1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

                    PEDIATRIC ADVISORY SUBCOMMITTEE

 

             OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

 

 

 

 

 

 

                        Wednesday, June 9, 2004

 

                               8:00 a.m.

 

 

                          ACS Conference Room

                               Room 1066

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                              PARTICIPANTS

 

         Joan P. Chesney, M.D., Chair

         Thomas H. Perez, M.P.H., Executive Secretary

      CONSULTANTS (VOTING):

 

         Mark Hudak, M.D.

         David Danford, M.D.

         Richard Gorman, M.D.

         Robert Nelson, M.D., Ph.D.

         Susan Fuchs, M.D.

         Victor Santana, M.D.

         Naomi Luban, M.D.

         Judith O'Fallon, Ph.D.

         Katherine L. Wisner, M.D.

 

      MEMBER OF THE ANTI-INFECTIVE DRUGS ADVISORY

      COMMITTEE (VOTING):

 

         Steve Ebert, Pharm.D., Consumer Representative

 

         FEDERAL GOVERNMENT EMPLOYEE (VOTING):

 

         Janet Cragan, M.D.

 

         INDUSTRY REPRESENTATIVE TO ANTI-INFECTIVE DRUGS

         ADVISORY COMMITTEE (NON-VOTING):

 

         Sam Maldonado, M.D., industry representative

 

      FDA STAFF:

 

         Solomon Iyasu, M.D.

         Susan Cummins, M.D.

         Shirley Murphy, M.D.

         Dianne Murphy, M.D.

                                                                 3

 

                            C O N T E N T S

 

      Call to Order and Introductions,

         Joan P. Chesney, M.D.                                   5

 

      Meeting Statement, Thomas H. Perez, M.P.H.                 7

 

      Welcome, Dianne Murphy, M.D.                              10

 

      Adverse Event Reports per Section 17 of Best

         Pharmaceutical for Children Act,

         Solomon Iyasu, M.D.                                    15

 

         Fexofenodine, Jane Filie, M.D.                         22

 

         Topotecan and Temozolomide, Susan McCune, M.D.         34

 

         Moxifloxacin and Ciprofloxacin,

            Harry Gunkel, M.D.                                  59

 

         Fosinopril, Larry Grylack, M.D.                        66

 

         Fentanyl, ShaAvhree Buckman, M.D.                      78

         David J. Lee, Ph.D.                                    89

         D. Elizabeth McNeil, M.D.                              91

 

      Discussion of Question 1                                  92

 

      Adverse Event Reports per Section 17 of BPCA

      (cont.), Venlafaxine, Hari Sachs, M.D.                   115

 

      Pediatric Update, Dianne Murphy, M.D.                    148

 

      Meeting Statement, Thomas H. Perez, M.P.H.               170

 

      Update on Neonatal Withdrawal Syndrome:

 

         Kathleen Phelan, R.Ph.                                174

         Robert Levin, M.D.                                    189

         Katherine Wisner, M.D.,

           Women's Behavioral Health CARE                      216

 

      Discussion of Questions 2 and 3                          254

 

      Update on Congenital Eye Malformations in Infants,

         Solomon Iyasu, M.D.                                   303

                                                                 4

 

                      C O N T E N T S (Continued)

 

      Open Public Hearing:

 

         Philip Sanford Zeskind, Ph.D., University

            of North Carolina                                  309

 

      Pediatric Research Equity Act,

         Shirley Murphy, M.D.                                  326

 

      Overview of Institute of Medicine Report, "Ethical

         Conduct of Clinical Research Involving

         Children," Robert Nelson, M.D.                        340

 

                                                                 5

 

  1                      P R O C E E D I N G S

 

  2                   Call to Order, Introductions

 

  3             DR. CHESNEY:  Good morning.  I think we

 

  4   are ready to get started.  I would like to welcome

 

  5   everybody to this meeting which, for those in the

 

  6   room who don't know, and Dr. Murphy will elaborate

 

  7   on this, this is the last meeting for this group of

 

  8   the Pediatric Subcommittee as currently

 

  9   constituted.  I would like to also mention that Dr.

 

 10   Mimi Glode will not be with us because her father

 

 11   became ill on Sunday and she had to cancel at the

 

 12   last minute.

 

 13             Tom has just told me that traffic is going

 

 14   to become very bad this afternoon because of

 

 15   President Reagan's funeral so we want to keep that

 

 16   in mind as we move on throughout the day.  So, I

 

 17   think we will start with introductions and, Dr.

 

 18   Maldonado, would you like to start?

 

 19             DR. MALDONADO:  Sam Maldonado, from

 

 20   Johnson & Johnson, the industry representative on

 

 21   this committee.

 

 22             DR. FUCHS:  Susan Fuchs, pediatric

 

                                                                 6

 

  1   emergency medicine physician from Children's

 

  2   Memorial Hospital in Chicago.

 

  3             DR. O'FALLON:  Judith O'Fallon,

 

  4   statistics, retired from the Mayo Clinic.

 

  5             DR. SANTANA:  Victor Santana, pediatric

 

  6   hematologist/oncologist from St. Jude's Children's

 

  7   Research Hospital in Memphis, Tennessee.

 

  8             DR. GORMAN:  Rich Gorman, pediatric

 

  9   private practice in Ellicott City, Maryland.

 

 10             DR. EBERT:  Steve Ebert, pharmacist,

 

 11   infectious diseases, Meriter Hospital and

 

 12   University of Wisconsin, Madison.

 

 13             DR. PEREZ:  Tom Perez, executive secretary

 

 14   to this committee meeting.

 

 15             DR. CHESNEY:  Joan Chesney, pediatric

 

 16   infectious disease at the University of Tennessee

 

 17   in Memphis, and also St. Jude's Children's Research

 

 18   Hospital.

 

 19             DR. HUDAK:  Mark Hudak, neonatologist,

 

 20   University of Florida, Jacksonville.

 

 21             DR. DANFORD:  Dave Danford, pediatric

 

 22   cardiology, University of Nebraska Medical Center,

 

                                                                 7

 

  1   Omaha.

 

  2             DR. NELSON:  Robert Nelson, pediatric

 

  3   critical care medicine, Children's Hospital,

 

  4   Philadelphia and University of Pennsylvania.

 

  5             DR. IYASU:  Solomon Iyasu, lead medical

 

  6   officer in pediatrics, FDA.

 

  7             DR. CUMMINS:  Susan Cummins, lead medical

 

  8   officer, pediatrics, FDA.

 

  9             DR. S. MURPHY:  Shirley Murphy, Division

 

 10   Director, Division of Pediatric Drug Development,

 

 11   FDA.

 

 12             DR. D. MURPHY:  Dianne Murphy, Office

 

 13   Director, Office of Counter-terrorism and Pediatric

 

 14   Drug Development, in the Office of Pediatric

 

 15   Therapeutics.

 

 16             DR. CHESNEY:  Thank you.  Now Tom Perez

 

 17   will read the meeting statement.

 

 18                        Meeting Statement

 

 19             DR. PEREZ:  Thank you and good morning.

 

 20   The following announcement addresses the issue of

 

 21   conflict of interest with regard to the adverse

 

 22   event reporting session and is made part of the

 

                                                                 8

 

  1   record to preclude even the appearance of such at

 

  2   this meeting.

 

  3             Based on the submitted agenda for the

 

  4   meeting and all financial interests reported by the

 

  5   committee participants, it has been determined that

 

  6   all interests in firms regulated by the Center for

 

  7   Drug Evaluation and Research present no potential

 

  8   for an appearance of a conflict of interest at this

 

  9   meeting, with the following exceptions:

 

 10             In accordance with 18 USC 208(b)(3), full

 

 11   waivers have been granted to the following

 

 12   participants, Dr. Richard Gorman for ownership of

 

 13   stock in a company with a product at issue, valued

 

 14   between $50,001 to $100,000; Dr. Judith O'Fallon

 

 15   for her and her sponsor's ownership of stock in a

 

 16   company with a product at issue, between $5,001 and

 

 17   $25,000; Dr. Katherine Wisner, for her speaker's

 

 18   bureau activities for a company with a product at

 

 19   issue for which she receives less than $10,001 per

 

 20   year; Dr. Patricia Chesney for her spouse's

 

 21   ownership of stock in a company with a product at

 

 22   issue, valued from $5,001 to $25,000 and unrelated

 

                                                                 9

 

  1   consultant earnings less than $10,001 per year.  In

 

  2   addition, Dr. Chesney's spouse owns stock in a

 

  3   company with a product at issue, worth less than

 

  4   $5,001.  Because this stock interest falls below

 

  5   the minimis exception allowed under 5 CFR

 

  6   2640.202(b)(2), a waiver under 18 USC 208 is not

 

  7   required.  Further, Dr. Chesney is recused from

 

  8   participating from the subcommittee's discussion

 

  9   regarding Duragesic due to a conflict of interest.

 

 10             A copy of the waiver statements may be

 

 11   obtained by submitting a written request to the

 

 12   agency's Freedom of Information Office, Room 12A-30

 

 13   of the Parklawn Building.  In the event that the

 

 14   discussions involve any other products or firms not

 

 15   already on the agenda for which an FDA participant

 

 16   has a financial interest, the participants are

 

 17   aware of the need to exclude themselves from such

 

 18   involvement and their exclusion will be noted for

 

 19   the record.

 

 20             We would also like to note that Dr. Samuel

 

 21   Maldonado has been invited to participate as an

 

 22   industry representative, acting on behalf of

 

                                                                10

 

  1   regulated industry.  Dr. Maldonado is employed by

 

  2   Johnson & Johnson.  With respect to all other

 

  3   participants, we ask in the interest of fairness

 

  4   that they address any current or previous financial

 

  5   involvement with any firm whose product they may

 

  6   wish to comment upon.  Thank you.

 

  7             DR. CHESNEY:  Thank you.  Our first

 

  8   speaker for the morning will be Dr. Dianne Murphy,

 

  9   Director of the Counter-terrorism and Pediatric

 

 10   Drug Development Office.

 

 11                             Welcome

 

 12             DR. D. MURPHY:  And just as you all

 

 13   understand how those two got to be combined, we

 

 14   have come to the end of an era.  That was really

 

 15   the substance of my opening comments this morning

 

 16   and I am going to talk more about this later in the

 

 17   day, that this is a milestone.

 

 18             But I wanted to take this morning to focus

 

 19   on the importance of the activity of this committee

 

 20   in the review of the safety or adverse events that

 

 21   occur after a product has been granted exclusivity.

 

 22   It has been clearly legislatively mandated that

 

                                                                11

 

  1   this is going to occur and that task has come to

 

  2   this committee.

 

  3             I wanted to make sure that you all

 

  4   realized how much you have contributed to this

 

  5   process.  We have received feedback from you during

 

  6   the time about what was useful and have tried to

 

  7   maintain a course, as we have to, that obeys the

 

  8   legislative intent and, yet, makes it more

 

  9   scientifically interesting within the constraints

 

 10   that we have.  I think probably years from now we

 

 11   could come and ask you all what are the problems

 

 12   with the AERS data reporting system.  So, you have

 

 13   been mandated to participate in a process in which

 

 14   you were told every meeting that you come here that

 

 15   the limitations are numerous with passive

 

 16   reporting; that when we do get reporting it is

 

 17   either poor or limited in nature; that there is

 

 18   little ability to go back and reconstruct in detail

 

 19   any of that information; and it basically doesn't

 

 20   have the same quality as a prospective surveillance

 

 21   or active process.  Yet, during this time I think

 

 22   we have evolved a process, again with your feedback

 

                                                                12

 

  1   and assistance, that has allowed us to make it more

 

  2   valuable.

 

  3             I would like to say that I think that what

 

  4   we have been able to identify over the past year or

 

  5   so has been the benefits of this system, and that

 

  6   is that it ensures that attention is focused on

 

  7   what is happening postmarketing to these products

 

  8   that the government initiates and rewards for

 

  9   studies being conducted.  As most of you are aware,

 

 10   one of the largest safety databases that occurs

 

 11   with any product is the postmarketing activities.

 

 12   That is where you find your rare serious events.

 

 13   And, this process has been critical for this

 

 14   committee and this has been a very important

 

 15   activity that I do think has focused and ensured

 

 16   that products that are marketed for children are

 

 17   looked at in a studied way, a reliable way, a

 

 18   predictable way, and I think that that is

 

 19   important.

 

 20             Now, why is it important?  Because I don't

 

 21   know how many times you have sat through these

 

 22   meetings where we said, "well, here are the

 

                                                                13

 

  1   problems and we didn't see anything.  Okay?"  But

 

  2   that is good news.  We would hope that the majority

 

  3   by far, if not 100 percent of these products that

 

  4   are studied and marketed don't have serious hidden

 

  5   adverse events.  So, in a say, it is like

 

  6   prophylaxis.  We hope we don't find major issues.

 

  7             But I think the other thing that this

 

  8   process has done that I wanted you all to know

 

  9   about that was important is that it has the effect

 

 10   on the agency of re-prioritizing pediatric safety

 

 11   assessments.  As everyone knows, there are many

 

 12   deadlines the agency has to meet and it is hard

 

 13   often to see the plate for all the things that are

 

 14   on it.  But clearly the legislation, your

 

 15   participation and our coming to you says we are

 

 16   having a public meeting and a discussion and it

 

 17   re-prioritizes this activity for the agency, as I

 

 18   said, and ensures that attention occurs.

 

 19             We are going to hear today about some

 

 20   activities that have evolved during this process,

 

 21   some questions that we want to bring to you because

 

 22   of information that, in essence, was moved forward

 

                                                                14

 

  1   a little faster because of this process, not that

 

  2   it was being neglected but because we basically

 

  3   made sure that we facilitated the assessments of

 

  4   some of these products and some of the issues.  In

 

  5   the past, as you know, we have had some reviews of

 

  6   the SSRIs and this whole process has been important

 

  7   in helping facilitate moving that activity forward

 

  8   also.

 

  9             I wanted to just thank you for your

 

 10   scientific input, your thoughtfulness and your

 

 11   feedback which we still would like to receive about

 

 12   the process on adverse event reporting, knowing

 

 13   that we have to work within the constraints of the

 

 14   systems that we presently have.  With that, I will

 

 15   speak a little more about the contributions of this

 

 16   committee and where we are going in the future

 

 17   later today.  Thank you very much.

 

 18             DR. CHESNEY:  Thank you, Dr. Murphy.  Our

 

 19   second speaker this morning, Dr. Solomon Iyasu, is

 

 20   going to talk to us about adverse event reports,

 

 21   per Section 17 of the Best Pharmaceuticals for

 

 22   Children Act.  Dr. Iyasu is a pediatrician, a

 

                                                                15

 

  1   medical epidemiologist who has fellowship training

 

  2   with the EIS of the CDC and residency training in

 

  3   preventive medicine at the CDC.  Prior to joining

 

  4   the FDA, just in 2002, he worked for 13 years as a

 

  5   medical epidemiologist at the CDC, in Atlanta,

 

  6   where he led research and programmatic programs in

 

  7   infant health.  He also served as the CDC liaison

 

  8   to the Committee on the Fetus and Newborn of the

 

  9   American Academy Pediatrics for many years, and has

 

 10   served on several HHS committees and inter-agency

 

 11   working groups, including the National Children's

 

 12   Study.  His research papers have involved maternal

 

 13   and child health issues.  In his current position

 

 14   at the FDA he serves as a medical team leader in

 

 15   the Division of Pediatric Drug Development and also

 

 16   serves as the lead medical officer for safety in

 

 17   the Office of Pediatric Therapeutics, which has

 

 18   become--always was but has become a particularly

 

 19   important office in function.  Dr. Iyasu?

 

 20           Adverse Event Reports per Section 17 of Best

 

 21                 Pharmaceuticals for Children Act

 

 22             DR. IYASU:  Thank you very much, Dr.

 

                                                                16

 

  1   Chesney, for that kind introduction.  Good morning.

 

  2             In the next few minutes I will provide you

 

  3   with an overview of today's agenda.  The theme for

 

  4   today is safety, safety of pediatric drugs.  A

 

  5   series of presentations will discuss postmarketing

 

  6   reviews of adverse events for drugs that have been

 

  7   granted exclusivity.

 

  8             The review of the post exclusivity adverse

 

  9   events is accomplished through the collaboration

 

 10   with the Office of Drug Safety, Office of Pediatric

 

 11   Therapeutics and Division of Pediatric Drug

 

 12   Development.  Therefore, at first I would like to

 

 13   acknowledge the contribution of the staff in the

 

 14   Office of Drug Safety for these reviews.

 

 15             In the morning you will hear adverse event

 

 16   reviews for eight drug products that were granted

 

 17   pediatric exclusivity.  These reviews will be

 

 18   presented by medical officers within the Division

 

 19   of Pediatric Drug Development.  Several of these

 

 20   presentations are informational while a few discuss

 

 21   important issues, ranging from a lack of

 

 22   age-appropriate pediatric formulations for

 

                                                                17

 

  1   fosinopril to a preventable safety signal

 

  2   associated with the use of fentanyl transdermal

 

  3   system or Duragesic.  You will be asked to discuss

 

  4   a question of risk management strategies in

 

  5   relation to fentanyl.  The morning will also

 

  6   include a time for open public hearing, followed by

 

  7   a short pediatric update by Dr. Dianne Murphy.

 

  8             We are doing the adverse event review a

 

  9   little differently than before.  In addition to the

 

 10   usual format which you are familiar with, we have

 

 11   incorporated some of the clinical trial data

 

 12   available in the public domain into these reviews.

 

 13   You are not going to see this component for all the

 

 14   drugs because the trial data are not yet in the

 

 15   public domain for some of the drug products that we

 

 16   will be discussing.

 

 17             This is a pediatric page on the external

 

 18   FDA website where you will find all the publicly

 

 19   available summaries of medical and clinical

 

 20   pharmacology of these pediatric studies for

 

 21   exclusivity.  The process of making these reviews

 

 22   available in the public domain is evolving,

 

                                                                18

 

  1   therefore, some of the reviews that I mentioned

 

  2   before may not be yet available on this website.

 

  3   Nevertheless, I invite you to use it as a resource

 

  4   and urge you to spread the word about this site.

 

  5             In the afternoon we will discuss two

 

  6   pediatric safety issues regarding the use of SSRIs

 

  7   and SNRIs during pregnancy.  As you recall, we

 

  8   discussed several case reports of neonatal

 

  9   withdrawal syndrome related to the use of Paxil and

 

 10   Celexa during the meeting of this committee last

 

 11   February.  At that time you requested more

 

 12   information on the syndrome and FDA's efforts to

 

 13   address it.

 

 14             To address this issue, we have lined up

 

 15   three presentations for you.  Kate Phelan, from the

 

 16   Office of Drug Safety, will present the

 

 17   postmarketing adverse event review for this class

 

 18   of drugs.  Dr. Bob Levin, from the Division of

 

 19   Neuropharmaceutical Drug Products, will speak on

 

 20   the new class labeling regarding neonatal

 

 21   withdrawal toxicity and its rationale.  Dr. Kathy

 

 22   Wisner will address the risk/benefit of treatment

 

                                                                19

 

  1   in child depression, a critical issue for both the

 

  2   practitioner and the patient.  At the end of this

 

  3   update you will be asked to discuss two questions.

 

  4             Next, I will present an update on

 

  5   congenital eye malformations, again, as a fallout

 

  6   to the February meeting when we reported a case

 

  7   report about possible congenital eye malformation

 

  8   related to the use of Celexa during pregnancy.

 

  9   This update will review all postmarketing reports

 

 10   of congenital eye malformations for Celexa and some

 

 11   newer anti-depressants.

 

 12             Before we present the specific adverse

 

 13   events, I will briefly review the data sources used

 

 14   in this review and their limitations.  The Adverse

 

 15   Event Reporting System is a spontaneous and

 

 16   voluntary system.  Because it is a passive system

 

 17   it suffers from a number of limitations, listed

 

 18   here on this slide, that you are already familiar

 

 19   with and we have discussed several times during

 

 20   previous presentations.

 

 21             Again the drug use data source and their

 

 22   limitations have also been presented before and are

 

                                                                20

 

  1   not new to you.  IMS National Prescription Audit

 

  2   Plus is used to estimate the number of outpatient

 

  3   prescriptions but lacks demographic information.

 

  4   The National Disease and Therapeutic Index can

 

  5   estimate drug mentions during office-based

 

  6   physician visits but pediatric use estimates can be

 

  7   unstable for less frequently used medications.

 

  8             Another outpatient data source is the IMS

 

  9   National Sales Perspectives which provides

 

 10   estimates of units sold from manufacturers to

 

 11   various channels of distribution and, therefore,

 

 12   may be a possible surrogate measure for drug use.

 

 13   An important limitation of this data source is

 

 14   absence of demographic information such as age and

 

 15   gender.

 

 16             Important drug use data sources and their

 

 17   limitations are well-known to you.  To refresh your

 

 18   memory, these are described in this slide and the

 

 19   next slide.  The main limitation with all the

 

 20   inpatient data sources, except for Premier, is the

 

 21   inability to make national projections of drug use.

 

 22   However, national estimates from Premier are

 

                                                                21

 

  1   available but are selective.  Furthermore, drug use

 

  2   cannot be linked to diagnosis or procedure and drug

 

  3   use in hospital or outpatient clinics is not

 

  4   captured in this data system.  Data from CHCA are

 

  5   limited to 29 children hospitals and cannot be

 

  6   projected nationally.

 

  7             This concludes my remarks and now let me

 

  8   turn to the presentations for this morning by

 

  9   introducing the first speaker.  But before I do

 

 10   that, I do want to recognize two individuals who

 

 11   have tirelessly worked behind the scenes to make

 

 12   this meeting possible.  Please stand up and be

 

 13   recognized, Miss Christine Phucas and Rosemary

 

 14   Addy.

 

 15             [Applause]

 

 16             Thank you.  Now the next speaker, Dr.

 

 17   Filie is a general pediatrician and pediatric

 

 18   rheumatologist.  She conducted research on

 

 19   molecular biology, connective tissue disorders and

 

 20   genetics at NIH for many years before going into

 

 21   private practice.  She joined the FDA from private

 

 22   practice about a year ago.  She will discuss

 

                                                                22

 

  1   adverse event reports for fexofenodine.  Dr. Filie?

 

  2                           Fexofenodine

 

  3             DR. FILIE:  Good morning, everyone.  I

 

  4   will proceed with the adverse event review for

 

  5   fexofenodine during the one-year post-exclusivity

 

  6   period.

 

  7             Fexofenodine, trade name Allegra, is an

 

  8   antihistamine by Aventis Pharmaceuticals.  The

 

  9   indications for adults and children are relief of

 

 10   symptoms associated with seasonal allergic rhinitis

 

 11   and non-complicated skin manifestations of chronic

 

 12   idiopathic urticaria.  It was originally approved

 

 13   in July, 1996 and pediatric exclusivity was granted

 

 14   in January, 2003.

 

 15             In order to fulfill the requirements for

 

 16   exclusivity, 3 pivotal studies were conducted and

 

 17   415 children, 6 months to 6 years of age, were

 

 18   treated for allergic rhinitis.  One study was a

 

 19   Phase 1 pharmacokinetic study characterizing the

 

 20   dose for children 6 months to 2 years of age.

 

 21   Another study was a Phase 3 study assessing safety

 

 22   and tolerability in 2 groups, 6 months to 2 years

 

                                                                23

 

  1   of age, weighing under 10.5 kg and weighing over

 

  2   10.5 kg.

 

  3             A previous safety and tolerability study

 

  4   on children 2-6 years of age was also submitted.

 

  5   The adverse events occurred at similar frequencies

 

  6   as for placebo, and no new safety signals were

 

  7   observed.

 

  8             Efficacy studies were not conducted due to

 

  9   the fact that the disease course and

 

 10   pathophysiology of allergic rhinitis and chronic

 

 11   idiopathic urticaria, as well as the drug's effect,

 

 12   are similar in children and adult patients.  The

 

 13   studies conducted on children 6 months to 6 years

 

 14   of age utilized fexofenodine powder mixed with

 

 15   apple sauce or rice cereal.  There is no marketable

 

 16   age-appropriate formulation for children 6 months

 

 17   to 6 years of age.

 

 18             Drug use trends for

 

 19   fexofenodine--currently, fexofenodine is the

 

 20   leading prescription for non-sedating antihistamine

 

 21   on the market since loratadine became

 

 22   over-the-counter in 2002.  The total number of

 

                                                                24

 

  1   fexofenodine product dispensed increased from

 

  2   approximately 20.9 million in 2000 to 29.6 million

 

  3   in 2003.  Pediatric patients accounted for

 

  4   approximately 2.5 million prescriptions of

 

  5   fexofenodine dispensed in 2003.  The most common

 

  6   diagnoses associated with the use in pediatric

 

  7   patients in 2003 were allergic rhinitis and

 

  8   allergic disorder.

 

  9             The adverse events from pediatric clinical

 

 10   trials that I just presented are as follows:

 

 11   Headache, accidental injury, cough, fever, pain,

 

 12   otitis media and upper respiratory infection, and

 

 13   least common, insomnia, nervousness, sleep

 

 14   disorders, rashes, urticaria, pruritus and

 

 15   hypersensitivity reactions.

 

 16             During the exclusivity period the total

 

 17   adverse event reports from the AERS database was

 

 18   158, 84 of them in the United States.  Among the

 

 19   158 reports there were 8 unduplicated pediatric

 

 20   reports which included 2 with serious outcomes, 1

 

 21   hospitalization and 1 life-threatening event.

 

 22   There were no pediatric deaths.

 

                                                                25

 

  1             In the 8 pediatric case reports the

 

  2   following unlabeled pediatric adverse events were

 

  3   reported, psychosis exacerbation with suicidal

 

  4   ideation and depression; seizure, visual

 

  5   disturbances; abnormal liver function; fungal

 

  6   urinary tract infection; non-accidental overdose of

 

  7   multiple drugs and prolonged QT, prematurity,

 

  8   maternal experience and medication error.

 

  9             I would like to present you with a

 

 10   synopsis of individual reports.  A 15 year-old with

 

 11   schizoaffective disorder and ADD, on multiple

 

 12   medications, experienced exacerbation of psychosis,

 

 13   suicidal ideation and depression which resolved

 

 14   after discontinuation of fexofenodine.

 

 15             A 13 year-old child presented with grand

 

 16   mal seizures.  The patient was also on multiple

 

 17   medications and one of them was bupropion which has

 

 18   a warning about the potential to cause seizures.

 

 19             A 7 year-old presented transient loss of

 

 20   color vision and visual disturbances such as black

 

 21   dots and bubbles.  It also resolved after

 

 22   discontinuation of the drug in a few days.

 

                                                                26

 

  1             A 10 year-old patient developed a

 

  2   bacterial UTI and abnormal liver function tests

 

  3   after receiving fexofenodine for one week.  The

 

  4   child was on concomitant medications and one of

 

  5   them was labeled for hepatic function impairment.

 

  6   We do not have the name of the drug on the report.

 

  7   The child recovered after discontinuation of

 

  8   fexofenodine.

 

  9             A 16 year-old who developed a fungal UTI

 

 10   and pyelonephritis was hospitalized.  This patient

 

 11   was also on multiple medications for depression and

 

 12   gastritis.

 

 13             A 13 year-old had an intentional overdose

 

 14   of fexofenodine, acetaminophen, metoclopramide and

 

 15   tramadol.  QT prolongation was observed in the

 

 16   emergency room which normalized the following day.

 

 17             The last two cases--a 27-week old

 

 18   premature baby, small for gestational age, was born

 

 19   by C-section due to pre-eclampsia.  There was a

 

 20   history of abnormal alpha-1 fetoprotein.  The

 

 21   mother was on concomitant medications.

 

 22             The last case--a prescription refill was

 

                                                                27

 

  1   mistakenly filled with Zyrtec-D instead of

 

  2   Allegra-D, but no adverse event was reported.

 

  3             Concluding the report, despite the large

 

  4   number of fexofenodine prescriptions, there were

 

  5   few pediatric adverse event reports during the

 

  6   one-year post-pediatric exclusivity period.  It is

 

  7   also very difficult to make any attributions of the

 

  8   adverse events of the drug when there are

 

  9   concomitant medications in the reports.  In this

 

 10   case, the FDA will continue to monitor the adverse

 

 11   event reports in all populations.  Any questions or

 

 12   comments?

 

 13             DR. CHESNEY:  Dr. Santana?

 

 14             DR. SANTANA:  Do you know if there are any

 

 15   similar adult reports with the use of this

 

 16   medication and concomitant anti-psychotic

 

 17   medications in adults?

 

 18             DR. FILIE:  I don't know that I can

 

 19   respond to that adequately.  From the information

 

 20   that we have on the label, the adverse events are

 

 21   very similar in both populations.  They resemble

 

 22   pretty much the two groups.

 

                                                                28

 

  1             DR. S. MURPHY:  Pete Stark I think is here

 

  2   from the Division.  Do you have any comments about

 

  3   adult report?

 

  4             DR. CHESNEY:  Dr. O'Fallon?

 

  5             DR. O'FALLON:  It seems to me that the way

 

  6   you keep your data may help you to find things.

 

  7   So, I am wondering when you have these reports, are

 

  8   you keeping track of the various concomitant

 

  9   medications so that you could be looking for trends

 

 10   developing that may be subtle, that there may be

 

 11   interactions, or something?

 

 12             DR. FILIE:  Yes.  The hope is to

 

 13   accumulate this data over a long time.

 

 14             DR. O'FALLON:  Yes, but I mean in a way so

 

 15   that you are able to go back, search and find those

 

 16   combos?  I am asking about how the data is being

 

 17   collected so that you are going to be able to

 

 18   search on it.

 

 19             DR. FILIE:  Yes, it is possible and we are

 

 20   doing that collecting and the Office of Drug Safety

 

 21   is also involved in this.  This is something that

 

 22   has accumulated and we can keep all this data

 

                                                                29

 

  1   without losing it.

 

  2             DR. O'FALLON:  But in a computer file that

 

  3   you can search?

 

  4             DR. FILIE:  I don't know.

 

  5             DR. IYASU:  Let me respond to this.  The

 

  6   AERS database has been in existence for a long time

 

  7   and the database is searchable both by high risk

 

  8   event terms as well as by the drug name or the

 

  9   trade name.  So, it is searchable by a number of

 

 10   parameters and there is an accumulated database

 

 11   which resides at FDA so you can look at one year or

 

 12   you can look at several years since the first time

 

 13   a report comes into existence for a particular

 

 14   product.  Once there is approval, there are going

 

 15   to be postmarketing reports that come in.  So,

 

 16   there is a way to look at that.  But there isn't a

 

 17   whole lot of information to try to look at multiple

 

 18   permutations of different confounders or looking up

 

 19   interactions.  It is a limited database in that

 

 20   way.

 

 21             DR. D. MURPHY:  I did want to respond that

 

 22   in your package it does tell you that fexofenodine

 

                                                                30

 

  1   has been looked at with the co-administration of

 

  2   acetyl console and erythromycin, the sip

 

  3   interactions.  So, what the agency does is where we

 

  4   know that a metabolism uses a certain sip enzyme

 

  5   that will cause increases or decreases, they will

 

  6   frequently look at that interaction but they can't

 

  7   look at all of them.  That often is actually a

 

  8   negotiated activity as to how many of them they do

 

  9   look at, and whether there are ones that are more

 

 10   likely to give serious adverse events by the normal

 

 11   drugs that might be used with this specific

 

 12   disease.  So, you could see that with an allergic

 

 13   indication you might think that antibiotics would

 

 14   be one of the set of drugs that they would look at.

 

 15             So, I just wanted to put on the table that

 

 16   prospectively the agency will sometimes ask,

 

 17   knowing what the metabolism is, for these

 

 18   interactions.  But, you can imagine that the list

 

 19   could get endless so the agency does not do all

 

 20   possible combinations.  Certainly, I think from

 

 21   allergic rhinitis to antidepressants--I mean,

 

 22   unless you had a mechanistic reason for doing that,

 

                                                                31

 

  1   you wouldn't up front do it.  Your question, I

 

  2   realize, was looking at statistical analysis post

 

  3   but up front there is a certain amount of activity

 

  4   in that area.

 

  5             DR. O'FALLON:  It seems to me that since

 

  6   you only have a handful of reports it might be

 

  7   worth it, that when you see something showing up

 

  8   you would say they took drug A, drug B, drug C,

 

  9   let's look and see if we have any reports in the

 

 10   database, especially in the adults or something, to

 

 11   see if you are seeing if that has been reported

 

 12   before.

 

 13             DR. D. MURPHY:  As noted, ODS has the

 

 14   database and it will have that information in it.

 

 15   So, you could go back and plug in certain drug

 

 16   names.  I think, as always, the caveat is that

 

 17   there are those who didn't enter that and were on

 

 18   it so there is always that question of what does it

 

 19   mean when you do it.  But, you are right, if you

 

 20   kept seeing that pattern, then it would be

 

 21   something you might wish to pursue further and ask

 

 22   for some additional studies.

 

                                                                32

 

  1             DR. CHESNEY:  Dr. Gorman?

 

  2             DR. GORMAN:  This is mainly for

 

  3   clarification from my reading of the labeling.  On

 

  4   page 7 of the label for this product there is a bar

 

  5   on the side and I wanted to know whether this was

 

  6   edited out of the label or is the present labeling

 

  7   wording which says that the safety and

 

  8   effectiveness of fexofenodine in pediatric patients

 

  9   under 6 years of age has not been established.  Is

 

 10   that in the label now or out of the label?

 

 11             DR. D. MURPHY:  It is not labeled under 6.

 

 12   Is that right?

 

 13             DR. GORMAN:  It is a question of the bar

 

 14   because it comes up several times later on in

 

 15   labeling.

 

 16             DR. D. MURPHY:  Right, right.  We will

 

 17   verify this but I think the point was that because

 

 18   there was no formulation that was available, it is

 

 19   not labeled under 6.

 

 20             DR. GORMAN:  I think one of the issues

 

 21   that was raised at the last meeting, and I would

 

 22   like to have it reemphasized again is that there is

 

                                                                33

 

  1   now data.  When we started this process two decades

 

  2   ago, that statement meant that there were no

 

  3   studies.  Now it means there may well be studies

 

  4   but it is not included in the label.  I noticed in

 

  5   the executive summary, which will be available on

 

  6   the web-based FDA data, that there is information

 

  7   about its use in children less than 6 months of

 

  8   age.

 

  9             DR. D. MURPHY:  I think you referred to

 

 10   the clinical pharmacology and biopharm study.

 

 11   Unfortunately, it doesn't have a page number but it

 

 12   is after the label.  It does say in there that no

 

 13   labeling changes for pediatric indication or dosing

 

 14   for children less than 6 years old will be made at

 

 15   this time because there are no age-appropriate

 

 16   formulations for fexofenodine for these children,

 

 17   and your point being that it was studied.  And,

 

 18   that is not going to be put in the label and I

 

 19   think that is an issue.

 

 20             DR. GORMAN:  That is the issue I wanted to

 

 21   raise and it will now be raised by others for the

 

 22   rest of the meeting.

 

                                                                34

 

  1             DR. CUMMINS:  Can I just provide one point

 

  2   of clarification?  The labels that we provide to

 

  3   you are ones that are publicly available and are

 

  4   the most recent labels.  Often the strikeouts are

 

  5   still present.  We download them from the labels

 

  6   that are posted on the web often--you know, that we

 

  7   post on the FDA website.  If you see a strikeout,

 

  8   as you see on page 7, then that strikeout will be

 

  9   removed in the published label by the company.

 

 10             DR. GORMAN:  Thank you.

 

 11             DR. CUMMINS:  You are welcome.

 

 12             DR. FILIE:  Given there are no further

 

 13   comments or questions, let me introduce the next

 

 14   speaker, Dr. Susan McCune.  Dr. McCune is a

 

 15   neonatologist whose previous experience includes

 

 16   academic neonatal practice at Johns Hopkins and

 

 17   Children's National Medical Center.  She recently

 

 18   received her masters degree in education and has

 

 19   worked on computer-based education models for

 

 20   pediatrics.  She will discuss two oncology

 

 21   products, topotecan and temozolomide.  Dr. McCune.

 

 22                    Topotecan and Temozolomide

 

                                                                35

 

  1             DR. MCCUNE:  Thank you very much, Dr.

 

  2   Filie.  Ladies and gentlemen of the committee and

 

  3   guests, Drs. Murphy told me to try to keep things a

 

  4   little bit light to keep you all awake and my Irish

 

  5   ancestry would allow me to tell shaggy dog stories

 

  6   but, unfortunately, I don't do very good jokes so I

 

  7   think we will just move along.

 

  8             As Dr. Filie mentioned, I will talk about

 

  9   two oncologic agents this morning.  The first is

 

 10   topotecan.  Topotecan, trade name Hycamtin, is an

 

 11   anti-tumor oncologic agent produced by

 

 12   GlaxoSmithKline.  The indication in adults is

 

 13   metastatic carcinoma of the ovary after failure of

 

 14   initial or subsequent chemotherapy and small cell

 

 15   cancer sensitive disease after failure of

 

 16   first-line chemotherapy.  There are no approved

 

 17   pediatric indications.  The original market

 

 18   approval was May 28, 1996 and the pediatric

 

 19   exclusivity was granted on November 20, 2002.

 

 20             I am going to tell you about the studies

 

 21   for exclusivity for this drug.  As you all

 

 22   mentioned, in terms of data that is available for

 

                                                                36

 

  1   the label, these studies were done based on what

 

  2   Dr. Iyasu told you already.  BPCA mandates that

 

  3   this information be available on the website and

 

  4   this information is available on the website,

 

  5   however, there were no changes to this label based

 

  6   on this information.

 

  7             The studies that were submitted for

 

  8   exclusivity were summaries of studies that were

 

  9   previously performed by the Pediatric Oncology

 

 10   Group.  They were initiated in 1992 and 1993.  This

 

 11   was a Phase 2 study in pediatric solid tumor that

 

 12   enrolled 108 patients that were less than 16 years

 

 13   of age.  The tumor types were Ewing's sarcoma,

 

 14   peripheral neuroectodermal tumor, neuroblastoma,

 

 15   osteoblastoma and rhabdomyosarcoma.  The study

 

 16   endpoint was tumor response rate.  Eighty-six

 

 17   percent of patients died, with 10 percent dying

 

 18   within 30 days of the last dose of topotecan.  The

 

 19   overall response rate was 8 percent but the

 

 20   response rate for patients with neuroblastoma was

 

 21   18 percent.  Of note, it is important to know that

 

 22   for alternative regimens using combinations of

 

                                                                37

 

  1   available drugs in pediatric patients with relapse

 

  2   neuroblastoma the response rates were 35-50

 

  3   percent.  In this case, no patients less than 2

 

  4   years of age showed any response.

 

  5             Eight of the 11 patients that died within

 

  6   30 days of the last dose of topotecan had

 

  7   progressive disease and 3 died with infection which

 

  8   is a known complication.  Forty-four percent of

 

  9   patients were hospitalized with adverse events,

 

 10   primarily febrile neutropenia, fever or sepsis.

 

 11             The Phase 2 study did determine a

 

 12   different dose from adults, a daily infusion for 5

 

 13   consecutive days every 21 days.  The adult dose is

 

 14   1.5 mg/m                                            2/day and the

pediatric dose that was given

 

 15   was either 1.4 mg/m                                                      

       2/day without granulocyte-colony

 

 16   stimulating factor or 2 mg/m                                             

                               2/day with

 

 17   granulocyte-colony stimulating factor.

 

 18             In terms of drug use trends in topotecan

 

 19   in the inpatient setting, between July, 2001 and

 

 20   June, 2003 there were 10.6 percent of discharges.

 

 21   Just to give you a rough idea, compared to the last

 

 22   drug which had a number of prescriptions, this was

 

                                                                38

 

  1   only 425 of 4,001.  Pediatric topotecan did

 

  2   increase annually in that time period, from 6.8 to

 

  3   18.6 percent.  It accounted for 407 discharges from

 

  4   29 CHCA free-standing pediatric hospitals, with the

 

  5   most frequent diagnosis being chemotherapy

 

  6   encounter followed by malignant neoplasm of the

 

  7   adrenal gland.  A significant limitation, as we

 

  8   have already discussed, of the analysis is that the

 

  9   FDA does not currently access data capture in the

 

 10   outpatient hospital clinic setting where most

 

 11   chemotherapy is administered.

 

 12             Now I am going to tell you about the

 

 13   adverse event reports for topotecan for the

 

 14   one-year post-exclusivity period.  There were 29

 

 15   total reports for all ages, 18 in the United

 

 16   States.  There were no pediatric reports that were

 

 17   submitted during this time.  Of note, in the 7-year

 

 18   period from 1996 there were some unlabeled

 

 19   pediatric reports, none of them during that 1-year

 

 20   post-exclusivity period.  There were 4 reports of

 

 21   convulsion, hypotension, edema  and speech

 

 22   disorder, and 3 reports each of arachnoiditis,

 

                                                                39

 

  1   ascites, Budd Chiari syndrome, caecitis and

 

  2   confusional state.

 

  3             In summary, the FDA will continue its

 

  4   routine monitoring of the adverse events in all

 

  5   populations.  I will stop here and take any

 

  6   questions on this particular drug.

 

  7             DR. CHESNEY:  Dr. Santana?

 

  8             DR. SANTANA:  I think I have made this

 

  9   point before and I will try to reinitiate it again.

 

 10   In contrast to some of the other drugs that we have

 

 11   in front of us, the oncology drugs are usually used

 

 12   in the setting of clinical research.  They are not

 

 13   used in the setting of common practice.  So, there

 

 14   is a wealth of data from protocols either initiated

 

 15   by the historically previous oncology groups or the

 

 16   current Children's Oncology Group and certainly by

 

 17   other large institutions like St. Jude's that do

 

 18   research in these drugs.  How is that data captured

 

 19   and reflected in these reports?  Because there is a

 

 20   wealth of adverse event data that is generated

 

 21   through that clinical research that will not show

 

 22   up through these voluntary reporting mechanisms but

 

                                                                40

 

  1   will show up in the databases of the clinical

 

  2   research infrastructure.

 

  3             DR. MCCUNE:  A lot of the reports that we

 

  4   get for these particular drugs are actually from

 

  5   study reports.  In terms of the studies that were

 

  6   done for exclusivity for this drug, they actually

 

  7   were, as you mentioned, part of the research

 

  8   protocols so they were independent studies

 

  9   conducted by the company.

 

 10             DR. SANTANA:  But I guess the point is

 

 11   that that is true but there is a lot more usage of

 

 12   this drug now, as you indicated in your brief

 

 13   summary of the trends of usage of this drug in

 

 14   pediatric oncology.  How is that data eventually

 

 15   going to make it into the adverse event reporting?

 

 16   Because it is not really part of the exclusivity

 

 17   because those studies have not been submitted for

 

 18   exclusivity.  Am I correct?

 

 19             DR. MCCUNE:  That is correct.

 

 20             DR. SANTANA:  These are studies that are

 

 21   ongoing.

 

 22             DR. MCCUNE:  That is correct.  This is the

 

                                                                41

 

  1   one-year post-exclusivity period.

 

  2             DR. SANTANA:  How will that data show up

 

  3   in the current study?

 

  4             DR. S. MURPHY:  It would have to come

 

  5   through the AERS.  It would have to be submitted to

 

  6   AERS for us to have that information.  Dr.

 

  7   Maldonado may want to comment, but the companies

 

  8   have to report any adverse events to the FDA.  So,

 

  9   the companies, you know, keep very close tabs on

 

 10   the medications, especially the medications that

 

 11   are in trials that are using their drugs.  So,

 

 12   there is a sort of cross-reference thing.  Then, it

 

 13   is even global with the pharmaceutical companies

 

 14   and with the international organizations with the

 

 15   FDA.  So, I think it is a very good question.  I

 

 16   think Don Mattison might want to make a comment,

 

 17   from NIH.

 

 18             DR. MATTISON:  Just a brief comment.  We

 

 19   are currently working with NCI and COG to develop

 

 20   full access to their databases and that information

 

 21   will be shared with FDA.

 

 22             DR. D. MURPHY:  Dr. Santana, I think if

 

                                                                42

 

  1   you look at what is in the label now, it just says

 

  2   that the effectiveness in children has not been

 

  3   demonstrated.  Then it goes ahead and it does

 

  4   describe the studies.  As you know, for cancer this

 

  5   has been a real issue because of the reasons you

 

  6   have stated.  The label is marketing approval and

 

  7   if it is not approved for that indication, you

 

  8   know, the agency is in this quandary of how do you

 

  9   make information available when you don't want to

 

 10   give a de facto indication that doesn't exist?  So,

 

 11   that is the tension here.  Depending on the

 

 12   product, depending on what comes out of the

 

 13   exclusivity studies if we don't have sufficient

 

 14   evidence to say it is efficacy and, as you know,

 

 15   and I don't want to say this over and over again,

 

 16   but these studies are not powered to do that.  So,

 

 17   how do we make that information available has been

 

 18   difficult.

 

 19             I think what they have done here is that

 

 20   they have been able to put into--by saying it has

 

 21   not been demonstrated, first, and saying yet we

 

 22   looked and here is what we found in a very limited

 

                                                                43

 

  1   way, and then having some adverse event reporting

 

  2   that came out.  Now, does it happen for every

 

  3   product, every time?  Not always because it may be

 

  4   that there were other issues with the studies and

 

  5   then what you may end up with in the label if there

 

  6   is a particular safety thing, they would say it was

 

  7   studied in so many kids; it wasn't effective or we

 

  8   couldn't determine effectiveness but we are going

 

  9   to tell you about these adverse events.  So, that

 

 10   can happen.  The adverse events in those studies

 

 11   could be put into the label if it is a safety

 

 12   issue.

 

 13             DR. SANTANA:  I guess what I am getting at

 

 14   is that the information that is derived from

 

 15   granting exclusivity is for the studies that the

 

 16   sponsor has put forth to reach that point.

 

 17             DR. D. MURPHY:  Right; that is correct.

 

 18             DR. SANTANA:  But there is another wealth

 

 19   of data that is being generated.  As I understand

 

 20   it, unless it is throught the sponsor or through

 

 21   some other mechanism that data becomes available to

 

 22   the FDA it is not part of the information that we

 

                                                                44

 

  1   have in front of us today or in the future.

 

  2             DR. D. MURPHY:  Well, it is required to be

 

  3   reported to the FDA.  It is required to be reported

 

  4   and if the agency sees a signal, then there is a

 

  5   re-review of the data and a determination if that

 

  6   additional information needs to be entered into the

 

  7   label.  I would say that if a researcher had access

 

  8   to data that they were concerned about and saw that

 

  9   it wasn't in the label, it is perfectly appropriate

 

 10   to ask--you know, again, it is a requirement.

 

 11   Companies get into big trouble if they have adverse

 

 12   events that they don't report to us.

 

 13             The other issue--I am not saying it

 

 14   happens, but if somehow you thought something

 

 15   wasn't getting reported, it is perfectly

 

 16   appropriate to call the agency and say I am aware

 

 17   of this; make sure you got those reports.

 

 18             DR. SANTANA:  I want to make it clear for

 

 19   the public record that I am not raising issues with

 

 20   this drug or the next oncology drug.  I am trying

 

 21   to understand the process.  I just want to make

 

 22   that clear.

 

                                                                45

 

  1             DR. D. MURPHY:  Yes, and we want to make

 

  2   it clear that it is part of companies' standard

 

  3   reporting activity.  Sam, maybe you could say

 

  4   something about the routine things that go on in

 

  5   reporting both during a trial and after a product

 

  6   is marketed.

 

  7             DR. MALDONADO:  Both of you are completely

 

  8   right.  Companies are not going to get in trouble

 

  9   by not reporting.  That is very enforceable.  A lot

 

 10   of not reported events happen when physicians don't

 

 11   report to companies.  So, that is where the problem

 

 12   is; it is the education.  We are not only talking

 

 13   about sending in the reports, but sending them

 

 14   within 15 days of occurrence.  Most of the

 

 15   non-reporting happens because of lack of education

 

 16   from clinicians.  In clinical trials it happens

 

 17   much less, or probably very, very close to zero

 

 18   because there is monitoring by the company.  Actual

 

 19   people go there and make sure they are doing it.

 

 20   Outside clinical trials it is more difficult

 

 21   because you cannot police physicians so it is up to

 

 22   them to report. But once it is reported to the

 

                                                                46

 

  1   companies, it is reported to the FDA and the FDA,

 

  2   of course, can always come to a company and check

 

  3   if we are doing it and actually FDA does that.

 

  4             DR. D. MURPHY:  I think what Sam has said

 

  5   is really important.  If a physician sees an

 

  6   adverse event on a product, particularly if you put

 

  7   them on a product, take them off and put them back

 

  8   on--you know, if you have evidence, but even if you

 

  9   don't, if you put a child on a product and you have

 

 10   some serious event and you are not sure whether it

 

 11   is related or not, you don't have to make

 

 12   attribution.  This is one of the problems I think

 

 13   physicians don't understand.  You don't have to

 

 14   determine individually that this product caused

 

 15   this adverse event.  If physicians would, please,

 

 16   make it part of their public health rule to report

 

 17   adverse events that they think are serious to the

 

 18   agency and to the company, I mean, that is a double

 

 19   way--or either way, you know, whichever way you

 

 20   know how to get that information in.  It will get

 

 21   to us if it gets to the company or it can come to

 

 22   us directly.  So, I would like to keep adding that

 

                                                                47

 

  1   commercial.  It is a very important part of

 

  2   activity.  I have been out there; I have practiced

 

  3   medicine and I know I haven't done it when I should

 

  4   have.  So, it is just a plea that we keep putting

 

  5   that out there because you can see how important it

 

  6   can become.

 

  7             DR. CHESNEY:  Dr. O'Fallon?

 

  8             DR. O'FALLON:  There is one other issue

 

  9   that is a possible problem.  I don't know these

 

 10   particular studies that COG is doing but if they,

 

 11   indeed, have closed patient accrual before the

 

 12   exclusivity period it is entirely possible that the

 

 13   acute toxicities wouldn't be available at this

 

 14   time.  You know, not all the data in these clinical

 

 15   trials gets reported out until the final study is

 

 16   done.  I mean, the company had to know about it

 

 17   ahead of time, but during this exclusivity period

 

 18   there maybe weren't any from those trials.

 

 19             DR. D. MURPHY:  I think that brings up the

 

 20   other issue just of any follow-up post-trial.  As

 

 21   you know, there was a legislative mandate also to

 

 22   put the 1-800 MedWatch number on labels and that

 

                                                                48

 

  1   process is proceeding.  I don't have any idea when

 

  2   actually you will see it but it is continuing to

 

  3   move forward.

 

  4             DR. CHESNEY:  Dr. Ebert?

 

  5             DR. EBERT:  Just a follow-up to that, is

 

  6   it feasible or even reasonable with these drugs

 

  7   that are specifically under exclusivity for the FDA

 

  8   to make pediatricians more aware of the fact that

 

  9   they are under this particular scrutiny?  And,

 

 10   would it heighten their level of interest with

 

 11   regards to reporting adverse events?

 

 12             DR. D. MURPHY:  Joan has a suggestion for

 

 13   you later today I think about maybe one way of

 

 14   doing it.  We have been trying to do that in a

 

 15   number of ways by working with the American Academy

 

 16   of Pediatrics newsletter that goes out and doing

 

 17   annual updates of changes in the label, talking

 

 18   about exclusivity, but I think you bring up a good

 

 19   point--have we really made an issue in that

 

 20   reporting about changes in label about reporting

 

 21   adverse events?  No.  And, that is a good point and

 

 22   we will take that back and pursue that as an

 

                                                                49

 

  1   additional piece of information we should try to

 

  2   get out to pediatricians, family practice, people

 

  3   who are taking care of children.  We are working

 

  4   with the Academy on the CME activity so that we can

 

  5   put in some case studies that might bring that up.

 

  6             DR. S. MURPHY:  Joan, just one more point,

 

  7   there are really two ways of reporting adverse

 

  8   events.  One is to the FDA and the other is to the

 

  9   companies.  The larger pharmaceutical companies

 

 10   have these 1-800 numbers and if you call and you

 

 11   say you have an adverse event, you are immediately

 

 12   put in touch with the Pharm.D. who has a whole

 

 13   scheme of questions to ask you right away.  All

 

 14   those reports, like Sam said, do go back to the FDA

 

 15   and the seriousness of the report triggers certain

 

 16   times to report it.  Having been on the other side

 

 17   in a pharmaceutical company, I was in charge of a

 

 18   drug that had a lot of adverse reactions and we

 

 19   were constantly reviewing all the cases that came

 

 20   in.  The company will often send somebody out to

 

 21   the hospital to look at the records and make sure

 

 22   of the accuracy of the reporting.  So, it is taken

 

                                                                50

 

  1   incredibly seriously on both sides.

 

  2             DR. CHESNEY:  Thank you.  We can move on

 

  3   to the next speaker.

 

  4             DR. MCCUNE:  Actually, I am doing the next

 

  5   drug.  You get to listen to me again.  The next

 

  6   drug I am going to talk about is temozolomide.  The

 

  7   trade name for this is Temodar.  Once again, this

 

  8   is an oncologic agent produced by Schering Plough

 

  9   Research Institute.  The indication in adults is

 

 10   that the capsules are indicated for the treatment

 

 11   of adult patients with refractory anaplastic

 

 12   astrocytoma, in other words, patients at first

 

 13   relapse who have experienced disease progression on

 

 14   a drug regimen containing a nitrosourea and

 

 15   procarbazine.  In pediatrics there are no approved

 

 16   pediatric indications.  The original market

 

 17   approval was August 11, 1999; the pediatric

 

 18   exclusivity was granted November 20, 2002.

 

 19             Once again, I am going to tell you about

 

 20   the studies for exclusivity.  These are available

 

 21   on the website.  In addition, for this particular

 

 22   label safety information is included in the

 

                                                                51

 

  1   pediatric section of the precautions part of the

 

  2   label and it does include a description of the

 

  3   clinical studies that were completed.

 

  4             The studies that were submitted for

 

  5   exclusivity were one Phase 1 and two Phase 2

 

  6   open-label, multicenter studies.  The Phase 1 study

 

  7   was dose escalation in 27 patients with advanced

 

  8   non-CNS and CNS cancers.  The first Phase 2 study

 

  9   was in 63 patients with recurrent brain stem glioma

 

 10   and high grade astrocytoma.  The second Phase 2

 

 11   study, a cooperative group-sponsored study, was in

 

 12   122 patients with various recurrent CNS tumors.

 

 13   The patients ranged in age from 1 to 23 years of

 

 14   age, with the majority of patients between 3 and 17

 

 15   years of age.

 

 16             The primary endpoint for these studies was

 

 17   tumor response rate.  In the first Phase 2 study

 

 18   there was 1 complete response and 3 partial

 

 19   responses among 27 patients.  In the second study

 

 20   there were no complete responses or partial

 

 21   responses in the brain stem glioma patients and no

 

 22   complete response and 12 percent partial responses

 

                                                                52

 

  1   in the high grade astrocytoma patients.  In the

 

  2   third study the overall response rate, combined

 

  3   complete response and partial response rate, was 5

 

  4   percent.  Only 1 patient achieved complete response

 

  5   and 5 patients had partial responses.

 

  6             Safety was assessed in 204 patients at

 

  7   doses of 100-200 mg/m                                                     

            2/day daily for 5 days every

 

  8   28 days.  The toxicity profile that was seen was

 

  9   similar to adults.  The most common adverse events

 

 10   that were reported were dizziness, neuropathy,

 

 11   paresthesia, nausea/vomiting, constipation and

 

 12   myelosuppression.

 

 13             Just to give you an idea of the drug use

 

 14   trends in the outpatient setting for temozolomide,

 

 15   the number of prescriptions dispensed has nearly

 

 16   doubled over the past 3 years from 50,000 in 2001

 

 17   to 93,000 in 2003, with the top prescribers, as you

 

 18   can imagine, being oncology/neoplastic, neurology

 

 19   and hematology.  Of note, only 1 percent of

 

 20   temozolomide prescriptions were written by

 

 21   pediatricians.

 

 22             The pediatric population of 1-16 years of

 

                                                                53

 

  1   age accounted for a small number of temozolomide

 

  2   prescriptions, 3.1 percent in 2002 and 3.9 percent

 

  3   in 2003, with the most frequent diagnosis being

 

  4   malignant neoplasm of the brain both in adults and

 

  5   pediatric patients.

 

  6             In terms of outpatient sales, they have

 

  7   been on the rise, from 1.8 million capsules to 2.2

 

  8   million capsules in the last 2 years, with the

 

  9   majority of sales through retail channels, 80

 

 10   percent of them going to chain and independent

 

 11   pharmacies and other retail channels.

 

 12             CHCA data demonstrated from 2002 to June,

 

 13   2003 that there were only 17 pediatric discharges

 

 14   associated with this drug.

 

 15             The limitations to drug use data in the

 

 16   outpatient setting for these drugs are important to

 

 17   note because we don't have sources that

 

 18   specifically examine outpatient hospital clinics

 

 19   where chemotherapy treatments are provided.  What

 

 20   is important to note though is that the retail

 

 21   sales do capture a number of those sources and it

 

 22   is felt that most of the use of this drug is

 

                                                                54

 

  1   captured through assessment of outpatient use.

 

  2             In terms of adverse event reporting for

 

  3   the post-exclusivity period from November, 2002 to

 

  4   December, 2003 there were 250 reports in all ages,

 

  5   160 of them in the United States.  There were 5

 

  6   unduplicated pediatric reports, 2 of them in the

 

  7   United States, all with serious outcomes and 1

 

  8   death.  There were 4 females and 1 male.  Three of

 

  9   the patients were aged 2-5 years; 2 of the patients

 

 10   6-11 years.  There was one patient each for the

 

 11   diagnoses of blastoma, adrenal metastatic

 

 12   neuroblastoma, anaplastic astrocytoma,

 

 13   medulloblastoma and brain stem tumor.

 

 14             The clinically significant unlabeled

 

 15   adverse events could be divided into 5 groups.  One

 

 16   was brain edema; 1 was death.  Another, hemangioma

 

 17   acquired; another ITP and another myelodysplastic

 

 18   syndrome.  All of these, although not specifically

 

 19   delineated in the label, are potentially related to

 

 20   either a labeled process or the underlying disease

 

 21   state.

 

 22             Just to take each one of these

 

                                                                55

 

  1   individually, brain edema in the patient was

 

  2   associated with concomitant radiation therapy.  The

 

  3   death was potentially due to the underlying

 

  4   condition.  The acquired hemangioma was potentially

 

  5   related to either the underlying condition, the

 

  6   concomitant medication or the radiation therapy.

 

  7   The ITP was a potentially labeled event or

 

  8   secondary to the underlying condition.  The

 

  9   myelodysplastic syndrome was also a potentially

 

 10   labeled event or secondary to the underlying

 

 11   condition.

 

 12             Just to give you a brief synopsis of these

 

 13   5 cases, the first was a 3 year-old that was

 

 14   treated for pineal blastoma who died of an

 

 15   unspecified cause.

 

 16             The second was a 6 year-old who was

 

 17   treated for recurrent anaplastic astrocytoma, was

 

 18   on concomitant medications including radiation

 

 19   therapy, and following temozolomide use, a

 

 20   cavernous hemangioma was noted on MRI.  Of note, it

 

 21   was not previously seen on prior MRIs.  Following

 

 22   temozolomide treatment, this patient also had

 

                                                                56

 

  1   thrombocytopenia requiring transfusions and was

 

  2   diagnosed with ITP and myelodysplastic syndrome.

 

  3   This patient was discharged with an improved

 

  4   clinical status 18 days after admission.

 

  5             The third case is a 4 year-old treated for

 

  6   medulloblastoma who suffered an infection and there

 

  7   was no outcome of the event that was documented.

 

  8             The fourth case is a 4 year-old treated

 

  9   for metastatic neuroblastoma who developed

 

 10   thrombocytopenia, anemia and fever which were

 

 11   managed with transfusions and antibiotics.  She

 

 12   recovered without sequelae and was given a second

 

 13   cycle of temozolomide without recurrence.

 

 14             The final case is an 8 year-old who was

 

 15   treated for brain stem tumor.  Routine MRI revealed

 

 16   radiation-induced cerebellum edema requiring

 

 17   hospitalization for intracranial drainage.  This

 

 18   patient was subsequently discharged in stable

 

 19   condition.

 

 20             In summary, for temozolomide there have

 

 21   been described both labeled and unlabeled adverse

 

 22   events.  The unlabeled events have also been

 

                                                                57

 

  1   reported in adults and are not unique to

 

  2   pediatrics, and the FDA will continue to do routine

 

  3   monitoring of adverse events in all of the

 

  4   populations.

 

  5             DR. CHESNEY:  Thank you very much.  I just

 

  6   wanted to bring to the committee's attention the

 

  7   fact that at 9:30, although we are getting

 

  8   significantly behind with the very full agenda, the

 

  9   FDA has asked us to address question one, which is

 

 10   at the back of the packet that we were given today

 

 11   with the agenda on it, which involves process

 

 12   issues.  So, I think unless you have specific

 

 13   questions related to this drug, if they are process

 

 14   issues, we will have an hour to discuss that later

 

 15   on.  So, does anybody have specific comments

 

 16   regarding this drug?  Shirley?

 

 17             DR. S. MURPHY:  Dr. Chesney, Dr. Starke

 

 18   from the Pulmonary Division has some late-breaking

 

 19   information on the first drug that we discussed.

 

 20   He was just going to tell us a follow-up on a

 

 21   question that the committee had, what the bar was

 

 22   beside the label.

 

                                                                58

 

  1             DR. STARKE:  I am Dr. Starke, from

 

  2   Pulmonary and Allergy Division.  I am a medical

 

  3   team leader.  I went upstairs and double-checked

 

  4   the label for you since there was a cross-out

 

  5   there.  That was simply something that was caught

 

  6   as the final label was approved.  The current

 

  7   labeling does say for 6 months and older.

 

  8             I just want to make the comment that even

 

  9   though the studies were done down to 6 months of

 

 10   age and, as you know, certain other antihistamines

 

 11   may be approved down to 2 for SAR and 6 months for

 

 12   PAR, this drug was not approved below age 6 because

 

 13   there was no marketed formulation.  A

 

 14   non-marketable formulation was used which, of

 

 15   course, is an issue which you may want to address.

 

 16   Thank you.

 

 17             DR. CHESNEY:  Thank you.  If there are no

 

 18   additional questions on your presentation, which I

 

 19   thank you for, I think we can move on to the next

 

 20   speaker.

 

 21             DR. MCCUNE:  It is my privilege to

 

 22   introduce Dr. Harry Gunkel to you.  He is the only

 

                                                                59

 

  1   person standing between me and the privilege of

 

  2   saying that I am the most junior member of the

 

  3   Pediatric Drug Development Office.  Like me, he is

 

  4   a neonatologist who has extensive experience in

 

  5   private practice, the pharmaceutical industry and

 

  6   academic medicine.  Many of you may know him for

 

  7   his significant work on surfactant.  He is going to

 

  8   talk to you today about two ophthalmologic

 

  9   anti-infective agents.

 

 10                  Moxifloxacin and Ciprofloxacin

 

 11             DR. GUNKEL:  Thank you, Susie.  Hello.  As

 

 12   Susie said, the next two products on the list are

 

 13   both ophthalmic antibacterials, both

 

 14   fluoroquinolones.  The first is ciprofloxacin,

 

 15   known under the trade name Ciloxan and sponsored by

 

 16   Alcon Laboratories.  It is indicated in adults and

 

 17   children greater than 1 year of age in a solution

 

 18   dosage form, and adults and children greater than 2

 

 19   years of age in the ointment dosage form for the

 

 20   treatment of bacterial conjunctivitis caused by the

 

 21   organisms shown on the slide.  The solution form is

 

 22   also indicated for corneal ulcer.  The original

 

                                                                60

 

  1   market approval was in 1990 and pediatric

 

  2   exclusivity was granted in January, 03.

 

  3             Drug use data shows that dispensed

 

  4   prescriptions for Ciloxan decreased slightly over

 

  5   the period of exclusivity.  Almost half of the

 

  6   prescriptions for this drug were for children

 

  7   between 1 and 16 years of age, and pediatricians

 

  8   wrote about a third of the prescriptions during the

 

  9   exclusivity period.

 

 10             The most common indication for the

 

 11   prescription was conjunctivitis, other or

 

 12   unspecified, and Ciloxan was the most mentioned

 

 13   product for this indication in pediatric patients.

 

 14             During the exclusivity period there were 9

 

 15   total reports for all ages; 3 were from the U.S.

 

 16   The age was not specified for 2 of the 9 reports.

 

 17   There were no pediatric reports.  We will continue

 

 18   to monitor the adverse event reports, of course.

 

 19             The next drug is moxifloxacin, also

 

 20   sponsored by Alcon Laboratories, also an ophthalmic

 

 21   antibacterial drug.  It is indicated for adults and

 

 22   children 1 year of age or greater for the treatment

 

                                                                61

 

  1   of bacterial conjunctivitis caused by a number of

 

  2   susceptible organisms, aerobic gram negative and

 

  3   gram positive organisms.  The market approval for

 

  4   this product was April of '03, less than a year

 

  5   ago.  So, that will become pertinent when we look

 

  6   at the data in just a moment.  Exclusivity was

 

  7   granted before market approval, in January of '03.

 

  8             Since approval didn't occur until April of

 

  9   last year, the drug use and adverse event data

 

 10   cover less than a 1-year period, unlike the other

 

 11   products you are reviewing today.  About 800,000

 

 12   prescriptions were dispensed since approval in

 

 13   April, '03.  About a quarter of the prescriptions

 

 14   were for pediatric patients.  Ophthalmologists

 

 15   wrote most of the prescriptions for this agent,

 

 16   just over half of the prescriptions, followed by

 

 17   pediatricians who wrote about a quarter of them.

 

 18   The most common indication, as for ciprofloxacin,

 

 19   was for conjunctivitis, other or unspecified and

 

 20   Vigamox, the trade name of the product, accounted

 

 21   for 4.6 percent of the mentions for children.

 

 22             There was 1 report in the exclusivity

 

                                                                62

 

  1   period and it was a pediatric report.  It was an

 

  2   incidence of subconjunctival hemorrhage in a 6.5

 

  3   year-old female that occurred 24 hours after the

 

  4   use of Vigamox.  The child was also using

 

  5   Augmentin.  The child recovered after

 

  6   discontinuation of the drug and this event,

 

  7   subconjunctival hemorrhage, is a labeled adverse

 

  8   event occurring in 1-6 percent of patients.  We

 

  9   will continue to monitor this product as well, of

 

 10   course.

 

 11             One study was done for the exclusivity and

 

 12   it actually involved both products.  It was a

 

 13   multicenter, randomized, double-blind, parallel

 

 14   group comparison of moxifloxacin and ciprofloxacin

 

 15   in neonates, with the endpoints of clinical cure at

 

 16   day 5 and the microbial eradication rate.

 

 17             From the data that is available in the

 

 18   public domain, these are the results.  The rates of

 

 19   clinical cure are shown for both the agents.  These

 

 20   rates are less than the generally expected vehicle

 

 21   rate, and the difference between the two was not

 

 22   significant.  Thank you.

 

                                                                63

 

  1             DR. CHESNEY:  I have two questions.  What

 

  2   do you mean by expected vehicle rate?

 

  3             DR. GUNKEL:  If you apply a vehicle to a

 

  4   case of bacterial conjunctivitis the expected cure

 

  5   rate is 70 percent.

 

  6             DR. CHESNEY:  That is what I thought you

 

  7   meant; I just wanted to be sure.  And, what were

 

  8   the side effects of Ciloxan?  There were 9 reports.

 

  9             DR. GUNKEL:  They weren't pediatric so I

 

 10   didn't see them.  I don't know.

 

 11             DR. CHESNEY:  Other questions?  Dr.

 

 12   Murphy?

 

 13             DR. D. MURPHY:  Go ahead and finish up

 

 14   with this topic because I was asked to make a

 

 15   clarification on the last one.

 

 16             DR. CHESNEY:  Dr. O'Fallon?

 

 17             DR. O'FALLON:  If I were the statistician

 

 18   on this study I would be very concerned.  I would

 

 19   be talking to the docs and saying, "wait a minute

 

 20   guys, this looks like it's doing harm."  Both of

 

 21   these agents look like they are not helping.  If

 

 22   they have a lower response rate or success rate,

 

                                                                64

 

  1   whatever you want to call it, than the placebo

 

  2   which is the vehicle without anything in it I would

 

  3   be worried that it is contra-effective.

 

  4             DR. GUNKEL:  I don't know whether that is

 

  5   the case.  The information that is in the public

 

  6   domain doesn't allow us to deduce that the rates

 

  7   that were shown in the study that I showed were

 

  8   significantly less than the expected vehicle cure

 

  9   rate.  But your point is well taken I would think.

 

 10             DR. CHESNEY:  Dr. Murphy?

 

 11             DR. D. MURPHY:  Dr. McCune has said that I

 

 12   may have confused things in efforts to answer Dr.

 

 13   Santana's question about how we get information in

 

 14   the label because you were talking about the

 

 15   topotecan when I read to you the information that

 

 16   was in the Temodar label.  I was trying to point

 

 17   out that there are various approaches depending on

 

 18   the quality of the data.  So, for the topotecan the

 

 19   actual information that is in the label now in

 

 20   pediatrics is that there is no safety or

 

 21   effectiveness that has been established versus the

 

 22   Temodar, which is the one that I read you.  I

 

                                                                65

 

  1   thought I read the product but they both start with

 

  2   T.  So, I want to make it clear that it is the

 

  3   Temodar that has all that information in it.

 

  4             DR. SANTANA:  My question was a process

 

  5   issue; it didn't relate to any specific--

 

  6             DR. D. MURPHY:  Yes, and I was trying to

 

  7   give a process where there can be different types

 

  8   of information put in.  Anyhow, I just wanted to

 

  9   make sure that I didn't confuse the committee with

 

 10   the Ts when I started talking about the second

 

 11   label before it was actually presented.  Thank you.

 

 12             DR. CHESNEY:  I think we are all looking

 

 13   at your last two slides and puzzling over the last

 

 14   one, but I think that wasn't really the issue of

 

 15   this morning's discussion so we will leave that for

 

 16   the moment and move on to the next speaker.

 

 17             DR. GUNKEL:  The next speaker is Dr. Larry

 

 18   Grylack.  Dr. Grylack began a career in the

 

 19   Commission for U.S. Public Health Service from

 

 20   1971-73.  His training is in pediatrics in

 

 21   neonatal/perinatal medicine.  He was in the

 

 22   practice of neonatal medicine at Columbia Hospital

 

                                                                66

 

  1   for Women, in Washington, for 26 years with a

 

  2   particular interest in neurodevelopmental follow-up

 

  3   of high risk newborn and apnea during infancy.  Dr.

 

  4   Grylack?

 

  5                            Fosinopril

 

  6             DR. GRYLACK:  Thank you, Dr. Gunkel, for

 

  7   the introduction.  It is a privilege to speak to

 

  8   the committee this morning.  In case there has been

 

  9   anything said so far this morning that has caused

 

 10   your blood pressure to rise, I will be discussing

 

 11   an antihypertensive drug at this time.

 

 12             The name of the drug is fosinopril, with

 

 13   the trade name of Monopril.  Its sponsor is

 

 14   Bristol-Myers Squibb.  Fosinopril is in the renin

 

 15   angiotensin antagonist subclass of

 

 16   antihypertensives.  Its mechanism of action is

 

 17   inhibition of angiotensin converting enzyme.

 

 18   Although fosinopril is approved for use in adults,

 

 19   there are no approved pediatric indications.

 

 20   Pediatric exclusivity was granted early last year.

 

 21             Despite a 20 percent increase in the

 

 22   prescribed use of renin angiotensin antagonist

 

                                                                67

 

  1   drugs in the outpatient setting, there was a 25

 

  2   percent decrease in the use of fosinopril during a

 

  3   recent 3-year period.  Conversely, there was a 33

 

  4   percent increase in the use of the combination drug

 

  5   fosinopril/hydrochlorothiazide during that same

 

  6   time period.  The ratio of the number of pediatric

 

  7   prescriptions for fosinopril alone to prescriptions

 

  8   for the combination drug was approximately 10:1.

 

  9             Let's focus on the inpatient usage data

 

 10   for fosinopril.  Two databases from recent 3-year

 

 11   periods report a very low percentage of pediatric

 

 12   inpatients using fosinopril during their hospital

 

 13   stays.  There were no pediatric adverse event

 

 14   reports submitted during the post-exclusivity

 

 15   period.

 

 16             Two studies were done for the purpose of

 

 17   achieving exclusivity.  A single-dose

 

 18   pharmacokinetic study showed an age-dependent

 

 19   increase in bioavailability in a population of 43

 

 20   patients between the ages of 1 month and 16 years.

 

 21   An oral solution containing a dose of 0.3 mg/kg of

 

 22   body weight was used.

 

                                                                68

 

  1             Secondly, an efficacy and safety dose did

 

  2   not demonstrate a dose-response relationship in a

 

  3   population of 253 patients between 6 and 16 years

 

  4   of age.  A tablet form of medication was used in

 

  5   this study.  No deaths or cases of angioedema were

 

  6   reported, the latter being an adverse event

 

  7   reported in adults.

 

  8             Pharmacokinetic parameters in the children

 

  9   studied are similar to those found in adults.

 

 10   Dosing information is available for children

 

 11   weighing more than 50 kg.  However, the

 

 12   formulations used in children in the exclusivity

 

 13   studies are not currently commercially available.

 

 14             This leads me to the broader issue of the

 

 15   need for age-appropriate formulations.  As

 

 16   physicians and parents know, non-liquid forms of

 

 17   medications are not appropriate for infants and

 

 18   preschool children, as for some school age children

 

 19   as well.  Therefore, sponsors are being encouraged

 

 20   to develop age-appropriate commercially available,

 

 21   marketable pediatric formulations during their

 

 22   exclusivity studies.

 

                                                                69

 

  1             The goal of the FDA, and especially of our

 

  2   Pediatric Drug Development Division, is to have

 

  3   commercially available formulations for the

 

  4   pediatric patient population.  If this cannot be

 

  5   done for certain drugs in a pharmacy--and I

 

  6   underscore pharmacy--compounded recipes should

 

  7   appear in the drug label.

 

  8             This concludes my remarks for today.

 

  9   Thank you for your attention.

 

 10             DR. CHESNEY:  Thank you very much.  Any

 

 11   non-process questions for the speaker?  Dr. Hudak?

 

 12             DR. HUDAK:  The slide that showed that

 

 13   there was no dose-response relationship in

 

 14   children, is that sort of a euphemism for no

 

 15   efficacy?

 

 16             DR. D. MURPHY:  Yes.  It is in our written

 

 17   request as one way for the cardiorenal drugs,

 

 18   hypertensive drugs, to demonstrate efficacy and it

 

 19   is a long description about what you have to do if

 

 20   you don't choose a placebo-controlled trial and you

 

 21   choose a dose effect trial and what sort of effect

 

 22   you have to demonstrate and, if you don't, then you

 

                                                                70

 

  1   failed.

 

  2             DR. CHESNEY:  Dr. Nelson?

 

  3             DR. NELSON:  With your indulgence, it is a

 

  4   process comment but it is not about risk process.

 

  5   We have heard two presentations where there has

 

  6   been a lack of an adequate formulation.  I guess my

 

  7   question, which may not be answerable today or we

 

  8   may not want to answer it today is that my

 

  9   understanding is a company doesn't get exclusivity

 

 10   unless the FDA determines--or doesn't get a

 

 11   request--that there is a significant health

 

 12   benefit.  It is unclear to me how you can decide

 

 13   that there is a significant health benefit to the

 

 14   population when at the end of the day there is no

 

 15   formulation available for them.

 

 16             DR. D. MURPHY:  Again, they have to fairly

 

 17   meet the terms of the written request.  A written

 

 18   request is based on what the public health benefit

 

 19   would be and it often will say that you must

 

 20   conduct this trial with an age-appropriate

 

 21   formulation.  If they conduct the trial with the

 

 22   age-appropriate formulation it does not say, nor do

 

                                                                71

 

  1   I think we would be allowed to legally say, you

 

  2   must market it.

 

  3             DR. NELSON:  Well, I guess I would go back

 

  4   to the attorneys and ask them to reflect on that

 

  5   because--

 

  6             DR. D. MURPHY:  We have.

 

  7             DR. NELSON:  --I guess I don't think that

 

  8   was the intent of Congress, that they would get the

 

  9   money and then have nothing available for that

 

 10   population.

 

 11             DR. D. MURPHY:  Yes, we have gone back

 

 12   actually because, as you can see, this is becoming

 

 13   an issue.  We have brought this back to them and we

 

 14   are in the process of discussing again, within our

 

 15   legal regulatory authority, what we can and cannot

 

 16   do.

 

 17             In balancing that, the other effect, the

 

 18   unintended effect is that you don't issue any

 

 19   written request because they aren't going to do

 

 20   them, or you can issue them and they won't do them

 

 21   at all.  So, is there a way we can balance the kind

 

 22   of information that we need--and I really can't

 

                                                                72

 

  1   give a final answer on this right now--is there a

 

  2   way that we can set it up so that we say you need

 

  3   to develop a marketable formulation that would be

 

  4   appropriate for children?  We have always had

 

  5   criteria that if you can't do that you have to tell

 

  6   us why but make that clear, more definitive.

 

  7             Then, if you can't--because there are

 

  8   reasons sometimes why you cannot develop certain

 

  9   formulations--the solvents become too large or

 

 10   other reasons, as you all I think know, with some

 

 11   of the proton pump inhibitor types of

 

 12   products--then we are looking at trying to define

 

 13   requirements that have to be met having to do with

 

 14   stability, bioavailability, for kids' use that

 

 15   would be appropriate.  We get into other issues for

 

 16   compounding and how do you avoid those issues.

 

 17             So, the bottom line, Dr. Nelson, is that

 

 18   we are very aware that this is an issue and we are

 

 19   trying to find a resolution that promotes

 

 20   development of products while, at the same time,

 

 21   does not end up in the situation where we have

 

 22   products that are then not available.

 

                                                                73

 

  1             DR. NELSON:  I appreciate the

 

  2   complexities.  In my simplistic view, I suspect

 

  3   that if you went back to those that drafted and

 

  4   then passed the Best Pharmaceuticals for Children

 

  5   Act, they would not interpret significant health

 

  6   benefit to mean that at the end of the day there is

 

  7   no formulation and nothing in the label.

 

  8             DR. CHESNEY:  Dr. Hudak?

 

  9             DR. HUDAK:  Can I just clarify this

 

 10   because I am trying to understand exactly what the

 

 11   data show.  The formulations used in children less

 

 12   than 50 kg were not commercially available?

 

 13             DR. GRYLACK:  That is correct.

 

 14             DR. HUDAK:  These are the same

 

 15   formulations used that assessed the PK issues?

 

 16             DR. GRYLACK:  Yes, the initial singe-dose

 

 17   PK study was done in patients between the ages of 1

 

 18   month and 16 years so, as you can determine, a

 

 19   number of those were less than 50 kg.  Then, the

 

 20   second study, the efficacy and safety study, was

 

 21   done in patients between 6 and 16 years and, again,

 

 22   a certain number of those would be less than 50 kg.

 

                                                                74

 

  1             DR. HUDAK:  So, essentially, the drug with

 

  2   this non-available preparation showed that, as

 

  3   given, it was absorbed and available in the

 

  4   bloodstream like in adults, but showed no efficacy.

 

  5             DR. GRYLACK:  Well, there was the

 

  6   age-dependent increase in bioavailability.

 

  7             DR. HUDAK:  I understand, but giving

 

  8   adequate levels of the drug, there was no

 

  9   level-related efficacy, no dose response--

 

 10             DR. GRYLACK:  No dose response.

 

 11             DR. HUDAK:  No dose response but if you

 

 12   control for the level of the drug in the blood

 

 13   there was still no response.  See what I am saying?

 

 14   There may be a difference depending upon the age.

 

 15             DR. GRYLACK:  Yes.

 

 16             DR. HUDAK:  So, the bottom line is that

 

 17   this drug did not work with the best possible

 

 18   formulation in this population and, therefore,

 

 19   there doesn't seem to be any reason to have a

 

 20   formulation available for pediatric patients.  Is

 

 21   that correct?  For this drug?

 

 22             DR. D. MURPHY:  Correct.

 

                                                                75

 

  1             DR. CHESNEY:  Dr. Danford?

 

  2             DR. DANFORD:  To Dr. Hudak's point, I

 

  3   wonder if the group in which this drug was studied

 

  4   actually had hypertension or not.  Hypertensive

 

  5   children, the younger you get, are harder and

 

  6   harder to come by and if you were just studying the

 

  7   bioavailability of the drug and giving it to

 

  8   volunteer children you would not necessarily expect

 

  9   a drop in blood pressure in a pediatric population.

 

 10   Do you know who these children were?

 

 11             DR. GRYLACK:  I would have to take a

 

 12   minute and go back and look at the detailed

 

 13   description of the studies.  I am sorry, I can't

 

 14   answer that off the top of my head.  Perhaps I can

 

 15   get back to you a little later.

 

 16             DR. D. MURPHY:  Was the question did we

 

 17   give it to normal children?

 

 18             DR. DANFORD:  Or children without

 

 19   hypertension.

 

 20             DR. D. MURPHY:  That is what I meant,

 

 21   children without hypertension.

 

 22             DR. DANFORD:  There could be a group that

 

                                                                76

 

  1   might conceivably benefit from this, who have

 

  2   congestive heart failure who would not have

 

  3   elevated blood pressure.  If you were looking at a

 

  4   response in blood pressure and it were given to a

 

  5   group of patients with VSD you might not be able to

 

  6   determine much of a change in their blood pressure.

 

  7             DR. D. MURPHY:  I think the first part of

 

  8   it is that we would not have done the studies in

 

  9   children who were not hypertensive.  Now, could we

 

 10   have selected a different population so that

 

 11   potentially mechanistically you could postulate a

 

 12   benefit?  You possibly could have but it was felt

 

 13   that the need was in this population so that is why

 

 14   it was written for this population.  Again, as this

 

 15   committee has discussed, it would have to be

 

 16   children who had the disease under study.

 

 17             DR. HUDAK:  I am happy to hear that

 

 18   because testing this antihypertensive medication in

 

 19   normotensive children I think would be a real--

 

 20             DR. GRYLACK:  I have some comment here.

 

 21   Thank you for waiting for me.  The patient

 

 22   population in the efficacy and safety study

 

                                                                77

 

  1   consisted of patients with hypertension or high

 

  2   normal blood pressure.

 

  3             DR. CHESNEY:  Dr. Nelson, one more

 

  4   question and then we really need to move along.

 

  5             DR. NELSON:  It just occurs to me that

 

  6   that question is answerable if you have the

 

  7   pharmaceutical review that is on the website.  So,

 

  8   maybe in the future just including that as part of

 

  9   the packet would enable us to have that at hand.  I

 

 10   am looking to see if that one is in here.

 

 11             DR. PEREZ:  Use the mike, please.

 

 12             DR. D. MURPHY:  It is in here in what is

 

 13   called the critical pharmacology and

 

 14   biopharmaceutics review; summary of findings--

 

 15             DR. S. MURPHY:  Just to remind you that we

 

 16   can only put what is in the public domain so, as we

 

 17   look at what is being posted on the web I think

 

 18   some of these are more extensive than others.  So,

 

 19   it is giving us an opportunity to see what is going

 

 20   on.

 

 21             DR. GRYLACK:  The PK study was done on all

 

 22   hypertensive patients.  Are we going to take a

 

                                                                78

 

  1   break now for the vote or are we going to pursue to

 

  2   the next one?

 

  3             DR. CHESNEY:  Assuming there are no more

 

  4   questions on this particular issue, Dr. Santana

 

  5   will cover the next drug as I am recused for stock

 

  6   reasons.  So, Dr. Santana?

 

  7             DR. SANTANA:  Let's go ahead and get

 

  8   started.  Dr. Buckman?

 

  9             DR. GRYLACK:  Yes, it is my pleasure to

 

 10   introduce Dr. ShaAvhree Buckman.  Dr. Buckman is a

 

 11   pediatrician who is not a neonatologist, who also

 

 12   has a Ph.D. in molecular cell biology and

 

 13   pharmacology.  Dr. Buckman has been a medical

 

 14   officer with the Division of Pediatric Drug

 

 15   Development for nearly two years, and I will add

 

 16   that Dr. Buckman has been a valued colleague of

 

 17   mine during the time I have been here at the FDA.

 

 18                             Fentanyl

 

 19             DR. BUCKMAN:  Good morning.  I will be

 

 20   discussing the one-year post-exclusivity adverse

 

 21   events for the fentanyl transdermal system.

 

 22             The fentanyl transdermal system or,

 

                                                                79

 

  1   trademark Duragesic, is marketed by Johnson &

 

  2   Johnson and its subsidiary ALZA.  It is indicated

 

  3   for the treatment of chronic pain such as that of

 

  4   malignancy that cannot be managed by lesser means,

 

  5   such as acetaminophen-opioid combinations,

 

  6   non-steroidal anti-inflammatory drugs or PRN dosing

 

  7   with short-acting opioids, and pain that requires

 

  8   continuous opioid administration.  It is approved

 

  9   for pediatric use in children down to the age of 2

 

 10   years.  The drug obtained original market approval

 

 11   in August of 1990 and pediatric exclusivity was

 

 12   granted in January of 2003.

 

 13             The Duragesic label carries a boxed

 

 14   warning that specifically states that due to the

 

 15   possibility of serious or life-threatening

 

 16   hypoventilation Duragesic is contraindicated in the

 

 17   management of acute or postoperative pain,

 

 18   including use in outpatient surgeries.  It is also

 

 19   contraindicated in the management of mild or

 

 20   intermittent pain responsive to PRN or non-opioid

 

 21   therapy.  It is also contraindicated in doses

 

 22   exceeding 25 mcg/hour at the initiation of opioid

 

                                                                80

 

  1   therapy.

 

  2             I have also outlined in red the pediatric

 

  3   safety information that is in the boxed warning,

 

  4   which specifically states that the safety of

 

  5   Duragesic has not been established in children

 

  6   under 2 years of age.  Duragesic should be

 

  7   administered only if they are opioid-tolerant at

 

  8   age 2 years or older.

 

  9             There is selected additional safety

 

 10   labeling which states that Duragesic should be

 

 11   prescribed only by persons knowledgeable in the

 

 12   continuous administration of potent opioids and the

 

 13   management of patients receiving potent opioids for

 

 14   treatment of pain and in the detection and

 

 15   management of hypoventilation, including the use of

 

 16   opioid antagonists.

 

 17             Now, the total number of prescriptions

 

 18   dispensed for the fentanyl transdermal systems in

 

 19   the United States have increased by 20 percent in

 

 20   the past 2 years, from 4.5 million in 2002 to 5.4

 

 21   million in 2003.  The top prescribers in 2003 for

 

 22   the fentanyl transdermal systems were internal

 

                                                                81

 

  1   medicine, family practice and anesthesiology.

 

  2   Approximately 0.2 percent of fentanyl transdermal

 

  3   system prescriptions dispensed were written by

 

  4   pediatricians.

 

  5             In the outpatient setting children and

 

  6   adolescents have accounted for very few dispensed

 

  7   fentanyl transdermal system prescriptions over the

 

  8   past 2 years, 4,535 prescriptions from February

 

  9   2002 to January of 2003 to 5,422 prescriptions from

 

 10   February, 2003 to January, 2004.  In both the

 

 11   outpatient and inpatient settings, adolescents age

 

 12   12-16 years accounted for 60 percent of the

 

 13   pediatric fentanyl transdermal system use over the

 

 14   past 3 years.

 

 15             In the outpatient setting the most

 

 16   frequent diagnoses associated with the fentanyl

 

 17   transdermal systems in the pediatric, as well as

 

 18   the adult, population were associated with diseases

 

 19   of the musculoskeletal system and connective

 

 20   tissues.  In the pediatric population the most

 

 21   predominant musculoskeletal diagnosis was spinal

 

 22   stenosis, followed by injuries involving fractured

 

                                                                82

 

  1   bones.  One must be mindful though that these are

 

  2   very small numbers that we are capturing.

 

  3             In the inpatient setting the primary

 

  4   discharge diagnoses most frequently associated with

 

  5   billing during hospitalization in the pediatric

 

  6   population were for cholesterol encounters and

 

  7   various blood disorders, including sickle cell

 

  8   disease.

 

  9             There was a total of 1,917 adult and

 

 10   pediatric adverse event reports for the fentanyl

 

 11   transdermal system during the 1-year

 

 12   post-exclusivity period.  Of these, there were 8

 

 13   unique pediatric cases.  Seven were from the U.S.

 

 14   and 1 was a foreign report.  All of these cases

 

 15   were described as serious outcomes, including 5

 

 16   deaths.  There were 4 reports in females and 4

 

 17   reports in males, and the ages ranged from 4-16

 

 18   years of age.  Of these 8 pediatric reports, most

 

 19   adverse events were mentioned only once.  The

 

 20   labeled adverse events that were captured twice

 

 21   included overdose drug abuser and medication error.

 

 22   Again, these are labeled adverse events.

 

                                                                83

 

  1             Of the unlabeled adverse events that were

 

  2   captured more than once, they included cardiac

 

  3   arrest, respiratory arrest and self-medication.

 

  4             There were 5 deaths that were reported

 

  5   during the 1-year post-exclusivity period for

 

  6   Duragesic and I would like to describe these

 

  7   reports to you.  The first was the case of an 8

 

  8   year-old female who was diagnosed with

 

  9   rhabdomyosarcoma who died 2 months after being

 

 10   switched from the fentanyl transdermal system to IV

 

 11   morphine.  This was a foreign case and it is

 

 12   believed that this child's death was due to

 

 13   progression of her underlying disease and not due

 

 14   to the patch itself.

 

 15             The second case is that of a 9 year-old

 

 16   male who was 2 days post tonsillectomy and

 

 17   adenoidectomy, who was treated with the fentanyl

 

 18   transdermal system 25 mcg patch with subsequent

 

 19   respiratory arrest resulting in death.  Concomitant

 

 20   medications that were given included acetaminophen

 

 21   with codeine elixir, although the timing of

 

 22   administration of this dosing is unclear from the

 

                                                                84

 

  1   report.

 

  2             This was a U.S. case and I have a couple

 

  3   of comments about this case.  One is that this is a

 

  4   case where a non-opioid tolerant patient was

 

  5   prescribed the drug for an acute postoperative pain

 

  6   situation.  As you recall from the boxed warning,

 

  7   Duragesic is contraindicated in the management of

 

  8   acute or postoperative pain.

 

  9             The next case was that of a 4 year-old

 

 10   female who died from cardiac arrest after having

 

 11   the fentanyl transdermal system applied by her

 

 12   grandmother for pain relief.  The details of this

 

 13   case are largely unknown.  This is a U.S. case, and

 

 14   the only additional information that we have is

 

 15   that the child had marks on her body that indicated

 

 16   that she may have had more than one patch applied

 

 17   because there was adhesive residue on her skin.

 

 18             The next case was that of a 16 year-old

 

 19   male with a history of drug abuse, including

 

 20   marijuana, methylphenidate and dextropropoxyphene,

 

 21   who was reported to have been using the fentanyl

 

 22   transdermal system several days prior to death and

 

                                                                85

 

  1   was found wearing a 100 mcg patch.  This was a U.S.

 

  2   case.

 

  3             The last of the 5 reported deaths was that

 

  4   of a 16 year-old male, with a history of alcohol

 

  5   and marijuana use, who died of cardiac arrest after

 

  6   using 100 mcg patches obtained from another

 

  7   student.  He was found wearing a 100 mcg/hour patch

 

  8   and this was a U.S. case.

 

  9             Now, there were 3 non-fatal adverse events

 

 10   that were reported during the 1-year

 

 11   post-exclusivity period.  These included a patient

 

 12   who experienced euphoria, hallucinations and weight

 

 13   loss after initiation of therapy with the fentanyl

 

 14   transdermal system.

 

 15             The second case was a child who

 

 16   experienced withdrawal symptoms from what was

 

 17   considered a loose patch, meaning that the patch

 

 18   had become non-adherent to the skin and the patient

 

 19   experienced withdrawal symptoms which resolved

 

 20   after replacement of a new patch.

 

 21             The last case was that of respiratory

 

 22   depression in a patient who had intentional misuse

 

                                                                86

 

  1   of the fentanyl patch.

 

  2             We have reported the adverse events that

 

  3   occurred during the 1-year post-exclusivity period.

 

  4   Due to our concern regarding the pediatric deaths

 

  5   occurring with this product, we decided to

 

  6   investigate the adverse events which occurred since

 

  7   the approval of Duragesic for adults, in 1990.

 

  8   There were 4 pediatric deaths before initiation of

 

  9   the pediatric exclusivity period.  There have been

 

 10   3 additional pediatric deaths since the end of the

 

 11   1-year post-exclusivity period.  Although we are

 

 12   continuing to monitor for adverse events, for the

 

 13   purpose of this presentation we set our internal

 

 14   cut-off for reporting to you at May 15th.

 

 15             Now I would like to describe briefly those

 

 16   deaths that occurred outside of the exclusivity

 

 17   reporting period.  The first was a case of

 

 18   accidental exposure.  The second was a case of

 

 19   misuse or abuse.  Most concerning are these cases

 

 20   of off-label use.  One is a case of a child with

 

 21   post-tonsillectomy and adenoidectomy pain.  Another

 

 22   is a case of a child with infectious mononucleosis

 

                                                                87

 

  1   and sore throat pain; a child with chronic

 

  2   headaches and infectious mononucleosis; and a child

 

  3   with acute migraine.  The last case that was

 

  4   reported was that of a child with rhabdomyosarcoma

 

  5   and, again, this was another situation where it was

 

  6   thought that the child died due to disease

 

  7   progression and not due to administration of the

 

  8   patch itself.

 

  9             In summary, the cumulative pediatric

 

 10   adverse events for the fentanyl transdermal system

 

 11   since original market approval in 1990 totaled 35

 

 12   unique cases.  Of these, 22 reports were for

 

 13   children who used the product appropriately for an

 

 14   indication of chronic pain.  Of these 22 reports,

 

 15   there were 2 pediatric deaths and these were both

 

 16   children with rhabdomyosarcoma which I described.

 

 17             By comparison, there were 13 reports in

 

 18   children using the medication for a non-chronic

 

 19   pain management indication.  Of these 13 reports,

 

 20   there were 10 pediatric deaths.  It is important to

 

 21   remember that the Adverse Event Reporting System is

 

 22   a voluntary reporting system which is subject to

 

                                                                88

 

  1   under-reporting and other influences, which you

 

  2   have heard described multiple times this morning.

 

  3             In conclusion, several of the serious

 

  4   pediatric adverse events captured occurred in

 

  5   patients who administered the product for an

 

  6   unlabeled indication, for example, treatment of

 

  7   acute pain in a non-opioid tolerant patient.  There

 

  8   is need for additional education regarding the

 

  9   proper use of the fentanyl transdermal system to

 

 10   help further minimize abuse, misuse and off-label

 

 11   use.

 

 12             In conclusion, instead of answering

 

 13   questions right now, because we have two subsequent

 

 14   presentations that deal with the same product, I

 

 15   would like to introduce the next speaker and then

 

 16   we can take questions at the end of all three

 

 17   presentations.  So, Dr. Lee will address the

 

 18   fentanyl pharmacokinetic characteristics following

 

 19   Duragesic application.  Dr. Lee is a clinical

 

 20   pharmacology and biopharmaceutics reviewer with the

 

 21   Office of Clinical Pharmacology and

 

 22   Biopharmaceutics, currently working with the

 

                                                                89

 

  1   Division of Anesthetic, Critical Care and Addiction

 

  2   Drug Products.  Dr. Lee?

 

  3             DR. LEE:  Thank you, Dr. Buckman.  Good

 

  4   morning, ladies and gentlemen.  I would like to

 

  5   present to you this morning on unique features of

 

  6   fentanyl pharmacokinetics after Duragesic patch

 

  7   application, but first, before I go into my slides,

 

  8   I would like to give you some overall background

 

  9   information on the Duragesic patch.

 

 10             First on the patch strengths, Duragesic

 

 11   patches are available as 25 mcg, 50 mcg, 75 mcg and

 

 12   100 mcg fentanyl delivered per hour patches.

 

 13   Secondly on the site of application, patches are

 

 14   applied mostly on a flat skin surface, mostly on

 

 15   the upper torso, such as chest, back, flank or

 

 16   upper arms.  In young children, however, the upper

 

 17   back is a preferred location to minimize the

 

 18   potential for the child to remove the patch.

 

 19   Lastly on the intended use, as we all know, each

 

 20   patch can be worn continuously up to 72 hours but,

 

 21   if analgesia for more than 72 hours is required, a

 

 22   new patch should be applied to a different skin

 

                                                                90

 

  1   site after removal of the previous patch.

 

  2             Gollowing the patch application the

 

  3   fentanyl drug molecules move from the patch

 

  4   reservoir through a rate-controlling membrane and

 

  5   continue to be absorbed into the skin.  At this

 

  6   juncture a depot of fentanyl concentrates in the

 

  7   upper skin layer and fentanyl then becomes

 

  8   available to the systemic circulation.  Peak serum

 

  9   concentrations of fentanyl generally occur between

 

 10   24 and 72 hours.

 

 11             However, after patch removal the serum

 

 12   fentanyl concentrations decline slowly, falling

 

 13   about 50 percent in approximately 17 hours, which

 

 14   is the elimination half-life of the fentanyl patch

 

 15   drug delivery system.  Due to the continued

 

 16   absorption of fentanyl from the skin because of the

 

 17   skin depot effect, fentanyl disappearance from the

 

 18   serum is slower than is seen after an IV infusion.

 

 19   The elimination half-life for the IV infusion route

 

 20   is approximately 7 hours compared to that of 17

 

 21   hours.

 

 22             So, what are some of the potential

 

                                                                91

 

  1   implications?  With respect to initial patch

 

  2   application, the full drug benefit, analgesic

 

  3   effect, may not be seen immediately.  Thus, there

 

  4   is a potential situation for applying another

 

  5   patch.  This can become a safety issue I think.

 

  6             With respect to post-patch removal,

 

  7   substantial drug effect may be felt for a

 

  8   significant period of time.  Thus, there is a

 

  9   potential safety situation for a patient who will

 

 10   be switching over to another opioid therapy.

 

 11             If you have any questions, I will be happy

 

 12   to answer any, otherwise I will introduce Dr.

 

 13   McNeil.  Dr. McNeil is a medical reviewer with

 

 14   HDF-170.  Prior to coming to the agency she trained

 

 15   in pediatric neurology and oncology.  Dr. McNeil?

 

 16             DR. MCNEIL:  Good morning.  I am with the

 

 17   Division of Anesthetic, Critical Care and Addiction

 

 18   Drug Products and, in collaboration with our

 

 19   pediatric colleagues, we have been considering ways

 

 20   to manage the risk of off-label use.

 

 21             We have been coming up with preliminary

 

 22   strategies for managing this risk, and the

 

                                                                92

 

  1   preliminary strategies that we have come up with

 

  2   are labeling changes; prescriber education through

 

  3   the company or, one thing that has been used in the

 

  4   past, are "dear healthcare professional" letters,

 

  5   or prescriber education through  physician groups.

 

  6   We will, of course, be in contact with the company

 

  7   and with our colleagues in pediatrics as we try to

 

  8   come up with a method of managing this risk.

 

  9             DR. SANTANA:  Did you have further

 

 10   comments, Dr. Buckman?

 

 11             DR. BUCKMAN:  We can go ahead and

 

 12   entertain questions at this time.

 

 13                     Discussion of Question 1

 

 14             DR. SANTANA:  Good.  I do have a question

 

 15   for Dr. Lee.  Is there any data either in

 

 16   pediatrics or in adults that other concomitant

 

 17   problems, like fever or skin rashes, change the

 

 18   absorption?  I was struck by a couple of the deaths

 

 19   in patients who had infectious diseases or had

 

 20   postoperative conditions that could be associated

 

 21   with fever or some of these associated skin rashes.

 

 22   So, is there any data to suggest that there is a

 

                                                                93

 

  1   different pharmacokinetic profile under those

 

  2   circumstances?

 

  3             DR. LEE:  As far as I know, I don't think

 

  4   we have any information from the pediatrics which

 

  5   were involved with PK studies.  However, Dr. McNeil

 

  6   may--she says no.

 

  7             DR. SANTANA:  Do we know from the adults

 

  8   about postoperative fever and things of that

 

  9   nature?

 

 10             DR. MCNEIL:  No, we don't.  It is actually

 

 11   in the label that if you apply heat externally to

 

 12   the drug patches you can increase the serum

 

 13   concentration of fentanyl, but that is what is

 

 14   known about it.

 

 15             DR. SANTANA:  Dr. O'Fallon?

 

 16             DR. O'FALLON:  I have been watching these

 

 17   things because my 93 year-old mother-in-law has

 

 18   been outcome this--now she is 96 and a half--for

 

 19   three and a half years.  When I first looked at it

 

 20   what bothered me was the slow--she is allergic to

 

 21   lots of different things; as it turns out she is

 

 22   fine with this, but with something that moves so

 

                                                                94

 

  1   slowly what would happen?  It would seem to me that

 

  2   after 24, 36, 48 hours, something like that, a

 

  3   person might reach a level where they would not be

 

  4   able to tolerate it.  Then, there is this 17-hour,

 

  5   which is really up to a whole day--before you can

 

  6   drop the levels down sufficiently.  What do you do

 

  7   if somebody--I don't see anything in the label

 

  8   about how to manage somebody that has a bad effect.

 

  9   How do you do it when it is in your system for so

 

 10   long?

 

 11             DR. LEE:  My first answer could have been

 

 12   that the person who is experiencing adverse events

 

 13   may just peel off the patch and then for 17 hours,

 

 14   for that I don't have any answers.

 

 15             DR. O'FALLON:  It is actually up to 24

 

 16   almost.  I mean, there is a terrific range on these

 

 17   things.

 

 18             DR. LEE:  Yes, the range is very large.

 

 19   Yes.

 

 20             DR. S. MURPHY:  Dr. Lee, could you show

 

 21   your backup slides with the kinetics?  I think they

 

 22   are very helpful.

 

                                                                95

 

  1             DR. LEE:  I would just like to remind you

 

  2   that the information in this study is from a

 

  3   limited number of patients and the pediatric

 

  4   subjects were non-opioid tolerant subjects.  This

 

  5   study had full pharmacokinetic profiling and,

 

  6   therefore, it was a very useful study for me.

 

  7             The Y axis is in nanograms per milliliter

 

  8   concentration versus time.  We put a patch on and

 

  9   take it off at 72 hours.  This is the adult

 

 10   population where we see the increase in the

 

 11   fentanyl concentration at approximately 22 to about

 

 12   40-some odd hours.

 

 13             Compared to the adults, this is a

 

 14   pediatric population and I would just like to

 

 15   mention at this time that the patch strength size

 

 16   was 50 mcg/hour for adults and 25 mcg/hour for the

 

 17   non-opioid tolerant pediatric patients.  As you can

 

 18   see, time to maximum concentration has shifted at

 

 19   earlier time points and it is higher.  Where I have

 

 20   marked it with the shaded ovals, that is where we

 

 21   need to kind of think again as far as having the

 

 22   pain relief because it takes so long in order to

 

                                                                96

 

  1   reach that plasma concentration.  And, then for the

 

  2   black square, because it takes so long in order to

 

  3   have the fentanyl concentration either eliminated

 

  4   from the system or what-have-you, it takes so long,

 

  5   even up to maybe 140 hours you could have some of

 

  6   the residual fentanyl concentration after patch

 

  7   removal.  So, I guess this is what we have.

 

  8             DR. MCNEIL:  Excuse me, I should mention

 

  9   that my answer on fever was related to the

 

 10   information we have, actual data from patients, but

 

 11   in the label, by PK modeling, there has been some

 

 12   association that fentanyl doses could theoretically

 

 13   increase up to a third but, again, that is from PK

 

 14   modeling and not from actual patients.

 

 15             DR. SANTANA:  And we have no postmortem

 

 16   information from any of these deaths regarding

 

 17   measurement of drugs in these patients?

 

 18             DR. BUCKMAN:  In looking at a couple of

 

 19   MedWatch reports we do have a couple of cases where

 

 20   we did get levels.  In one case that I reported to

 

 21   you, the 16 year-old that died from an overdose of

 

 22   the fentanyl patch had an autopsy that was

 

                                                                97

 

  1   performed.  The cause of death was cardiac arrest

 

  2   due to highly toxic levels of fentanyl.  The

 

  3   fentanyl level was 16 ng/ml.  He also had

 

  4   cannabinoids in his bloodstream as well.  So, that

 

  5   was one case where we did actually have a

 

  6   concentration.

 

  7             DR. SANTANA:  Dr. Fuchs?

 

  8             DR. FUCHS:  Well, two things that strike

 

  9   me from reading all your cases are that three of

 

 10   them were used in kids with tonsillectomy or mono,

 

 11   and if you have ever looked at kids with

 

 12   mononucleosis, those are kissing tonsils and, yes,

 

 13   they do hurt.  That may be something where we might

 

 14   add a warning, "do not use when there is any airway

 

 15   problem or tonsillitis or mono" because that is an

 

 16   airway issue to begin with and then if you have

 

 17   respiratory depression, which this drug is known to

 

 18   cause, and you have no airway obviously you will

 

 19   get hypoxia and that will then lead to respiratory

 

 20   arrest and then lead to cardiac arrest.

 

 21             The second thing is that in the cases

 

 22   where you mentioned cardiac arrest, I suspect

 

                                                                98

 

  1   mostly in kids this is respiratory arrest.  Once

 

  2   again, we can't really tell from the reports but I

 

  3   suspect they are all respiratory related.

 

  4             DR. BUCKMAN:  That is a very good point.

 

  5   We can only report to you exactly what is captured

 

  6   there but I agree with you that in most pediatric

 

  7   cases it is respiratory arrest leading to cardiac

 

  8   arrest.  But that is how it was captured in the

 

  9   reports.

 

 10             DR. SANTANA:  Dr. Nelson?

 

 11             DR. NELSON:  Looking at the label, my

 

 12   understanding is the strongest warning that the FDA

 

 13   can do is the black box, which is what you have at

 

 14   the front.  So, unless we think it needs to be

 

 15   worded differently, there is already a black box.

 

 16   The only thing that doesn't seem to be in that

 

 17   black box that is elsewhere is the comment about

 

 18   the qualifications of who should prescribe this.

 

 19   Working in critical care and having used this in

 

 20   the past and no longer using it in the way that I

 

 21   had used it simply because of the labeling change,

 

 22   it is unclear to me how much stronger you could

 

                                                                99

 

  1   make this, other than perhaps moving the

 

  2   information about prescribers to the black box.

 

  3   And, it is unclear to me--I am assuming there was a

 

  4   pretty good malpractice loss for these deaths, or

 

  5   there should be--so it is unclear to me how much

 

  6   more you can do in your labeling if, in fact,

 

  7   people are going to use it when it says not to use

 

  8   it that way.  It seems pretty straightforward to

 

  9   me.

 

 10             DR. BUCKMAN:  Can I respond to that

 

 11   briefly?  That was why in the presentation we

 

 12   wanted at the outset to show you exactly what was

 

 13   in the labeling because that is what we need to

 

 14   hear from you as far as comments as far as how can

 

 15   we get that word out there anymore so.  It seems as

 

 16   if the greater propensity of what is happening is

 

 17   that patients are being administered this product

 

 18   for an unlabeled or contraindicated use.  So, that

 

 19   is the feedback that we want to get from you all.

 

 20   You know, what other things can we do?  That is

 

 21   going to be the question that we will be asking.

 

 22             DR. SANTANA:  Dr. O'Fallon first and then

 

                                                               100

 

  1   Dr. Hudak.

 

  2             DR. O'FALLON:  I think that the letter to

 

  3   patients is very helpful that is included in our

 

  4   packet.  Is that normally given to the patients?  I

 

  5   don't know your process here.  Between the

 

  6   executive summary and the actual label there is a

 

  7   patient information thing.

 

  8             DR. MCNEIL:  Patient information?

 

  9             DR. O'FALLON:  Yes, and I don't know where

 

 10   that comes into the Act.

 

 11             DR. MCNEIL:  In theory, what happens is

 

 12   when you buy your box of Duragesic is that you

 

 13   should get this.

 

 14             DR. O'FALLON:  Yes, I don't think we did.

 

 15   She said theoretically we should get it when we buy

 

 16   our box but I don't remember that we did.

 

 17             DR. D. MURPHY:  Remember, it is not

 

 18   required to be given to every patient.

 

 19             DR. O'FALLON:  That is what I was

 

 20   wondering.

 

 21   The other thing is that I don't think it addresses

 

 22   the issue.  You see, I was worried the first time I

 

                                                               101

 

  1   saw this about the long-lastingness of this drug.

 

  2   What happens if they get into trouble?  Is there

 

  3   any information that the patients could have if

 

  4   they are seeing something?  I don't even see that

 

  5   it says call your emergency room immediately, or

 

  6   something.  I don't see anything about what to do

 

  7   in case the kid gets in trouble or the person gets

 

  8   in trouble, the 90-odd year-old gets in trouble.

 

  9             DR. MCNEIL:  Under "how do I use

 

 10   Duragesic" in the patient information section it

 

 11   does say if you use too much Duragesic or overdose

 

 12   get emergency medical help right away.  But I guess

 

 13   from what you are saying that is not enough.

 

 14             DR. O'FALLON:  Well, I didn't see it in

 

 15   the patient letter but maybe I missed it.

 

 16             DR. SANTANA:  Dr. Hudak?

 

 17             DR. HUDAK:  I guess in comment to Dr.

 

 18   Nelson's comment, I am not sure what can be done

 

 19   for language and what the limitations are but I

 

 20   think many physicians are sort of jaded when they

 

 21   see "serious" or "life-threatening" written down

 

 22   somewhere because that seems to be on a lot of

 

                                                               102

 

  1   different drugs, and maybe something very specific

 

  2   about deaths have occurred due to, you know,

 

  3   inappropriate use in these situations should be in

 

  4   there in some form that makes it very concrete.

 

  5             DR. SANTANA:  Do we know from these

 

  6   adverse event reports if, in the cases that were

 

  7   postoperative, those were actually prescribed by a

 

  8   person before the procedure or subsequently by a

 

  9   pediatrician or family physician?  I mean, what is

 

 10   the sequence of prescriptions here?

 

 11             DR. BUCKMAN:  In one case it was

 

 12   prescribed by a family physician.  In another case

 

 13   it was prescribed by the pain control team in the

 

 14   ICU, and the mother had asked--and Joe Wyeth, our

 

 15   ODS person, please correct me if I am wrong; she

 

 16   has done an incredible job of helping us get all

 

 17   these reports together--but in another case it was

 

 18   prescribed in the ICU by the pain control team for

 

 19   this child.  The mother asked that two of the vital

 

 20   checks be suspended.  They were overnight vital

 

 21   checks.  She wanted the child to rest, and by the

 

 22   morning when they did the next vital check the

 

                                                               103

 

  1   child was dead.

 

  2             DR. SANTANA:  Dr. Gorman, I would like to

 

  3   hear your opinion on this since you are a

 

  4   practicing pediatrician in the community.

 

  5             DR. GORMAN:  First of all, all of these

 

  6   patches as they have come out, these long-acting

 

  7   patches--I think I remember the same event with a

 

  8   patch that came out for hypertension with another

 

  9   product where children had it applied

 

 10   inappropriately or retrieved it from wastepaper

 

 11   baskets.  There were several adverse outcomes which

 

 12   were slightly different than these.

 

 13             I would have to echo Dr. Hudak's very

 

 14   explicit comments.  I think the hypothetical that

 

 15   is put in the black box warning now is a reality

 

 16   and there should be a statement--and I understand

 

 17   that labels are a negotiated legal document between

 

 18   the FDA and the pharmaceutical company, but a

 

 19   simple statement that deaths have occurred through

 

 20   the inappropriate use of this in the following

 

 21   settings, and then a listing that you have

 

 22   contraindicated would take this out of the realm of

 

                                                               104

 

  1   hypothetical and say it is real.

 

  2             Then to echo a little bit of what Dr.

 

  3   Nelson said, there could be a little asterisk on

 

  4   the bottom--which I know you are not allowed to

 

  5   use--that says and big malpractice awards were

 

  6   awarded.

 

  7             [Laughter]

 

  8             DR. SANTANA:  We don't want to get into

 

  9   that!  Any other comments?  Dr. Lee?

 

 10             DR. LEE:  I just wanted to make a

 

 11   clarification that for the data that I presented

 

 12   for the non-opioid tolerant patients, the age range

 

 13   was from 1.5-5.  I just wanted you to understand

 

 14   that.  It doesn't give us an overall 2-16 year-old

 

 15   range.

 

 16             DR. SANTANA:  Dr. Luban, you deal with

 

 17   patients with sickle cell who have chronic pain

 

 18   issues.  Would you like to comment on this issue?

 

 19             DR. LUBAN:  I think the biggest issue

 

 20   there is the complex use of more than one

 

 21   analgesic, and the occasional failure of families,

 

 22   when discharged, to follow the pain team's

 

                                                               105

 

  1   recommendation and to really abuse the medications

 

  2   because of continuing needs of the child.  So, I

 

  3   see sickle cell disease and the use of this as a

 

  4   real avenue of education that really should be

 

  5   followed up on.

 

  6             DR. SANTANA:  Dr. Murphy?

 

  7             DR. D. MURPHY:  Do you think that it is

 

  8   clear--getting back to Dr. O'Fallon's

 

  9   question--from the patient insert that after you

 

 10   remove this product it is still absorbed?  Do you

 

 11   think that is clear enough in here, for longer

 

 12   periods of time?

 

 13             DR. SANTANA:  Dr. Luban?

 

 14             DR. LUBAN:  I think that is not at all

 

 15   clear.  I think that this is written at a very

 

 16   sophisticated level for some families to interpret.

 

 17   We certainly don't have high level language use

 

 18   when we are doing informed consent, so why should

 

 19   we if we are trying to educate patients and

 

 20   families?

 

 21             DR. MCNEIL:  Thank you.  We will talk more

 

 22   with the folks--there is actually a whole team of

 

                                                               106

 

  1   people who help us write these patient information

 

  2   inserts and they are supposed to be geared to the

 

  3   sixth to eighth grade level.  By the giggles in the

 

  4   room, I guess we have not hit that mark so I will

 

  5   talk with people and we will see what we can do.

 

  6   If I understand you correctly, we should make it

 

  7   slightly simpler.

 

  8             DR. LUBAN:  Speaking for our patient

 

  9   populations, I would say yes.  The use of the term

 

 10   "opioid tolerant" is not a term that most parents

 

 11   can understand.

 

 12             DR. SANTANA:  And I am not even sure a lot

 

 13   of physicians understand it.

 

 14             [Laughter]

 

 15             No, that is a fair observation.

 

 16             DR. MCNEIL:  The reason that we used

 

 17   "opioid tolerant"--I mean, I understand your

 

 18   comment but the reason that we used "opioid

 

 19   tolerant" was just to reflect the language in the

 

 20   boxed warning, but I do understand what you are

 

 21   saying and we will try to come up with something.

 

 22             DR. SANTANA:  Dr. Gorman and then Dr.

 

                                                               107

 

  1   Nelson.

 

  2             DR. GORMAN:  It strikes me how attractive

 

  3   this product would have to be to people doing ear,

 

  4   nose and throat surgery on tonsils.  You have a

 

  5   population with generally poor options for oral

 

  6   medications in terms of their taste and

 

  7   tolerability and adverse events of vomiting.  So,

 

  8   you have a product that looks really attractive to

 

  9   them because it is applied to the outside to an

 

 10   obstreperous 4 year-old and you don't have to try

 

 11   to get them to drink something.  If I was targeting

 

 12   my educational process, ear, nose and throat

 

 13   physicians and ambulatory surgery centers would be

 

 14   at the top of my list.

 

 15             DR. MCNEIL:  Excuse me, may I just go back

 

 16   to Drs. Luban and O'Fallon?  I just want to make

 

 17   certain that what we were speaking about before,

 

 18   that the language is a bit too sophisticated is in

 

 19   the patient information section, not the actual

 

 20   label?  Correct?

 

 21             DR. LUBAN:  Correct.

 

 22             DR. O'FALLON:  The statement "call your

 

                                                               108

 

  1   healthcare provider right away of get emergency

 

  2   help if you have trouble breathing or have other

 

  3   serious side effects," that is in there on the

 

  4   fourth page, without a bullet in a wholly bulleted

 

  5   thing.  I think you should move it up to what is

 

  6   the most important information I should know.  It

 

  7   should go there.

 

  8             DR. MCNEIL:  Thank you.

 

  9             DR. CHESNEY:  Dr. Nelson, you had your

 

 10   hand up?

 

 11             DR. NELSON:  Well, I think my comment

 

 12   follows from both of the last two, which is to also

 

 13   look at the order within which you are putting

 

 14   things, particularly given Dr. Gorman's comment.

 

 15   The first thing probably shouldn't be only use it

 

 16   in the way that your healthcare professional tells

 

 17   you to.

 

 18             [Laughter]

 

 19             Because we are talking about healthcare

 

 20   professionals not using it appropriately.

 

 21             DR. SANTANA:  Dr. Hudak?

 

 22             DR. HUDAK:  I guess this is sort of

 

                                                               109

 

  1   getting at the question here, but the other avenue

 

  2   for education, it seems to me, since some of these

 

  3   more egregious events occurred in the hospital

 

  4   setting, is perhaps to have a letter that goes out

 

  5   to the hospital pharmacies, pediatric pharmacies

 

  6   about this, and in this day and age where there are

 

  7   computerized physician order entry systems it seems

 

  8   that this would be a big way to sort of capture

 

  9   that before it might become an issue.

 

 10             DR. DANFORD:  Does the FDA ever

 

 11   communicate directly with risk management

 

 12   individuals for hospitals and clinics?  Several of

 

 13   the speakers have suggested that the adverse events

 

 14   might most likely be prevented by having a general

 

 15   understanding that lawsuits can happen over misuse.

 

 16   Perhaps the lawyers from hospitals and clinics who

 

 17   try to reduce their exposure to big settlements, if

 

 18   they received something from the FDA about the

 

 19   misuse of such products might actually do a lot of

 

 20   work of educating the people who work in their

 

 21   institutions.

 

 22             DR. SANTANA:  Dr. Nelson?

 

                                                               110

 

  1             DR. NELSON:  I think, at least in my

 

  2   setting, if a letter went out to the pharmacist you

 

  3   effectively would accomplish that because it would

 

  4   then go to the control mechanisms for prescribing

 

  5   that would be used within a facility at least to

 

  6   establish risk management strategies.  I would

 

  7   probably prefer going that way because it is at

 

  8   least then directed to the provision of care rather

 

  9   than the other way.

 

 10             DR. SANTANA:  I would support that.  It is

 

 11   within the scope of their care of what they should

 

 12   be doing with patients in terms of educating as

 

 13   they get prescriptions filled, and so on and so

 

 14   forth.  So, I would support that too.  Any other

 

 15   comments?  Dr. Murphy?

 

 16             DR. D. MURPHY:  I just wanted to summarize

 

 17   and ask the Division to also pitch in here if they

 

 18   don't think I have summarized correctly what we

 

 19   have heard from the committee.

 

 20             DR. SANTANA:  I took some notes.  Would

 

 21   you allow me to do that?  I think the committee

 

 22   would like the FDA to move in three directions that

 

                                                               111

 

  1   you have pointed out in this slide.  One of the

 

  2   comments I heard very strongly from the committee

 

  3   is that the label needs to be re-looked at in the

 

  4   context of maybe providing stronger statements,

 

  5   regarding the inappropriate use resulting in deaths

 

  6   that have already been observed, somewhere earlier

 

  7   in the actual label so that physicians and others

 

  8   prescribing this can see that clearly early on.

 

  9             I also heard a comment that there is a

 

 10   section about qualifications of the prescriber and

 

 11   those qualifications were kind of hidden in the

 

 12   back of the information, and it should be brought

 

 13   forward into the label too.  So, it is not a matter

 

 14   of re-writing the label but maybe providing some of

 

 15   the information in different sections, particularly

 

 16   at the beginning that would be more evident to

 

 17   those that are prescribing.  Those are the comments

 

 18   that I heard about the label.

 

 19             I heard a lot of comments about patient

 

 20   information and using the patient as an advocate

 

 21   for him or herself.  I heard comments that probably

 

 22   the reading language was inappropriate for the

 

                                                               112

 

  1   populations that are being targeted in which this

 

  2   medication could be used.  So, that needs to be

 

  3   looked at very carefully.

 

  4             I also heard some comments that I think

 

  5   were very appropriate about clearer statements in

 

  6   the patient information regarding how, when this

 

  7   medication or patch is removed, there will be

 

  8   sustained levels that may continue to put you at

 

  9   risk of having respiratory depression and

 

 10   associated side effects.

 

 11             Related to the patient information, I also

 

 12   heard some comments about how the information in

 

 13   that patient information leaflet should be

 

 14   reorganized to put some of the highlights earlier

 

 15   on and make them more self-evident.

 

 16             Then I heard a brief discussion about

 

 17   education, primarily to prescribers.  I heard

 

 18   various comments about some of the incident cases

 

 19   that received care that had been by ENT, by

 

 20   anesthesiologists, by pain teams.  I didn't hear a

 

 21   lot of discussion about how we could accomplish

 

 22   that so I am going to seek a little bit more advice

 

                                                               113

 

  1   from the committee on how potentially that could be

 

  2   accomplished.  But I did hear that there needs to

 

  3   be reeducation of people prescribing this and

 

  4   potentially starting with some target populations

 

  5   and then moving it more openly, including

 

  6   pharmacists, of course.

 

  7             Then I also heard a very strong statement

 

  8   about educating our patients who are using these

 

  9   products and parents, and how we can best

 

 10   accomplish that.

 

 11             So, maybe the committee wants to spend

 

 12   maybe one more minute probably advising the agency

 

 13   on potentially what educational systems may already

 

 14   be in place that they could target or the company

 

 15   could target.  If anybody wants to add to that?

 

 16   Dr. Murphy?

 

 17             DR. D. MURPHY:  Thank you very much.  I

 

 18   only have one question I want to clarify, and that

 

 19   is the label--the statement you had, Dr. Santana,

 

 20   was that we want a stronger statement concerning

 

 21   the deaths early in the label.  I thought I heard

 

 22   that you wanted it in the black box.

 

                                                               114

 

  1             DR. SANTANA:  Yes, in the black box.  That

 

  2   is what I meant.  That is correct.

 

  3             DR. D. MURPHY:  Thank you.

 

  4             DR. SANTANA:  Any further sort of advice

 

  5   to the agency on this issue?  I think we have

 

  6   discussed question one actually.  Am I correct?

 

  7             DR. MCNEIL:  Thank you for your comments.

 

  8   It is very helpful to us.  I am going to take them

 

  9   back for further discussions with the company.

 

 10             DR. SANTANA:  Thank you so much.  I think

 

 11   we are going to take a ten-minute break and start a

 

 12   little bit after 10:30.  Thank you.

 

 13             [Brief recess]

 

 14             DR. CHESNEY:  While everybody is finding

 

 15   their seats, I wanted to thank the FDA for

 

 16   clarifying one issue which had to do with the use

 

 17   of ciprofloxacin and moxyfloxacin in ophthalmic

 

 18   preparations.  In the last two slides the expected

 

 19   cure rate of 70 percent, is that for conjunctivitis

 

 20   in adults?  This study was actually done in

 

 21   neonates.  So, probably one can't extrapolate from

 

 22   one to the other, just for clarification.  Dr.

 

                                                               115

 

  1   Iyasu is going to introduce our next speaker.

 

  2             DR. IYASU:  Thank you.  Our next speaker

 

  3   is Dr. Hari Cheryl Sachs.  Dr. Hari Sachs is a

 

  4   professor of pediatrics at GW and  Children's

 

  5   Hospital National Medication Center.  She has over

 

  6   15 years of experience in private practice.  She

 

  7   also served on the FDA non-prescription drug

 

  8   advisory committee and is one of the FDA liaisons

 

  9   to the AAP committee on drugs.  She will be

 

 10   presenting the adverse events for venlafaxine.

 

 11           Adverse Event Reports per Section 17 of BPCA

 

 12                       (cont.), Venlafaxine

 

 13             DR. SACHS:  Thank you very much.  I am

 

 14   glad to be here to talk to you, guys.  It is

 

 15   actually nice to see some familiar faces among the

 

 16   crowd.

 

 17             I will be discussing the adverse events

 

 18   for venlafaxine, and I think you, guys, are

 

 19   familiar now with the basic organization of the

 

 20   talk.  Venlafaxine, or trade name Effexor, has been

 

 21   on the market since December, 1993 for the

 

 22   treatment of major depressive disorder, generalized

 

                                                               116

 

  1   anxiety disorder and social anxiety disorder.

 

  2   Although these are the indications in adults, there

 

  3   are no approved pediatric indications despite the

 

  4   fact that exclusivity was granted in December,

 

  5   2002, and the sponsor now goes by the name of Wyeth

 

  6   Pharmaceuticals.

 

  7             Venlafaxine and its active metabolite,

 

  8   whose name I am not going to try to pronounce, is a

 

  9   potent inhibitor of both serotonin and

 

 10   norepinephrine reuptake so this is actually an SNRI

 

 11   but for convenience I am going to refer to the

 

 12   whole class as SRIs.  It also is a weak inhibitor

 

 13   of dopamine reuptake.  These actions, along with

 

 14   the lack of significant muscarinic cholinergic and

 

 15   histaminergic effects, do alter the side effect

 

 16   profile of the drug.  The half-life, which is about

 

 17   5 hours for venlafaxine and 11 hours for the active

 

 18   metabolite, is relevant for the timing of potential

 

 19   discontinuation symptoms when they occur.

 

 20             Venlafaxine was the fourth most commonly

 

 21   prescribed antidepressant in the U.S. during 2003

 

 22   and, as with other SRIs, prescriptions have been

 

                                                               117

 

  1   rising in both pediatric and adult populations.

 

  2   Although pediatric use seems to account for only

 

  3   about 2.5 percent, this represents almost half a

 

  4   million prescriptions.  This use is all off-label.

 

  5   Disorders of mood and anxiety, along with ADHD are

 

  6   the most common indications that kids have been

 

  7   treated for with venlafaxine.

 

  8             I will now briefly describe the results of

 

  9   the studies performed for exclusivity.  There were

 

 10   4 large, multicenter, double-blind,

 

 11   placebo-controlled, parallel group, flexible dose

 

 12   studies for each indication, that is, major

 

 13   depressive disorder and general anxiety disorder.

 

 14   The dose used was flexible dosing between 37.5 mg

 

 15   and 225 mg, and the age was 6-17 years.  None of

 

 16   the studies in major depressive disorder showed a

 

 17   significant difference in placebo and,

 

 18   interestingly enough, only one of the studies for

 

 19   generalized anxiety disorder showed a positive

 

 20   study result.

 

 21             The endpoints in both the trials were

 

 22   age-appropriate clinical symptom rating scales for

 

                                                               118

 

  1   major depressive disorder.  It was the CDRS

 

  2   revised.  For the GAD trial it was the Columbia

 

  3   Kiddy Scale for Affective Disorders, or the KSADS.

 

  4   Since only one study showed efficacy, that is why

 

  5   no approval was granted.

 

  6             Safety information was based in part on

 

  7   these 4 studies, as well as 2 open-label trials, a

 

  8   6-month trial in major depressive disorder and

 

  9   another study in conduct disorder.  In these

 

 10   studies decreased weight gain and growth was noted

 

 11   which was unrelated to treatment emergent-anorexia.

 

 12   You can see the numbers for the approximate weight

 

 13   loss and weight gain in the placebo population, and

 

 14   the height.  If you actually read the results of

 

 15   the studies posted on the web, these numbers differ

 

 16   slightly from that because the FDA received

 

 17   additional information and analyzed it.  The other

 

 18   thing that is kind of interesting is that it is

 

 19   actually important that the height effect was seen

 

 20   in the exclusivity studies.  It is pretty

 

 21   significant because it was a very short period of

 

 22   time that the drugs were studied.

 

                                                               119

 

  1             The other adverse event that was noted,

 

  2   mild adverse event, is that there were elevations

 

  3   in cholesterol and blood pressure that were similar

 

  4   to those seen in adults.  That also was added to

 

  5   the label.

 

  6             Since we are speaking of the label, let's

 

  7   turn to the relevant safety labeling.  I would like

 

  8   to highlight several things about the labeling,

 

  9   some of which is relevant to the safety discussion

 

 10   or the adverse events that we see, but also many of

 

 11   the changes are physically highlighted in yellow to

 

 12   kind of emphasize that these are the new changes

 

 13   that have been added actually since March.

 

 14             In terms of neonates and pregnancy,

 

 15   venlafaxine is considered a category C drug.  That

 

 16   means it should be used in pregnancy only if

 

 17   clearly needed.  Language regarding the

 

 18   discontinuation syndrome in newborns was added

 

 19   fairly recently, first in January, 2003 and then

 

 20   updated last month.  It is found in the section

 

 21   under "non-teratogenic effects."  What the labeling

 

 22   describes is that you can see discontinuation

 

                                                               120

 

  1   effects in newborns with complications that may

 

  2   require prolonged hospitalization or respiratory

 

  3   support that may arise even as soon as delivery.

 

  4   You may also see some clinical findings, including

 

  5   neurologic, respiratory and systemic symptoms.

 

  6   These symptoms are consistent either with

 

  7   discontinuation of the drug or potentially actually

 

  8   a direct toxic effect of the serotonin.

 

  9             As you know, in part because of the

 

 10   deliberations in February, a warning recommending

 

 11   close observation for deterioration or emergence of

 

 12   psychiatric symptoms in patients that are treated

 

 13   with these SRIs was added in May, 2004 to the

 

 14   label, and this warning actually supersedes and

 

 15   replaces some of the information that was in the

 

 16   label previously regarding the association of

 

 17   suicide with depression and other co-morbid

 

 18   disorders, and a statement that Wyeth had added on

 

 19   its own that there were some suicidality seen in

 

 20   the pediatric trials.  The other thing that is

 

 21   mentioned is the occurrence of sustained

 

 22   hypertension.

 

                                                               121

 

  1             These slides show an extensive list of

 

  2   precautions which are listed in the order that they

 

  3   appear in the label.  Most of these things were

 

  4   seen in the top 20 adverse events that you have in

 

  5   the main report for venlafaxine, and we see some of

 

  6   these in the post-exclusivity adverse events that

 

  7   occurred during the year.  I draw your attention to

 

  8   the risk of bleeding and also the problems with

 

  9   seizures, and then in the new labeling which is

 

 10   regarding the weight loss and slower rate of growth

 

 11   in children.

 

 12             In addition, under adverse reactions the

 

 13   risk of symptoms with discontinuation, and this is

 

 14   in adults and older children, include both physical

 

 15   and psychiatric symptoms.  In March there was some

 

 16   labeling added to the postmarketing reports on

 

 17   dyskinesia and rhabodomyolysis.

 

 18             So, now that you are familiar with all the

 

 19   changes in the label, let's look at the adverse

 

 20   events for the year.  These are actually the raw

 

 21   counts of all the adverse events.  There were

 

 22   approximately 1,500, of which about half are in the

 

                                                               122

 

  1   U.S. and they may represent some duplicates.

 

  2   Pediatric reports are really a relatively small

 

  3   proportion, less than 4 percent of total reports

 

  4   and this has been pretty consistent over the past

 

  5   several years since marketing.  There were only 2

 

  6   deaths that occurred, and I will be discussing them

 

  7   in a few moments.

 

  8             Turning to the specific 1-year

 

  9   post-exclusivity period, there were 49 unduplicated

 

 10   events.  I apologize for the busy nature of this

 

 11   slide.  There were 19 events that involved in utero

 

 12   or maternal exposures and 30 that were direct

 

 13   pediatric exposures.  The gender and age

 

 14   distribution is seen here.  Of interest, there is a

 

 15   male predominance of the adverse events in the

 

 16   infants and neonates while the gender distribution

 

 17   is pretty similar in the older children.  Outside

 

 18   the neonatal period, most of the direct exposures

 

 19   involved adolescents and children, as would be

 

 20   expected.

 

 21             Looking more closely at the in utero

 

 22   events, there were actually no deaths reported

 

                                                               123

 

  1   among the 19 in utero events, 3 of which also had

 

  2   concomitant breast feeding.  There were 4 unrelated

 

  3   congenital anomalies; 2 had cardiac malformations,

 

  4   1 with an ASD and the other with dextrocardia.

 

  5   Another infant had hypospadias and the last infant

 

  6   had extra syndactyly, which is a fusion and webbing

 

  7   of the digits.  Co-morbidities and other

 

  8   medications were actually involved in all these

 

  9   congenital anomalies.

 

 10             Neurologic events were described in 11

 

 11   infants.  We saw 2 infants that had hypotonia; 3

 

 12   infants who developed seizures; and 6 infants who

 

 13   had disordered movements.

 

 14             Just to illustrate how difficult it is to

 

 15   sort out causality for these events, on follow-up

 

 16   for one of the infants who had seizures the event

 

 17   was considered unrelated to venlafaxine because the

 

 18   patient had experienced a subarachnoid hemorrhage.

 

 19   But, if you will recall, abnormal bleeding can be

 

 20   associated with venlafaxine.  So, it is potentially

 

 21   possible that the baby had subarachnoid hemorrhage

 

 22   related to the medication.  Of course, that is

 

                                                               124

 

  1   conjecture but just to show how hard it is to sort

 

  2   out the information.

 

  3             The losartan in utero exposure events were

 

  4   really 4 reports that detail complications that

 

  5   occurred in babies with co-morbid conditions and

 

  6   medications.  They are described here.  While it is

 

  7   less serious, it is something that has emerged in

 

  8   the literature so it is interesting that we did see

 

  9   2 cases here as well.

 

 10             Co-morbid disease and medications, as I

 

 11   have explained, may contribute to some of these

 

 12   events.  Although 2 events were coded specifically

 

 13   as neonatal withdrawal, there are actually up to 5

 

 14   others where symptoms that emerged, like

 

 15   jitteriness or tremor or seizure, could have

 

 16   reflected neonatal withdrawal but it was just not

 

 17   coded that way.

 

 18             Prematurity was reported in 4 infants but

 

 19   in 8 cases there actually was insufficient

 

 20   information in the case report to determine whether

 

 21   or not a baby was premature.  Three infants were

 

 22   breast fed.  One mother reported smoking and

 

                                                               125

 

  1   drinking but that information about tobacco or

 

  2   substance exposure or illicit drugs is actually not

 

  3   present in the majority of the reports.  About half

 

  4   the infants were exposed to concomitant

 

  5   medications, 4 of which were psychotropic.  When I

 

  6   looked back, 5 included benzodiazepines.  In only 2

 

  7   the case report expressly stated that there were no

 

  8   other medications involved, and whether or not

 

  9   medicines were involved in 7 of the other cases is

 

 10   not known.

 

 11             So, in looking at the neonatal events,

 

 12   they do seem to reflect the ones that are labeled

 

 13   in adults, for example tremor, convulsion and

 

 14   hypotonia.  The role of concomitant medicines and

 

 15   co-morbid conditions, such as prematur