Literature Scan
• 85.9 % vs . 41.0 %, respectively , in those without del17p mutation ( HR = 0.19 ; 95 % CI 0.12-0.32 )
Prespecified secondary efficacy measures , including the complete response rate [ 26.8 % vs . 8.2 %], the overall response rate [ 92.3 % vs . 72.3 %], and overall survival [ 91.9 % vs . 86.6 %], also favored venetoclax plus rituximab , the researchers reported ( p values not provided ). They added that , among the 366 patients ( 94.1 %) who were evaluable for minimal residual disease ( MRD ) assessment , venetoclax was associated “ with substantial rates of clearance of MRD on the basis of both peripheralblood samples [ 62.4 % vs . 13.3 %; p value not provided ] and bone marrow aspirate [ 27.3 % vs . 1.5 %; p value not provided ; TABLE 2 ].”
MRD status was predictive of subsequent PFS , the authors noted . The high rates of MRD with venetoclax “ may indicate improved disease control over a longer term , even when therapy is discontinued ,” they wrote .
The time to subsequent treatment was numerically , but not significantly longer in the venetoclax group : At two years , 90.0 percent of patients in the venetoclax group and 52.1 percent in the bendamustine group had not received another CLL treatment ( HR = 0.19 ; 95 % CI 0.12-0.31 ).
ADVATE [ Antihemophilic Factor ( Recombinant )]
Rx Only
Lyophilized Powder for Reconstitution for Intravenous Injection BRIEF SUMMARY : Consult the Full Prescribing Information for complete product information .
INDICATIONS AND USAGE
ADVATE is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A for :
• Control and prevention of bleeding episodes .
• Perioperative management .
• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes . ADVATE is not indicated for the treatment of von Willebrand disease .
CONTRAINDICATIONS
ADVATE is contraindicated in patients who have life-threatening hypersensitivity reactions , including anaphylaxis , to mouse or hamster protein or other constituents of the product ( mannitol , trehalose , sodium chloride , histidine , Tris , calcium chloride , polysorbate 80 , and / or glutathione ).
WARNINGS and PRECAUTIONS
Hypersensitivity Reactions
Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with ADVATE . Symptoms include dizziness , paresthesia , rash , flushing , facial swelling , urticaria , dyspnea , pruritus , and vomiting .
ADVATE contains trace amounts of mouse immunoglobulin G ( MuIgG ) ≤0.1 ng / IU ADVATE , and hamster proteins ≤1.5 ng / IU ADVATE . Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins .
Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment .
Neutralizing Antibodies
Neutralizing antibodies ( inhibitors ) have been reported following administration of ADVATE predominantly in previously untreated patients ( PUPs ) and previously minimally treated patients ( MTPs ). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing . If expected plasma factor VIII activity levels are not attained , or if bleeding is not controlled with an expected dose , perform an assay that measures factor VIII inhibitor concentration .
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained when clinically indicated .
• Monitor for development of factor VIII inhibitors . Perform the Bethesda assay to determine if factor VIII inhibitor is present . If expected factor VIII activity plasma levels are not attained , or if bleeding is not controlled with the expected dose of ADVATE , use Bethesda Units ( BU ) to titer inhibitors .
– If the inhibitor titer is less than 10 BU per mL , the administration of additional antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response .
– If the inhibitor titer is above 10 BU per mL , adequate hemostasis may not be achieved . The inhibitor titer may rise following ADVATE infusion as a result of an anamnestic response to factor VIII . The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents .
ADVERSE REACTIONS
Serious adverse reactions seen with ADVATE are hypersensitivity reactions , including anaphylaxis , and the development of high-titer inhibitors necessitating alternative treatments to factor VIII .
The most common adverse reactions observed in clinical trials ( frequency greater than 5 % of subjects ) were pyrexia , headache , cough , nasopharyngitis , arthralgia , vomiting , upper respiratory tract infection , limb injury , nasal congestion , and diarrhea .
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 clinical trials of another drug and may not reflect the rates observed in clinical practice .
ADVATE has been evaluated in eleven clinical trials in previously treated patients ( PTPs ) and one trial in previously untreated patients ( PUPs ) with severe to moderately severe hemophilia A ( factor VIII ≤2 % of normal ). A total of 418 subjects have been treated with ADVATE as of January 2012 . Total exposure to ADVATE was 63,188 infusions . The median duration of participation per subject was 397 ( min-max : 2−1620 ) days and the median number of exposure days to ADVATE per subject was 97 ( min-max : 1−709 ).
The summary of adverse reactions with a frequency > 5 % are shown in Table 1 below .
No subject was withdrawn from a clinical trial due to an adverse reaction .
Table 1 Summary of Adverse Reactions ( ARs ) a with a Frequency Greater than 5 % in 418 b Subjects
MedDRA c System Organ Class
General Disorders and Administration Site Conditions
Nervous System Disorders
Respiratory , Thoracic and Mediastinal Disorders
Infections and Infestations
Musculoskeletal and Connective Tissue Disorders
Gastrointestinal Disorders
Infections and Infestations
Injury , Poisoning and Procedural Complications
Respiratory , Thoracic and Mediastinal Disorders
Gastrointestinal Disorders
Injury , Poisoning and Procedural Complications
Respiratory , Thoracic and Mediastinal Disorders
Infections and Infestations
MedDRA Preferred Term
Number of Adverse Reactions
Number of Subjects
Percent of Subjects
Pyrexia 110 66 16
Headache 114 56 13
Cough 86 54 13
Nasopharyngitis 72 49 12
Arthralgia 49 32 8
Vomiting 41 31 7
Upper Respiratory Tract Infection
35 29 7
Limb Injury 56 25 6
Nasal Congestion 32 25 6
Diarrhea 29 24 6
Procedural Pain 26 22 5
Oropharyngeal Pain
25 22 5
Ear Infection 30 21 5 a
Adverse reactions are defined as all adverse events that occurred ( a ) within 24 hours after being infused with investigational product , or ( b ) all adverse events assessed related or possibly related to investigational product , or ( c ) adverse events for which the investigator ’ s or sponsor ’ s opinion of causality was missing or indeterminate . b The ADVATE clinical program included 418 treated subjects from 11 completed studies in PTPs and 1 completed trial in PUPs . c MedDRA version 8.1 was used .