CLINICAL NEWS
Written in Blood
Study Provides New Molecular Insight
into the Increased Risk of VTE in African
Americans
African Americans are at a dramatically higher risk for developing venous
thromboembolism (VTE), with a 30- to
60-percent higher risk than other ethnicities. The reasons behind this increased
incidence are largely unknown, but the
authors of a study published in Blood
have found that certain genetic variants
may be responsible for African Americans’ susceptibility to VTE.
Previous studies of white and European patients with VTE have identified
specific genetic risk variants, prompting
Wenndy Hernandez, PhD, from the
Department of Medicine in the Section
of Genetic Medicine at the University of
Chicago, and colleagues to study whether
genetic factors could also contribute to
VTE risk in African Americans.
“Clinicians know that VTE is a multifactorial disease with genetics explain-
FEIBA [Anti-Inhibitor Coagulant Complex]
For Intravenous Use, Lyophilized Powder for Solution
Brief Summary of Prescribing Information. Please see package insert for full Prescribing Information.
WARNING: THROMBOEMBOLIC EVENTS
• Thromboembolic events have been reported during post-marketing
surveillance following infusion of FEIBA, particularly following the
administration of high doses and/or in patients with thrombotic
risk factors.
• Monitor patients receiving FEIBA for signs and symptoms of
thromboembolic events.
INDICATIONS AND USAGE
FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B
patients with inhibitors for:
• Control and prevention of bleeding episodes
• Perioperative management
• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
FEIBA is not indicated for the treatment of bleeding episodes resulting from
coagulation factor deficiencies in the absence of inhibitors to coagulation
factor VIII or coagulation factor IX.
CONTRAINDICATIONS
• Known anaphylactic or severe hypersensitivity reactions to FEIBA or any if
its components, including factors of the kinin generating system.
• Disseminated intravascular coagulation (DIC).
• Acute thrombosis or embolism (including myocardial infarction).
WARNINGS AND PRECAUTIONS
Thromboembolic Events
Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial
infarction, and stroke) can occur with FEIBA, particularly following the administration of
high doses (above 200 units per kg per day) and/or in patients with thrombotic risk factors
[see ADVERSE REACTIONS].
Patients with DIC, advanced atherosclerotic disease, crush injury, septicemia, or
concomitant treatment with recombinant factor VIIa have an increased risk of developing
thrombotic events due to circulating tissue factor or predisposing coagulopathy. Potential
benefit of treatment with FEIBA shou ld be weighed against the potential risk of these
thromboembolic events.
Monitor patients receiving more than 100 units per kg of body weight of FEIBA for
the development of DIC, acute coronary ischemia and signs and symptoms of other
thromboembolic 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, discontinue the infusion and initiate appropriate
diagnostic and therapeutic measures.
Hypersensitivity Reactions
Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can
occur following the infusion of FEIBA. The symptoms include urticaria, angioedema,
gastrointestinal manifestations, bronchospasm, and hypotension. These reactions can be
severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and
circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have
also been reported. If signs and symptoms of severe allergic reactions occur, immediately
discontinue administration of FEIBA and provide appropriate supportive care.
Transmission of Infectious Agents
Because FEIBA is made from human plasma it may carry a risk of transmitting infectious
agents, e.g., viruses, and the variant Creutzfeldt-Jakob disease (vCJD) agent and,
theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk has been minimized by
screening plasma donors for prior exposure to certain viruses, by testing for the presence
of certain current virus infections and by inactivating and removing certain viruses during
the manufacturing process [see DESCRIPTION in full Prescribing Information]. Despite
these measures, the product may still potentially transmit human pathogenic agents.
There is also the possibility that unknown infectious agents may still be present.
All infections thought by a physician to have been possibly transmitted by this product
should be reported by the physician or other healthcare providers to Baxter Healthcare
Corporation, at 1-800-423-2862 (in the U.S.) and /or to FDA Med Watch (1-800-FDA-1088
or www.fda.gov/medwatch).
ADVERSE REACTIONS
The most frequently reported adverse reactions observed in >5% of subjects in the
prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody
positive, nausea, and vomiting.
Baxalta and Feiba are trademarks of Baxalta Incorporated January 2016 USBS/145/15-0065
The serious adverse reactions seen with FEIBA are hypersensitivity reactions and
thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety assessment of FEIBA is based on the review of the data from two
prospective clinical trials in which FEIBA was used for the treatment of acute bleeding
episodes and a prospective trial that compared the use of FEIBA prophylactically
versus on-demand treatment.
The adverse reactions reported from two prospective clinical trials in which FEIBA
was used for the treatment of acute bleeding episodes were chills, chest pain, chest
discomfort, dizziness, dysgeusia, dyspnea, hypoesthesia, increase of inhibitor titer
(anamnestic response), nausea, pyrexia, and somnolence. Specifically, the first trial was
a multicenter randomized, double-blind trial in 15 hemophilia A subjects with inhibitors to
factors VIII. The second trial was a multicenter FEIBA study conducted in 44 hemophilia
A subjects with inhibitors, 3 hemophilia B subjects with inhibitors and 2 acquired factor
VIII inhibitor subjects. Of the 489 infusions used to treat acute bleeds during the second
trial, 18 (3.7%) caused minor transient reactions of chills, fever, nausea, dizziness and
dysgeusia. Out of 49 subjects, 10 (20%) had a rise in their inhibitor titers after treatment
with FEIBA. Five of these subjects (50%) had increases that were, tenfold or more, and
3 (30%) of these subjects received factor VIII or IX concentrates within 2 weeks prior
to treatment with FEIBA. These anamnestic rises were not associated with decreased
efficacy of FEIBA.
Table 2 lists the adverse reactions in >5% of subject reported in the randomized,
prospective prophylaxis trial comparing FEIBA prophylaxis with on-demand treatment
in 36 hemophilia A and B subjects with inhibitors to factors VIII or IX. The trial population
included 33 (92%) subjects with hemophilia A and 3 (8.3%) subjects with hemophilia B.
Four (11%) subjects were ≥7 to <12 years of age, 5 (14%) were ≥12 to <16 years of age,
and 27 (75%) were ≥16 years of age. A total of 29 (80.6%) subjects were Caucasian, 3
(8.3%) Asian, 2 (5.6%) Black/African American, and 2 (5.6%) other. The subjects received
a total of 4,513 infusions (3,131 for prophylaxis and 1,382 for on-demand). Adverse
reactions were defined as adverse events that occurred (a) within 24 hours after being
infused or (b) adverse events assessed related or possibly related or (c) adverse events for
which the investigator’s or sponsor’s opinion of causality was missing or indeterminate.
Table 2 Prophylaxis Study Adverse Reactions (ARs) in >5% of Subjects
MedDRA System Organ Class
Blood And Lymphatic System
Disorders
Gastrointestinal Disorders
Investigations
Musculoskeletal And
Connective Tissue Disorders
Number
of ARs
Preferred Term
Number of
Subjects
Percent of
Subjects
(N=36)
Anemia
2
2
5.6
Diarrhea
Nausea
Vomiting
Hepatitis B Surface
Antibody Positive
2
2
2
2
2
2
5.6
5.6
5.6
4
4
11.1
5
3
8.3
Hemarthrosis
Post-Marketing Experience
Because post-marketing reporting of adverse reactions is voluntarily and from a
population of uncertain size, it is not always possible to reliably estimate the frequency of
these reactions or establish a causal relationship to product exposure.
BLOOD AND LYMPHATIC SYSTEM DISORDERS: disseminated intravascular coagulation
CARDIAC D ISORDERS: tachycardia, flushing
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: bronchospasm, wheezing
GASTROINTESTINAL DISORDERS: abdominal discomfort
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: pruritus
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: malaise, feeling hot,
injection site pain
DRUG INTERACTIONS
Concomitant Medications
Consider the possibility of thrombotic events when systemic antifibrinolytics such as
tranexamic acid and aminocaproic acid are used during treatment with FEIBA. No
adequate and wellcontrolled studies of the combined or sequential use of FEIBA and
recombinant factor VIIa or antifibrinolytics have been conducted. Use of antifibrinolytics
within approximately 6 to 12 hours after the administration of FEIBA is not recommended.
ing only one piece of the risk,” Minoli A.
Perera, PharmD, PhD, corresponding
author of the study, told ASH Clinical
News. “Our study shows that the genetic
tests used clinically for VTE risk assessment are not informative for African
Americans because, though they have a
higher prevalence of the disease, they do
not carry these genetic mutations as a
population.”
Dr. Hernandez and investigators
conducted a genome-wide association study that included a two-stage
analysis of African-American patients with VTE: a discovery cohort
followed by an examination of the
most significant single nucleotide
polymorphisms (SNPs) in an independent replication cohort.
Patients included in both parts
of the study were unrelated, selfdescribed as African-American, and
were 18 years old or older. The following data related to potential risk
factors for VTE were collected:
• Age
• Height
• Weight
• Ethnicity
• Sex
Patients had a documented history of
VTE (specifically proximal deep-vein
thrombosis or pulmonary embolism)
and did not have strong known risk
factors such as prolonged hospitalization, surgery, active cancer or
history of malignancy, pregnancy or
puerperium, oral contraceptive use,
menopausal replacement therapy, or
protein C/S deficiency.
The discovery cohort included
146 patients with VTE and 433 controls, while the replication cohort had
94 patients with VTE and 65 controls.
In the discovery cohort, seven
SNPs were identified that more than
doubled the risk of VTE. The following SNPs reached genome-wide
significance:
• rs73692310 on chromosome 7
(odds ratio [OR] = 3.04; 95% CI
2.0-4.7; p=0.1.73x109)
• rs58952918 on chromosome
18 (OR=2.48; 95% CI 1.7-3.7;
p=1.07x10-8)
• rs28496996 on chromosome
18 (OR=2.44; 95% CI 1.6-3.6;
p=1.0x10-8)
The following SNPs also had a strong
suggestive association with VTE risk:
• rs2144940 on chromosome
20 (OR=2.18; 95% CI 1.6-2.9;
p=3.52x10-7)
• rs2567617 on chromosome
20 (OR=2.17; 95% CI 1.6-2.9;
p=4.01x10-7)
February 2016