This information is intended for use by health professionals

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

250 IU

Each vial contains nominally 250 IU human coagulation factor VIII and 500 IU human von Willebrand factor (VWF).

8Y contains 25 IU/ml of human coagulation factor VIII and 50 IU/ml of VWF after reconstitution with 10 ml of water for injections, Ph.Eur.

500 IU

Each vial contains nominally 500 IU human coagulation factor VIII and 1000 IU human von Willebrand factor (VWF).

8Y contains 25 IU/ml of human coagulation factor VIII and 50 IU/ml of VWF after reconstitution with 20 ml of water for injections, Ph.Eur.

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

The specific activity of VWF:RCo 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 compared to the International Standard for von Willebrand factor concentrate (WHO).

Produced from the plasma of human donors.

Excipient with known effect:

8Y contains approximately 125 mmol/l (2.9 mg/ml) sodium.

For the full list of excipients, see section 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

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

Posology

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 preferably in International Units (relative to an International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in 1 ml of normal human plasma.

Treatment monitoring

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. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on body weight may require adjustment in underweight or overweight patients.

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.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients' blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

On demand treatment

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) x desired factor VIII rise (%) or (IU/dl) x 0.5

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 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 VIII level required (%) or (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 post-operative)

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).

Prophylaxis

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.

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.

Continuous infusion

Prior to surgery, a pharmacokinetic analysis should be performed to obtain an estimate of clearance.

The initial infusion rate can be calculated as follows:

Clearance x desired steady state level = infusion rate (IU/kg/hr).

After the initial 24 hours of continuous infusion, the clearance should be calculated again every day using steady state equation with the measured level and the known rate of infusion.

Paediatric population

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

Von Willebrand disease

Generally 1 IU/kg VWF:RCo raises the circulating level of VWF:RCo by 0.02 IU/ml (2%).

Levels of VWF:RCo of 0.6 IU/ml (60%) and of FVIII:C of 0.4 IU/ml (40%) should be achieved.

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

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

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 factor VIII-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, in order to avoid an excessive rise in FVIII:C, reduced doses and/or prolongation of the dose interval or the use of a von Willebrand factor product containing a low level of factor VIII should be considered.

Paediatric population

Children under 6 years of age

There is no data from a clinical study to characterise the response for the use of 8Y in children with VWD less than 6 years of age (see section 5.2).

Method of administration

Intravenous use.

8Y should be administered via the intravenous route at a rate not exceeding 3 ml per minute (note that increasing the rated of administration may result in side effects). 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.

4.4 Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity

Allergic type hypersensitivity reactions are possible with 8Y. The product contains traces of human proteins other than factor VIII and von Willebrand factor. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. 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.

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), and for the non-enveloped hepatitis A virus. The measures taken may be of limited value against non-enveloped viruses such as 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 VIII products.

It is strongly recommended that every time 8Y 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 (see section 4.8).

Haemophilia A

Inhibitors

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 pro-coagulant 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 severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. 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 haemophilia and factor VIII inhibitors.

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increase the cardiovascular risk.

Catheter-related complications

If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.

Von Willebrand disease

There is a risk 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 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.

Patients with von Willebrand disease, 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.

Sodium content

This medicinal product contains approximately 125 mmol/l (2.9 mg/ml) sodium, equivalent to 0.15% of the WHO recommended maximum daily intake of 2 g sodium.

Paediatric population

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 VIII or von Willebrand factor products with other medicinal products have been reported.

4.6 Fertility, pregnancy and lactation

Fertility

Animal reproduction studies have not been conducted with 8Y.

Pregnancy and lactation

Experience regarding the use of factor VIII or VWD during pregnancy and breast-feeding is not available.

8Y should be administered to pregnant and lactating women with haemophilia A or VWD only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients.

4.7 Effects on ability to drive and use machines

8Y has no influence on ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

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).

Patients treated for VWD, on rare occasions, fever has been observed.

For safety information with respect to transmissible agents, see section 4.4.

Haemophilia A

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with 8Y(see section 5.1). 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.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to 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).

MedDRA Standard System Organ Class

Adverse Reactions

Frequency

Blood and lymphatic system disorders

Factor VIII inhibition

Uncommon (PTPs)*

Very common (PUPs)*

* Frequency is based on studies with all factor VIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients.

Von Willebrand disease

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 all such cases, it is recommended that a specialised haemophilia centre be contacted.

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.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No symptoms of overdose with human coagulation factor VIII or von Willebrand factor 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.

Mechanism of action

Haemophilia A

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) 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 results 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.

Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

In addition to its role as a factor VIII protein, von Willebrand factor mediates platelet adhesions to sites of vascular injury and plays a role in platelet aggregation.

Paediatric population

No data available.

Von Willebrand disease

8Y behaves in the same was 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 (VWD) 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 (von Willebrand factor product with a low factor VIII level) restores the FVIII:C level to normal as a secondary effect after the first infusion. Administration of a FVIII:C containing von Willebrand factor preparation restores the FVIII:C level to normal immediately after the first infusion.

5.2 Pharmacokinetic properties

The half-life of factor VIII is approximately 12 hours. When injected into a patient with VWD, von Willebrand factor antigen and RCo are recovered with high efficiency in the circulation and disappear with a half-life of approximately 12-24 hours. Since injected von Willebrand factor 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 factor VIII 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

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:

sodium chloride

trisodium citrate

trometamol

calcium chloride

sucrose

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/von Willebrand factor adsorption to the internal surfaces of some injection sets.

6.3 Shelf life

Freeze dried at 2°C-8°C 36 months

Freeze dried at 25°C 3 months

After reconstitution, chemical and physical in-use stability has been demonstrated for 1 hour up to 25°C.

From a microbiological point of view, unless the method of opening/reconstitution precludes the risk of microbial contamination, the reconstituted medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 1 hour up to 25°C.

6.4 Special precautions for storage

Store between 2°C and 8°C.

Do not freeze.

May be stored for short periods (up to 3 months) up to 25°C. Where Dried Factor VIII Fraction, 8Y is for home use, a domestic refrigerator is suitable for storage.

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

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

6.5 Nature and contents of container

250 IU

- 250 IU powder in a 10 ml vial (type 1 glass) with a stopper (halobutyl rubber), with an overseal (aluminium) and tamper evident flip-off cap (polypropylene).

500 IU

- 500 IU powder in a 20 ml vial (type 1 glass) with a stopper (halobutyl rubber), with an overseal (aluminium) and tamper evident flip-off cap (polypropylene).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

8Y should only be reconstituted with water for injections provided with the product.

The container of the 8Y and water for injections should be brought to between 20°C and 30°C prior to the removal of the flip-off cap. Remove the caps from the powder and s water for injections 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 water for injections and transfer to the vial containing factor VIII powder. 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.

or

b) Remove the cover guard from one end of a double ended transfer needle and insert through the stopper into the vial of water for injections. 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.

or

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 10 minutes.

Reconstituted medicinal product should be inspected visually for particulate matter and discolouration prior to administration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Use the product immediately after reconstitution or within 1 hour.

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

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 8Y.

7. Marketing authorisation holder

Bio Products Laboratory Limited

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom

8. Marketing authorisation number(s)

PL 08801/0021

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 21 March 1991

Date of latest renewal: 10 December 2010

10. Date of revision of the text

08/2019