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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 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 ®
(An tihemophilic 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.
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
Diarrhea
Nausea Number of
Subjects n (%)
(N=234)
1 (0.4%)
2 (0.8%) 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
MedDRA
Preferred Term
Rate of AEs per 100
Infusions (N=30865)
0.003
0.006
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 subsid iary 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