Pulling Back the Curtain: Fred Schiffman, MD
be an expert in research, patient
care, and teaching, you may end
up being good at many of these
things, but you probably won’t be
a virtuoso in all three.
Also, have no regrets about
a meandering path. Early in my
career, I spent time in the lab at
the National Cancer Institute,
but I really felt drawn to the
bedside. This wasn’t wasted time,
though: What I learned from basic
research continues to inform my
patient and family interactions.
Self-care is essential in humanistic medicine, as well. So, when I
mentor people, I try to emphasize
the need to set personal goals and
add balance back to your life. For
me, mentoring involves working
with the whole person, not just
that person’s career pathway.
Lastly, put family first and try
to organize your life and your
days in a way that you can be a
parent to your children and a
good partner to your spouse. It’s
not always the kids’ scheduled
meetings and games where that
happens, – it’s the small, amazing
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
Table 2: Adverse Reactions Reported for ADYNOVATE
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%
MedDRA
System Organ Class
Gastrointestinal Disorders
• 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), 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 [see Dosage and Administration (2)].
• 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
Common adverse reactions (≥1% of subjects) reported in the
clinical studies were headache and nausea.
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
treatment efficacy, altered PK parameters or adverse reactions.
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 s pecificity 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.
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 2 lists the adverse
reactions reported during clinical studies.
Baxalta, Advate, Adynovate, and Baxject are trademarks of
Baxalta US Inc.
Patented: see www.baxalta.com/productpatents/.
Baxalta US Inc.
Westlake Village, CA 91362 USA
U.S. License No. 2020
Issued 11/2015
15E001-ADY-US
times when you’re shopping or
discussing things at home that can
be the most wonderful parenting
events. Keep your eyes open for
the moments of grace that suddenly appear at home and at the
hospital.
How do you achieve that
balance between work and
family in your own life?
My wife, Gerri, has allowed it all
to happen. I’m very fortunate. We
met in the summer of 1969 and
married a year later. She was the
anchor for all our children until
our youngest turned 12, and then
she started an astonishing career
in real estate. She also defines
herself by her rowing. She’s a
competitive rower; I call her a
world champion, since she won a
gold medal in Montreal in a coxed
four in 2001.
Luckily, we lived very close
to the hospital, so I never missed
dinner with the kids. I read them
their bedtime stories, and after
they went to sleep, I could go back
to the hospital and finish up some
work.
We have four amazing
children. Josh, who’s now 42,
was born in the middle of my
internship. When he was 15, he
developed Hodgkin lymphoma.
He and I drove to Boston several
times a week for several months
for his radiation treatment; those
were poignant, heart-wrenching,
and remarkable hours we shared.
It wasn’t the most challenging
thing that happened to a family,
but it was difficult for ours. Josh
went to college and then medical
school at Brown, and trained in
pediatrics and hematology/oncology at Stanford. During his training he started to take an interest
in pediatric cancer and hereditary
cancer syndromes. Josh is now an
endowed professor in pediatric
oncology at the University of Utah
and the Huntsman Cancer Institute, researching why elephants
don’t get cancer and hoping to
prevent it in children. He and his
wife Maureen have three wonderful children, Noah, Ben, and Lily.
Jessica, our daughter, took after
my wife and rowed at the University of Pennsylvania. She and her
husband David (who was one of our
medical residents at Brown!) have
two terrific children, Jackson and
Sydney. David is a gastroenterologist and Jessica is using her MPH
degree to help organize equine
therapy for autistic children.
Our son Jake was always the
March 2016