WILLFACT 2000 I.U POWDER AND SOLVENT FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Willfact 2000 IU Powder and solvent for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Willfact is presented as powder and solvent for solution for injection containing nominally 500 IU, 1000 IU or 2000 IU of human von Willebrand factor per vial.

The product contains approximately 100 IU/ml of human von Willebrand factor when reconstituted with 5 ml (500 IU), 10 ml (1000 IU) or 20 ml (2000 IU) of water for injection.

Before the addition of albumin, the specific activity of Willfact is > 60 IU VWF:RCo/mg protein.

The von Willebrand factor potency (IU) is measured according to ristocetin cofactor activity (VWF:RCo) compared to the International Standard for von Willebrand factor concentrate.

The quantity of human factor VIII in Willfact is < 10 IU/100 IU VWF:RCo. The FVIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay.

Excipient with known effect:

This medicinal product contains sodium:

– One 5 ml vial (500 IU) of Willfact contains 0.15 mmol (3.4 mg) sodium.

– One 10 ml vial (1000 IU) of Willfact contains 0.3 mmol (6.9 mg) sodium.

– One 20 ml vial (2000 IU) of Willfact contains 0.6 mmol (13.8 mg) sodium.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

The powder should be white or pale yellow lyophilised powder or friable solid.

The solvent should be clear and colourless.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Willfact is indicated in the prevention and treatment of haemorrhages or surgical bleeding in von Willebrand disease when desmopressin (DDAVP) treatment alone is ineffective or contraindicated.

Willfact should not be used in the treatment of haemophilia A.

4.2 Posology and method of administration

Treatment of von Willebrand disease should be supervised by a physician experienced in the treatment of haemostatic disorders.

Posology

Generally, 1 IU/kg of von Willebrand factor 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.

Haemostasis cannot be ensured until FVIII coagulant activity (FVIII:C) has reached 0.4 IU/ml (40 %). A single injection of von Willebrand factor will only lead to a maximum increase in FVIII:C after at least 6–12 hours. The single administration of von Willebrand factor cannot immediately correct the FVIII:C level. If the patient’s baseline plasma FVIII:C level is below this critical level, in all situations where a rapid correction of haemostasis should be achieved, such as the treatment of haemorrhage, severe trauma or emergency surgery, it is necessary to administer a factor VIII product with the first injection of von Willebrand factor, in order to achieve a haemostatic plasma level of FVIII:C.

However, if an immediate rise in FVIII:C is not necessary, for example in a planned operation, or if the baseline FVIII:C level is sufficient to ensure haemostasis, the physician may decide to omit the co-administration of FVIII at the first injection.

Start of treatment

The first dose of Willfact is 40 to 80 IU/kg for the treatment of haemorrhage or trauma, in conjunction with the required amount of factor VIII product, calculated according to the patient's baseline plasma level of FVIII:C, in order to achieve an appropriate plasma level of FVIII:C, immediately before the intervention or as soon as possible after the onset of the bleeding episode or severe trauma. In case of surgery, it should be given 1 hour before the procedure.

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

For elective surgery, treatment with Willfact should start 12–24 hours before surgery and should be repeated 1 hour before the procedure. In this case, co-administration of factor VIII product is not required since endogenous FVIII:C has usually reached the critical level of 0.4 IU/ml (40 %) before surgery. However, this should be confirmed in each patient.

Subsequent injections

If required, treatment should be continued with an appropriate dose of Willfact, with 40 – 80 IU/kg per day in 1 or 2 injections daily over one to several days. 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.

Long-term prophylaxis

Willfact can be administered as long-term prophylaxis in a dose which is determined individually for each patient. Willfact doses between 40 and 60 IU/kg, administered two to three times per week, reduce the number of haemorrhagic episodes.

Paediatric population

There is no data from a clinical study to characterise the response to use of Willfact in children less than 6 years of age.

The use of Willfact in children under 12 years of age is only documented in individual cases; the use of Willfact in patients previously untreated with von Willebrand factor is not documented in the clinical studies.

Method of administration

The product should be administered via the intravenous route at a maximum rate of 4 ml/minute.

For instructions on reconstitution of the medicinal product before administration, see section 6.6

4.3 Contraindications

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

4.4 Special warnings and precautions for use

In actively bleeding patients it is recommended to co-administer a FVIII product with the von Willebrand factor product with a low FVIII content as a first line treatment.

Hypersensitivity

As with any intravenous administration of a plasma-derived protein, allergy type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the injection period. Patients should be informed of the early signs of hypersensitivity reactions such as hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, administration should be discontinued immediately. 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 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 erythropoesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatitis A and hepatitis B) should be considered for patients regularly receiving human plasma-derived von Willebrand factor.

Note that the name and batch number of the drug must be documented for every administration of Willfact to help establish a link between the patient and the batch number.

Thromboembolism

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 thromboembolisms should be instituted according to the current recommendations.

When using a FVIII-containing von Willebrand factor preparation, 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.

Immunogenicity

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 the bleeding cannot be controlled with an appropriate dose, an 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.

Excipient related considerations (sodium content)

This medicinal product contains sodium. For more than 3300 IU injected (more than 1 mmol sodium), to be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

Animal studies are insufficient to assess its safety with respect to fertility, reproduction, pregnancy, embryonic/fretal development or peri- and postnatal development.

The safety of Willfact during pregnancy and lactation has not been investigated in controlled clinical studies.

Willfact should be administered to pregnant and lactating von Willebrand factor deficient women only if clearly indicated.

4.7 Effects on ability to drive and use machines

Willfact has no influence on the 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 infrequently, and may in some cases progress to severe anaphylaxis (including shock). On rare occasions, fever has been observed.

Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to von Willebrand factor. Patients treated with von Willebrand factor should be carefully monitored for the development of inhibitors using appropriate clinical observations and laboratory tests. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitating and occur in close association with anaphylactic reactions. In all such cases, it is recommended that a specialised haemophilia centre be contacted.

Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor.

After correction of the factor Willebrand deficiency, due to the risk of a thrombotic episode in certain risk situations, monitoring for early signs of thrombosis or disseminated intravascular coagulation and prevention of thromboembolic complications should be undertaken according to current practices.

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

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

Tabulated list of adverse reactions

The frequency of adverse event occurrence has been estimated according 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).

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: „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 case of overdose with Willfact has been reported.

Thromboembolic events may occur in case of major overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-haemorrhagics: von Willebrand factor ATC code: B02BD10

Willfact 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 at two levels:

VWF re-establishes platelet adhesion to the vascular subendothelium at the site of vascular damage (as it binds both to the vascular subendothelium and to the platelet membrane) providing primary haemostasis as shown by the shortening of the bleeding time. This effect is known to depend to a large extent on the level of multimerisation of the active substance.

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 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

A pharmacokinetic study with Willfact was carried out on 8 patients with type 3 von Willebrand disease. It demonstrated that for VWF:RCo:

The mean AUC0– / is 3444 IU.h/dl after single dose of 100 IU/kg Willfact,

The plasma peak is reached between 30 minutes and 1 hour after injection,

The mean recovery is 2.1 [IU/dl]/[IU/kg] of the injected preparation,

The half-life is between 8 and 14 hours, with a mean value of 12 hours,

The mean clearance is 3.0 ml/h/kg.

Normalisation of FVIII level is progressive, varies and usually requires between 6 and 12 hours. This effect is sustained for 2 to 3 days.

The increase in FVIII level is progressive and returns to normal after 6 to 12 hours. The FVIII level increases by a mean of 6 % (IU/dl) per hour. Thus, even in patients with an initial FVIII:C level less than 5 % (IU/dl), the FVIII:C level increases to around 40 % (IU/dl) 6 hours after the injection, and this level is maintained over 24 hours.

5.3 Preclinical safety data

Based on data obtained from several preclinical studies using animal models, there is no evidence for other toxic effect of Willfact than those related to the immunogenicity of human proteins in laboratory animals. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models.

The preclinical safety data do not suggest that Willfact has any mutagenic potential.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

human albumin,

arginine hydrochloride,

glycine,

sodium citrate and

calcium chloride dihydrate.

Solvent: water for injections.

6.2 Incompatibilities

Willfact must not be mixed with other medicinal products except for plasma-derived coagulation FVIII produced by LFB-BIOMEDICAMENTS, with which a compatibility study was carried out. This FVIII coagulation factor is however not marketed in all European countries.

Only licensed polypropylene injection sets should be used, because treatment failure can occur as a consequence of human von Willebrand factor adsorption to the internal surface of some injection equipment.

6.3 Shelf life

3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from light. Do not freeze.

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

6.5 Nature and contents of container

1 pack contains: powder in a vial (Type I glass) with a bromobutyl stopper, solvent in an injection vial (Type I glass) with a chlorobutyl (5 and 20 ml) / bromobutyl (10 ml) stopper, and a transfer system.

6.6 Special precautions for disposal