A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven®)

Abstract

Summary. Recombinant activated factor VII (rFVIIa, NovoSeven 1 ) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa 'megadose' (300 mg kg À1 bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 mg kg À1 every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 mg kg À1 ) was higher than with standard boluses (180-270 mg kg À1 ), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL À1 ; range: 19.8-54 U mL À1 ). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.

The use of recombinant factor VIIa in the treatment of bleeding disorders

“…Recent developments suggest that doses higher than those recommended may be more efficacious in patients with hemophilia and may require dosing at less frequent intervals. 32,33 Constant infusion regimens for the use of rfVIIa have also been described and have been used successfully. 34 With this regimen it may be possible to use less rfVIIa when compared with treatment regimens using bolus doses.…”

“…33 Of 114 bleeding episodes, 95 responded to a single 300-g dose of rfVIIa without side effects. The remaining patients responded to subsequent similar doses of rfVIIa.…”

“…Although the number of patients in these studies is small, the data suggest that higher doses are not only more effective but are also safe. 33 It has been noted that with higher doses of VIIa, peak thrombin generation is higher and is thought to result in a more stable and less porous fibrin clot. 36,37 It has also been reported that sequential therapy with factor VIIa and prothrombin complex concentrates may be more beneficial than factor VIIa alone, suggesting a synergistic effect between the 2 agents.…”

A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an In Vitro Model of Hemophilia

“…Children especially seem to require higher doses per injection than adults for an optimal effect. 7,8 In most cases an optimal dose seems to be achievable if doses are individualized. 8 -10 However, in some special situations the rapid formation of a strong fibrin plug may be necessary to restore hemostasis.…”

Hemophilia: New Protein Therapeutics

“…However, its short plasma half-life requires a short interval for follow-up dosing and limits its application in prophylaxis. In addition, clinical studies have suggested that higher initial doses may result in a more rapid onset of hemostasis, 39,40 and the time from initiation of bleeding to initiation of treatment may have a significant impact on efficacy. 41 Accordingly, several bioengineering strategies have been implemented in an attempt to improve rFVIIa functionality.…”