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