ASH Clinical News April 2017 New | Page 30

Literature Scan

— RAYMOND A . VAN ADRICHEM , MD

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 should 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 .

© 2017 Shire US Inc ., Lexington , MA 02421 . All rights reserved . 1-800-828-2088 . SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates . Feiba is a registered trademark of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc . S27124 01 / 17 absolute difference in risk of 0.3 percentage points ( 95 % CI -0.6 to 1.2 ).

Major bleeding occurred in one patient ( 0.1 %) in each group : hemarthrosis of the knee in the treatment cohort and surgicalsite bleeding in the control group ( absolute difference of risk = 0 ; 95 % CI -0.6 to -0.7 ). Minor bleeding occurred in 69 patients ( 9.5 %) in the LMWH cohort and 39 patients ( 5.4 %) in the placebo cohort . No patient deaths were reported .

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

Preferred Term

Number of ARs

Number of Subjects

Percent of Subjects ( N = 36 )

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 DISORDERS : 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 .

POT-CAST POT-CAST included adult patients ( mean age = 46 ± 16.5 years ) who presented to the emergency department ( ED ) and were treated for at least one week with lower-leg casting . Between March 2012 and January 2016 , 1,519 patients were randomized , of whom 1,435 were included in the intention-to-treat population : 719 LMWH-treated patients and 716 controls . LMWH was administered for the full period of immobilization , with the first dose administered in the ED .

Ten patients in the treatment group experienced

VTE ( 1.4 %; 6 DVTs , 3 PEs , and 1 DVT + PE ), compared with 13 patients in the control group ( 1.8 %; 8 DVTs , 4 PEs , and 1 DVT + PE ). The RR for VTE was 0.8 ( 95 % CI 0.3- 1.7 ), with an absolute difference in risk of -0.4 percentage points ( 95 % CI -1.8 to 1.0 ). Two patients ( one in each group ) also had a distal , superficial VTE .

No patients experienced major bleeding in either cohort , although one clinically relevant non-major bleeding event occurred in one LMWH-treated patient ( 0.1 %). Rates of minor bleeding were also similar : 55 LMWH-treated patients ( 7.6 %) and 49 control patients ( 6.8 %). One patient in the control group died .

In both the POT-KAST and POT- CAST trials , the most common adverse event was infection .

The results of the POT-KAST and POT-CAST trials appear to contradict previous meta-analyses of randomized , controlled trials that suggested anticoagulation therapy reduced the risk of VTE in both settings , but Dr . van Adrichem and co-authors noted that those trials were conducted with stricter exclusion criteria and therefore limit generalizability . “ A strength of our trials was the pragmatic design , with conditions set to approximate general clinical practice as much as possible ,” they wrote .

“ In light of the high frequency of knee arthroscopy and casting worldwide , a considerable number of cases of VTE will nevertheless occur , and any possible prevention of these events should still be pursued ,” the researchers concluded , noting that a higher dose or longer duration of treatment may be suitable only for patients at the highest risk of developing VTE .

“ It can be hypothesized that patients who have symptomatic VTE treatment have a high baseline risk and that casting or knee arthroscopy is a relatively small trigger that , when added to the baseline risk , leads to thrombosis ,” they continued . “ We speculate that , for the patients at the highest risk , the routine prophylactic dose is insufficient .”

The studies were limited by the nonblinded trial design . In addition , the lack of effect of anticoagulation could have been related to the dose , type , or duration of treatment . ●

REFERENCE

van Adrichem RA , Nemeth B , Algra A , et al . Thromboprophylaxis after knee arthroscopy and lower-leg casting . N Engl J Med . 2017 ; 376:515-25 .

April 2017