AlphaNine^®

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, 1000 or 1500 I.U. Human Coagulation Factor IX per container.

AlphaNine^® 500 I.U. contains approximately 50 I.U./ml Human Coagulation Factor IX when reconstituted with 10 ml Sterile Water for Injections, Ph. Eur.

AlphaNine^® 1000 I.U. contains approximately 100 I.U./ml Human Coagulation Factor IX when reconstituted with 10 ml Sterile Water for Injections, Ph. Eur.

AlphaNine^® 1500 I.U. contains approximately 150 I.U./ml Human Coagulation Factor IX when reconstituted with 10 ml Sterile Water for Injections, Ph. Eur.

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

Each container is labelled with the number of International Units of Factor IX activity.

The product may contain clinically irrelevant levels of Factor II, Factor VII and Factor X.

For excipients see section 6.1.

Powder and solvent for solution for injection.

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

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 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 (I.U.), 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 (I.U.) 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 (I.U.) Factor IX per kg bodyweight raises the plasma Factor IX activity by about 1.0% of normal activity. The required dosage is determined using the following formula:

Required Units = Bodyweight (kg) x desired Factor IX rise (%) x 1.0 I.U./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.

The following table can be used to guide dosing in bleeding episodes and surgery. It is recommended that the Factor IX activity should not fall below the given plasma activity level in % of normal (I.U./dl) in the corresponding period.

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 I.U. 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.

Currently there are insufficient data to recommend the use of AlphaNine^® 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 4.4.

Method of administration

Dissolve the preparation as described in section 6.6. The product should be administered slowly by intravenous injection or infusion. The injection speed should not exceed 10 ml per minute.

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

As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. The product contains traces of human proteins other than Factor IX (Factor II, Factor VII and Factor X). 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 are to be observed.

When medicinal products prepared from human blood or plasma are administered, infectious diseases due to the transmission of infective agents cannot be totally excluded. This also applies to pathogens of hitherto unknown nature. The risk of transmission of infective agents is however, reduced by:

· Selection of donors by a medical interview and screening of individual donations and plasma pools for HBsAg and antibodies to HIV and HCV;

· Testing plasma pools for HCV genomic material;

· Removal/inactivation procedures included in the production process that have been validated using model viruses and are considered effective for HBV, HCV and HIV.

The viral inactivation/removal procedures may be of limited value against non-enveloped viruses such as HAV and/or Parvovirus B19 and other transmissible agents.

Appropriate vaccination (hepatitis A and B) for patients receiving plasma-derived Factor IX concentrates is recommended.

Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased red cell production (e.g. haemolytic anaemia).

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 neonates, 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.

In the interest of patients, it is recommended that, whenever possible, every time AlphaNine^® is administered to them, the name and batch number of the product is recorded.

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 breast-feeding is not available. Therefore, Factor IX should be used during pregnancy and lactation only if clearly indicated.

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

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 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.

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 lower 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 information on viral safety see 4.4.

No symptoms of overdose with Human Coagulation Factor IX have been reported.

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 to thrombin. Thrombin 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.

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 I.U. 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 halflife 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.I.U.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.

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 I.U. 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.

Heparin

Dextrose

Sodium hydroxide

Hydrochloric acid

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.

AlphaNine^® has a shelf life of 30 months when stored in a refrigerator (2 ºC - 8 ºC), protected from light.

Storage at no more than 30 ºC for 3 months within this period is acceptable.

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

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

AlphaNine^® is a white to slightly yellow freeze-dried powder containing 500, 1000 or 1500 I.U. of Factor IX.

The glass containers are made of Type I glass and closed with grey butyl rubber stoppers, aluminium crimp seal (bearing the lot number) and plastic “flip-off” dust cover.

Each vial of AlphaNine^® 500, 1000 or 1500 I.U. 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 adapter, filter, butterfly needle and two alcohol swabs.

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

Check assay value on label carefully before use.

Use aseptic technique during reconstitution and administration.

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

Solution preparation:

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

AlphaNine^® 500 I.U. PL 12930/0012

AlphaNine^® 1000 I.U. PL 12930/0013

AlphaNine^® 1500 I.U. PL 12930/0014

10 December 2003

January 2006