FEIBA for Hemophilia

Last updated July 14, 2022, by Marta Figueiredo, PhD

Fact-checked by Joana Carvalho, PhD


What is FEIBA for Hemophilia?

FEIBA (factor eight inhibitor bypassing activity), also known as activated prothrombin complex concentrate and anti-inhibitor coagulant complex, is a bypassing agent to prevent or reduce bleeding events in hemophilia A and hemophilia B patients with inhibitors, or neutralizing antibodies, against their missing blood clotting factors.

It was originally developed by Baxter Healthcare and marketed by its spinoff Baxalta, which is now part of Takeda.

How does FEIBA work?

Marked by prolonged and excessive bleeding, hemophilia A and B are caused by missing or defective blood clotting factors due to mutations in the genes that code them. A deficiency in factor VIII (FVIII) is the root cause of hemophilia A, while the lack of factor IX (FIX) is associated with hemophilia B.

Replacement therapy, a form of treatment wherein patients receive a version of the clotting factor they are missing, is considered a current standard of care for both types of hemophilia. However, up to 30% of hemophilia A patients and about 5% of those with hemophilia B may develop inhibitors against these clotting factors, rendering replacement therapy ineffective.

As a bypassing agent, FEIBA is designed to “bypass” the need for replacement therapy to prevent or control bleeds. It contains several clotting factors that act at multiple sites in the clotting cascade to help restore the production of thrombin, a key protein in the formation of stable blood clots.

As such, the therapy is expected to promote efficient blood clotting in hemophilia A and B patients with inhibitors.

Who can take FEIBA?

In use for on-demand treatment of hemophilia patients with inhibitors since the 1970s, FEIBA was approved in the U.S. for that indication in 1986. Its U.S. label was extended in 2013 to include use as a routine preventive treatment, or prophylaxis, to prevent or reduce bleeds in these patients. The therapy is also available to prevent bleeds during surgery.

FEIBA is approved in more than 70 countries worldwide and indicated for prophylaxis in more than 60 of them.

Who should not take FEIBA?

FEIBA should not be taken by patients with:

  • known allergic reactions to the therapy or any of its components
  • disseminated intravascular coagulation, or signs of small blood vessel clots throughout the body
  • sudden formation of blood clots (thrombosis) or blood vessel blockage (embolism), including heart attack

How is FEIBA administered?

FEIBA is given as an infusion directly into the bloodstream. It’s available as a dry powder in single-use glass vials containing 500, 1,000, or 2,500 units per vial. The powder must be diluted in an appropriate liquid solution that is provided in a separate vial along with a high-flow device and a syringe.

The recommended dose for on-demand treatment to control bleeds is an infusion of 50 to 100 units per kilogram (unit/kg) every six to 12 hours, depending on the type of bleeding, and until the bleed or pain — in the case of joint bleeds — is resolved.

Patients undergoing surgery should receive a single dose of 50–100 unit/kg before surgery and additional infusions of the same dose after the procedure until bleed resolution and healing is achieved. The recommended dose for prophylaxis is 85 unit/kg every other day.

Adjustments of doses and administration intervals may be considered for each case based on the clinical response. Single doses should not exceed 100 unit/kg and daily doses should not be higher than 200 unit/kg. Maximum injection or infusion rate must not exceed 2 unit/kg per minute.

FEIBA in clinical trials

The safety and effectiveness of FEIBA for on-demand treatment of bleeds were mainly assessed in two prospective clinical trials.

The first involved 15 hemophilia A patients with inhibitors against FVIII, who were randomly assigned to receive either FEIBA or a control preparation with a nonactivated prothrombin complex concentrate for treating 150 muscle and joint bleeds over 15 months. Results showed a greater proportion of bleeding episodes were resolved with FEIBA relative to the control preparation (64% vs. 52%). The bypassing agent was also found to be significantly superior to the control preparation at stopping bleeds in the same joint or muscle and at improving joint mobility.

In the second trial, FEIBA was used to treat 165 bleeding episodes in 44 hemophilia A patients with FVIII inhibitors, three hemophilia B patients with FIX inhibitors, and two patients with acquired FVIII inhibitors. The study demonstrated that more than 90% of the bleeding episodes were controlled with one or more infusions.

ProFEIBA trial

The Phase 2/3 ProFEIBA study (NCT00221195) evaluated the effects of prophylactic versus on-demand treatment with FEIBA in 34 severe hemophilia A patients, ages 2 years and older, with high levels of FVIII inhibitors. Participants first received the therapy three times a week for the first six months (prophylaxis regimen) followed by a three-month treatment-free period and a subsequent six-month period of on-demand treatment.

Results showed the prophylaxis regimen was generally safe and it reduced bleeding episodes by 62% and target-joint bleeding by 72%, compared with the on-demand regimen.

FEIBA PROOF trial

A global Phase 3 trial, known as FEIBA PROOF (NCT00851721), compared FEIBA’s prophylactic treatment with on-demand use in hemophilia A and B patients, ages 4 to 65 years, with inhibitors. A total of 17 patients were given the therapy as prophylaxis, while 19 were treated on-demand over a year.

Prophylactic treatment was associated with a significant 72.5% drop in the median annualized bleeding rate relative to the on-demand regimen. Three patients (17.6% of all patients) on prophylaxis experienced no bleeding episodes compared to none in the on-demand group. Also, the total use of FEIBA was significantly higher in the on-demand group. The rates of treatment-related adverse events were comparable between the two regimens.

FEIBA STAR trial

A Europe-based Phase 3b/4 study, called FEIBA STAR (NCT02764489), assessed the safety and tolerability of FEIBA when reconstituted in a regular versus 50% reduced volume, and with faster infusion rates in 32 hemophilia A or B adult patients with inhibitors. Results have not yet been announced.

FEIBA-GO study

An international, observational study called FEIBA-GO (EUPAS6691) evaluated the four-year safety and effectiveness of FEIBA, used as on-demand or prophylactic treatment, in a real-world setting. The study enrolled 53 hemophilia A and B male patients, ages 2–71, with inhibitors.

Preliminary findings from the study showed that at six months, prophylaxis with FEIBA prevented joint bleeding similarly to that reported in hemophilia patients without inhibitors and on prophylactic replacement therapy. Updated interim results, of more than 18 months of follow-up, confirmed FEIBA’s safety and effectiveness.

Ongoing trials

Due to potential safety concerns with combined treatment of FEIBA and the approved therapy Hemlibra (emicizumab), a Phase 4 trial (NCT04205175) is investigating FEIBA’s safest dose range in up to 20 hemophilia A male patients with inhibitors who are on Hemlibra for at least two months. The study is expected to be completed in October 2022. Hemlibra is a hemophilia A approved therapy that mimics the activity of FVIII.

Common side effects of FEIBA

The most common side effects associated with FEIBA are:

  • anemia, or low red blood cell counts
  • diarrhea
  • bleeding into a joint
  • positive test for hepatitis B surface antibody
  • nausea
  • vomiting

Blood clotting events

Thromboembolic, or blood clotting, events such as blood vessel blockage in the lungs, stroke, heart attack, and deep vein blood clots, can occur with FEIBA, particularly after high doses have been administered (above 200 unit/kg per day) and/or in patients with risk factors for blood clots.

These events may also occur with FEIBA when given along with medications that may prevent blood clot breakdown, such as tranexamic acid and aminocaproic acid. Such therapies should not be used within about six to 12 hours after a FEIBA infusion.

Cases of thrombotic microangiopathy (TMA) were reported in a clinical trial where patients received on-demand FEIBA after prophylaxis with Hemlibra. TMA is a rare condition marked by red blood cell destruction, low platelet counts, and the formation of blood clots in small blood vessels that can injure the kidneys.

The potential benefits of FEIBA should be weighed against the potential risk of these thromboembolic events and patients on the therapy should be monitored for signs and symptoms of blood clot events. If clinical signs or symptoms occur, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling, and/or pain, patients are advised to discontinue treatment.

Allergic reactions

Allergic reactions, which can include hives, chest tightness, wheezing, difficulty breathing, gastrointestinal manifestations, and/or swelling of the face, have been reported with FEIBA. If such a reaction is suspected, the medication should be immediately discontinued and the patient should be given appropriate therapy to manage it.

Other infusion reactions, such as chills, fever, and high blood pressure have also been reported.

Transmission of infectious agents

FEIBA is made from human blood and, despite several safety and preventive measures being implemented in its manufacturing process, the therapy may still carry a risk of transmitting infectious agents.

Use in pregnancy and breastfeeding

No animal or human studies to date have evaluated whether FEIBA can cause harm to a developing fetus or affect a person’s reproductive ability, and whether it can pass into breast milk. Patients should talk with their healthcare professionals about using FEIBA during pregnancy and breastfeeding to see if the benefits justify potential risks.

 


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