders and administration site conditions’ and have been observed rarely.

The frequency of adverse event occurrence has been estimated on a per-exposure day basis according 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)._

Previously untreated patients :

In one clinical study, 11 previously untreated patients were treated with BETAFACT. Total exposure to BETAFACT was 662 exposure days. No inhibitors have been reported.

On all clinical studies, none of the 14 patients (including 6 previously untreated patients) with severe haemophilia B (FIX < 1%) and exclusively treated with BETAFACT has developed factor IX inhibitor. The median number of exposure days at the last visit was 63 days (range 5-205) with a minimum follow-up of 8 months.

Two cases of activity-neutralizing antibodies (inhibitors) in one previously untreated patient and in one previously treated patient have been reported with BETAFACT in the post-marketing period.

Paediatric population:

Among the 109 patients included in the safety analysis, 44 were less than 12 years, including 24 under the age of 6 at the first injection.

Frequency, type and severity of adverse reactions in children are not different from those observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 ‘national reporting system’.

4.9 Overdose

No case of overdose has been reported.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 synthesised 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 levels of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Paediatric population

In a clinical study, 13 children aged less than 6 years old (out of them 10 were previously untreated patients) have been treated with BETAFACT. The median dose per exposure day for treatment: minor bleeding episodes or prophylaxis was between 37    and    39    IU    /    kg    body    weight.

In a post-marketing study, 11 children between 6 and 12 years received BETAFACT at a dose similar to that administered in 31 patients aged between 12 and 65 years.

5.2 Pharmacokinetic properties

A pharmacokinetic study with BETAFACT was carried out in 11 haemophilia B patients over 12 years of age. Each patient received an intravenous bolus dose of BETAFACT containing 60 IU of FIX:C/kg bodyweight. The analysis of plasma samples was conducted in a central laboratory using a one-stage clotting assay. Pharmacokinetic parameters are summarised below:

-    The plasma peak of factor IX usually occurs between 15 and 30 minutes after injection.

-    The mean incremental recovery is 1.08 ± 0.21 IU/dl per IU/kg bodyweight.

-    The area under the curve 0A» is equivalent to 1888 ± 387 IU.h/dl .

-    The mean residence time is 44.2 ± 4.9 h.

-    The terminal half-life is 33 ± 4 hours.

-    The clearance is 3.3 ± 0.5ml/h/kg.

Paediatric population

There is limited documentation of pharmacokinetic profile in paediatric patients. The incremental recovery determined from 8 children between 6 and 11 years of age is similar to adolescents and adults. The mean incremental recovery determined from 8 children less than 6 years of age tends to be lower than other age groups (0.72 ± 0.17 IU/dl per IU/kg bodyweight). Due to limited experience close monitoring of factor IX levels is advised to guide the dose and the frequency of repeated infusion.

5.3 Preclinical safety data

The factor IX contained in this preparation is a normal constituent of human plasma and behaves in the same manner as endogenous factor IX.

No reproduction studies have been performed in animals.

The available preclinical data (Ames test) do not suggest any mutagenic effects from human coagulation factor IX. A local tolerability study in rabbits demonstrated that human coagulation factor IX was well tolerated using an intravenous administration and even tolerated in the case of an accidental perivenous or intra-arterial administration.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder: sodium chloride, sodium heparin, lysine hydrochloride, arginine, sodium citrate.

Solvent: water for injections.

6.2 Incompatibilities

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

Only polypropylene 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 injection/infusion equipment.

6.3    Shelf life

30 months.

Reconstituted solution: this medicinal product should be used immediately. However, chemical and physical in-use stability has been demonstrated for 3 hours at +25°C.

6.4    Special precautions for storage

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

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

For the purpose of ambulatory use, before opening, the product may be taken out of the refrigerator, without being replaced, for a maximum period of 6 months at a temperature not above 25°C.

The date when the medicine is taken out and the new expiry date should be written on the outer packaging. This new expiry date should never exceed the one initially mentioned on the outer carton. If the medicine has not been used before the new expiry date, it should be disposed of.

6.5 Nature and contents of container

Powder in a vial (glass type I) + 5 ml of solvent in a vial (glass type II) with a transfer system and a filter needle - pack size of 1.

Powder in a vial (glass type I) + 10 ml of solvent in a vial (glass type II) with a transfer system and a filter needle - pack size of 1.

Powder in a vial (glass type I) + 20 ml of solvent in a vial (glass type II) with a transfer system and a filter needle - pack size of 1.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Reconstitution:

Use current guidelines for aseptic procedure.

•    If necessary, bring the two vials (powder and solvent) to ambient temperature.

•    Remove the protective cap from the solvent vial (water for injections) and from the powder vial.

•    Disinfect the surface of each stopper.

•    Remove the translucent protective sheath from the transfer system and completely insert the exposed needle through the centre of the stopper of the solvent vial while simultaneously twisting the needle.

•    Remove the second protective sheath from the other end of the transfer system.

•    Keeping both vials horizontal (vented spike pointing upwards), quickly push the free end of the needle into the centre of the stopper of the powder vial.

•    Ensure that the needle always remains immersed in the solvent to avoid releasing the vacuum prematurely.

•    Immediately place the system upright in a vertical position, keeping the solvent vial directly above the powder vial, to allow the solvent to transfer into the powder.

•    During the transfer, direct the jet of solvent over the whole surface of the powder. Ensure that all of the solvent is transferred.

•    The vacuum is automatically released at the end of the transfer procedure (sterile air).

•    Remove the empty vial (solvent) with the transfer system.

•    Gently swirl for a few minutes with a rotating movement to avoid the formation of foam until the powder has completely dissolved.

•    The powder generally dissolves instantaneously and should be completely dissolved in less than 5 minutes.

•    Draw the product into a sterile syringe using the filter needle provided.

•    Remove the needle from the syringe.

Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.

Administration:

Once reconstituted, the solution must be administered immediately, intravenously, as a single dose. Connect the syringe to an intravenous or epicranial needle; expel the air from the syringe, disinfect the skin and inject into the vein.

Inject slowly, intravenously, as a single dose immediately after reconstitution, without exceeding a flow rate of 4 ml/minute.

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

7 MARKETING AUTHORISATION HOLDER

LFB-BIOMEDICAMENTS

3, avenue des Tropiques - BP 305 - LES ULIS - 91958 Courtaboeuf Cedex -FRANCE

Telephone: + 33 1 69 82 70 10

8 MARKETING AUTHORISATION NUMBER(S)

PL 28315/0001 PL 28315/0002 PL 28315/0003 PL 28315/0004

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/06/2009

10    DATE OF REVISION OF THE TEXT

14/05/2014