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 .
INDICATIONS AND USAGE
ADYNOVATE , Antihemophilic Factor ( Recombinant ), PEGylated , is a human antihemophilic factor indicated in adolescent and adult patients ( 12 years and older ) with hemophilia A ( congenital factor VIII deficiency ) for :
• On-demand treatment and control of bleeding episodes
• Routine prophylaxis to reduce the frequency of bleeding episodes
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 onestage 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 169 previously treated patients ( PTPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 2 multi-center , prospective , open label clinical studies and 3 ongoing clinical studies . The median duration of participation per subject was 333 ( min-max : 1-593 ) days and the median number of exposure days to ADYNOVATE per subject was 96 ( min-max : 1-170 ). Table 1 lists the adverse reactions reported during clinical studies .
Table 1 : Adverse Reactions Reported for ADYNOVATE
MedDRA System Organ Class
Gastrointestinal Disorders
MedDRA Preferred Term
Number of Subjects n (%) ( N = 169 )
Percent per Infusion ( N = 13579 )
Diarrhea 1 ( 0.6 %) 0.01 %
Nausea 2 ( 1.2 %) 0.01 %
Nervous System Disorders Headache 5 ( 3.0 %) 0.06 %
Vascular Disorders Flushing 1 ( 0.6 %) 0.01 %
No events of hypersensitivity were reported .
Immunogenicity
The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical trials . Study subjects consisted of adult ( n = 143 with ≥ prior 150 EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 3 ), ≥6 years of age with ≥150 prior EDs ( n = 23 )]. In 120 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 0.03 ) for the risk of any factor VIII inhibitor . None of the 169 individual subjects 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 . None of the 169 treated subjects with at least one infusion of ADYNOVATE developed a persistent binding antibody response to any of these antigens . Thirteen subjects in total showed pre-existing antibodies to factor VIII ( n = 1 ), PEG-factor VIII ( n = 12 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Eight subjects who tested negative at screening developed transient IgG antibodies against factor VIII ( n = 5 ), or PEG-FVIII ( n = 3 ) at one or two consecutive study visits . Binding antibodies that were detected prior to exposure to ADYNOVATE or that transiently developed during the study could not be correlated to an impaired treatement efficacy , altered OK parameteres or adverse reactions . No subject had pre-existing or treatmentemergent 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 .
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Patented : see www . shire . com / productpatents /.
Shire Westlake Village , CA 91362 USA U . S . License No . 2020
Issued 11 / 2015 15E001-ADY-US S17777 11 / 16