Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Novo Nordisk A/S, Novo Allé, DK-2880, Bagsværd, Denmark
Pharmacotherapeutic group: Blood coagulation factors
ATC code: B02BD08
NovoSeven 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 activate factor X directly on the surface of activated platelets, localized 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.
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, the median dose for long term prophylaxis against bleeding in 22 paediatric patients (below 12 years of age) with Factor VII deficiency and a severe clinical phenotype was 30 μg/kg (range 17 μg/kg to 200 μg/kg; the dose most often used was 30 μg/kg in 10 patients) with a median dose frequency of 3 doses per week (range 1 to 7; the dose frequency most often reported was 3 per week in 13 patients).
In the same registry 3 out of 91 surgical patients experienced thromboembolic events.
An observational registry (F7HAEM-3521) covered 133 subjects with Glanzmann’s thrombasthenia treated with NovoSeven. The median dose per infusion for treatment of 333 bleeding episodes was 90 μg/kg (range 28 to 450 μg/kg). NovoSeven was used in 157 surgical procedures, at a median dose of 92 μg/kg (up to 270 μg/kg). Treatment with NovoSeven, alone or in combination with antifibrinolytics and/or platelets, was defined as effective when bleeding was stopped for at least 6 hours. The efficacy rates were 81% and 82%, respectively, in patients with positive or negative refractoriness to platelet transfusions, and 77% and 85%, respectively, in patients testing positive or negative for antibodies to platelets. Positive status indicates at least one positive test at any admission.
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 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/h×kg.
The mean terminal half-life ranged from 3.9 to 6.0 hours.
The pharmacokinetic profiles indicated dose proportionality.
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. Mean volume of distribution at steady state was 196 ml/kg in paediatric patients versus 159 ml/kg in adults.
Mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus 53 ml/h×kg), whereas the mean terminal half-life was determined to 2.3 hours in both groups. Clearance appears related with age, therefore in younger patients clearance may be increased by more than 50%.
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).
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/h×kg) and mean residence time (3.75–3.80 h).
The mean in vivo plasma recovery was approximately 20%.
Pharmacokinetics of NovoSeven 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.
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.
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