ASH Clinical News November 2016 | Page 36

Written in Blood was observed . In most patients , PFTs showed an initial decline in diffusing capacity of the lung for carbon monoxide for hemoglobin ( DLCO-Hb ) after four cycles of BV + AVD ; the addition of ISRT , though , did not worsen DLCO- Hb . At 12 months , PFTs also showed an improvement in mean DLCO-Hb and forced expiratory volume that was even higher than

PFT measurements at baseline , which was “ likely due to resolution of intrathoracic HL ,” the authors wrote .

After four cycles of BV + AVD , 93 percent of patients ( n = 27 ) had a negative PET scan . One-year progressionfree survival ( PFS ; secondary endpoint ) in all patients was 93.3 percent ( 95 % CI 84-102 ),

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 .

TABLE 1 . PET Results During and Following Treatment

PET = positron emission tomography ; ISRT = involved-site radiation therapy

* PET-negative response was defined as Deauville 1-3 . † For one patient , repeat PET scan remained positive , but subsequent biopsy demonstrated granulomatous inflammation consistent with sarcoid . For the second patient , repeat PET after two months was negative ( Deauville 3 ). Thus both patients achieved a complete response .

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 .

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

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 . and all 25 patients who received BV + AVD and ISRT achieved a complete response . After a median follow-up of 18.8 months , no relapses occurred among these 25 patients . ( See TABLE 1 for PET results during and after treatment .) Ninety percent of patients ( n = 26 ) achieved a PET-negative response after two treatment cycles , including 11 of the 13 patients ( 85 %) with bulky disease ( defined as > 7 cm in maximal transverse diameter or > 7 cm in maximal coronal diameters ). “ Preliminarily , BV + AVD compares favorably to standard ABVD in terms of early conversion to PET-negativity after two cycles ,” the authors wrote , “ suggesting it is a highly active treatment program in this group of early-stage HL patients with substantial tumor bulk and extensive disease .”

The study is limited by its small sample size and limited follow-up time , the authors noted . In addition , this study “ was not designed to definitively assess the efficacy of BV + AVD [ after ] four cycles followed by 30 Gy ISRT , and we cannot formally compare our results to previous trials due to differences in eligibility , type , and number of cycles of chemotherapy and radiotherapy field and dose ,” the authors wrote .

Dr . Kumar and researchers have expanded this pilot study to include an additional 29 patients who will receive a decreased dose of ISRT ( 20 Gy ) to further explore the efficacy of this combined modality . “ Future studies to test whether radiation therapy can be eliminated or its volume further reduced in PET-negative , bulky , early-stage HL patients treated with BV + AVD chemotherapy are warranted ,” they concluded .

REFERENCE

Kumar A , Casulo C , Yahalom J , et al . Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage , unfavorable risk Hodgkin lymphoma . Blood . 2016 ; 128:1458-64 .

November 2016