Dried Factor Viii Fraction Type 8y 25 Iu/Ml Powder For Solution For Injection

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dried Factor VIII Fraction, Type 8Y®, 25 IU/mL powder for solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Dried Factor VIII Fraction, Type 8Y®, is presented as a powder for injection containing nominally 250 IU or 500 IU of FVIII per vial. The vials also contain at least 260 IU or 520 IU von Willebrand Factor.

The product contains approximately 25 IU/mL human coagulation factor VIII per mL (measured by activity assay) and at least 26 IU/mL human von Willebrand Factor (measured by VWF:RCo) when reconstituted with 10 mL (250 IU) or 20 mL (500 IU) of Sterilised Water for Injections, (Ph.Eur.).

The FVIII potency is determined using the European Pharmacopoeia chromogenic assay. The specific activity of FVIII in 8Y® is not less than 2 IU/mg protein.

The VWF potency (IU) is measured according to Ristocetin Cofactor activity (VWF:RCo), and ELISA antigen method, compared to an in-house standard calibrated against the International Standard for von Willebrand Factor concentrate (WHO). The ratio of FVIII to VWF antigen is approximately 1 IU:3 IU. The specific activity of VWF:RCo in 8Y® is not less than 2 IU/mg protein.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

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

4.2 Posology and method of administration

Posology

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

Haemophilia A

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 (IU), 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 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 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2.5% of normal activity 2.5 IU/dL. The required dosage is determined using the following formula:

Required units = body weight (kg) desired factor VIII 0.5

rise (%) (IU/dL)

The amount to be administered and the frequency of administration should always be orientated 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; 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	F actor VIII level required (%) (IU/dL)	Frequency of doses (hours)/Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding or oral bleeding	20-40	Repeat every 12 to 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 12 to 24 hours for 3 to 4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages	60-100	Repeat infusion every 8 to 24 hours until threat 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 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dL).

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 IU of factor VIII per kg 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.

Children: The dose for young children with haemophilia A should be calculated on a recovery of 1.5 IU/dL/IU/kg to achieve the same desired levels as in the Table in this section. The equivalent formula is as follows:

Required units = body weight (kg) x desired factor VIII rise (%) (IU/dL) x 0.7

4.3 Contraindications

Hypersensitivity to any of the constituents.

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 VIII and VWF. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. 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.

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 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 of plasma pools for HCV genomic material

inactivation/removal procedures included in the production process that have been validated using model viruses. These procedures are considered effective for HIV, hepatitis B and hepatitis C viruses. These procedures are of limited value against non-enveloped viruses such as hepatitis A virus and parvovirus B19.

Appropriate vaccination (hepatitis A and B) for patients in receipt of plasma-derived FVIII and VWF 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. in haemolytic anaemia).

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors. Therefore, patients at risk must be monitored for early signs of thrombosis. Prophylaxis against venous thromboembolism should be instituted, according to the current recommendations. When using a factor VIII-containing von Willebrand Factor product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving factor VIII-containing von Willebrand Factor products, plasma levels of FVIII:C should be monitored to avoid sustained excessive FVIII:C plasma levels, which may increase the risk of thrombotic events.

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 the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure 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 4.8 Undesirable effects.

Patients with VWD, especially type 3 patients, may develop neutralising antibodies (inhibitors) to von Willebrand Factor. If the expected VWF:RCo activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a von Willebrand Factor inhibitor is present. In patients with high levels of inhibitor, von Willebrand Factor therapy may not be effective and other therapeutic options should be considered.

In the interest of patients, it is recommended that, whenever possible, every time that Dried Factor VIII Fraction, type 8Y®, is administered to them, the name and batch number of the product is registered.

Interactions with other medicinal products and other forms of interaction

4.5

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

4.6 Fertility, pregnancy and lactation

Animal reproduction studies have not been conducted with Dried Factor VIII Fraction, type 8Y®. The safety of Dried Factor VIII Fraction, type 8Y®, for use in human pregnancy has not been established. Dried Factor VIII Fraction, type 8Y® should be administered to pregnant and lactating women only if clearly indicated.

4.7 Effects on ability to drive and use machines

No effects on 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, and may in some cases progress to severe anaphylaxis. Other side effects are back and other pain, dizziness, bradycardia, palpitations, coughing, dysgeusia, drowsiness and blurred vision.

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. Experience with 8Y® in haemophilia A has indicated that the occurrence of inhibitors is rare.

Patients with VWD, 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 all such cases it is recommended that a specialised haemophilia centre be contacted. There are no known reports of inhibitors to 8Y® in patients treated for VWD.

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 plasma levels may increase the risk of thrombotic events.

In long-term trials, 1 out of 57 (0.2%) previously untreated patients (PUPs) treated with 8Y developed a transient inhibitor (titre 0.7 BU). The median exposure was in excess of 200 days over follow-up periods of up to about 12 years.

In clinical trials, no previously treated patients (PTPs) developed inhibitors. From post-marketing experience, 17 patients have been reported to develop inhibitors in more than 20 years use of 8Y®.

For information on viral safety see 4.4.

4.9 Overdose

No symptoms of overdose with human coagulation factor VIII or VWF have been reported. Thromboembolic events may occur in case of major overdose in patients with VWD.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group :

Antihaemorrhagics: blood coagulation factors, von Willebrand factor and coagulation factor VIII in combination. ATC code: B02BD06.

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

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:C 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.

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 the 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. Because of this, administration of a pure von Willebrand factor (VWF product with a low FVIII level) restores the FVIII:C level to normal as a secondary effect after the first infusion. Administration of a FVIII:C containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

5.2 Pharmacokinetic properties

The half life of FVIII is approximately 12 hours. When injected into a patient with VWD, VWF antigen and RCo are recovered with high efficiency in the circulation and disappear with a half-life of approximately 12-24 hours. Since injected VWF stimulates the release of factor VIII, synthesised normally in VWD, plasma factor VIII levels may continue to rise for many hours after the increment attributable to factor VIII in the concentrate.

From clinical trials the mean incremental recovery of FVIII is 2.0 IU/dL/IU/kg; and the mean incremental recovery of VWF:RCo is 1.9 IU/dL/IU/kg.

5.3 Preclinical safety data

Dried Factor VIII Fraction, 8Y® is a human plasma protein; therefore safety testing in animals is not particularly relevant to the safety of use in man.

However, acute toxicity studies in rat and mouse showed that a single intravenous injection of the product produced a maximum non-lethal dose of 1020 IU per kg in the rat and mouse. This is approximately equivalent to 20 times the maximal dose in man.

Repeated dose toxicity testing in animals is impracticable due to interference with developing antibodies to heterologous protein.

Since clinical experience provides no evidence of tumorigenic and mutagenic effects of human plasma coagulation factor VIII, experimental studies, particularly in heterologous species, are not considered imperative.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The reconstituted solution contains: protein, sucrose, sodium, chloride, citrate, Tris, glycine and heparin.

6.2 Incompatibilities

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

Only the provided or Health Authority approved injection sets should be used because treatment failure can occur as a consequence of human plasma coagulation Factor VIII adsorption to the internal surfaces of some injection sets.

6.3. Shelf Life

Reconstituted (25°C) 1 hour

Freeze dried at 2°C - 8°C(in the dark) 36 months

Freeze dried at 25°C (in the dark) 2-3 months

6.4 Special precautions for storage

Dried Factor VIII Fraction, 8Y®, should be stored between 2°C and 8°C. However, it may be stored for short periods (up to 2-3 months) at ambient temperature (25°C). Where Dried Factor VIII Fraction, 8Y® is for home use, a domestic refrigerator is suitable for storage. DO NOT FREEZE.

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

The expiry date of the product is printed on the label.

Sterilised Water for Injections, (Ph.Eur.), should be stored between 2°C and 25°C and must not be used beyond the expiry date printed on the label or if signs of particulate matter are visible.

6.5 Nature and contents of container

Dried Factor VIII Fraction, 8Y® is supplied in single dose vials of 250 IU or 500 IU nominal for reconstitution in 10 mL (250 IU vial) or 20 mL (500 IU vial) of Sterilised Water for Injections, (Ph.Eur.), supplied with the product. Vials are freeze-drying vials made of Type 1, Ph.Eur., glass with a halobutyl rubber freeze-drying stopper. Product is stoppered under vacuum. The vial stopper is oversealed with a snap-off polypropylene cap and lacquered skirt.

6.6 Special precautions for disposal

Reconstitution:

Dried Factor VIII Fraction, 8Y®, should only be reconstituted with Sterilised Water for Injections, (Ph.Eur.), provided with the product.

The container of the factor VIII concentrate and the Sterilised Water for Injections, (Ph.Eur.), should be brought to between 20°C and 30°C prior to the removal of the 'flip-off closures. Remove the caps from the concentrate and Sterilised Water for

Injections, Ph.Eur., and clean stoppers with a spirit swab. Either of the following methods of reconstitution can then be used.

a) Using a sterile disposable needle and syringe draw up the required

volume of Sterilised Water for Injections, Ph.Eur., and transfer to the vial containing factor VIII concentrate. On piercing the seal of the factor VIII vial, the water will be drawn into the vial which is under vacuum.

NB: THE FILTER NEEDLE PROVIDED MUST NOT BE USED TO DRAW UP

THE WATER FOR INJECTIONS.

b) Remove the cover guard from one end of a double ended transfer

needle and insert through the stopper into the vial of Sterilised Water for Injections, Ph.Eur. Remove the other end of the needle guard, invert the water vial over the product vial and insert the free end of the needle through the stopper into the vial of factor VIII. On piercing the seal of the factor VIII vial the water will be drawn into the vial which is under vacuum. A small amount of water will remain in the water vial.

If the water to be used for reconstitution is not drawn into the vial containing factor VIII this indicates loss of vacuum. If the vial does not contain a vacuum or if the reconstituted factor VIII forms a gel or a clot, the vial must not be used.

The container should be agitated to wet the product and the vacuum then released by either:

a) Removing the syringe from the needle before removing the needle from the product vial.

b) Disconnecting the two vials by first removing the transfer needle from the water vial and then removing the transfer needle from the product vial.

Continue to agitate gently until dissolution is complete. A clear or slightly opalescent solution should be obtained within 15 minutes. If a gel or clot forms discard the vial. Discard any unused Sterilised Water for Injections, Ph.Eur.

Standard precautions for infusion of sterile solutions should be observed. Discard any unused material or used materials by normal safety practices.

The reconstituted solution should be administered within one hour of reconstitution.

After cleaning the stopper with a spirit swab the solution should be drawn from the

vial into a plastic disposable syringe through the sterile filter needle provided which

will remove particulate matter. For intravenous injection attach a suitable needle or

'butterfly' to the syringe and inject the product at a rate not exceeding 3 mL per minute (note that increasing the rate of administration may result in side effects).

Patients who are to receive the contents of more than one vial may pool these contents into an appropriate size syringe by drawing up the contents of each vial through a separate sterile filter needle. Sterile filter needles are intended to filter the contents of a single bottle of Dried Factor VIII Fraction, 8Y®.

7. MARKETING AUTHORISATION HOLDER

Bio Products Laboratory Limited

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

8. Marketing Authorization Number

PL 08801/0021

9. Date of First Authorisation/Renewal of Authorisation

First granted 21.3.91. / Relicenced 22.12.99.

10 DATE OF REVISION OF THE TEXT

03/07/2013