Name: Coagulation Factor VIIa (recombinant)

NovoSeven® - Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ

Description/Contents: Factor VII is a serine protease and a vitamin K-dependent coagulation factor. The primary sequence of FVII is similar to other vitamin K dependent coagulation proteases and it circulates in blood as a single chain zymogen of 406 residues. The primary site of synthesis in humans is the liver.

Production of recombinant human factor VIIa requires a mammalian expression system. The gene for human FVII, isolated from chromosome 13, is transfected into a baby hamster kidney (BHK) cell line that secretes FVII into the culture medium in its single chain form. The product is purified with murine monoclonal anti-FVII antibodies and is subjected to treatment with 0.1% Triton X-100 to inactivate enveloped viruses. Subsequent ion exchange chromatography further purifies the product and causes auto-activation, producing an activated form of FVII.

FVIIa promotes hemostasis by enhancing thrombin generation through direct activation of FX after complexing with Tissue Factor (TF) at the site of injury. FVIIa by itself does not have proteolytic activity. In normal individuals a small amount of thrombin formed via the FVIIa/TF pathway activates FV and FVIII as well as platelets accumulated at the site of injury. The activated platelets then provide negatively charged surfaces for further thrombin generation. The administration of rFVIIa enhances thrombin generation through direct activation of FX independent of FVIII or FIX, on thrombin-activated platelet surfaces, ensuring a full thrombin burst needed for formation of a fully stabilized fibrin plug. NovoSeven may also directly activate platelets at the site of injury.

• rFVIIa is FDA approved for treatment of bleeding episodes in patients with hemophilia A or B, when inhibitors to these factors are present.

• Currently, the safety and efficacy of rFVIIa is being investigated in a number of trials designed to establish the efficacy of rFVIIa as a rescue treatment in episodes of severe life-threatening bleeding, stem cell transplantation, intra-cerebral haemorrhage and trauma. Several case reports in the literature support the use of rFVIIa in bleeding non-hemophiliac patients and thrombocytopenic patients, but no formal randomized trials have been presented and the drug is not licensed for these indications.

Dosage and Administration: The product is freeze-dried (lyophilized) in 1.2, 2.4 or 4.8 mg vials and is stable at 2 to 8oC for at least 2 years. rFVIIa is for IV administration only. The product should be administered within 3 hours of reconstitution.

The dose for hemophiliac patients with inhibitors is 90 ?g/kg every 2 hours until hemostasis is achieved or until the treatment is judged ineffective. Laboratory coagulation parameters, such as PT and aPTT, may be used as an adjunct to the clinical evaluation of hemostasis for monitoring the effectiveness of NovoSeven, although they have not shown direct correlation with hemostasis achieved.

Case report studies suggest that lower doses may be effective at halting bleeding in non-hemophiliac patients without inhibitors.

Patients should be monitored for signs and symptoms of activation of the coagulation system and /or thrombosis. Thrombotic events may be increased in patients with prothrombotic conditions such as DIC, advanced atherosclerosis, sepsis, cancer or crush injury.

Alternative Therapy: The treatment options available for hemophilia patients with inhibitors include Porcine FVIII or Prothrombin complex concentrate (PCC). In some cases intense plasmapheresis may lower inhibitor levels sufficiently to allow replacement of the missing factor.

Hedner U, Erhardtsen E. Potential role of rFVIIa in transfusion medicine. Transfusion 2002:42:114-124.

Kessler C. New products for managing inhibitors to coagulation factors: a focus on recombinant factor VIIa concentrate. Current Opinion in Hematology: 2000;7:408-413.

NovoSeven product monograph and package insert (revised January 2002).

Transfusion Guidelines

Plasma Guidelines	Antithrombin III Guidelines
Platelet Guidelines	Activated Protein Guidelines
Red Cell Guidelines	Factor IX Guidelines
Cryoprecipitate Guidelines	Factor VIII Guidelines
AICC/Porcine Factor VIII Guidelines	IVIG Guidelines Coagulation Factor VII Guidelines

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