Control and Prevention of Bleeding Episodes

The efficacy of FEIBA in the treatment of bleeding episodes has been demonstrated by two prospective clinical trials.1,2

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 necessary.

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 Bethesda Units (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 BU 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.

Routine Prophylaxis

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 pre-specified 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 therapy.

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 on-demand arm, all subjects experienced a bleeding episode.

ABR by age category between on-demand and prophylaxis regimens is provided in Table 5. One adolescent subject on prophylaxis had a higher rate of bleeding possibly due to increased physical activity after study enrollment.