FOOD AND DRUG ADMINISTRATION














                        Wednesday, June 9, 2004


                               8:00 a.m.



                          ACS Conference Room

                               Room 1066

                           5630 Fishers Lane

                          Rockville, Maryland





         Joan P. Chesney, M.D., Chair

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



         Mark Hudak, M.D.

         David Danford, M.D.

         Richard Gorman, M.D.

         Robert Nelson, M.D., Ph.D.

         Susan Fuchs, M.D.

         Victor Santana, M.D.

         Naomi Luban, M.D.

         Judith O'Fallon, Ph.D.

         Katherine L. Wisner, M.D.





         Steve Ebert, Pharm.D., Consumer Representative




         Janet Cragan, M.D.





         Sam Maldonado, M.D., industry representative


      FDA STAFF:


         Solomon Iyasu, M.D.

         Susan Cummins, M.D.

         Shirley Murphy, M.D.

         Dianne Murphy, M.D.



                            C O N T E N T S


      Call to Order and Introductions,

         Joan P. Chesney, M.D.                                   5


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


      Welcome, Dianne Murphy, M.D.                              10


      Adverse Event Reports per Section 17 of Best

         Pharmaceutical for Children Act,

         Solomon Iyasu, M.D.                                    15


         Fexofenodine, Jane Filie, M.D.                         22


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


         Moxifloxacin and Ciprofloxacin,

            Harry Gunkel, M.D.                                  59


         Fosinopril, Larry Grylack, M.D.                        66


         Fentanyl, ShaAvhree Buckman, M.D.                      78

         David J. Lee, Ph.D.                                    89

         D. Elizabeth McNeil, M.D.                              91


      Discussion of Question 1                                  92


      Adverse Event Reports per Section 17 of BPCA

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


      Pediatric Update, Dianne Murphy, M.D.                    148


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


      Update on Neonatal Withdrawal Syndrome:


         Kathleen Phelan, R.Ph.                                174

         Robert Levin, M.D.                                    189

         Katherine Wisner, M.D.,

           Women's Behavioral Health CARE                      216


      Discussion of Questions 2 and 3                          254


      Update on Congenital Eye Malformations in Infants,

         Solomon Iyasu, M.D.                                   303



                      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




  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




  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,




  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




  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




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


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


  3   company with a product at issue, worth less than


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


  5   the minimis exception allowed under 5 CFR


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


  7   required.  Further, Dr. Chesney is recused from


  8   participating from the subcommittee's discussion


  9   regarding Duragesic due to a conflict of interest.


 10             A copy of the waiver statements may be


 11   obtained by submitting a written request to the


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


 13   of the Parklawn Building.  In the event that the


 14   discussions involve any other products or firms not


 15   already on the agenda for which an FDA participant


 16   has a financial interest, the participants are


 17   aware of the need to exclude themselves from such


 18   involvement and their exclusion will be noted for


 19   the record.


 20             We would also like to note that Dr. Samuel


 21   Maldonado has been invited to participate as an


 22   industry representative, acting on behalf of




  1   regulated industry.  Dr. Maldonado is employed by


  2   Johnson & Johnson.  With respect to all other


  3   participants, we ask in the interest of fairness


  4   that they address any current or previous financial


  5   involvement with any firm whose product they may


  6   wish to comment upon.  Thank you.


  7             DR. CHESNEY:  Thank you.  Our first


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


  9   Director of the Counter-terrorism and Pediatric


 10   Drug Development Office.


 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




  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




  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




  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




  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




  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.




  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




  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,




  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




  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




  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




  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




  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




  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




  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.




  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.




  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




  1   mistakenly filled with Zyrtec-D instead of


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


  3             Concluding the report, despite the large


  4   number of fexofenodine prescriptions, there were


  5   few pediatric adverse event reports during the


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


  7   also very difficult to make any attributions of the


  8   adverse events of the drug when there are


  9   concomitant medications in the reports.  In this


 10   case, the FDA will continue to monitor the adverse


 11   event reports in all populations.  Any questions or




 13             DR. CHESNEY:  Dr. Santana?


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


 15   similar adult reports with the use of this


 16   medication and concomitant anti-psychotic


 17   medications in adults?


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


 19   respond to that adequately.  From the information


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


 21   very similar in both populations.  They resemble


 22   pretty much the two groups.




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


  2   from the Division.  Do you have any comments about


  3   adult report?


  4             DR. CHESNEY:  Dr. O'Fallon?


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


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


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


  8   you keeping track of the various concomitant


  9   medications so that you could be looking for trends


 10   developing that may be subtle, that there may be


 11   interactions, or something?


 12             DR. FILIE:  Yes.  The hope is to


 13   accumulate this data over a long time.


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


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


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


 17   collected so that you are going to be able to


 18   search on it.


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


 20   doing that collecting and the Office of Drug Safety


 21   is also involved in this.  This is something that


 22   has accumulated and we can keep all this data




  1   without losing it.


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


  3   you can search?


  4             DR. FILIE:  I don't know.


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


  6   AERS database has been in existence for a long time


  7   and the database is searchable both by high risk


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


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


 10   parameters and there is an accumulated database


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


 12   you can look at several years since the first time


 13   a report comes into existence for a particular


 14   product.  Once there is approval, there are going


 15   to be postmarketing reports that come in.  So,


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


 17   whole lot of information to try to look at multiple


 18   permutations of different confounders or looking up


 19   interactions.  It is a limited database in that


 20   way.


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


 22   in your package it does tell you that fexofenodine




  1   has been looked at with the co-administration of


  2   acetyl console and erythromycin, the sip


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


  4   know that a metabolism uses a certain sip enzyme


  5   that will cause increases or decreases, they will


  6   frequently look at that interaction but they can't


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


  8   negotiated activity as to how many of them they do


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


 10   likely to give serious adverse events by the normal


 11   drugs that might be used with this specific


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


 13   indication you might think that antibiotics would


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


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


 16   prospectively the agency will sometimes ask,


 17   knowing what the metabolism is, for these


 18   interactions.  But, you can imagine that the list


 19   could get endless so the agency does not do all


 20   possible combinations.  Certainly, I think from


 21   allergic rhinitis to antidepressants--I mean,


 22   unless you had a mechanistic reason for doing that,




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


  2   realize, was looking at statistical analysis post


  3   but up front there is a certain amount of activity


  4   in that area.


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


  6   you only have a handful of reports it might be


  7   worth it, that when you see something showing up


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


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


 10   database, especially in the adults or something, to


 11   see if you are seeing if that has been reported


 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.




  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




  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.




  1             DR. CUMMINS:  Can I just provide one point


  2   of clarification?  The labels that we provide to


  3   you are ones that are publicly available and are


  4   the most recent labels.  Often the strikeouts are


  5   still present.  We download them from the labels


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


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


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


  9   removed in the published label by the company.


 10             DR. GORMAN:  Thank you.


 11             DR. CUMMINS:  You are welcome.


 12             DR. FILIE:  Given there are no further


 13   comments or questions, let me introduce the next


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


 15   neonatologist whose previous experience includes


 16   academic neonatal practice at Johns Hopkins and


 17   Children's National Medical Center.  She recently


 18   received her masters degree in education and has


 19   worked on computer-based education models for


 20   pediatrics.  She will discuss two oncology


 21   products, topotecan and temozolomide.  Dr. McCune.


 22                    Topotecan and Temozolomide




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


  2   Filie.  Ladies and gentlemen of the committee and


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


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


  5   ancestry would allow me to tell shaggy dog stories


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


  7   think we will just move along.


  8             As Dr. Filie mentioned, I will talk about


  9   two oncologic agents this morning.  The first is


 10   topotecan.  Topotecan, trade name Hycamtin, is an


 11   anti-tumor oncologic agent produced by


 12   GlaxoSmithKline.  The indication in adults is


 13   metastatic carcinoma of the ovary after failure of


 14   initial or subsequent chemotherapy and small cell


 15   cancer sensitive disease after failure of


 16   first-line chemotherapy.  There are no approved


 17   pediatric indications.  The original market


 18   approval was May 28, 1996 and the pediatric


 19   exclusivity was granted on November 20, 2002.


 20             I am going to tell you about the studies


 21   for exclusivity for this drug.  As you all


 22   mentioned, in terms of data that is available for




  1   the label, these studies were done based on what


  2   Dr. Iyasu told you already.  BPCA mandates that


  3   this information be available on the website and


  4   this information is available on the website,


  5   however, there were no changes to this label based


  6   on this information.


  7             The studies that were submitted for


  8   exclusivity were summaries of studies that were


  9   previously performed by the Pediatric Oncology


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


 11   was a Phase 2 study in pediatric solid tumor that


 12   enrolled 108 patients that were less than 16 years


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


 14   peripheral neuroectodermal tumor, neuroblastoma,


 15   osteoblastoma and rhabdomyosarcoma.  The study


 16   endpoint was tumor response rate.  Eighty-six


 17   percent of patients died, with 10 percent dying


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


 19   overall response rate was 8 percent but the


 20   response rate for patients with neuroblastoma was


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


 22   for alternative regimens using combinations of




  1   available drugs in pediatric patients with relapse


  2   neuroblastoma the response rates were 35-50


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


  4   years of age showed any response.


  5             Eight of the 11 patients that died within


  6   30 days of the last dose of topotecan had


  7   progressive disease and 3 died with infection which


  8   is a known complication.  Forty-four percent of


  9   patients were hospitalized with adverse events,


 10   primarily febrile neutropenia, fever or sepsis.


 11             The Phase 2 study did determine a


 12   different dose from adults, a daily infusion for 5


 13   consecutive days every 21 days.  The adult dose is


 14   1.5 mg/m                                            2/day and the

pediatric dose that was given


 15   was either 1.4 mg/m                                                      

       2/day without granulocyte-colony


 16   stimulating factor or 2 mg/m                                             

                               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




  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,




  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




  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




  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




  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




  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




  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.




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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.




  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




  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




  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




  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




  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.




  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,




  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




  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




  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




  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.




  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.




  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




  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




  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




  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.




  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.




  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.




  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




  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




  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




  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,




  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




  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




  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




  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.




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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.




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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.




  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




  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




  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?




  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




  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




  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




  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.




  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.




  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




  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




  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




  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.




  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




  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.




  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




  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




  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




  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




  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