Source: Medicines Authority (MT) Revision Year: 2019 Publisher: CSL Behring GmbH, Emil-von-Behring-Str. 76, 35041 Marburg, Germany
Pharmacotherapeutic group: antihaemorrhagics: blood coagulation factors.
ATC code: B02BD02
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions.
When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation.
Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X 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 factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
In addition to its role as a factor VIII protecting protein, von Willebrand mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.
Data on treatment of 16 children less than 6 years of age are available and the clinical efficacy and safety results obtained were in line with the experience in older patients.
Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.
Following intravenous administration, factor VIII activity decreases mono- or biexponentially. The terminal half-life varies between 5 and 22 hours with a mean value of approximately 12 hours. The increase in factor VIII activity following administration of 1 IU factor VIII/kg bodyweight (incremental recovery) was approximately 2% with interindividual variability (1.5-3%). The mean residence time (MRT) was found to be 17 hours (standard deviation 5.5 hours), the mean area under the data completed by extrapolation (AUDC) was 0.4 h x kg/ml (standard deviation 0.2), the mean clearance 3 ml/h/kg (standard deviation 1.5 ml/h/kg).
Limited pharmacokinetic data are available in the paediatric population.
Toxicological studies with repeated dosage have not been performed due to development of antibodies against heterologous protein.
Even doses of several times the recommended human dosage per kilogram body weight show no toxic effects on laboratory animals.
The tests of the heat-treated factor VIII preparation with polyclonal precipitating antibodies (rabbit) in the Ouchterlony assay and in the passive cutaneous anaphylaxis test in the guinea pig did not show changed immunological reactions, compared with untreated protein.
Since clinical experience provides no hint for tumorigenic and mutagenic effects of human plasma coagulation factor VIII, experimental studies, particularly in heterologous species, are not considered meaningful.
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