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
Joan P. Chesney, M.D., Chair
Thomas H. Perez, M.P.H., Executive Secretary
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
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
Solomon Iyasu, M.D.
Susan Cummins, M.D.
Shirley Murphy, M.D.
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,
C O N T E N T S (Continued)
Open Public Hearing:
Philip Sanford Zeskind, Ph.D., University
Pediatric Research Equity Act,
Shirley Murphy, M.D. 326
Conduct of Clinical Research Involving
Children," Robert Nelson,
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.
DR. FUCHS: Susan Fuchs, pediatric
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
19 DR. HUDAK: Mark Hudak, neonatologist,
20 University of Florida, Jacksonville.
21 DR. DANFORD: Dave Danford, pediatric
cardiology, University of Nebraska Medical Center,
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,
12 DR. D. MURPHY: Dianne Murphy, Office
13 Director, Office of Counter-terrorism and Pediatric
14 Drug Development, in the Office of Pediatric
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
event reporting session and is made part of the
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
issue, valued from $5,001 to $25,000 and unrelated
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
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.
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.
has been clearly legislatively mandated that
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
have evolved a process, again with your feedback
1 and assistance, that has allowed us to make it more
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
20 Now, why is it important? Because I don't
21 know how many times you have sat through these
meetings where we said, "well, here are the
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
information that, in essence, was moved forward
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
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
Children Act. Dr. Iyasu is a
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
DR. IYASU: Thank you very much,
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
age-appropriate pediatric formulations for
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
available in the public domain is evolving,
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
Wisner will address the risk/benefit of treatment
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
limitations have also been presented before and are
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
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.
However, national estimates from Premier are
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
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
practice about a year ago. She
1 adverse event reports for fexofenodine. Dr. Filie?
3 DR. FILIE: Good morning, everyone. I
4 will proceed with the adverse event review for
5 fexofenodine during the one-year post-exclusivity
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
tolerability in 2 groups, 6 months to 2 years
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
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
over-the-counter in 2002. The
total number of
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.
There were no pediatric deaths.
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
discontinuation of the drug in a few days.
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
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
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.
The last case--a prescription refill was
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
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
pretty much the two groups.
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
accumulated and we can keep all this data
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
21 DR. D. MURPHY: I did want to respond that
your package it does tell you that fexofenodine
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,
unless you had a mechanistic reason for doing that,
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
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
some additional studies.
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
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
like to have it reemphasized again is that there is
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
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
rest of the meeting.
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
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
mentioned, in terms of data that is available for
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
alternative regimens using combinations of
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
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
drug which had a number of prescriptions, this was
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
disorder, and 3 reports each of arachnoiditis,
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
through these voluntary reporting mechanisms but
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
DR. MCCUNE: That is correct. This is the
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.
DR. D. MURPHY: Dr. Santana, I
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
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
looked and here is what we found in a very limited
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
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
FDA it is not part of the information that we
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
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
them to report. But once it is reported to the
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
directly. So, I would like to keep
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
the 1-800 MedWatch number on labels and that
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
will take that back and pursue that as an
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
the accuracy of the reporting. So, it is
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
label safety information is included in the
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
complete response and 12 percent partial responses
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
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
The pediatric population of 1-16 years of
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
felt that most of the use of this drug is
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
Just to take each one of these
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
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
temozolomide treatment, this patient also had
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
20 In summary, for temozolomide there have
21 been described both labeled and unlabeled adverse
events. The unlabeled events have
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
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
beside the label.
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
21 DR. MCCUNE: It is my privilege to
introduce Dr. Harry Gunkel to you.
He is the only
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
also indicated for corneal ulcer.
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
children 1 year of age or greater for the treatment
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.
There was 1 report in the exclusivity
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
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
significant. Thank you.
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.
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
they have a lower response rate or success rate,
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
Temodar, which is the one that I read you. I
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
practice of neonatal medicine at Columbia Hospital
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.
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
prescribed use of renin angiotensin antagonist
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
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
body weight was used.
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
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
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
have to demonstrate and, if you don't, then you
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
age-appropriate formulation it does not say, nor do
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
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
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
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
information that we need--and I really can't
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
products that are then not available.
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,
certain number of those would be less than 50 kg.
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?
DR. D. MURPHY: Correct.
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
20 DR. D. MURPHY: That is what I meant,
21 children without hypertension.
DR. DANFORD: There could be a
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
population in the efficacy and safety study
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
21 DR. GRYLACK: The PK study was done on all
hypertensive patients. Are we
going to take a
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.
19 DR. BUCKMAN: Good morning. I will be
20 discussing the one-year post-exclusivity adverse
21 events for the fentanyl transdermal system.
The fentanyl transdermal system or,
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
exceeding 25 mcg/hour at the initiation of opioid
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
fentanyl transdermal systems were internal
1 medicine, family practice and anesthesiology.
2 Approximately 0.2 percent of fentanyl transdermal
3 system prescriptions dispensed were written by
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
stenosis, followed by injuries involving fractured
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
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.
Again, these are labeled adverse events.
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
administration of this dosing is unclear from the
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
transdermal system several days prior to death and
1 was found wearing a 100 mcg patch. This was a U.S.
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
depression in a patient who had intentional misuse
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
a case of a child with infectious mononucleosis
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
voluntary reporting system which is subject to
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
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
Biopharmaceutics, currently working with the
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
patch should be applied to a different skin
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
So, what are some of the potential
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
strategies for managing this risk, and the
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.
is there any data to suggest that there is a
1 different pharmacokinetic profile under those
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
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
fine with this, but with something that moves so
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
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
18 DR. LEE: Yes, the range is very large.
20 DR. S. MURPHY: Dr. Lee, could you show
21 your backup slides with the kinetics? I think they
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
pain relief because it takes so long in order to
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
fentanyl patch had an autopsy that was
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
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
where you mentioned cardiac arrest, I suspect
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
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,
is unclear to me how much stronger you could
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
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.
DR. SANTANA: Dr. O'Fallon first
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
21 The other thing is that I don't think it addresses
issue. You see, I was worried the first
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
somewhere because that seems to be on a lot of
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
morning when they did the next vital check the
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
contraindicated would take this out of the realm of
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
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
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,
when discharged, to follow the pain team's
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
21 DR. MCNEIL: Thank you. We will talk more
with the folks--there is actually a whole team of
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.
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.
DR. SANTANA: Dr. Gorman and then
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.
DR. O'FALLON: The statement
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.
19 Because we are talking about healthcare
20 professionals not using it appropriately.
21 DR. SANTANA: Dr. Hudak?
DR. HUDAK: I guess this is sort
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
DR. SANTANA: Dr. Nelson?
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
would like the FDA to move in three directions that
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
reading language was inappropriate for the
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
that so I am going to seek a little bit more advice
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
that you wanted it in the black box.
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
to the other, just for clarification.
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
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
treatment of major depressive disorder, generalized
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
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
and, as with other SRIs, prescriptions have been
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
age-appropriate clinical symptom rating scales for
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
time that the drugs were studied.
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
describes is that you can see discontinuation
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
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
approximately 1,500, of which about half are in the
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
21 Looking more closely at the in utero
events, there were actually no deaths reported
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
to the medication. Of course, that is
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
breast fed. One mother reported
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