ADYNOVATE [ Antihemophilic Factor ( Recombinant ) PEGylated ]
Rx Only
Lyophilized Powder for Reconstitution for Intravenous Injection BRIEF SUMMARY : Consult the Full Prescribing Information for complete product information .
INDICATIONS AND USAGE
ADYNOVATE 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 ), 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 , diarrhea , rash , nausea , dizziness and urticaria .
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 365 previously treated patients ( PTPs ) and previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 6 completed multi-center , prospective , open label clinical studies and 1 ongoing clinical study . The total number of infusions within the safety database is 74487 . Following are the adverse reactions reported during clinical studies .
Adverse reactions reported for ADYNOVATE as shown by Percent of Subjects , Number of subjects (%, n ) ( N = 365 ). Reported adverse reactions are listed by MedDRA Preferred Term . Diarrhea ( 6.8 %, n = 25 ), Nausea ( 2.2 %, n = 8 ), Ocular Hyperaemia ( 0.8 %, n = 3 ), Hypersensitivity a ( 0.5 %, n = 2 ), Headache ( 11.2 %, n = 41 ), Dizziness ( 1.9 %, n = 7 ), Rash ( 2.7 %, n = 10 ), Urticaria ( 1.9 %, n = 7 ), Drug Eruption ( 0.3 %, n = 1 ), Flushing ( 0.27 %, n = 1 ), Eosinophil Count Increased ( 0.5 %, n = 2 ), Infusion Related Reaction ( 0.5 %, n = 2 ).
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 216 subjects . Administration of ADYNOVATE continued and both cases resolved .
Immunogenicity Clinical trial subjects were monitored for neutralizing ( inhibitory ) antibodies to FVIII . Of the 6 completed clinical trials in previously treated patients ( PTPs ), in the randomized controlled trial comparing different dosing regimens of ADYNOVATE , one previously treated patient developed a transient low titer FVIII inhibitor at 0.6 BU while receiving more frequent dosing with ADYNOVATE .
In a continuation study with ADYNOVATE , one patient developed a transient low titer ( 0.6 BU ) FVIII inhibitor . Repeat testing did not confirm the presence of inhibitor . Both of these subjects continued treatment without change in the dose of ADYNOVATE .
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 .
Persistent treatment-emergent binding antibodies against FVIII , PEG-FVIII or PEG were not detected . Out of 365 subjects , thirty-six subjects in total showed pre-existing antibodies to factor VIII ( n = 5 ), PEG-factor VIII ( n = 31 ) and / or PEG ( n = 6 ) prior to the first exposure to ADYNOVATE . Twenty-four subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 10 ), PEG-FVIII ( n = 16 ) and / or PEG ( n = 3 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Two 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 .
From an ongoing study in previously untreated patients < 6 years with severe hemophilia A , 9 cases of FVIII inhibitor development associated with treatment with ADYNOVATE were reported .
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 .
USE IN SPECIFIC POPULATIONS
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Pregnancy : Risk Summary There are no data with ADYNOVATE use in pregnant women to inform a drug-associated risk . Animal reproduction studies have not been conducted with ADYNOVATE . It is unknown whether ADYNOVATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity . In the U . S . general population , the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively .
Lactation : Risk Summary There is no information regarding the presence of ADYNOVATE in human milk , the effect on the breastfed infant , or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for ADYNOVATE and any potential adverse effects on the breastfed infant from ADYNOVATE or from the underlying maternal condition .
Pediatric Use Safety and efficacy studies have been performed in 91 previously treated , pediatric patients age 1 year to < 18 years who received at least one dose of ADYNOVATE as part of routine prophylaxis , on-demand treatment of bleeding episodes , or perioperative management . Adolescent subjects age 12 to < 18 ( n = 25 ) were enrolled in the adult and adolescent safety and efficacy trial , and subjects < 12 years of age ( n = 66 ) were enrolled in a pediatric trial . The safety and efficacy of ADYNOVATE in routine prophylaxis and the treatment of bleeding episodes were comparable between children and adults . Pharmacokinetic studies in children (< 12 years ) have demonstrated higher clearance , a shorter half-life and lower incremental recovery of factor VIII compared to adults . Because clearance ( based on per kg body weight ) has been demonstrated to be higher in children (< 12 years ), dose adjustment or more frequent dosing based on per kg body weight may be needed in this population .
Geriatric Use Clinical studies of ADYNOVATE did not include subjects aged 65 and over .
© 2021 Takeda Pharmaceuticals U . S . A ., Inc . 300 Shire Way , Lexington , MA 02421 . 1-877-TAKEDA-7 . All rights reserved . TAKEDA and the TAKEDA logo are trademarks or registered trademarks of Takeda Pharmaceutical Company Limited . ADVATE and ADYNOVATE are registered trademarks of Baxalta Incorporated , a Takeda company .
Patented : see https :// www . takeda . com / en-us / patents /
U . S . License No . 2020 Issued : 06 / 2021
US-ADY-0090v2.0 06 / 21