Statement on Prophylaxis with FEIBA - Study Results Published Today in The New England Journal of Medicine

Wed Nov 2, 2011 5:05pm EDT

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Statement on Prophylaxis with FEIBA - Study Results Published Today in The New England Journal of Medicine

Results from an investigator-initiated study, which evaluated whether prophylactic use of FEIBA [Anti-inhibitor Coagulant Complex] can achieve a decrease in the frequency of joint and other bleeding events in patients with severe hemophilia A and inhibitors compared to on-demand therapy, were published today in The New England Journal of Medicine. Patients with severe hemophilia A and inhibitors are at increased risk for serious bleeding complications. Effective strategies to prevent bleeding in inhibitor patients have not yet been established. Prophylaxis, where approved, is used to prevent a bleed and on-demand treatment is used only at the time of a bleeding episode.

“The single greatest remaining challenge in the management of hemophilia is the development of inhibitors, often occurring in young patients, that can lead to more difficult to control and sometimes life-threatening bleeding,” said Bruce Ewenstein, M.D., Ph.D., vice president, clinical affairs in Baxter’s BioScience business. “The Pro-FEIBA investigator-initiated study is the first randomized, prospective, controlled clinical trial to evaluate the ability of FEIBA prophylaxis to reduce bleeding events, which is particularly encouraging given that there are limited treatment options available for these patients.”

The Prophylaxis with Factor Eight Inhibitor Bypassing Activity (Pro-FEIBA) study reported that patients with severe hemophilia A treated with FEIBA prophylactically during a six-month period experienced a 62 percent reduction in all bleeds in the prophylaxis period, an average of 5 bleeding events compared to an average of 13.1 during the on-demand treatment period. Sixty two percent of patients (16 of 26) were in the group that responded well to prophylaxis treatment, defined as those who had a greater than or equal to 50 percent reduction in overall bleeding, the target for success defined in the study protocol. In this “good responder group,” the overall reduction in bleeding rate was 84 percent. Thirty eight percent of patients (10 of 26) had a less than 50 percent reduction in bleeding events during the prophylactic period. In this group, bleeding was reduced by 28 percent. Two patients had an increase in bleeding events in the prophylaxis period.

Secondary outcome measurements were joint bleeding and target joint bleeding. During the prophylaxis period, patients experienced a 61 percent reduction in joint bleeding, an average of 4.2 joint bleeds versus an average of 10.8 during the on-demand treatment period. In target joints (those most prone to frequent bleeding, such as the elbow, knee and ankle), patients experienced a 72 percent reduction in bleeding. The number of patients with bleeding in target joints decreased from 18 to 11. Of those patients in the study achieving a reduction in bleeds, all were achieved with three doses of FEIBA (85 U/kg ± 15 percent) per week.

One adverse event related to the study drug was an allergic reaction. Three patients (9 percent) had multiple events related to central venous access devices, including infection, bleeding, and line placement and removal.

A limitation of the study was its relatively short duration. While joint and other bleeding episodes were reduced during the six-month prophylaxis period, a longer, larger, parallel design trial is needed to determine if regular FEIBA infusions are a safe and effective treatment option for hemophilia A patients with inhibitors. In addition, the authors state it is not possible to draw conclusions regarding relationships between patient age and the benefits of prophylaxis. A Baxter-sponsored clinical study, FEIBA PROOF, is evaluating the efficacy and safety of FEIBA prophylaxis compared to on-demand treatment in those living with hemophilia with high-titer inhibitors.

The Pro-FEIBA study was conducted by lead investigators Cindy Leissinger, M.D., from the Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center, New Orleans, USA, and Alessandro Gringeri, M.D., from the Department of Medicine and Medical Specialties, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico and Università degli Studi di Milano, Milan, Italy. The lead investigators oversaw all aspects of the study including design, data collection and analysis and manuscript development and submission. Baxter supplied the study drug (FEIBA) and provided a financial grant to support the study and authoring of the manuscript. The manuscript was subsequently revised by the authors who assumed responsibility for its accuracy and completeness.

About the Study Design

The objective of the investigator-initiated Pro-FEIBA study was to test if prophylaxis with FEIBA over a six-month period may be safe and effective in preventing joint and other bleeds in severe hemophilia A patients with inhibitors compared to on-demand treatment. Following the initial six-month study period (with 12 patients receiving on-demand therapy and 14 receiving prophylaxis), each group crossed-over to the alternate treatment period for six months after a three-month wash-out period. The crossover design produced valid results with fewer patients than required for a parallel study design1. Thirty-four patients were enrolled in the study, with 26 patients evaluated in the final analysis.

About Hemophilia (A & B) and Inhibitors

Hemophilia is a rare genetic blood clotting disorder that primarily affects males. People living with hemophilia do not have enough of, or are missing, one of the blood clotting proteins naturally found in blood. In people with hemophilia A, clotting factor VIII is not present in sufficient amounts or is absent. People with hemophilia do not bleed more profusely or faster than normal but bleed for a longer period of time.

Hemophilia is usually inherited, and about one in every 5,000 males is born with the disorder. About one third of new cases are caused by a new mutation of the gene in the mother or the child. In these cases, there is no previous history of hemophilia in the family. According to the World Federation of Hemophilia, more than 400,000 people in the world have hemophilia. All races and economic groups are affected equally.

Inhibitor development is considered one of the most serious adverse reactions associated with hemophilia treatment. Studies suggest this may occur in three out of every 10 people with severe hemophilia A and one out of every 20 people with hemophilia B. Inhibitors are antibodies that people with hemophilia can generate following exposure to blood clotting factor replacement therapy. These antibodies neutralize (inhibit) the action of clotting factor, which increases the risk of bleeding in people with inhibitors. Hemophilia patients with inhibitors have an increased risk of uncontrolled bleeding and bleeds are much more difficult to control compared to patients without inhibitors. Consequently, these patients can develop complications such as increased need for surgery and increased complexity of surgery.

The information in this statement is intended for scientific exchange only and is not intended for any other purpose.

About FEIBA

FEIBA is not indicated for prophylaxis use in the United States. Canada, Italy, The Netherlands, Israel, Australia/New Zealand, Japan, South Korea, and Taiwan also do not have a prophylaxis indication.

Indications

In the US, FEIBA NF [Anti-Inhibitor Coagulant Complex] is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors.

Clinical experience suggests that patients with a Factor VIII inhibitor titer of less than 5 B.U. may be successfully treated with Antihemophilic Factor.

Patients with titers ranging between 5 and 10 B.U. may either be treated with Antihemophilic Factor or FEIBA NF. Cases with Factor VIII inhibitor titers greater than 10 B.U. have generally been refractory to treatment with Antihemophilic Factor.

Detailed Risk Information About FEIBA NF

Thrombotic and thromboembolic events have been reported during postmarketing surveillance following infusion of FEIBA VH or FEIBA NF, particularly following the administration of high doses and/or in patients with thrombotic risk factors.

The use of FEIBA NF is contraindicated:

  • In patients who have known anaphylactic or severe hypersensitivity reactions to the product
  • In patients who are known to have a normal coagulation mechanism
  • For the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX
  • In patients with significant signs of disseminated intravascular coagulation (DIC)
  • In patients with acute thrombosis or embolism (including myocardial infarction)

At first sign or symptoms of an infusion/hypersensitivity reaction or a thrombotic/thromboembolic event, FEIBA NF administration should be stopped immediately and diagnostic and therapeutic measures initiated as appropriate.

Allergic-type hypersensitivity reactions, including severe anaphylactoid reactions, have been reported following the infusion of FEIBA. The symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be severe and can be systemic.

Many of the reported cases of thromboembolic events occurred with doses above 200 units/kg/day or in patients with other risk factors.

Infusion of FEIBA NF should not exceed single dosage of 100 U/kg and daily doses of 200 U/kg of body weight. Patients receiving more than 100 U/kg of FEIBA NF must be monitored for the development of DIC and/or symptoms of acute coronary ischemia. High doses of FEIBA NF should be given only as long as absolutely necessary to stop bleeding.

FEIBA VH or FEIBA NF should be used with particular caution and only if there are no therapeutic alternatives in patients at risk of DIC, arterial or venous thrombosis.

If clinical signs of intravascular coagulation occur, which include changes in blood pressure, changes in pulse rate, respiratory distress, chest pain and/or cough, infusion of FEIBA NF should be stopped promptly.

Non-hemophilic patients with acquired inhibitors against factors VIII, IX or XII may have both a bleeding tendency and an increased risk of thrombosis at the same time.

FEIBA NF is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) prion.

Adverse reactions reported in clinical studies with FEIBA were anamnestic response, somnolence, dizziness, dysgeusia, dyspnea, hypoesthesia, nausea, chills, pyrexia, chest pain and chest discomfort.

For information on FEIBA use in the United States, please visit: http://www.baxter.com/healthcare_professionals/products/feiba_nf.html

Licenses and licensing conditions may vary from country to country; therefore please always consult your local full prescribing information. Please check FEIBA website for information on indications approved in other countries.

About Baxter International Inc.

Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with hemophilia, immune disorders, infectious diseases, kidney disease, trauma and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.

Baxter and Feiba are registered trademarks of Baxter International Inc., its subsidiaries or affiliates.

1. Louis TA, Lavori PW, Bailar JC, 3rd, Polansky M. Crossover and self-controlled designs in clinical research. N Engl J Med 1984;310:24-31.

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