Hemophilia

FEIBA^® is an anti-inhibitor coagulant complex used to control, prevent, or reduce bleeding episodes and for perioperative management in hemophilia A and B patients who have developed inhibitors.¹ 

Treating hemophilia requires the infusion of clotting factor concentrates that will replace a specific missing clotting factor. However, the production of antibodies, also called inhibitors, to the infused therapy may occur, often preventing the treatment to be successful.^2,3 Inhibitors may develop at any age; however, they typically appear in young children.⁴ Patients presenting simultaneous severe hemophilia and inhibitors may develop complications such as uncontrollable bleedings since their bleeding episodes are challenging to manage.³ Additionally, these patients are at higher risk of being admitted to a hospital and are also at an increased risk of death.²

FEIBA was initially approved by the US Food and Drug Administration (FDA) in 1986 and is a trademark of Baxalta, a Takeda company. It is FDA-approved for the treatment of hemophilia A and B patients with inhibitors, and it is not recommended for treating bleeding episodes in patients who have not developed inhibitors.¹

FEIBA Mechanism of Action, Usage, and Adverse Reactions

FEIBA contains many key proteins involved in blood clotting in the activated (F VII) and nonactivated forms (FII, IX and X) as well as prothrombin complex factors that increase thrombin generation required for adequate hemostasis.^1,5 By acting at different sites in the clotting cascade, instead of directly replacing FVIII or FIX, FEIBA bypasses the factor that is inactivated by the inhibitor.³

The recommended dose of FEIBA is dependent on the type and severity of the bleeding episode, with doses of 50-100 unit/kg recommended for control and prevention of bleeding and perioperative management determined by the type of bleeding episode or type of surgical intervention. . The recommended dose for bleeding prophylaxis is 80 unit/kg every other day. ¹

Frequent adverse reactions to FEIBA include anemia, diarrhea, hemarthrosis, and vomiting. Serious adverse reactions associated with the use of FEIBA are hypersensitivity reactions and embolic and thromboembolic events such as stroke, pulmonary embolism and deep vein thrombosis. The possibility of thrombotic events should be considered especially with concomitant use of systemic antifibrinolytics such as tranexamic acid and aminocaproic acid. As FEIBA is produced from pools of human plasma, there is also a risk associated with the transmission of infectious agents.¹

Get full prescribing information about FEIBA VH Immuno at MPR.

Efficacy and Safety of FEIBA

The efficacy of the treatment of bleeding episodes with FEIBA was evaluated in 2 prospective clinical trials.^6,7 A double-blind, randomized trial studied the effect of FEIBA in 15 patients with hemophilia A and inhibitors. These patients received FEIBA or a control preparation containing a nonactivated prothrombin-complex concentrate for the treatment of 150 bleeding episodes. Results of the trial showed that FEIBA was effective in 64% of the episodes with significant improvement of joint mobility, while the control preparation was effective in 52% of the cases.⁶ In the second trial, FEIBA efficacy was studied in 46 patients with FVIII inhibitors and in 3 patients with FIX inhibitors. This study revealed that 93% of the 165 bleeding episodes treated with FEIBA were effectively controlled.⁷

The ProFEIBA study (NCT00221195) was designed to evaluate if FEIBA was able to reduce the number of bleeding episodes in patients with hemophilia A and elevated levels of inhibitors.⁸ For this randomized, prospective, and crossover study, 34 patients were enrolled, and the effect of a prophylactic infusion administered for 6 months was compared to a subsequent 6-month, on-demand therapy after a washout period of 3 months. The results of this trial showed prophylaxis with FEIBA promoted a 62% reduction in all bleeding episodes, a 61% reduction in hemarthroses, and a 72% reduction in target-joint bleeding.⁸

A phase-3, randomized, multicenter, open-label, 2-arm, parallel trial evaluated the safety of prophylaxis using FEIBA (NCT00851721).⁹ In this trial, 17 patients were treated in a prophylaxis regimen with FEIBA, while 19 patients received the drug on demand for a 1-year period. The primary outcome of this trial was a reduction in the annualized bleeding rate within patients prophylactically treated as compared with on-demand treatment. Data showed a 72.5% reduction in annualized bleeding rate for the patients on prophylaxis. Results also revealed that the total use of FEIBA was significantly higher in on-demand treatment.⁹

Another ongoing study is FEIBA STAR (NCT02764489), focused on evaluating the safety and tolerability of FEIBA after its reconstitution in a reduced volume and administered at increased infusion rates. FEIBA-GO is also an ongoing noninterventional study that aims to gather information on the long-term effectiveness, safety, and quality of life in hemophilia A and B patients who present high-responding inhibitors.¹⁰ The initial results published reported that the prevention of joint bleeding promoted by FEIBA administered in prophylaxis was comparable to the prevention reported in patients who underwent prophylaxis and did not present inhibitors.¹⁰ This efficacy was subsequently confirmed in an interim analysis of real-world data and after more than 18 months of follow-up.¹¹

References

1. FEIBA (anti-inhibitor coagulant complex): highlights of prescribing information. Baxalta US Inc. Updated February 2020. Accessed December 23, 2021.

2. Inhibitors. National Hemophilia Foundation. Accessed December 21, 2021.

3. Inhibitors and hemophilia. Centers for Disease Control and Prevention. Updated July 17, 2020. Accessed December 21, 2021.

4. Inhibitors, A to B. Takeda Pharmaceutical Company Limited. 2020. Accessed December 21, 2021.

5. Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia. 2004;10(Suppl 2):10-16. doi:10.1111/j.1365-2516.2004.00935.x

6. Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial. N Engl J Med. 1981;305(13):717-721. doi:10.1056/NEJM198109243051301

7. 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. 1983;61(1):36-40.

8. Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011;365(18):1684-1692. doi:10.1056/NEJMoa1104435. Erratum in: N Engl J Med. 201;365(25):2441.

9. Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014;20(1):65-72. doi:10.1111/hae.12246

10. C Ettingshausen CE, Windyga J, Hermans C, et al. “FEIBA Global Outcome Study (FEIBA GO)” data read-out: real world bleeding frequency in inhibitors patients on prophylaxis with APCC. Blood. 2017;130(Suppl 1):4880. doi.org/10.1182/blood.V130.Suppl_1.4880.4880

11. Windyga J, Holme PA, Hermans C, et al. Real-world clinical management of patients with hemophilia and inhibitors: effectiveness and safety of aPCC in patients with >18 months’ follow-up in the FEIBA Global Outcome Study (FEIBA GO). Blood. 2019;134(Suppl 1):2418. doi:https://doi.org/10.1182/blood-2019-124324

Reviewed by Kyle Habet, MD, on 12/31/2021.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.