Feasibility of Using Recombinant Factor VIIa in Continuous Infusion

Abstract

SummaryRecombinant factor Vila (rFVIIa; NovoSeven®) is a recent addition to the hemostatic alternatives for the treatment of hemophiliacs with inhibitors. A drawback in the use of rFVIIa has been its half-life of only about 2 h, which necessitates very frequent and punctual injections. We evaluated the stability of reconstituted, but not further diluted, rFVIIa in 3 infusion systems (WalkMedTM 350 and CADD®-Plus minipumps and Meddex 2001 syringe pump). The factor VII (F VII) activity was maintained for at least 3 days at room temperature with only a minor and clinically insignificant increase in oxidized forms of rFVIIa and minimal leaching of the plastic softeners di-butylphthalate and di-octylphthalate after 24–48 h. Addition of heparin, 5–10 U/ml, to reconstituted rFVIIa caused a loss of about 50% of the activity within 4 h of storage in the infusion system, whereas low molecular weight heparin had no such effect. Repeated samples showed that the infusion systems maintained sterility. Reconstituted rFVIIa did not support bacterial growth when inoculated with Staphylococcus aureus or Escherichia coli to any greater extent than did reconstituted factor VIII, lidocaine in saline or heparin in saline. Two patients were treated with continuous infusion of rFVIIa on 4 occasions (total knee arthroplasty, wound revision, and twice straightening of a 90° contracture of the knee under general anaesthesia). A preoperative pharmacokinetic evaluation was performed, and the clearance was used to calculate the maintenance dose, aiming at a FVII level of 10 U/ml, which proved to be a hemostatic level. The first patient had no change in the clearance during the two treatment episodes. He suffered from repeated thrombophlebitis at the infusion site. The second patient had a progressive decrease of the clearance from 86.4 to 24.7 ml/h/kg. He received during the first treatment a parallel infusion with heparin (≈250 U/24 h) to the same venous access and did not develop thrombophlebitis during 3.5 days of therapy. For the second episode low molecular weight heparin was added directly to the infusion bag, and no adverse effects were observed. Continuous infusion with rFVIIa is thus feasible with the minipumps used by us, eliminates the need for 2 h injections and reduces the total dose of rFVIIa by 50–75%, depending on the behaviour of the clearance.