Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program

J Thromb Haemost. 2019 Sep;17(9):1470-1477. doi: 10.1111/jth.14491. Epub 2019 Jun 17.


Background: Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven® , Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra® ; F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications. Roche and Novo Nordisk collaboratively analyzed all available data on the use of rFVIIa in patients receiving emicizumab prophylaxis in the Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN) clinical development program.

Objective: Obtain further insights into the concomitant clinical use and safety of rFVIIa and emicizumab.

Methods: The initial individual rFVIIa dose, dosing intervals and cumulative dosing were evaluated in the HAVEN 1, HAVEN 2, and HAVEN 4 trials. All adverse events reported in each of the three trials in patients treated with rFVIIa, including available narratives, were assessed.

Results: The vast majority of bleeds occurred in HAVEN 1. When rFVIIa was used to treat a bleeding episode, a 100 ± 20 μg/kg dose was used to initiate treatment in the majority of cases. The dosing interval, as well as cumulative dosing were consistent with prescribing information and current practice. No serious adverse events, no thrombotic microangiopathy cases, or thromboembolic events were assessed to be associated with rFVIIa when used in conjunction with emicizumab prophylaxis in the HAVEN trials.

Conclusion: rFVIIa use in the context of emicizumab prophylaxis does not change the rFVIIa safety profile as described in the product information.

Keywords: emicizumab; hemophilia A; recombinant FVIIa; safety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Bispecific / administration & dosage
  • Antibodies, Bispecific / adverse effects*
  • Antibodies, Bispecific / therapeutic use
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Blood Loss, Surgical / prevention & control
  • Clinical Trials as Topic / statistics & numerical data
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • Factor VIII / immunology
  • Factor VIIa / administration & dosage
  • Factor VIIa / adverse effects*
  • Factor VIIa / therapeutic use
  • Hemophilia A / drug therapy*
  • Hemorrhage / drug therapy
  • Hemorrhage / etiology
  • Hemorrhage / prevention & control
  • Humans
  • Isoantibodies / immunology
  • Multicenter Studies as Topic / statistics & numerical data
  • Postoperative Hemorrhage / prevention & control
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Retrospective Studies
  • Risk
  • Thrombosis / chemically induced*
  • Thrombosis / prevention & control


  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • Isoantibodies
  • Recombinant Proteins
  • emicizumab
  • F8 protein, human
  • Factor VIII
  • recombinant FVIIa
  • Factor VIIa