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Alphanine 500 I.U. Powder And Solvent For Solution For Injection

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

AlphaNine® 500 I.U., powder and solvent for solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

AlphaNine® is a high purity solvent-detergent treated and nanofiltered preparation of human coagulation factor IX, freeze-dried, Ph. Eur.

AlphaNine® is presented as a powder and solvent for solution for injection with nominally 500 IU human coagulation factor IX per container.

AlphaNine® 500 IU contains approximately 50 IU/ml human coagulation factor IX when reconstituted with 10 ml sterile water for injections, Ph. Eur.

The potency (IU) is determined using the European Pharmacopoeia one-stage clotting test. The specific activity of AlphaNine® is approximately 150 IU factor IX per mg of total protein.

Excipient(s) with known effect:

AlphaNine® contains 1.3 to 3.0 mmol sodium per 10 ml (syringe).

AlphaNine® contains small amounts of heparin.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Solvent (Water for Injections, PL 4447/0016).

Vial containing white or pale yellow powder and syringe with water for injections (solvent).

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 dosage 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. The calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg bodyweight raises the plasma factor IX activity by about 1% of normal activity. The required dosage is determined using the following formula:

Required Units = Bodyweight (kg) x desired factor IX rise (%) x 1.0 IU/kg

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 or IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

Degree of haemorrhage/ Type of surgical procedure

Factor IX level required (%) (IU/dL)

Frequency of doses (hours)/ Duration of therapy (days)

Haemorrhage

Early haemarthrosis, muscle bleeding or oral bleeding

20 - 40

Repeat every 24 hours. 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 disability are resolved.

Life threatening haemorrhages

60 - 100

Repeat infusion every 8 to 24 hours until threat is resolved.

Surgery

Minor

including tooth extraction

30 - 60

Every 24 hours, at least 1 day, until healing is achieved.

Major

80 - 100 (pre- and postoperative)

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).

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 kilogram of bodyweight at intervals of 3 to 4 days.

In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

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.

Paediatric population

The safety and efficacy of AlphaNine® in children aged less than 6 years has not been established. No data are available.

See section 4.4.

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6. The product should be administered slowly via the intravenous route. The injection speed should not exceed 10 ml per minute.

4.3


Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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, generalised 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 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 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 AlphaNine® 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.

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, the initial administrations of 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.

Since the use of factor IX concentrates has historically been associated with the development of thromboembolic complications, the risk being higher in low purity preparations, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and 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 AlphaNine® should be weighed against the risk of these complications.

Special warnings about excipients:

AlphaNine® contains 1.3 to 3.0 mmol sodium per 10 ml (syringe). This should be taken into account by patients on a controlled sodium diet.

AlphaNine® contains small amounts of heparin. Heparin may cause allergic reactions and reduced platelet 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.

4.5    Interaction with other medicinal products and other forms of interaction

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

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 pregnancy and lactation only if clearly indicated.

4.7    Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed.

4.8    Undesirable effects

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 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).

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 as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. Currently there is not enough information available to determine the incidence of inhibitor formation with AlphaNine®.

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 AlphaNine® is rarely associated with such side effects.

For safety with respect to transmissible agents see section 4.4.

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

4.9    Overdose

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

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic Group: Anti-haemorrhagics: 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 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.

5.2    Pharmacokinetic properties

In a randomised, double blind, cross-over study, the pharmacokinetics of AlphaNine® were compared with a non virus-filtered version of the same product. Haemophilia B patients (< 1 IU factor IX/dl) were dosed to achieve peak plasma factor IX levels of about 50 units/dl. Blood samples were withdrawn up to 72 hours post-infusion. The median half-life for AlphaNine® was 21.3 hours and the mean in vivo recovery was 58.8%. After adjustment for the dose infused, the mean AUC was determined as 1293.7 h.IU.dl. The mean residence time for AlphaNine® was calculated as 28.14 hours and the clearance was 3.27 dl/h. Comparison of these values for AlphaNine® against published data indicate that these results are comparable with the values specified in the literature.

Depending on the degree of bleeding, injury or tissue damage the biological half-life may decrease. This has to be taken into account when determining the dosage.

5.3    Preclinical safety data

Human plasma coagulation factor IX is a normal constituent of human plasma and has the same activity as endogenous factor IX.

Doses of a few times the recommended human dosage per kg bodyweight do not show any toxic effects in experimental animals. Single dosage toxicity examination is not appropriate because the high doses necessary result in fluid overload.

Thrombogenicity of AlphaNine® in animals is markedly lower that that of factor IX complex. AlphaNine® failed to show any evidence of thrombogenicity when tested directly in the Wessler rabbit stasis model for thrombogenicity at a dose of 200 IU factor IX/kg bodyweight.

Repeated dosage toxicity examination in experimental animals is impractical because of interference from the development of antibodies against heterologous proteins.

As clinical experience does not give any indications of carcinogenic or mutagenic effects of human coagulation factor IX, experimental studies, in particular in heterologous species, are not considered necessary.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Heparin

Dextrose

Sodium hydroxide Hydrochloric acid

6.2    Incompatibilities

AlphaNine® should not be mixed with other medicinal products. Only the injection/infusion sets provided should be used because treatment failure can occur as a consequence of adsorption of factor IX to the internal surfaces of some injection/infusion equipment.

6.3    Shelf life

AlphaNine® has a shelf life of 3 years when stored in a refrigerator (2 °C - 8 °C), protected from light.

Storage at no more than 30 °C for 1 month within this period is acceptable.

AlphaNine® does not contain any preservative and should be administered immediately after reconstitution.

6.4    Special precautions for    storage

Store in a refrigerator (2 °C - 8 °C). Do not freeze. Protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

AlphaNine is supplied in Type I glass vials containing nominally 500 IU of factor IX and closed with rubber stoppers, aluminium crimp seal and plastic cover.

Each vial of AlphaNine® 500 IU is supplied with a Type I glass syringe containing 10 ml of water for injections Ph. Eur. (solvent).

The accessories supplied with AlphaNine® for reconstitution and administration of the product are: vial adaptor, filter, two alcohol swabs and butterfly needle.

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

6.6 Special precautions for disposal

Do not use after the expiry date shown on the vial label.

Use aseptic technique during reconstitution and administration.

Left-over product must never be stored for later use, nor stored in a refrigerator.

To prepare the solution:

1.    Warm the vial and syringe but not above 30 °C

2.    Attach plunger to syringe containing solvent.

3.    Remove filter from packaging. Remove cap from syringe tip and attach syringe to filter.

4.    Remove vial adaptor from packaging and attach to syringe and filter.

5.    Remove cap from vial and wipe stopper with swabs provided.

6.    Pierce vial stopper with adaptor needle.

7.    Transfer all solvent from syringe to vial.

8.    Gently shake vial until all product is dissolved. As with other parenteral solutions, do not use if product is not properly dissolved or particles are visible.

9.    Briefly separate the syringe/filter from vial/adaptor to release the vaccum.

10.    Turn the vial upside down and draw the solution into the syringe.

11.    Prepare injection site, separate syringe and inject product using the butterfly needle provided.

Administer slowly at a rate not exceeding 10 ml/minute.

After reconstitution with the water for injections solvent provided, the product should be used immediately.

Do not re-use the administration sets.

Any unused medicinal 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.

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MARKETING AUTHORISATION HOLDER

Instituto Grifols, S.A. Can Guasch, 2 - Parets del Valles 08150 Barcelona - SPAIN


MARKETING AUTHORISATION NUMBER(S)

AlphaNine® 500 IU PL 12930/0012 Water for injections PL 4447/0016


DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 December 2003


DATE OF REVISION OF THE TEXT

03/06/2015