Literature Scan
While the intent of the study was to compare safety and efficacy of momelotinib and BAT other than ruxolitinib , 46 patients ( 89 %) in the BAT cohort received ruxolitinib while on study , and 14 patients ( 27 %) received ruxolitinib plus additional therapies ( including hydroxyurea [ n = 9 ; 17 %] and corticosteroids [ n = 6 ; 12 %]). “ At the time the study protocol was developed , [ we ] anticipated that most patients in the BAT group would be receiving drugs [ other than ruxolitinib ] or would be on
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 of 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 Baxalta US Inc ., at 1-800-423-2090 ( 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 .
The serious adverse reactions seen with FEIBA are hypersensitivity reactions and thromboembolic events , including stroke , pulmonary embolism and deep vein thrombosis .
sub-therapeutic doses of ruxolitinib ,” the authors noted . “ However , as dosing guidelines become more widely available for ruxolitinib , … patients were increasingly being maintained on ruxolitinib at therapeutic doses .”
The median treatment exposure duration was 23.9 weeks ( interquartile range [ IQR ] = 15.9-24.0 weeks ) for momelotinib and 24.1 weeks ( IQR = 23.7-24.3 weeks ) for BAT . Patients were followed for a median of 168 days in both groups ( IQR = 142-170 days and
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 1 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 1 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
Anemia |
2 |
2 |
5.6 |
Diarrhea |
2 |
2 |
5.6 |
Nausea |
2 |
2 |
5.6 |
Vomiting |
2 |
2 |
5.6 |
|
Hepatitis B Surface
4
Antibody Positive
|
4 |
11.1 |
Hemarthrosis |
5 |
3 |
8.3 |
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 well-controlled 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 .
Baxalta and Feiba are trademarks of Baxalta Incorporated . Baxalta US Inc . Westlake Village , CA 91362 USA U . S . License No . 2020 Issued : 04 / 2017 S30108 04 / 17
165-169 days , respectively ).
More than one-third of patients ( n = 35 ; 34 %) in the momelotinib group discontinued treatment within the first 24 weeks , most frequently because of adverse events ( AEs ; n = 14 ; 14 %). Seventeen patients receiving momelotinib required dose reductions or interruptions , most frequently because of AEs ( n = 14 ; 14 %). Data on treatment discontinuation in the BAT cohort were inconsistently reported because changes in therapy or change to no active therapy were permissible options for this group .
Primary endpoint analysis was available in 70 momelotinib- ( 67 %) and 39 BATtreated patients ( 75 %). Only seven people ( 7 %) in the momelotinib group and three people ( 6 %) in the BAT group experienced spleen volume reduction of ≥35 percent or more from baseline ( proportion difference = 0.01 ; 95 % CI – 0.09-0.10 ; p = 0.90 ). All responders in the BAT group were receiving ruxolitinib , the authors reported . They suggested that the poor responses in both groups “ could be explained by the fact that there was no washout period for patients receiving MF therapy before study entry or the unique patient population … who had either suboptimal responses or hematologic toxic effects with ruxolitinib .”
The most common grade ≥3 AEs associated with momelotinib and BAT were anemia ( n = 14 [ 14 %] vs . 7 [ 14 %]), thrombocytopenia ( n = 7 [ 7 %] vs . n = 3 [ 6 %]), and abdominal pain ( n = 1 [ 1 %] vs . n = 3 [ 6 %]). Eleven patients ( 11 %) treated with momelotinib reported peripheral neuropathy , while this did not occur in the BAT group . Three momelotinibtreated patients discontinued treatment because of peripheral neuropathy .
“ Although this study did not meet the primary endpoint of spleen volume reduction , [ these data ] suggest that momelotinib therapy might provide meaningful results for patients previously treated with ruxolitinib , including improved anemia responses , fewer transfusion requirements , and symptom improvement ,” the authors reported .
More patients in the momelotinib group ( n = 27 / 103 ; 26 %) had a > 50 percent reduction in TSS from baseline , compared with those in the BAT group ( n = 3 / 51 ; 6 %; p values not reported ), “ indicating greater symptomatic improvement .” Momelotinib treatment also appeared to reduce transfusion burden . At baseline , approximately half of the patients in each group ( n = 58 / 104 [ 56 %] for momelotinib and n = 27 / 54 [ 52 %] for BAT ) were transfusiondependent ; at week 24 , more patients who received momelotinib were transfusion-independent ( n = 45 / 104 [ 43 %] vs . n = 11 / 52 [ 21 %]; p = 0.0012 ).
The study is limited by the amount of missing or incomplete data about patients ’ duration of ruxolitinib treatment prior to randomization . Longer-term follow-up is needed to confirm any observed benefit in secondary endpoints , the researchers added . ●
The authors report financial relationships with Novartis , Gilead Sciences , CTI BioPharma , and Shire .
REFERENCE
Harrison CN , Vannucchi AM , Platzbecker U , et al . Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib ( SIMPLIFY 2 ): a randomised , open-label , phase 3 trial . Lancet Haematol . 2017 December 20 . [ Epub ahead of print ]
February 2018