Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
FEIBA-NF (Baxter Healthcare)
vials containing 500 or 1000 units of powder for reconstitution
Approved indication: haemophilia A or B in patients with inhibitors
Australian Medicines Handbook section 7.4
Patients with haemophilia A (factor VIII deficiency) or B (factor IX deficiency) are unable to form a functional tenase complex (calcium, factors VIII, IX and X) which converts factor X to factor Xa and allows normal clotting to occur. Management of these patients usually involves giving a recombinant form of the missing factor. However, patients can develop inhibitory antibodies which neutralise the activity of these clotting factors. Currently in Australia the action of these inhibitors is bypassed by giving patients recombinant factor VIIa to activate the extrinsic clotting cascade (see New drugs, Aust Prescr 1999;22:95-8).
If factor VIIa therapy fails or is contraindicated, these patients can be treated with factor VIII inhibitor bypassing fraction. This contains prothrombin, factors IX and X (mainly non-activated), and factor VII (mainly activated).
Factor VIII inhibitor bypassing fraction is administered intravenously. The timing interval of subsequent doses depends on the site and severity of the bleed. As there is a risk of thrombosis, single doses of factor VIII inhibitor bypassing fraction should not exceed 100 units per kg of body weight and the infusion rate should not be greater than 2 units per kg of body weight per minute. The maximum daily dose should be less than 200 units per kg of body weight.
An open-label trial compared intravenous factor VIII inhibitor bypassing fraction and recombinant factor VIIa in 48 patients with haemophilia A. Each patient was started on one treatment after their first bleeding episode, then crossed over to the alternative treatment for the second bleeding episode. Both products were found to be effective in about 80% of patients six hours after treatment.1 Similar levels of efficacy have been observed in other trials.
With blood-derived products such as factor VIII inhibitor bypassing fraction, there is always a risk that it may contain infectious agents. A French study collected information about 433 bleeding episodes in 60 patients treated with factor VIII inhibitor bypassing fraction between 1978 and 1993. Of patients who were regularly evaluated, 1 of 52 became positive for human immunodeficiency virus (HIV) and 41 patients became positive for hepatitis C virus.2 Plasma from which this product is derived now undergoes viral serologic testing for hepatitis B, hepatitis C and HIV-1 and HIV-2 antibodies. In an effort to remove viruses, the product also undergoes vapour heat treatment and nanofiltration. However, despite the plasma screening and viral removal procedures, there is still a theoretical risk that viruses such as parvovirus B19 and hepatitis A could be transmitted via this product.
In the French study, 17 of 54 evaluable patients had increased inhibitor levels (by more than 50%) after infusion of factor VIII inhibitor bypassing fraction. However, this did not affect the response of these patients to therapy.2
Thrombosis is a recognised complication of factor VIII inhibitor bypassing fraction. In a pharmacovigilance study from 1999 to 2002, the incidence of thrombotic adverse events in patients treated with factor VIII inhibitor bypassing fraction was found to be 8.24 per 100 000 infusions. The most common event was myocardial infarction which occurred five times. Cerebrovascular thrombosis, pulmonary embolism and disseminated intravascular coagulation were also reported.3
Doctors should be aware that tests used to determine clotting time such as activated partial thromboplastin time (APTT) do not correlate with clinical improvement in patients being treated with factor VIII inhibitor bypassing fraction. Therefore clinical outcomes rather than results of these tests should be used to monitor the efficacy of this drug.
Factor VIII inhibitor bypassing fraction provides a second-line therapy for patients who fail to respond to factor VIIa therapy or for whom factor VIIa is contraindicated. However, prescribers should be aware that this product is derived from human plasma and can potentially transmit infectious agents.
- Astermark J, Donfield SM, Di Michele DM, Gringeri A, Gilbert SA, Waters J, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA Novo Seven Comparative (FENoC) Study. Blood 2007;109:546-51.
- Negrier C, Goudemand J, Sultan Y, Bertrand M, Rothschild C, Lauroua P, et al. Multi center retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. Thromb Haemost 1997;77:1113-9.
- Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004;2:1700-8.