Safety of Recombinant Activated Coagulation Factor VII in Non-Hemophilia Patients.

Background and Purpose: The safety of recombinant activated coagulation factor VII (rFVIIa) has been studied in a variety of clinical settings including von Willebrand disease, thrombocytopenia, trauma, liver surgery, and vitamin-K antagonist therapy, as well as upper gastrointestional and central nervous system bleeding. Although multiple interventions have been developed to treat bleeding through revised surgical management and blood product transfusions, current treatment often remains inadequate. Seventeen clinical trials have been conducted in the seven therapeutic areas described above to evaluate the efficacy and safety of rFVIIa for the reduction or elimination of excessive bleeding. The safety data are presented in this summary.

Methods: A comprehensive review of rFVIIa safety data was performed, which included 1630 patients (rFVIIa: 1086; placebo: 544) from international studies in 7 therapeutic areas where patients received single or repeated doses ranging from 5–200 μg/kg, with a maximum of 8 doses.

Results: Serious adverse events (SAEs) were evenly distributed among treatment groups: 350/1086 (32%) rFVIIa-treated patients experienced 491 SAEs, and 213/544 (39%) placebo-treated patients experienced 333 SAEs. Fifty-one thromboembolic SAEs occurred in 48 patients (4.4%) in the rFVIIa treatment group (frequency per patient: 5%), and 20 thromboembolic SAEs occurred in 20 patients (3.7%) in the placebo group (frequency: 4%). Of the 51 thromboembolic SAEs in the rFVIIa group, 28 were arterial (frequency: 2.6%) and 23 were venous (frequency: 2.1%). Of the 20 thromboembolic SAEs that occurred in the placebo group, 8 were arterial (frequency: 1.5%) and 12 were venous (frequency: 2.2%). Thromboembolic SAEs considered by the investigator to be related to treatment represented thirty-four thromboembolic SAEs in the rFVIIa group (frequency of events per patient: 3.1%) and 13 thromboembolic SAEs in the placebo group (frequency: 2.4%). A total of 231 deaths occurred among both treatment groups: 144 (13%) from the rFVIIa group (11 thromboembolic-related deaths), and 87 (16%) from the placebo group (3 thromboembolic-related deaths). Of the 11 (1%) thromboembolic deaths that occurred in the rFVIIa group, 6 were considered by the investigator to be possibly/probably related to treatment. Of the 3 (0.6%) thromboembolic deaths that occurred in the placebo group, 2 were considered by the investigator to be possibly/probably related to treatment.

Conclusions: Recombinant FVIIa appears to be safely administered at total doses ranging from 5–1120 μg/kg for the treatment of a wide range of bleeding disorders. Continued safety and efficacy evaluations are underway to further elaborate on these observations.