- von willebrand factor
POM: Prescription only medicine
This information is intended for use by health professionals
Excipient with known effect:This medicinal product contains sodium:One 10 ml vial (1000 IU) of Willfact contains 0.3 mmol (6.9 mg) sodium.For a full list of excipients, see section 6.1.
PosologyGenerally, 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 treatmentThe 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 injectionsIf 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 prophylaxisWillfact 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 populationThere 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 administrationThe 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
HypersensitivityAs 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 agentsStandard 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). The measures taken may be of limited value against non-enveloped viruses such as hepatitis A 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. It is strongly recommended that every time Willfact 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.
ThromboembolismThere 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 VWF 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.
ImmunogenicityPatients with von Willebrand disease, especially Type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. 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 VWF 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.
Summary of the safety profileHypersensitivity 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 VWF. Patients treated with VWF 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 VWF 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 reactionsThe 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).
|System Organ Class according to the MedDRA||Adverse reactions||Frequency|
|Immune system disorders||Hypersensitivity or allergic reactions. These may in some cases progress to severe anaphylaxis (including shock).||Uncommon|
|Nervous system disorders||Headache, tingling, lethargy||Uncommon|
|Vascular disorders||Hypotension, flushing||Uncommon|
|Respiratory thoracic and mediastinal disorders||Wheezing||Uncommon|
|Gastrointestinal disorders||Nausea, vomiting||Uncommon|
|Skin and subcutaneous tissue disorders||Angioedema, generalised urticaria, hives||Uncommon|
|General disorders and administration site conditions||Burning and stinging at the infusion site, chills, tightness of the chest Fever||Uncommon Rare|
|Investigations||Neutralising antibodies (inhibitors) to VWF||Very rare|
Reporting of suspected adverse reactionsReporting 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".
Reconstitution:The currently applicable guidelines for aseptic procedures must be followed. The transfer system is only used to reconstitute the drug, as described below. It is not intended in administering the drug to the patient.
|• Bring the two vials (powder and solvent) to a temperature not above 25°C.|
|• Remove the protective cap from the solvent vial (water for injections) and from the powder vial. • Disinfect the surface of each stopper.|
|• Remove the cap from the Mix2Vial device. Without removing the device from its packaging, attach the blue end of the Mix2Vial to the stopper of the solvent vial.|
|• Remove and discard the packaging. Take care not to touch the newly-exposed part of the device.|
|• Turn the solvent vial-device assembly over and attach to the powder vial using the transparent part of the device. The solvent will automatically transfer to the powder vial. Hold the assembly and gently swirl to completely dissolve the product.|
|• Now, holding the reconstituted product part in one hand and the solvent part in the other, unscrew the Mix2Vial device to separate the vials.|
|• Hold the vial of reconstituted product in vertical position while screwing a sterile syringe onto the Mix2Vial device. Then slowly draw the product up into the syringe. • Once the product has been transferred to the syringe, firmly hold the syringe (with the piston pointing downward), unscrew the Mix2Vial device and replace it with an intravenous or butterfly needle. • Expel the air from the syringe and insert into the vein after disinfecting the surface. • Inject slowly by intravenous route immediately after reconstitution as a single dose at a maximum rate of 4 ml/minute.|
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