Mechanism Of Action
Multiple interactions of the components in FEIBA restore the impaired thrombin generation of
hemophilia patients with inhibitors. In vitro, FEIBA shortens the activated partial thromboplastin time
(aPTT) of plasma containing factor VIII inhibitor.4,5
Control And Prevention Of Bleeding Episodes
The efficacy of FEIBA in the treatment of bleeding episodes has been demonstrated by two prospective
clinical trials1,2 .
The first trial was a multicenter, randomized, double-blind trial comparing the effect of FEIBA and a
non-activated prothrombin complex concentrate in 15 subjects with hemophilia A and inhibitors to factor
VIII. The inclusion criteria were history of high titer inhibitors, high responder status, more than 1
bleeding episode per month in the prior year and no signs of liver failure. A total of 150 bleeding
episodes including 117 joint, 20 musculoskeletal and 4 mucocutaneous bleeds, were treated. A single
dose of 88 units per kg of body weight was used uniformly for treatments with FEIBA. A second
treatment was allowed for muscle bleeds after 12 hours and 6 hours after mucocutaneous bleeds, if
Subjects and investigators were asked to rate hemostatic efficacy based on a scale of effective, partially
effective, not effective or not sure. The criteria for evaluation of the effectiveness were severity of
pain, subjective improvement, circumference of muscle or joint, restriction of joint mobility, cessation
of open bleeding, start of rebleeding and quantity and nature of analgesics. FEIBA was effective in 41%
and partly effective in 25% of episodes (i.e. combined effectiveness of 66%), while prothrombin
complex concentrate was rated effective in 25% and partly effective in 21% of episodes (i.e., combined
effectiveness of 46%).
The second trial with FEIBA was a multicenter randomized, prospective trial. This trial was conducted
in 44 hemophilia A subjects with inhibitors, 3 hemophilia B subjects with inhibitors and 2 acquired
factor VIII inhibitor subjects. It was designed to evaluate the efficacy of FEIBA in the treatment of joint,
mucous membrane, musculocutaneous and emergency bleeding episodes such as central nervous system
hemorrhages and surgical bleedings. The inclusion criteria used were age >4 years, history of
inhibitor titer ≥4 BU and without chronic liver disease. Subjects were excluded if they had a history of
thromboembolic events or allergic reactions to FEIBA.
Forty-nine (49) subjects with inhibitor titers of greater than 5 Bethesda Units were enrolled from nine
co-operating hemophilia centers. Subjects were treated with 50 units per kg of body weight, repeated at
12-hour intervals (6-hour intervals in mucous membrane bleedings), if necessary. A total of 489
infusions were given for the treatment of 165 bleeding episodes (102 joint, 33 muscle and soft tissue,
20 mucous membrane, and 10 emergency bleeds, including 3 central nervous system bleeds and 4
surgical procedures). Bleeding was controlled in 153 episodes (93%). In 130 (78%) of the episodes,
hemostasis was achieved with one or more infusions within 36 hours. Of these, 36% were controlled
with one infusion within 12 hours. An additional 14% of episodes responded after more than 36 hours.
In a multicenter, open-label, prospective, randomized clinical trial comparing subjects receiving FEIBA
for prophylaxis with subjects receiving FEIBA for on-demand treatment, 36 hemophilia A and B
subjects with inhibitors to factor VIII or IX were analyzed in the intent-to-treat analysis. Study
population included 29 (80.6%) Caucasian, 3 (8.3%) Asian, 2 (5.6%) Black/African American, and 2
(5.6%) other. Inclusion criteria were subjects with a history of high titer inhibitors or low titer
refractory to increased factor VIII or IX dosing, age range between 4 and 65, and subjects receiving
bypassing agents with ≥12 bleeds in the 12 months prior to trial entry. Subjects with a history of
thromboembolic events, symptomatic liver disease, or a platelet count <100,000 per mL, and those
receiving immune tolerance induction or routine prophylaxis were excluded.
Subjects were randomized to receive 12 months of prophylactic or on-demand treatment with FEIBA.
Seventeen subjects randomized to the prophylaxis arm received 85 units per kg of FEIBA every other
day. Nineteen subjects randomized to the on-demand arm received FEIBA for the treatment of acute
bleeding episodes per the dose and dosing regimen recommended. Target joints were defined as ≥4
bleeding episodes within 6 months. In this trial, ankles, knees, elbows and hips were target joint
locations. Preexisting target joints were not considered as new target joints.
Hemostatic efficacy for treatment of acute bleeds was evaluated at 6 and 24 hours according to a prespecified
four-point scale of excellent, good, fair, or none. An evaluation of "none" was considered a
treatment failure. The criteria for evaluation of the effectiveness were relief of pain, cessation of
bleeding, and number of infusions required to treat a bleed.
A total of 825 bleeding episodes were reported including 196 that occurred during prophylaxis and
629 that occurred during on-demand therapy. A majority (78%) of the 794 bleeding episodes that were
rated for efficacy were treated with 1 or 2 infusions. Hemostatic efficacy was rated as excellent or
good for 74% of bleeding episodes rated at 6 hours post infusion and for 87% of the bleeding
episodes at 24 hour post infusion. A total of 19 (2.4%) bleeds were rated as "none" at 6 hours post
infusion; 1 bleed (0.1%) was rated "none" at 24 hours.
Hemostatic efficacy for routine prophylaxis was evaluated against subjects who received on-demand
The overall median annual bleed rate (ABR) for the on-demand arm was 28.7 compared to 7.9 for the
prophylaxis arm, which represents a 72% reduction in median ABR with prophylaxis. When analyzed by
site (e.g. joint, non-joint) and cause of bleed (e.g. spontaneous, traumatic), prophylactic treatment with FEIBA resulted in a greater than 50% reduction in ABR. There were fewer subjects in the prophylaxis
arm who developed new target joints (7 new target joints in 5 subjects treated with prophylaxis
compared to 23 new target joints in 11 subjects in the on-demand arm). Target joints developed in two
subjects in the on-demand arm and three in the prophylaxis arm who did not have reported target joints at
trial enrollment. A total of 3 of 17(18%) subjects had no bleeding episodes on prophylaxis. In the ondemand
arm, all subjects experienced a bleeding episode.
ABR by age category between on-demand and prophylaxis regimens is provided in Table 4. One
adolescent subject on prophylaxis had a higher rate of bleeding possibly due to increased physical
activity after study enrollment.
Table 4 ABR by Age Category
|Number of Subjects
|Number of Subjects
(≥7 to <12 years old)
(≥12 to <16 years
(≥16 years old)
1. Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP, van Geijlswijk JL, van Houwelingen H, van
Asten P, Sixma JJ. The effect of Activated Prothrombin-Complex Concentrate (FEIBA) on joint
and muscle bleeding in patients with Hemophilia A and antibodies to Factor VIII. N Engl J Med.
2. Hilgartner MW, Knatterud GL. The use of Factor-Eight-Inhibitor-By-Passing-Activity (FEIBA
IMMUNO) product for treatment of bleeding episodes in Hemophiliacs with inhibitors. Blood.
4. Turecek PL, Varadi K, Gritsch H, Auer W, Pichler L, Eder G, Schwarz HP. Factor Xa and
prothrombin: mechanism of action of FEIBA. Vox Sanguinis 1999;77 Suppl 1:72-79.
5. Turecek PL, Varadi K, Gritch H, Schwarz HP. FEIBA: Mode of action Haemophilia 2004;10: