1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
PEDIATRIC ADVISORY
SUBCOMMITTEE
OF THE ANTI-INFECTIVE DRUGS
ADVISORY COMMITTEE
ACS Conference Room
Room 1066
2
PARTICIPANTS
Joan P. Chesney, M.D., Chair
Thomas H. Perez, M.P.H., Executive
Secretary
CONSULTANTS (VOTING):
Mark Hudak, M.D.
David Danford, M.D.
Richard Gorman, M.D.
Robert Nelson, M.D., Ph.D.
Susan Fuchs, M.D.
Victor
Santana, M.D.
Naomi Luban, M.D.
Judith
O'Fallon, Ph.D.
Katherine L. Wisner, M.D.
MEMBER OF THE ANTI-INFECTIVE DRUGS
ADVISORY
COMMITTEE (VOTING):
Steve Ebert, Pharm.D., Consumer
Representative
FEDERAL GOVERNMENT EMPLOYEE (VOTING):
Janet Cragan, M.D.
INDUSTRY REPRESENTATIVE TO
ANTI-INFECTIVE DRUGS
ADVISORY COMMITTEE (NON-VOTING):
Sam Maldonado, M.D., industry
representative
FDA STAFF:
Solomon Iyasu, M.D.
Susan Cummins, M.D.
Shirley Murphy, M.D.
Dianne
Murphy, M.D.
3
C O N T E N T S
Call to Order and
Introductions,
Joan P. Chesney, M.D. 5
Meeting Statement, Thomas H. Perez,
M.P.H. 7
Welcome, Dianne Murphy, M.D. 10
Adverse Event Reports per Section 17 of
Best
Pharmaceutical for Children Act,
Solomon Iyasu, M.D. 15
Fexofenodine, Jane Filie, M.D. 22
Topotecan and Temozolomide, Susan
McCune, M.D. 34
Moxifloxacin and Ciprofloxacin,
Harry Gunkel, M.D. 59
Fosinopril, Larry Grylack, M.D. 66
Fentanyl, ShaAvhree Buckman, M.D. 78
David J. Lee, Ph.D. 89
D.
Elizabeth McNeil, M.D. 91
Discussion of Question 1 92
Adverse Event Reports per Section 17 of
BPCA
(cont.), Venlafaxine, Hari
Sachs, M.D. 115
Pediatric Update, Dianne
Murphy, M.D. 148
Meeting Statement, Thomas H. Perez,
M.P.H. 170
Update on Neonatal Withdrawal Syndrome:
Kathleen Phelan, R.Ph. 174
Robert Levin, M.D. 189
Katherine Wisner, M.D.,
Women's Behavioral Health CARE 216
Discussion of Questions 2 and 3 254
Update on Congenital Eye Malformations in
Infants,
Solomon
Iyasu, M.D.
303
4
C O N T E N T S
(Continued)
Open Public Hearing:
Philip Sanford Zeskind, Ph.D.,
University
of
Pediatric Research Equity Act,
Shirley Murphy, M.D. 326
Overview of
Conduct of Clinical Research Involving
Children," Robert Nelson,
M.D. 340
5
1 P R O C E E D I N G S
2 Call to Order, Introductions
3
DR. CHESNEY: Good morning. I think we
4 are
ready to get started. I would like to
welcome
5
everybody to this meeting which, for those in the
6
room who don't know, and Dr. Murphy will elaborate
7 on
this, this is the last meeting for this group of
8 the
Pediatric Subcommittee as currently
9
constituted. I would like to also
mention that Dr.
10
Mimi Glode will not be with us because her father
11
became ill on Sunday and she had to cancel at the
12
last minute.
13
Tom has just told me that traffic is going
14 to
become very bad this afternoon because of
15
President Reagan's funeral so we want to keep that
16 in
mind as we move on throughout the day.
So, I
17
think we will start with introductions and, Dr.
18
Maldonado, would you like to start?
19
DR. MALDONADO: Sam Maldonado,
from
20
Johnson & Johnson, the industry representative on
21
this committee.
22
DR. FUCHS: Susan Fuchs, pediatric
6
1
emergency medicine physician from Children's
2
Memorial Hospital in Chicago.
3
DR. O'FALLON: Judith O'Fallon,
4
statistics, retired from the Mayo Clinic.
5
DR. SANTANA: Victor Santana,
pediatric
6
hematologist/oncologist from St. Jude's Children's
7
Research Hospital in Memphis, Tennessee.
8
DR. GORMAN: Rich Gorman,
pediatric
9
private practice in Ellicott City, Maryland.
10
DR. EBERT: Steve Ebert,
pharmacist,
11
infectious diseases, Meriter Hospital and
12
University of Wisconsin, Madison.
13
DR. PEREZ: Tom Perez, executive
secretary
14 to
this committee meeting.
15
DR. CHESNEY: Joan Chesney,
pediatric
16
infectious disease at the University of Tennessee
17 in
Memphis, and also St. Jude's Children's Research
18
Hospital.
19
DR. HUDAK: Mark Hudak,
neonatologist,
20
University of Florida, Jacksonville.
21
DR. DANFORD: Dave Danford,
pediatric
22
cardiology, University of Nebraska Medical Center,
7
1
Omaha.
2
DR. NELSON: Robert Nelson,
pediatric
3
critical care medicine, Children's Hospital,
4
Philadelphia and University of Pennsylvania.
5
DR. IYASU: Solomon Iyasu, lead
medical
6
officer in pediatrics, FDA.
7
DR. CUMMINS: Susan Cummins, lead
medical
8
officer, pediatrics, FDA.
9
DR. S. MURPHY: Shirley Murphy,
Division
10
Director, Division of Pediatric Drug Development,
11
FDA.
12
DR. D. MURPHY: Dianne Murphy,
Office
13
Director, Office of Counter-terrorism and Pediatric
14
Drug Development, in the Office of Pediatric
15
Therapeutics.
16
DR. CHESNEY: Thank you. Now Tom Perez
17
will read the meeting statement.
18 Meeting Statement
19
DR. PEREZ: Thank you and good
morning.
20 The
following announcement addresses the issue of
21
conflict of interest with regard to the adverse
22
event reporting session and is made part of the
8
1
record to preclude even the appearance of such at
2
this meeting.
3
Based on the submitted agenda for the
4
meeting and all financial interests reported by the
5
committee participants, it has been determined that
6 all
interests in firms regulated by the Center for
7
Drug Evaluation and Research present no potential
8 for
an appearance of a conflict of interest at this
9
meeting, with the following exceptions:
10
In accordance with 18 USC 208(b)(3), full
11
waivers have been granted to the following
12
participants, Dr. Richard Gorman for ownership of
13
stock in a company with a product at issue, valued
14
between $50,001 to $100,000; Dr. Judith O'Fallon
15 for
her and her sponsor's ownership of stock in a
16
company with a product at issue, between $5,001 and
17
$25,000; Dr. Katherine Wisner, for her speaker's
18
bureau activities for a company with a product at
19
issue for which she receives less than $10,001 per
20
year; Dr. Patricia Chesney for her spouse's
21
ownership of stock in a company with a product at
22
issue, valued from $5,001 to $25,000 and unrelated
9
1
consultant earnings less than $10,001 per year. In
2
addition, Dr. Chesney's spouse owns stock in a
3
company with a product at issue, worth less than
4
$5,001. Because this stock
interest falls below
5 the
minimis exception allowed under 5 CFR
6
2640.202(b)(2), a waiver under 18 USC 208 is not
7
required. Further, Dr. Chesney is
recused from
8
participating from the subcommittee's discussion
9
regarding Duragesic due to a conflict of interest.
10
A copy of the waiver statements may be
11
obtained by submitting a written request to the
12
agency's Freedom of Information Office, Room 12A-30
13 of
the Parklawn Building. In the event that
the
14
discussions involve any other products or firms not
15
already on the agenda for which an FDA participant
16 has
a financial interest, the participants are
17
aware of the need to exclude themselves from such
18
involvement and their exclusion will be noted for
19 the
record.
20
We would also like to note that Dr. Samuel
21
Maldonado has been invited to participate as an
22 industry representative, acting on behalf of
10
1
regulated industry. Dr. Maldonado
is employed by
2
Johnson & Johnson. With
respect to all other
3
participants, we ask in the interest of fairness
4
that they address any current or previous financial
5
involvement with any firm whose product they may
6
wish to comment upon. Thank you.
7
DR. CHESNEY: Thank you. Our first
8
speaker for the morning will be Dr. Dianne Murphy,
9
Director of the Counter-terrorism and Pediatric
10
Drug Development Office.
11 Welcome
12
DR. D. MURPHY: And just as you
all
13
understand how those two got to be combined, we
14
have come to the end of an era.
That was really
15 the
substance of my opening comments this morning
16 and
I am going to talk more about this later in the
17
day, that this is a milestone.
18
But I wanted to take this morning to focus
19 on
the importance of the activity of this committee
20 in
the review of the safety or adverse events that
21
occur after a product has been granted exclusivity.
22 It
has been clearly legislatively mandated that
11
1
this is going to occur and that task has come to
2
this committee.
3
I wanted to make sure that you all
4
realized how much you have contributed to this
5
process. We have received
feedback from you during
6 the
time about what was useful and have tried to
7
maintain a course, as we have to, that obeys the
8
legislative intent and, yet, makes it more
9
scientifically interesting within the constraints
10
that we have. I think probably
years from now we
11
could come and ask you all what are the problems
12
with the AERS data reporting system.
So, you have
13
been mandated to participate in a process in which
14 you
were told every meeting that you come here that
15 the
limitations are numerous with passive
16
reporting; that when we do get reporting it is
17
either poor or limited in nature; that there is
18
little ability to go back and reconstruct in detail
19 any
of that information; and it basically doesn't
20
have the same quality as a prospective surveillance
21 or
active process. Yet, during this time I
think
22 we
have evolved a process, again with your feedback
12
1 and
assistance, that has allowed us to make it more
2
valuable.
3
I would like to say that I think that what
4 we
have been able to identify over the past year or
5 so
has been the benefits of this system, and that
6 is
that it ensures that attention is focused on
7
what is happening postmarketing to these products
8
that the government initiates and rewards for
9
studies being conducted. As most
of you are aware,
10 one
of the largest safety databases that occurs
11
with any product is the postmarketing activities.
12
That is where you find your rare serious events.
13
And, this process has been critical for this
14 committee and this has been a very important
15
activity that I do think has focused and ensured
16
that products that are marketed for children are
17
looked at in a studied way, a reliable way, a
18
predictable way, and I think that that is
19
important.
20
Now, why is it important? Because
I don't
21
know how many times you have sat through these
22
meetings where we said, "well, here are the
13
1
problems and we didn't see anything.
Okay?" But
2
that is good news. We would hope
that the majority
3 by
far, if not 100 percent of these products that
4 are
studied and marketed don't have serious hidden
5
adverse events. So, in a say, it
is like
6
prophylaxis. We hope we don't
find major issues.
7
But I think the other thing that this
8
process has done that I wanted you all to know
9
about that was important is that it has the effect
10 on the agency of re-prioritizing pediatric
safety
11
assessments. As everyone knows,
there are many
12
deadlines the agency has to meet and it is hard
13
often to see the plate for all the things that are
14 on
it. But clearly the legislation, your
15
participation and our coming to you says we are
16
having a public meeting and a discussion and it
17
re-prioritizes this activity for the agency, as I
18
said, and ensures that attention occurs.
19
We are going to hear today about some
20
activities that have evolved during this process,
21
some questions that we want to bring to you because
22 of
information that, in essence, was moved forward
14
1 a
little faster because of this process, not that
2 it
was being neglected but because we basically
3
made sure that we facilitated the assessments of
4
some of these products and some of the issues. In
5 the
past, as you know, we have had some reviews of
6 the
SSRIs and this whole process has been important
7 in
helping facilitate moving that activity forward
8
also.
9
I wanted to just thank you for your
10
scientific input, your thoughtfulness and your
11
feedback which we still would like to receive about
12 the
process on adverse event reporting, knowing
13
that we have to work within the constraints of the
14
systems that we presently have.
With that, I will
15
speak a little more about the contributions of this
16
committee and where we are going in the future
17
later today. Thank you very much.
18
DR. CHESNEY: Thank you, Dr.
Murphy. Our
19
second speaker this morning, Dr. Solomon Iyasu, is
20
going to talk to us about adverse event reports,
21 per
Section 17 of the Best Pharmaceuticals for
22
Children Act. Dr. Iyasu is a
pediatrician, a
15
1 medical
epidemiologist who has fellowship training
2
with the EIS of the CDC and residency training in
3
preventive medicine at the CDC.
Prior to joining
4 the
FDA, just in 2002, he worked for 13 years as a
5
medical epidemiologist at the CDC, in Atlanta,
6
where he led research and programmatic programs in
7
infant health. He also served as
the CDC liaison
8 to
the Committee on the Fetus and Newborn of the
9
American Academy Pediatrics for many years, and has
10 served
on several HHS committees and inter-agency
11
working groups, including the National Children's
12
Study. His research papers have
involved maternal
13 and
child health issues. In his current
position
14 at
the FDA he serves as a medical team leader in
15 the
Division of Pediatric Drug Development and also
16
serves as the lead medical officer for safety in
17 the
Office of Pediatric Therapeutics, which has
18
become--always was but has become a particularly
19 important
office in function. Dr. Iyasu?
20
Adverse Event Reports per Section 17 of Best
21 Pharmaceuticals for Children
Act
22
DR. IYASU: Thank you very much,
Dr.
16
1
Chesney, for that kind introduction.
Good morning.
2
In the next few minutes I will provide you
3
with an overview of today's agenda.
The theme for
4
today is safety, safety of pediatric drugs. A
5
series of presentations will discuss postmarketing
6
reviews of adverse events for drugs that have been
7
granted exclusivity.
8
The review of the post exclusivity adverse
9
events is accomplished through the collaboration
10
with the Office of Drug Safety, Office of Pediatric
11
Therapeutics and Division of Pediatric Drug
12
Development. Therefore, at first
I would like to
13
acknowledge the contribution of the staff in the
14
Office of Drug Safety for these reviews.
15
In the morning you will hear adverse event
16
reviews for eight drug products that were granted
17
pediatric exclusivity. These
reviews will be
18
presented by medical officers within the Division
19 of
Pediatric Drug Development. Several of
these
20
presentations are informational while a few discuss
21
important issues, ranging from a lack of
22
age-appropriate pediatric formulations for
17
1
fosinopril to a preventable safety signal
2
associated with the use of fentanyl transdermal
3
system or Duragesic. You will be
asked to discuss
4 a
question of risk management strategies in
5
relation to fentanyl. The morning
will also
6
include a time for open public hearing, followed by
7 a
short pediatric update by Dr. Dianne Murphy.
8
We are doing the adverse event review a
9
little differently than before.
In addition to the
10
usual format which you are familiar with, we have
11
incorporated some of the clinical trial data
12
available in the public domain into these reviews.
13 You
are not going to see this component for all the
14
drugs because the trial data are not yet in the
15
public domain for some of the drug products that we
16
will be discussing.
17
This is a pediatric page on the external
18 FDA
website where you will find all the publicly
19
available summaries of medical and clinical
20
pharmacology of these pediatric studies for
21
exclusivity. The process of
making these reviews
22
available in the public domain is evolving,
18
1
therefore, some of the reviews that I mentioned
2
before may not be yet available on this website.
3
Nevertheless, I invite you to use it as a resource
4 and
urge you to spread the word about this site.
5
In the afternoon we will discuss two
6
pediatric safety issues regarding the use of SSRIs
7 and
SNRIs during pregnancy. As you recall,
we
8
discussed several case reports of neonatal
9
withdrawal syndrome related to the use of Paxil and
10
Celexa during the meeting of this committee last
11
February. At that time you
requested more
12
information on the syndrome and FDA's efforts to
13
address it.
14
To address this issue, we have lined up
15
three presentations for you. Kate
Phelan, from the
16
Office of Drug Safety, will present the
17
postmarketing adverse event review for this class
18 of
drugs. Dr. Bob Levin, from the Division
of
19
Neuropharmaceutical Drug Products, will speak on
20 the
new class labeling regarding neonatal
21
withdrawal toxicity and its rationale.
Dr. Kathy
22
Wisner will address the risk/benefit of treatment
19
1 in
child depression, a critical issue for both the
2
practitioner and the patient. At
the end of this
3
update you will be asked to discuss two questions.
4
Next, I will present an update on
5
congenital eye malformations, again, as a fallout
6 to
the February meeting when we reported a case
7
report about possible congenital eye malformation
8
related to the use of Celexa during pregnancy.
9
This update will review all postmarketing reports
10 of
congenital eye malformations for Celexa and some
11
newer anti-depressants.
12
Before we present the specific adverse
13
events, I will briefly review the data sources used
14 in
this review and their limitations. The
Adverse
15
Event Reporting System is a spontaneous and
16
voluntary system. Because it is a
passive system
17 it
suffers from a number of limitations, listed
18
here on this slide, that you are already familiar
19
with and we have discussed several times during
20
previous presentations.
21
Again the drug use data source and their
22
limitations have also been presented before and are
20
1 not
new to you. IMS National Prescription
Audit
2
Plus is used to estimate the number of outpatient
3
prescriptions but lacks demographic information.
4 The
National Disease and Therapeutic Index can
5
estimate drug mentions during office-based
6
physician visits but pediatric use estimates can be
7
unstable for less frequently used medications.
8
Another outpatient data source is the IMS
9
National Sales Perspectives which provides
10
estimates of units sold from manufacturers to
11
various channels of distribution and, therefore,
12 may
be a possible surrogate measure for drug use.
13 An
important limitation of this data source is
14
absence of demographic information such as age and
15
gender.
16
Important drug use data sources and their
17
limitations are well-known to you.
To refresh your
18
memory, these are described in this slide and the
19
next slide. The main limitation
with all the
20
inpatient data sources, except for Premier, is the
21
inability to make national projections of drug use.
22
However, national estimates from Premier are
21
1
available but are selective.
Furthermore, drug use
2
cannot be linked to diagnosis or procedure and drug
3 use
in hospital or outpatient clinics is not
4
captured in this data system.
Data from CHCA are
5
limited to 29 children hospitals and cannot be
6
projected nationally.
7
This concludes my remarks and now let me
8
turn to the presentations for this morning by
9
introducing the first speaker.
But before I do
10
that, I do want to recognize two individuals who
11
have tirelessly worked behind the scenes to make
12
this meeting possible. Please
stand up and be
13
recognized, Miss Christine Phucas and Rosemary
14
Addy.
15
[Applause]
16
Thank you. Now the next speaker,
Dr.
17
Filie is a general pediatrician and pediatric
18
rheumatologist. She conducted
research on
19
molecular biology, connective tissue disorders and
20
genetics at NIH for many years before going into
21
private practice. She joined the
FDA from private
22
practice about a year ago. She
will discuss
22
1
adverse event reports for fexofenodine.
Dr. Filie?
2 Fexofenodine
3
DR. FILIE: Good morning,
everyone. I
4
will proceed with the adverse event review for
5
fexofenodine during the one-year post-exclusivity
6
period.
7
Fexofenodine, trade name Allegra, is an
8
antihistamine by Aventis Pharmaceuticals. The
9
indications for adults and children are relief of
10
symptoms associated with seasonal allergic rhinitis
11 and
non-complicated skin manifestations of chronic
12
idiopathic urticaria. It was
originally approved
13 in
July, 1996 and pediatric exclusivity was granted
14 in
January, 2003.
15
In order to fulfill the requirements for
16
exclusivity, 3 pivotal studies were conducted and
17 415
children, 6 months to 6 years of age, were
18
treated for allergic rhinitis.
One study was a
19
Phase 1 pharmacokinetic study characterizing the
20
dose for children 6 months to 2 years of age.
21
Another study was a Phase 3 study assessing safety
22 and
tolerability in 2 groups, 6 months to 2 years
23
1 of
age, weighing under 10.5 kg and weighing over
2
10.5 kg.
3
A previous safety and tolerability study
4 on
children 2-6 years of age was also submitted.
5 The
adverse events occurred at similar frequencies
6 as
for placebo, and no new safety signals were
7
observed.
8
Efficacy studies were not conducted due to
9 the
fact that the disease course and
10
pathophysiology of allergic rhinitis and chronic
11
idiopathic urticaria, as well as the drug's effect,
12 are
similar in children and adult patients.
The
13
studies conducted on children 6 months to 6 years
14 of
age utilized fexofenodine powder mixed with
15
apple sauce or rice cereal. There
is no marketable
16
age-appropriate formulation for children 6 months
17 to
6 years of age.
18
Drug use trends for
19
fexofenodine--currently, fexofenodine is the
20
leading prescription for non-sedating antihistamine
21 on
the market since loratadine became
22
over-the-counter in 2002. The
total number of
24
1
fexofenodine product dispensed increased from
2
approximately 20.9 million in 2000 to 29.6 million
3 in
2003. Pediatric patients accounted for
4
approximately 2.5 million prescriptions of
5
fexofenodine dispensed in 2003.
The most common
6
diagnoses associated with the use in pediatric
7
patients in 2003 were allergic rhinitis and
8
allergic disorder.
9
The adverse events from pediatric clinical
10
trials that I just presented are as follows:
11
Headache, accidental injury, cough, fever, pain,
12
otitis media and upper respiratory infection, and
13
least common, insomnia, nervousness, sleep
14
disorders, rashes, urticaria, pruritus and
15
hypersensitivity reactions.
16
During the exclusivity period the total
17
adverse event reports from the AERS database was
18
158, 84 of them in the United States.
Among the
19 158
reports there were 8 unduplicated pediatric
20
reports which included 2 with serious outcomes, 1
21
hospitalization and 1 life-threatening event.
22
There were no pediatric deaths.
25
1
In the 8 pediatric case reports the
2
following unlabeled pediatric adverse events were
3
reported, psychosis exacerbation with suicidal
4
ideation and depression; seizure, visual
5
disturbances; abnormal liver function; fungal
6
urinary tract infection; non-accidental overdose of
7
multiple drugs and prolonged QT, prematurity,
8
maternal experience and medication error.
9 I would like to present you with a
10
synopsis of individual reports. A
15 year-old with
11
schizoaffective disorder and ADD, on multiple
12
medications, experienced exacerbation of psychosis,
13
suicidal ideation and depression which resolved
14
after discontinuation of fexofenodine.
15
A 13 year-old child presented with grand
16 mal
seizures. The patient was also on
multiple
17
medications and one of them was bupropion which has
18 a
warning about the potential to cause seizures.
19
A 7 year-old presented transient loss of
20
color vision and visual disturbances such as black
21
dots and bubbles. It also
resolved after
22
discontinuation of the drug in a few days.
26
1
A 10 year-old patient developed a
2
bacterial UTI and abnormal liver function tests
3
after receiving fexofenodine for one week. The
4
child was on concomitant medications and one of
5
them was labeled for hepatic function impairment.
6 We
do not have the name of the drug on the report.
7 The
child recovered after discontinuation of
8
fexofenodine.
9
A 16 year-old who developed a fungal UTI
10 and
pyelonephritis was hospitalized. This
patient
11 was
also on multiple medications for depression and
12
gastritis.
13
A 13 year-old had an intentional overdose
14 of
fexofenodine, acetaminophen, metoclopramide and
15
tramadol. QT prolongation was
observed in the
16
emergency room which normalized the following day.
17
The last two cases--a 27-week old
18
premature baby, small for gestational age, was born
19 by
C-section due to pre-eclampsia. There
was a
20
history of abnormal alpha-1 fetoprotein.
The
21
mother was on concomitant medications.
22
The last case--a prescription refill was
27
1
mistakenly filled with Zyrtec-D instead of
2
Allegra-D, but no adverse event was reported.
3
Concluding the report, despite the large
4
number of fexofenodine prescriptions, there were
5 few
pediatric adverse event reports during the
6
one-year post-pediatric exclusivity period. It is
7
also very difficult to make any attributions of the
8
adverse events of the drug when there are
9
concomitant medications in the reports.
In this
10
case, the FDA will continue to monitor the adverse
11
event reports in all populations.
Any questions or
12
comments?
13
DR. CHESNEY: Dr. Santana?
14
DR. SANTANA: Do you know if there
are any
15
similar adult reports with the use of this
16
medication and concomitant anti-psychotic
17
medications in adults?
18
DR. FILIE: I don't know that I
can
19
respond to that adequately. From
the information
20
that we have on the label, the adverse events are
21
very similar in both populations.
They resemble
22
pretty much the two groups.
28
1
DR. S. MURPHY: Pete Stark I think
is here
2
from the Division. Do you have
any comments about
3
adult report?
4
DR. CHESNEY: Dr. O'Fallon?
5
DR. O'FALLON: It seems to me that
the way
6 you
keep your data may help you to find things.
7 So,
I am wondering when you have these reports, are
8 you
keeping track of the various concomitant
9
medications so that you could be looking for trends
10
developing that may be subtle, that there may be
11
interactions, or something?
12
DR. FILIE: Yes. The hope is to
13
accumulate this data over a long time.
14
DR. O'FALLON: Yes, but I mean in
a way so
15
that you are able to go back, search and find those
16
combos? I am asking about how the
data is being
17
collected so that you are going to be able to
18
search on it.
19
DR. FILIE: Yes, it is possible
and we are
20
doing that collecting and the Office of Drug Safety
21 is
also involved in this. This is something
that
22 has
accumulated and we can keep all this data
29
1
without losing it.
2
DR. O'FALLON: But in a computer
file that
3 you
can search?
4
DR. FILIE: I don't know.
5
DR. IYASU: Let me respond to this. The
6
AERS database has been in existence for a long time
7 and
the database is searchable both by high risk
8
event terms as well as by the drug name or the
9
trade name. So, it is searchable
by a number of
10
parameters and there is an accumulated database
11
which resides at FDA so you can look at one year or
12 you
can look at several years since the first time
13 a
report comes into existence for a particular
14
product. Once there is approval,
there are going
15 to
be postmarketing reports that come in.
So,
16
there is a way to look at that.
But there isn't a
17
whole lot of information to try to look at multiple
18
permutations of different confounders or looking up
19
interactions. It is a limited
database in that
20
way.
21
DR. D. MURPHY: I did want to
respond that
22 in
your package it does tell you that fexofenodine
30
1 has
been looked at with the co-administration of
2
acetyl console and erythromycin, the sip
3
interactions. So, what the agency
does is where we
4
know that a metabolism uses a certain sip enzyme
5
that will cause increases or decreases, they will
6
frequently look at that interaction but they can't
7
look at all of them. That often
is actually a
8
negotiated activity as to how many of them they do
9
look at, and whether there are ones that are more
10
likely to give serious adverse events by the normal
11
drugs that might be used with this specific
12
disease. So, you could see that
with an allergic
13
indication you might think that antibiotics would
14 be
one of the set of drugs that they would look at.
15
So, I just wanted to put on the table that
16
prospectively the agency will sometimes ask,
17
knowing what the metabolism is, for these
18
interactions. But, you can
imagine that the list
19 could
get endless so the agency does not do all
20
possible combinations. Certainly,
I think from
21
allergic rhinitis to antidepressants--I mean,
22
unless you had a mechanistic reason for doing that,
31
1 you
wouldn't up front do it. Your question,
I
2
realize, was looking at statistical analysis post
3 but
up front there is a certain amount of activity
4 in
that area.
5
DR. O'FALLON: It seems to me that
since
6 you
only have a handful of reports it might be
7
worth it, that when you see something showing up
8 you
would say they took drug A, drug B, drug C,
9
let's look and see if we have any reports in the
10
database, especially in the adults or something, to
11 see
if you are seeing if that has been reported
12
before.
13
DR. D. MURPHY: As noted, ODS has
the
14
database and it will have that information in it.
15 So,
you could go back and plug in certain drug
16
names. I think, as always, the
caveat is that
17
there are those who didn't enter that and were on
18 it
so there is always that question of what does it
19
mean when you do it. But, you are
right, if you
20 kept
seeing that pattern, then it would be
21
something you might wish to pursue further and ask
22 for
some additional studies.
32
1
DR. CHESNEY: Dr. Gorman?
2 DR. GORMAN: This is mainly for
3
clarification from my reading of the labeling. On
4
page 7 of the label for this product there is a bar
5 on
the side and I wanted to know whether this was
6
edited out of the label or is the present labeling
7
wording which says that the safety and
8
effectiveness of fexofenodine in pediatric patients
9
under 6 years of age has not been established. Is
10
that in the label now or out of the label?
11
DR. D. MURPHY: It is not labeled
under 6.
12 Is
that right?
13
DR. GORMAN: It is a question of
the bar
14
because it comes up several times later on in
15
labeling.
16
DR. D. MURPHY: Right, right. We will
17
verify this but I think the point was that because
18
there was no formulation that was available, it is
19 not
labeled under 6.
20
DR. GORMAN: I think one of the
issues
21
that was raised at the last meeting, and I would
22
like to have it reemphasized again is that there is
33
1 now
data. When we started this process two
decades
2
ago, that statement meant that there were no
3
studies. Now it means there may
well be studies
4 but
it is not included in the label. I
noticed in
5 the
executive summary, which will be available on
6 the
web-based FDA data, that there is information
7
about its use in children less than 6 months of
8
age.
9
DR. D. MURPHY: I think you
referred to
10 the
clinical pharmacology and biopharm study.
11
Unfortunately, it doesn't have a page number but it
12 is
after the label. It does say in there
that no
13
labeling changes for pediatric indication or dosing
14 for
children less than 6 years old will be made at
15
this time because there are no age-appropriate
16
formulations for fexofenodine for these children,
17 and
your point being that it was studied. And,
18
that is not going to be put in the label and I
19
think that is an issue.
20
DR. GORMAN: That is the issue I
wanted to
21
raise and it will now be raised by others for the
22
rest of the meeting.
34
1
DR. CUMMINS: Can I just provide
one point
2 of
clarification? The labels that we
provide to
3 you
are ones that are publicly available and are
4 the
most recent labels. Often the strikeouts
are
5
still present. We download them
from the labels
6
that are posted on the web often--you know, that we
7
post on the FDA website. If you
see a strikeout,
8 as
you see on page 7, then that strikeout will be
9
removed in the published label by the company.
10
DR. GORMAN: Thank you.
11
DR. CUMMINS: You are welcome.
12
DR. FILIE: Given there are no
further
13
comments or questions, let me introduce the next
14 speaker, Dr. Susan McCune. Dr. McCune is a
15
neonatologist whose previous experience includes
16
academic neonatal practice at Johns Hopkins and
17
Children's National Medical Center.
She recently
18
received her masters degree in education and has
19
worked on computer-based education models for
20
pediatrics. She will discuss two
oncology
21
products, topotecan and temozolomide.
Dr. McCune.
22 Topotecan and Temozolomide
35
1
DR. MCCUNE: Thank you very much,
Dr.
2
Filie. Ladies and gentlemen of
the committee and
3
guests, Drs. Murphy told me to try to keep things a
4
little bit light to keep you all awake and my Irish
5
ancestry would allow me to tell shaggy dog stories
6
but, unfortunately, I don't do very good jokes so I
7
think we will just move along.
8
As Dr. Filie mentioned, I will talk about
9 two
oncologic agents this morning. The first
is
10
topotecan. Topotecan, trade name
Hycamtin, is an
11
anti-tumor oncologic agent produced by
12
GlaxoSmithKline. The indication
in adults is
13
metastatic carcinoma of the ovary after failure of
14
initial or subsequent chemotherapy and small cell
15
cancer sensitive disease after failure of
16
first-line chemotherapy. There
are no approved
17
pediatric indications. The
original market
18
approval was May 28, 1996 and the pediatric
19 exclusivity
was granted on November 20, 2002.
20
I am going to tell you about the studies
21 for
exclusivity for this drug. As you all
22
mentioned, in terms of data that is available for
36
1 the
label, these studies were done based on what
2 Dr.
Iyasu told you already. BPCA mandates
that
3
this information be available on the website and
4
this information is available on the website,
5
however, there were no changes to this label based
6 on
this information.
7
The studies that were submitted for
8
exclusivity were summaries of studies that were
9
previously performed by the Pediatric Oncology
10
Group. They were initiated in
1992 and 1993. This
11 was
a Phase 2 study in pediatric solid tumor that
12
enrolled 108 patients that were less than 16 years
13 of
age. The tumor types were Ewing's
sarcoma,
14
peripheral neuroectodermal tumor, neuroblastoma,
15
osteoblastoma and rhabdomyosarcoma.
The study
16
endpoint was tumor response rate.
Eighty-six
17
percent of patients died, with 10 percent dying
18
within 30 days of the last dose of topotecan. The
19
overall response rate was 8 percent but the
20
response rate for patients with neuroblastoma was
21 18
percent. Of note, it is important to
know that
22 for
alternative regimens using combinations of
37
1
available drugs in pediatric patients with relapse
2
neuroblastoma the response rates were 35-50
3
percent. In this case, no
patients less than 2
4
years of age showed any response.
5
Eight of the 11 patients that died within
6 30
days of the last dose of topotecan had
7
progressive disease and 3 died with infection which
8 is
a known complication. Forty-four percent
of
9
patients were hospitalized with adverse events,
10
primarily febrile neutropenia, fever or sepsis.
11
The Phase 2 study did determine a
12
different dose from adults, a daily infusion for 5
13
consecutive days every 21 days.
The adult dose is
14 1.5
mg/m
2/day and the
pediatric
dose that was given
15 was
either 1.4 mg/m
2/day without granulocyte-colony
16
stimulating factor or 2 mg/m
2/day with
17
granulocyte-colony stimulating factor.
18
In terms of drug use trends in topotecan
19 in
the inpatient setting, between July, 2001 and
20
June, 2003 there were 10.6 percent of discharges.
21
Just to give you a rough idea, compared to the last
22
drug which had a number of prescriptions, this was
38
1
only 425 of 4,001. Pediatric
topotecan did
2
increase annually in that time period, from 6.8 to
3
18.6 percent. It accounted for
407 discharges from
4 29
CHCA free-standing pediatric hospitals, with the
5
most frequent diagnosis being chemotherapy
6
encounter followed by malignant neoplasm of the
7
adrenal gland. A significant
limitation, as we
8
have already discussed, of the analysis is that the
9 FDA
does not currently access data capture in the
10
outpatient hospital clinic setting where most
11
chemotherapy is administered.
12
Now I am going to tell you about the
13
adverse event reports for topotecan for the
14
one-year post-exclusivity period.
There were 29
15
total reports for all ages, 18 in the United
16
States. There were no pediatric
reports that were
17
submitted during this time. Of
note, in the 7-year
18
period from 1996 there were some unlabeled
19
pediatric reports, none of them during that 1-year
20
post-exclusivity period. There
were 4 reports of
21 convulsion,
hypotension, edema and speech
22
disorder, and 3 reports each of arachnoiditis,
39
1
ascites, Budd Chiari syndrome, caecitis and
2
confusional state.
3
In summary, the FDA will
continue its
4
routine monitoring of the adverse events in all
5
populations. I will stop here and
take any
6
questions on this particular drug.
7
DR. CHESNEY: Dr. Santana?
8
DR. SANTANA: I think I have made
this
9
point before and I will try to reinitiate it again.
10 In
contrast to some of the other drugs that we have
11 in
front of us, the oncology drugs are usually used
12 in
the setting of clinical research. They
are not
13
used in the setting of common practice.
So, there
14 is
a wealth of data from protocols either initiated
15 by
the historically previous oncology groups or the
16
current Children's Oncology Group and certainly by
17 other
large institutions like St. Jude's that do
18
research in these drugs. How is
that data captured
19 and
reflected in these reports? Because
there is a
20
wealth of adverse event data that is generated
21
through that clinical research that will not show
22 up
through these voluntary reporting mechanisms but
40
1
will show up in the databases of the clinical
2
research infrastructure.
3
DR. MCCUNE: A lot of the reports
that we
4 get
for these particular drugs are actually from
5
study reports. In terms of the
studies that were
6
done for exclusivity for this drug, they actually
7
were, as you mentioned, part of the research
8
protocols so they were independent studies
9
conducted by the company.
10
DR. SANTANA: But I guess the
point is
11
that that is true but there is a lot more usage of
12
this drug now, as you indicated in your brief
13
summary of the trends of usage of this drug in
14
pediatric oncology. How is that
data eventually
15
going to make it into the adverse event reporting?
16
Because it is not really part of the exclusivity
17
because those studies have not been submitted for
18
exclusivity. Am I correct?
19
DR. MCCUNE: That is correct.
20
DR. SANTANA: These are studies
that are
21
ongoing.
22
DR. MCCUNE: That is correct. This is the
41
1
one-year post-exclusivity period.
2
DR. SANTANA: How will that data
show up
3 in
the current study?
4
DR. S. MURPHY: It would have to
come
5
through the AERS. It would have
to be submitted to
6
AERS for us to have that information.
Dr.
7
Maldonado may want to comment, but the companies
8
have to report any adverse events to the FDA. So,
9 the
companies, you know, keep very close tabs on
10 the
medications, especially the medications that
11 are
in trials that are using their drugs.
So,
12
there is a sort of cross-reference thing. Then, it
13 is
even global with the pharmaceutical companies
14 and
with the international organizations with the
15
FDA. So, I think it is a very
good question. I
16
think Don Mattison might want to make a comment,
17
from NIH.
18
DR. MATTISON: Just a brief
comment. We
19 are
currently working with NCI and COG to develop
20
full access to their databases and that information
21
will be shared with FDA.
22
DR. D. MURPHY: Dr. Santana, I
think if
42
1 you
look at what is in the label now, it just says
2
that the effectiveness in children has not been
3
demonstrated. Then it goes ahead
and it does
4
describe the studies. As you
know, for cancer this
5 has
been a real issue because of the reasons you
6
have stated. The label is
marketing approval and
7 if
it is not approved for that indication, you
8
know, the agency is in this quandary of how do you
9
make information available when you don't want to
10
give a de facto indication that doesn't exist? So,
11
that is the tension here.
Depending on the
12
product, depending on what comes out of the
13
exclusivity studies if we don't have sufficient
14
evidence to say it is efficacy and, as you know,
15 and
I don't want to say this over and over again,
16 but
these studies are not powered to do that.
So,
17 how
do we make that information available has been
18
difficult.
19
I think what they have done here is that
20
they have been able to put into--by saying it has
21 not
been demonstrated, first, and saying yet we
22
looked and here is what we found in a very limited
43
1
way, and then having some adverse event reporting
2
that came out. Now, does it
happen for every
3
product, every time? Not always
because it may be
4
that there were other issues with the studies and
5
then what you may end up with in the label if there
6 is a particular safety thing, they would say
it was
7
studied in so many kids; it wasn't effective or we
8
couldn't determine effectiveness but we are going
9 to
tell you about these adverse events. So,
that
10 can
happen. The adverse events in those
studies
11
could be put into the label if it is a safety
12
issue.
13
DR. SANTANA: I guess what I am
getting at
14 is
that the information that is derived from
15
granting exclusivity is for the studies that the
16
sponsor has put forth to reach that point.
17
DR. D. MURPHY: Right; that is
correct.
18
DR. SANTANA: But there is another
wealth
19 of
data that is being generated. As I
understand
20 it,
unless it is throught the sponsor or through
21
some other mechanism that data becomes available to
22 the
FDA it is not part of the information that we
44
1
have in front of us today or in the future.
2
DR. D. MURPHY: Well, it is
required to be
3
reported to the FDA. It is
required to be reported
4 and
if the agency sees a signal, then there is a
5
re-review of the data and a determination if that
6
additional information needs to be entered into the
7
label. I would say that if a
researcher had access
8 to
data that they were concerned about and saw that
9 it
wasn't in the label, it is perfectly appropriate
10 to
ask--you know, again, it is a requirement.
11
Companies get into big trouble if they have adverse
12
events that they don't report to us.
13
The other issue--I am not saying it
14
happens, but if somehow you thought something
15
wasn't getting reported, it is perfectly
16
appropriate to call the agency and say I am aware
17 of
this; make sure you got those reports.
18
DR. SANTANA: I want to make it
clear for
19 the
public record that I am not raising issues with
20
this drug or the next oncology drug.
I am trying
21 to
understand the process. I just want to
make
22
that clear.
45
1
DR. D. MURPHY: Yes, and we want
to make
2 it
clear that it is part of companies' standard
3
reporting activity. Sam, maybe
you could say
4
something about the routine things that go on in
5
reporting both during a trial and after a product
6 is
marketed.
7
DR. MALDONADO: Both of you are
completely
8
right. Companies are not going to
get in trouble
9 by
not reporting. That is very
enforceable. A lot
10 of
not reported events happen when physicians don't
11
report to companies. So, that is
where the problem
12 is;
it is the education. We are not only
talking
13
about sending in the reports, but sending them
14
within 15 days of occurrence.
Most of the
15
non-reporting happens because of lack of education
16
from clinicians. In clinical
trials it happens
17
much less, or probably very, very close to zero
18
because there is monitoring by the company. Actual
19
people go there and make sure they are doing it.
20
Outside clinical trials it is more difficult
21
because you cannot police physicians so it is up to
22
them to report. But once it is reported to the
46
1
companies, it is reported to the FDA and the FDA,
2 of
course, can always come to a company and check
3 if
we are doing it and actually FDA does that.
4
DR. D. MURPHY: I think what Sam
has said
5 is
really important. If a physician sees an
6
adverse event on a product, particularly if you put
7
them on a product, take them off and put them back
8
on--you know, if you have evidence, but even if you
9
don't, if you put a child on a product and you have
10
some serious event and you are not sure whether it
11 is
related or not, you don't have to make
12
attribution. This is one of the
problems I think
13
physicians don't understand. You
don't have to
14
determine individually that this product caused
15
this adverse event. If physicians
would, please,
16
make it part of their public health rule to report
17
adverse events that they think are serious to the
18
agency and to the company, I mean, that is a double
19
way--or either way, you know, whichever way you
20
know how to get that information in.
It will get
21 to
us if it gets to the company or it can come to
22 us
directly. So, I would like to keep
adding that
47
1
commercial. It is a very important
part of
2
activity. I have been out there;
I have practiced
3
medicine and I know I haven't done it when I should
4
have. So, it is just a plea that
we keep putting
5
that out there because you can see how important it
6 can
become.
7
DR. CHESNEY: Dr. O'Fallon?
8
DR. O'FALLON: There is one other
issue
9
that is a possible problem. I
don't know these
10
particular studies that COG is doing but if they,
11
indeed, have closed patient accrual before the
12
exclusivity period it is entirely possible that the
13
acute toxicities wouldn't be available at this
14
time. You know, not all the data
in these clinical
15
trials gets reported out until the final study is
16 done. I mean, the company had to know about it
17
ahead of time, but during this exclusivity period
18
there maybe weren't any from those trials.
19
DR. D. MURPHY: I think that
brings up the
20
other issue just of any follow-up post-trial. As
21 you
know, there was a legislative mandate also to
22 put
the 1-800 MedWatch number on labels and that
48
1
process is proceeding. I don't
have any idea when
2
actually you will see it but it is continuing to
3
move forward.
4
DR. CHESNEY: Dr. Ebert?
5
DR. EBERT: Just a follow-up to
that, is
6 it
feasible or even reasonable with these drugs
7
that are specifically under exclusivity for the FDA
8 to
make pediatricians more aware of the fact that
9
they are under this particular scrutiny?
And,
10
would it heighten their level of interest with
11
regards to reporting adverse events?
12
DR. D. MURPHY: Joan has a suggestion for
13 you
later today I think about maybe one way of
14
doing it. We have been trying to
do that in a
15
number of ways by working with the American Academy
16 of
Pediatrics newsletter that goes out and doing
17
annual updates of changes in the label, talking
18
about exclusivity, but I think you bring up a good
19
point--have we really made an issue in that
20
reporting about changes in label about reporting
21
adverse events? No. And, that is a good point and
22 we
will take that back and pursue that as an
49
1
additional piece of information we should try to
2 get
out to pediatricians, family practice, people
3 who
are taking care of children. We are
working
4
with the Academy on the CME activity so that we can
5 put
in some case studies that might bring that up.
6
DR. S. MURPHY: Joan, just one
more point,
7 there
are really two ways of reporting adverse
8
events. One is to the FDA and the
other is to the
9
companies. The larger
pharmaceutical companies
10
have these 1-800 numbers and if you call and you
11 say
you have an adverse event, you are immediately
12 put
in touch with the Pharm.D. who has a whole
13
scheme of questions to ask you right away. All
14
those reports, like Sam said, do go back to the FDA
15 and
the seriousness of the report triggers certain
16
times to report it. Having been
on the other side
17 in
a pharmaceutical company, I was in charge of a
18
drug that had a lot of adverse reactions and we
19
were constantly reviewing all the cases that came
20
in. The company will often send
somebody out to
21 the
hospital to look at the records and make sure
22 of
the accuracy of the reporting. So, it is
taken
50
1
incredibly seriously on both sides.
2
DR. CHESNEY: Thank you.
We can move on
3 to
the next speaker.
4
DR. MCCUNE: Actually, I am doing
the next
5
drug. You get to listen to me
again. The next
6
drug I am going to talk about is temozolomide. The
7 trade
name for this is Temodar. Once again,
this
8 is
an oncologic agent produced by Schering Plough
9
Research Institute. The
indication in adults is
10
that the capsules are indicated for the treatment
11 of
adult patients with refractory anaplastic
12
astrocytoma, in other words, patients at first
13
relapse who have experienced disease progression on
14 a
drug regimen containing a nitrosourea and
15
procarbazine. In pediatrics there
are no approved
16
pediatric indications. The
original market
17
approval was August 11, 1999; the pediatric
18
exclusivity was granted November 20, 2002.
19
Once again, I am going to tell you about
20 the
studies for exclusivity. These are
available
21 on the
website. In addition, for this
particular
22
label safety information is included in the
51
1
pediatric section of the precautions part of the
2
label and it does include a description of the
3
clinical studies that were completed.
4
The studies that were submitted for
5
exclusivity were one Phase 1 and two Phase 2
6
open-label, multicenter studies.
The Phase 1 study
7 was
dose escalation in 27 patients with advanced
8
non-CNS and CNS cancers. The
first Phase 2 study
9 was
in 63 patients with recurrent brain stem glioma
10 and
high grade astrocytoma. The second Phase
2
11
study, a cooperative group-sponsored study, was in
12 122
patients with various recurrent CNS tumors.
13 The
patients ranged in age from 1 to 23 years of
14
age, with the majority of patients between 3 and 17
15
years of age.
16
The primary endpoint for these studies was
17
tumor response rate. In the first
Phase 2 study
18
there was 1 complete response and 3 partial
19
responses among 27 patients. In
the second study
20
there were no complete responses or partial
21
responses in the brain stem glioma patients and no
22
complete response and 12 percent partial responses
52
1 in
the high grade astrocytoma patients. In
the
2
third study the overall response rate, combined
3 complete response and partial response rate,
was 5
4
percent. Only 1 patient achieved
complete response
5 and
5 patients had partial responses.
6
Safety was assessed in 204 patients at
7
doses of 100-200 mg/m
2/day daily for 5 days every
8 28
days. The toxicity profile that was seen
was
9
similar to adults. The most
common adverse events
10
that were reported were dizziness, neuropathy,
11 paresthesia, nausea/vomiting, constipation
and
12
myelosuppression.
13
Just to give you an idea of the drug use
14
trends in the outpatient setting for temozolomide,
15 the
number of prescriptions dispensed has nearly
16 doubled
over the past 3 years from 50,000 in 2001
17 to
93,000 in 2003, with the top prescribers, as you
18 can
imagine, being oncology/neoplastic, neurology
19 and
hematology. Of note, only 1 percent of
20
temozolomide prescriptions were written by
21
pediatricians.
22
The pediatric population of 1-16 years of
53
1 age
accounted for a small number of temozolomide
2
prescriptions, 3.1 percent in 2002 and 3.9 percent
3 in
2003, with the most frequent diagnosis being
4
malignant neoplasm of the brain both in adults and
5
pediatric patients.
6
In terms of outpatient sales, they have
7
been on the rise, from 1.8 million capsules to 2.2
8
million capsules in the last 2 years, with the
9
majority of sales through retail channels, 80
10
percent of them going to chain and independent
11
pharmacies and other retail channels.
12
CHCA data demonstrated from 2002 to June,
13
2003 that there were only 17 pediatric discharges
14
associated with this drug.
15
The limitations to drug use data in the
16
outpatient setting for these drugs are important to
17
note because we don't have sources that
18
specifically examine outpatient hospital clinics
19
where chemotherapy treatments are provided. What
20 is
important to note though is that the retail
21
sales do capture a number of those sources and it
22 is
felt that most of the use of this drug is
54
1
captured through assessment of outpatient use.
2
In terms of adverse event reporting for
3 the
post-exclusivity period from November, 2002 to
4
December, 2003 there were 250 reports in all ages,
5 160
of them in the United States. There were
5
6
unduplicated pediatric reports, 2 of them in the
7
United States, all with serious outcomes and 1
8 death. There were 4 females and 1 male. Three of
9 the
patients were aged 2-5 years; 2 of the patients
10
6-11 years. There was one patient
each for the
11
diagnoses of blastoma, adrenal metastatic
12
neuroblastoma, anaplastic astrocytoma,
13
medulloblastoma and brain stem tumor.
14
The clinically significant unlabeled
15
adverse events could be divided into 5 groups. One
16 was
brain edema; 1 was death. Another,
hemangioma
17
acquired; another ITP and another myelodysplastic
18
syndrome. All of these, although
not specifically
19
delineated in the label, are potentially related to
20
either a labeled process or the underlying disease
21
state.
22
Just to take each one of these
55
1
individually, brain edema in the patient was
2
associated with concomitant radiation therapy. The
3
death was potentially due to the underlying
4
condition. The acquired
hemangioma was potentially
5
related to either the underlying condition, the
6
concomitant medication or the radiation therapy.
7 The
ITP was a potentially labeled event or
8
secondary to the underlying condition.
The
9 myelodysplastic
syndrome was also a potentially
10
labeled event or secondary to the underlying
11
condition.
12
Just to give you a brief synopsis of these
13 5
cases, the first was a 3 year-old that was
14
treated for pineal blastoma who died of an
15
unspecified cause.
16
The second was a 6 year-old who was
17
treated for recurrent anaplastic astrocytoma, was
18 on
concomitant medications including radiation
19
therapy, and following temozolomide use, a
20
cavernous hemangioma was noted on MRI.
Of note, it
21 was
not previously seen on prior MRIs.
Following
22
temozolomide treatment, this patient also had
56
1 thrombocytopenia
requiring transfusions and was
2
diagnosed with ITP and myelodysplastic syndrome.
3
This patient was discharged with an improved
4
clinical status 18 days after admission.
5
The third case is a 4 year-old treated for
6
medulloblastoma who suffered an infection and there
7 was
no outcome of the event that was documented.
8
The fourth case is a 4 year-old treated
9 for
metastatic neuroblastoma who developed
10
thrombocytopenia, anemia and fever which were
11
managed with transfusions and antibiotics. She
12
recovered without sequelae and was given a second
13
cycle of temozolomide without recurrence.
14
The final case is an 8 year-old who was
15
treated for brain stem tumor.
Routine MRI revealed
16
radiation-induced cerebellum edema requiring
17
hospitalization for intracranial drainage. This
18
patient was subsequently discharged in stable
19
condition.
20
In summary, for temozolomide there have
21
been described both labeled and unlabeled adverse
22
events. The unlabeled events have
also been
57
1
reported in adults and are not unique to
2
pediatrics, and the FDA will continue to do routine
3
monitoring of adverse events in all of the
4
populations.
5
DR. CHESNEY: Thank you very
much. I just
6
wanted to bring to the committee's attention the
7
fact that at 9:30, although we are getting
8
significantly behind with the very full agenda, the
9 FDA
has asked us to address question one, which is
10 at
the back of the packet that we were given today
11
with the agenda on it, which involves process
12
issues. So, I think unless you
have specific
13
questions related to this drug, if they are process
14
issues, we will have an hour to discuss that later
15
on. So, does anybody have
specific comments
16
regarding this drug? Shirley?
17
DR. S. MURPHY: Dr. Chesney, Dr.
Starke
18
from the Pulmonary Division has some late-breaking
19
information on the first drug that we discussed.
20 He
was just going to tell us a follow-up on a
21
question that the committee had, what the bar was
22
beside the label.
58
1
DR. STARKE: I am Dr. Starke, from
2
Pulmonary and Allergy Division. I
am a medical
3
team leader. I went upstairs and
double-checked
4 the
label for you since there was a cross-out
5
there. That was simply something
that was caught
6 as
the final label was approved. The
current
7
labeling does say for 6 months and older.
8 I just want to make the comment
that even
9
though the studies were done down to 6 months of
10 age
and, as you know, certain other antihistamines
11 may
be approved down to 2 for SAR and 6 months for
12
PAR, this drug was not approved below age 6 because
13
there was no marketed formulation.
A
14
non-marketable formulation was used which, of
15
course, is an issue which you may want to address.
16
Thank you.
17
DR. CHESNEY: Thank you. If there are no
18
additional questions on your presentation, which I
19
thank you for, I think we can move on to the next
20
speaker.
21
DR. MCCUNE: It is my privilege to
22
introduce Dr. Harry Gunkel to you.
He is the only
59
1
person standing between me and the privilege of
2
saying that I am the most junior member of the
3
Pediatric Drug Development Office.
Like me, he is
4 a
neonatologist who has extensive experience in
5
private practice, the pharmaceutical industry and
6
academic medicine. Many of you
may know him for
7 his
significant work on surfactant. He is
going to
8
talk to you today about two ophthalmologic
9 anti-infective
agents.
10 Moxifloxacin and
Ciprofloxacin
11
DR. GUNKEL: Thank you,
Susie. Hello. As
12
Susie said, the next two products on the list are
13
both ophthalmic antibacterials, both
14
fluoroquinolones. The first is
ciprofloxacin,
15
known under the trade name Ciloxan and sponsored by
16
Alcon Laboratories. It is
indicated in adults and
17
children greater than 1 year of age in a solution
18
dosage form, and adults and children greater than 2
19
years of age in the ointment dosage form for the
20
treatment of bacterial conjunctivitis caused by the
21
organisms shown on the slide. The
solution form is
22
also indicated for corneal ulcer.
The original
60
1
market approval was in 1990 and pediatric
2
exclusivity was granted in January, 03.
3
Drug use data shows that dispensed
4
prescriptions for Ciloxan decreased slightly over
5 the
period of exclusivity. Almost half of
the
6
prescriptions for this drug were for children
7
between 1 and 16 years of age, and pediatricians
8
wrote about a third of the prescriptions during the
9
exclusivity period.
10
The most common indication for the
11
prescription was conjunctivitis, other or
12
unspecified, and Ciloxan was the most mentioned
13
product for this indication in pediatric patients.
14
During the exclusivity period there were 9
15
total reports for all ages; 3 were from the U.S.
16 The
age was not specified for 2 of the 9 reports.
17
There were no pediatric reports.
We will continue
18 to
monitor the adverse event reports, of course.
19
The next drug is moxifloxacin,
also
20
sponsored by Alcon Laboratories, also an ophthalmic
21
antibacterial drug. It is
indicated for adults and
22
children 1 year of age or greater for the treatment
61
1 of
bacterial conjunctivitis caused by a number of
2
susceptible organisms, aerobic gram negative and
3
gram positive organisms. The
market approval for
4
this product was April of '03, less than a year
5
ago. So, that will become
pertinent when we look
6 at
the data in just a moment. Exclusivity
was
7
granted before market approval, in January of '03.
8
Since approval didn't occur until April of
9
last year, the drug use and adverse event data
10
cover less than a 1-year period, unlike the other
11
products you are reviewing today.
About 800,000
12
prescriptions were dispensed since approval in
13
April, '03. About a quarter of
the prescriptions
14 were for pediatric patients. Ophthalmologists
15
wrote most of the prescriptions for this agent,
16
just over half of the prescriptions, followed by
17
pediatricians who wrote about a quarter of them.
18 The
most common indication, as for ciprofloxacin,
19 was
for conjunctivitis, other or unspecified and
20
Vigamox, the trade name of the product, accounted
21 for
4.6 percent of the mentions for children.
22
There was 1 report in the exclusivity
62
1
period and it was a pediatric report.
It was an
2
incidence of subconjunctival hemorrhage in a 6.5
3
year-old female that occurred 24 hours after the
4 use
of Vigamox. The child was also using
5
Augmentin. The child recovered
after
6
discontinuation of the drug and this event,
7
subconjunctival hemorrhage, is a labeled adverse
8
event occurring in 1-6 percent of patients. We
9
will continue to monitor this product as well, of
10
course.
11
One study was done for the exclusivity and
12 it
actually involved both products. It was
a
13
multicenter, randomized, double-blind, parallel
14
group comparison of moxifloxacin and ciprofloxacin
15 in
neonates, with the endpoints of clinical cure at
16 day
5 and the microbial eradication rate.
17
From the data that is available in the
18
public domain, these are the results.
The rates of
19
clinical cure are shown for both the agents. These
20
rates are less than the generally expected vehicle
21
rate, and the difference between the two was not
22
significant. Thank you.
63
1 DR. CHESNEY: I have two questions. What
2 do
you mean by expected vehicle rate?
3
DR. GUNKEL: If you apply a
vehicle to a
4
case of bacterial conjunctivitis the expected cure
5
rate is 70 percent.
6
DR. CHESNEY: That is what I
thought you
7
meant; I just wanted to be sure.
And, what were
8 the
side effects of Ciloxan? There were 9
reports.
9
DR. GUNKEL: They weren't
pediatric so I
10
didn't see them. I don't know.
11
DR. CHESNEY: Other
questions? Dr.
12
Murphy?
13
DR. D. MURPHY: Go ahead and
finish up
14
with this topic because I was asked to make a
15
clarification on the last one.
16
DR. CHESNEY: Dr. O'Fallon?
17
DR. O'FALLON: If I were the
statistician
18 on
this study I would be very concerned. I
would
19 be
talking to the docs and saying, "wait a minute
20
guys, this looks like it's doing harm." Both of
21
these agents look like they are not helping. If
22
they have a lower response rate or success rate,
64
1
whatever you want to call it, than the placebo
2
which is the vehicle without anything in it I would
3 be
worried that it is contra-effective.
4
DR. GUNKEL: I don't know whether
that is
5 the
case. The information that is in the
public
6
domain doesn't allow us to deduce that the rates
7
that were shown in the study that I showed were
8
significantly less than the expected vehicle cure
9
rate. But your point is well
taken I would think.
10
DR. CHESNEY: Dr. Murphy?
11
DR. D. MURPHY: Dr. McCune has
said that I
12 may
have confused things in efforts to answer Dr.
13
Santana's question about how we get information in
14 the
label because you were talking about the
15
topotecan when I read to you the information that
16 was
in the Temodar label. I was trying to
point
17 out
that there are various approaches depending on
18 the
quality of the data. So, for the
topotecan the
19
actual information that is in the label now in
20
pediatrics is that there is no safety or
21
effectiveness that has been established versus the
22
Temodar, which is the one that I read you. I
65
1
thought I read the product but they both start with
2
T. So, I want to make it clear
that it is the
3
Temodar that has all that information in it.
4
DR. SANTANA: My question was a
process
5
issue; it didn't relate to any specific--
6
DR. D. MURPHY: Yes, and I was
trying to
7
give a process where there can be different types
8 of
information put in. Anyhow, I just
wanted to
9
make sure that I didn't confuse the committee with
10 the
Ts when I started talking about the second
11
label before it was actually presented.
Thank you.
12
DR. CHESNEY: I think we are all
looking
13 at
your last two slides and puzzling over the last
14
one, but I think that wasn't really the issue of
15
this morning's discussion so we will leave that for
16 the
moment and move on to the next speaker.
17
DR. GUNKEL: The next speaker is
Dr. Larry
18
Grylack. Dr. Grylack began a
career in the
19
Commission for U.S. Public Health Service from
20
1971-73. His training is in
pediatrics in
21
neonatal/perinatal medicine. He
was in the
22
practice of neonatal medicine at Columbia Hospital
66
1 for
Women, in Washington, for 26 years with a
2
particular interest in neurodevelopmental follow-up
3 of
high risk newborn and apnea during infancy.
Dr.
4
Grylack?
5 Fosinopril
6
DR. GRYLACK: Thank you, Dr.
Gunkel, for
7 the
introduction. It is a privilege to speak
to
8 the
committee this morning. In case there
has been
9
anything said so far this morning that has caused
10
your blood pressure to rise, I will be discussing
11 an
antihypertensive drug at this time.
12
The name of the drug is fosinopril, with
13 the
trade name of Monopril. Its sponsor is
14
Bristol-Myers Squibb. Fosinopril
is in the renin
15
angiotensin antagonist subclass of
16
antihypertensives. Its mechanism
of action is
17
inhibition of angiotensin converting enzyme.
18
Although fosinopril is approved for use in adults,
19
there are no approved pediatric indications.
20
Pediatric exclusivity was granted early last year.
21
Despite a 20 percent increase in the
22
prescribed use of renin angiotensin antagonist
67
1
drugs in the outpatient setting, there was a 25
2
percent decrease in the use of fosinopril during a
3
recent 3-year period. Conversely,
there was a 33
4
percent increase in the use of the combination drug
5
fosinopril/hydrochlorothiazide during that same
6
time period. The ratio of the
number of pediatric
7
prescriptions for fosinopril alone to prescriptions
8 for
the combination drug was approximately 10:1.
9
Let's focus on the inpatient usage data
10 for
fosinopril. Two databases from recent
3-year
11
periods report a very low percentage of pediatric
12
inpatients using fosinopril during their hospital
13
stays. There were no pediatric
adverse event
14
reports submitted during the post-exclusivity
15
period.
16
Two studies were done for the purpose of
17
achieving exclusivity. A
single-dose
18
pharmacokinetic study showed an age-dependent
19
increase in bioavailability in a population of 43
20
patients between the ages of 1 month and 16 years.
21 An
oral solution containing a dose of 0.3 mg/kg of
22
body weight was used.
68
1
Secondly, an efficacy and safety dose did
2 not
demonstrate a dose-response relationship in a
3
population of 253 patients between 6 and 16 years
4 of
age. A tablet form of medication was
used in
5
this study. No deaths or cases of
angioedema were
6
reported, the latter being an adverse event
7
reported in adults.
8
Pharmacokinetic parameters in the children
9
studied are similar to those found in adults.
10
Dosing information is available for children
11
weighing more than 50 kg.
However, the
12
formulations used in children in the exclusivity
13
studies are not currently commercially available.
14
This leads me to the broader
issue of the
15
need for age-appropriate formulations.
As
16
physicians and parents know, non-liquid forms of
17
medications are not appropriate for infants and
18
preschool children, as for some school age children
19 as
well. Therefore, sponsors are being
encouraged
20 to
develop age-appropriate commercially available,
21
marketable pediatric formulations during their
22
exclusivity studies.
69
1
The goal of the FDA, and especially of our
2
Pediatric Drug Development Division, is to have
3
commercially available formulations for the
4
pediatric patient population. If
this cannot be
5
done for certain drugs in a pharmacy--and I
6
underscore pharmacy--compounded recipes should
7
appear in the drug label.
8
This concludes my remarks for today.
9
Thank you for your attention.
10
DR. CHESNEY: Thank you very
much. Any
11
non-process questions for the speaker?
Dr. Hudak?
12
DR. HUDAK: The slide that showed
that
13
there was no dose-response relationship in
14
children, is that sort of a euphemism for no
15
efficacy?
16 DR. D. MURPHY: Yes.
It is in our written
17
request as one way for the cardiorenal drugs,
18
hypertensive drugs, to demonstrate efficacy and it
19 is
a long description about what you have to do if
20 you
don't choose a placebo-controlled trial and you
21
choose a dose effect trial and what sort of effect
22 you
have to demonstrate and, if you don't, then you
70
1
failed.
2
DR. CHESNEY: Dr. Nelson?
3
DR. NELSON: With your indulgence,
it is a
4
process comment but it is not about risk process.
5 We
have heard two presentations where there has
6
been a lack of an adequate formulation.
I guess my
7 question,
which may not be answerable today or we
8 may
not want to answer it today is that my
9
understanding is a company doesn't get exclusivity
10
unless the FDA determines--or doesn't get a
11
request--that there is a significant health
12
benefit. It is unclear to me how
you can decide
13
that there is a significant health benefit to the
14
population when at the end of the day there is no
15
formulation available for them.
16
DR. D. MURPHY: Again, they have
to fairly
17
meet the terms of the written request.
A written
18
request is based on what the public health benefit
19
would be and it often will say that you must
20
conduct this trial with an age-appropriate
21
formulation. If they conduct the
trial with the
22
age-appropriate formulation it does not say, nor do
71
1 I
think we would be allowed to legally say, you
2
must market it.
3
DR. NELSON: Well, I guess I would
go back
4 to
the attorneys and ask them to reflect on that
5
because--
6
DR. D. MURPHY: We have.
7
DR. NELSON: --I guess I don't
think that
8 was
the intent of Congress, that they would get the
9
money and then have nothing available for that
10
population.
11
DR. D. MURPHY: Yes, we have gone
back
12
actually because, as you can see, this is becoming
13 an
issue. We have brought this back to them
and we
14 are
in the process of discussing again, within our
15
legal regulatory authority, what we can and cannot
16 do.
17
In balancing that, the other effect, the
18
unintended effect is that you don't issue any
19 written
request because they aren't going to do
20
them, or you can issue them and they won't do them
21 at
all. So, is there a way we can balance
the kind
22 of
information that we need--and I really can't
72
1
give a final answer on this right now--is there a
2 way
that we can set it up so that we say you need
3 to
develop a marketable formulation that would be
4
appropriate for children? We have
always had
5
criteria that if you can't do that you have to tell
6 us
why but make that clear, more definitive.
7
Then, if you can't--because there are
8
reasons sometimes why you cannot develop certain
9
formulations--the solvents become too large or
10
other reasons, as you all I think know, with some
11 of
the proton pump inhibitor types of
12
products--then we are looking at trying to define
13
requirements that have to be met having to do with
14
stability, bioavailability, for kids' use that
15
would be appropriate. We get into
other issues for
16
compounding and how do you avoid those issues.
17
So, the bottom line, Dr. Nelson, is that
18 we
are very aware that this is an issue and we are
19
trying to find a resolution that promotes
20
development of products while, at the same time,
21
does not end up in the situation where we have
22
products that are then not available.
73
1
DR. NELSON: I appreciate the
2
complexities. In my simplistic
view, I suspect
3
that if you went back to those that drafted and
4
then passed the Best Pharmaceuticals for Children
5
Act, they would not interpret significant health
6
benefit to mean that at the end of the day there is
7 no
formulation and nothing in the label.
8
DR. CHESNEY: Dr. Hudak?
9
DR. HUDAK: Can I just clarify
this
10
because I am trying to understand exactly what the
11
data show. The formulations used
in children less
12
than 50 kg were not commercially available?
13
DR. GRYLACK: That is correct.
14
DR. HUDAK: These are the same
15 formulations used that assessed the PK issues?
16
DR. GRYLACK: Yes, the initial
singe-dose
17 PK
study was done in patients between the ages of 1
18
month and 16 years so, as you can determine, a
19
number of those were less than 50 kg.
Then, the
20
second study, the efficacy and safety study, was
21
done in patients between 6 and 16 years and, again,
22 a
certain number of those would be less than 50 kg.
74
1
DR. HUDAK: So, essentially, the
drug with
2
this non-available preparation showed that, as
3
given, it was absorbed and available in the
4
bloodstream like in adults, but showed no efficacy.
5
DR. GRYLACK: Well, there was the
6
age-dependent increase in bioavailability.
7
DR. HUDAK: I understand, but
giving
8
adequate levels of the drug, there was no
9
level-related efficacy, no dose response--
10
DR. GRYLACK: No dose response.
11
DR. HUDAK: No dose response but
if you
12
control for the level of the drug in the blood
13
there was still no response. See
what I am saying?
14
There may be a difference depending upon the age.
15 DR. GRYLACK: Yes.
16
DR. HUDAK: So, the bottom line is
that
17
this drug did not work with the best possible
18
formulation in this population and, therefore,
19
there doesn't seem to be any reason to have a
20 formulation
available for pediatric patients. Is
21
that correct? For this drug?
22
DR. D. MURPHY: Correct.
75
1
DR. CHESNEY: Dr. Danford?
2
DR. DANFORD: To Dr. Hudak's point, I
3
wonder if the group in which this drug was studied
4
actually had hypertension or not.
Hypertensive
5
children, the younger you get, are harder and
6
harder to come by and if you were just studying the
7
bioavailability of the drug and giving it to
8
volunteer children you would not necessarily expect
9 a
drop in blood pressure in a pediatric population.
10 Do
you know who these children were?
11
DR. GRYLACK: I would have to take
a
12
minute and go back and look at the detailed
13
description of the studies. I am
sorry, I can't
14
answer that off the top of my head.
Perhaps I can
15 get
back to you a little later.
16
DR. D. MURPHY: Was the question
did we
17
give it to normal children?
18
DR. DANFORD: Or children without
19
hypertension.
20
DR. D. MURPHY: That is what I
meant,
21
children without hypertension.
22
DR. DANFORD: There could be a
group that
76
1
might conceivably benefit from this, who have
2
congestive heart failure who would not have
3
elevated blood pressure. If you
were looking at a
4
response in blood pressure and it were given to a
5
group of patients with VSD you might not be able to
6
determine much of a change in their blood pressure.
7
DR. D. MURPHY: I think the first
part of
8 it
is that we would not have done the studies in
9
children who were not hypertensive.
Now, could we
10
have selected a different population so that
11
potentially mechanistically you could postulate a
12
benefit? You possibly could have
but it was felt
13
that the need was in this population so that is why
14 it
was written for this population. Again,
as this
15
committee has discussed, it would have to be
16
children who had the disease under study.
17
DR. HUDAK: I am happy to hear
that
18
because testing this antihypertensive medication in
19
normotensive children I think would be a real--
20
DR. GRYLACK: I have some comment
here.
21
Thank you for waiting for me. The
patient
22
population in the efficacy and safety study
77
1
consisted of patients with hypertension or high
2
normal blood pressure.
3
DR. CHESNEY: Dr. Nelson, one more
4 question
and then we really need to move along.
5
DR. NELSON: It just occurs to me
that
6
that question is answerable if you have the
7
pharmaceutical review that is on the website. So,
8
maybe in the future just including that as part of
9 the
packet would enable us to have that at hand.
I
10 am
looking to see if that one is in here.
11
DR. PEREZ: Use the mike, please.
12
DR. D. MURPHY: It is in here in
what is
13
called the critical pharmacology and
14
biopharmaceutics review; summary of findings--
15
DR. S. MURPHY: Just to remind you
that we
16 can
only put what is in the public domain so, as we
17
look at what is being posted on the web I think
18
some of these are more extensive than others. So,
19 it
is giving us an opportunity to see what is going
20 on.
21
DR. GRYLACK: The PK study was
done on all
22
hypertensive patients. Are we
going to take a
78
1
break now for the vote or are we going to pursue to
2 the
next one?
3
DR. CHESNEY: Assuming there are
no more
4
questions on this particular issue, Dr. Santana
5
will cover the next drug as I am recused for stock
6
reasons. So, Dr. Santana?
7
DR. SANTANA: Let's go ahead and
get
8
started. Dr. Buckman?
9
DR. GRYLACK: Yes, it is my
pleasure to
10
introduce Dr. ShaAvhree Buckman. Dr.
Buckman is a
11
pediatrician who is not a neonatologist, who also
12 has
a Ph.D. in molecular cell biology and
13
pharmacology. Dr. Buckman has
been a medical
14
officer with the Division of Pediatric Drug
15
Development for nearly two years, and I will add
16
that Dr. Buckman has been a valued colleague of
17
mine during the time I have been here at the FDA.
18 Fentanyl
19
DR. BUCKMAN: Good morning. I will be
20
discussing the one-year post-exclusivity adverse
21
events for the fentanyl transdermal system.
22
The fentanyl transdermal system or,
79
1
trademark Duragesic, is marketed by Johnson &
2
Johnson and its subsidiary ALZA.
It is indicated
3 for
the treatment of chronic pain such as that of
4
malignancy that cannot be managed by lesser means,
5
such as acetaminophen-opioid combinations,
6
non-steroidal anti-inflammatory drugs or PRN dosing
7
with short-acting opioids, and pain that requires
8
continuous opioid administration.
It is approved
9 for
pediatric use in children down to the age of 2
10
years. The drug obtained original
market approval
11 in
August of 1990 and pediatric exclusivity was
12
granted in January of 2003.
13
The Duragesic label carries a boxed
14
warning that specifically states that due to the
15
possibility of serious or life-threatening
16
hypoventilation Duragesic is contraindicated in the
17
management of acute or postoperative pain,
18
including use in outpatient surgeries.
It is also
19
contraindicated in the management of mild or
20
intermittent pain responsive to PRN or non-opioid
21
therapy. It is also
contraindicated in doses
22
exceeding 25 mcg/hour at the initiation of opioid
80
1
therapy.
2
I have also outlined in red the pediatric
3
safety information that is in the boxed warning,
4
which specifically states that the safety of
5
Duragesic has not been established in children
6
under 2 years of age. Duragesic
should be
7
administered only if they are opioid-tolerant at
8 age
2 years or older.
9
There is selected additional safety
10
labeling which states that Duragesic should be
11
prescribed only by persons knowledgeable in the
12
continuous administration of potent opioids and the
13
management of patients receiving potent opioids for
14
treatment of pain and in the detection and
15
management of hypoventilation, including the use of
16
opioid antagonists.
17
Now, the total number of prescriptions
18
dispensed for the fentanyl transdermal systems in
19 the
United States have increased by 20 percent in
20 the
past 2 years, from 4.5 million in 2002 to 5.4
21
million in 2003. The top
prescribers in 2003 for
22 the
fentanyl transdermal systems were internal
81
1
medicine, family practice and anesthesiology.
2
Approximately 0.2 percent of fentanyl transdermal
3
system prescriptions dispensed were written by
4
pediatricians.
5
In the outpatient setting children and
6
adolescents have accounted for very few dispensed
7
fentanyl transdermal system prescriptions over the
8
past 2 years, 4,535 prescriptions from February
9
2002 to January of 2003 to 5,422 prescriptions from
10
February, 2003 to January, 2004.
In both the
11
outpatient and inpatient settings, adolescents age
12
12-16 years accounted for 60 percent of the
13
pediatric fentanyl transdermal system use over the
14
past 3 years.
15
In the outpatient setting the most
16
frequent diagnoses associated with the fentanyl
17
transdermal systems in the pediatric, as well as
18 the
adult, population were associated with diseases
19 of
the musculoskeletal system and connective
20
tissues. In the pediatric
population the most
21
predominant musculoskeletal diagnosis was spinal
22
stenosis, followed by injuries involving fractured
82
1
bones. One must be mindful though
that these are
2
very small numbers that we are capturing.
3
In the inpatient setting the primary
4
discharge diagnoses most frequently associated with
5
billing during hospitalization in the pediatric
6
population were for cholesterol encounters and
7
various blood disorders, including sickle cell
8
disease.
9
There was a total of 1,917 adult and
10
pediatric adverse event reports for the fentanyl
11
transdermal system during the 1-year
12
post-exclusivity period. Of
these, there were 8
13
unique pediatric cases. Seven
were from the U.S.
14 and
1 was a foreign report. All of these
cases
15
were described as serious outcomes, including 5
16
deaths. There were 4 reports in
females and 4
17
reports in males, and the ages ranged from 4-16
18
years of age. Of these 8
pediatric reports, most
19
adverse events were mentioned only once.
The
20
labeled adverse events that were captured twice
21
included overdose drug abuser and medication error.
22
Again, these are labeled adverse events.
83
1
Of the unlabeled adverse events that were
2
captured more than once, they included cardiac
3
arrest, respiratory arrest and self-medication.
4
There were 5 deaths that were reported
5
during the 1-year post-exclusivity period for
6
Duragesic and I would like to describe these
7
reports to you. The first was the
case of an 8
8
year-old female who was diagnosed with
9
rhabdomyosarcoma who died 2 months after being
10
switched from the fentanyl transdermal system to IV
11
morphine. This was a foreign case
and it is
12
believed that this child's death was due to
13
progression of her underlying disease and not due
14 to
the patch itself.
15
The second case is that of a 9 year-old
16
male who was 2 days post tonsillectomy and
17
adenoidectomy, who was treated with the fentanyl
18
transdermal system 25 mcg patch with subsequent
19
respiratory arrest resulting in death.
Concomitant
20 medications
that were given included acetaminophen
21
with codeine elixir, although the timing of
22
administration of this dosing is unclear from the
84
1
report.
2
This was a U.S. case and I have
a couple
3 of
comments about this case. One is that
this is a
4
case where a non-opioid tolerant patient was
5
prescribed the drug for an acute postoperative pain
6
situation. As you recall from the
boxed warning,
7
Duragesic is contraindicated in the management of
8
acute or postoperative pain.
9
The next case was that of a 4 year-old
10
female who died from cardiac arrest after having
11 the
fentanyl transdermal system applied by her
12
grandmother for pain relief. The
details of this
13
case are largely unknown. This is
a U.S. case, and
14 the
only additional information that we have is
15
that the child had marks on her body that indicated
16 that
she may have had more than one patch applied
17
because there was adhesive residue on her skin.
18
The next case was that of a 16 year-old
19
male with a history of drug abuse, including
20
marijuana, methylphenidate and dextropropoxyphene,
21 who
was reported to have been using the fentanyl
22
transdermal system several days prior to death and
85
1 was
found wearing a 100 mcg patch. This was
a U.S.
2
case.
3
The last of the 5 reported deaths was that
4 of
a 16 year-old male, with a history of alcohol
5 and
marijuana use, who died of cardiac arrest after
6
using 100 mcg patches obtained from another
7
student. He was found wearing a
100 mcg/hour patch
8 and
this was a U.S. case.
9
Now, there were 3 non-fatal adverse events
10
that were reported during the 1-year
11
post-exclusivity period. These
included a patient
12 who
experienced euphoria, hallucinations and weight
13
loss after initiation of therapy with the fentanyl
14
transdermal system.
15
The second case was a child who
16
experienced withdrawal symptoms from what was
17
considered a loose patch, meaning that the patch
18 had
become non-adherent to the skin and the patient
19
experienced withdrawal symptoms which resolved
20
after replacement of a new patch.
21
The last case was that of respiratory
22
depression in a patient who had intentional misuse
86
1 of
the fentanyl patch.
2
We have reported the adverse events that
3
occurred during the 1-year post-exclusivity period.
4 Due
to our concern regarding the pediatric deaths
5
occurring with this product, we decided to
6
investigate the adverse events which occurred since
7 the
approval of Duragesic for adults, in 1990.
8
There were 4 pediatric deaths before initiation of
9 the
pediatric exclusivity period. There have
been
10 3
additional pediatric deaths since the end of the
11
1-year post-exclusivity period.
Although we are
12
continuing to monitor for adverse events, for the
13 purpose of this presentation we set our
internal
14
cut-off for reporting to you at May 15th.
15
Now I would like to describe briefly those
16
deaths that occurred outside of the exclusivity
17
reporting period. The first was a
case of
18
accidental exposure. The second
was a case of
19
misuse or abuse. Most concerning
are these cases
20 of
off-label use. One is a case of a child
with
21
post-tonsillectomy and adenoidectomy pain. Another
22 is
a case of a child with infectious mononucleosis
87
1 and
sore throat pain; a child with chronic
2
headaches and infectious mononucleosis; and a child
3
with acute migraine. The last case
that was
4
reported was that of a child with rhabdomyosarcoma
5
and, again, this was another situation where it was
6
thought that the child died due to disease
7
progression and not due to administration of the
8
patch itself.
9
In summary, the cumulative pediatric
10
adverse events for the fentanyl transdermal system
11
since original market approval in 1990 totaled 35
12
unique cases. Of these, 22
reports were for
13
children who used the product appropriately for an
14
indication of chronic pain. Of
these 22 reports,
15
there were 2 pediatric deaths and these were both
16
children with rhabdomyosarcoma which I described.
17
By comparison, there were 13 reports in
18 children using the medication for a
non-chronic
19
pain management indication. Of
these 13 reports,
20
there were 10 pediatric deaths.
It is important to
21
remember that the Adverse Event Reporting System is
22 a
voluntary reporting system which is subject to
88
1
under-reporting and other influences, which you
2
have heard described multiple times this morning.
3
In conclusion, several of the serious
4
pediatric adverse events captured occurred in
5
patients who administered the product for an
6
unlabeled indication, for example, treatment of
7
acute pain in a non-opioid tolerant patient. There
8 is
need for additional education regarding the
9
proper use of the fentanyl transdermal system to
10
help further minimize abuse, misuse and off-label
11
use.
12
In conclusion, instead of answering
13
questions right now, because we have two subsequent
14
presentations that deal with the same product, I
15
would like to introduce the next speaker and then
16 we
can take questions at the end of all three
17
presentations. So, Dr. Lee will
address the
18
fentanyl pharmacokinetic characteristics following
19
Duragesic application. Dr. Lee is
a clinical
20
pharmacology and biopharmaceutics reviewer with the
21
Office of Clinical Pharmacology and
22
Biopharmaceutics, currently working with the
89
1
Division of Anesthetic, Critical Care and Addiction
2
Drug Products. Dr. Lee?
3
DR. LEE: Thank you, Dr.
Buckman. Good
4
morning, ladies and gentlemen. I
would like to
5 present
to you this morning on unique features of
6
fentanyl pharmacokinetics after Duragesic patch
7
application, but first, before I go into my slides,
8 I
would like to give you some overall background
9
information on the Duragesic patch.
10
First on the patch strengths, Duragesic
11
patches are available as 25 mcg, 50 mcg, 75 mcg and
12 100
mcg fentanyl delivered per hour patches.
13
Secondly on the site of application, patches are
14
applied mostly on a flat skin surface, mostly on
15 the
upper torso, such as chest, back, flank or
16
upper arms. In young children,
however, the upper
17
back is a preferred location to minimize the
18
potential for the child to remove the patch.
19 Lastly
on the intended use, as we all know, each
20
patch can be worn continuously up to 72 hours but,
21 if
analgesia for more than 72 hours is required, a
22 new
patch should be applied to a different skin
90
1
site after removal of the previous patch.
2
Gollowing the patch application the
3
fentanyl drug molecules move from the patch
4
reservoir through a rate-controlling membrane and
5
continue to be absorbed into the skin.
At this
6
juncture a depot of fentanyl concentrates in the
7
upper skin layer and fentanyl then becomes
8
available to the systemic circulation.
Peak serum
9
concentrations of fentanyl generally occur between
10 24
and 72 hours.
11
However, after patch removal the serum
12
fentanyl concentrations decline slowly, falling
13
about 50 percent in approximately 17 hours, which
14 is
the elimination half-life of the fentanyl patch
15
drug delivery system. Due to the
continued
16
absorption of fentanyl from the skin because of the
17
skin depot effect, fentanyl disappearance from the
18
serum is slower than is seen after an IV infusion.
19 The
elimination half-life for the IV infusion route
20 is
approximately 7 hours compared to that of 17
21
hours.
22
So, what are some of the potential
91
1
implications? With respect to
initial patch
2
application, the full drug benefit, analgesic
3
effect, may not be seen immediately.
Thus, there
4 is
a potential situation for applying another
5
patch. This can become a safety
issue I think.
6
With respect to post-patch removal,
7
substantial drug effect may be felt for a
8
significant period of time. Thus,
there is a
9
potential safety situation for a patient who will
10 be
switching over to another opioid therapy.
11
If you have any questions, I
will be happy
12 to
answer any, otherwise I will introduce Dr.
13
McNeil. Dr. McNeil is a medical
reviewer with
14
HDF-170. Prior to coming to the
agency she trained
15 in
pediatric neurology and oncology. Dr.
McNeil?
16
DR. MCNEIL: Good morning. I am with the
17
Division of Anesthetic, Critical Care and Addiction
18
Drug Products and, in collaboration with our
19
pediatric colleagues, we have been considering ways
20 to
manage the risk of off-label use.
21
We have been coming up with preliminary
22
strategies for managing this risk, and the
92
1
preliminary strategies that we have come up with
2 are
labeling changes; prescriber education through
3 the
company or, one thing that has been used in the
4
past, are "dear healthcare professional" letters,
5 or
prescriber education through physician
groups.
6 We
will, of course, be in contact with the company
7 and
with our colleagues in pediatrics as we try to
8
come up with a method of managing this risk.
9
DR. SANTANA: Did you have further
10
comments, Dr. Buckman?
11
DR. BUCKMAN: We can go ahead and
12
entertain questions at this time.
13 Discussion of Question 1
14
DR. SANTANA: Good. I do have a question
15 for
Dr. Lee. Is there any data either in
16
pediatrics or in adults that other concomitant
17
problems, like fever or skin rashes, change the
18
absorption? I was struck by a
couple of the deaths
19 in
patients who had infectious diseases or had
20
postoperative conditions that could be associated
21 with fever or some of these associated skin
rashes.
22 So,
is there any data to suggest that there is a
93
1
different pharmacokinetic profile under those
2
circumstances?
3 DR. LEE: As far as I know, I don't think
4 we
have any information from the pediatrics which
5
were involved with PK studies.
However, Dr. McNeil
6
may--she says no.
7
DR. SANTANA: Do we know from the
adults
8
about postoperative fever and things of that
9
nature?
10
DR. MCNEIL: No, we don't. It is actually
11 in
the label that if you apply heat externally to
12 the
drug patches you can increase the serum
13
concentration of fentanyl, but that is what is
14
known about it.
15
DR. SANTANA: Dr. O'Fallon?
16
DR. O'FALLON: I have been
watching these
17
things because my 93 year-old mother-in-law has
18
been outcome this--now she is 96 and a half--for
19
three and a half years. When I
first looked at it
20
what bothered me was the slow--she is allergic to
21
lots of different things; as it turns out she is
22
fine with this, but with something that moves so
94
1
slowly what would happen? It
would seem to me that
2
after 24, 36, 48 hours, something like that, a
3
person might reach a level where they would not be
4
able to tolerate it. Then, there
is this 17-hour,
5
which is really up to a whole day--before you can
6
drop the levels down sufficiently.
What do you do
7 if
somebody--I don't see anything in the label
8
about how to manage somebody that has a bad effect.
9 How
do you do it when it is in your system for so
10
long?
11
DR. LEE: My first answer could
have been
12
that the person who is experiencing adverse events
13 may
just peel off the patch and then for 17 hours,
14 for
that I don't have any answers.
15
DR. O'FALLON: It is actually up
to 24
16
almost. I mean, there is a
terrific range on these
17
things.
18
DR. LEE: Yes, the range is very
large.
19
Yes.
20
DR. S. MURPHY: Dr. Lee, could you
show
21
your backup slides with the kinetics?
I think they
22 are
very helpful.
95
1
DR. LEE: I would just like to
remind you
2
that the information in this study is from a
3
limited number of patients and the pediatric
4
subjects were non-opioid tolerant subjects. This
5
study had full pharmacokinetic profiling and,
6
therefore, it was a very useful study for me.
7
The Y axis is in nanograms per milliliter
8
concentration versus time. We put
a patch on and
9
take it off at 72 hours. This is
the adult
10
population where we see the increase in the
11
fentanyl concentration at approximately 22 to about
12
40-some odd hours.
13
Compared to the adults, this is a
14
pediatric population and I would just like to
15
mention at this time that the patch strength size
16 was
50 mcg/hour for adults and 25 mcg/hour for the
17
non-opioid tolerant pediatric patients.
As you can
18
see, time to maximum concentration has shifted at
19
earlier time points and it is higher.
Where I have
20
marked it with the shaded ovals, that is where we
21
need to kind of think again as far as having the
22
pain relief because it takes so long in order to
96
1
reach that plasma concentration.
And, then for the
2
black square, because it takes so long in order to
3
have the fentanyl concentration either eliminated
4
from the system or what-have-you, it takes so long,
5
even up to maybe 140 hours you could have some of
6 the
residual fentanyl concentration after patch
7
removal. So, I guess this is what
we have.
8
DR. MCNEIL: Excuse me, I should
mention
9
that my answer on fever was related to the
10
information we have, actual data from patients, but
11 in
the label, by PK modeling, there has been some
12
association that fentanyl doses could theoretically
13
increase up to a third but, again, that is from PK
14
modeling and not from actual patients.
15
DR. SANTANA: And we have no
postmortem
16
information from any of these deaths regarding
17
measurement of drugs in these patients?
18
DR. BUCKMAN: In looking at a
couple of
19
MedWatch reports we do have a couple of cases where
20 we
did get levels. In one case that I
reported to
21
you, the 16 year-old that died from an overdose of
22 the
fentanyl patch had an autopsy that was
97
1
performed. The cause of death was
cardiac arrest
2 due
to highly toxic levels of fentanyl. The
3
fentanyl level was 16 ng/ml. He
also had
4
cannabinoids in his bloodstream as well.
So, that
5 was
one case where we did actually have a
6
concentration.
7
DR. SANTANA: Dr. Fuchs?
8 DR. FUCHS: Well, two things that strike
9 me
from reading all your cases are that three of
10
them were used in kids with tonsillectomy or mono,
11 and
if you have ever looked at kids with
12
mononucleosis, those are kissing tonsils and, yes,
13
they do hurt. That may be
something where we might
14 add
a warning, "do not use when there is any airway
15
problem or tonsillitis or mono" because that is an
16
airway issue to begin with and then if you have
17 respiratory depression, which this drug is
known to
18
cause, and you have no airway obviously you will
19 get
hypoxia and that will then lead to respiratory
20
arrest and then lead to cardiac arrest.
21
The second thing is that in the cases
22
where you mentioned cardiac arrest, I suspect
98
1
mostly in kids this is respiratory arrest. Once
2
again, we can't really tell from the reports but I
3 suspect they are all respiratory related.
4
DR. BUCKMAN: That is a very good
point.
5 We
can only report to you exactly what is captured
6
there but I agree with you that in most pediatric
7
cases it is respiratory arrest leading to cardiac
8
arrest. But that is how it was
captured in the
9
reports.
10
DR. SANTANA: Dr. Nelson?
11
DR. NELSON: Looking at the label,
my
12
understanding is the strongest warning that the FDA
13 can
do is the black box, which is what you have at
14 the
front. So, unless we think it needs to
be
15
worded differently, there is already a black box.
16 The
only thing that doesn't seem to be in that
17
black box that is elsewhere is the comment about
18 the
qualifications of who should prescribe this.
19
Working in critical care and having used this in
20 the
past and no longer using it in the way that I
21 had
used it simply because of the labeling change,
22 it
is unclear to me how much stronger you could
99
1
make this, other than perhaps moving the
2
information about prescribers to the black box.
3
And, it is unclear to me--I am assuming there was a
4
pretty good malpractice loss for these deaths, or
5
there should be--so it is unclear to me how much
6
more you can do in your labeling if, in fact,
7
people are going to use it when it says not to use
8 it
that way. It seems pretty
straightforward to
9 me.
10
DR. BUCKMAN: Can I respond to
that
11
briefly? That was why in the
presentation we
12
wanted at the outset to show you exactly what was
13 in
the labeling because that is what we need to
14
hear from you as far as comments as far as how can
15 we
get that word out there anymore so. It
seems as
16 if
the greater propensity of what is happening is
17
that patients are being administered this product
18 for
an unlabeled or contraindicated use. So,
that
19 is
the feedback that we want to get from you all.
20 You
know, what other things can we do? That
is
21
going to be the question that we will be asking.
22
DR. SANTANA: Dr. O'Fallon first
and then
100
1 Dr.
Hudak.
2
DR. O'FALLON: I think that the
letter to
3
patients is very helpful that is included in our
4
packet. Is that normally given to
the patients? I
5
don't know your process here.
Between the
6
executive summary and the actual label there is a
7
patient information thing.
8
DR. MCNEIL: Patient information?
9
DR. O'FALLON: Yes, and I don't
know where
10
that comes into the Act.
11
DR. MCNEIL: In theory, what
happens is
12
when you buy your box of Duragesic is that you
13
should get this.
14
DR. O'FALLON: Yes, I don't think
we did.
15 She
said theoretically we should get it when we buy
16 our
box but I don't remember that we did.
17
DR. D. MURPHY: Remember, it is
not
18
required to be given to every patient.
19
DR. O'FALLON: That is what I was
20 wondering.
21 The
other thing is that I don't think it addresses
22 the
issue. You see, I was worried the first
time I
101
1 saw
this about the long-lastingness of this drug.
2
What happens if they get into trouble?
Is there
3 any
information that the patients could have if
4
they are seeing something? I
don't even see that
5 it
says call your emergency room immediately, or
6
something. I don't see anything
about what to do
7 in
case the kid gets in trouble or the person gets
8 in
trouble, the 90-odd year-old gets in trouble.
9
DR. MCNEIL: Under "how do I
use
10
Duragesic" in the patient information section it
11
does say if you use too much Duragesic or overdose
12 get
emergency medical help right away. But I
guess
13
from what you are saying that is not enough.
14
DR. O'FALLON: Well, I didn't see
it in
15 the
patient letter but maybe I missed it.
16
DR. SANTANA: Dr. Hudak?
17
DR. HUDAK: I guess in comment to
Dr.
18
Nelson's comment, I am not sure what can be done
19 for
language and what the limitations are but I
20
think many physicians are sort of jaded when they
21 see
"serious" or "life-threatening" written down
22
somewhere because that seems to be on a lot of
102
1
different drugs, and maybe something very specific
2 about deaths have occurred due to, you know,
3
inappropriate use in these situations should be in
4
there in some form that makes it very concrete.
5
DR. SANTANA: Do we know from
these
6
adverse event reports if, in the cases that were
7
postoperative, those were actually prescribed by a
8
person before the procedure or subsequently by a
9
pediatrician or family physician?
I mean, what is
10 the
sequence of prescriptions here?
11
DR. BUCKMAN: In one case it was
12
prescribed by a family physician.
In another case
13 it
was prescribed by the pain control team in the
14
ICU, and the mother had asked--and Joe Wyeth, our
15 ODS
person, please correct me if I am wrong; she
16 has done an incredible job of helping us get
all
17
these reports together--but in another case it was
18
prescribed in the ICU by the pain control team for
19
this child. The mother asked that
two of the vital
20
checks be suspended. They were
overnight vital
21
checks. She wanted the child to
rest, and by the
22
morning when they did the next vital check the
103
1
child was dead.
2
DR. SANTANA: Dr. Gorman, I would
like to
3
hear your opinion on this since you are a
4
practicing pediatrician in the community.
5
DR. GORMAN: First of all, all of
these
6
patches as they have come out, these long-acting
7
patches--I think I remember the same event with a
8
patch that came out for hypertension with another
9
product where children had it applied
10
inappropriately or retrieved it from wastepaper
11
baskets. There were several
adverse outcomes which
12
were slightly different than these.
13
I would have to echo Dr. Hudak's very
14
explicit comments. I think the
hypothetical that
15 is
put in the black box warning now is a reality
16 and
there should be a statement--and I understand
17
that labels are a negotiated legal document between
18 the
FDA and the pharmaceutical company, but a
19
simple statement that deaths have occurred through
20 the
inappropriate use of this in the following
21
settings, and then a listing that you have
22
contraindicated would take this out of the realm of
104
1
hypothetical and say it is real.
2
Then to echo a little bit of what Dr.
3
Nelson said, there could be a little asterisk on
4 the
bottom--which I know you are not allowed to
5
use--that says and big malpractice awards were
6
awarded.
7
[Laughter]
8
DR. SANTANA: We don't want to get
into
9
that! Any other comments? Dr. Lee?
10
DR. LEE: I just wanted to make a
11
clarification that for the data that I presented
12 for
the non-opioid tolerant patients, the age range
13 was
from 1.5-5. I just wanted you to
understand
14
that. It doesn't give us an
overall 2-16 year-old
15
range.
16
DR. SANTANA: Dr. Luban, you deal
with
17
patients with sickle cell who have chronic pain
18
issues. Would you like to comment
on this issue?
19
DR. LUBAN: I think the biggest
issue
20
there is the complex use of more than one
21
analgesic, and the occasional failure of families,
22
when discharged, to follow the pain team's
105
1
recommendation and to really abuse the medications
2
because of continuing needs of the child. So, I
3 see
sickle cell disease and the use of this as a
4
real avenue of education that really should be
5
followed up on.
6
DR. SANTANA: Dr. Murphy?
7
DR. D. MURPHY: Do you think that
it is
8
clear--getting back to Dr. O'Fallon's
9
question--from the patient insert that after you
10
remove this product it is still absorbed? Do you
11
think that is clear enough in here, for longer
12
periods of time?
13
DR. SANTANA: Dr. Luban?
14
DR. LUBAN: I think that is not at
all
15
clear. I think that this is
written at a very
16
sophisticated level for some families to interpret.
17 We
certainly don't have high level language use
18
when we are doing informed consent, so why should
19 we
if we are trying to educate patients and
20
families?
21
DR. MCNEIL: Thank you. We will talk more
22
with the folks--there is actually a whole team of
106
1
people who help us write these patient information
2
inserts and they are supposed to be geared to the
3
sixth to eighth grade level. By
the giggles in the
4
room, I guess we have not hit that mark so I will
5
talk with people and we will see what we can do.
6 If
I understand you correctly, we should make it
7
slightly simpler.
8
DR. LUBAN: Speaking for our
patient
9
populations, I would say yes. The
use of the term
10
"opioid tolerant" is not a term that most parents
11 can
understand.
12
DR. SANTANA: And I am not even
sure a lot
13 of
physicians understand it.
14
[Laughter]
15
No, that is a fair observation.
16
DR. MCNEIL: The reason that we
used
17
"opioid tolerant"--I mean, I understand your
18
comment but the reason that we used "opioid
19
tolerant" was just to reflect the language in the
20
boxed warning, but I do understand what you are
21
saying and we will try to come up with something.
22
DR. SANTANA: Dr. Gorman and then
Dr.
107
1
Nelson.
2
DR. GORMAN: It strikes me how
attractive
3
this product would have to be to people doing ear,
4
nose and throat surgery on tonsils.
You have a
5
population with generally poor options for oral
6
medications in terms of their taste and
7
tolerability and adverse events of vomiting. So,
8 you
have a product that looks really attractive to
9
them because it is applied to the outside to an
10
obstreperous 4 year-old and you don't have to try
11 to
get them to drink something. If I was
targeting
12 my
educational process, ear, nose and throat
13
physicians and ambulatory surgery centers would be
14 at
the top of my list.
15
DR. MCNEIL: Excuse me, may I just
go back
16 to
Drs. Luban and O'Fallon? I just want to
make
17
certain that what we were speaking about before,
18
that the language is a bit too sophisticated is in
19 the
patient information section, not the actual
20
label? Correct?
21
DR. LUBAN: Correct.
22
DR. O'FALLON: The statement
"call your
108
1
healthcare provider right away of get emergency
2
help if you have trouble breathing or have other
3
serious side effects," that is in there on the
4
fourth page, without a bullet in a wholly bulleted
5
thing. I think you should move it
up to what is
6 the
most important information I should know.
It
7
should go there.
8
DR. MCNEIL: Thank you.
9
DR. CHESNEY: Dr. Nelson, you had
your
10
hand up?
11
DR. NELSON: Well, I think my
comment
12
follows from both of the last two, which is to also
13
look at the order within which you are putting
14
things, particularly given Dr. Gorman's comment.
15 The
first thing probably shouldn't be only use it
16 in
the way that your healthcare professional tells
17 you
to.
18
[Laughter]
19
Because we are talking about healthcare
20
professionals not using it appropriately.
21
DR. SANTANA: Dr. Hudak?
22
DR. HUDAK: I guess this is sort
of
109
1
getting at the question here, but the other avenue
2 for
education, it seems to me, since some of these
3
more egregious events occurred in the hospital
4
setting, is perhaps to have a letter that goes out
5 to
the hospital pharmacies, pediatric pharmacies
6
about this, and in this day and age where there are
7
computerized physician order entry systems it seems
8
that this would be a big way to sort of capture
9
that before it might become an issue.
10
DR. DANFORD: Does the FDA ever
11
communicate directly with risk management
12
individuals for hospitals and clinics?
Several of
13 the
speakers have suggested that the adverse events
14
might most likely be prevented by having a general
15
understanding that lawsuits can happen over misuse.
16
Perhaps the lawyers from hospitals and clinics who
17 try
to reduce their exposure to big settlements, if
18
they received something from the FDA about the
19
misuse of such products might actually do a lot of
20
work of educating the people who work in their
21
institutions.
22
DR. SANTANA: Dr. Nelson?
110
1
DR. NELSON: I think, at least in
my
2
setting, if a letter went out to the pharmacist you
3
effectively would accomplish that because it would
4
then go to the control mechanisms for prescribing
5
that would be used within a facility at least to
6
establish risk management strategies.
I would
7
probably prefer going that way because it is at
8
least then directed to the provision of care rather
9 than the other way.
10
DR. SANTANA: I would support
that. It is
11
within the scope of their care of what they should
12 be
doing with patients in terms of educating as
13
they get prescriptions filled, and so on and so
14 forth. So, I would support that too. Any other
15
comments? Dr. Murphy?
16
DR. D. MURPHY: I just wanted to
summarize
17 and
ask the Division to also pitch in here if they
18
don't think I have summarized correctly what we
19
have heard from the committee.
20
DR. SANTANA: I took some
notes. Would
21 you
allow me to do that? I think the
committee
22
would like the FDA to move in three directions that
111
1 you
have pointed out in this slide. One of
the
2
comments I heard very strongly from the committee
3 is
that the label needs to be re-looked at in the
4
context of maybe providing stronger statements,
5
regarding the inappropriate use resulting in deaths
6
that have already been observed, somewhere earlier
7 in
the actual label so that physicians and others
8
prescribing this can see that clearly early on.
9
I also heard a comment that there is a
10
section about qualifications of the prescriber and
11
those qualifications were kind of hidden in the
12
back of the information, and it should be brought
13
forward into the label too. So,
it is not a matter
14 of
re-writing the label but maybe providing some of
15 the
information in different sections, particularly
16 at
the beginning that would be more evident to
17
those that are prescribing. Those
are the comments
18
that I heard about the label.
19
I heard a lot of comments about patient
20
information and using the patient as an advocate
21 for
him or herself. I heard comments that
probably
22 the
reading language was inappropriate for the
112
1
populations that are being targeted in which this
2
medication could be used. So,
that needs to be
3
looked at very carefully.
4
I also heard some comments that I think
5
were very appropriate about clearer statements in
6 the
patient information regarding how, when this
7
medication or patch is removed, there will be
8
sustained levels that may continue to put you at
9
risk of having respiratory depression and
10
associated side effects.
11
Related to the patient information, I also
12
heard some comments about how the information in
13
that patient information leaflet should be
14
reorganized to put some of the highlights earlier
15 on
and make them more self-evident.
16
Then I heard a brief discussion about
17
education, primarily to prescribers.
I heard
18
various comments about some of the incident cases
19
that received care that had been by ENT, by
20
anesthesiologists, by pain teams.
I didn't hear a
21 lot
of discussion about how we could accomplish
22
that so I am going to seek a little bit more advice
113
1 from
the committee on how potentially that could be
2
accomplished. But I did hear that
there needs to
3 be
reeducation of people prescribing this and
4
potentially starting with some target populations
5 and
then moving it more openly, including
6
pharmacists, of course.
7
Then I also heard a very strong statement
8
about educating our patients who are using these
9
products and parents, and how we can best
10
accomplish that.
11
So, maybe the committee wants to spend
12
maybe one more minute probably advising the agency
13 on
potentially what educational systems may already
14 be
in place that they could target or the company
15
could target. If anybody wants to
add to that?
16 Dr.
Murphy?
17
DR. D. MURPHY: Thank you very
much. I
18
only have one question I want to clarify, and that
19 is
the label--the statement you had, Dr. Santana,
20 was
that we want a stronger statement concerning
21 the
deaths early in the label. I thought I
heard
22
that you wanted it in the black box.
114
1
DR. SANTANA: Yes, in the black
box. That
2 is
what I meant. That is correct.
3
DR. D. MURPHY: Thank you.
4
DR. SANTANA: Any further sort of
advice
5 to
the agency on this issue? I think we
have
6
discussed question one actually.
Am I correct?
7
DR. MCNEIL: Thank you for your
comments.
8 It
is very helpful to us. I am going to
take them
9
back for further discussions with the company.
10
DR. SANTANA: Thank you so
much. I think
11 we
are going to take a ten-minute break and start a
12
little bit after 10:30. Thank
you.
13
[Brief recess]
14
DR. CHESNEY: While everybody is
finding
15
their seats, I wanted to thank the FDA for
16
clarifying one issue which had to do with the use
17 of
ciprofloxacin and moxyfloxacin in ophthalmic
18
preparations. In the last two
slides the expected
19
cure rate of 70 percent, is that for conjunctivitis
20 in
adults? This study was actually done in
21
neonates. So, probably one can't
extrapolate from
22 one
to the other, just for clarification.
Dr.
115
1
Iyasu is going to introduce our next speaker.
2
DR. IYASU: Thank you. Our next speaker
3 is
Dr. Hari Cheryl Sachs. Dr. Hari Sachs is
a
4
professor of pediatrics at GW and
Children's
5
Hospital National Medication Center.
She has over
6 15
years of experience in private practice.
She
7
also served on the FDA non-prescription drug
8
advisory committee and is one of the FDA liaisons
9 to
the AAP committee on drugs. She will be
10
presenting the adverse events for venlafaxine.
11
Adverse Event Reports per Section 17 of BPCA
12 (cont.), Venlafaxine
13
DR. SACHS: Thank you very
much. I am
14
glad to be here to talk to you, guys.
It is
15
actually nice to see some familiar faces among the
16
crowd.
17
I will be discussing the adverse events
18 for
venlafaxine, and I think you, guys, are
19
familiar now with the basic organization of the
20
talk. Venlafaxine, or trade name
Effexor, has been
21 on
the market since December, 1993 for the
22
treatment of major depressive disorder, generalized
116
1
anxiety disorder and social anxiety disorder.
2
Although these are the indications in adults, there
3 are
no approved pediatric indications despite the
4
fact that exclusivity was granted in December,
5
2002, and the sponsor now goes by the name of Wyeth
6
Pharmaceuticals.
7
Venlafaxine and its active metabolite,
8
whose name I am not going to try to pronounce, is a
9 potent
inhibitor of both serotonin and
10
norepinephrine reuptake so this is actually an SNRI
11 but
for convenience I am going to refer to the
12
whole class as SRIs. It also is a
weak inhibitor
13 of
dopamine reuptake. These actions, along
with
14 the
lack of significant muscarinic cholinergic and
15
histaminergic effects, do alter the side effect
16
profile of the drug. The
half-life, which is about
17 5
hours for venlafaxine and 11 hours for the active
18
metabolite, is relevant for the timing of potential
19
discontinuation symptoms when they occur.
20
Venlafaxine was the fourth most commonly
21
prescribed antidepressant in the U.S. during 2003
22
and, as with other SRIs, prescriptions have been
117
1
rising in both pediatric and adult populations.
2
Although pediatric use seems to account for only
3
about 2.5 percent, this represents almost half a
4
million prescriptions. This use
is all off-label.
5
Disorders of mood and anxiety, along with ADHD are
6 the
most common indications that kids have been
7
treated for with venlafaxine.
8
I will now briefly describe the results of
9 the
studies performed for exclusivity. There
were
10 4
large, multicenter, double-blind,
11
placebo-controlled, parallel group, flexible dose
12
studies for each indication, that is, major
13
depressive disorder and general anxiety disorder.
14 The
dose used was flexible dosing between 37.5 mg
15 and
225 mg, and the age was 6-17 years. None
of
16 the
studies in major depressive disorder showed a
17
significant difference in placebo and,
18
interestingly enough, only one of the studies for
19
generalized anxiety disorder showed a positive
20
study result.
21
The endpoints in both the trials were
22
age-appropriate clinical symptom rating scales for
118
1
major depressive disorder. It was
the CDRS
2
revised. For the GAD trial it was
the Columbia
3
Kiddy Scale for Affective Disorders, or the KSADS.
4
Since only one study showed efficacy, that is why
5 no approval was granted.
6
Safety information was based in part on
7
these 4 studies, as well as 2 open-label trials, a
8
6-month trial in major depressive disorder and
9
another study in conduct disorder.
In these
10 studies
decreased weight gain and growth was noted
11
which was unrelated to treatment emergent-anorexia.
12 You
can see the numbers for the approximate weight
13
loss and weight gain in the placebo population, and
14 the
height. If you actually read the results
of
15 the
studies posted on the web, these numbers differ
16
slightly from that because the FDA received
17
additional information and analyzed it.
The other
18
thing that is kind of interesting is that it is
19 actually
important that the height effect was seen
20 in
the exclusivity studies. It is pretty
21
significant because it was a very short period of
22
time that the drugs were studied.
119
1
The other adverse event that was noted,
2
mild adverse event, is that there were elevations
3 in
cholesterol and blood pressure that were similar
4 to
those seen in adults. That also was
added to
5 the
label.
6
Since we are speaking of the label, let's
7
turn to the relevant safety labeling.
I would like
8 to
highlight several things about the labeling,
9
some of which is relevant to the safety discussion
10 or
the adverse events that we see, but also many of
11 the
changes are physically highlighted in yellow to
12
kind of emphasize that these are the new changes
13
that have been added actually since March.
14
In terms of neonates and pregnancy,
15
venlafaxine is considered a category C drug. That
16
means it should be used in pregnancy only if
17
clearly needed. Language
regarding the
18
discontinuation syndrome in newborns was added
19
fairly recently, first in January, 2003 and then
20
updated last month. It is found
in the section
21
under "non-teratogenic effects." What the labeling
22
describes is that you can see discontinuation
120
1 effects
in newborns with complications that may
2
require prolonged hospitalization or respiratory
3
support that may arise even as soon as delivery.
4 You
may also see some clinical findings, including
5
neurologic, respiratory and systemic symptoms.
6
These symptoms are consistent either with
7
discontinuation of the drug or potentially actually
8 a
direct toxic effect of the serotonin.
9
As you know, in part because of the
10
deliberations in February, a warning recommending
11
close observation for deterioration or emergence of
12
psychiatric symptoms in patients that are treated
13
with these SRIs was added in May, 2004 to the
14
label, and this warning actually supersedes and
15 replaces
some of the information that was in the
16
label previously regarding the association of
17
suicide with depression and other co-morbid
18
disorders, and a statement that Wyeth had added on
19 its
own that there were some suicidality seen in
20 the
pediatric trials. The other thing that
is
21
mentioned is the occurrence of sustained
22
hypertension.
121
1
These slides show an extensive list of
2
precautions which are listed in the order that they
3
appear in the label. Most of
these things were
4
seen in the top 20 adverse events that you have in
5 the
main report for venlafaxine, and we see some of
6
these in the post-exclusivity adverse events that
7
occurred during the year. I draw
your attention to
8 the
risk of bleeding and also the problems with
9
seizures, and then in the new labeling which is
10
regarding the weight loss and slower rate of growth
11 in
children.
12
In addition, under adverse reactions the
13
risk of symptoms with discontinuation, and this is
14 in
adults and older children, include both physical
15 and
psychiatric symptoms. In March there was
some
16
labeling added to the postmarketing reports on
17
dyskinesia and rhabodomyolysis.
18
So, now that you are familiar with all the
19
changes in the label, let's look at the adverse
20
events for the year. These are
actually the raw
21
counts of all the adverse events.
There were
22
approximately 1,500, of which about half are in the
122
1
U.S. and they may represent some duplicates.
2
Pediatric reports are really a relatively small
3
proportion, less than 4 percent of total reports
4 and
this has been pretty consistent over the past
5
several years since marketing.
There were only 2
6
deaths that occurred, and I will be discussing them
7 in
a few moments.
8
Turning to the specific 1-year
9
post-exclusivity period, there were 49 unduplicated
10
events. I apologize for the busy
nature of this
11
slide. There were 19 events that
involved in utero
12 or
maternal exposures and 30 that were direct
13
pediatric exposures. The gender
and age
14
distribution is seen here. Of
interest, there is a
15
male predominance of the adverse events in the
16
infants and neonates while the gender distribution
17 is
pretty similar in the older children.
Outside
18 the
neonatal period, most of the direct exposures
19
involved adolescents and children, as would be
20
expected.
21
Looking more closely at the in utero
22
events, there were actually no deaths reported
123
1
among the 19 in utero events, 3 of which also had
2
concomitant breast feeding. There
were 4 unrelated
3 congenital
anomalies; 2 had cardiac malformations,
4 1
with an ASD and the other with dextrocardia.
5
Another infant had hypospadias and the last infant
6 had
extra syndactyly, which is a fusion and webbing
7 of
the digits. Co-morbidities and other
8
medications were actually involved in all these
9
congenital anomalies.
10
Neurologic events were described in 11
11
infants. We saw 2 infants that
had hypotonia; 3
12
infants who developed seizures; and 6 infants who
13 had
disordered movements.
14
Just to illustrate how difficult it is to
15
sort out causality for these events, on follow-up
16 for
one of the infants who had seizures the event
17 was
considered unrelated to venlafaxine because the
18
patient had experienced a subarachnoid hemorrhage.
19
But, if you will recall, abnormal bleeding can be
20
associated with venlafaxine. So,
it is potentially
21
possible that the baby had subarachnoid hemorrhage
22 related
to the medication. Of course, that is
124
1
conjecture but just to show how hard it is to sort
2 out
the information.
3
The losartan in utero exposure events were
4
really 4 reports that detail complications that
5
occurred in babies with co-morbid conditions and
6
medications. They are described
here. While it is
7
less serious, it is something that has emerged in
8 the
literature so it is interesting that we did see
9 2
cases here as well.
10
Co-morbid disease and medications, as I
11
have explained, may contribute to some of these
12
events. Although 2 events were
coded specifically
13 as
neonatal withdrawal, there are actually up to 5
14
others where symptoms that emerged, like
15
jitteriness or tremor or seizure, could have
16
reflected neonatal withdrawal but it was just not
17
coded that way.
18
Prematurity was reported in 4 infants but
19 in
8 cases there actually was insufficient
20
information in the case report to determine whether
21 or
not a baby was premature. Three infants
were
22
breast fed. One mother reported
smoking and
125
1
drinking but that information about tobacco or
2
substance exposure or illicit drugs is actually not
3
present in the majority of the reports.
About half
4 the
infants were exposed to concomitant
5
medications, 4 of which were psychotropic. When I
6
looked back, 5 included benzodiazepines.
In only 2
7 the
case report expressly stated that there were no
8
other medications involved, and whether or not
9
medicines were involved in 7 of the other cases is
10 not
known.
11
So, in looking at the neonatal events,
12
they do seem to reflect the ones that are labeled
13 in
adults, for example tremor, convulsion and
14
hypotonia. The role of
concomitant medicines and
15 co-morbid conditions, such as prematur