Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Blood coagulation factors, ATC code: B02BD08.

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, 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.

Pharmacodynamic effects
The pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin.

The time to peak coagulant activity after administration of NovoSeven RT was approximately 10 minutes in healthy subjects and patients with haemophilia.

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.

Clinical efficacy and safety

Congenital FVII deficiency
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.

Glanzmann’s thrombasthenia

An observational registry (F7HAEM-3521) covered 133 subjects with Glanzmann’s thrombasthenia treated with NovoSeven RT. The median dose per infusion for treatment of 333 bleeding episodes was 90 µg/kg (range 28 to 450 µg/kg). NovoSeven RT was used in 157 surgical procedures, at a median dose of 92 µg/kg (up to 270 µg/kg). Treatment with NovoSeven RT, 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.

Severe postpartum haemorrhage

The efficacy and safety of NovoSeven RT was assessed in 84 women with severe postpartum haemorrhage in a multicentre, open-label clinical trial. Patients were randomised either to treatment with a single dose of 60 μg/kg of NovoSeven RT (in addition to standard of care; N=42) or to reference therapy (standard of care alone; N=42), following failure of uterotonics (sulprostone). The treatment groups were well balanced in terms of demographic characteristics and postpartum haemorrhage treatment prior to randomisation. Fibrinogen and tranexamic acid were part of standard of care. Information on fibrinogen/tranexamic acid use was available from approximately 57% of patients in the NovoSeven RT group and 43% of patients in the reference group. Of these, about 40% of the patients in both groups received fibrinogen and/or tranexamic acid. Bleeding was considered to have stopped (i.e. treatment success) if the estimated blood flow decreased to less than 50 ml per 10 minutes within the 30 minutes following randomisation. If the bleeding was uncontrolled or intractable, invasive procedures were considered.

In the primary analysis, fewer women in the NovoSeven RT group (21 vs 35) had at least one embolisation and/or ligation procedure compared to the reference group, corresponding to a statistically significant 40% relative reduction in risk for the NovoSeven RT group compared to the reference group (relative risk = 0.60 (95% confidence interval: 0.43 – 0.84, p=0.0012)).

In the reference group, 8 of the 42 patients received late NovoSeven RT as a compassionate treatment in an attempt to avoid salvage hysterectomy, which succeeded in 2 cases.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
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 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.

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.
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).



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/h×kg) and mean residence time (3.75 – 3.80 h).
The mean in vivo plasma recovery was approximately 20%.

Glanzmann’s thrombasthenia

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.

Severe postpartum haemorrhage

Pharmacokinetics of NovoSeven RT in patients with severe postpartum haemorrhage have not been investigated.