Pharmacotherapeutic group: Blood coagulation factors. ATC Code: B02BD08.
Pharmacology: Pharmacodynamics: Mechanism of action: NovoSeven RT contains activated recombinant coagulation factor VII. The mechanism of action includes the binding of factor VIIa to exposed tissue factor. This complex activates factor IX into factor IXa and factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin into thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the haemostatic plug by converting fibrinogen into fibrin. Pharmacological doses of NovoSeven RT activate factor X directly on the surface of activated platelets, localised to the site of injury, independently of tissue factor. This results in the conversion of prothrombin into large amounts of thrombin independently of tissue factor.
Pharmacodynamic effects: The pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin.
A theoretical risk for the development of systemic activation of the coagulation system in patients suffering from underlying diseases predisposing them to DIC cannot be totally excluded.
In an observational registry (F7HAEM-3578) covering subjects with congenital FVII deficiency, 3 out of 91 surgical patients experienced thromboembolic events.
Pharmacokinetics: Healthy subjects: Distribution, elimination and linearity: Using the FVII clotting assay, the pharmacokinetics of rFVIIa were investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to sex and ethnic group and dosed with 40, 80 and 160 μg rFVIIa per kg body weight (3 doses each) and/or placebo. The pharmacokinetic profiles indicated dose proportionality. The pharmacokinetics were similar across sex and ethnic groups. The mean steady state volume of distribution ranged from 130 to 165 ml/kg, the mean values of clearance ranged from 33.3 to 37.2 ml/hxkg, and the mean terminal half-life ranged from 3.9 to 6.0 hours.
Haemophilia A and B with inhibitors: Distribution, elimination and linearity: Using the FVIIa assay, the pharmacokinetic properties of rFVIIa were studied in 12 paediatric (2-12 years) and 5 adult patients in non-bleeding state. Dose proportionality was established in children for the investigated doses of 90 and 180 μg per kg body weight, which is in accordance with previous findings at lower doses (17.5-70 μg/kg rFVIIa). The mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus 53 ml/hxkg), whereas the mean terminal half-life was determined to 2.3 hours in both groups. Mean volume of distribution at steady state was 196 ml/kg in paediatric patients versus 159 ml/kg in adults. Clearance appears related with age, therefore in younger patients clearance may be increased by more than 50%.
Factor VII deficiency: Distribution and elimination: Single dose pharmacokinetics of rFVIIa, 15 and 30 μg per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters: Volume of distribution at steady state (280-290 ml/kg), half-life (2.82-3.11 h), total body clearance (70.8-79.1 ml/hxkg) and mean residence time (3.75-3.80 h). The mean in vivo plasma recovery was approximately 20%.
Glanzmann's thrombasthenia: The pharmacokinetics of NovoSeven RT in patients with Glanzmann's thrombasthenia have not been investigated, but are expected to be similar to the pharmacokinetics in haemophilia A and B patients.
Toxicology: Preclinical safety data: All findings in the preclinical safety programme were related to the pharmacological effect of rFVIIa.
A potential synergistic effect of combined treatment with rFXIII and rFVIIa in an advanced cardiovascular model in cynomolgus monkey resulted in exaggerated pharmacology (thrombosis and death) at a lower dose level than when administering the individual compounds.