Alphanate^®, powder for injection.

Alphanate^® is a high purity solvent detergent and heat treated preparation of human coagulation factor VIII, freeze-dried, Ph. Eur. Alphanate^® also contains human von Willebrand factor at pharmacologically effective levels.

Alphanate^® is presented as a powder and solvent for solution for injection containing nominally 500 I.U., 1000 I.U. or 1500 I.U. human coagulation factor VIII per container. Alphanate^® contains no less than 400 I.U. of von Willebrand factor activity per 1000 I.U. of factor VIII activity (i.e. VWF:RCo/FVIII:C ratio 0.4).

Alphanate^® 500 I.U. contains approximately 100 I.U./ml human coagulation factor VIII and no less than approximately 40 I.U./ml human von Willebrand factor activity when reconstituted with 5 ml sterile Water for Injections, Ph. Eur.

Alphanate^® 1000 I.U. contains approximately 100 I.U./ml human coagulation factor VIII and no less than approximately 40 I.U./ml human von Willebrand factor activity when reconstituted with 10 ml sterile Water for Injections, Ph. Eur.

Alphanate^® 1500 I.U. contains approximately 150 I.U./ml human coagulation factor VIII and no less than approximately 60 I.U./ml human von Willebrand factor activity when reconstituted with 10 ml sterile Water for Injections, Ph. Eur.

Each container is labelled with the number of International Units of factor VIII and von Willebrand factor activity.

The factor VIII potency is determined using the Activated Partial Thromboplastin Time method, which gives results comparable to the European Pharmacopoeia chromogenic assay, and a reference standard calibrated against the WHO International Standard (FVIII:C I.U.).

The von Willebrand factor potency is determined by measuring the Ristocetin Cofactor Activity using a reference standard calibrated against the WHO International Standard (VWF:RCo I.U.).

The specific activity of Alphanate^®, prior to the addition of albumin, is greater than 100 I.U. factor VIII/mg protein and, as finished product, is greater than 5 I.U. factor VIII/mg protein.

For a full list of excipients see section 6.1.

Powder for injection.

Solvent (Water for Injections).

Vial containing white or pale yellow powder and syringe with Water for Injections (solvent).

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

Prevention and treatment of haemorrhage or surgical bleeding in patients with von Willebrand disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or contra-indicated.

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

Posology

Factor VIII deficiency

The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.

The number of units of factor VIII administered is expressed in International Units (I.U.), which are related to the current WHO standard for factor VIII products. Factor VIII 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 VIII in plasma).

One International Unit (I.U.) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that 1 International Unit (I.U.) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2% of normal activity. The required dosage is determined using the following formula:

Required Units = Body weight (kg) x desired factor VIII rise (%) (I.U./dl) x 0.5

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 VIII activity should not fall below the given plasma activity level (in % of normal or I.U./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 VIII 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 VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 I.U. of factor VIII per kg of body weight at intervals of 2 to 3 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 VIII inhibitors. If the expected factor VIII 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 VIII inhibitor is present. In patients with high levels of inhibitor, factor VIII 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.

Von Willebrand disease

Generally, 1 I.U./kg VWF:RCo raises the circulating level of VWF:RCo by 2%. Levels of VWF:RCo of> 0.6 I.U./ml (60%) and of FVIII:C of> 0.4 I.U./ml (40%) should be achieved.

Usually 40 - 80 I.U./kg of von Willebrand factor (VWF:RCo) and 20 - 40 I.U./kg of FVIII:C are recommended to achieve haemostasis.

An initial dose of 80 I.U./kg of von Willebrand factor may be required, especially in patients with type 3 von Willebrand disease where maintenance of adequate levels may require greater doses than in other types of von Willebrand disease.

An appropriate dose should be re-administered every 12 - 24 hours. The dose and duration of the treatment depend on the clinical status of the patient, the type and severity of bleeding, and both VWF:RCo and FVIII:C levels.

When using a FVIII-containing von Willebrand factor product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. After 24 - 48 hours of treatment, reduced doses and/or prolongation of the dose interval or the use of a VWF product containing a low level of FVIII should be considered.

There are insufficient data to recommend the use of Alphanate^® in children less than 6 years of age for the authorised indications.

Method of administration

Dissolve the preparation as described in section 6.6. The product should be administered via the intravenous route. 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 VIII. 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 HIV, HBV and HCV. The measures taken may be of limited value against non-enveloped viruses such as 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 receipt of human plasma-derived factor VIII products.

The formation of neutralising antibodies, inhibitors, to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda units (BU) per ml of plasma using Nijmegen's modified assay. The risk of developing inhibitors is correlated to the exposure to antihaemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. See also section 4.8 Undesirable effects.

Reports in the literature suggest that patients with Type 3 (severe) von Willebrand Disease may occasionally develop alloantibodies to von Willebrand factor.

It is strongly recommended that every time that Alphanate^® 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.

No interactions of human coagulation factor VIII or von Willebrand factor products with other medicinal products are known.

Animal reproduction studies have not been conducted with Alphanate^®.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of human coagulation factor VIII during pregnancy and breast-feeding is not available.

There is no data from a clinical study regarding the use of von Willebrand factor in pregnant or lactating women.

Therefore, Alphanate^® should be used during pregnancy and lactation only if clearly indicated.

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

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).

On rare occasions, fever has been observed.

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. 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 no data available regarding the development of inhibitors in previously untreated patients treated with Alphanate^®.

Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to von Willebrand factor. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies may occur in close association with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor. In such cases, it is recommended that a specialised haemophilia centre be contacted.

When using this product for patients with von Willebrand disease, there is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors.

In patients receiving factor VIII-containing von Willebrand factor products sustained excessive FVIII:C levels may increase the risk of thrombotic events.

For information on transmissible agents safety, see section 4.4.

No symptoms of overdose with human coagulation factor VIII and/or von Willebrand factor have been reported. Thromboembolic events may occur in case of major overdose.

Pharmacotherapeutic Group: Anti-haemorrhagics: blood coagulation factors, ATC code: B02BD06.

In Alphanate^®, factor VIII is presented as a complex with von Willebrand factor.

The factor VIII / von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions.

Factor VIII deficiency

When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII 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 VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Von Willebrand disease

Alphanate^® behaves in the same way as endogenous von Willebrand factor.

Administration of von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from von Willebrand factor deficiency (von Willebrand disease) at two levels:

- Von Willebrand factor re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds both to the vascular sub-endothelium and to the platelet membrane), providing primary haemostasis as shown by the shortening of the bleeding time. This effect occurs immediately and is known to depend to a large extent on the level of polymerisation of the protein;

- Von Willebrand factor produces delayed correction of the associated factor VIII deficiency. Administered intravenously, von Willebrand factor binds to endogenous factor VIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation.

Administration of a FVIII:C containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

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

Haemophilia A

In an open, randomised, crossover study, the pharmacokinetics of Alphanate^® were compared with the non heat-treated version of the same product. Haemophilia A patients (< 3 I.U. factor VIII/dL) were dosed to achieve peak plasma factor VIII levels of about 100 units/dL. Blood samples were withdrawn up to 28 hours post-infusion. The median half-life for Alphanate^® was 12.2 hours and the mean in vivo recovery was 86.5%. In these studies the mean AUC was 895 I.U. h/dL, the mean residence time was 9.9 hours and the clearance was 4.4 mL/h/kg.

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.

Von Willebrand Disease

A pharmacokinetic study of Alphanate^® was conducted in 18 non-bleeding subjects with von Willebrand Disease (3 Type 1, 3 Type 2A, and 12 Type 3). Subjects received a single intravenous dose of Alphanate^® at 60 VWF:RCo I.U./kg (75 VWF:RCo I.U./kg in subjects younger than 18 years of age). Blood samples were withdrawn up to 48 hours post-infusion. The mean plasma levels of VWF:RCo rose from 12.3 ± 4.8% at baseline to 206.0 ± 98.7% 15 minutes post-infusion, mean plasma levels of FVIII:C rose from 23.2 ± 31.2% to 215.4 ± 86.3%, and mean plasma levels of VWF:Ag rose from 13.0 ± 20.0% to 325.1 ± 133.9%. The mean skin bleeding time prior to infusion was 29.1 ± 3.9 minutes, which shortened to 10.4 ± 3.1 minutes 1 hour post-infusion. Similar results were observed in the subset of 12 subjects with Type 3 VWD.

The mean half-lives for VWF:RCo, FVIII:C, and VWF:Ag were 7.5 ± 3.2 hours, 21.5 ± 7.2 hours, and 13.0 ± 2.1 hours, respectively, and the mean incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.1 ± 1.5% / VWF:RCo I.U./kg and 2.2 ± 0.6% / VWF:RCo I.U./kg, respectively.

For VWF:RCo, FVIII:C and VWF:Ag, mean AUC was 1737, 5022 and 4891%*hr respectively; mean residence time was 10.7, 31.6 and 18.7 hours, respectively; and clearance was 0.05, 0.01 and 0.01 (I.U./kg) / (%*hr) respectively.

Following infusion of Alphanate^® there was a predictable increase in the size of von Willebrand factor multimers, which persisted for at least 24 hours. The shortening of the bleeding time was transient, generally lasting less than 6 hours following treatment.

Human plasma coagulation factor VIII and von Willebrand factor (active ingredients for Alphanate^®) are normal constituents of human plasma and act like the corresponding endogenous proteins.

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.

Albumin

Histidine

Arginine

Water for Injections Ph. Eur. (Solvent)

Alphanate^® should not be mixed with other medicinal products.

Only the provided infusion set should be used because treatment failure can occur as a consequence of FVIII/VWF complex adsorption to the internal surfaces of some infusion equipment.

Lyophilised Alphanate^® has a shelf life of 24 months at 2 °C – 8 °C.

Storage at no more than 30 °C for 6 months within this period is acceptable.

Reconstituted Alphanate^® has a shelf life of 3 hours at 25 °C.

Lyophilised Alphanate^® should be stored in a refrigerator (2 °C – 8 °C), protected from light. Do not freeze.

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

Alphanate^® is a white to slightly yellow freeze dried powder containing 500, 1000 or 1500 I.U. of factor VIII (nominal) and no less than 400 I.U. of von Willebrand factor activity per 1000 I.U. of factor VIII activity. 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 Alphanate^® is supplied with a Type I glass syringe containing 5 ml (for the presentation of 500 I.U. factor VIII) or 10 ml (for the presentations of 1000 and 1500 I.U. factor VIII) of Water for Injections Ph. Eur. (PL 4447/0016).

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

Not all pack sizes may be marketed.

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 vacuum.

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. Injection rate should be 3 ml/min into a vein and never more than 10 ml/min to avoid vasomotor reactions.

After reconstitution with the Water for Injections solvent provided, the product should be used immediately.

Do not re-use the administration sets.

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.

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

PL 12930/0015

10 December 2003

03/2009