On Location ASH Annual Meeting
a recommendation that you monitor for increased risk of AEs or don ’ t use strong inhibitors of CYP3A4 , which includes voriconazole and posaconazole ,” Dr . Michaelis noted . “ We have to remember , however , that fungal and mold [ infections ] are a devastating complication for our patients , so in our institution , in the absence of any evidence that there is an increased risk of AEs , we include voriconazole or posaconazole for prophylaxis in our patients .”
INDICATIONS AND USAGE
ADYNOVATE , Antihemophilic Factor ( Recombinant ), PEGylated , is a human antihemophilic factor indicated in children and adults with hemophilia A ( congenital factor VIII deficiency ) for :
• On-demand treatment and control of bleeding episodes
• Perioperative management
• Routine prophylaxis to reduce the frequency of bleeding episodes
Limitation of Use ADYNOVATE is not indicated for the treatment of von Willebrand disease . CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ADVATE ® ( Antihemophilic Factor [ Recombinant ]), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).
WARNINGS AND PRECAUTIONS Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .
Neutralizing Antibodies
Formation of neutralizing antibodies ( inhibitors ) to factor VIII can occur following administration of ADYNOVATE . Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests . Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected , or if bleeding is not controlled with expected dose .
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained .
• Monitor for the development of factor VIII inhibitors . Perform the Bethesda inhibitor 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 ADYNOVATE , use Bethesda Units ( BU ) to determine inhibitor levels .
ADVERSE REACTIONS The most common adverse reactions ( ≥1 % of subjects ) reported in the clinical studies were headache and nausea .
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 practice .
The safety of ADYNOVATE was evaluated in 237 previously treated patients ( PTPs ) and 6 previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 3 completed multicenter , prospective , open label clinical studies and 4 ongoing clinical studies . The median duration of participation per subject was 401 ( min-max : 3-1034 ) days and the median number of exposure days to ADYNOVATE per subject was 111 ( min-max : 1-322 ). Table 1 lists the adverse reactions reported during clinical studies .
There are larger logistical challenges to incorporating midostaurin into AML treatment algorithms , Dr . Michaelis noted , such as the urgency to determine FLT3 status . Although some centers can provide results in-house , the typical turnaround time from external laboratories is 10 days . Without the results , physicians have to “ guess ” about which induction therapy to use , “ which is frustrating and scary ,” she said . “ It shows that , as a care community ,
ADYNOVATE ® [ Antihemophilic Factor ( Recombinant ), PEGylated ] Lyophilized Powder for Solution For Intravenous Injection Brief Summary of Prescribing Information : Please see package insert for full Prescribing Information .
Table 1 : Adverse Reactions Reported for ADYNOVATE
MedDRA System Organ Class
Gastrointestinal Disorders Immune System Disorder Nervous System Disorders Skin and Subcutaneous Tissue Disorders Vascular Disorders
MedDRA Preferred Term
Number of Subjects n (%) ( N = 234 )
Rate of AEs per 100 Infusions ( N = 30865 )
Diarrhea |
1 ( 0.4 %) |
0.003 |
Nausea |
2 ( 0.8 %) |
0.006 |
Hypersensitivity a 1 ( 0.4 %) 0.003
Headache 5 ( 2.1 %) 0.026 Rash 1 ( 0.4 %) 0.003 Flushing 1 ( 0.4 %) 0.003 a
The event of hypersensitivity was a mild transient non-serious rash , occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE .
Two cases of acute pancreatitis , with no precipitating cause identified in one case , were reported in adults during an extension study of the clinical trial which evaluated 137 subjects . Administration of ADYNOVATE continued and both cases resolved .
Immunogenicity
The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials . Subjects consisted of adolescent and adult ( n = 148 with ≥150 prior EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 32 ), ≥6 years of age with ≥150 prior EDs ( n = 57 )], and pediatric PUPs ( n = 6 ). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE , the factor VIII inhibitor frequency was 0 ( 95 % CI of 0 to 0.019 ). One PUP subject from an ongoing study , who received at least one infusion of ADYNOVATE , developed neutralizing antibodies to factor VIII .
Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII , PEGylated ( PEG ) -factor VIII , PEG and Chinese hamster ovary ( CHO ) protein using validated ELISA assays . The majority of subjects ( 238 / 243 ) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens . Twenty-eight subjects in total showed pre-existing antibodies to factor VIII ( n = 3 ), PEG-factor VIII ( n = 25 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 6 ), or PEG-FVIII ( n = 8 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff . Binding antibodies that were detected prior to exposure to ADYNOVATE , that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters . There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data . No subject had pre-existing or treatment-emergent antibodies to CHO protein .
The detection of antibodies that are reactive to factor VIII is highly dependent on many factors , including : the sensitivity and specificity of the assay , sample handling , timing of sample collection , concomitant medications and underlying disease . For these reasons , comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading .
Baxalta , Advate , Adynovate , and Baxject are trademarks of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .
Baxalta US Inc . Westlake Village , CA 91362 USA U . S . License No . 2020 Issued 12 / 2016 16I045-ADY-US S24588 01 / 17 we ’ re still catching up with these approvals and figuring out how to use them .”
CPX-351 In a presentation titled , “ What ’ s Old Is New Again ,” reviewer Aviva C . Krauss , MD , medical officer of the Division of Hematology Products at the FDA , discussed CPX-351 , a liposomal formulation of daunorubicin and cytarabine , the longstanding backbone of AML therapy .
The new formulation was granted regular approval based on results from the phase III CLTR0310-301 trial . This pivotal trial included patients aged 60 to 75 years with newly diagnosed t-AML or AML-MRC and unfavorable-risk cytogenetics , meaning that “ the trial exclusively enrolled patients … who have traditionally been excluded from clinical trials of this disease , due to their particularly poor prognosis , compared with other patients with de novo AML ,” Dr . Krauss noted .
OS was selected as the relevant endpoint for the agent ’ s approval , “ given that [ patients ’] expected survival is so short ,” she explained , with “ only 20 percent of patients expected to be alive at one year .”
Compared with patients who received standard daunorubicin and cytarabine , those treated with CPX-351 had a longer median OS ( 9.56 vs . 5.95 months ; p value not provided ).
The safety profile of the new formulation was similar to each of the agents separately , with two exceptions : prolonged cytopenias and delayed neutrophil recovery , and concerns about acute elemental copper exposure . Because copper is required to create CPX-351 ’ s stable formulation , patients are exposed to 70 times the permitted daily exposure , which could prove dangerous for patients with Wilson disease .
Another safety concern unique to CPX-351 was the potential for serious errors in the prescription and use of daunorubicin and cytarabine , owing to confusion or misconceptions about the interchangeability of each formulation . “ Given the availability of various formulations of cytarabine and daunorubicin individually , the agency was concerned that the agents could be substituted for or with the combination liposomal product ,” Dr . Krauss said . Because these errors could have considerable consequences for both safety and efficacy , the drug was approved with a boxed warning .
When would hematologists select induction therapy with CPX-351 or standard care ? The decision process should consider “ patient status , patient wishes , and AML biology ,” Dr . Michaelis said , and the choice of treatment depends on the answers to several questions : “ Does the patient fit the trial entry criteria ? Does [ he or she ] have fitness for induction ? Will [ he or she ] be referred for a stem cell transplant ? Importantly , what is [ his or her ] prior anthracycline exposure ?”
Patients should be made aware of the hospitalization time required for treatment , which will be burdensome for most . “ With CPX-351 , the prolonged neutrophil recovery and infectious risk [ windows ] can put [ patients ] at risk for unusual infections [ with fungus and molds ], so I emphasize the
February 2018