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Immunogenicity
The development of factor VIII inhibitors with the use of ADVATE was evaluated in clinical trials with pediatric PTPs (< 6 years of age with ≥50 factor VIII exposures ) and PTPs ( ≥10 years of age with ≥150 factor VIII exposures ). Of 276 subjects who were treated with ADVATE for at least 10 exposure days or on study for a minimum of 120 days , 1 adult developed a low-titer inhibitor ( 2 BU in the Bethesda assay ) after 26 exposure days . Eight weeks later , the inhibitor was no longer detectable , and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant factor VIII concentrate . This event results in a factor VIII inhibitor frequency in PTPs of 0.4 % ( 95 % CI of 0.01 and 2 % for the risk of any factor VIII inhibitor development ). No factor VIII inhibitors were detected in the 53 treated pediatric PTPs .
In clinical trials that enrolled previously untreated subjects ( defined as having had up to 3 exposures to a factor VIII product at the time of enrollment ), 16 ( 29.1 %) of 55 subjects who received ADVATE developed inhibitors to factor VIII . Seven subjects developed high titer (> 5 BU ) and nine subjects developed low-titer inhibitors . Inhibitors were detected at a median of 13 exposure days ( min-max : 6−26 exposure days ) to the product .
Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins . When assessed for anti-Chinese hamster ovary ( CHO ) cell protein antibodies , of 229 treated subjects , 3 showed an upward trend in antibody titer over time and 10 showed repeated but transient elevations of antibodies . When assessed for muIgG protein antibodies , of the 229 treated subjects , 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies . Four subjects who demonstrated antibody elevations to CHO cell or muIgG proteins , reported isolated events of urticaria , pruritus , rash , and slightly elevated eosinophil counts . All of these subjects had numerous repeat exposures to the product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established .
When assessed for the presence of anti-human von Willebrand Factor ( VWF ) antibodies , of the 228 treated subjects , none displayed laboratory evidence indicative of a positive serologic response .
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of the incidence of antibodies to ADVATE with the incidence of antibodies to other products may be misleading .
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of ADVATE . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
Table 2 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms .
Table 2 Post-Marketing Experience
USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary
There are no data with ADVATE use in pregnant women to inform a drug-associated risk . Animal reproduction studies have not been conducted with ADVATE . It is not known whether ADVATE can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive 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 ADVATE 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 ADVATE and any potential adverse effects on the breastfed child from ADVATE or from the underlying maternal condition . Pediatric Use
Pharmacokinetic studies in children have demonstrated higher clearance , a shorter half-life and lower recovery of factor VIII compared to adults . This may be explained by differences in body composition and should be taken into account when dosing or following factor VIII levels in the pediatric population . Because clearance ( based on per kg body weight ) has been demonstrated to be higher in the pediatric population , dose adjustment or more frequent dosing based on per kg body weight may be needed in this population . In the ADVATE routine prophylaxis clinical trial , 3 children aged 7 to < 12 and 4 adolescents aged 12 to < 16 were included in the per-protocol analysis . The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children , adolescents , and adults .
Geriatric Use
Clinical trials of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects . Individualize dose selection for geriatric patients .
Organ System [ MedDRA Primary SOC ]
Immune system disorders
Blood and lymphatic system disorders
Preferred Term
Anaphylactic reaction a
Hypersensitivity a
Factor VIII inhibition
General disorders and administration site conditions
Injection site reaction Chills Fatigue / Malaise Chest discomfort / pain Decreased therapeutic effect a
These reactions have been manifested by dizziness , paresthesias , rash , flushing , face swelling , urticaria , and / or pruritus .
© 2018 Shire US Inc ., Lexington , MA 02421 . All rights reserved . 1-800-828-2088 .
ADVATE ® is a trademark of Baxalta Incorporated , a wholly-owned , indirect subsidiary of Shire plc . SHIRE and the Shire logo are trademarks or registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates .
Patented : see https :// www . shire . com / legal-notice / product-patents
Baxalta US , Inc . Lexington , MA 02421 USA US License No . 2020 Issued : 12 / 2018
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