FEASIBILITY OF USING RECOMBINANT FACTOR VIIA IN CONTINUOUS-INFUSION

Recombinant factor VIIa (rFVIIa; NovoSeven(R)) is a recent addition to the hemostatic alternatives for the treatment of hemophiliacs with in hibitors. A drawback in the use of rFVIIa has been its half-life of on ly 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 (WalkMed(TM) 350 and CADD(R)-Plus minip umps and Meddex 2001 syringe pump). The factor VII (F VII) activity wa s 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 dibutylphthalate and di-oct ylphthalate after 24-48 h. Addition of heparin, 5-10 U/ml, to reconsti tuted rFVIIa caused a loss of about 50% of the activity within 4 h of storage in the infusion system, whereas low molecular weight heparin h ad no such effect. Repeated samples showed that the infusion systems m aintained sterility. Reconstituted rFVIIa did not support bacterial gr owth when inoculated with Staphylococcus aureus or Escherichia coli to any greater extent than did reconstituted factor VIII, lidocaine in s aline or heparin in saline. Two patients were treated with continuous infusion of rFVIIa on 4 occasions (total knee arthroplasty, wound revi sion, and twice straightening of a 90 degrees 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 hemosta tic 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 t he clearance from 86.4 to 24.7 ml/h/kg. He received during the first t reatment a parallel infusion with heparin (approximate to 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 hepar in was added directly to the infusion bag, and no adverse effects were observed. Continuous infusion with rFVIIa is thus feasible with the m inipumps used by us, eliminates the need for 2 h injections and reduce s the total dose of rFVIIa by 50-75%, depending on the behaviour of th e clearance.