- factor VIII
- von willebrand factor
POM: Prescription only medicine
This information is intended for use by health professionals
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 ATreatment and prophylaxis of bleeding in patients with haemophilia A (congenital FVIII deficiency).
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. Usually, about 20 to 50 IU Wilate/kg BW are necessary to achieve adequate haemostasis. This will raise the VWF:RCo and FVIII:C in the patients by approx. 30 to 100%.An initial dose of 50 to 80 IU Wilate/kg BW 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.
Paediatric populationThere are insufficient data to recommend the use of Wilate in children less than 6 years old. Prevention of haemorrhage in case of surgery or severe trauma: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 bodyweight should be administered 2 or 3 times per week. In some cases, such as in patients with gastrointestinal bleeds, higher doses may be necessary.
Haemophilia AThe dose and duration of the substitution therapy depend on the severity of the FVIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.The number of units of FVIII administered is expressed in International Units (IU), which are related to the current WHO standard for FVIII products. FVIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for FVIII in plasma).One IU of FVIII activity is equivalent to that quantity of FVIII in one ml of normal human plasma.
On demand treatment:The calculation of the required dose of FVIII is based on the empirical finding that 1 IU FVIII:C/kg BW raises the plasma level by 1.5-2% of normal activity. The required dose is determined using the following formula:Required IU = BW (kg) x desired FVIII rise (%) (IU/dl) x 0.5 IU/kgThe 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.Treatment scheme for Haemorrhages and Surgery
|Degree of haemorrhage/Type of surgical procedure||FVIII level required (%) (IU/dl)||Frequency of Doses (hours)/Duration of Therapy (days)|
|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 disability are resolved.|
|Life threatening haemorrhages||60 100||Repeat infusion every 8 to 24 hours until threat is resolved.|
|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 FVIII activity of 30% to 60% (IU/dl).|
Infusion rate (IU/kg/h) = clearance (mL/kg/h) 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.During the course of treatment, appropriate determination of FVIII:C levels is ad-vised 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 (FVIII:C) is indispensable. Individual patients may vary in their response to FVIII treatment, achieving different half-lives and recoveries.
Previously untreated patientsCurrently available data are described in section 4.8.
Paediatric populationThere are insufficient data to recommend the use of Wilate in haemophilia A in children less than 6 years old.Method of administrationIntravenous use.The injection or infusion rate should not exceed 2-3 ml per minute.For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Von Willebrand disease (VWD)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.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.
HypersensitivityAllergic type hypersensitivity reactions are possible with Wilate. The product contains traces of human proteins other than FVIII. 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.
InhibitorsThe formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the FVIII 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 FVIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days. Cases of recurrent inhibitor (low titre) have been observed after switching from one FVIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.In general, all patients treated with coagulation FVIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected FVIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for FVIII inhibitor presence should be performed. In patients with high levels of inhibitor, FVIII 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 FVIII inhibitors.This medicinal product contains up to 2.55 mmol sodium (58.7 mg) per vial for 500 IU VWF and FVIII /vial and up to 5.1 mmol sodium (117.3 mg) per vial for 1000 IU VWF and FVIII /vial. To be taken into consideration by patients on a controlled sodium diet.
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 ABased 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.
Summary of the safety profileHypersensitivity or allergic reactions (which may include angiooedema, 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). In rare occasions, fever has been observed.
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.No cases of inhibitors for von Willebrand factor have been reported from clinical studies or from post marketing experience for Wilate so far.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 APatients with haemophilia A may develop neutralising antibodies (inhibitors) to FVIII. If such inhibitors occur, the condition will manifest as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.The experience with Wilate in previously untreated patients (PUPs) is limited. In a clinical trial involving 24 PUPs with a minimum of 50 exposure days treated with Wilate, only three patients with a persistent and clinically manifest inhibitor above 5 BU/ml could be detected. Three patients developed low titre, transient inhibitors without any clinical manifestations, and two patients had a low titre inhibitor on a single occasion with no follow-up result.See also section 4.2. There were no inhibitor developments observed in previously treated patients.For safety information with respect to transmissible agents, see section 4.4
Tabulated list of adverse reactionsThe 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).
|System Organ Class||Uncommon||Rare||Very rare|
|Immune system disorders||hypersensitivity reaction||anaphylactic shock|
|General disorders and administration site conditions||fever|
|Investigations||FVIII inhibitors||VWF inhibitors|
Von Willebrand disease (VWD)The VWF (from the concentrate) is a normal constituent of the human plasma and behaves in the same way as endogenous VWF.Administration of VWF allows correction of the haemostatic abnormalities exhibited in patients who suffer from VWF deficiency (VWD) at two levels:VWF 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 to the level of polymerisation of the protein;VWF produces delayed correction of the associated FVIII deficiency. Administered intravenously, VWF binds endogenous FVIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation. Because of this, administration of pure VWF (VWF product with a low FVIII level) restores the FVIII:C level to normal as a secondary effect after first infusion. Administration of a FVIII-containing VWF preparation restores the FVIII:C level to normal immediately after first infusion.In addition to its role as a FVIII-protecting protein, VWF mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.
Haemophilia AThe FVIII/VWF complex consists of two molecules (FVIII and VWF) with different physiological functions. When infused into a haemophilia patient, FVIII binds to VWF in the patient´s circulation. Activated FVIII (FVIIIa) acts as a cofactor for activated factor IX (FIXa), accelerating the conversion of factor X to activated factor X (FXa). FXa 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 FVIII: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 FVIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Von Willebrand disease (VWD)VWF (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous VWF.Based on meta-analysis of three pharmacokinetic studies involving 24 evaluable patients with all VWD types, the following results were observed.
|All VWD types||VWD type 1||VWD type 2||VWD type 3|
|AUC (0-inf) (h*%)||23||1981||960||593||4831||2||2062||510||1701||2423||5||2971||1383||1511||4831||16||1662||622||593||2606|
|T 1/2 (h)||24||23.3||12.6||7.4||58.4||2||39.7||18.3||26.7||52.7||5||34.9||16||17.5||58.4||17||18||6.2||7.4||30.5|
Haemophilia AFVIII (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous FVIII. After injection of the product, approximately two thirds to three quarters of the FVIII remain in the circulation. The level of FVIII:C reached in the plasma should be between 80-120% of the predicted FVIII:C.FVIII:C decreases by a two-phase exponential decay. In the initial phase, distribution between the intravascular and other compartments (body fluids) occurs with a half-life of elimination from the plasma of 3 to 6 hours. In the subsequent slower phase, the half-life varies between 8 to 18 hours, with an average of 15 hours. This corresponds to the true biological half-life.The following results were observed in one clinical study in 12 patients (chromogenic assay, double measurement):
|Parameter||Baseline visit||6-month visit|
|Recovery %/IU/kg||FVIII:C 2.27||1.20||FVIII:C 2.26||1.19|
|AUCnorm % * h/IU/kg||FVIII:C 31.3||7.31||FVIII:C 33.8||10.9|
|Half-life (h)||FVIII:C 11.2||2.85||FVIII:C 11.8||3.37|
|MRT (h)||FVIII:C 15.3||3.5||FVIII:C 16.3||4.6|
|Clearance mL/h/kg||FVIII:C 3.37||0.86||FVIII:C 3.24||1.04|
Instructions for Preparing the Solution:1. Do not use the product directly from the refrigerator. Allow the solvent and the powder in the closed vials to reach room temperature. 2. Remove the flip off caps from both vials and clean the rubber stoppers with one of the provided alcohol swabs.3. The Mix2vial is depicted in Fig. 1. Place the solvent vial on an even surface and hold it firmly. Take the Mix2Vial and turn it upside down. Place the blue part of the Mix2Vial on top of the solvent vial and press firmly down until it snaps (Fig. 2 + 3).
|4. Place the powder vial on an even surface and hold it firmly. Take the solvent vial with the attached Mix2Vial and turn it upside down. Place the transparent part on top of the powder vial and press firmly down until it snaps (Fig. 4). The solvent flows automatically into the powder vial.|
|5. With both vials still attached, gently swirl the powder vial until the product is dissolved. The dissolving is completed in less than 10 minutes at room temperature. Slight foaming might occur during preparation. Unscrew the Mix2Vial into two parts (Fig. 5). Foaming will disappear. Dispose the empty solvent vial with the blue part of the Mix2Vial.|