Von Willebrand factor

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels. Therefore, patients at risk have to be monitored for early signs of thrombosis, and prophylaxis measures against thromboembolism should be instituted according to current recommendations and standard of care.

Animal reproduction studies have not been conducted with von Willebrand factor.

Experience in the treatment of pregnant or breast-feeding women is not available. Von Willebrand factor should be administered to pregnant women only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients.

It is unknown whether von Willebrand factor is excreted in human milk. Therefore, von Willebrand factor should be administered to lactating von Willebrand factor deficient women only if clearly indicated. Healthcare professionals should balance the potential risks and only prescribe von Willebrand factor if needed.

Fertility

The effects of von Willebrand factor on fertility have not been established.

Von Willebrand factor has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

During treatment with von Willebrand factor the following adverse reactions may occur: hypersensitivity or allergic reactions, thromboembolic events, inhibitor formation against VWF.

Tabulated list of adverse reactions

The following table lists the adverse reactions reported in clinical trials, post-authorisation safety studies or post-marketing reporting. Frequency categories are defined 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Summary of adverse reactions reported in clinical trials, post-authorisation safety studies or post-marketing with von Willebrand factor in von Willebrand disease:

^* Adverse reactions identified during post-marketing surveillance.

Description of selected adverse reactions

Hypersensitivity

There is a possibility of developing hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, rhinoconjunctivitis, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) which may in some cases progress to anaphylaxis (including shock).

Patients with VWD, especially type 3, may very rarely develop neutralising antibodies (inhibitors) to von Willebrand factor. If such inhibitors occur, the condition may manifest itself as an inadequate clinical response. Such antibodies may occur in close association with hypersensitivity or anaphylactic reactions. Therefore, patients experiencing hypersensitivity or anaphylactic reactions should be tested and evaluated for the presence of an inhibitor.

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

Thrombogenicity

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors including low ADAMTS13 levels. Therefore, patients at risk have to be monitored for early signs of thrombosis, and prophylaxis measures against thromboembolism should be instituted according to current recommendations and standard of care.

Immunogenicity

The immunogenicity of von Willebrand factor was assessed in clinical trials by monitoring the development of neutralising antibodies against VWF and FVIII, as well as binding antibodies against VWF, Furin, Chinese Hamster Ovary (CHO) protein and mouse IgG. No treatment-emergent development of neutralising antibodies against human VWF or neutralising antibodies against human rFVIII was observed. One of the 132 subjects who received von Willebrand factor peri-operatively in clinical trials developed treatment-emergent binding antibodies against VWF following a surgery for whom no adverse events or lack of haemostatic efficacy has been reported. Binding antibodies against impurities such as rFurin, CHO-protein or mouse IgG were not observed after treatment with von Willebrand factor.

Paediatric population

The frequency, type and severity of adverse reactions in children receiving von Willebrand factor for the treatment of haemorrhage are expected to be the same as in adults.