4.1. Therapeutic indications

Von Willebrand disease (VWD)

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

Haemophilia A

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

4.2. Posology and method of administration

Treatment should be under the supervision of a physician experienced in the treatment of coagulation disorders. The product is of single use and the full content of the vial should be administered. In case any content remains, it should be disposed of in accordance with local requirements.

Von Willebrand disease (VWD)

The ratio between VWF:RCo and FVIII:C is 1:1. Generally, 1 IU/kg BW VWF:RCo and FVIII:C raises the plasma level by 1.5-2% of normal activity for the respective protein.

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

Usually, about 20 to 50 IU Wilate/kg BW are necessary to achieve adequate haemostasis.

An initial dose of 50 to 80 IU Wilate/kg may be required, especially in patients with VWD type 3, where the maintenance of adequate plasma levels may require higher doses than in other types of VWD.

For prevention of bleeding in case of surgery, Wilate should be given 1-2 hours before start of the surgical procedure. Levels of VWF:RCo of ≥ 60 IU/dl (≥ 60%) and FVIII:C levels of ≥ 40 IU/dl (≥ 40%) should be achieved.

An appropriate dose should be re-administered every 12-24 hours of treatment. 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.

In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be monitored to reveal sustained excessive FVIII:C plasma levels, which may increase the risk of thrombotic events, particularly in patients with known clinical or laboratory risk factors. In case excessive FVIII:C plasma levels are observed, reduced doses and/or prolongation of the dose interval or the use of VWF product containing a low level of FVIII should be considered.

Prophylaxis:

For long term prophylaxis against bleeds in VWD patients, doses of 20-40 IU/kg should be administered 2 or 3 times per week. In some cases, such as in patients with gastrointestinal bleeds, higher doses may be necessary.

Paediatric population

Wilate can be used in children of all ages. Dosing is based on the same guidance as for adults and should be adjusted to the clinical condition of the patient, as well as their VWF:RCo and FVIII:C plasma levels. In younger patients, shorter dose intervals or higher doses may be necessary due to lower recovery and shorter half-life compared to adults (see Section 5.2). For the treatment of haemorrhage in children <6 years of age, initial doses of 50 to 80 IU/kg and maintenance doses of 30 to 50 IU/kg are recommended. For initiation of long-term prophylaxis against bleeds in children <6 years of age, doses of 30 to 50 IU/kg administered 2 or 3 times per week should be considered.

Haemophilia A

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 treatment, demonstrating different half‑lives and recoveries. Dose based on bodyweight 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.

Posology

The dose 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 concentrate 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 one ml of normal human plasma.

On demand treatment:

The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma level by 1.5 to 2% of normal activity. The required dose is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 IU/kg

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 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 (%)

(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 is resolved.

Surgery

Minor surgery including tooth extraction

30 – 60

Every 24 hours, at least 1 day, until healing is achieved.

Major surgery

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).

Prophylaxis:

For long-term prophylaxis against bleedings 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.

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:

Infusion rate (IU/kg/hr) = clearance (mL/kg/hr) x desired steady state level (IU/mL)

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

Paediatric population

There are insufficient data to recommend the use of Wilate in haemophilia A in children less than 6 years old.

Method of administration

Intravenous use.

The injection or infusion rate should not exceed 2-3 ml per minute. For children weighing between 6 kg to less than 10 kg, the infusion rate should not exceed 2 ml per minute. For children weighing less than 6 kg, the infusion rate should not exceed 1 ml per minute.

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

4.3. Contraindications

Hypersensitivity to the active substances 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 Wilate. The product contains traces of human proteins other than factor VIII. 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 VWF/factor VIII products.

It is strongly recommended that every time that Wilate 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.

Von Willebrand disease (VWD)

Thromboembolic events

When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving FVIII-containing VWF 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.

There is a risk of occurrence of thrombotic events when using FVIII-containing VWF products, 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.

Inhibitors

Patients with VWD, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. 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 VWF inhibitor is present. In patients with high levels of inhibitor, VWF 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 haemostatic disorders.

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 FVIII 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.

This medicinal product contains up to 58.7 mg sodium per vial for 500 IU VWF and FVIII/vial, and up to 117.3 mg sodium per vial for 1000 IU VWF and FVIII/vial, equivalent to 2.94% and 5.87%, respectively, of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Paediatric population

The listed warnings and precautions apply to both adults and children.

4.5. Interaction with other medicinal products and other forms of interaction

No interactions of human coagulation factor VIII with other medicinal products have been reported.

4.6. Fertility, pregnancy and lactation

Animal reproduction studies have not been conducted with VWF/factor VIII.

Von Willebrand disease (VWD)

Experience in the treatment of pregnant or lactating women is not available.

Wilate should be administered to pregnant or lactating VWF deficient women only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients.

Haemophilia A

Based on the rare occurrence of haemophilia A in women, experience regarding the treatment during pregnancy and breastfeeding is not available. Therefore, Wilate should be used during pregnancy and lactation only if clearly indicated.

4.7. Effects on ability to drive and use machines

Wilate 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 angiooedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, erythema, pruritus, rash, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, dyspnoea, tingling, vomiting, wheezing) have been observed rarely, and may in some cases progress to severe anaphylaxis (including shock).

Von Willebrand disease (VWD)

Patients with VWD, especially type 3 patients, may very rarely develop neutralising antibodies to VWF. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies 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. Prophylaxis against venous thromboembolism should be instituted, according to the current recommendations.

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

Haemophilia A

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Wilate 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.

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

Tabulated list of adverse reactions

The following table shows an overview of adverse reactions observed in clinical studies, post-marketing safety studies, and from other post-marketing sources, categorised according the MedDRA System Organ Class (SOC), Preferred Term Level (PT) and frequency.

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).

For spontaneously reported post-marketing adverse reactions, the reporting frequency is categorised as not known.

MedDRA Standard System Organ Class (SOC)

Adverse Reaction

Frequency

Immune system disorders

Hypersensitivity

Anaphylactic shock

Common

Very rare

General disorders and administration site conditions

Fever

Chest pain

Common

Not known

Blood and lymphatic system disorders

Factor VIII inhibition

Von Willebrand's factor inhibition

Uncommon (PTPs)*

Very common (PUPs)*

Very rare

Respiratory, thoracic and mediastinal disorders

Cough

Not known

Nervous system disorders

Dizziness

Uncommon

Gastrointestinal disorders

Abdominal pain

Not known

Musculoskeletal and connective tissue disorders

Back pain

Not known

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

Description of selected adverse reactions

For description of selected adverse reactions, see section 4.4

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 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 VWF or factor VIII have been reported. Thromboembolic events may occur in case of major overdose.