Hemophilia therapy NovoSeven® RT, recombinant human coagulation factor VIIa (rFVIIa), is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues that is structurally similar to endogenous human coagulation factor VIIa (FVIIa).1 NovoSeven RT is a sterile, white lyophilized powder for reconstitution for intravenous injection supplied in single-dose vials containing 1, 2, 5, or 8 mg of rFVIIa. After reconstitution with a specified volume of histidine diluent, the final solution contains 1 mg/mL (1000 mcg/mL) of rFVIIa.1

NovoSeven RT is indicated for the treatment of bleeding episodes and perioperative management in adults and children with hemophilia A or B with inhibitors, congenital factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia with refractoriness to platelet transfusions, as well as in adults with acquired hemophilia. The drug was initially approved by the US Food and Drug Administration (FDA) in 1999.1

The human coagulation FVII gene is cloned and expressed in baby hamster kidney cells (BHK cells). During the chromatographic purification process, recombinant FVII is released into the culture medium (including newborn calf serum) in its single-chain form and is subsequently proteolytically transformed to the active two-chain form, rFVIIa, by autocatalysis. Exogenous viruses are removed using the purifying method (MuLV, SV40, poxvirus, reovirus, BEV, IBR virus), and no human serum or other proteins are used in the production or formulation of NovoSeven RT.1

Mechanism of Action

NovoSeven RT is a recombinant FVIIa that activates coagulation factor X to factor Xa as well as coagulation factor IX to factor IXa when complexed with tissue factor. Factor Xa then converts prothrombin to thrombin in complex with other factors, resulting in the creation of a hemostatic plug by converting fibrinogen to fibrin and inducing local hemostasis.1

The effect of NovoSeven RT on coagulation in patients with and without hemophilia has been studied in several model systems. The addition of rFVIIa to an in vitro model of tissue factor-initiated blood coagulation increased both the rate and level of thrombin generation in normal and hemophilia A blood.2 In a separate model, increasing rFVIIa dosages in hemophilia plasma, resulted in a dose-dependent increase in thrombin generation.3

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Clinical Studies

A double-blind, randomized comparison trial of 2 dose levels of NovoSeven RT (35 mcg/kg and 70 mcg/kg) in the treatment of joint, muscle, and mucocutaneous hemorrhages was conducted in 78 hemophilia A and B patients with and without inhibitors. According to the investigators’ subjective assessment, the efficacy rates for the 35 mcg/kg and 70 mcg/kg groups were: excellent 59% and 60%, effective 12% and 11%, and partially effective 17% and 20%, respectively. The mean number of doses necessary to achieve hemostasis was 2.7 in the 35 mcg/kg group and 3.1 in the 70 mcg/kg group.4

To evaluate the safety and efficacy of NovoSeven RT administration during and after surgery in hemophilia A and B patients with inhibitors, a randomized, double-blind, parallel-group clinical trial (28 hemophilia A and B patients with inhibitors and 1 patient with acquired inhibitors to factor VIII undergoing major or minor surgical procedures) was conducted. Intraoperative hemostasis was achieved in 28/29 (97%) patients. At 48 hours, satisfactory hemostasis was achieved in 14/14 (100%) patients in the 90 mcg/kg dose group and 11/15 (73%) in the 35 mcg/kg dose group; at 5 days, satisfactory hemostasis was achieved in 13/14 (93%) patients in the 90 mcg/kg dose group and 11/15 (73%) in the 35 mcg/kg dose group.5

Warnings, Precautions, and Adverse Reactions

In clinical trials and postmarketing surveillance, serious arterial and venous thrombotic events have been reported. Patients who may be at increased risk of developing thrombotic events include those with congenital hemophilia who are receiving activated prothrombin complex concentrates concomitantly; older patients, particularly those with acquired hemophilia who are receiving other hemostatic agents; patients with a history of cardiac or vascular disease; and those who are predisposed to thrombotic events. Patients receiving NovoSeven RT should be monitored for indications or symptoms of coagulation system activation or thrombosis.1

NovoSeven RT can cause hypersensitivity reactions, including anaphylaxis. Patients who have a history of allergies to mouse, hamster, or bovine proteins may be more susceptible to hypersensitivity reactions.1

Patients with FVII deficiency should be monitored for prothrombin time (PT) and FVII coagulant activity before and after NovoSeven RT administration. If FVIIa activity does not reach the expected level, the PT is not corrected, or bleeding is not controlled following therapy with the recommended doses, antibody formation may be suspected and antibody testing should be done.1

Thrombotic events were the most common and serious adverse reactions in clinical studies. Thrombotic adverse reactions occurred in 4% of patients with acquired hemophilia and 0.2% of patients with congenital hemophilia after receiving NovoSeven RT in clinical studies.1

References

  1. NovoSeven RT. Prescribing information. Novo Nordisk; 2020. Accessed December 30, 2021.
  2. Butenas S, Brummel KE, Branda RF, Paradis SG, Mann KG. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood. 2002;99(3):923-930. doi:10.1182/blood.v99.3.923
  3. Allen GA, Monroe DM III, Roberts HR, Hoffman M. The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation. Blood Coagul Fibrinolysis. 2000;11 Suppl 1:S3-S7. doi:10.1097/00001721-200004001-00002
  4. Lusher JM, Roberts HR, Davignon G, et al.; rFVIIa Study Group. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. Haemophilia. 1998;4(6):790-798. doi:10.1046/j.1365-2516.1998.00209.x
  5. Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost. 1998;80(5):773-778.

Reviewed by Harshi Dhingra, MD, on 1/2/2022.

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