FDA Hives Urticaria

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                   UNITED STATES OF AMERICA

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         DEPARTMENT OF HEALTH AND HUMAN SERVICES

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                 FOOD AND DRUG ADMINISTRATION

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         CENTER FOR DRUG EVALUATION AND RESEARCH

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     NONPRESCRIPTION DRUGS ADVISORY COMMITTEE WITH
       CONSULTANTS FROM PULMONARY - ALLERGY AND
        DERMATOLOGIC DRUGS ADVISORY COMMITTEES

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                              MONDAY
                          APRIL 22, 2002

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             The Advisory Committee met in Versaille Room
II in the Holiday Inn, Bethesda, 8120 Wisconsin Avenue,
Bethesda, Maryland, at 8:00 a.m., Louis R. Cantilena,
Jr., M.D., Ph.D., Chairman, presiding.

PRESENT:
Louis R. Cantilena, Jr., M.D., Ph.D., Chairman
Sandra Titus, Ph.D., Executive Secretary
Leslie Clapp, M.D., Member
Frank F. Davidoff, M.D., Member
Edwin E. Gilliam, Ph.D., Member
Julie A. Johnson, Pharm.D., Member
Edward P. Krenzelok, Pharm.D., Member
Y.W. Francis Lam, Pharm.D., Member
Hari C. Sachs, M.D., Member
Donald L. Uden, Pharm.D., Member

PRESENT:       (con't.)


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Henry W. Williams, Jr., M.D., Member
Alastair Wood, M.D., Member
Ralph D'Agostino, Ph.D., Nonprescription Drugs SGEs
Mark Dykewicz, M.D., Allergists SGEs
Jesse Joad, M.D., Allergists SGEs
Stan Szefler, M.D., Allergists SGEs
Lloyd King, M.D., Ph.D., Dermatology SGEs
William Rosenberg, M.D., Dermatology SGEs
Michael C. Alfano, D.M.D., Ph.D., Industry Guest

ALSO PRESENT:

Jonca Bull, M.C., FDA
Badrul Chowdhury, M.D., FDA
Charles Ganley, M.D., FDA
Matthew Holman, Ph.D., FDA
Linda Katz, M.D., FDA
Sandy Kweder, M.D., FDA
Charles Lee, FDA
Robert Temple, M.D., FDA
Jonathan Wilkin, M.D., FDA
John Clayton, Ph.D., Schering-Plough
Eugene W. Monroe, M.D. Schering-Plough
Stephen Neuman, Schering-Plough
Patricia Rohane, Schering-Plough
Janet P. Engle, Pharm.D.
Joseph Ferguson, M.D.
Gary Kay, Ph.D.




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                    A-G-E-N-D-A

                                                page no.

Call to Order, Introductions
Louis Cantilena, M.D., Ph.D., Chair                       5

Conflict of Interest Statement
Sandra Titus, Ph.D., Executive Secretary                  8

Welcome and introduction to Today's Issues
Charles Ganley, M.D., Director
Over-the-Counter Drugs                                   10

Schering Plough Presentations:
Overview
John Clayton, Ph.D., Sr., VP
Scientific and Regulatory Affairs                        12

Clinical Overview of Urticaria
Eugene W. Monroe, M.D.
Dept. of Dermatology
Medical College of Wisconsin                             17

Schering Studies on CIU
Stephen Neuman, Senior Director
Marketing Support Services                               29

Risk-Benefit Analysis on CIU
John Clayton, Ph.D.                                      48

Questions                                                60

FDA Presentations
Urticaria: An Overview and OTC Considerations
Jonathan Wilkin, M.D.
Director, Dermatologic Drugs                             97

Clinical Study Design Issues for the Approved
H1 Antihistamines and CIU Indication
Badrul Chowdhury, M.D., Ph.D., Team Leader
Pulmonary and Allergy Drugs                            108


                 I-N-D-E-X (con't.)


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                                              page no.

OTC Issues: US Regulatory History, Foreign
Marketing and Label Comprehensive Study
Matthew Holman, Ph.D.                                121
Interdisciplinary Scientist
Over-the-Counter Drugs

Summary of Issues on Urticaria as an OTC Indication
Charles Ganley, MD.                               135

Questions

Open Public Hearing

        Dr. Gary Kay                                 172
        Dr. Janet Engle                              189
        Dr. Joseph Ferguson                          184

Questions and Committee Discussion




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

2                                                               8:04 a.m.

3                   DR. CANTILENA:         I'm Doctor Lou Cantilena,

4    head of Clinical Pharmacology at the Uniform Services

5    University and chair of this committee.            This is the April

6    22, 2002 meeting of the Nonprescription Drug Advisory

7    Committee.

8                   What    I'd     like     to    do   is     start     with

9    introductions.        I just introduced myself and perhaps

10   there's less empty seats on this side of the table so

11   perhaps we can start here and have everyone sort of say

12   who you are and your affiliation with the committee.

13                  DR. ALFANO:       My name is Michael Alfano and

14   I'm Dean of the Dental School at New York University

15   College of Dentistry.

16                  DR. DYKEWICZ:          I'm Mark Dykewicz.            I am

17   Director of the training program in allergy and immunology

18   at St. Louis University School of Medicine.

19                  DR. JOAD:     I'm Jesse Joad.        I'm a pediatric

20   pulmonologist and allergist at University of California

21   at Davis.

22                  DR. SZEFLER:           Stan Szefler at National



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1    Jewish Medical and Research Center.

2                   DR.   D'AGOSTINO:         Ralph   D'Agostino     from

3    Boston University, biostatistician and consultant to the

4    committee.

5                   DR.   KRENZELOK:        Good morning.        I'm Ed

6    Krenzelok.     I'm Director of the Pittsburgh Poison Center

7    and a professor of pharmacy and pediatrics at the

8    University of Pittsburgh.

9                   DR. UDEN:       I'm Don Uden, University of

10   Minnesota College of Pharmacy and NDAC member.

11                  DR. JOHNSON:      I'm Julie Johnson, Professor

12   of Pharmacy Practice and Medicine at the University of

13   Florida and a member of NDAC.

14                  DR. LAM:   I'm Francis Lam from the Department

15   of Pharmacology and Medicine at the University of Texas

16   Health Center in San Antonio.         I'm also a member of NDAC.

17                  DR. DAVIDOFF:      I'm Frank Davidoff.      I'm the

18   editor emeritus of Annals of Internal Medicine.              I'm an

19   internist, and I'm a member of the committee.

20                  DR. GILLIAM:        I'm Eddie Gilliam.         I'm a

21   family nurse practitioner with -- Medical Group in Tucson,

22   Arizona.



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1                   DR. TITUS:         I'm Sandy Titus.            I'm the

2    Executive Secretary and the designated federal official

3    at this meeting.

4                   DR. WOOD:     I'm Alastair Wood.        I'm Assistant

5    Vice Chancellor at Vanderbilt and I'm also a member of

6    the committee.

7                   DR. WILLIAMS:        I'm Henry Williams, Acting

8    Chair of the Community Health and Family Practice at

9    Howard University and a member of NDAC.

10                  DR. CLAPP:       I'm Leslie Clapp, pediatrics,

11   Main    Pediatrics   in    Buffalo,      New    York   and    clinical

12   associate professor of pediatrics at SUNY Buffalo.

13                  DR.   KING:        I'm     Lloyd    King,     Chief    of

14   Dermatology     at     Vanderbilt        University.            I'm        a

15   dermatologist.

16                  DR. ROSENBERG:        I'm Bill Rosenberg.            I'm a

17   dermatologist    and      Chairman      of     Dermatology     at     the

18   University of Tennessee College of Medicine.

19                  DR. CHOWDHURY:        I'm Badrul Chowdhury.           I am

20   with the U.S. Food and Drug Administration, Division of

21   Pulmonary and Allergy Drug Products.

22                  DR. GANLEY:       I'm Charlie Ganley, Director



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1    of the Division of Over-the-Counter Drugs at FDA.

2                   DR. KWEDER:      I'm Sandra Kweder.          I'm the

3    Director of the Office of Drug Evaluation II at FDA.

4                   DR. CANTILENA:      Okay.    Thank you, everyone.

5                   We'll now ask Doctor Sandy Titus to read the

6    conflict of interest statement.

7                   DR.   TITUS:      The    following    announcement

8    addresses the issue of conflict of interest with regard

9    to this meeting and is made a part of the record to preclude

10   even the appearance of such at this meeting.               Based on

11   the submitted agenda for the meeting and all financial

12   interests reported by the committee participants, it has

13   been determined that all interests in firms regulated

14   by the Center for Drug Evaluation and Research present

15   no potential for an appearance of a conflict of interest

16   at this meeting with the following exceptions.

17                  In accordance with 18 USC 208B3, Doctor Ralph

18   D'Agostino has been granted a waiver for his role as a

19   member of the Safety Monitoring Committee and his services

20   as a consultant to a Safety Monitoring Committee for a

21   competitor on an unrelated matter.          He receives fees of

22   less than $10,001 for each of these activities.



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1                    Doctor Stanley Szefler has been granted a

2    waiver under 18 USC 208B3 for his consulting for a firm

3    that has a financial interest in a competitive product.

4     He receives less than $10,001 a year.

5                    In addition, Doctor Harry Sachs has been

6    granted waivers under 18 USC 208B3 and 21 USC 355C4,

7    amendment      of   Section   505    of     the   Food   and    Drug

8    Administration Modernization Act for her ownership of

9    stock in the sponsor and competitors valued between $5,001

10   to $25,000.

11                   A copy of the waiver statements may be

12   obtained by submitting a written request to the agency's

13   Freedom of Information Office, Room 12A30 of the Parklawn

14   Building.

15                   In addition, we would like to disclose that

16   Doctor Michael Alfano is participating at this meeting

17   as an industry guest acting on behalf of regulated

18   industry.      As such, he has reported to the FDA that he

19   has no conflicts of interest in the issues to be discussed

20   at today's meeting.

21                   In the event that the discussions involve

22   any other products or firms not already on the agenda



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1    for which an FDA participant has a financial interest,

2    the participants are aware of the need to exclude

3    themselves from such involvement and their exclusion will

4    be noted for the record.

5                   With respect to all other participants, we

6    ask in the interest of fairness that they address any

7    current or previous financial involvement with any firm

8    whose products they may wish to comment upon.

9                   Thank you.

10                  DR. CANTILENA:      Okay.   Thank you, Doctor

11   Titus.     We're almost ready for our first break at this

12   point after the conflict of interest statement.              But

13   let's instead move to Doctor Charles Ganley who will

14   introduce us to the issues for discussion.

15                  DR. GANLEY:   We would just like to thank the

16   members of today's Advisory Committee for taking time

17   from their busy schedules to participate in this meeting.

18    This committee includes members from the Nonprescription

19   Drugs Advisory Committee, selected members from the

20   Pulmonary Allergy Drugs Advisory Committee and the

21   Dermatologic Ophthalmologic Drugs Advisory Committee and

22   some additional FDA consultants.



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1                      It    was   not    quite       a    year   ago   when     the

2    Nonprescription Drugs Advisory Committee and Pulmonary

3    Allergy Drugs Advisory Committee discussed the merits

4    of taking Loratadine Fexofenadine and Cetirizine from

5    prescription to over-the-counter for allergic rhinitis.

6     Today the committee is asked to discuss the merits of

7    taking Loratadine over-the-counter for treatment of

8    chronic idiopathic urticaria.              Unlike allergic rhinitis,

9    the indication chronic idiopathic urticaria, urticaria

10   or hives are not approved for any over-the-counter drug

11   products nor is it included in the antihistamine final

12   monograph.

13                     So it is important for the committee to

14   understand today that the discussion will not only impact

15   the supplemental application submitted by Schering Plough

16   but it will also impact other antihistamine manufacturers

17   that hope to market their product over-the-counter for

18   urticaria and hives.

19                     That concludes my comments right now.

20                     DR. CANTILENA:         Okay.         Thank you, Doctor

21   Ganley, and I would now like to introduce Doctor John

22   Clayton        from    Schering     Plough       to   start    the    sponsor



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1    presentation.           Doctor Clayton will then introduce his

2    co-presenters and then I believe we'll close the session.

3                      DR.     CLAYTON:         Good      morning,     Doctor

4    Cantilena, members of the Advisory Committee, consultants

5    and FDA colleagues.             I'm John Clayton, Senior Vice

6    President, Scientific and Regulatory Affairs for Schering

7    Plough Health Care Products.                    On behalf of Schering

8    Corporation, we appreciate this opportunity to present

9    a brief overview of the NDE submissions we made to the

10   FDA for the approval of Claritin tablets and syrup for

11   over-the-counter status for the indication of chronic

12   idiopathic urticaria.

13                     The proposed labeling of this indication in

14   consumer terms is that of chronic hives of an unknown

15   source.        Discussions with FDA have raised the possibility

16   of a broader hives indication OTC.                  The research that

17   we are presenting today has been focused on CIU, the

18   current prescription indication.                 However, we are open

19   to exploring the broader hives indication, as will be

20   discussed by FDA today.

21                     Specifically, the products for discussion

22   today are Claritin tablets, Claritin syrup, Claritin



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1    ready tabs rapidly disintegrating tablets, all in 10

2    milligram daily doses.

3                      By way of background, as Doctor Ganley

4    mentioned, Loratadine was reviewed by this committee

5    along with the Pulmonary Allergy Advisory Committee on

6    last May 11 for the OTC indication of allergic rhinitis.

7     The majority of the Joint Advisory Committee concluded

8    that Loratadine in 10 milligram daily doses is safe for

9    OTC use in allergic rhinitis.

10                     Therefore, the focus of this meeting today

11   is to consider Loratadine for treating the symptoms of

12   chronic        idiopathic   urticaria      as     an   OTC   indication

13   following an initial physician diagnosis.

14                     Schering's presentation this morning will

15   follow the outline shown here.                 Following my overview,

16   Doctor Eugene Monroe, a practicing dermatologist with

17   Advanced Health Care in Milwaukee and Assistant Clinical

18   Professor of Dermatology at Medical College of Wisconsin,

19   will present a brief overview of urticaria including the

20   current standards in the diagnosis and treatment.

21                     Mr. Stephen Neuman of Schering will then

22   present the results of four new studies conducted by



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1    Schering       which     provide    strong       evidence     on     the

2    appropriateness of CIU as an OTC indication.

3                     This will be followed by a risk benefit

4    analysis of Claritin OTC for this indication and our

5    conclusions and recommendations.               At that point, we'll

6    be pleased to respond to any questions you may have.

7                     In arriving at the conclusion that CIU is

8    an appropriate OTC indication for Loratadine, Schering

9    has completed several analyses and studies.                 First, we

10   undertook an in-depth review of the condition and the

11   current standards and practices of management.                     This

12   included       medical    literature      as    well   as     practice

13   parameters.       We've also conducted four new studies to

14   evaluate patient and physician habits and practices in

15   CIU, the ability of consumers to self-recognize recurring

16   episodes of CIU following initial physician diagnosis

17   and a label comprehension study of draft OTC labeling

18   for this indication.

19                    We completed an in-depth review of the safety

20   profile of Claritin from clinical trial data as well as

21   the world-wide marketing experience for both allergic

22   rhinitis and CIU and the broad experience with Claritin



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1    OTC for skin allergies.         We also reviewed poison center

2    data.

3                      And lastly but importantly, we reviewed these

4    findings with a panel of experts in allergy, dermatology

5    and     anaphylaxis       to    gain          their   insights       and

6    recommendations on the appropriateness of the pero

7    switch.        This panel included Doctor Randy Jewel, Doctor

8    Ron Simon, Doctor Philip Lieberman, Doctor Richard

9    Aarons, and Doctor Eugene Monroe, who's with us today.

10                     I'd like to summarize the most significant

11   findings from these efforts.           First, we learned that CIU

12   is a medical condition that is generally not associated

13   or confused with more serious conditions.               Secondly, we

14   also learned that through the use of OTC antihistamines

15   and/or multiple prescription refills CIU is currently

16   managed as a self-treated condition.

17                     We found that CIU patients and physicians

18   alike     are     comfortable   with     consumers'      ability      to

19   accurately self-recognize recurring outbreaks of CIU

20   which was confirmed through a self-recognition study.

21                     As you will hear from our study results, 62

22   percent of CIU sufferers surveyed reported they used OTC



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1    antihistamines for their hives prior to seeking medical

2    diagnosis.         So   consumers    already    self-treat     their

3    urticaria symptoms with OTC antihistamines without the

4    benefit of labeling for this use.

5                      And focusing on the drug Loratadine, through

6    an analysis of our adverse event database as well as poison

7    center data, we confirmed that Claritin has an extremely

8    safe record of use and provides a strong risk benefit

9    and we confirmed that adequate labeling can be developed

10   for Claritin for safe and effective use for OTC following

11   an initial physician diagnosis.

12                     I would now like to introduce Doctor Eugene

13   Monroe.        Doctor Monroe is a practicing dermatologist at

14   Advanced Health Care and assistant clinical professor

15   of dermatology at the Medical College of Wisconsin.

16   In addition to his medical practice and teaching, Doctor

17   Monroe has a distinguished research career with numerous

18   publications concerning urticaria.             Doctor Monroe.

19                     DR. MONROE:    Thank you and I would like to

20   thank the committee for the opportunity to speak before

21   you today.       The presentation I'm going to present today

22   has two major objectives.         First, I would like to present



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1    an overview of urticaria or hives with an emphasis on

2    the classification of this condition, the diagnostic

3    evaluation, and the management of urticaria and secondly,

4    I would like to try to answer the question what, if any,

5    potential consequences could arise if a patient or a

6    consumer misdiagnoses or confuses another condition for

7    chronic idiopathic urticaria.

8                   Urticaria or hives is a skin reaction pattern

9    characterized by transient, pruritic, edematous, lightly

10   erythematous papules or wheals that frequently have

11   central clearing.     To the patient, urticaria is a very

12   itchy bothersome condition and also embarrassing with

13   raised visible wheals.       It has a significant negative

14   impact no quality of life affecting the patients' ability

15   to sleep or their daily activities.

16                  Urticaria is basically classified as acute

17   or chronic.    Acute urticaria has a duration ranging from

18   a few days to a few weeks.    Its incidence is approximately

19   15 to 20 percent of the general population.    The ideology

20   of acute urticaria is usually detectable and most cases

21   are mild and are never seen by the physician.

22                  Chronic urticaria is arbitrarily defined as



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1    an episode of urticaria whose duration is greater than

2    six weeks.       It can range from a continuous problem

3    occurring almost daily to a recurring problem where there

4    may be symptom-free periods from days to many weeks.

5    The course is variable from months to years.                       The

6    incidence in the general population is up to three

7    percent.

8                    The etiology of chronic urticaria, unlike

9    acute urticaria, is not found in 90 to 95 percent of cases

10   and, therefore, most patients with urticaria of a chronic

11   nature have chronic idiopathic urticaria meaning that

12   the cause is unknown or not determined.

13                   The potential causes of urticaria or hives

14   is quite extensive.     The most common causes, particularly

15   for acute urticaria, are drugs.             Some of the common ones

16   would      be    the   penicillins,           the    NSAIDs,       the

17   anti-hypertensives.       Foods are another common cause.

18   This may be the food itself or an additive to the food.

19    Infections that are systemic, -- viral, bacterial,

20   fungal can also underlie urticaria.

21                   There are multiple other causes that are much

22   less frequent as a source, psychogenic factors, physical



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1    agents, inhalants, contactants, genetic factors and

2    internal diseases.          I would mention under internal

3    diseases that some of the potentially more serious

4    conditions     such   as    connective        tissue    diseases      or

5    vasculitis are probably underlying causes in less than

6    one or two percent of the cases.

7                   In making a diagnosis of chronic idiopathic

8    urticaria, the most important diagnostic test is a

9    thorough detailed history by the physician.             This history

10   would focus on a thorough review of systems and a very

11   thorough review of all the potential causes of urticaria

12   that I listed on the previous slide.                      A physical

13   examination is also important to detect any underlying

14   problems.      Laboratory and diagnostic tests are only

15   ordered based on clues that would be obtained from that

16   thorough history and physical examination.                     Chronic

17   idiopathic urticaria is a diagnosis of exclusion made

18   by the physician.

19                  I would now like to address the current

20   standards of care for managing urticaria.                In cases of

21   acute urticaria, the first critical part of the work-up

22   is to eliminate or reduce an underlying cause since in



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1    the vast majority of these cases a cause can be identified.

2

3                   Patient education is very important.            One

4    wants to review with the patient the natural course of

5    the disease and possible ideologies underlying the

6    condition.     It is also important to discuss possible

7    complications and associated conditions and what actions

8    might be appropriate to deal with those situations.

9                   The drug therapy for acute urticaria centers

10   around the use of H1 antihistamines, preferably the

11   non-sedating class.

12                  The   management      of    chronic   idiopathic

13   urticaria assumes that an evaluation has already been

14   made by the physician to rule out an underlying etiology.

15    The first step in the management approach would be to

16   reduce or avoid any of the non-specific aggravating

17   factors that often cause vasal dilatation.           These would

18   be things like stress, physical exertion, alcohol,

19   exercise, aspirin, etcetera.

20                  Patient education is very important again

21   in alerting the patient to the natural course of the

22   disease and possible underlying etiologies and again the



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1    patient        should    be     thoroughly         informed    of    possible

2    complications and appropriate actions to take.

3                      The    major      maintenance        of   patients       with

4    chronic idiopathic urticaria centers around drug therapy.

5     I would like to briefly summarize what I would consider

6    the   treatment         algorithm       for    patients       with    chronic

7    idiopathic urticaria.

8                      The standard of care and the first line of

9    therapy is the use of H1 antihistamines with again the

10   non-sedating class being preferred.                           Sometimes the

11   monotherapy with an H1 antihistamine is insufficient to

12   control the problem and, therefore, other medications

13   are   sometimes         added    for    symptomatic         relief    of    the

14   condition.        These would include other H1 antihistamines,

15   H2 receptor blockers, inhibitors of other mediators such

16   as    leukotriene        antagonists          or     inhibitors       of    the

17   inflammatory and cellular reaction which is also part

18   of the urticarial reaction.

19                     Urticaria presents a spectrum of patients.

20    The spectrum involves the severity of the condition which

21   ranges from a very mild to a more serious form.                            Most

22   of the patients with acute urticaria have a mild form



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1    of this disease.     Most patients with chronic urticaria

2    have a mild to moderate condition and then a small subset

3    have a much more severe refractory condition.

4                   The spectrum of urticaria patients also

5    involves the amount of participation and involvement and

6    interaction that occurs between the patient and the

7    physician.     In acute urticaria, as I stated earlier, most

8    of these patients never even consult with a physician.

9     In chronic urticaria, for the majority of cases that

10   are mild to moderate, patients often self-manage this

11   condition after an initial physician diagnosis and have

12   subsequently infrequent physician contact.      The smaller

13   subset of more severe refractory chronic urticaria

14   patients require active physician involvement.

15                  The treatment of the spectrum of urticaria

16   patients centers around the same common theme, the use

17   of H1 antihistamines.

18                  I would now like to turn our attention to

19   the possible question of what would happen in potential

20   situations where a patient or a consumer confuses or

21   misdiagnoses another condition for chronic idiopathic

22   urticaria.     What, if any, are the potential consequences



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1    if he or she then self-treats the condition with a

2    non-sedating over-the-counter antihistamine?             To put

3    these situations in context, it is important to recognize

4    what occurs in today's health care environment.

5                   I want to focus on those conditions that would

6    most likely be confused or misdiagnosed as chronic

7    idiopathic urticaria.        That would include acute or

8    chronic urticaria.      It would include the category of

9    eczema and dermatitis such as contact dermatitis and it

10   would include the condition of angioedema.           There are

11   other conditions where potential misdiagnosis may occur

12   which are rare or much less frequent such as anaphylaxis,

13   and I'll briefly discuss those later as well.

14                  Let's look first at the condition of acute

15   urticaria.     The vast majority of cases of acute urticaria

16   are mild and self-limiting.          An appropriate treatment

17   for acute hives is an antihistamine, as I stated earlier.

18    So the conclusion here is that there are no serious

19   clinical concerns or consequences if a person would take

20   an antihistamine for acute urticaria because that's the

21   appropriate thing to do.

22                  Let's look at chronic urticaria.     As I stated



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1    earlier, approximately five to 10 percent of patients

2    with chronic urticaria have an identifiable underlying

3    cause.     The consequences of confusing chronic urticaria

4    from chronic idiopathic urticaria are that there is a

5    delay in diagnosing the underlying condition which may

6    have alternative treatments.        The concern is not serious

7    because these patients will usually be driven to the

8    physician due to the severity and persistence of their

9    itching, the failure of their underlying urticaria to

10   respond to self-treatment, or the presence of other signs

11   and symptoms that might suggest a more serious underlying

12   condition.     These might include things such as joint

13   pain, fever, discoloration of the hives, etcetera.

14                  There   are   many   itchy    rashes   which    the

15   consumer might confuse with hives.          Some of these would

16   include eczema, contact dermatitis, etcetera.                  The

17   symptoms of itch in these cases might be helped by the

18   antihistamine but other treatment such as the use of

19   topical cortico-steroids might be required to treat the

20   rash.     While the potential for delay in diagnosis and

21   initiation of more appropriate therapy exists, this delay

22   will cause no serious clinical concern or consequence



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1    because, again, these patients will usually seek a

2    physician's care when the symptoms or severity of the

3    condition persists and fails to respond to the treatment

4    initiated.

5                     Angioedema is another condition that I want

6    to   briefly     mention.       Angioedema        and      urticaria     can

7    co-exist       approximately     40   percent         of   the    time   and

8    sometimes can be confused with each other.                       Angioedema

9    would be defined as giant hives or hives involving mucous

10   membranes and tissues around the eyes, lips, or genitalia.

11    There is a subset of individuals who can also develop

12   laryngeal or oral angioedema, but this is a very rare

13   situation in chronic urticaria.

14                    Histologically,        angioedema         involves       the

15   deeper layers of the skin than urticaria and very often

16   the angioedema lesions are not pruritic.

17                    Although      visually        more    noticeable        than

18   urticaria, angioedema presents no additional serious

19   consequences to the patient if the diagnosis of angioedema

20   is confused with urticaria.             In general, there are no

21   differences       with   the    clinical        treatment        of   these

22   conditions which often coexist.



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1                         An area of potential concern in the acute

2    setting relates to the rare situation in which acute

3    urticaria is the presenting symptom of an anaphylactic

4    reaction.           Anaphylaxis would be defined as an immediate

5    systemic allergic reaction produced by the                  release of

6    mediators from the mass cell or the basophil.               This would

7    simultaneously involve skin manifestations, hives being

8    present in about 90 percent of these cases, but it would

9    also involve other systemic manifestations.                      If the

10   respiratory system is involved, one would have dyspnea

11   and wheezing.          If the cardiovascular system is involved,

12   dizziness, syncope and hypotension may be present and

13   if the GI system is involved, nausea, vomiting and

14   diarrhea may occur.               The incidents of anaphylaxis is

15   rare.

16                        Chronic urticaria is not associated with nor

17   is it a risk factor for the development of anaphylaxis.

18    Acute     urticaria         is    an   associated      symptom      with

19   anaphylaxis           but   the    rapid    simultaneous     onset     of

20   cardiovascular or respiratory symptoms will cause the

21   patient        to    seek   immediate      medical   attention.       The

22   respiratory and cardiovascular symptoms most always occur



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1    within 30 minutes of the presentation of the hives.

2                   I'd like to make the following conclusions.

3     The cardinal features of urticaria, whether acute or

4    chronic, are cutaneous wheals, redness and itching.                    The

5    diagnosis of chronic idiopathic urticaria is a diagnosis

6    of exclusion made by the physician.                 The consequences

7    of patient misdiagnosis represents a very low safety risk.

8                   The    availability      of     an   over-the-counter

9    non-sedating H1 antihistamine in chronic idiopathic

10   urticaria would represent a significant benefit to the

11   patient or consumer in two ways.             It would provide better

12   safety than exists with the current over-the-counter

13   antihistamines and it would create an opportunity for

14   better care through labeling and patient education.

15                  Thank you and at this time I would like to

16   introduce Mr. Stephen Neuman who will present the findings

17   of the Schering chronic idiopathic urticaria studies.

18                  MR. NEUMAN:     Thank you, Doctor Monroe.              Good

19   morning, Doctor Cantilena and members of the committee.

20    My name is Steve Neuman and I'm here today to present

21   the results of four studies that we conducted to better

22   understand     both    patient    and        physician     habits      and



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1    practices around CIU.

2                    We sponsored four studies on CIU.             Many of

3    these were standard studies which would be used to support

4    the switch of a drug of this safety profile.               The first

5    was a study among 388 patients who have received a prior

6    physician diagnosis for CIU. The goals of this study were

7    to really understand the fundamental dynamics of the

8    condition such as duration of suffering, the symptoms

9    that    are    suffered,    patient      interaction    with     their

10   physician, and the modalities and treatment methods that

11   are used to manage the disorder.

12                   We   also    commissioned      a   study     among        a

13   representative physician specialties that treat CIU to

14   understand and practice behaviors and perceptions from

15   a physician viewpoint.         We conducted a study to determine

16   if consumers that had been diagnosed by a physician as

17   having CIU can accurately self-recognize the condition

18   and the symptoms upon recurrence.                  And finally, we

19   conducted a label comprehension study.

20                   One of the key points that I hope you take

21   away from my presentation this morning is the remarkable

22   consistency and findings from these studies, particularly



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1    with regard to the patient's ability to self-recognize

2    CIU upon recurrence of symptoms.

3                      Let's   begin      with       the   consumer      study.

4    Members of a large Internet panel were sent an email

5    questionnaire to help identify physician-diagnosed CIU

6    sufferers.        The question that was posed to them was have

7    you ever been diagnosed by a medical doctor as having

8    chronic or recurrent hives that have no known discernible

9    cause, also known as chronic idiopathic urticaria?

10                     A random sample was drawn from among those

11   who responded to the question, and they were sent an email

12   that asked them to log onto a website where they completed

13   a more detailed questionnaire.                  Importantly, when they

14   logged         on,    they      were        rescreened        to      have

15   physician-diagnosed CIU.

16                     A concern might exist that these respondents

17   were not actually CIU sufferers and, in fact, FDA has

18   raised that concern in their briefing book to you.                     This

19   is unlikely, I think, due to the fact that the literature

20   on consumer research supports that most respondents

21   provide        accurate   responses      to      survey   questions      on

22   personal health unless the topic is a sensitive health



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1    issue.     And also, the study remuneration here had a very

2    nominal $8 - $10 value that would be unlikely to attract

3    false claimants in great numbers.                     And perhaps as

4    important is that the approach to the subject validation

5    used in this study is consistent with what's used in many

6    label comprehension studies.

7                         The study population here was representative

8    of the random sample that was drawn from the larger CIU

9    pool.          The    demographic    profile     of   this   group    was

10   consistent with that which has been reported in the

11   literature with CIU.           That is, being female and age 40

12   to 60.    I would also point out that it's consistent with

13   the demographics that are reported in the integrated

14   summary of efficacy section of the CIU clinical study

15   provided by FDA in their briefing book to the committee.

16                        I'll speak about the design now.                 The

17   questions that were asked consisted primarily of a

18   variation of closed end or multiple choice type questions.

19    However, subjects could type in responses whenever list

20   did not meet their needs and all of the questions

21   pertaining to important patient behaviors had this option

22   available to them.           To further minimize the impact or



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1    bias in the presentation of these lists, the items in

2    the list were randomly rotated.

3                   In their briefing book, FDA took issue with

4    the use of closed ended questions in this study and while

5    certainly open ended questions do have a role, the

6    modified closed ended questions used in a study of this

7    type are commonly employed and they offer a number of

8    advantages to us.    The first is that they're a good choice

9    when options are limited and responses can be anticipated

10   for questions such as where did the wheals occur, what

11   was the length of suffering, items like that.

12                  They also permit a direct comparison of

13   response from subject to subject.              They help address the

14   issue that most respondents will not write elaborate

15   answers,       particularly     in         a      self-administered

16   questionnaire.      And they avoid issues with having the

17   interviewer not carefully record or misinterpret what

18   the subject is saying and they can avoid the errors that

19   are associated with coding or categorization of responses

20   on the back end as well.

21                  What I'd like to do now is move into the

22   findings of the study.        The way I'm going to approach



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1    this is for each finding I'm going to show the question

2    that was asked and then I'll report the results as well

3    as draw a conclusion.

4                     The first question that was ask is in a

5    typical year, how many episodes of chronic hives do you

6    experience?           Two-thirds,     66    percent   of     sufferers,

7    experienced three or more outbreaks each year and the

8    mean number of outbreaks for the study population is

9    three.         This    results   in    a   sufferer   base     who   are

10   experienced, frequent sufferers making CIU a recognizable

11   condition, and this ability to self-recognize CIU will

12   be confirmed, as I mentioned earlier, in several of the

13   studies that I'm presenting today.

14                    We also asked, please indicate the symptoms

15   you experience when your hives recur.                   The symptoms

16   of hives are quit discreet with nine in 10 naming itching

17   as a symptom.         Hives, wheals, redness, rash also received

18   high    level    of     mentions    as     key   symptoms.     There's

19   significant       consistency       in     the   symptoms    that    are

20   described by CIU sufferers and, as Doctor Monroe discussed

21   in his section, the key symptom of itching is quite intense

22   and highly bothersome to patients.



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1                     It's also noteworthy that symptoms that could

2    be confused with the most threatening manifestations of

3    anaphylaxis such as breathing problems are rare.

4                     An important question that produced key

5    insights for us was thinking about when the hives appeared

6    prior to seeing a physician, what, if anything, did you

7    do to treat or relieve the condition?                   The question

8    context here is again prior to diagnosis of CIU.

9                     While OTC antihistamines in the U.S. are not

10   currently labeled to treat symptoms of CIU, the study

11   subjects often used antihistamines to self-treat hives

12   prior to consulting a physician for diagnosis.                    Nearly

13   two-thirds, 62 percent of patients who've been diagnosed

14   by a physician as having CIU took an OTC antihistamine

15   for their hives prior to physician diagnosis.                   I point

16   out also that the use of OTC topicals is also a prevalent

17   first    step.         So   we   can    conclude     from    this   that

18   self-medication prior to physician diagnosis is common

19   behavior and OTCs are commonly used.

20                    One    question       that     we   asked   regarding

21   physician contact is, in the past year, how often have

22   you seen a physician for this condition?                 One-third of



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1    patients, 33 percent, have not seen a physician for CIU

2    within the past year and nearly 20 percent have not seen

3    a physician since their initial diagnosis.             Thus, many

4    patients are not under the continual care of a physician

5    for CIU.

6                   To   understand      typical      behavior       upon

7    recurrence we asked, when your chronic hives recur, please

8    indicate what you normally do.             Over half, 52 percent

9    of the subjects, indicate use of a prescribed medication

10   already on hand.    Just over four in 10, 43 percent, use

11   an OTC medication and 20 percent indicate that they call

12   their doctor.

13                  So we see that self-management with both

14   prescription and OTCs are common behavior.             Looking at

15   this in more detail, particularly at the 20 percent of

16   subjects who typically don't call or visit their doctor

17   when their hives recur, seven percent do so when their

18   symptoms don't respond and another two percent make

19   contact when more serious symptoms occur.

20                  Hence, we would conclude or to summarize,

21   most physician contact comes about when symptoms don't

22   respond or when more serious symptoms occur.



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1                   Another important question for us was now

2    that your condition has been diagnosed by a physician,

3    how easy is it for you to identify this condition when

4    it reappears? Once diagnosed by a physician as having

5    CIU, 80 percent of study subjects felt that it was very

6    easy to identify the condition when it recurs and 94

7    percent felt that it was very or somewhat easy.            No

8    respondents felt that it was difficult to identify the

9    condition upon recurrence.

10                  Finally we asked, what would you do if you

11   experienced other symptoms such as difficulty breathing,

12   fever or trouble swallowing with your hives?        Over 95

13   percent of the study subjects indicate that they would

14   seek medical care or call or visit their physician.

15   Importantly, this response is without the benefit of

16   labeling to direct them to an appropriate action.

17                  In their briefing book, FDA indicated that

18   it's not clear whether those subjects who would call or

19   visit a physician would act with a sense of urgency and

20   suggested that a follow-up question on timing would have

21   been helpful.     I think while this question might have

22   clarified the results here, I would draw attention to



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1    the finding that 55 percent of respondents indicated that

2    they would seek emergency care which implies immediacy.

3     The agency also pointed this out in their discussion

4    of the studies as well.

5                     So to draw conclusions from the consumer

6    study.     First, consumers appear comfortable that based

7    on the frequency of suffering and the discrete symptoms,

8    recurrent episodes of CIU are easy to recognize.                        Once

9    diagnosed by a physician, CIU is largely self-managed

10   and most patients are not under continual care.

11                    Importantly,           treatment             with        OTC

12   antihistamines prior to physician diagnosis is common

13   behavior       today   and   consumers          know   to   seek     medical

14   attention if serious symptoms occur.

15                    Now I would like to focus our attention on

16   the study that we conducted among physicians who regularly

17   see patients with CIU to help better understand the

18   practices among those physicians.                 This sample was drawn

19   from a pool of physicians with Internet access, and the

20   pool     was     comprised        of   over       200,000       physicians

21   representing       over      40    percent        of    AMA     registered

22   physicians.



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1                    The panel was pre-screened as to specialty

2    and treatment of patients suffering CIU and a longer,

3    more detailed survey was conducted among the sample of

4    the screened physicians.        The sample was representative

5    of and projectable to the universe of office-based

6    physicians with Internet access, which is 96 percent of

7    the physicians in the specialties that we studied, and

8    the sample reflected the primary CIU treatment groups

9    of     PCPs    defined   here   as     internists    and     FP-GPs,

10   dermatologists,      allergists      and     pediatricians      which

11   incidentally,      according    to    an     independent    tracking

12   service of office visits, accounts for 89 percent of the

13   office visits for chronic hives.             The ending sample was

14   359.

15                   The first question we asked physicians, what

16   terminology do you typically use when explaining the

17   initial diagnosis to your patients?           Chronic or recurring

18   hives are the most prevalent descriptors used by nearly

19   75 percent of physicians for CIU.             This information was

20   a source of learning that helped us with labeling which

21   we later tested in a label comprehension study and I'll

22   review it with you.



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1                   After   receiving     a      diagnosis   of   chronic

2    idiopathic urticaria from a physician, how likely do you

3    feel that a sufferer is able to self-identify or recognize

4    recurrent episodes of the condition?             This question is

5    very similar to the one that was asked of the consumers.

6     Ninety six percent of the physicians believed that it

7    is either very or somewhat likely that their patients

8    can recognize a recurrence.         Six in every 10 physicians

9    believed that it's very likely that a recurrence can be

10   recognized.    Again, this level is extremely comparable

11   to that which we saw in a    similar question in the consumer

12   study.

13                  Another question was, thinking of all the

14   patients you have counseled for chronic idiopathic

15   urticaria, what percentage do you recommend keep a

16   medicine on hand in anticipation of a recurrent episode?

17    Counseling at least some CIU patients to keep medications

18   on hand in case of outbreak of hives is nearly universal

19   behavior and interestingly, just under 60 percent of

20   physicians counsel all of their previously diagnosed CIU

21   patients to keep medications on hand in case of an

22   outbreak.      Hence, the physician behavior encourages



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1    self-management.

2                      So     what      can     we      conclude      from     this

3    representative and projectable study among physicians

4    first?     Physicians appear aligned in the terminology they

5    use to describe CIU patients, either chronic hives or

6    recurrent hives.          Like the 94 percent of consumers who

7    believe        that    recurrent      episodes       of   CIU    are    easily

8    self-recognized, a similar proportion, 96 percent, of

9    physicians believe that once diagnosed, it's likely that

10   patients can self-recognize recurrent outbreaks.

11                     Finally,          physician         prescribing           and

12   recommending            behavior         reinforces        CIU         patient

13   self-management.

14                     Now I'd like to direct our attention to a

15   study    of     consumers'        ability       to   self-recognize         the

16   condition of CIU upon recurrence.                         This study was

17   conducted in conjunction with a label comprehension

18   study. A key focus of the study was to understand whether

19   consumers who have been diagnosed by a physician as having

20   CIU can accurately self-recognize the condition and the

21   symptoms upon recurrence.

22                     The design of this study permitted all



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1    comers, that is anyone who believes they've been diagnosed

2    by   a   physician          with   CIU,   to      come    forward      and   to

3    participate.         The ending sample was 196 CIU sufferers.

4     CIU patients were recruited from 21 regionally dispersed

5    cities and the patients were required to bring the name

6    and telephone number of the doctor that diagnosed them.

7     This brings greater credibility to the fact that all

8    the enrollees were CIU sufferers.

9                        The subjects that were enrolled in the study,

10   first of all, had a medical history taken along with a

11   photograph of their lesions if they were suffering and

12   willing to be photographed.               The patients who were not

13   suffering      or     refused      photographic          consent    reviewed

14   alternative textbook type photos of lesions and selected

15   the one that looked the most like theirs.

16                       These    materials      were    then     sent      to    and

17   reviewed       by    the     investigating        physician      who    asked

18   additional questions via teleconference with the patient

19   and then the physician investigator and overseeing

20   dermatologist          reviewed     all     of     the    information        to

21   determine if the subject had accurately self-recognized

22   their condition as CIU.             Nearly all, 94 percent, of the



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1    subjects who believed they had CIU actually did have the

2    condition.

3                    So    what     can     we       conclude     from     this?

4    Previously      diagnosed       CIU     patients      can      accurately

5    self-recognize the symptoms and the condition upon

6    recurrence and this is consistent again with the findings

7    of both the consumer and the physician studies.

8                    We also conducted a label comprehension

9    study.     This was an all comer study to understand the

10   consumer's ability to comprehend specific communications

11   points on the draft labeling.               There were five cohorts

12   in this study.       There was a cohort of 196 CIU sufferers.

13    There    was   a    cohort    representative         of    the     general

14   population.     There was a cohort of individuals screened

15   to read at a maximum 7th - 8th grade level.                     There was

16   a cohort of patients for whom the labeling for Claritin

17   was contraindicated.           That is, those who were either

18   nursing or breast feeding or had liver or kidney disease.

19    And a cohort of acute hive sufferers who, according to

20   the label, should not use the product.                Please note that

21   the number of subjects here in each cohort does not add

22   up to 565 as subjects count toward more than one cohort.



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1                   The study method here was the CIU cohort was

2    recruited via advertising and the other cohorts were

3    recruited via mall intercepts and intercepts at special

4    locations      for   the    enriched          populations.       Label

5    comprehension was assessed by asking both direct and

6    scenario-based questions and self-selection was assessed

7    by posing a question to determine if consumers understood

8    that they personally could use Claritin.

9                   In response to the scenarios that were

10   presented, consumers in all of the cohorts demonstrated

11   a strong understanding of the general warnings and that

12   Claritin should not be used in situations where serious

13   symptoms are present.       Either responses that were correct

14   such as "do not take the product" or those that were

15   acceptable such as "I would ask my doctor before using"

16   were mentioned by between 75 and 96 percent depending

17   on the cohort.

18                  Similarly, there was strong understanding

19   of who can and can not use Claritin.                The correct and

20   acceptable levels here were in the range of 75 to 99

21   percent.

22                  End of condition such as pregnancy or liver



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1    disease under which one must ask a doctor before use.

2    The correct and acceptable levels here are in the range

3    94 to 100 percent and of conditions under which the product

4    should be used correct and acceptable levels, 95 to 100

5    percent.       These responses, taken with the information

6    from the consumer study, that 95 percent of subjects will

7    seek medical attention if serious symptoms are present

8    supports the perspective that labeling can be developed

9    to adequately convey the warnings and an understanding

10   not to use the product if serious symptoms occur.

11                   Response among the CIU sufferers to the

12   scenarios and to the questions was particularly strong

13   with responses ranging from 91 to 99 percent providing

14   either correct or acceptable responses to these questions

15   and CIU patients also universally demonstrate appropriate

16   self-selection for personal use.

17                   A majority of the acute hives cohort, 54

18   percent, correctly de-selected the product for personal

19   use.    I'd like to note that the principal display panel

20   of the package labeling that we tested stated that

21   Claritin, quote, "relieves and reduces itching and rash

22   due to chronic and recurring hives."         Unquote.       We



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1    believe this inclusion of broader symptom descriptors

2    likely led to more acute hive sufferers believing that

3    the product is for their use.

4                    In response to a separate scenario question

5    that asked, what should be done in a situation in which

6    an outbreak of acute hives has occurred, 75 percent of

7    the acute hives cohort correctly comprehended that the

8    product should not be used.         This level of self-selection

9    and comprehension leads us to believe that labeling can

10   be improved.

11                   Turning    out     attention   to   the     general

12   population, seven in 10 members of the general population

13   cohort provided a correct or an acceptable response, i.e.,

14   do not use, ask a doctor before use, to the personal use

15   question.      We believe that this level can be strengthened

16   even more with revised labeling.

17                   So   our   conclusions.        Reaction     to    the

18   scenarios across the cohorts demonstrates understanding

19   of general warning situations in which Claritin should

20   and should not be used and the directions for us.

21                   Results of the self-selection and personal

22   use question reveal that the majority of the general



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1    population can appropriately self-select the product for

2    use.

3                   Over half, 54 percent, of the acute hives

4    cohort indicated that they would not use the product when

5    asked a question about personal use and the response to

6    the scenarios underscores that this study population

7    understands the warnings.

8                   These encouraging results were achieved with

9    draft labeling that would benefit from refinement, and

10   we are committed to work with FDA to refine the labeling

11   and improve comprehension among these consumers.

12                  Based on responses to both the self-selection

13   question and to the scenarios, consumers with a physician

14   diagnosis of CIU understand that Claritin is appropriate

15   for their use and are likely to use it correctly.              These

16   findings are again aligned with what we have learned in

17   the other studies.

18                  I would like to ask Doctor Clayton to return

19   and complete our presentation.             Thank you.

20                  DR. CLAYTON:    I would now like to turn the

21   focus to risk benefit analysis for Claritin for OTC

22   treatment of CIU.      As I mentioned at the outset, the



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1    safety of Claritin was reviewed with this committee by

2    FDA last May.       FDA's analysis included experience in

3    allergic rhinitis patients as well as CIU patients.       This

4    analysis was included in the Schering briefing book that

5    FDA provided to you.

6                    This morning I'd like to highlight the

7    significant additional world-wide marketing experience

8    on Loratadine and CIU and other skin allergies which also

9    supports OTC status.      We believe that the risk benefit

10   analysis strongly supports a CIU indication for Claritin

11   OTC which is similar to allergic rhinitis.

12                   As you're well aware, Claritin is not a new

13   drug.     It has enjoyed world-wide marketing experience

14   in just over 14 years since its initial launch in Belgium

15   in 1988.       While Claritin has ultimately been approved

16   in a total of 114 countries, it is especially important

17   to today's discussion that it has been approved OTC in

18   some 33 countries including Canada since 1990 and the

19   UK since 1993.      It is important also that most of these

20   OTC approvals have included indications beyond chronic

21   idiopathic urticaria including urticaria or skin itching

22   and hives.      Hence, our adverse experience database on



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1    these products covers even broader use experience than

2    CIU alone.

3                      Claritin has been marketed by prescription

4    for CIU in the U.S. since 1995 following its initial launch

5    for allergic rhinitis in 1993.                 World-wide patient

6    exposure to Claritin has been substantial totalling

7    approximately 14 billion patients days since its initial

8    commercial launch.         Almost half of that exposure has been

9    within the U.S.         Based on an average treatment regimen

10   of 30 days, this represents 457 million courses of

11   therapy.         With this extensive patient exposure, we

12   believe we have a clear indication of the safety of this

13   drug.      Our analysis of our internal database as well as

14   that of poison control centers shows that Claritin has

15   an excellent safety profile with only two adverse event

16   reports per 100,000 courses of treatment.

17                     Serious adverse events are rare and important

18   to OTC consideration, Claritin is not a drug of abuse.

19    It   is       also   important   to   note    that   adverse    event

20   experience in CIU has not shown any event signals

21   different than those reported in allergic rhinitis.

22                     As I mentioned, we've also received poison



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1    center data from the toxics exposure surveillance system

2    database for the past five years and confirmed no new

3    adverse event signals in this base and no new medical

4    issues from that in the Claritin database.

5                   Further testing to the safety of Claritin

6    for OTC CIU.    The Schering database includes significant

7    OTC experience from 33 countries where Claritin has been

8    sold OTC and in most the OTC indications include skin

9    allergies, urticaria, hives, and skin itching.

10                  Looking    specifically        at   two   of    these

11   countries which have had the most significant OTC exposure

12   and where the labeled indications include hives and

13   allergic skin conditions, the marketing experience in

14   Canada and the U.K. include over 38 million patient days

15   of exposure.        These data demonstrate that the safety

16   profile of Claritin OTC is very similar to the extensive

17   world-wide prescription experience and the CIU experience

18   is similar to the allergic rhinitis experience.

19                  To    summarize,    the      extensive    world-wide

20   experience with Claritin supports the appropriateness

21   of this drug for OTC use based on both Rx experience for

22   CIU as well as OTC experience for hives.



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1                    In examining the benefits of OTC availability

2    of Claritin with CIU labeling, our research showed that

3    the current practices and standards of care by physicians

4    and patients treats CIU as a self-managed condition

5    following initial physician diagnosis.            Through multiple

6    refills of prescription drugs, primarily non-sedating

7    antihistamines,       the      combination      of     non-sedating

8    antihistamines and current OTC medications and the lack

9    of continual physician care indicate that with the limited

10   physician oversight that this is a self-managed condition

11   largely.

12                   Secondly, consumers already self-treat with

13   sedating OTC antihistamines despite the lack of label

14   indications for this use.              A safe OTC product which

15   provides       appropriate        directions,     warnings,         and

16   precautions as well as education for proper use including

17   when to see a physician, will provide a significant

18   benefit.

19                   CIU patients who physicians and patients

20   alike      acknowledge      can      accurately      self-recognize

21   recurrent outbreaks should have ready access to first

22   line non-sedating therapy as needed to relieve their



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1    symptoms.

2                   Making    a    first        line,    non-sedating

3    antihistamine available OTC with proper labeling and

4    patient education as proposed by Schering will be a

5    benefit to public health.       Based on these facts and the

6    current significant use of prescription Claritin for CIU

7    in the U.S., we believe it would be inappropriate to switch

8    Claritin OTC without labeling for this indication.

9    Otherwise, we will continue to facilitate off label use

10   of OTC antihistamines for urticaria.

11                  In sum, we conclude the risk of OTC indication

12   of CIU for Claritin is low and the benefit to public health

13   is significant.      In addition to easily understandable

14   OTC labeling, Schering is committed to consumer education

15   programs to better educate CIU sufferers as to proper

16   care for their disease.         While the specifics of the

17   program have not been finalized, we expect to include

18   education on allergic rhinitis as well as CIU and to focus

19   on educating about the conditions, helping the consumer

20   understand if Claritin is the appropriate drug for their

21   situation, advising when to consult their physician or

22   seek medical care and when emergency care is appropriate.



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1                     There are a number of platforms that we expect

2    to utilize in this program including Internet-based

3    information, toll free telephone, print and continuing

4    education for health professionals.

5                     In the briefing book that FDA provided to

6    you, FDA has asked the committee to address a number of

7    questions which we believe are appropriate for the

8    decision to switch Claritin for CIU in an OTC setting.

9     We believe that the answers to all of these questions

10   are supported by data presented this morning and are

11   supportive of OTC approval.

12                    First,      the     data   support        the     accurate

13   self-selection of consumers following a physician's

14   diagnosis.       Overwhelmingly, physicians and CIU sufferers

15   indicate       that   they    can    comfortably      and        accurately

16   self-recognize recurrent episodes.              Although FDA raised

17   some issues about some aspects of certain of these

18   studies, it is clear that the results are remarkably

19   consistent        across       all      studies       in         confirming

20   self-management.

21                    The self-recognition study demonstrates 94

22   percent accuracy in patient self-recognition of episodes



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1    following initial physician diagnosis.               As pointed out

2    in Schering's briefing book to the committee, there is

3    adequate precedent for the proposed approach of requiring

4    an initial physician diagnosis for OTC products including

5    the vaginal antifungals which were introduced OTC in 1991

6    and the most recent example of OTC migraine products.

7                   You will note that the label of the OTC

8    migraine products has a statement, "Ask a doctor before

9    use if you've never had migraines diagnosed by a health

10   professional."      We would propose similar wording for an

11   OTC hives indication.

12                  In   light    of    the      common    use     of    OTC

13   antihistamines for hives, OTC labeling for CIU will

14   unquestionably be a positive step forward.             We recognize

15   that there may be likely use by some of Claritin OTC by

16   acute hive sufferers.        However, we know that this is

17   occurring today with sedating antihistamines OTC without

18   benefit of any labeling to instruct the consumer how to

19   properly use the product or when to see a physician.

20                  We also acknowledge that there's a benefit

21   in use of Claritin for symptomatic relief of acute hives

22   and there's likely little increased risk in doing so.



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1    However, we believe it is more appropriate and prudent

2    as a first step to label the product solely for chronic

3    hives of an unknown source and encourage proper diagnosis

4    for all other hives sufferers.               We are, however, open

5    to continued discussions with FDA to explore broadening

6    the   indication    for   general      gives     with     appropriate

7    labeling and label comprehension testing.

8                   We believe that the OTC labeling for CIU can

9    be improved and we are working to do just that.                However,

10   the results to date clearly indicate that this can be

11   achieved.      We will work with the agency to refine the

12   labeling to make it even better than the labeling that

13   we tested.      We are strongly encouraged by the results

14   of the first study and are confident that we can accomplish

15   this.

16                  We are also committed to an unprecedented

17   consumer and health education professional program to

18   better educate both the treatment of allergic rhinitis

19   and CIU.

20                  You will be asked in you deliberations to

21   consider a number of questions by FDA.            I'd like to share

22   Schering's point of view on those questions.                       First



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1    question, is urticaria a disease process appropriate for

2    an OTC indication?           Based on a careful review of the

3    disease, standards of care and consumer and physician

4    practices and self-management, we believe the answer is

5    yes.

6                   The second question.               If yes, should the

7    indication be for chronic idiopathic urticaria or hives

8    or should it be broader such that it includes acute

9    urticaria and hives?           Our data, as we presented this

10   morning, support the indication of chronic idiopathic

11   urticaria following an initial physician diagnosis.

12                  The next question is, if your answer to

13   question one is yes, are there sufficient data to support

14   an OTC switch of Loratadine for CIU or a more general

15   urticaria claim?       We believe that the data we presented

16   this morning are sufficient to justify a switch of

17   Loratadine     for    CIU.        The    safety     and    efficacy      of

18   Loratadine     in    this    indication         along     with    the   OTC

19   international        experience       are       consistent       with   OTC

20   standards.     While we will refine the labeling for this

21   indication, we believe no additional studies beyond that

22   are necessary.



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1                      The second part of the question.                If not,

2    what other types of data are needed such as clinical

3    trials, safety, efficacy, label comprehension or actual

4    use.    As I mentioned, for CIU with an initial physician

5    diagnosis,        we     believe        no   additional   studies       are

6    necessary.        But if the committee and FDA determine that

7    a broader hives indication is warranted, we do not believe

8    additional clinical trials are warranted or necessary.

9     It is recognized that acute hives and CIU have common

10   mechanisms.           The standard of care is the same for both.

11    Efficacy is acknowledged as the first line therapy for

12   both of these is non-sedating antihistamines.

13                     In the case of Loratadine, the safety has

14   clearly        been    established        through   international       OTC

15   experience in treating hives including acute hives.

16   Further, we do not believe the actual use studies in this

17   condition are either practical to conduct or of value.

18    We believe that any questions could be answered through

19   additional label comprehension testing.

20                     The final question reads, if your answer to

21   question two is yes, what are your recommendations for

22   appropriate           labeling     of    Loratadine   with    regard     to



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1    indications, warnings and directions?                   We have provided

2    draft labeling in our NDA submission which we believe

3    provides       the    appropriate     indications,        warnings      and

4    directions.          Specifically, the use statement, relieves

5    and reduces itching and rash due to recurring or chronic

6    hives of an unknown source.            Use only after being told

7    by a doctor that you have recurring or chronic hives of

8    an unknown source.

9                     In     conclusion,     based      on    the   extremely

10   favorable risk benefit analysis and in light of the

11   current consumer/physician practices, we recommend that

12   Claritin be approved as an appropriate safe and effective

13   therapy for treating symptoms of previously diagnosed

14   chronic idiopathic urticaria in an OTC setting following

15   an initial physician diagnosis.                Our expert panel review

16   concurred with this recommendation.

17                    Although we believe this approach for OTC

18   labeling is conservative and prudent, we remain open to

19   exploring a broader hives indication through additional

20   label development validated through label comprehensive

21   studies if the advisory committee and FDA                 recommend this

22   approach.



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1                     Thank you very much for your attention this

2    morning.       My colleagues and I will be pleased to respond

3    to any questions that you may have at this time.                 Thank

4    you, Doctor Cantilena.

5                     DR. CANTILENA:      Okay.    Thank you, Doctor

6    Clayton and other members of you team.              I think we have

7    plenty of time now for questions for the sponsor.             I guess

8    you can identify who specifically of the sponsor team

9    that you're asking or just ask in general and it'll be

10   handled by Doctor Clayton.         Questions from the committee

11   members.       Doctor D'Agostino.

12                    DR. D'AGOSTINO:       My comments are dealing

13   with the particular consumer studies and the label

14   comprehension.         I'm   not     sure    from    the   way     the

15   presentation is made that these questions I think are

16   profound or needed because we keep hearing that even if

17   the consumer doesn't have the CIU but has some other type

18   of hives and what have you, you still should give

19   antihistamines and so I think a question that ultimately

20   we have to or will get to is how do you handle this whole

21   bag of conditions that antihistamines work for.

22                    I'd like to have on the record that I don't



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1    think that the consumer study and the label comprehension

2    study     are   necessarily     powerful        studies   for     the

3    comprehension that is being suggested.              I think a 70

4    percent comprehension leaves a lot to be desired and I

5    think that we may say it doesn't make a difference whether

6    the consumer understands a particular condition, he or

7    she still should be taking the drug, but 70 percent with

8    a margin of error of 10 percent is not very large so I'd

9    like to ask the company, the sponsor, to comment on why

10   you're     suggesting   70     percent     is    indicating     good

11   comprehension.

12                   DR. CLAYTON:     I think our intention there

13   was to indicate that we are encouraged that we can get

14   there to the level we would like to achieve.               As Steve

15   Neuman mentioned, the principal display panel was broader

16   probably in terms of stating what the product use was.

17    The drugs facts box that I showed you in the next to

18   last slide was a lot more specific.         We believe that the

19   labeling can be improved and our standard is higher than

20   the 70 percent, too.     We would expect to achieve that.

21                   DR. D'AGOSTINO:       I have just two other

22   questions and I'll move fast because I know that people



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1    have a lot of questions.      With the random sample and the

2    consumer study, you took a random sample and they were

3    supposedly a validation procedure where you rescreened

4    the individual.    Could you tell us how many individuals

5    were selected for the random sample and how many out of

6    those didn't actually have the CIU condition on the

7    rescreening in terms of the validation.         I'm not sure

8    I heard that number.

9                   DR. CLAYTON:    Steve, would you please come

10   forward and respond.     He's checking his notes.

11                  DR. D'AGOSTINO:     And my last question, while

12   you're fishing that out, it again may sound naive but

13   if we're saying that these potpourri of conditions can

14   be handled by antihistamines and you're focusing on the

15   CIU, I know it's in the Rx, but why aren't we hearing

16   a presentation for the broader condition?      You're telling

17   us that people are using it for broader conditions and

18   it appears to me once it goes OTC, if it goes OTC with

19   this label, physicians are going to be telling patients

20   to use it for the broader array of conditions.      Why aren't

21   we hearing the sponsor saying something in defense of

22   that as opposed to that's what you do and it's off label?



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1     Those are my three questions.

2                    DR. CLAYTON:     I can respond to that one while

3    Steve is preparing.         The prescription indication is

4    chronic idiopathic urticaria and that's what led us to

5    do    the      research   that     we        conducted       about      the

6    appropriateness for OTC use.            So that is the basis for

7    our interest in CIU and that is the research that we've

8    conducted.       So that is the area where we are most

9    comfortable that the data support OTC use and indication.

10                   I   mentioned    that        there   is     wide-spread

11   international experience OTC with a broader indication

12   and we are open to continuing to pursue that, discuss

13   that with FDA.      It's certainly not a closed door but our

14   research today most strongly supports CIU following an

15   initial physician diagnosis.

16                   DR. D'AGOSTINO:       Thank you.

17                   DR. CLAYTON:     Steve I think has the response.

18                   MR. NEUMAN:      There were 81 individuals who

19   did not suffer CIU at the re-qualification phase.

20                   DR. D'AGOSTINO:      So about 25 percent of the

21   sample --

22                   MR. NEUMAN:     The outgo was 834.           One hundred



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1    ninety two did not log in.          One individual was not 18.

2     Eighty one worked in a sensitive occupation such as

3    marketing research, advertising and so forth.               Then 81

4    did not suffer CIU at the re-qualification phase and

5    another logged on after the survey period closed.

6                   DR. D'AGOSTINO:         So 10 - 20 percent said CIU.

7                   MR. NEUMAN:       About 20 percent.

8                   DR. D'AGOSTINO:         Thank you.

9                   DR. CANTILENA:       Okay, Doctor Krenzelok.

10                  DR. KRENZELOK:          Thank you.   This question

11   is for Doctor Monroe.        The literature that we received

12   from the sponsor indicated that urticaria is often an

13   expression     of   a   number    of    very   serious   diseases,

14   urticarial vasculitis, thyroid conditions, cancer and

15   so on.    I just wondered if chronic use of something like

16   Loratadine would mask the diagnosis of some of these more

17   serious diseases and delay their treatment.

18                  DR. MONROE:       Approximately 90 to 95 percent

19   of the cases of chronic urticaria are idiopathic so the

20   percentage that have an underlying disease would be very

21   small to begin with and the more serious ones that would

22   concern me the most that are systemic in nature such as



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1    a connective tissue disease or vasculitis, I would say

2    the incidents might be less than one to two percent of

3    the total.       Those patients also should have other signs

4    and symptoms.        So for example, on the connective tissue

5    diseases, one would expect arthralges, fever, fatigue,

6    other systemic signs.        There are in urticarial vasculitis

7    signals such as the lesions persist longer.                  There are

8    some signs and symptoms that I think would lead those

9    patients to go consult the physician.

10                     So I think the concern potentially in that

11   small subset is a delay in getting to the physician but

12   I think the persistence of their condition since the

13   underlying cause for the urticaria is there and the

14   possible accompaniment of these other signs and symptoms

15   would eventually leave them with a mild delay to the

16   physician anyway.

17                     DR.   CANTILENA:       Okay.       We have Doctor

18   Szefler and then Doctor Sachs.

19                     DR. SZEFLER:        Two questions for Doctor

20   Monroe.        In treating the disease and also looking at all

21   the review articles that were provided, it was a very

22   nice    package.        I   didn't     get     any   indication     that



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1    Loratadine had a specific effect on chronic urticaria.

2     In   other     words,   if   a   physician    was    choosing      an

3    antihistamine, would they choose Loratadine over the

4    other three drugs?       Is there any reason to believe that

5    Loratadine confirms unique features in terms of drug

6    selection?      And then also the situation a physician runs

7    into is the necessity of using higher doses to treat the

8    disease.       How will the package insert or how do you

9    anticipate physicians will handle the use of higher doses

10   potentially for prolonged periods of time and is there

11   any unique feature that the physician should be concerned

12   about in the OTC application?

13                   DR. MONROE:       Your first question I think

14   centered on did Loratadine have any unique properties

15   versus you said the other three.              You mean the other

16   approved for prescription?

17                   DR. SZEFLER:      Yes.

18                   DR. MONROE:       Okay.      I believe that the

19   currently available second generation H1 antihistamines

20   are all relatively equally efficacious and the difference

21   lies that at least one of them is sedating.              So I think

22   that Loratadine doesn't offer any unique property.                  It



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1    offers an equally excellent property.

2                    The second question I think centered around

3    a concern over exceeding the currently recommended dose

4    and my answer to that would be there are anecdotal stories

5    from patients and certainly use by some physicians

6    exceeding      the   recommended    doses    of   all   the    second

7    generation antihistamines.             I am not aware of any

8    scientific study to show that doses beyond the approved

9    doses are more effective and, as a matter of fact, in

10   the initial Loratadine approval or clinical studies,

11   doses ranged from 10 to 40 in chronic urticaria and there

12   was no added efficacy beyond the 10.              So it does occur

13   in practice.     I can't support it from any scientific study

14   and I think that I'm not a labeling expert but one would

15   just deal with it in the labeling like they did for the

16   prescription.

17                   DR. SZEFLER:       So your suggestion might be

18   in labeling that a preferred route of additional treatment

19   might be to use an additional drug rather than increasing

20   dose.

21                   DR. MONROE:    I'm not a labeling expert.           My

22   recommendation, if they came to my office, would be that



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1    they should see the physician at that point.                     If the

2    standard of care wasn't sufficient, I think that's where

3    the physician should be involved.

4                   DR. CANTILENA:      Doctor Sachs and then Doctor

5    Davidoff.

6                   DR. SACHS:    Hi. You guys look like the label

7    indication is going to go down to age six.                    From the

8    studies presented today, it sounded like most of the

9    studies were people over 18.                The study packet we

10   received, I think the lower age limit was 12.                  So I was

11   just curious about pediatric data.             Unfortunately, in

12   my experience, one of the differential diagnoses of

13   chronic urticaria in children is leukemia and granted,

14   the symptoms would persist and cause a parent to seek

15   help for their child, but I was just curious what the

16   studies in kids were.

17                  DR.   CLAYTON:      I'd      like   to    call     on   my

18   colleague,     Doctor   Patricia     Rohane,       a    physician      in

19   Schering-Plough, to respond to that question.

20                  DR. ROHANE:    Yes.     Thank you.        With respect

21   to the safety data that we have in pediatric subjects,

22   we've conducted three        placebo-controlled studies.               In



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1    these    studies    there    have     been     enrolled      around     350

2    children.      The ages have ranged from six months up to

3    12 years and, as I said, the safety events in these

4    children have been compared to placebo and the adverse

5    event profile has not been different.                   In other words,

6    the events we saw in the children on the active treatment

7    were the same as; those seen in the placebo groups.

8                   DR. CLAYTON:        I would also like to mention

9    the syrup product is labeled as approved down to age two

10   and our experience in Canada and the U.K. with OTC

11   products, those products are labeled down to age two

12   including skin allergies as well as allergic rhinitis.

13    So our database of experience includes down to that age

14   group.

15                  DR. CANTILENA:         Okay, Doctor Davidoff.

16                  DR. DAVIDOFF:        Yes.       I think the studies on

17   the population with pretty well defined CIU are at least

18   moderately reassuring but I think the larger or perhaps

19   the more important question lies with the understanding

20   and behavior of everybody else because 97 percent of the

21   population     or   more    doesn't      have     CIU    and   yet    this

22   medication would be available to them as are now of course



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1    the more sedating antihistamines.             Seems to me that your

2    data    rather    elegantly     demonstrate      that    before    the

3    diagnosis is made the great majority or at least the

4    majority of the population either don't read the labels

5    or they don't understand them or don't believe them

6    because they don't follow them.                 They use sedating

7    antihistamines now for any itchy condition that they don't

8    understand.      So I was rather struck by the minimal amount

9    of data on the general population.              Perhaps you could

10   give us some thoughts on whether more data really are

11   needed before we go ahead.

12                    DR. CLAYTON:    Steve, do you want to comment

13   on the label comprehensive studies that relates to the

14   general population?

15                    MR. NEUMAN:     Yes.       The general population

16   in terms of the label comprehension.           Label comprehension

17   was sound on all of the general warnings.               It was really

18   in the self-selection area that there was probably one

19   of the largest issues with 30 percent inappropriately

20   selecting the products and, as we indicated earlier, we

21   think that that's not as high as it should be and we would

22   definitely recommend continued work on the label to



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1    improve that level.

2                    DR. CLAYTON:    As you pointed out certainly,

3    the current practice now is that there is significant

4    off-label use and, as we improve the label, we think we

5    will set a higher standard of education for the general

6    population with labeling that specifically advises on

7    the appropriate use and the appropriate precautions and

8    warning statements.

9                    DR. DAVIDOFF:      Thank you.     Could I ask a

10   brief related follow-up question and that is I was curious

11   about     the    low   literacy      population    because       my

12   understanding is it's somewhere in the range of 15 to

13   25 percent of the population is functionally illiterate

14   and particularly when it comes to medical information.

15    I was curious how you were able to get the low literate

16   population to read the labels.

17                   DR. CLAYTON:    Steve.

18                   MR. NEUMAN:    The low literate population was

19   recruited from special sites that have been targeted as

20   places where these individuals can be found at higher

21   proportions in the population.          The label was presented

22   to them just as they were in a store potentially looking



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1    at it for purchase and the numbers actually were fairly

2    encouraging among that cohort.             They were lower than the

3    general population by a few points but across the board

4    there was relatively good understanding of most of the

5    general warnings.

6                    DR. CANTILENA:          Okay.      Doctor Dykewicz,

7    please.

8                    DR. DYKEWICZ:       I have several questions and

9    comments.      The first would be about the consumer study.

10    As Doctor Monroe has pointed out, one of the concerns

11   historically that would identify potentially a more

12   serious underlying problem might be the symptom of joint

13   complaint.      In the consumer study, was there any question

14   that addressed that particular issue?

15                   DR. CLAYTON:       Steve.

16                   As he's coming to the microphone, I would

17   point    out   that   the     draft     labeling    did   include         a

18   precautionary statement on joint pain to not use the

19   product but seek medical care as far.                As the testing

20   is concerned, Steve can respond to that.

21                   DR. DYKEWICZ:        And as he's approaching the

22   microphone, besides the joint ache question, it would



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1    be how representative the study group was in terms of

2    education versus the general population.

3                   DR. CLAYTON:    Okay.

4                   MR. NEUMAN:     I can address both of those

5    questions.     There was a question that was asked regarding

6    symptoms that have been experienced and joint pain was

7    experienced by 14 percent of the sample CIU population.

8     There's not a lot of specificity beyond that as to what

9    type of joint pain or the characteristics of that joint

10   pain but 14 percent did experience that.

11                  With regard to the Internet and less educated

12   populations, the Internet does under-represent less

13   educated populations to some degree but what we did was

14   we did an analysis where we looked at those who were less

15   educated among our consumer population which was high

16   school and less and compared that to those with a

17   bachelor's degree and higher.         What we saw across most

18   of the key questions was that there was really no

19   difference in response.

20                  DR. DYKEWICZ:       Okay.   I guess it still

21   raises the issue in my mind though relative to the joint

22   complaints that that was not something that was focused



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1    on relative to whether this would be a cause for seeking

2    attention of a medical provider.

3                     Another      question          about       the        label

4    comprehension study.         I guess I'm a bit perplexed.                On

5    one hand, we see that 30 percent of the respondents gave

6    incorrect answers for self-selection and sponsor I think

7    appropriately is saying that some improvement of the draft

8    labeling would be required.           But it also is the position

9    of the sponsor that no additional label comprehension

10   studies would be required in that vein?

11                    DR. CLAYTON:        No.       If that has been the

12   message we've delivered, that is not the correct message.

13    We believe the labeling can be improved and we would

14   test    the    labeling     that    we     believe      would     be   more

15   appropriate for the market place.

16                    DR. DYKEWICZ:       Okay.      Thank you.        And one

17   last comment.      The statement which I think is generally

18   correct that chronic urticaria is not associated nor is

19   it a risk factor for anaphylaxis is mostly valid but I

20   would    point    out   I   was    involved       with      Northwestern

21   University's       series     of     patients        with    idiopathic

22   anaphylaxis who did have life-threatening manifestations



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1    at anaphylaxis and looking back historically, about 50

2    percent of the patients in that series did have a

3    pre-existing     history   of    idiopathic   urticaria      and

4    angioedema.     So while I agree that in general for the

5    population the presence of urticaria probably does not

6    identify a significant major risk for development of more

7    severe manifestations including anaphylaxis, there may

8    be certain notable exceptions to that.

9                   DR. CANTILENA:       Other questions from the

10   committee?     Doctor Rosenberg.

11                  DR. ROSENBERG:     I have questions, not about

12   the presentation we heard but about the written submission

13   from Schering and specifically under Tab 7, confidential

14   physician habits and practices study and specifically

15   on page 24 which is your slide for question 15b.             I'd

16   like to ask, I suppose, Doctor Monroe, to comment on it.

17    What this addresses is, of course, if it's not OTC, it's

18   in the hands of the profession and I think I don't know

19   if this is the only time, maybe this afternoon, but we

20   ought to look at what the profession does.

21                  A couple of points I wanted to make.         One,

22   under primary care practitioners, it's a mix of family



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1    doctors and internists and our experience in a medium

2    size city and a disease that's not so serious and where

3    it's    hard   to     get   an    appointment     with     a    doctor,

4    particularly a specialist, that much of the urticaria

5    patient population we see have come from a walk-in clinic,

6    a minor, open late hours type store front clinics which

7    some of them are under hospital ownership but which are

8    a feature of medical care in our community and I think

9    were they to have been included, 100 percent of those

10   people got prednisone.           They all get prednisone.

11                  The line I want to talk about is where

12   systemic steroids are, as I understand the question, the

13   medication     most    often      prescribed     by   the      treating

14   physician and it shows that these primary care internists,

15   pediatricians -- I mean pediatricians, 28 percent choose

16   systemic steroids first .           The allergists in my opinion

17   do somewhat better at 22 percent.The primary care people,

18   as I say, 41 percent and if you include the walk-in clinics

19   and    emergency      rooms,     it's     100   percent,       and   the

20   dermatologists, only 12 percent which I think is certainly

21   the best of those and I want to ask Doctor Monroe, A)

22   which he thinks would be more likely to mask some serious



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1    underlying disease.    The use of Loratadine or prednisone.

2     And B) would he comment on the appropriateness of

3    prednisone under most circumstances as a first treatment

4    and would he be more comfortable prescribing prednisone

5    if the patient had first treated themselves with, when

6    available, OTC antihistamine and came in and said I can't

7    sleep despite I take all that stuff.            Can you help me?

8                   DR. MONROE:    Okay.        I am not familiar with

9    the section that you're referring to but I think I

10   understand your question and I appreciate the compliment

11   that the dermatologist had the best percentage of not

12   using systemic steroids.

13                  I think there is a concern that primary care

14   physicians as well as ER or urgent care physicians tend

15   to turn more, particularly in acute urticaria, to the

16   use of systemic steroids.        In a treatment algorithm of

17   what I believe is appropriate therapy, in acute urticaria,

18   I believe that the first choice is the use of the H1

19   antihistamines and the second choice for a severe case

20   would be the use of systemic steroids because you assume

21   you've got a fairly self-limited condition.

22                  I'm very reluctant to suggest that systemic



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1    steroids should play a regular part in the treatment of

2    chronic urticaria where I think you have more risk of

3    introducing more serious problems from the treatment than

4    you do from the condition that you're treating.

5                     I   think    systemic      steroids   have     a    very

6    possible likelihood of masking the underlying problem

7    but if the underlying problem is there, I'm assuming we're

8    talking about a short course of let's say oral steroids.

9     The steroids will wear off and I think you're again back

10   to the baseline that if you have a persistence of the

11   signs or symptoms of the urticaria or of some other

12   systemic       symptoms,     the     patient    should    see       their

13   physician.      I think if a physician gave systemic steroids

14   in an IM form, something which I don't recommend, you

15   might mask it for a longer period but I think you're again

16   back to the situation that if there's an underlying

17   problem, whether it's the antihistamine or the steroid,

18   masking will be very temporary and you're back to

19   hopefully seeing a physician for further evaluation.

20   I hope that answered your question.

21                    DR. CLAYTON:       Perhaps we're on target with

22   our commitment to an educational campaign that includes



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1    health professionals if we go forward here.

2                    Doctor Joad.

3                    DR. JOAD:     Yes, I have a question follow-up

4    to Doctor Sachs' question which is it's not                  clear to

5    me that we have a study that shows how well people

6    recognize hives versus non-hives.             For instance, how able

7    are people to recognize hives as compared to purpura or

8    something      that   would   be    not      even   hives.     So    the

9    differential that we've been talking about is a high

10   differential but what about all other ashes that might

11   also be really important to look into?              Are there studies

12   like that or is your company considering doing or should

13   your company do it?

14                   DR. CLAYTON:       I'm not aware -- I don't know

15   whether Doctor Monroe is aware -- of studies that are

16   as you describe.         Certainly our experience in the

17   self-recognition study showed a very good correlation

18   of patient and physician recognition or diagnosis, if

19   you will, in this case, of chronic idiopathic urticaria.

20                   Doctor Monroe.

21                   DR. JOAD:      But those patients had that

22   condition.



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1                     DR. CLAYTON:       That is correct.

2                     DR.    JOAD:        That       is   not    the    general

3    population.

4                     DR. CLAYTON:       That is correct.

5                     DR. MONROE:       And I think that's one of the

6    reasons why there's a higher comfort level for the chronic

7    idiopathic urticaria indication because those people by

8    definition have usually consulted a physician, understand

9    what they have whereas what you're saying, there could

10   easily be a broader array of confusing dermatologic

11   problems       that    the   layperson      might    not    be    able    to

12   accurately diagnose.          I think that can be addressed, but

13   the comfort level in CIU is that there is a significantly

14   high recognition level.            In the broader population, I

15   think that presents more of an issue.                I think the point

16   I tried to stress was the situations where that confusion

17   would occur would most likely not result in a serious

18   problem but if somebody had, for example, purpura that

19   you alluded to, I consider that a much more significant

20   issue that would require seeing a physician.                       Whether

21   the patient or consumer would be comfortable in making

22   that distinction is very debatable.



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1                      DR. CLAYTON:      On additional point is as we

2    are evolving our labeling, the labeling that was tested,

3    we've tried to put precautionary statements that would

4    steer a consumer to a physician if in fact they don't

5    experience relief within a matter of a few days and, again,

6    as we move forward in refining that labeling, that will

7    be a consideration that we would certainly take.

8                      DR. CANTILENA:      Doctor Johnson.

9                      DR. JOHNSON:      I'm wondering if Doctor Monroe

10   can educate me a little bit about angioedema since this

11   might be one of the conditions confused.                  I guess my

12   confusion is based in part on my general impression of

13   angioedema and there's also a drug under review by

14   cardio-renal that has angioedema as a side effect.

15   There's        apparently   very,    very      significant    concern,

16   certainly in the community that would use it, if that

17   drug is approved.       My understanding is that in most cases

18   the angioedema was not serious and so I guess the

19   presentation here presented angioedema as something that

20   is not serious and yet in other settings it seems to be

21   something that's taken very seriously.              So I'm wondering

22   if you can sort of clarify.



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1                    DR. MONROE:    The vast majority of people who

2    have angioedema who have it in soft tissue areas, let's

3    take the non-laryngio, non-oral, which is the vast

4    majority, I view that as a more visually upsetting but

5    similar process to urticaria.           I think the issue with

6    maybe the drug you're alluding to and the medical concern

7    would be angioedema affecting the oral cavity, the larynx

8    so that you might then develop the respiratory compromise

9    and that kind of concern and that I do consider a serious

10   issue.     It's a much, much less frequent issue than the

11   general angioedema because I think the studies would

12   indicate that about 40 percent of the patients who have

13   urticaria have concomitant angioedema and maybe another

14   20 percent have urticaria alone and another 20 percent

15   have angioedema alone.

16                   So angioedema is not that uncommon of a

17   problem.       It's that rare situation when you have, for

18   example, the lorengio edema that causes us concern and

19   that causes me concern as well and that's why I think

20   there was an attempt to state that any symptoms of

21   respiratory      distress,    wheezing,     difficulty   of   that

22   nature, would have to be appropriately labeled and



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1    patients educated as to the seriousness of that potential.

2                   So I think what the concern is on that very

3    small percentage who have angioedema in that anatomical

4    region.

5                   DR. JOHNSON:    So those people, the 40 or 60

6    percent that have angioedema but not lorengio, they're

7    not at risk for lorengio angioedema?

8                   DR. MONROE:    The vast majority of people who

9    have angioedema have it in other soft tissue areas that

10   would not be of medical significance and, again, we're

11   not talking about the exceptions like the hereditary

12   angioedema in that either.          So the vast majority, I

13   believe it's just concomitant as part of their general

14   urticaria and the treatment would be the same as the

15   general urticaria.

16                  DR. CLAYTON:     I'd just like to underscore

17   Doctor Monroe's comment about labeling because we do have

18   in our graph labeling any respiratory difficulties as

19   seek emergency medical care.        We're certainly sensitive

20   to that possibility.

21                  DR. CANTILENA:       Doctor Uden, then Doctor

22   Szefler.



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1                   DR. UDEN:      I'd like to know the incidents

2    of chronic idiopathic urticaria across races and I didn't

3    see any information presented in your documentation about

4    the     demographics,      racial         demographics         of     your

5    self-recognition study and your label comprehension

6    study.     Do you have that information?

7                   DR. CLAYTON:       Yes.        Steve.

8                   MR. NEUMAN:        As for race and CIU, in the

9    literature that's been reviewed, there is no proclivity

10   for any one race to have or any sort of racial skew toward

11   any group to have CIU.

12                  With regard to our studies, the profile of

13   the     consumer   study      did     somewhat          under-represent

14   non-whites, particularly blacks, but there was a bit of

15   a confusion here in that some of those subjects indicated

16   that they would not respond to the question.                      So it's

17   a little difficult to determine in that study exactly

18   what the African-American population was.

19                  And the label comprehension study, I'll have

20   to look that one up.

21                  DR. UDEN:       While you're looking that up,

22   could    you   clarify     what     you       just     said   about     the



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1    African-American population.             I didn't understand that.

2                     MR. NEUMAN:       I'm sorry.         About the effort

3    in the Internet study or in --

4                     DR. UDEN:     You just made a comment about the

5    African American population, that they didn't respond

6    and what study was that?

7                     DR. CLAYTON:          Oh, that was the consumer

8    study.     In the consumer study, there was a relatively

9    low proportion of blacks who were indicated in the

10   demographic profile.         However, it was a little confusing

11   because it was like in the four percent range.                 But there

12   was about six percent, as I recall, who just did not

13   respond to the question at all.                 So it's difficult to

14   determine what the racial profile of those individuals

15   might     have    been.          So     it's    hard     to    say     how

16   under-represented it is.              Is that clear?

17                    DR. UDEN:     I'm a little closer but not there

18   yet.

19                    MR. NEUMAN:       It's not definitive.          We have

20   four percent that actually signified African-American.

21    There were six percent that didn't declare.                   So we can

22   confirm        that   four        percent       did      say     they're



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1    African-American.     The other six percent we don't know

2    how it's made up according to race.

3                   In the label comprehension study, the white

4    population was 84 percent, black African-American two

5    percent.

6                   DR. CANTILENA:      Okay.    Doctor Szefler and

7    then Doctor Joad.

8                   DR. SZEFLER:    I'll speak to Doctor Clayton.

9     Much of the discussion this morning and much of the

10   literature that came to us was centered around the product

11   information or the labeling, but another big area of

12   contact with patients is direct patient advertising

13   through television, through magazines.          When I looked

14   at your list of consumer health profession education

15   programs, I didn't see this included.          I wondered what

16   your thoughts were.    Was it intentional not to put these

17   sources and what's your plans for the future in terms

18   of advertising since this is such a confusing issue and

19   since the chronic urticaria is a minor population in terms

20   of the urticaria presentation.             How do you plan to

21   interact with the public in terms of these media?

22                  DR. CLAYTON:    Obviously advertising is not



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1    set so I really can't comment on the composition.

2    Hopefully our advertising would be educational also to

3    help patients clearly understand the appropriate product

4    or if this is an appropriate product for their condition.

5     We think that there's very limited, certainly in the

6    media, the non-print media, it's very limited time element

7    to provide that kind of education.            Our better hope would

8    be through print.      In the draft, the outline of our

9    educational program that included a number of different

10   vehicles including print along with Internet and other

11   forms or other platforms of communication.

12                  But the answer is we have not established

13   that but we certainly understand the importance and value

14   of educating the consumer about this drug and its uses,

15   not just urticaria but also allergic rhinitis.

16                  DR. CANTILENA:        Doctor Joad.

17                  DR. JOAD:     For Doctor Monroe.       What percent

18   of the patients with chronic idiopathic urticaria are

19   children?      I think some of the articles said it was a

20   middle age disease primarily.             I'm just trying to get

21   a sense.

22                  DR. MONROE:       I don't know the answer.          The



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1    highest incidents of chronic idiopathic urticaria is in

2    middle aged women and definitely the urticaria we see

3    in the pediatric age group is more commonly the acute,

4    but I don't know the exact number for chronic idiopathic

5    urticaria.      It would be small.

6                    DR. CANTILENA:           Doctor Davidoff.

7                    DR. DAVIDOFF:         Also a question for Doctor

8    Monroe.        It   gets    back    to    the     issue   of   potential

9    difficulties or harms that might come from delay in

10   diagnosis because you pointed out that if there is a

11   negative effect of release as over-the-counter drug, it's

12   not likely to be negative in the sense of direct harm

13   from the drug but rather from delay or some non-optimal

14   care pathway.

15                   On the other hand, it's also pointed out that

16   there's been no reporting of signals of events that might

17   be red flags that there might be some such problems

18   occurring.      On the other hand, it's also known that the

19   under-reporting problem is enormous, even for direct

20   harms from drugs.          So what I'd like to ask you to do is

21   to give us your best estimate.                  What would be found if

22   reporting of delays and the potential harms that came



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1    from them were perfect?      What would you speculate would

2    be the kinds of harms and less than optimal care that

3    might result from such delays, both in the CIU population

4    and perhaps in the more general population?

5                   DR. MONROE:      In the CIU population, I'm

6    making the assumption that they have seen a physician

7    to get that diagnosis, so I don't see any added harm.

8    Obviously there are some people that we would diagnose

9    as CIU that as time evolves maybe we come up with an answer

10   for an underlying reason.      So I don't think that changes

11   the CIU scenario.

12                  In the general population, I tried to give

13   a quick overview.    I think there are situations with some

14   very common conditions.       The acute urticaria that may

15   be confused.    I think that in that situation the treatment

16   is what the physician would have prescribed anyway except

17   that we're introducing a safer treatment than the OTC.

18    I think in the common dermatologic conditions that are

19   not urticaria, the dermatoses, I think the patient is

20   not necessarily capable of distinguishing an itchy rash.

21    For physicians in the room, we often get calls, I have

22   a rash, what can you prescribe?            And I say there are a



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1    million different rashes.            So I think that's a problem.

2     Fortunately, I believe most of those rashes don't present

3    a serious consequence if there's a delay.                     There may be

4    a quality of life consequence that they have a few extra

5    days or weeks of less than the appropriate therapy.

6                     I think there would be the rare rash, if

7    there's purpura or some severe vesicular bullous disease

8    that the patient would not be able to identify, but I

9    think those would be extremely infrequent.                     So I think

10   in general my message would be that there would be delays

11   of inappropriate diagnosis and treatment but I don't think

12   they would be causing harm.

13                    DR.   CANTILENA:            Any      other    questions?

14   Doctor Wood.

15                    DR. WOOD:      It seems to me that we heard a

16   fair amount of data that patients with CIU can diagnose

17   it probably and treat the condition on their own.                       The

18   issue though that's still unclear to me at least whether

19   patients       who   don't    have     CIU      and    might    be   using

20   antihistamines even now incorrectly and I'm surprised

21   there's no data to really address that because you've

22   really sort of addressed, kind of answered the question



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1    before you've done the study almost the way it's designed

2    right now, it seems to me.           I was pondering here about

3    how one would do that study.

4                      I guess one way to address that would be to

5    look at patients who are using currently over-the-counter

6    antihistamines and see what the conditions they're

7    treating are with them.          I'm not sure what conclusion

8    you'd necessarily draw from that but that would certainly

9    be educational in terms of trying to more appropriately

10   steer patients to the right therapy.

11                     DR. CLAYTON:    The only comment I could offer

12   is to your point.        I think there is widespread use of

13   over-the-counter antihistamines for those conditions now

14   and, as we've learned in our research, particularly with

15   acute urticaria, most patients don't seek physician care

16   anyway.        So it's not a good answer.      I don't think that

17   the data exists.        Just observations.

18                     DR. CANTILENA:       Okay.    Thank you.       Any

19   other questions from the committee for the sponsor?

20   Doctor D'Agostino.

21                     DR. D'AGOSTINO:     The consumer study and the

22   physician was done by the Internet.            Is this sort of a



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1    wave to do them by Internet?       I mean you leave out a whole

2    class of individuals who can't participate because

3    they're still illiterate computer-wise.

4                   MR. NEUMAN:   Yes, it is actually a wave and,

5    in fact, most of the major purveyors of research services

6    have instituted Internet divisions.           About 60 percent

7    of the population is on the Internet now and I think that

8    there is an opportunity to see that grow over the next

9    several years.

10                  DR.   D'AGOSTINO:       We   all   have    personal

11   experiences.    I have a few experiences where the Internet

12   connection collapsed so I'm not so sure that it's a wave

13   of the future that is completely solid.               Aren't you

14   concerned that you're leaving out whole segments of the

15   population, there's still a 40 percent, who take drugs?

16                  MR. NEUMAN:    Well, actually, there are --

17   as you well may know -- there are issues with nearly every

18   research method.      Telephone studies have their issues

19   of non-response and mall intercepts have issues of

20   socio-economic skews, the Internet has some issues as

21   well.    So it's, I guess, a little bit of pick your poison.

22



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1                   DR. D'AGOSTINO:         The label comprehension was

2    an all comer study.           Could you just remind me how you

3    recruited that sample.

4                   MR. NEUMAN:       Yes.     It was recruited through

5    malls.

6                   DR. D'AGOSTINO:         Through malls.         Thank you.

7                   DR. CLAYTON:           And to your point, Doctor

8    D'Agostino, obviously the most critical study, the label

9    comprehension        study,     is     the    old   fashioned         way.

10   Individual contact, not through Internet.

11                  DR. D'AGOSTINO:          Not necessarily the best

12   but at least --

13                  DR. CLAYTON:          Accepted.

14                  DR.    D'AGOSTINO:            --   you    hope    to    see

15   everybody.

16                  MR. NEUMAN:       One other point though.               The

17   CIU population was recruited through advertising in the

18   papers.

19                  DR.    CANTILENA:         Okay.          And   our   final

20   question from Doctor Gilliam.

21                  DR. GILLIAM:          Getting back to Doctor Uden's

22   question about other populations that were surveyed for



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1    the     label    comprehension.            How   about    Hispanic

2    populations?     Spanish labeling.         Anything done in that

3    area?

4                    DR. CLAYTON:   No.    Nothing has been done to

5    this point in that area.

6                    DR. CANTILENA:    Okay.      I wish to thank the

7    sponsor and the committee for their questions.             We will

8    now take a 30 minute break and report back at 10:30 for

9    the FDA presentation.

10                   (Off the record at 9:57 for a 33 minute

11   break.)

12                   DR. CANTILENA:       The next section of the

13   agenda deals with the presentation by the Food and Drug

14   Administration.     The lead-off speaker for the FDA will

15   be Doctor Jonathan Wilkin and then he will introduce the

16   subsequent FDA speakers.       Doctor Wilkin.

17                   DR. WILKIN:    Thank you, Doctor Cantilena.

18                   Members of the Advisory Committee, I will

19   give some brief comments, much briefer than what I had

20   originally planned after the very nice presentation of

21   Doctor Monroe and his colleagues.

22                   Doctor Monroe has seen this slide before.



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1    I've nominally plagiarized it for today but actually he

2    published this in 1977 with Earl Jones, and I've used

3    it since 1978 to the present at least 15 times to give

4    the conceptual architecture of urticaria to sophomore

5    medical students and, of course, the residents in our

6    training program.        Basically, the very nice piece is

7    we've got the immunologic factors that act on the mast

8    cell or basophil and the non-immunologic factors that

9    connect on the mast cell or basophil.        So a wide variety

10   of etiologies, different causes that can act on the mast

11   cell.    And then there are some modulating factors, those

12   things which can either act on the mast cell itself or

13   can act on the small blood vessels to increase the diameter

14   and potentiate the effect of the released mediators.

15                    But at any rate, the mast cell has only one

16   basic trick.       It releases this vesicle exocytotically,

17   release mediators, histamine is the principal one, and

18   it acts on the small blood vessels and the upper skin

19   to produce urticaria.

20                    This is another slide plagiarized from Doctor

21   Monroe.        What I did in the medical school classes was

22   I started out with just the membrane receptors and then



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1    I added the intracellular cyclic nucleotide story and

2    I kept adding different intracellular processes until

3    finally at the end the microtubials and the microfilaments

4    steered        these   vesicles   containing   hepron    and    the

5    histamine and all of the other vaso goodies to the surface

6    and then the exocytotic release into the extracellular

7    area.

8                      Where this happens in the skin -- this is

9    Frank Netter's nice drawing of the skin and up here at

10   the top you can see arranged in layers like baklava the

11   epidermis and then from here down to here is the dermis.

12    Here's the subcutaneous fat, the butter, and it's in

13   this very upper layer here where there's a superficial

14   vascular plexus and that's where the mast cells release

15   the histamine that leads to the urticaria.

16                     We'll see the two plexus because there's

17   another plexus that's down deep in the next slide so that

18   for the typical urticarial kind of lesion, it's going

19   to be leakage in the superficial vascular plexus.           That's

20   where the histamine is released and acts on these vessels.

21    For angioedema it's going to be the vasculature that

22   is in the superficial subcutaneous tissue and the very



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1    lower dermis at that interface.       But they are very similar

2    processes.     One of the key differences is that the nerve

3    endings, the C fibers, the itch fibers, are predominantly

4    located up in these finger-like extensions up into the

5    epidermis, the dermal papillae.            So hives itch a lot more

6    than the angioedema kind of lesions that will form deeper.

7                   This is looking at one of those finger-like

8    projections up into the epidermis.           Here's the arteriolar

9    part of the superficial vascular plexus and it goes up

10   through the arteriolar side of this capillary loop and

11   finally back down on the venular side of the capillary

12   loops to the post-capillary venial and this is the site

13   right here that really is where histamine acts and the

14   endothelial cells pull apart and the fluid leaks out.

15   That is where the urticarial lesion really occurs.                 And

16   so it's a very superficial kind of leakage of fluid, so

17   superficial that it puffs up and you can actually run

18   your finger over lesions of urticaria and at the edge

19   you can find that it'll actually lift up to this flat

20   kind of surface.

21                  Over a few hours time, the edges of the

22   typical urticarial lesion will migrate and so they're



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1    not fixed kind of lesions.

2                   These   are   the     smaller,   average      size

3    urticarial lesions.     Sometimes they can be really large.

4     They're not necessarily angioedema.         Angioedema, when

5    you put your hand on the skin, it feels like wood.                  I

6    mean it's really got a thick indurated kind of quality

7    to it.

8                   So the key piece is that there are literally

9    hundreds of causes of urticaria and they either act

10   directly or through the immune system to cause mast cell

11   mediator release which then these mediators are released

12   in the area of the small blood vessels and principally

13   histamine leads to the itching and the edema, the fluid

14   leakage.

15                  But there's also another way of looking at

16   urticaria, the heuristic or clinical ways of looking at

17   it.    This is very similar to the industry's presentation

18   because I think most physicians use the same system.

19   Acute urticaria is less than six weeks in duration, has

20   an incredibly good prognosis.          Most of it is actually

21   gone by six weeks.     It's only down in the five percent

22   range that extends beyond.      History implicates the cause



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1    in approximately half of the patients.          If they come to

2    the emergency room or to the dermatology clinic, they're

3    seeking symptomatic care but very often they know what

4    the inciting event was.

5                   I think it would be very difficult to study

6    acute urticaria in clinical trials just because you would

7    almost have to know who's at risk for developing acute

8    urticaria before they actually developed it and since

9    it has such a great prognosis and may only last a week

10   or two, it would be hard to get these people in in time

11   to actually give them medication and monitor them for

12   any length of time to get a signal.           So very difficult

13   to study in clinical trials.

14                  There's   a    distinction      between    chronic

15   urticaria and chronic idiopathic urticaria.               Chronic

16   urticaria means greater than six weeks.            A work-up is

17   indicated because perhaps five to 10 percent of those

18   patients will have a definable cause that can be detected

19   in the office of the allergist or the dermatologist.

20   These would be much easier to study in clinical studies

21   because often they are persistent.          So you can give them

22   medication for a period of time and they're not likely



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1    to have a spontaneous remission.

2                   The distinction between chronic urticaria

3    and chronic idiopathic urticaria means that someone

4    really looked in a sensible way to see if there is a cause

5    and they couldn't find it and so then you can add the

6    word    idiopathic.      But    it's    the    subset    of   chronic

7    urticaria in which a good work-up fails to pinpoint the

8    cause.     It's a diagnosis by exclusion and obviously it's

9    not homogeneous.       There's still a lot of different types

10   of causes.     Some of them are going to be direct mast cell

11   mediators.     Some are going to be through the immune system

12   of causes of chronic idiopathic urticaria.

13                  Again I borrowed this one from Doctor Monroe.

14    This is his schema for treating and managing acute

15   urticaria.       For    the    mild    and    moderate   types,    he

16   recommends non-sedating H1 antihistamines.                    I think

17   generally that's the approach most physicians take.                So

18   the kind of medication we're talking about today is

19   actually the first choice for most patients who have acute

20   urticaria.

21                  So observations.         Urticaria really is not

22   a single disease.       It's a reaction pattern mediated by



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1    histamine      release   in   the   superficial      skin.       Acute

2    urticaria and chronic urticaria are not single diseases.

3     They're useful for clinical decision making.                     Most

4    urticaria will respond to an antihistamine which is found

5    safe and effective in patients in chronic idiopathic

6    urticaria.

7                    There are some caveats when thinking about

8    what an OTC label might look like.               I think that some

9    of the things that we've already heard discussed.                   The

10   OTC consumer could be informed.              I think there are some

11   varieties of urticaria that are more likely to get

12   patients into trouble, not because they might be taking

13   this medication but because they might not be seeking

14   the intervention of a physician early on.              In fact, for

15   all of these conditions, I'm not sure but what they might

16   actually get a medication like this as part of the therapy.

17    It's just that they need some additional evaluations.

18                   The first kind of urticaria.         I think if the

19   patient believes that it's possibly related to peanut

20   or latex allergy because that can ultimately -- the second

21   time around, there may be anaphylaxis.            I think that would

22   be a subset that they ought to go and see a physician



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1    early on.       Persisting beyond six weeks.             Again, that's

2    the group where the work-up is indicated and where perhaps

3    up to 10 percent of patients you can actually find an

4    identifiable cause.        Often it's something that they can

5    eliminate so that they will not have the continuing

6    urticaria.       Or they may have some underlying disease

7    that's leading to the urticaria and the work-up will

8    detect that.

9                     There   is     a   condition      called    urticarial

10   vasculitis.      One of the features in urticarial vasculitis

11   is the lesion.      Unlike usual urticaria, it doesn't really

12   migrate.       The edges stay in the same place.              You could

13   take a skin marker or a fountain pen or something and

14   draw a ring around where the urticarial lesion is and

15   it will be there 24 hours later.                    That's not what

16   urticaria usually does.                 I don't think that point

17   probably would translate in an OTC labeling but because

18   these    generally       leave      a   bruising    or    pigmentation

19   post-inflammatory pigmentary changes, I think that might

20   be something that would get these patients alerted that

21   they need medical help.

22                    Also, when there's something beyond the



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1    urticaria that also involves the skin.                Blistering is

2    one or again the bruising part.              It could be part of the

3    vasculitis or bullous penfogoid.

4                   Serum sickness.         Like reactions can have

5    urticaria as some of the features and the connective

6    tissue diseases.     But if we had something on labeling

7    that would say something about fever, joint pain, just

8    feeling unwell, systemic features in general, that if

9    that accompanies the urticaria, then it's important to

10   seek    medical   help.       Any     urticaria      that's     poorly

11   responsive to oral antihistamines also ought to be checked

12   out by a physician and then that variety of angioedema,

13   not the kind that occurs on the arms and the legs and

14   perhaps the skin over the trunk.             But if there's swelling

15   of the lips, tongue or throat, again that can be a very

16   worrisome prognostic feature and they should be also seen

17   by a physician.

18                  And then the urticaria which looks like

19   urticaria but it doesn't itch and those may be the

20   infiltrates into the skin of a leukemic process or there

21   are some varieties of urticaria that don't itch so much,

22   the     delayed   physical       kinds        of   urticaria,       and



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1    antihistamines don't work really great and so that really

2    means that if it doesn't itch, patient really should see

3    a physician.

4                   Some of these statements I've taken from the

5    sponsor's briefing package, modified them a little.

6    Urticarial lesions are generally easy to recognize since

7    they    typically   occur   in   visible    locations    and    are

8    associated with intense itching.           That's on page seven

9    of sponsor's briefing document.            I think that's true.

10   I've seen a lot of patients with urticaria and they

11   generally come in and say I've got hives, doc.           What can

12   we do?

13                  I would also agree with a second point that

14   they made and this is found on page 18 in the sponsor's

15   briefing document except I added the word sedating in

16   here because I think that's part of the context in which

17   one must think about this.       It is likely that acute hive

18   sufferers are already using sedating OTC antihistamines.

19    And so I think this is an opportunity, if this goes

20   over-the-counter for hives, it's an opportunity to put

21   some things in labeling that will direct patients to

22   physicians for some conditions that might be confused



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1    with or associated with hives and actually it could be

2    better than the current situation which is they're just

3    using it but they're not getting that message.

4                   And then I think the core piece in Doctor

5    Monroe's message and I think throughout the literature

6    is that the hive and the associated itching of almost

7    all urticaria is mediated by histamine and so one would

8    anticipate that for almost all varieties of urticaria,

9    an H1 non-sedating antihistamine is going to provide

10   patient relief. And so I think that it would be possible

11   with proper labeling but I think that's really the key

12   thing is how does one get some of these extra conditions

13   in there and explain them to an OTC consumer.          It just

14   may be that the hives could be the preferable OTC

15   indication.

16                  The next speaker is Doctor Chowdhury.

17                  DR. CHOWDHURY:     Thank you.   Good morning,

18   members of the Advisory Committee.        I will be talking

19   about the clinical development program that the various

20   companies have done that has resulted in the indication

21   for H1 antihistamines for chronic idiopathic urticaria.

22    The antihistamines that I'll be covering are the newer



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1    ones     which        includes       Loratadine,      Desloratadine,

2    Cetirizine and Fexofenadine.

3                     In    your       briefing       package   you      have

4    Desloratadine medical officer review as an example, an

5    example only, of a recent development program for an

6    antihistamine that has the CIU indication.

7                     I will be talking initially very briefly

8    about urticaria in general and then in a very global sense

9    about the clinical development program for antihistamines

10   for urticaria.        Then I'll be talking about specifically

11   clinical programs for antihistamines elaborating more

12   on Loratadine which is a point of discussion and touching

13   on the other antihistamines.                And then I'll have some

14   summary remarks.

15                    As we heard before, urticaria is classified

16   as acute and chronic -- duration, the cut-off being six

17   weeks.     One thing to keep in consideration which we also

18   heard before that acute urticaria can occur as an early

19   manifestation of anaphylaxis.               Urticaria, in addition,

20   can also be intermittent which is in between acute and

21   chronic.       Patients have urticaria lasting for days and

22   weeks with intervals which is pretty long in terms of



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1    days, weeks or months.

2                   In addition, there can be urticaria where

3    the causes are known, some of the examples being physical

4    urticarias, cholinergic urticarias and so on.                  As you

5    heard before, the clinical development program the

6    companies have focused on CIU because these patients have

7    recurrent hives and are expected to have recurrent hives

8    during the clinical trials, therefore, can be studied.

9                   The   patients    with      clinical     hives      have

10   repeated dermal mast cell degeneration -- antihistamine

11   and other mediators and these cause the typical wheals

12   or the -- lesions.     It can occur anywhere on the skin.

13    There are varieties of sizes and shapes and they're paler

14   in the center with redness in the surrounding area and

15   the individual wheals last for a short duration and

16   there's entrance itching around the wheals and there is

17   often -- redness of the skin.           These are the features

18   that are used in evaluating efficacy end points for

19   patient evaluation in the clinical urticaria trials which

20   I'll go into later on.

21                  For the CIU indication, the FDA requires

22   evidence of efficacy from at least two clinical studies



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1    including        exploration      of     the      proper     dose     and

2    demonstration of the safety of the proposed dose.                     The

3    pivotal efficacy studies are randomized, multi-center,

4    double-blinded, placebo-controlled and often they are

5    active-controlled.         Most of the pivotal efficacy studies

6    are four to six weeks in duration.                  In addition, the

7    safety of the proposed dose must be demonstrated.

8                     In addition to the pivotal efficacy studies,

9    the companies often does what is called a wheal and flare

10   study.     These are pharmacodynamic studies where small

11   amount of antihistamine is injected under the skin to

12   cause an artificial urticarial-like lesion and histaminic

13   effect is tested on those lesions.                    These are peer

14   pharmacodynamic studies and are not taken as reflective

15   of evidence for an antihistamine effect or for an evidence

16   of efficacy for urticaria.

17                    The patients enrolled in the CIU studies are

18   generally adults.          In various studies, they have been

19   12 years or older.         In others, 18 years and older.             And

20   they're        free   of   clinically          significant   diseases.

21   Pediatric indications for urticaria are usually given

22   by -- based on pharmacodynamic program.                 The diagnosis



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1    of CIU is based clinically and patients with other causes

2    of urticaria, which we have heard about before such as

3    the physical urticarias, urticarias from known causes

4    like insect sting, drugs and so on, urticarias associated

5    with underlying disease or patients with angioedema are

6    excluded from all of the studies.

7                   Also   important       differentials        which     are

8    listed in the slides are also looked at by the physician

9    and those patients are excluded.

10                  On entry, the patients are expected to be

11   symptomatic so that an efficacy can be seen during the

12   clinical trials.      Typically in various studies, that has

13   meant the patients should have a flare lasting for at

14   least three weeks in some studies or six weeks in other

15   studies and on entry they have symptoms lasting for two

16   days per week or three days per week or approximately

17   50 percent of the days.

18                  The patients on entry were required to have

19   some response to antihistamine in the past and on entry

20   they    were   required    to    have        high   symptoms     cause.

21   Typically, two or above on a scale of zero to three, three

22   being higher.    Medications that can confound the disease



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1    or evaluation of the efficacy end points were excluded.

2                   The primary efficacy variables for these

3    urticarial studies are based on patient symptoms which

4    are basically pruritus and hives.         The symptoms in the

5    older studies were recorded by physicians.           Currently

6     we prefer patient recording.        The recordings are done

7    either instantaneously which means how the patient felt

8    at the time of recording or reflective which means how

9    they felt for the previous 12 hours or so.     The recordings

10   were done either once a day or twice a day.

11                  The typical efficacy end points has been

12   pruritus severity, number of hives, size of largest hives

13   on a scale of zero to three which are explained here,

14   typically zero being less symptomatic, three being more

15   symptomatic.

16                  In the studies, -- secondary end points.

17   For example, arrhythmic severity, overall condition,

18   overall therapeutic response and so on.

19                  A safety assessment for the antihistamines

20   for CIU indication usually has not been a question because

21   the urticarial indications were secondary after the

22   antihistamines has been studied for allergic rhinitis



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1    and the dose for allergic rhinitis and the dose for

2    urticaria for the currently marketed newer antihistamines

3    are   the      same.     However,    to    look   for    disease/drug

4    interactions in these pivotal studies, adverse events,

5    clinical laboratory and ECGs were looked at and all the

6    antihistamines, the newer ones on the market, are safe

7     and effective for urticaria.

8                     Now I would like to spend the rest of my talk

9    talking about clinical programs.              My focus again will

10   be on Loratadine which is the point of discussion today.

11    I will show the clinical studies and some of the results

12   that we have.          I'll very briefly touch on the design

13   issues on the other three antihistamines and I will not

14   show any data on these.

15                    The Loratadine clinical program had two

16   pivotal studies, 67 and 44.         Both were placebo-controlled

17   and one study was active-controlled.              In addition, there

18   were a couple of supporting studies.              One study, 56, was

19   a small dose-ranging study.               I showed the design and

20   results of Studies 56, 44 and 67.

21                    The dose-ranging study, Study 56, was a small

22   study conducted in adult patients with CIU.                  The study



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1    was placebo-controlled and active-controlled with one

2    day of baseline followed by seven days of double blind

3    treatment.       The treatment arms were Loratadine 10 mg,

4    20 mg or 40 mg.          The active treatment was hydroxyzine

5    and there was also placebo arm.

6                     On     entry,      the     patients    were      quite

7    symptomatic.          For example, the scores for pruritus,

8    erythema, number of hives and size of largest hives were

9    all around two in a scale of zero to three.                  Here are

10   the results for pruritus, erythema, number of hives, and

11   size of largest hive scores.              On the vertical axis, it

12   is percentage change from baseline for all the variables.

13    In the horizontal axis, the first three bars are the

14   three doses of Loratadine 10 mg, 20 mg, 40 mg.             The fourth

15   bar is the active control hydroxyzine and the last bar

16   is placebo.

17                    As is seen from the slides, for all the

18   efficacy       end    points,    all   doses    of   Loratadine    were

19   numerically      --     to   placebo,     was   also   comparable     to

20   hydroxyzine and there was no definite dose response.

21   The company took Loratadine 10 mg dose for further

22   development through two pivotal studies.                  One of the



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1    pivotal studies was Study 44.        This was a seven-center

2    U.S. study, again conducted on adult CIU patients.            It

3    was placebo-controlled with one day baseline and 28 days

4    double-blind treatment.

5                   On entry, the patients were again quite

6    symptomatic with the scores being two or around two for

7    all the end points on a scale of zero to three.              The

8    treatment was Loratadine 10 mg compared to placebo and

9    the symptoms here were scored by investigators and a

10   primary efficacy end point was not defined.

11                  The four end points which I showed earlier

12   are shown here again and on the horizontal axis now it

13   is the weeks, weeks one, two, three and four.       The small

14   asterisks here denote significance versus placebo at a

15   level of P4, 5 or less.

16                  For pruritus and other scores, the active

17   treatment, which is Loratadine 10 mg, was numerically

18   and for most of the time statistically superior to

19   placebo.

20                  The second study, Study 67, was again a

21   seven-center study conducted in adult patients.          Again,

22   on entry the patients were symptomatic.       The study had



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1    one day baseline followed by 28 days of double-blind

2    treatment and this was an active control study.                         The

3    comparator was hydroxyzine 25 mg three times a day.                     The

4    primary efficacy end point in this study was measured

5    or assessed by patients and the end point was defined

6    as day seven change compared to baseline.                   This is the

7    primary end point which is the pruritus curve.                          I'm

8    showing here day seven which is week one and other time

9    points.        At the primary end point, which is the day seven,

10   both the drugs were almost super-imposable and they were

11   both secreted to placebo.           Over time, the separation of

12   placebo        was    maintained.              However,     hydroxyzine

13   numerically tended to be better than Loratadine.

14                     An important secondary end point is change

15   in the number of hives and, again, the active treatments

16   were -- placebo although there was no -- significant

17   differences here.

18                     The Loratadine clinical program that you have

19   the medical officer review in your briefing book had two

20   pivotal studies.        The designs were very similar to the

21   Loratadine program except that these studies lasted a

22   bit longer, for six weeks.                These two studies were



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1    adequate       to    support     approval         for    these   drugs     for

2    Loratadine for CIU indication.               Also, there was a -- study

3    which was pharmacodynamic study.

4                        The Cetirizine program also had two pivotal

5    studies.       They were both placebo-controlled.                 One study

6    was a fixed dose ranging study where multiple doses of

7    Cetirizine were compared to placebo.                      The second study

8    allowed for dose titration where patients were allowed

9    to increase the dose based on physician's supervision.

10    In addition, the two supporting studies which looked

11   at patients who had idiopathic dry skin pruritus which

12   was meant to indicate the patients did not necessarily

13   have an allergic -- and these studies were not generally

14   supportive of efficacy so Cetirizine currently has the

15   indication of CIU like other antihistamines.

16                       The Fexofenadine program also had two pivotal

17   studies.       They were both four week studies and in both

18   the studies dose effects of Fexofenadine ranging from

19   20 mg to 240 mg twice a day was explored.                    All the doses

20   of Fexofenadine were -- to placebo and there was no dose

21   response beyond 60 mg bid doses.                        Based on these two

22   studies, Fexofenadine is currently approved for CIU.



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1                      In the prescription world right now, the

2    newer antihistamines that have the indication for CIU

3    symptom control are the four that I went through very

4    briefly.           These     are     Cetirizine,       Desloratadine,

5    Fexofenadine, and Loratadine.                   The indication states

6    treatment of CIU symptoms.

7                      The older antihistamines, which are often

8    called first generation, also has some approvals for

9    urticaria or urticaria-like symptoms.                For example, the

10   combination product which is antihistamines and Extendryl

11   hydroxyzine,        cyproheptadine         and      promethazine      has

12   indications which states, might complicate uncomplicated

13   allergic manifestations of urticaria or angioedema or

14   both.          Specific    language     varies     slightly    for    the

15   different drugs.

16                     Currently in the over-the-counter situation,

17   there are no drug products that are approved for the

18   treatment of CIU, urticaria of other forms or itching

19   due to hives.

20                     Based on the clinical studies submitted to

21   the FDA for the NDA and subsequent post-marketing -- the

22   currently available newer antihistamines are safe and



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1    effective for treatment of CIU symptoms.               Of the various

2    types of CIUs or urticaria I should call it myself, are

3    the various types of urticaria.               In the clinical trials,

4    CIU was studied because, for reasons we explained earlier

5    on, CIU is amenable because the patients are symptomatic

6    and the disease        -- to be studied in -- clinical trials.

7      Generally, if antihistamine is found to be efficacious

8    for CIU, it is possibly reflective of efficacy in

9    urticaria for the times and in clinical practice, actually

10   that's     the   way    the   antihistamines         are   used,     not

11   necessarily limited for CIU.

12                    One has to keep in mind if H1 antihistamines

13   are marketed OTC, they're likely to be used for all types

14   of urticaria including acute urticaria which may or may

15   not be often a manifestation of anaphylactic reactions.

16                    Thank you.

17                    The next speaker is Doctor Ganley.

18                    DR. CANTILENA:         Actually, I think it's

19   Doctor Holman.

20                    DR. HOLMAN:       Good morning.           My name is

21   Matthew Holman and I'm an interdisciplinary scientist

22   in the Division of Over-the-Counter Drug Products at the



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1    FDA.     Today I'll be talking about U.S. regulations,

2    foreign        marketing,    and    label       comprehension    studies

3    conducted by the sponsor.

4                      As indicated by the title of my talk, my talk

5    will be divided into three sections.                 First, I'll talk

6    about U.S. regulations regarding OTC antihistamines and

7    specifically with regard to the CIU or hives indication.

8     I will then look at a specific antihistamine, that is

9    Loratadine, and look at its marketing around the world

10   and then lastly I will just briefly highlight some key

11   points to the label comprehension study conducted by the

12   sponsor followed by a summary of my presentation.

13                     As Doctor Chowdhury mentioned, there are two

14   routes that a drug going OTC can go by. The first is an

15   NDA which is product-specific and sponsor-specific.                    The

16   second         route    is         the      monograph       which       is

17   ingredient-specific.           As Doctor Chowdhury mentioned,

18   there are currently no approved OTC oral antihistamines

19   with a CIU or hives indication.             Therefore, I'm not going

20   to discuss the NDA route but rather I'm going to focus

21   on the monograph system.

22                     The monograph system is a three step process



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1    open to the public.      The first step is the advance notice

2    of proposed rule making or the ANPR.              This contains the

3    Advisory Panel report and this is published to notify

4    the public of the agency's intentions regarding specific

5    ingredients and indications and is to request comments

6    from the public.

7                    The    second   step     is   a   tentative      final

8    monograph.      Based upon comments received from the ANPR,

9    the agency publishes a TFM containing a proposed rule

10   making and it requests comments from the public.

11                   The last step is the final monograph.              This

12   is again based on comments from the TFM.                 The agency

13   develops final regulations regarding specific products

14   and ingredients and publishes these.                Once the final

15   monograph is effective, any ingredient within that final

16   monograph can be marketed without prior approval from

17   the FDA as long as regulations are followed.

18                   Now that I've given you a general description

19   of the monograph process, let's look specifically at how

20   this has to do with OTC or antihistamines.           About 25 years

21   ago, the ANPR was published and this was published for

22   a   pretty     broad   category    of    cold,    cough,     allergy,



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1    bronchodilator and anti-asthmatic drug products of which

2    antihistamines were part of.        Again, the Advisory Panel

3    report was published.    In that report, which again covers

4    this entire drug category, there was no mention of CIU

5    or hives.

6                   A few years later, the Tentative Final

7    Monograph was issued and, rather than describe this whole

8    entire drug category, the Tentative Final Monograph in

9    this case referred specifically to OTC antihistamine drug

10   products.      In the TFM there was one comment referring

11   to hives that requested indication of hives.          However,

12   there is no data submitted and, as I mentioned, the panel

13   did not report on hives.       Therefore, the agency declined

14   this request.

15                  There was a final monograph issued shortly

16   after TFM and, again, the final monograph was specific

17   for the OTC antihistamines.          In this, there were two

18   comments relating to CIU or hives.         The first comment

19   requested symptomatic treatment of allergic itching.

20   This comment was subsequently withdrawn, so the agency

21   did not respond.

22                  The    second     comment    referenced       the



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1    literature, data in the literature that supported relief

2    of itching skin caused by, among other things, hives.

3    The agency did not agree with this comment based upon

4    primarily three points.            The first is that hives are a

5    component of anaphylactic reaction.                 The second and

6    related        point   is   that   the    average   person   can    not

7    distinguish between mild and life threatening conditions

8    with similar symptoms, i.e., hives.

9                      And the last point was that one of the

10   references cited by this comment stated that the ideal

11   treatment for urticaria was identification and removal

12   of the cause.          The agency agreed with this comment and,

13   therefore, did not allow this indication.

14                     Now that we've discussed a little bit about

15   the marketing of OTC oral antihistamines within the U.S.,

16   I'd like to focus our attention outside the U.S. by

17   focusing on the marketing of Loratadine.              I'll give you

18   a brief picture of the marketing of this drug outside

19   the U.S.       It is prescription medication in approximately

20   80 countries.          It's prescription-free in 33 countries.

21    However, of those 33 countries, only 29 of those

22   countries allow a hives or CIU indication.



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1                   I'll further define this by letting you know

2    that of those 29 countries, 22 of the countries sell this

3    product behind the counter.           That is, it has to be

4    purchased at a pharmacy through a pharmacist.                However,

5    no prescription is required.

6                   The other seven countries sell this drug,

7    market this drug over the counter.             Again, similar to

8    the U.S., Loratadine can be purchased in these seven

9    countries without a prescription, without a pharmacist

10   intervention from a variety of sources such as gas

11   stations, convenience stores.

12                  Rather than talk about all these countries,

13   I'm going to focus just on two of those and those are

14   Canada and the United Kingdom and hopefully give you a

15   flavor for how this drug is marketed in these two countries

16   and around the world.

17                  First,   let's    take      a   look     at    Canada.

18   Loratadine has been marketed in Canada since about 1990.

19    It has always been marketed over the counter in this

20   country, never behind the counter, and it's never required

21   a prescription.    In Canada, it's allowed two indications

22   and those are allergic rhinitis and hives.



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1                   Now let's just take a look at again just one

2    example of the labeling used in Canada for         Loratadine.

3     The labels I've shown here are for a 10 mg tablet.            You

4    can see on the left there's a product labeled for allergy.

5     Again, 10 mg tablet.       There's no mention on the front

6    panel or the rear back panel of CIU or hives.           However,

7    on the right you can see that there's again, the 10 mg

8    tablet labeled for skin itch.          In this case, the front

9    label reads, fast relief from skin allergic conditions,

10   bullet, skin itch, bullet, hives.

11                  Now let's take a look at United Kingdom.

12   In the United Kingdom, Loratadine was initially marketed

13   in the pharmacy class.       This corresponds to behind the

14   counter meaning a prescription was not required but it

15   had to be purchased through the pharmacist.             However,

16   about four months ago in December, Loratadine was switched

17   to general sales list.     This again equates to OTC meaning

18   that it can now be purchased directly by consumers without

19   a pharmacist intervention.

20                  Just an interesting note that in the United

21   Kingdom, once the switch to GSL was made, the packaging

22   was limited to seven tablets or a seven day supply.



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1    Again, like Canada, the two indications are allergic

2    rhinitis and hives.

3                    The last point I'd like to make is that in

4    the    United    Kingdom     there's      only   one     other      oral

5    antihistamine which is on the GSL list and that is

6    Ceterizine and, again, this was switched back in December.

7     Again, I'd like to just show you an example of some of

8    the labeling in United Kingdom.                This label here is

9    labeled allergy tablets for hay fever or other allergies.

10    I've blown up a statement on the back panel that refers

11   to hives or CIU and that reads, "Claritin Allergy may

12   also be taken for allergic skin conditions including rash,

13   itching and urticaria (hives)."

14                   Now that I've talked a little bit about these

15   two countries, I'd like to step back and sort of summarize

16   the labeling around the world.            Rather than look at all

17   29 prescription-free countries, we reviewed labelings

18   from 19 of these countries including six of the seven

19   OTC countries.     I've sort of just summarized the labeling

20   and references to CIU or hives in these countries.

21                   Only   one   of    the    19   countries      was    CIU

22   completely indicated on the label and that label read,



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1    "Chronic urticaria of an unknown source."          However, in

2    12 countries the label read simply "Chronic urticaria

3    or chronic hives."       It did not mention the source of the

4    hives."        Further, there were three more countries that

5    simply listed urticaria or hives and another three

6    countries which combined urticaria with a broader term

7    of allergic skin condition.

8                      I'd like to make one last point and that is

9    that of these 19 countries, not a single country indicated

10   that the consumer should be diagnosed by a physician prior

11   to using this product.        Actually, I'd like to pause just

12   one more minute to sort of put this into context by telling

13   you that of all these statements that I just described,

14   less than half of those statements were on the carton

15   labeling.       Rather, the majority of these statements were

16   on the package insert meaning that consumers could not

17   read these indications at the time of purchase.

18                     And now let's just take a look at the label

19   proposed by the sponsor.          Again, I'm just looking here

20   at the 10 mg tablet.        You can see that this package is

21   labeled on the front for recurring hives.           It says it

22   "relieves and reduces itching and rash due to recurring



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1    or chronic hives."    Again, I've blown up a statement on

2    the back panel from the uses section of the drug facts

3    label.     There's two bullets.       The first bullet refers

4    to CIU and it reads "relieves and reduces itching and

5    rash due to recurring or chronic hives of an unknown

6    source."

7                   The second bullet, which is in bold font,

8    indicates that the consumer should be diagnosed by a

9    physician and it reads "Use only after being told by a

10   doctor that you have recurring or chronic hives (chronic

11   idiopathic urticaria).

12                  And similar to Canada, the 10 mg tablet also

13   has a second carton labeling.         This time it is labeled

14   for allergy.    However, it does refer to CIUs.         It says

15   "Non-sedating relief of itching and rash due to recurring

16   or chronic hives."    And again on the rear panel, the same

17   two statements, just this time combined into one bullet

18   and again the second statement referring consumers to

19   be diagnosed by a doctor is in bold font.

20                  And now I'll just briefly summarize just a

21   few points from the label comprehension study conducted

22   by the sponsor.    The label comprehension study consisted



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1    of 565 subjects divided into five cohorts.             The first

2    cohort was self-recognized CIU sufferers.            These were

3    participants who had claimed to be diagnosed previously

4    by a physician as having CIU.       The second and third cohort

5    were the general population and the low literacy group.

6

7                    The   fourth cohort was that they had a

8    contraindication on the labeling.           These were subjects

9    who were pregnant or nursing or who had liver or kidney

10   disease.       And then fifth cohort were the acute hive

11   sufferers.      These were subjects who had previously had

12   hives or currently had hives but had never been diagnosed

13   by a physician as having CIU.

14                   For the label comprehension study, all those

15   subjects were allowed to look at labeling similar to that

16   which I have just shown you proposed by the sponsor and

17   then respond to a series of questions.          I'm just going

18   to highlight a few of the questions and the responses,

19   again to try to give you a flavor for the type of responses

20   we saw in the label comprehension study.

21                   The first question was an open-ended question

22   that read, "Based on the label, what is this product used



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1    for?"      Approximately two-thirds of the participants

2    answered this question correctly or acceptably.               To

3    answer this correctly or acceptably, the respondents had

4    to say that the product was used for CIU.      However, they

5    could also say that it was used for another appropriate

6    indication such as allergic rhinitis.

7                    Of the third of the respondents who got this

8    answer incorrect, nearly all of them simply mentioned

9    hives as the indication, did not mention the chronic

10   nature of the hives or the source of the hives.

11                   I'd also like to just point out a couple of

12   other potentially concerning responses that were seen,

13   and that is that some subjects believed that this product

14   could be used if you had trouble speaking or swallowing,

15   drooling, food or medication allergy, had a fever or had

16   breathing problems.

17                   The second and final question which I'm going

18   to discuss from the label comprehension study was a

19   close-ended question similar to the first.      It read, "Is

20   this product intended to be used for the following

21   conditions?" with a list of 10 indications following this

22   question.      I'm not going to talk about all 10 indications



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1    but instead going to focus on just three. In this table,

2    the columns here represent the five cohorts and then this

3    far left column here represents the total of all five

4    cohorts combined.    These percentages, I should point out,

5    represent the percentage of respondents who believe this

6    was a correct indication for the product.

7                   The first indication or recurring or chronic

8    hives of an unknown source.        That is, CIU.    And you can

9    see that nearly all the respondents correctly identified

10   this as an indication for the product.             However, the

11   second indication, food allergies which is incorrect,

12   a little over 10 percent of the respondents believed this

13   was an appropriate indication for the product.        Moreover,

14   if you focus on the acute hives sufferers here at the

15   far right of the table, you can see that number is almost

16   double.

17                  And then lastly, a one time outbreak of hives,

18   i.e., acute hives.      You can see that about a third of

19   the respondents believe this product could be used for

20   a one time outbreak of hives.         Moreover, if you ignore

21   the first cohort of CIU sufferers who have been diagnosed

22   by a physician as having CIU, that number is basically



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1    double.        Excuse me, not double.         But about 40 percent

2    of the respondents in the other four cohorts believe they

3    could use this product for a one time outbreak of hives.

4                     And then lastly I'd just like to mention the

5    self-selection portion of this study and that consisted

6    of the following question.           "Considering everything on

7    the package label, is this product intended for you

8    personally to take home and start using?"               There were

9    three possible responses that the participants could give

10   to this question.        The first is yes, I can take this

11   product.       The second is I can only take this product after

12   asking a doctor and third, no, I should not use this

13   product.

14                    Again, I've summarized the results in a table

15   here and you can see in the first cohort the CIU sufferers,

16   100 percent of that cohort got this answer correct and

17   that is because all three responses were considered

18   correct or acceptable for this cohort.             However, if you

19   look to the far right, the acute hives sufferer, you can

20   see that just over 50 percent of the respondents got this

21   correct meaning that nearly 50 percent of acute hives

22   sufferers believed they could use this product without



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1    asking a physician first.

2                   And then lastly, I'd just like to provide

3    you with the take-home points and those are this.                  OTC

4    or antihistamines can not be marketed currently for CIU

5    or hives under the monograph system.                  The second.

6    Chronic hives was the most common indication on the

7    labeling from around the world and also Loratadine

8    typically is marketed prescription or behind the counter.

9     That is, it's not typically marketed as over-the-counter

10   outside the U.S.

11                  And then lastly, it seems obvious from the

12   consumer study conducted by the sponsor that consumers

13   will use this product for all types of hives.

14                  Now I'd like to introduce Doctor Ganley.

15                  DR. GANLEY:     Okay.        What I'm going to just

16   do in the next five minutes or so is just give a quick

17   overview to highlight some of the issues.             I think that

18   just     hearing   the   questions          after   the   sponsors'

19   presentations, you sort of get the idea where the issues

20   are.    So this may be somewhat redundant.

21                  What I've listed here are safety criteria

22   for OTC drugs, and these are actually taken from our



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1    regulations.    There's probably additional thoughts that

2    could be captured in these, but there should be a low

3    incidence of adverse reactions or significant side

4    effects under adequate directions for use.     The key words

5    here are "adequate directions for use and the incidence

6    of adverse reactions."      There should also be warnings

7    against unsafe use and there should be low potential for

8    harm which may result from abuse under conditions of

9    wide-spread availability.

10                  I think inherent in this is that a product

11   in the over-the-counter market can be accurately selected

12   and deselected by the general population and not just

13   a subset or a cohort of that population.     I don't include

14   a slide regarding the efficacy of this product and I'm

15   somewhat remiss in that after hearing Doctor Chowdhury's

16   talk where we talked about efficacy.      One of the reasons

17   for doing that is that if the committee decides that

18   urticaria or hives is an acceptable OTC indication but

19   it should be for the general population, that would

20   include a population that would include acute hives, does

21   the efficacy data that sponsor have on hand support the

22   treatment of acute hives?      So that would be one of the



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1    issues that you would have to also address.

2                   These are just some observations that I just

3    want to make clear.    First with regard to the FDA position

4    on urticaria as an OT indication.           We don't really have

5    a position.      Many of our reviews, although somewhat

6    critical of some of the things the sponsor has done, is

7    not an indication of our position on this.                We really

8    are depending on the committee providing some insight

9    on   whether   this   should   be    an    OTC    claim   and    also

10   specifically     whether    the     application      at   hand     is

11   acceptable.

12                  The other thing, which has been recounted

13   earlier, is urticaria or hives as an OTC indication in

14   other    countries.    We   also     have    to   recognize      that

15   pharmaceutical marketing in other countries is different.

16    Consumer behavior is somewhat different in some cases

17   and pharmacy practices vary among countries.               Clearly,

18   the fact that the OTC-ness of this in other countries

19   is based on having some type of health care provider or

20   pharmacist be the one distributing the medication.

21                  The last thing that we really I think are

22   in agreement with the sponsor is consumers may be already



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1    using OTC antihistamines for urticaria.         Some of the data

2    they provide actually indicates that.                It would be

3    interesting to understand how does that happen?             Why is

4    that    so?     Consumers   can    be   influenced    by   various

5    information resources.      The Internet is a prime example.

6     You could go into the Internet and do a search for

7    urticaria and it quickly takes you to resources where

8    it tells you how to treat urticaria.

9                    The other thing that we don't really have

10   a good understanding of is how these products are

11   marketed.      One example would be the brand names.       There's

12   many brand names out there that include the term allergy.

13    How do consumers interpret that?           Do they extrapolate

14   a lot of different diseases and illnesses?

15                   As far as urticaria or hives as an OTC use,

16   one of the important things to understand is for acute

17   or chronic hives, what is the frequency and significance

18   of associated conditions?         Some of those were touched

19   on this morning as far as angioedema and anaphylaxis.

20    I've heard the term rare and infrequent.            It's hard to

21   really get an understanding of what that actually means,

22   especially when you have a product that would go OTC and



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1    be available to tens of millions or hundreds of millions

2    of people.         Things that are rare in one setting may become

3    a little more common in another setting in terms of the

4    distribution.

5                       Clearly, the consequences leading to serious

6    adverse outcomes are important to understand here.                           I

7    think, just hearing the discussion of the committee with

8    the sponsor's presentation, they touched on some of those

9    issues.

10                      Also, what's important is the condition is

11   misdiagnosed by the consumer as urticaria.                    They were

12   discussed also earlier.             Physician intervention.          When

13   is it necessary?         Delay in seeking physician advice are

14   important issues that need to be better understood or

15   discussed, I guess.           Consumer behavior.         Will the OTC

16   availability encourage self-treatment without diagnosis

17   for chronic urticaria?             Now if you have a product out

18   there that is marketed for that, will consumers have less

19   of a tendency to go see a health provider and, if they

20   do, was there a negative consequence to that?

21                      Consumer         self-diagnosis            condition.

22   Clearly,       I     think    a   chronic        idiopathic   urticaria



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1    population who goes to a physician and is given that

2    diagnosis, I could believe that they would be able to

3    diagnose that condition should it occur again.            I'm not

4    sure I need a study to tel me that.        But I guess the issue

5    comes down to what will the general population do with

6    that and what things can we do to influence behavior

7    because the bottom line here really is to reduce risk

8    and how can we manage risk here in a prospective way?

9                   As far as the sponsor's proposal, as you've

10   heard, they've wanted to limit the indication to chronic

11   idiopathic urticaria by a physician.         In support of that,

12   they've submitted surveys and label comprehension.                    I

13   reviewed the surveys and wrote the review and I'm not

14   going to go over all the details again.           The important

15   things were, in my view, that I'm not surprised by the

16   results of the study.     If you go to any population that

17   has a disease that has intermittent symptoms and they've

18   gone to a health care provider who is treating them with

19   some medication and ask them to take that medication when

20   the symptoms recur, I think most people are capable of

21   doing that. So the outcome that a CIU population could

22   actually use this medication is just not really that



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1    surprising.

2                   As far as the consumer survey, I had some

3    critique about the multiple choice questions being used

4    and open-ended.     The sponsor addressed that.          I don't

5    see a need for me to address that again.         Most of those

6    individuals in that survey had used oral antihistamines

7    prior to getting a physician's diagnosis and I think

8    that's likely to continue in the future.

9                   One other thing is that chronic idiopathic

10   urticaria is not a commonly used term, particularly in

11   telling an individual what the diagnosis is.

12                  The sponsor proposed to limit this indication

13   by simply having labeling that states, use only after

14   being told by a doctor that you have recurring or chronic

15   hives of an unknown source, chronic idiopathic urticaria.

16    As I mentioned, we have had some experience with that.

17    Not all of it has been great.         The vaginal anti-fungal

18   products have a warning that says do not use if you have

19   never had a vaginal yeast infection diagnosed by a doctor.

20    Subsequent studies have suggested that as many as 40

21   percent of individuals that use those products have never

22   had that diagnosis.



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1                   So the problems with the sponsor's approach

2    is that the product is likely to be used for any type

3    of urticaria.      Twenty to 25 percent of subjects who

4    experience hives have chronic hives.         That means 75 to

5    80 percent of a population would have-- there'd be more

6    people that use that have acute hives than would have

7    chronic hives that would have access to this product.

8                   There was no data provided to demonstrate

9    accurate self-selection and de-selection in a general

10   population, not just a CIU population.           There is no

11   consensus for consumers on the name CIU.       Hives is likely

12   to be translated broadly by the consumer.        The labeling

13   restriction proposed by the sponsor will not likely limit

14   use to CIU subjects.

15                  So the issue for the committee is whether

16   urticaria should be an OTC claim in any form.            If the

17   committee decides that the answer is no to that, that

18   means there is just no studies or anything that the sponsor

19   can do that would ever provide sufficient information

20   for that to be an OTC claim.           So if you come to that

21   conclusion, the meeting is going to end early today.

22                  The second part would be if you believe that



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1    it's a possible claim, whether the data submitted by the

2    sponsor is adequate or whether there is other data that

3    they need to collect and provide.

4                   With that, I'll conclude my discussion.

5                   DR. CANTILENA:     Okay.   Thank you, Doctor

6    Ganley and other members of the FDA team for their

7    presentations.

8                   We now have time slotted for questions to

9    the FDA presenters.     We'll just sort of use our open

10   format that we used earlier.        Doctor D'Agostino.

11                  DR. D'AGOSTINO:     The question is probably

12   to Doctor Holman but maybe Chowdhury would also be

13   appropriate.     You presented that the drug is used in a

14   number of non-U.S.A. countries and the actual indication

15   does say hives.   Is there a body of data?   I mean I realize

16   that the FDA does its own reviews and so forth, but is

17   there a body of data, publications and what have you,

18   where the drug has been effective, proven to be effective

19   or substantial evidence that it is effective?         Also, we

20   keep hearing over and over again that the field thinks

21   it is.     What are they basing this decision that it is

22   appropriate on?    What database do we actually have?        I'm



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1    not talking about the Rx.         I'm talking about the OTC

2    aspect of it.

3                   DR. CHOWDHURY:      Yes.    Let me give you the

4    answer from the prescription standpoint and then I'll

5    ask Doctor Holman to answer the question, too.                  In

6    response to your question, the studies in-house that we

7    have reviewed for the antihistamines are for t CIU

8    indication and I'm not aware of any data that we have

9    that looks at the efficacy for other types of urticaria.

10                  DR. D'AGOSTINO:       There are a substantial

11   number of countries where the indication is high.              You

12   said it's OTC.     What's the database?

13                  DR. HOLMAN:   I'm not really sure exactly what

14   the database is.     I talked to some of my counterparts

15   in Canada and the U.K. and there are regulatory bodies

16   there.     We never really discussed the database.        I think

17   it was just sort of assumed that because they were

18   effective for CIU, they would be effective for hives.

19   All they indicated when I specifically addressed the

20   question, is this a hives indication or is this a CIU

21   indication, they indicated that it was a hives indication

22   because they did not feel the consumers would understand



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1    the term CIU or any statement referring to CIU.

2                   DR.    D'AGOSTINO:        Why   is   the   field    so

3    convinced that it is appropriate treatment?

4                   DR. HOLMAN:      I think, as Doctor Wilkin and

5    Doctor Monroe mentioned, the pathway seems to be common

6    between whether it's chronic or acute urticaria, seems

7    to be a common pathway, and that is the release of

8    histamines.    Therefore, antihistamines are effective in

9    preventing CIU or treating CIU would be effective at

10   treating really a more broad hives or urticaria.

11                  DR. D'AGOSTINO:       i'll get off but I just want

12   to understand.       We're saying we don't think that there's

13   a database for hives.

14                  DR. HOLMAN:     No, there's none that I'm aware

15   of.    I think again, as mentioned earlier, it's just an

16   ability to conduct the study to determine that.

17                  DR. D'AGOSTINO:        Thank you.

18                  DR.    CHOWDHURY:         In    response   to    your

19   question, I would probably also ask Schering to see if

20   they have any data in hives of other types because they

21   have two of the four antihistamines that has a CIU

22   indication in the U.S.



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1                     DR. CLAYTON:         We do not have any clinical

2    data on acute hives.         I think, back to Doctor Wilkin's

3    presentation, the mechanism of action is the same and

4    it is still the first line therapy for acute hives, as

5    was in his presentation.          But no clinical data that I'm

6    aware of.

7                     DR. CANTILENA:          Other questions, Doctor

8    Szefler.

9                     DR. SZEFLER:         This is perhaps for Doctor

10   Chowdhury.       As I looked at the literature, and it's not

11   an area that I look at intensively, but as I tried to

12   look    at     it,   I   tried   to    understands   what   are    the

13   pharmacodynamics of the effects of the antihistamines

14   and does it reduce the course of episodes?            Does it just

15   merely reduce the itching?              If it just merely reduces

16   the itching, then how does that differ from acute hives

17   where that would be the main purpose would be to reduce

18   the itching?         So I'm trying to kind of sort out the

19   dynamics in terms of time-related effects, magnitude of

20   effects.       Statistically it's there in a lot of these

21   parameters, but I'd kind of like to get a feeling of what

22   you would select as a primary outcome variable if you



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1    had to look at this area.

2                     DR.     WILKIN:         I       can    speak      to    that.

3    Basically, it's a symptomatic kind of therapy.                          If you

4    want to think of it as the where is the disease, if it's

5    the IGE mediated, it's the B-cells, the -- arm of the

6    immune system recognizing something that really doesn't

7    pose that much of a threat to the body being recognized

8    as   foreign     and     then    being     over-reacted          to     by   the

9    production of IGE that will bind to the mast cell.                      That's

10   probably the disease part.                   Where the histamine is

11   downstream from the mast cell, how the antihistamines

12   work is they just work for that particular episode but

13   they don't have any effect on long-term prognosis over

14   the course of the disease.            Sometimes patients will have

15   IGE and later they'll develop IGG blocking antibodies

16   are sort of      things that they'll have a natural tolerance

17   develop,       but   that's     not   because          they   were      on   the

18   antihistamine          therapy.        Antihistamine            therapy       is

19   symptomatic.         It blocks the histamine receptors that

20   mediate the itch and also the vasodilation and the

21   vascular permeability.

22                    DR. SZEFLER:         Let me just tease it out a



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1    little bit more.    Is this something that -- again, when

2    I was looking at the pharmacodynamics, there weren't

3    diagrams jumping out.          There were tables in terms of

4    durations.     is this something that you expect to see at

5    12 hours a statistical difference, 24 hours?                     There's

6    not a lot of literature and the literature is not kind

7    of crystal clear in terms of these effects.                  I'm trying

8    to look at how do you look at it in terms of if you were

9    to look at acute urticaria, what could you see and what

10   would be the primary outcomes that you could measure and

11   look at?

12                  DR. WILKIN:      Well, acute urticaria, although

13   it gives the picture of a single episode where one breaks

14   out and the hives are there for maybe 24 - 36 hours,

15   something like that.       In point of fact, the hives migrate

16   around so it's mast cells releasing the mediators in

17   different portions of the skin at different times.                      If

18   at the beginning of one of those episodes one takes the

19   antihistamines,     you     can    actually       then    shorten      the

20   particular course.        Does that speak to the question?

21                  DR. SZEFLER:       Yes.        i'm trying to decide in

22   my own mind whether this is an area that's been poorly



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1    studied because there's been just not enough direction

2    and there's been so much assumption there, we don't have

3    to study this in depth and it's really not been looked

4    at as a discipline the same as, say, things like asthma

5    have been looked at and defining primary outcomes and

6    getting a real good -- area because what I get the

7    impression of is that well, it's a tough area to study

8    and it's kind of hopeless and maybe we shouldn't go for

9    acute urticaria but then, on the other hand, maybe the

10   incentive has not been there to come up with clever methods

11   to really look at this in depth.

12                  DR. WILKIN:   I think you've actually touched

13   on the real piece and that's the methodology.         How does

14   one actually look at acute urticaria?       You would almost

15   need to be clairvoyant to know who's going to get acute

16   urticaria to capture them in time to give them a medication

17   so that you could follow them for what very often is just

18   a couple of days of an acute urticaria episode.          I mean

19   we talk about the six week point being the time where

20   we then will define it as chronic urticaria but most of

21   the patients who have acute urticaria don't have six weeks

22   worth of acute urticaria.      That time point is just simply



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1    to separate those who have the bad prognosis.           It's very

2    likely theirs is not going to go away.          Most urticaria

3    goes away in the first couple of days or the first week.

4     So it would be very difficult to recruit patients, study

5    them, give them drug or give them placebo and make the

6    comparisons because there's going to be a high spontaneous

7    disappearance of the urticaria during that time period.

8     I think acute urticaria is just incredibly difficult

9    to study.

10                     Now, what you can say about acute urticaria

11   and chronic urticaria, many of the etiologies if you will,

12   the things that ultimately are outside of the mast cell

13   that then impact on the mast cell, many of those are in

14   common.        The mast cell only has one trick.      It's got the

15   same little vesical filled with all of these things that

16   it releases.        It is an identical vesical, regardless of

17   what the difference etiologies, be they immunologic or

18   direct mast cell media release, it still releases that

19   same vesical which still has the same effects on the

20   vasculature and the afferent nerve endings.

21                     So I do think that it's not data.     It's going

22   from first principles but I think it's acceptable to



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1    approach urticaria as being very homogeneous in its final

2    terminal pathways unless you've got one of the mechanisms

3    that we know about, one of the compliment deficiencies

4    or other sorts of things that it's a special variety and

5    there are some findings that could, I think, be crafted

6    into    labeling   that   would     alert    patients   about    the

7    additional associated features or the notion that the

8    urticaria doesn't itch.

9                   DR. SZEFLER:        I guess, again, I kind of

10   wonder just how much time has been spent in terms of trying

11   to come up with studies because I recall one of the slides

12   that said food is a precipitant in about 10 percent of

13   the patients and you could challenge patients as long

14   as you didn't think that this would cause anaphylaxis

15   if that wasn't a component so you could time the challenge.

16    As long as you looked at what was your primary outcome

17   variable, I think you could measure in a suitable enough

18   population whether there was an effect on this kind of

19   parameter.     So again, I'm just kind of wondering how much.

20    Maybe it's been assumed that because the sedating

21   antihistamines work in these areas that it's not an area

22   of concentrated studies.         But I think I could sit back



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1    and design studies on this.      As long as you had some feel

2    from the literature what were primary outcome variables,

3    what would you measure.

4                   DR. CANTILENA:     Actually, I think some of

5    these issues will come up this afternoon, if we can hold

6    that, because then we have Doctor Wood, Doctor Davidoff

7    and Doctor Sachs next.

8                   DR. WOOD:   I have two questions.      I'd like

9    to ask them separately because they're sort of unrelated.

10    I guess I'd like to address them to Lloyd and Doctor

11   Rosenberg.     As I hear this, it seems to me that as we

12   try to put it together, we're hearing evidence that the

13   drugs are effective in the treatment of CIU and the worry

14   seems to be that patients with other types or urticaria

15   and potentially other skin diseases will use this therapy.

16

17                  So my question to the dermatologists is

18   should I care about that?    I mean does that really matter

19   if other patients use it because if it doesn't, then these

20   other issues that are kind of just bubbling up here and,

21   although they're interesting, they're not really relevant

22   to the decision on the table.



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1                     So the question I'm really putting to you

2    is there bad things that are going to happen to patients

3    who have other skin diseases and, apart from delay, who

4    might take this acute urticaria or for other diseases

5    or whatever?

6                     DR. ROSENBERG:     I would say no based on long

7    experience and being in dermatology for a long time.

8    Also, I'll ask the chairman about this afternoon's

9    meeting.       Have the Academy of Dermatology, the Allergy

10   Society, sent people here and request a place on this

11   meeting?

12                    DR. CANTILENA:    No, it actually doesn't look

13   like that.       We only have three individuals who have

14   registered for this afternoon.

15                    DR. ROSENBERG:      I think that answers your

16   question, Doctor Wood, like the dog that didn't bark.

17   I've been involved in these proceedings when we talked

18   about Acutane and the pediatricians were here in force

19   and when some of us were trying to have over-the-counter

20   hydrocortisone made a legal prescription in this country,

21   the Academy of Dermatology expressed at that time grave

22   reservations about the safety of things being missed and



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1    it just went on and on over many, many meetings.      I think

2    that those bodies all pay close attention to what goes

3    on at FDA and would have sent somebody here had they raised

4    any issues at all.

5                   DR. KING:   I have to agree, having been on

6    the Acutane study in which everybody got on a campaign

7    about all the regulations that should be in place. It

8    is a dog that didn't bark.     Many of the folks we see come

9    in and we have them fill out lots of sheets about what

10   they've done.     They know more about Benedryl sometimes

11   than our residents do.     So I think they're going to be

12   taking it because mama, the neighbors, particularly

13   people who are English as a second language are going

14   to take it anyway.   I can't remember a case in which taking

15   a first or second generation antihistamine blocked or

16   in any way endangered a patient from taking it prior to

17   coming to see a dermatologist or other physician.

18                  DR. WOOD:   So the answer to that is thaI

19   shouldn't care.

20                  DR. KING:   Shouldn't care.

21                  DR. WOOD:   The second question I have is a

22   sort of question from a simple guy in Tennessee.            I'm



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1    interested in the labeling idea, that you should only

2    take the drug if you've been told by a physician that

3    you have chronic idiopathic urticaria, but just in the

4    patients I see in Tennessee, I don't think many of them

5    leave our hospital saying to themselves as they walk out

6    the door, I've got chronic idiopathic urticaria.                  That

7    doesn't sound like a phrase that drops off the lips of

8    the average patient somehow.

9                    So I wonder if that's the right label and

10   if there's something that's more commonly used by lay

11   people and this gets back to the question of the hives.

12    That seems to me something that people would use more

13   commonly.      I just worry about demanding a label be given

14   to   something    that   patients        don't   customarily     use,

15   certainly not my patients.               Maybe other people, the

16   sophisticated people in the northeast.              Lloyd, what's

17   you feeling about that?

18                   DR. KING:     Well, actually I'm biased because

19   I'm from Tennessee, too.          Is there anyone here who's not

20   from Tennessee?      Well, there are several.          We have had

21   notoriety because of Vice President Gore.              I think the

22   issue as I thought about it is if we're going to have



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1    across the world, you almost have an issue of labeling

2    which is what do you do about groups of people in which

3    English is a second language or conversely in which French

4    or Russian is a second language, so to speak.                You really

5    have to talk about the issues of access to drugs which

6    potentially can hurt you and what percentage of those

7    people will be hurt.        Having worked for cause of orphan

8    drugs, one percent of a huge number is still a huge number.

9     And so I think the issue would be how many people would

10   actually be hurt if we just put chronic hives on the label.

11    I suspect it wouldn't be that many in any case and so

12   if you had to put on there that for aspirin it can trigger

13   fatal reactions, it almost did my mother times two, you

14   could get into a labeling nightmare.                 So I would have

15   no trouble putting on there indicated for chronic hives,

16   see your doctor, and I'd like to see something like a

17   big eye ball and MD or its equivalent and then whatever

18   language saying see your doctor if there's --

19                   DR. WOOD:    In my mind, it would seem like

20   insisting      that   patients   with        a   diagnosis   of   acute

21   myocardial infarction rather than a heart attack which

22   for most patients is what they're really going to carry



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1    in their conversation.       So both of these seem to circle

2    back to the conclusion that if we are not worried about

3    patients taking the drug for other types of hives because

4    of risk to them and, in addition, the vernacular that

5    patients use is hives rather than chronic idiopathic

6    urticaria, then that seems to me to answer some of the

7    other issues that are on the table which are more

8    scientifically       interesting      perhaps    but     are     not

9    practically enforceable.         Is that fair?

10                    DR. KING:   I agree.       I think if you have,

11   as I often times approach a Palm Pilot or some of these

12   PDA kind of things, if you don't know how to use it or

13   you don't understand that, I'd rather have something

14   straightforward, chronic hives as opposed to see your

15   doctor if you have chronic hives of undetermined etiology.

16    I like your thought.

17                    DR. CANTILENA:    Doctor Davidoff and Sachs,

18   then Gilliam.

19                    DR. DAVIDOFF:      Yes.     I have a question

20   primarily for Doctor Chowdhury.              Others may want to

21   comment.       It has to do with the efficacy data because,

22   even though I realize, as I understand, the OTC decisions



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1    rest primarily on issues of safety, it's really more,

2    I think, a balance of safety and efficacy because even

3    if a drug is not very toxic, if it's ineffective, that's

4    not a very good equation.       Which raises the question about

5    how to interpret the data on efficacy in CIU.              The data

6    that were presented there, comparing the non-sedating

7    antihistamines to placebo are really, as was commented

8    on in the materials provided, fairly under-whelming.

9    The difference is, I guess, about a mean of half a point

10   on a four point scale.          But beyond that, there were no

11   confidence intervals, so I don't know how to interpret

12   that since I don't know what the possible range of quote

13   "true" effects was or wasn't.

14                  But underlying all of that is the question

15   of well, even accepting .5 on a scale of total of four,

16   that may be statistically significant, which I guess it

17   was, but is that clinically significant or maybe others

18   could    comment    on   what     is   felt   to   be   clinically

19   significant?       To help with that, it would help to know

20   the distribution of responses because it could be that

21   a substantial portion of the patients so treated really

22   got very strikingly positive responses but it might be



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1    sort of a bell shaped curve.           Maybe you could elaborate

2    a bit on the meaning of significance here.

3                    DR.   CHOWDHURY:         Well,       this      is   a    very

4    difficult      question    to   answer        what   is    a   clinically

5    meaningful difference versus a statistically significant

6    difference and for evidence of efficacy we compare to

7    placebo and if the drug is statistically significantly

8    superior in situations like this where we did not really

9    have a prior understanding what difference is clinically

10   meaningful.       The     differences,         as    you   saw,     in   the

11   urticaria trials were not that remarkable.                     Really, for

12   antihistamines, were there indications also like allergic

13   rhinitis. The differences from placebo are usually not

14   that remarkable.        And also there is a significant -- not

15   statistically so but just numerically a placebo response

16   there for the two arms as the time goes on comes closer

17   and closer.

18                   So it's very difficult really to put a number

19   on that that kind of difference would be clinically

20   meaningful.      We don't have that, and the data, as you

21   correctly pointed out, are from CIU patients and how that

22   translates to acute urticaria is not known.                     As Doctor



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1    Szefler mentioned, those studies are not done, not

2    necessarily that it can not be done.             It has just not

3    been approached, not been done.           Perhaps one could design

4    clever studies to answer these questions.

5                     DR. DAVIDOFF:     I understand about the later

6    data on acute hives, but do you have any information on

7    what the distribution of responses is within the study

8    population?

9                     DR. CHOWDHURY:      I don't have it right on top

10   of my head here and I would ask Schering to see if they

11   can share some of the data that they have from their

12   studies.       I do not.

13                    DR. CANTILENA:        Doctor Temple might have

14   that somewhere.

15                    DR. TEMPLE:     I only want to point out that

16   the same questions arise in studies of angiolytics,

17   antidepressants and things like that.             If you look at

18   the mean difference from placebo, it's relatively small

19   compared to the spontaneous improvement in the untreated

20   placebo group and we don't really know whether that's

21   a condition of the study.          For example, with respect to

22   allergic rhinitis, if you do so-called field studies,



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1    the differences are small, hard to detect.             Most trials

2    fail.     If you do chamber studies where you control the

3    antigen and introduce it, it's very easy to show effects

4    and dose response and all that kind of thing.

5                   Nobody   quite    knows     whether     this     is       a

6    phenomenon of the study or is really true because people

7    certainly have the impression that they have visible

8    effects from antihistamines and yet if you look at the

9    study results, the results are puny.           So as was said,

10   we consider it quite remarkable if you can actually beat

11   placebo in these settings.       We have in a number of cases

12   tried to look at the distribution of responses.             It turns

13   out if the median effect is tiny, the distribution of

14   responses isn't very different either as a rule.                There

15   could be exceptions to that, I suppose, and we always

16   look for tails on the thing.        But that on the whole has

17   been remarkably unproductive.         So that's unsatisfactory

18   in some ways but that does seem to be how a lot of these

19   turn out.

20                  DR. CANTILENA:      Okay.     Thank you, Doctor

21   Temple.

22                  Doctor Sachs and then Doctor Gilliam.



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1                   DR.   SACHS:      In   the   past    we   have   been

2    presented with actual use studies of the drug kind of

3    as it would be given OTC and I was just wondering if that

4    was not going to be done this time, #1.            #2, sine we met

5    in May, has the FDA received any more of the indicators,

6    for example, from Poison Control or overdose or things

7    like that which we usually look at in having the drugs

8    go OTC.

9                   DR. CANTILENA:      Doctor Ganley.

10                  DR. GANLEY:    As far as an actual use study,

11   that was the determination of the sponsor that they didn't

12   need a study.    We didn't have many discussions with them

13   before they submitted their application to even discuss

14   that.    So that would need to be addressed by the sponsor.

15    Quite frankly, I think an actual use study in a general

16   population to look at hives is probably a tough study

17   to do because you can imagine if you have a population

18   that you're actually trying to look at acute hives, how

19   frequently does that occur and how many people would you

20   have to actually enroll in a study like that over how

21   many month period of time to follow up to just get 200

22   events of hives and did they use it correctly.              You may



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1    be talking thousands or tens of thousands of people to

2    be followed for several months.            So that's one of the

3    issues that you would have to discuss today is whether

4    an actual use study is the best mechanism if you needed

5    additional information or other alternative mechanisms

6    to address that.

7                   I don't believe we have more data.           Doctor

8    Chowdhury may be able to address that as far as the Poison

9    Control information.    The company had submitted some data

10   regarding the safety of the drug and I don't believe there

11   were many cases, particularly in reports reported to them

12   and the agency with regard to people using it for a hives

13   indication or chronic idiopathic urticaria indication

14   where they ran into a lot of problems.         There were a few

15   serious cases, and I think we have someone here who could

16   address those if you have questions regarding that.

17                  MR. LEE: I'm Charles Lee, medical reviewer

18   in Division of Pulmonary Allergy Drug Products.

19                  As far as the overdose information, there

20   didn't appear to be any signal in the data that the sponsor

21   submitted.     There did seem to be a difference, however,

22   in the proportion of serious adverse events that were



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1    due to anaphylaxis in patients who had so to speak CIU

2    as compared with patients who had allergic rhinitis.

3    In the initial submission, 11 percent of serious adverse

4    events were for -- how do I want to say this?         Of patients

5    with CIU who had anaphylaxis, there were 11 percent of

6    the entire population of patients who had serious adverse

7    events as compared with two percent of patients with

8    allergic rhinitis.

9                    Probably saying to say it more clearly, the

10   proportion of patients with serous adverse events due

11   to anaphylaxis was higher in patients who had so to speak

12   CIU compared with patients who had allergic rhinitis.

13   If one looks at those reports, most of those patients,

14   in fact, did not have CIU.            Only one of those patients

15   had CIU.       The others were actually patients who had

16   urticaria for other reasons.            So I think what that kind

17   of may suggest is that perhaps there is a little bit of

18   a difference in the risk profile in patients who will

19   be taking the product urticaria as compared to the

20   population that would take it for allergic rhinitis.

21                   DR. WOOD:     Is that what you're saying or that

22   more patients had anaphylaxis and were confused in the



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1    situation?     I mean I'm not understanding, I guess, what

2    you're saying. I would not interpret that to imply that

3    more patients developed anaphylaxis due to the drug in

4    that group than patients who were treating for allergic

5    rhinitis rather than there was more of a background of

6    an anaphylaxis that was mistakenly being treated.              Have

7    I got that wrong?

8                   DR. GANLEY:      Yes.     I think that's what he

9    meant is that if there's an increased frequency of

10   anaphylaxis in the urticaria population to begin with,

11   then you would expect potentially to see a difference

12   in the percentage comparing allergic rhinitis versus the

13   urticaria population.       I think that gets back to one of

14   the issues that I raised in my summary is what is the

15   frequency of these events.           Are they of a high enough

16   frequency that we should have cause for concern or is

17   it something that should be addressed in labeling or how

18   do you handle that situation?

19                  There was clearly, I think, one case and

20   Charlie can clarify it was the case, of a person who had

21   an allergy to shrimp, I believe.

22                  MR. LEE:     Right.      The one fatality due to



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1    anaphylaxis was in a seafood allergic patient or seafood

2    sensitive patient who apparently chose to ingest a pizza

3    with the seafood removed from the pizza apparently

4    developed urticaria, early symptoms of anaphylaxis, took

5    the product in what appears to be an attempt to treat

6    the symptoms and who eventually died from the anaphylaxis.

7     It's one single case.                However, I think that in

8    conjunction with what Doctor Holman had on his slide with

9    16 percent of the general population believing that the

10   product is intended for food allergy, I think it does

11   raise some concerns about potential misuse of the product

12   in    patients       who     had      inappropriately              selected,

13   particularly     if    one     takes     into       account      that    that

14   population making that inappropriate choice, when you

15   throw    in,   say    for    instance,          a   direct    to    consumer

16   advertising, how patients perceive advertising, if that

17   in fact might increase the risk of that happening or

18   increase the likelihood of increasing the percentage of

19   patients that might make a poor choice like that.

20                  DR. CANTILENA:         Okay. Well, thank you.              Some

21   of those issues I'm sure will come up this afternoon and

22   then our final question for this morning would be with



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1    Doctor Gilliam.

2                   DR. GILLIAM:    I was wondering if the FDA or

3    maybe Doctor Monroe knows.      What's the incidence of CIU

4    in general or of hives in general and what made me think

5    of this was the package insert that was going around.

6    I'm a little concerned that they're going to come out

7    with separate packaging just for CIU.      It would make me

8    much comfortable if it was on the box with allergy

9    indication.    Also, I just see this as being maybe them

10   using this to make a whole other market for something

11   that's not really a big issue and if somebody could shed

12   some light on that.

13                  DR. CANTILENA:    Charlie, do you want to try

14   that one?

15                  DR. GANLEY:    Well, I think in our executive

16   summary we sort of threw that in as an issue for how do

17   you market and what is the -- you know, you look at these

18   numbers and it's hard to get a sense of how many patients

19   per year have hives I think is really what you're asking

20   because a lot of the percentages that are provided is

21   the cumulative prevalence over time.       The issue really

22   comes down to well, are there 10 million cases of hives



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1    in the United States each year and 20 percent of those

2    are chronic and 80 percent are acute or something related

3    to that.       That's I think what you're asking and I think

4    that's an important question to understand.        I don't know

5    what the answer is because most of the figures I've seen

6    are cumulative prevalence over a lifetime.

7                     DR. CANTILENA:      Is there anyone from the

8    sponsor who would like to add to that?

9                     DR. MONROE:    I would agree.     As we said,

10   about 15 to 20 percent of the population experiences

11   urticaria and only about up to three percent of those

12   in their lifetime have chronic idiopathic urticaria but

13   at one point in time what the incidence is, I'm not aware.

14                    DR. GILLIAM:    My question is is there really

15   an indication for CIU if the prevalence of this is so

16   small, is it really needed?

17                    DR. CANTILENA:     Well, I think probably the

18   answer is obvious if you ask the sponsor because that's

19   why they're here.       So maybe on that note we will break

20   for lunch and actually if you wouldn't mind, can we come

21   back at 1:15.      We'll go an extra 15 minutes.     We'll have

22   the public comment session start at 1:15.          Thank you.



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1                  (Whereupon, off the record at 12:07 p.m. to

2   reconvene at 1:15 p.m.)

3




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1                   A-F-T-E-R-N-O-O-N      S-E-S-S-I-O-N

2                                                        (1:19 p.m.)

3                    DR. CANTILENA:      I have just one carryover

4    from this morning's question and answer session of Dr.

5    Clayton, I believe, would like to share with us some

6    information that was in response to a question from Dr.

7    Uden.     They have some information that they would like

8    to show us.

9                    Do you have that, Dr. Clayton or Mr. Neuman?

10                   DR. CLAYTON:    Mr. Neuman.

11                   MR. NEUMAN:      This was in regard to the

12   question on the race regarding the label comprehension

13   study.     I had the wrong chart when we spoke.        The African

14   American population in that study was significantly

15   larger than what I had portrayed it to be.                It was 20

16   percent in total.

17                   In the CIU population it was 10, in the

18   general population it was 22 percent, 52 percent of the

19   low literacy group, and 20 percent of the special

20   population, and 11 percent of the acute hives cohort.

21                   DR.   UDEN:     And     do   you   have    Hispanic

22   information from Dr. Gilliam?



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1                   MR. NEUMAN:       Yes.     The Hispanic population

2    was 5 percent over all.      It was largest in the low literacy

3    cohort where it was 10 percent.

4                   DR. UDEN:      Okay.     So 65 percent of the low

5    literacy group were African American and Hispanic?

6                   MR. NEUMAN:       That is correct.       62 percent

7    actually.

8                   DR. UDEN:      Thank you.

9                   DR. CANTILENA:         Okay.   Thank you for that

10   information.

11                  We'll now move to the public comment section

12   of the agenda.     We have three speakers.            Each speaker

13   is reminded that they have five minutes for their entire

14   talk.    Our first speaker will be Dr. Gary Kay.

15                  DR. KAY:     Good afternoon, Dr. Cantilena, and

16   members of the committee, I'm Gary Kay.         I'm the Associate

17   Clinical       Professor       of       Neurology.          I'm          a

18   Neuropsychologist from Georgetown and also Director of

19   the Washington Neuropsychological Institute.                By means

20   of disclosure, nobody has sponsored my trip.            I live here

21   in Bethesda so it wouldn't be much sponsorship anyway.

22



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1                     Other than that, with respect to financial

2    support I have received grant and research contracts

3    support        from   Schering-Plough         and     from     Aventis

4    Pharmaceutical in the area of antihistamines.                I've been

5    a consultant to Schering and to UCB in the area of

6    antihistamines in the past.

7                     My   comments   are     on   chronic       idiopathic

8    urticaria and considerations related to quality of life

9    and to CNS issues.       First of all, I think it hasn't been

10   really brought out today in our discussions of CIU the

11   impact this has on patients besides the symptoms of their

12   rash, the amount of itch and scratch and all this.

13                    These patients really suffer a great deal

14   of distress and discomfort.            One of the most prominent

15   quality of life impacts are on their sleep.                       These

16   patients report very disturbed sleep.               Also there is the

17   social    embarrassment.         The   disruption      of    sleep    is

18   probably due to a combination of the disease and the

19   treatment that is often used, the sedating antihistamine

20   treatment for the chronic idiopathic urticaria.

21                    Running a simple Medline search typing in

22   the words chronic idiopathic urticaria in combination



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1    with any of the OTC antihistamines like diphenhydramine,

2    chlorpheniramine, triproladine (phonetic).                       If you run

3    that, you are going to find about 24 current articles

4    in there about efficacy and use of the over-the-counter

5    sedating           antihistamines         for      chronic       idiopathic

6    urticaria.

7                        Run the same search with the words again

8    chronic idiopathic urticaria, loratadine, desloratadine,

9    fexofenadine, cetirizine, and you get a list of 67 current

10   studies on efficacy.

11                       Obviously these medications are widely used.

12    There's       a    lot    of   description        in    these    articles,

13   especially review articles, that this is a mainstay of

14   treatment for chronic idiopathic urticaria.

15                       Well, I think we all have to recognize we're

16   talking about risks of medications.                     All of the current

17   over-the-counter antihistamines used for treatment of

18   CIU    carry        a    precautionary        statement,       "May     cause

19   drowsiness.             Use caution when driving or operating

20   dangerous machinery."

21                       Obviously you have concerns about people

22   reading labels and following labels and how seriously



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1    do they consider those labels.           I would just suggest that

2    you take a look at the findings from the hearing that

3    was held for the FDA NTSB hearing in November, the hearings

4    on sedation and impairment, to take a look at particular

5    issue.     We are not going to recover that again today.

6                      The fact is that if you look at the studies

7    I mentioned, those 24 studies where they review the

8    adverse events in those chronic idiopathic urticaria

9    trials, the most common AEs that are found in those studies

10   is sedation in combination with those medications.

11                     Another issue in CIU is that there's an

12   attitude among many of the physicians that one of the

13   things they are going to do to treat this patient is to

14   help them sleep at night and so administer to them a

15   sedating antihistamine at bedtime.            That may help them

16   with the scratch and the itch and may help them because

17   they've been complaining of not sleeping well at night

18   but, in fact, that may not be so recommended.

19                     Still, you are going to find if you look in

20   the current literature even references to AM and PM

21   dosing.        Treat the patient with a sedating antihistamine

22   at bedtime and give them a non-sedating antihistamine



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1    in the morning so they won't have a sedating effect.

2                   The reality is that you can treat CIU with

3    non-sedating     antihistamines        and     actually    improve

4    people's reported sleep and daytime wakefulness and

5    daytime functioning treating them with a non-sedating

6    antihistamine.

7                   The study that we did at Georgetown was to

8    give people an 8 or 12 milligram dose of chlorpheniramine

9    at bedtime at 10:00 at night and in the morning we gave

10   them a dose of terfenadine.           We followed the Harvard

11   Pilgrim Healthcare AM/PM dosing regime.

12                  And we studied their sleep latency the

13   following day all day long from 9:00 a.m. to 5:00 at night.

14    Every two hours they took a nap.            With the EG we could

15   see when sleep latency began.           We got the average for

16   sleep latency for the whole next day after a night time

17   dose of 8 or 12 milligrams chlorpheniramine.               What we

18   found was that patients getting placebo had a greater

19   than 10 minute MSLT, which is normal.

20                  Those   receiving     the     chlorpheniramine     at

21   bedtime and terfenadine in the morning had a sleep latency

22   diminished down to six minutes which is about where a



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1    sleep apnea patient would be.       It's not inconsequential.

2                   What is also disturbing from that particular

3    study was the patients receiving the 8 milligram dose

4    of chlorpheniramine did not report feeling any more sleepy

5    than the patients on placebo.              Yet they were clearly

6    physiologically impaired in their ability to stay awake.

7                   You can also look at a study we recently

8    submitted to the FDA, a contract research study that we

9    did at Georgetown, showing impairment seven hours after

10   dosing even with doses as low as two or four milligrams

11   chlorpheniramine.     Seven hours post-dosing is impairment

12   on tracking testing.

13                  Summarizing, successful treatment of CIU

14   does not depend upon sedating the patient.           Sedation in

15   CIU is an adverse event and one that can be avoided.

16   Non-sedating antihistamines are as effective as sedating

17   antihistamines in treatment of CIU.

18                  Patients who have been previously diagnosed

19   with CIU, as I think we saw this morning, maybe they're

20   not good at self-diagnosis but the issue of recognition.

21    Can they recognize the disease?               I think that was

22   demonstrated.     Obviously I think these patients would



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1    benefit from access to a non-sedating over-the-counter

2    antihistamines.

3                   Finally, the impact and risks of sedation

4    can be reduced by making a non-sedating antihistamine

5    available over the counter.         Thank you very much.

6                   DR. CANTILENA:       Thank you, Dr. Kay.              Our

7    next speaker is Dr. Engle, Dr. Janet Engle.

8                   DR. ENGLE:      Good afternoon.         Thank you for

9    the opportunity to present the views of the American

10   Pharmaceutical      Association,     a      national    professional

11   society of pharmacists.

12                  I am Jan Engle.           I'm Associate Dean for

13   Academic Affairs and Clinical Professor of Pharmacy

14   Practice at the University of Illinois in Chicago.                   I'm

15   also President of APHA.

16                  My   comments    focus       on   the   role    of    the

17   pharmacist in helping consumers navigate the use of

18   loratadine in the OTC environment.            Particularly if they

19   may need to seek care for chronic conditions such as

20   chronic idiopathic urticaria.

21                  APHA's 50,000 members include pharmacist

22   practitioners, pharmaceutical scientists, and student



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1    pharmacists.      APHA members provide care in all practice

2    settings       such   as    community      pharmacies,        hospitals,

3    long-term care facilities, managed care organizations,

4    hospice settings, and the military.

5                     In each of these settings pharmacists help

6    consumers      manage      and   improve        their   medication      use

7    including the appropriate selection and monitoring of

8    prescription and over-the-counter products.                      Ensuring

9    the public's health and safety, especially with respect

10   to medication use, is the pharmacist's and APHA's highest

11   priority.

12                    In the interest of full disclosure, APHA

13   frequently partners with federal agencies, consumer

14   groups, and the pharmaceutical industry and others to

15   help develop educational programs.                 The association did

16   not receive funding to participate in today's meeting

17   and the views that I'm presenting are solely those of

18   the association and its membership.

19                    The pharmacist's role in OTC drug use is

20   different from the role that is provided by other

21   healthcare providers.            Most OTC products are purchased

22   at a pharmacy positioning pharmacists to work with



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1    consumers at the point of decision making and purchase.

2

3                   Pharmacists serve as the bridge between

4    consumer self-care activities and interaction with the

5    formal healthcare system.         Today I will address the

6    pharmacist's role in bridging these two systems in the

7    context of loratadine and its use for CIU.

8                   APHA agrees that the proposed switch of

9    loratadine from prescription to nonprescription status

10   may potentially improve patient safety and clinical

11   outcomes by expanding consumer access to therapy with

12   fewer sedating side effects than with the available OTC

13   products.

14                  Important to the safety equation, however,

15   is the appropriate use of the TOC product and this is

16   where pharmacists can help.      Pharmacists can and do play

17   and valuable role in helping consumers use OTC products

18   for short-term treatment or symptom control in acute and

19   chronic situations and recommend physician or other

20   prescriber involvement when acute or chronic conditions

21   requiring additional attention are identified.

22                  Pharmacists    work        with   consumers      and



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1    prescribers          every     day      to        selected     appropriate

2    medications.         The proposed switch of loratadine to OTC

3    status    for    the    treatment          of   allergic     rhinitis      and

4    diagnosed chronic idiopathic urticaria can be successful.

5                    Proper symptom identification by consumers

6    and pharmacists will be essential to appropriate use.

7    Each day pharmacists assist in the proper identification

8    of nonprescription medicines to treat a number of clearly

9    identified and easily treatable conditions.

10                   OTC products have been used to treat allergic

11   rhinitis       for     many     years.            Expanding     access      to

12   non-sedating antihistamines will improve OTC management

13   of this condition.            Currently we have no OTC options to

14   treat CIU.      Approving loratadine for the OTC treatment

15   of previously diagnosed CIU after analysis of appropriate

16   studies of safety and efficacy and labeling comprehension

17   will improve management of this condition.

18                   Pharmacists can help assure that consumers

19   using the product to treat CIU have had this condition

20   diagnosed by a physician, are not experiencing an acute

21   anaphylactic         reaction,       and     are    using    this    product

22   appropriately.         I think those are some of the issues that



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1    came up this morning.

2                   The success of the pharmacists efforts in

3    this role, however, will be directly related to the amount

4    of information available to them.                Product labeling

5    should clearly articulate the situations where self care

6    or OTC use is appropriate and direct consumers to their

7    pharmacist or their physician when the use of the product

8    falls outside of label parameters.

9                   Additionally,      an        extensive     educational

10   campaign geared toward pharmacists to equip them with

11   the proper tools to identify triage and select OTC

12   treatment for CIU will be needed.               Pharmacists are in

13   an excellent position to work both with physicians and

14   consumers as well as the industry and government agencies

15   to     improve    patient      outcomes          associated         with

16   nonprescription medicines.

17                  Whether   it     be     by     patient       compliance

18   strategies, medication assessment, counseling on proper

19   usage and side effects, and identification of patients

20   who need therapy, pharmacists are committed to engaging

21   in activities to promote better healthcare for all

22   consumers.



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1                         My comments today are supported by the action

2    taken by our APHA's House of Delegates which is our policy

3    making body for our association.                     In March of 2001 the

4    delegates debated and adopted policy on this issue.                       Our

5    adopted        policy    reads,       "The    American     Pharmaceutical

6    Association as an issue of public safety encourages

7    manufacturers and the food and drug administration to

8    transition non-sedating antihistamines from prescription

9    to nonprescription status."

10                        The nation's pharmacists encourage the FDA

11   and manufacturers of second generation antihistamines

12   to embark on a reasoned path to increase access to these

13   products.        Thank you for your consideration of the views

14   of the nation's pharmacists.

15                        DR. CANTILENA:        Thank you, Dr. Engle.          Our

16   third and final speaker in the public comment section

17   will be Dr. Joseph Ferguson.

18                        DR. FERGUSON:       Distinguished members of the

19   FDA, distinguished representatives of Schering, ladies

20   and gentlemen, including the man in the back who has been

21   snoring        all    day,   I     am    very       appreciative   of   this

22   opportunity to speak before you.                     It is truly an honor



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1    for me.

2                      In the interest of disclosure, I have worked

3    as a consultant for Schering as well as Pfizer, the makers

4    of Zyrtec, and I am currently doing clinical research

5    for Adventis, the makers of Allegra.

6                      I'm      here    today        after    a      Schering

7    representative suggested that I speak at this meeting.

8     Neither        Schering    nor    any     other    corporation        nor

9    individual has offered compensation for my appearance

10   today.         No one has stated or implied that I will be

11   rewarded in any way.         My expenses for attendance at this

12   meeting will not be reimbursed.

13                     I'll be speaking today for only a few minutes

14   and I'll limit my comments to the question of whether

15   loratadine should be allowed to have over-the-counter

16   chronic idiopathic urticaria indication.                  I will leave

17   to   others      the    question    of    whether   to    broaden      the

18   indication.

19                     The title of the talk is, "To deny loratadine,

20   the over-the-counter indication for chronic idiopathic

21   urticaria, is to misinform the American people."                     It's

22   my opinion that a prescription antihistamine that has



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1    been proven to be effective in treating chronic idiopathic

2    urticaria should not have that indication striped simply

3    because the drug has been found to be appropriate for

4    over-the-counter use.

5                   Instead, the antihistamines should have a

6    label that might read as follows, "This medication can

7    be useful in the treatment of chronic idiopathic urticaria

8    (unexplained hives that keep coming back).                 Anyone

9    considering the use of this product for urticaria (hives)

10   should first seek prompt medical attention."

11                  I'll repeat that.       "This medication can be

12   useful in the treatment of chronic idiopathic urticaria

13   (unexplained hives that keep coming back).                 Anyone

14   considering the use of this product for urticaria (hives)

15   should first seek prompt medical attention."

16                  Such a label would be an education for the

17   American public.    A man who has been using antihistamines

18   for what he thinks are recurrent hives would realize that

19   maybe it's time for him to check in with his primary care

20   doctor before he continues to self-treat.

21                  So what if the man does not want to see his

22   physician?     If a person who should be getting medical



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1    attention makes an informed decision not to do so, it

2    is not the place of our government to step in and force

3    medical attention on that person obviously.

4                    Nor is it the place of our government to

5    withhold information from the public such as the fact

6    that a certain antihistamine was found to be safe and

7    effective      in   the    treatment     of   chronic   idiopathic

8    urticaria.

9                    It is not the place of our government to

10   withhold information from the public just because there

11   are people who would make informed but unwise decisions

12   with that information.

13                   Nor is it the place of our government to seek

14   out those who are eating too many cheeseburgers and send

15   in nannies to make them eat broccoli.            It just doesn't

16   make sense.

17                   I would appreciate it now if you would allow

18   me   to   finish    this   talk    by indulging in a bit of

19   speculation, speculation about an America in which

20   loratadine has been approved for over-the-counter use,

21   but the makers of loratadine have been forced to keep

22   quiet about the fact that the drug has been found to be



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1    safe and effective in the treatment of chronic idiopathic

2    urticaria.

3                   A woman, a long-distance truck driver, has

4    chronic idiopathic urticaria.        She has seen her physician

5    who has ruled out the dangerous causes and a prescription

6    antihistamines has been quite effective in controlling

7    her symptoms over the years.

8                   But here she is now.        She's 2,000 miles away

9    from home and she is struck with the most ferocious case

10   of hives she's ever experienced and she realizes that

11   she forgot to bring her prescription antihistamines.

12   She is itching like crazy.       It's even dangerous for her

13   to be driving but she manages to make it to a truck stop.

14

15                  She runs inside and she finds the isle with

16   the allergy pills.     She picks up a body of loratadine

17   which is the only one that doesn't put her to sleep, and

18   she is crestfallen when she realizes that that bottle

19   says that this medication is only for runny nose type

20   symptoms, not hives.

21                  Clawing at her skin she slumps back to the

22   truck and figures she'll drive and get in touch with her



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1    doctor in the morning.       She shutters.       It's going to be

2    a long night.

3                   Distinguished       members       of      the       FDA,

4    representatives of Schering, ladies and gentlemen, thank

5    you so much for your time and attention.

6                   DR. CANTILENA:      Thank you, Dr. Ferguson.

7                   Before   we   get    to     the   open      committee

8    discussion, what I would like to do is offer the members

9    of the committee an opportunity to get an unanswered

10   questions, anything that they would like to ask of the

11   sponsor or of the FDA presenters, anything that was not

12   completely covered in their minds this morning that they

13   would like to first obtain information before we get into

14   the open discussion.     Does anyone have any questions?

15                  DR. DYKEWICZ:     I would like to follow up a

16   bit on some of the data that was discussed earlier about

17   the actual usage of medications when there has been a

18   stipulation or a statement within the product labeling

19   for the patient not to use it.             I believe the example

20   that was given was for the antifungal products to be used

21   for vaginal infections.

22                  It really gets at the whole question about



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1    actual usage versus what is being placed upon the product

2    labeling.      We   know     apparently       in   that   particular

3    over-the-counter usage that many patients are using the

4    medication, if you will, inappropriately despite the

5    statements.

6                   Now, in terms of label comprehension, is the

7    FDA aware of any studies that show that people or women

8    were appropriately understanding what the label said but

9    despite that went forward and used it inappropriately

10   anyway?

11                  DR. KATZ:      Back when these products first

12   went over the counter, there actually were no label

13   comprehension or actual use studies for the vaginal

14   antifungal products.        There have subsequently been some

15   literature that has been published suggesting that, in

16   fact, there are a group of women who may be using the

17   product inappropriately.           Not all women who are using

18   the product have previously seen a physician and have

19   had a previously diagnosis.

20                  We don't really have the data that would

21   correlate how well they understood what was in the label

22   and if the reason why they are using the product is that



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1    they didn't understand the labeled instructions, or that

2    they had just chose to use the product because they thought

3    that they really had a vaginal yeast infection even though

4    they have never actually been diagnosed as having one.

5                   DR. CANTILENA:     Okay.      Dr. Alfano next and

6    then I saw another hand.

7                   DR. ALFANO:      Yes.       The sponsor presented

8    some data and Dr. Ganley referred to it that 62 percent

9    of people with CIU self-medicated prior to a physician

10   diagnosis.

11                  My question either to the sponsor or to the

12   agency is do we know what percent of people with acute

13   hives premedicate seeking medical attention?

14                  DR. CANTILENA:     Dr. Clayton, would you like

15   to try that one?

16                  DR. CLAYTON:     We do not have that specific

17   information, but since these individuals use an OTC

18   antihistamine prior to diagnosis, we will assume that

19   episode was an acute episode but it was prior to a

20   physician diagnosis of CIU.

21                  DR. CANTILENA:      Dr. Ganley, is there any

22   other information that you have other applications or



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1    products?      Okay.

2                    Dr. Joad.

3                    DR. JOAD:   I was curious for the FDA about

4    how they felt in general about the general concept of

5    having a drug OTC that prior to that they had to see a

6    physician one time for a diagnosis and then thereafter

7    everything should be OTC.

8                    That strikes me as something I wouldn't like

9    very much because I would like to see a patient back so

10   I could have another shot at that diagnosis if I was wrong.

11    Is that something you plan to do in general or are you

12   comfortable with it and is it a direction for the FDA?

13                   DR. GANLEY:    Actually, that's what we were

14   hoping you would answer for us today.       I think, though,

15   if you really -- you know, that's why it's pivotal to

16   try to think of this spectrum of patients that are going

17   to take it and try to figure out what's the down side

18   of that.

19                   I think it would be every difficult based

20   on just the facts that we know in this case to ever create

21   any label that unequivocally is going to ensure that

22   people only with CIU are going to use this product.                I



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1    think it's virtually impossible to do that.

2                   That's why it becomes important to understand

3    what is the frequency and significance of these other

4    conditions such as angioedema that may be associated with

5    urticaria or acute urticaria.         Is that acute urticaria

6    somehow different than this population of chronic in terms

7    of the frequency and severity of conditions.

8                   I think it would be difficult based on the

9    facts we have that people already use it and there's a

10   perception out there that you can use it for these

11   conditions to just believe that we are going to limit

12   it by putting something on a label.

13                  In the converse then if you go down a path

14   that says this could be just for the treatment of hive

15   and then you actually put in labeling or something that

16   defines the parameters of when someone needs to see a

17   physician, repeated episodes and daily for seven days.

18    I think we are having the cart lead the horse here where

19   you're saying that it's only this population that has

20   a diagnosis of chronic urticaria.

21                  Actually if you put on a label that it's for

22   recurring episodes of hives and people just ignore that



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1    they should see a doctor for that actually to get a

2    diagnosis of exclusion, then you may have people that

3    actually use it thinking this is for recurring hives.

4                        DR. CANTILENA:       Dr. Temple.

5                        DR. TEMPLE:     In some sense this is an issue

6    that arises every time you make an OTC switch whether

7    it's heartburn that may or may not have been bad esophageal

8    disease        or     the   use     of     low-dose    hydrocortisone

9    preparation.           Prior to their availability over the

10   counter, there was always a doctor intervening and

11   deciding whether this was serious enough to require

12   recurrent visits.

13                       Every time we do that, that is why we have

14   public discussion of whether it seems like the same thing.

15    The vaginal anti-candidiasis drugs was a very difficult

16   one for us.         As you may remember, we turned it down several

17   times before we finally concluded it was okay.                  This is

18   not unfamiliar territory.             That's why we need advice.

19                       DR. JOAD:     Just as a follow-up, it seems to

20   me   different        between     saying    somebody    can    diagnose

21   themselves and, therefore, they go get the OTC versus

22   it's complicated enough that a physician has to diagnose



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1    it but then now it's OTC.        Those seem like very different

2    things to me.

3                    DR.    TEMPLE:        You    mean     the    explicit

4    requirement that it be diagnosed first?

5                    DR. JOAD:    Right.

6                    DR.    TEMPLE:       That's    why     the    vaginal

7    candidiasis was just a problem because that's what the

8    labeling said and obviously people knew that not everybody

9    would go to the doctor first for that.

10                   There had been a view that dermatosis that

11   might be steroid sensitive ought to be considered the

12   same way, that you ought to go to the doctor and find

13   out what to do first.        We have survived switching them,

14   at least for low-dose drugs, to let patients give

15   themselves a crack at it.          But that's why it's hard.

16                   DR. CANTILENA:      Yes, Dr. Clapp.

17                   DR. CLAPP:       I have two questions.          First,

18   could someone from the FDA addressed the data from the

19   UK and Canada.        As I recall, since 1990 Canada has had

20   hives as an OTC indication for use.           They mentioned that

21   there    were   no     adverse    effects     noted    in    Canadian

22   literature.      Could you address that more precisely in



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1    the UK?        That's the first question.

2                      DR. GANLEY:     The data I think you may be

3    referring to, and you can correct me if I'm wrong, is

4    the data that Dr. Lee had talked about, and that was

5    information that had actually been reported.             We focused

6    mainly on serious adverse events.

7                      As he had said, there were some cases of

8    anaphylaxis and things like that.               I think one of the

9    difficulties, and it's a problem in this country as well

10   as in Canada and the UK, is the reporting of these events.

11    You have to have -- there has to be some type of faith

12   in that things are going to get reported that may be a

13   problem.

14                     I think there are some cases that Dr. Lee

15   had talked about which is of some concern, if people would

16   actually have food allergies and think that mistakenly

17   that you could prevent the allergy by just taking the

18   medicine and you may end up with numerous cases like the

19   woman who ate the seafood pizza.              She took it after the

20   fact.

21                     Here, though, if you have a drug on the market

22   where they are advocating use for allergy or urticaria,



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1    is this going to create a problem and how do you -- it's

2    really coming down to if it is a problem, how can you

3    prevent that problem whether it's through labeling or

4    education or whatever.

5                   DR. CLAPP:    What I was interested in the

6    Canadian experience.

7                   DR. GANLEY:    As I said, there are cases of

8    anaphylaxis that have been associated with the use of

9    the drug for the treatment of urticaria.    Unless you have

10   more specific, clearly that is one of the issues here

11   is what are the significant adverse events.         We would

12   be less concerned with very minor adverse events if

13   someone reports a headache or anything like that.

14                  DR. CLAPP:     I certainly understand that.

15   What I was wondering is in the body of research that you

16   have gleaned from, UK and Canada, whether or not there

17   have been a significant number of adverse events, serious

18   adverse events reported because of the longevity of their

19   experience having used it as an over-the-counter drug

20   for hives.     I don't think they mentioned recurring hives

21   but included hives as well as seasonal allergic rhinitis

22   as an indication.



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1                    DR. KATZ:      I think the question that you're

2    asking, we can only give you some sketchy information

3    because we don't keep track of other countries' adverse

4    event data.     We do have one table that was provided to

5    us but the total end that they provide for the adverse

6    events is an end of 26 so we're talking a low number.

7                    Now, I can't tell you over what period of

8    time it is because it doesn't state in the information

9    that's here.        But if you look at it, actually it looks

10   like there may be a response from Schering.                   The adverse

11   events that are being reported here would be things along

12   the    line    of    pain,    dyspepsia,          headache,    urticaria

13   aggravated abdominal pain, back pain.

14                   All of these are numbers that are less than

15   three or three and below.           Again, it doesn't really help

16   you because I can't put it into a perspective of what

17   time frame we're talking about.                 If this is coming from

18   their adverse event reporting like our Medwatch system,

19   you don't have a denominator.

20                   The numbers are low and the reporting system

21   is whatever gets reported back.                 There doesn't look like

22   from this that we have that there is anything that would



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1    be unusual or unexpected as compared to our own database

2    where the product is Rx.

3                   DR. CLAPP:       Thanks.         I would like Dr.

4    Chowdhury to address some data he mentioned.                   In the

5    literature we received it said 79 percent of those who

6    read the labels incorrectly mentioned or identified the

7    use of the drug for just hives, not the CIU indication

8    that is being promoted by the drug company.

9                   In that the interest is inadequate directions

10   for use, how does the FDA feel comfortable representing

11   this drug without addressing the fact that most of those

12   who use it will likely use it incorrectly?                Should we

13   address the fact in the direct way that the likelihood

14   is that most of those who use it will use it incorrectly

15   and then guide them in appropriate usage of the drug?

16                  DR. CANTILENA:        I think that was to Dr.

17   Chowdhury.     Is that correct?

18                  DR. CHOWDHURY:       Is it directed to me?        I was

19   not really present on the use study.

20                  DR.   CLAPP:        You    did   mention   that    the

21   likelihood     was   that     it    was     going   to    be     used

22   inappropriately in your presentation.



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1                   DR.   CHOWDHURY:          Correct.     That     was       a

2    statement that I made, that if the drug is going to be

3    made over the counter for chronic idiopathic urticaria,

4    as we have been talking about this indication, the drug

5    possibly is going to be used for all kinds of urticaria.

6                   DR. CLAPP:       With that likelihood, as you

7    mentioned, you said the likelihood was that it would be

8    used for broader indications or other indications for

9    acute urticaria.      I think the next gentleman mentioned

10   the label study quoting 79 percent of those who read the

11   label as identifying its use incorrectly as for acute

12   hives or any type of hives.

13                  How do you reconcile giving the public

14   appropriate guidance in the usage if we are pretty clear

15   on the fact that it won't be used correctly by the majority

16   of those who purchase the drug?

17                  DR. CANTILENA:       Sure.     Dr. Wood will comment

18   on that and then we'll go to the sponsor.             I think they

19   have a comment.

20                  DR. WOOD:     I think we have to be careful about

21   saying it's being used incorrectly.             I think we need to

22   define that.    That was sort of the interaction that Lloyd



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1    and I had before lunch.

2                    DR. CLAPP:       Not for the indication as the

3    CIU indicates.

4                    DR. WOOD:     Well, hang on.        The CIU, they are

5    going for a limited indication.                That doesn't mean that

6    the other indications will be incorrect, No. 1.                  No. 2,

7    incorrect implies a sort of value judgement that if you

8    were to give it for these other indications, something

9    bad would happen to you.

10                   That was what I tried to put light on this

11   morning.       I guess the response I got was that nothing

12   bad does happen to you if you use it for these other

13   indications.        The   acute      urticaria       may   not   be    an

14   appropriate indication.

15                   It's just that it is impossible.                   As I

16   understood the responses, it's just that it's impossible

17   to study.      At least to me, we're not exposing people to

18   increased risk because of that which seems to me the

19   absolute clear bottom line.

20                   DR. CLAPP:      I agree but my question is are

21   we guiding them on how to use if appropriately?                  Are we

22   giving them some indication and guidance for the use other



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1    than CIU and recognizing clearly that most of it will

2    be   used      for   the   non-CIU     indication.     Is    that        a

3    responsibility to then appropriately direct them for the

4    usage in other than the CIU indication?                  That's my

5    question.

6                     DR. CANTILENA:      Right.    I think that's a key

7    point.      Dr. Temple and then Dr. Clayton from the sponsor.

8                     DR. TEMPLE:     Dr. Ganley wasn't trying to push

9    anybody around but if you read his review, he's clearly

10   interested in a labeling that goes toward a more general

11   statement about urticaria than about the CIU.                Part of

12   the reasoning, I think, is just that.            A lot of the use

13   is going to be for people who don't meet that test.

14                    If labeling is directed toward that, you are

15   better able to give the best advice you can.                 Charlie

16   may want to say more about that but that is really one

17   of the questions here.          Do you pick out something that

18   happens already to be in the Rx labeling so it's nice

19   and solid and you don't have to worry about where the

20   evidence is even if you know people will use it outside

21   that which, as Alastair said, is not necessarily the wrong

22   thing to do.



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1                        It's just not the labelled thing to do.             Or

2    do you try to write a broader indication and do you have

3    the data that allows you to do it and then give advice

4    that corresponds to how it is actually going to be used.

5     I think if you read his review, he raises that very

6    question also.

7                        DR. CANTILENA:       Yes, Dr. Clayton.

8                        DR. CLAYTON:     There's a number of questions

9    on the table since I stood up.                   I really stood to try

10   to clarify the Canadian experience if that was still

11   needed.         I    think   Dr.    Katz helped to put that in

12   perspective.          The database was with the 10 years of

13   marketing experience since the product was launched in

14   Canada so it is over quite an excessive time period.

15                       The adverse event experience tracks very

16   clearly the experience with allergic rhinitis overall

17   with types of adverse events, both the prescription

18   experience and the OTC experience, CIU, and allergic

19   rhinitis.       We can address specifically the numbers if

20   there is still confusion if that would help.

21                       I think there is also a question about the

22   survey     in       terms    of    the   respondents     who    answered



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1    incorrectly.    The 79 percent number was of the 30 percent,

2    the 79 percent of the 30 percent who answered incorrectly.

3     If there is any confusion there, hopefully that can help

4    to explain it.

5                   Is there any value in pursuing the Canadian?

6     We could get into the specifics if that is still an issue.

7                   DR.   CANTILENA:       No.   I   think   that    is

8    probably okay of that's all right with you, Dr. Clapp.

9                   Dr. King.

10                  DR. KING:   I'm just reminded that all these

11   kind of things they've gone through often times you say

12   you have to see your doctor first so it's like justice

13   delayed is justice denied.           Denying people access to

14   these medications brings up the issue of education and

15   accessibility.

16                  Dr. Engle's presentation that pharmacists

17   are in a primary position to be available 24/7 and then

18   to advise folks there, there is a counterweight to that.

19    People either go to the emergency room or they go to

20   the pharmacist in general.       They may stop at truck stops.

21    I'm not in that crowd.

22                  Anyway, it seems to me the issue is if we



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1    are going to talk about why would the FDA considering

2    broadening the indications, we have to talk about what

3    are the real indications and what is the real affect.

4                   It seems to me if you have available a system

5    of pharmacists, the change of labeling and just basically

6    a good old fashioned spin of TV and web kinds of things

7    where you educate the public, I think everybody has a

8    right to do something dumb and stupid.      Just because 40

9    million people do something dumb and stupid, it's still

10   dumb and stupid.

11                  I'm not going to get into that issue.    I think

12   the issue is education and accessibility.      I think there

13   is everything on the table to think about maybe broadening

14   it through access and to general limitations on this

15   application are not going to work.

16                  I think people are going to take what they

17   want to take and have a system of pharmacist and education

18   and labeling actually could improve the overall use of

19   this drug and prevent lots of people not doing something

20   dumb and stupid.

21                  They will know in multiple directions from

22   the label, from the pharmacist, and their back door



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1    neighbors.     They are likely to get much better care than

2    they are right now.

3                   DR. CANTILENA:      Yes.     Dr. Ganley, do you

4    have any idea in terms of the amount or the percent of

5    over-the-counter drugs that are actually sold outside

6    of a pharmacy like in the truck stop or the gas station?

7

8                   DR.   GANLEY:       No,     we   don't   have     any

9    information like that.

10                  DR. UDEN:   Dr. Engle's talk had a reference

11   in there that 61 percent of prescriptions are purchased

12   in a pharmacy.

13                  DR. CANTILENA:     Thank you, Dr. Uden.

14                  DR. UDEN:    Not of prescriptions.           All of

15   prescriptions are purchased in a pharmacy.          You mean OTC

16   meds.

17                  DR. CANTILENA:     Yes.

18                  DR. SZEFLER:      I'm going to ask a simple

19   question, and maybe I missed it in the reading, but if

20   loratadine was not going up for OTC and if they presented

21   these two studies for chronic idiopathic urticaria, would

22   that be sufficient to approve labeling for prescription



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1    use?

2                   DR. CHOWDHURY:      Yes.

3                   DR. SZEFLER:     For that indication.

4                   DR.   CHOWDHURY:        For     chronic    idiopathic

5    urticaria.     Those studies were the basis for approval

6    for chronic idiopathic urticaria.

7                   DR. SZEFLER:     Okay.       So you don't have any

8    trouble in terms of its indication for that?

9                   DR.   CHOWDHURY:         That's    correct.          For

10   indication only.

11                  DR. WOOD:    It's already approved for that.

12    That needs to be clarified.

13                  DR. CHOWDHURY:      I mean, that was a question.

14                  DR. WOOD:    Right.

15                  DR.   CHOWDHURY:         Were    the    two    studies

16   adequate for approval for chronic idiopathic urticaria

17   and the answer is yes, there are two.

18                  DR. CANTILENA:       And how about in terms of

19   the indication of just hives in general?                 Do you have

20   efficacy data that would support that indication?

21                  DR. CHOWDHURY:        Well, I mean, currently

22   Claritin is not approved for anything beyond symptom



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1    control of chronic idiopathic urticaria.          That really

2    has not been an application.        In other ways would those

3    studies be adequate just to give their approval in a

4    prescription setting for urticaria of other kinds?            The

5    answer possibly is going to be no without really probably

6    going into the full rationale for that and --

7                   (Whereupon, off the record.)

8                   DR. CHOWDHURY:     -- which perhaps can be done

9    for other types of urticaria.

10                  DR. CANTILENA:     So the purpose of -- I mean,

11   sort of question 1A then, you don't have efficacy data

12   that would support an indication of hives then?

13                  DR. CHOWDHURY:     That is a question, I think,

14   for the committee to discuss, but there is no data outside

15   the chronic idiopathic urticaria.

16                  DR. CANTILENA:     Thank you.

17                  Dr. Wood.

18                  DR. WOOD:   I think we are sort of getting

19   hoisted by a patod that goes something like this, that

20   when drugs are approved for prescription indications,

21   they are approved on the basis of the studies that were

22   done with sometimes incredibly complex.         If you think



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1    of some of the heart failure indications, some of the

2    indications there were incredibly complex based on the

3    studies that were performed.

4                   Once you try to translate that into an

5    over-the-counter indication, it seems to be we need to

6    be less rigid.     There is little point just because CIU

7    was the prescription indication insisting on that wording

8    in   an    over-the-counter     label.     It   seems    to    me

9    counterproductive and doesn't serve patients well.

10                  I think we need to step back from a rigid

11   position that says this is what the study said, this is

12   what the definition was in the paper that was published,

13   and move towards the sort of, if you like, the Tennessee

14   view that preferred earlier on.

15                  We need to translate it into words that mean

16   something to patients.       I don't think CIU, which is now

17   being tossed around here as though we use that term

18   everyday, is really going to be helpful to the majority

19   of patients who walk into Dr. Engle's Walgreens or

20   whatever.

21                  DR. CANTILENA:     Dr. Temple.

22                  DR. TEMPLE:    Based on conversations among



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1    the people at FDA at least who are supposed to know about

2    these things, it seems quite uncertain as to whether we

3    would think new data would be needed for a claim of simple

4    hives or not.

5                   Mechanistically there's a belief that we're

6    talking about the same thing.            I don't want to dismiss

7    the concern, although I think Alistair is right.              Maybe

8    you owe some practical look.             I don't think there has

9    been an internal decision that we don't have that data

10   or do and it's something we need to think about.                 I'm

11   sure advice would be welcome.

12                  DR. WOOD:     Bob, the issue I think is not the

13   one that you're dwelling on.          For the average person they

14   would translate -- they would see urticaria and hives

15   as being words of equivalent meaning, hives being a word

16   that is much more in widespread use than urticaria in

17   the population that is going to buy drugs over the counter.

18

19                  I don't think we should force ourselves into

20   a box that says the only vocabulary that can be used for

21   the label is the vocabulary that was used in New England

22   Journal that got the drug approved for Rx indication.



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1                     That's different from the -- that's one

2    issue.     Then the acute hives is an additional argument

3    that can be entered into.               Just translating urticaria

4    into hives doesn't seem to me to need a study.

5                     DR. TEMPLE:       No.     That's perfectly right.

6    If people eventually concluded that CIU was a really

7    distinct       disease   from     one    episode   in    response      to

8    something, then you would have to ask do those data apply.

9     That seems like a legitimate question, but I don't

10   believe there's an agreed on answer internally yet.                    It

11   does appear that there haven't been any, or very few at

12   best, actual studies of acute episodes of hives.

13                    DR. WOOD:      But you would be comfortable with

14   chronic idiopathic hives?

15                    DR. TEMPLE:      Oh, I don't think anybody mines

16   that.

17                    DR. WOOD:       As idiopathic would mean very

18   little to most people, you would be prepared to drop

19   idiopathic?

20                    DR. TEMPLE:      No.     Whether you translate the

21   language that you do think you have -- sorry, the disease

22   that you do think you have data for into a different



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1    language is the sort of thing you have to think about

2    all the time.

3                   There's always worry about whether people

4    understand     your   indications.          There   is   a   separate

5    question of whether there is a different disease here.

6     I certainly have no opinion but there was a divided view

7    when we were talking about it, or an unsettled view anyway.

8                   DR. CANTILENA:       Okay.     Dr. D'Agostino and

9    then Dr. Wilkin.

10                  DR. D'AGOSTINO:        Yeah.     Well, some of my

11   comments have just been aired there.                I don't see any

12   problem with having hives being used for this condition

13   when we're talking about long-term and so forth.                     My

14   difficulty comes with the acute.            If hives is being used

15   in just a generic sense, it encompasses the acute also

16   and what do we have on that.

17                  When I started with the FDA back in the '70s

18   they used to have this grasp, "Generally recognized as

19   safe and effective."      I hear a lot of that going on here

20   that somehow or the other the field is comfortable with

21   the use of the drug.    I don't know enough about the process

22   and what have you to object to that.



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1                   I think that in many ways once we move to

2    hives, to me that's our real issue, do we have enough

3    sense that the acute is going to be included.      If we don't,

4    then I think we are going to get ourselves in a real bind

5    with how to handle that with new studies and what have

6    you.

7                   DR. CANTILENA:    Dr. Wilkin.

8                   DR. WILKIN:      Yeah.      I actually have a

9    concern that some patients who have CIU suffer from a

10   nomilism kind of issue that if they are told they have

11   chronic idiopathic urticaria, they think they have

12   something that is fairly specific.            What they really

13   have, as you have translated it, the urticarial hives.

14    Idiopathic means they had a workup but nothing was found.

15    Chronic means it's been there longer than six weeks.

16                  Maybe it's because I trained in Tennessee

17   but I've always had the notion that you call it chronic

18   idiopathic urticaria perhaps because you can charge more

19   than if you say you have hives, you've had it longer than

20   six weeks, and I don't know what it is.

21                  There's a point to this.       It could be many

22   different kinds of things still.          Calling it CIU is not



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1    a thing.       It is the residue after you've taken the things

2    that you know out.

3                     DR. WOOD:      Right.

4                     DR.   D'AGOSTINO:          Are   you   answering      my

5    question?       Are you saying that acute hives is really just

6    the same and it's all vocabulary?

7                     DR. WOOD:     No.    That's a different question.

8     There are two questions on the table.              One is, is acute

9    hives the same as chronic hives in terms of response.

10   I think the answer to that is we don't know.                   At least

11   that is the answer I'm hearing.

12                    The second question is does telling a patient

13   that they have chronic idiopathic urticaria, which

14   translated into the vernacular means chronic, it's been

15   there for a while, idiopathic meaning the physician

16   doesn't know what's causing it, and urticaria being hives,

17   if you translate that into you've got chronic hives and

18   forget that the physician doesn't know what caused it,

19   I don't see that adds much or loses much frankly.

20                    DR. D'AGOSTINO:         I think that's great.              I

21   think it's the acute hives that --

22                    DR. WOOD:     We can show results on the issues



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1    if we take some of them and deal with them, I think.

2                   DR. CANTILENA:     Yes, Dr. Rosenberg.

3                   DR. ROSENBERG:    If I may, I'll try and answer

4    what I think is a good question.           Is acute urticaria one

5    thing and chronic idiopathic urticaria another thing,

6    or is it just that chronic is the same thing but we still

7    haven't figured it out?

8                   In preparation for this meeting, I tried to

9    do some reading and I must say I was very taken with this

10   supplement to the Journal of Investigative Dermatology

11   which is our premier research journal.

12                  It's   the   official       journal   of   both     the

13   European Society for Investigative Dermatology and the

14   American one.    This was released in November 2001.              It's

15   the account of a proceeding held in Europe the preceding

16   year, I must say, under the auspices of the -- in Berlin

17   in the year 2000.

18                  Somewhere it mentions that the UDC company

19   sponsored this meeting.      It has really all the very good

20   people from Europe, or many of the very good people from

21   Europe there.    I know these names and I know some of these

22   people.



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1                   They say that acute urticaria you usually

2    know the cause.    Maybe not the first time but the second

3    time.    It hits very quickly and the sufferer can get an

4    idea what's happened, or somebody makes sense of it very

5    quickly.

6                   Apparently the feeling here, and they are

7    quoting work from Switzerland and Berlin, it's a bonafide

8    allergy and there's an instant reaction.          It's on and

9    off.    The juxtaposition in time makes it.

10                  The word that was unfamiliar to me turns up

11   in here called pseudo-allergy.             Most of the other

12   material -- I can show some of this stuff in a little

13   bit.    Most of the other that accounted for what we are

14   calling chronic idiopathic urticaria is not that kind

15   of an immediate reaction.        It does not show up on the

16   allergy skin test.

17                  In fact, what it is it's all the other

18   material that was on Jonathan's slide that he showed where

19   all the other parts of the immune system come into play

20   and act on the final cells including the mass cells rather

21   than just the particular allergen.

22                  That's an explanation for why analgesics --



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1    it's not just aspirin.         It's things that look and work

2    like aspirin all seem to do it.               They divert the immune

3    response system somehow.          There's work in here that if

4    it's really a food to which you are allergic, or a product

5    which you are allergic, you are better in a few days when

6    you stop it.

7                     But if you're dealing with what they are

8    calling pseudo-allergy, you have to be off the food or

9    whatever       and   certain   natural        foods.   Tomatoes      are

10   mentioned and others that have these properties in some

11   people.        You have to be off of it for some months.

12   There's one claim in here that patients who do this

13   conscientiously that 60 percent get better which is much

14   better than anything we are doing over here.

15                    Again, I'll keep reverting to the enormous

16   use of prednisone in the practice of medicine in all the

17   different       specialties     for    this      condition.        It's

18   inappropriate in my opinion.            Thank you.

19                    DR. CANTILENA:       Is there a comment from Dr.

20   Monroe, the sponsor?

21                    DR. MONROE:     I would just like to say that

22   I'm not from Tennessee but I'm going to try and make this



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1    as simple as I can.         I view urticaria as a spectrum of

2    a disease and it can be classified as acute or chronic

3    and that is a totally arbitrary time limit.

4                     As   Dr.   Wilkins     pointed          out,   the   basic

5    pathophysiology of all urticaria is that slide he showed

6    with the mass cell at the center, the release of the

7    mediators, multiple mediators, but the best documented

8    mediator is histamine and that's the same in acute

9    urticaria, that's the same in chronic urticaria, that's

10   the same in chronic idiopathic urticaria.

11                    I think if you're looking at what's going

12   on, there's a common theme.            Are there differences?                  I

13   think you alluded to some excellent differences.                      If any

14   chronic        idiopathic    urticaria         is    a     more    complex

15   pathophysiology        where    you've         got   a     cellular      and

16   inflammatory response on top of the more simplistic acute

17   urticarial response.         That's what makes that subset any

18   harder to treat.

19                    I think the message that I would carry away

20   is histamine is the mediator involved in the whole

21   spectrum.       We have different causes on the acute side.

22    They are usually identifiable causes but what we're



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1    treating is the symptom that is being generated by the

2    release of the histamine.

3                     We're not curing the problem.            The reason

4    acute urticaria is an easier problem is we can usually

5    identify the cause and move it out.               The drug therapy

6    is totally symptomatic to affect what has already been

7    released whether it's acute or chronic.

8                     To me the issue of are antihistamines, H1

9    antihistamines, going to be effective in acute.                    The

10   answer is they are the standard of care approved in all

11   algorithms published by the leading specialties in

12   allergy and dermatology where urticaria is in their domain

13   heavily.       I think clearly that is the way to treat.

14                    It is very difficult, however, to do a

15   scientifically      controlled     study     in   acute    urticaria

16   because it's a very self-limited short disease.                Again,

17   if you look at the basic underlying chemical that is

18   causing the problem, it's histamine.

19                    If you look at the accepted standards of care

20   it's H1 antihistamines.        If you look at the real world,

21   most of those patients are self-treating, never seen a

22   doctor, and using much less safe medicines with side



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1    effects right now.      I think we have clear scientific

2    evidence that urticaria as a whole has the same basic

3    mediator and the same first line treatment.

4                   DR. CANTILENA:       Okay.        Thank you.        Dr.

5    Davidoff.

6                   DR.   DAVIDOFF:       This   has     been    a   very

7    interesting somewhat academically oriented discussion

8    and through a rather sort of tunnel vision, it seems to

9    me, in terms of the broader problem.             I think that the

10   average person coming into the drug store with a skin

11   problem that's bothering them because it's itchy and maybe

12   somewhat red isn't going to be trying to make this fine

13   distinction between is it acute hives or is it chronic

14   hives.

15                  I suspect that -- well, I guess my question

16   really is are there data on how the general public decides

17   to call something hives?         My suspicion is that they

18   frequently     refer   to    something      as    hives     that        a

19   dermatologist or an internist or family practitioner

20   would not call hives.       Even if you use hives as the word

21   on the package, my question is how frequently will that

22   be helpful in guiding people?



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1                    The flip side of that question is since a

2    great fraction of all skin conditions itch, are there

3    data on how frequently that itch is relieved in things

4    other    than   hives    by   antihistamines?     If   they     are

5    frequently relieved, then that's going to be positive

6    reinforcement they will continue taking it and then not

7    be seeing the dermatologist or whoever to try to get a

8    proper diagnosis made.

9                    I wonder if there are data in those two areas?

10    How do people define something as hives and how often

11   is that correct?        Secondly, how often do non-hives and

12   itchy skin conditions respond to antihistamines?

13                   DR. ROSENBERG:     If I could answer that.      The

14   antihistamines are really not very good for itch per se.

15    They are not very effective atopic dermatitis.               They

16   work more as sedatives, the more sedating the better.

17   They are really not -- atopic dermatitis doesn't go this

18   way or it's got a little piece to it.           Eczema Dr. King

19   says for those.

20                   This really is a histamine induced disease,

21   as Dr. Monroe has said.       The antihistamines really shine

22   here.    This is where they have a place in treatment of



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1    itch.

2                   DR. CANTILENA:       Yes, Dr. Lam.

3                   DR. LAM:       I still have a concern that

4    consumer is placed a tremendous burden in terms of knowing

5    not to use the product without seeing a physician.             Usage

6    data from fungal vaginitis would suggest that's not the

7    case.

8                   My question to sponsor is given this fact

9    of all the educational program that they have proposed

10   in slide No. 78 in the presentation, in their experience

11   which one actually is most successful in terms of reducing

12   this type of misuse behavior?                If none of them is

13   reasonable or successful, do they have any innovative

14   program on the drawing board?

15                  DR. CANTILENA:       Dr. Clayton, would you like

16   to address that for Dr. Lam?

17                  DR. LAM:      Do you want me to repeat the

18   question?

19                  DR. CLAYTON:      Yes, please.

20                  DR. LAM:   Of all the educational program that

21   they have proposed in slide No. 78 in the presentation,

22   in their experience which one actually is most successful



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1    in terms of reducing this type of misuse behavior meaning

2    that they should actually not use it without seeing a

3    physician      and   if   none   of    them   is   appropriate      or

4    successful, do they have any innovative program on the

5    drawing board?

6                    DR. CLAYTON:     We have used this approach with

7    prescription drugs.        We have not used it to this point

8    with OTC drugs.      We'll be building off of that experience.

9     I don't think that there have -- I'm not aware of any

10   test data that point out which path is the most successful

11   but rather a combination of approaches to achieve the

12   end result.      Education is clearly key.

13                   There has been a lot of discussion about

14   experience with vaginal yeast products and has been a

15   success, I believe, on migraine which uses the very same

16   approach.      I think it is important to point out that the

17   experience now 11 years OTC with vaginal yeast products

18   has been a very positive one in terms of the safety

19   experience.

20                   There are certainly cases we acknowledge of

21   failure to achieve a physician diagnosis in advance.

22   There are studies out there also that support that the



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1    incidence of inappropriate use is low.

2                      There are also studies that show people

3    self-treat with home remedies at a fairly high percentage

4    that tend to do harm.           I think it's a combination of

5    various approaches to education to really work toward

6    solving the problem.

7                      DR. CANTILENA:      Yes, Dr. Sachs.

8                      DR. SACHS:    Anyway, it seems like we are kind

9    of circulating around the main issue which would be that

10   if we agree that an OTC indication for CIU would be given

11   that were basically kind of approving it for a more broader

12   indication of hives, versus the other which would be to

13   just continue it for the allergic rhinitis indication

14   and educate the affected patients who are seeing their

15   doctors        anyway,   that   would    be    permissible   to   take

16   something that's already OTC for their condition which

17   is kind of a backhand look at it, okay?

18                     DR. UDEN:     Dr. Sachs, do you believe that

19   if Claritin went OTC for allergic rhinitis that if they

20   went to see their physician, they wouldn't walk out with

21   a prescription for Clarinex instead?

22                     DR. SACHS:    Actually, I don't like writing



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1    prescriptions so it would be recommended at least in my

2    practice.

3                   DR. CANTILENA:        Yes, Dr. King.

4                   DR. KING:       I guess if I understand that

5    you're saying that if we left it like that, you're going

6    to encourage the physician to promote the off-label use

7    of a drug?     I don't think the FDA would want to be in

8    that position if you understand what I'm saying.              Either

9    it's a yes or no.

10                  DR. SACHS:        If it was approved over the

11   counter for the indication of allergic rhinitis and it's

12   also approved for chronic idiopathic urticaria, then

13   would it have two classes, I guess.           At a practical level

14   I didn't think it would.

15                  DR. KING:     I just have that problem.       I think

16   there is one way to get some data here.          One of the things

17   I thought about is that the most common cause of workman's

18   compensation claims are for skin problems.                The most

19   common workman's compensation disability is for joint

20   and muscle pains.

21                  There's a whole batch of data from the NIOSH

22   and so forth and companies who are in a financial position



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1    to keep up with nurses and the workforce and so forth.

2     I think you could get at that database for how many

3    patients had itchy rashes, whether it's urticaria or it's

4    contact allergy or irritants from manufacturing or

5    whatever.

6                    I   think    the    FDA    is   not   in   a   position

7    necessarily to talk across the government lines, but I

8    think there is a database there we are just ignoring

9    because there's going to be a whole lot of antihistamines

10   and a whole lot of other things given for workman

11   compensation kind of things so I think we could look at

12   that.    I just don't want to get in a position recommending

13   that physicians do with federal sanction off-label use

14   of drugs.      That puts everybody at risk.

15                   DR. CANTILENA:         Yes, Dr. Johnson and then

16   Dr. D'Agostino.

17                   DR. JOHNSON:       I have a couple questions that

18   I would like the dermatologist to answer and then the

19   latter question I would like the sponsor to also address.

20    The first centers around what the actual need is for

21   the physician diagnosis in most of these situations.

22   Is it, in fact, necessary to be diagnosed or will most



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1    people if they self-treat for a period of time and don't

2    have resolutions seek medical care anyhow?                    That's my

3    first question.

4                      DR. KING:     I'll start.        One of the things

5    that keep allergists and dermatologists in business is

6    itching.        People are just not going to ignore itching

7    for a long time.        It's just one of Mother Nature's kind

8    of thing from the cave.

9                      If you've got bugs on your skin, you start

10   itching and you're really going to go after it so I think

11   the dermatologists take the viewpoint it's often times

12   that you're just not ready access and that people are

13   going to self-treat first and then they are going to go

14   to primary care doctors or pharmacists or whatever.

15                     I think the fundamental issue is that I don't

16   think it's a problem from the dermatologist point of view

17   saying you can't charge or you can't whatever.                   It's a

18   matter of access.

19                     If people have it persistently, then you are

20   going to have to do the workup because there is this five

21   percent        that   have   related     to     cancers,    related    to

22   connective tissue disease and so forth.                    We're at the



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1    end of a long tunnel and for my purposes, the land of

2    the rare, the rare is common.

3                     I have a misperception of I don't see nearly

4    as many people with urticaria as the pharmacists do.

5    I have no problem with their education system, their

6    labeling system.      When they get to me it's already tests

7    for thyroid, tests for other things so it's a very limited

8    population.

9                     DR. ROSENBERG:     If I could take a crack, the

10   question is is it all right if people should treat

11   themselves without prior diagnosis by a physician.                     I

12   have something I want to say about that.

13                    First of all, there's the acute severe

14   urticaria that no one is talking about here.            When it's

15   very severe, people know that it's severe and they medical

16   attention the only way they can get it which is in an

17   urgent clinic or emergency room or they dial 911.

18                    We know that people in general make the right

19   choices.       There are lots and lots of studies that show

20   that self-medicators have more education and do better

21   and have better health outcomes than people who seek

22   medical care on all occasions.          The really bad cases that



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1    need epinephrine are not part of this system.

2                   Now, there are two more cases.        There's acute

3    urticaria that's not life threatening.             All of a sudden

4    you've got itchy hives.        You've never had it before.

5    Then there's the other case where you've had episodes

6    before and before and before and now you have it again.

7                   Let's talk about the two of them.               First,

8    acute urticaria.      It's the first time you've ever had

9    it.     It's hard to see a dermatologist without waiting

10   a couple of weeks for an appointment.              I don't think I

11   see much acute urticaria except in family members and

12   in house officers and nurses.

13                  To go back to this symposium that I'm so taken

14   with, it's a discussion of urticaria in general.                   One

15   of the items in here is a consensus statement, "The

16   Management of Urticaria - A Consensus Report" by these

17   professors from prominent people in Europe, Vienna,

18   London, Berlin, and so forth.

19                  First, type of urticaria A, acute urticaria.

20    The standard treatment, non-sedating H1 antihistamine.

21    This     standard   treatment     for     acute    urticaria       is

22   non-sedating    H1   antihistamine.         That    has    a   little



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1    superscript A which says, "Efficacy proven by double blind

2    placebo        controlled   studies,"      but    I   can't    find    the

3    references here in this paper.                 I'm sure it will show

4    up otherwise.

5                      An alternative treatment, second choice for

6    acute urticaria is initially prednisolone 50 milligrams

7    a day for three days.            You don't see many three-day

8    prescriptions around our way.           That's their second choice

9    if this didn't help.

10                     Next   we go to chronic urticaria.                   The

11   standard therapy, the first therapy for chronic urticaria

12   according to these European professors, non-sedating H1

13   antihistamines, again with a superscript A, proven in

14   double blind.

15                     The second standard treatment if that doesn't

16   work, increase the dose if necessary.                   Now there is a

17   list of alternative treatments.                  They are listed as

18   alternative treatments.          I'll read down the list of them

19   because there are 12 or so.            I'll go quickly.

20                     Combination      dapsone        and     pentoxiline,

21   combination H1 and H2 blockers, combination H1 blocker

22   and beta sapathomymedic (phonetic), i.e., terabutaline,



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1    combination H1 blocker and cykatrophic (phonetic) drug,

2    trisiclic (phonetic) antidepressant doxipen (phonetic),

3    danisol,       stanisol     (phonetic),        lucotriantagonsis

4    (phonetic), selfosalozine (phonetic).            Corticosteroids

5    come in after all this other.                Cyclosporin A, wow.

6    Interferon, poova (phonetic), plasmaforesis (phonetic),

7    and immunoglobulants.         The corticosteroids coming in

8    about 12.

9                   Again, that data we saw from the company

10   showed that 40 percent of primary care doctors, that's

11   their first treatment, not non-sedating antihistamines,

12   not non-sedating antihistamines at a higher dose but

13   first.     And 28 percent of the pediatricians and so forth.

14

15                  I mean, if you talk in terms of what's the

16   worse thing that could happen if somebody got hold of

17   some of this, aside from the 911 cases, what's the worse

18   thing that could happen?          They are right in line with

19   the European standard for both diseases and better than

20   they are going to get in most medical offices in the United

21   States of America.

22                  DR. WOOD:     But the worse thing that could



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1    happen is they go to the doctor.            Isn't that right?

2                   DR. ROSENBERG:       If we force them to go to

3    the doctor because they can't get an over-the-counter

4    thing without waiting until a week from next Friday, yeah.

5                   DR.   CANTILENA:       Did you have a second

6    question, Dr. Johnson?

7                   DR. JOHNSON:      My second question probably

8    is more directed at the sponsor.             If I recall in the

9    background materials that we were provided, there was

10   an expert panel that was convened and it said that their

11   recommendation was to pursue or that the indication should

12   be limited to CIU.

13                  I guess from what I've been hearing today,

14   is that because that expert panel really perceived that

15   there were risks associated with sort of the broader

16   indication or it just seemed to be the safer easier route

17   to pursue?

18                  DR. CANTILENA:      Yes, Dr. Monroe.

19                  DR. MONROE:     I was a member of that expert

20   panel.     The expert panel simply addressed the issue of

21   taking the prescription indication over the counter and

22   felt very comfortable with that.            That would be the CIU



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1    indication.

2                   The expert panel did not address the broader

3    indication.      Personally     as   one   member,   and   in    my

4    presentation, I don't see any harm in the broader

5    indication but that panel simply addressed the narrower.

6     They did not have reservations and didn't address that

7    issue.

8                   DR. CANTILENA:     Yes, Dr. Sachs and then Dr.

9    Dykewicz.

10                  DR. SACHS:    It has been stated to my kind

11   of surprise by both the FDA and by the sponsor that it

12   would be very difficult to do a study in acute urticaria.

13

14                  As a clinician participating sometimes in

15   research trials in my office, I'm kind of struck by I

16   don't think it would be that hard given that we do studies,

17   for example, on croup which is an acute self-limited

18   disease that last maybe two to three days, that can be

19   either spasmatic and may occur one time in the middle

20   of the night type thing.

21                  It would not be a tough thing to do to do

22   such a study in the ER other than the fact that it might



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1    be a little more difficult to do placebo because of the

2    wider acceptance of antihistamines already.

3                   Having said that, I'm not sure I have such

4    a big difficulty in the use of these antihistamines and

5    hives.     I am just wondering more about the broader sense

6    that it's okay for us to say, sure, without efficacy data

7    it's okay to broaden an indication for a drug that would

8    be used so widely over the counter.

9                   DR. CANTILENA:     Yes.

10                  DR. WOOD:    I don't think I was arguing for

11   broadly an indication.       The issue we're discussing is

12   the risk of it being misused in an indication for which

13   it's not approved.      That seems to me a fundamentally

14   different argument.

15                  DR. CANTILENA:      I think actually question

16   1A is asking us should it be broader.

17                  DR. SACHS:    I think the reason that we're

18   asking that question should it be broader is because it

19   is totally unrealistic to expect that it wouldn't be used

20   for acute hives or other urticarial as demonstrated by

21   the sponsor data, by our experience with use.

22                  DR. CANTILENA:     Yes, Dr. Dykewicz and then



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1    Dr. D'Agostino.

2                   DR. DYKEWICZ:     I would like to direct the

3    question head on as to what the potential adverse outcomes

4    would be of inappropriate use by the consumer of this

5    medication for urticaria of all sorts of ilk, acute versus

6    chronic idiopathic.

7                   I can see several potential areas where there

8    would be potential adverse outcome.        Take, for instance,

9    the example of use for acute urticaria for food.          There,

10   on one hand, would be the concern maybe based upon

11   particularly, I think, the specter of what Dr. Lee had

12   presented this morning about some of the patients who

13   are developing anaphylaxis on the antihistamine agent.

14

15                  I think there would be the consideration that

16   you would have some people who would feel, shall we say,

17   comfortable dealing with food induced urticaria by the

18   availability and the indication over the counter for

19   treatment of urticaria by this product.

20                  They might be kind of lulled into a false

21   sense of security that they can treat this themselves,

22   that they can suppress maybe even a food allergic reaction



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1    from occurring, and they may miscalculate with the result

2    being anaphylaxis and death.          I actually think if you're

3    looking at worse case scenario, that is something that

4    is going to happen.

5                    I think one of the things then that would

6    have to be considered is the frequency of that happening

7    and that for the greater benefit of society is that a

8    risk that is balanced by the greater benefit to society.

9     Unfortunately, I think in terms of trying to assess what

10   the frequency of that would be, we are really not going

11   to know.

12                   Another food related issue that comes up,

13   and I do see this when patients come into the office,

14   is the patients have been under the belief that their

15   urticaria is food related so they have been self-treating

16   themselves with currently available over-the-counter

17   antihistamines.

18                   The reality is that they have inappropriately

19   assessed that they are allergic to foods and they are,

20   in fact, getting nutritionally deficient diets as a

21   result.        They've   eliminated      wheat   products,     dairy

22   products, meat products.        You really are seeing a patient



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1    who, I think, is having some adverse outcome on that basis.

2

3                   Then, of course, the other issue is, and this

4    is why the original indication was trying to be restricted

5    to chronic idiopathic urticaria where there has already

6    been a prior physician evaluation, and that would be these

7    less common but real issues of a patient who has maybe

8    some connective tissue disorder or urticaria vasculitis

9    where they may be getting some benefit with their skin

10   condition by the use of the over-the-counter product,

11   but then we less likely to seek the attention of a

12   physician of medical intervention and, thereby, allow

13   the progression of the underlying disease process leading

14   to, among other things, some renal disease.

15                  I think there are certainly a number of

16   situations or scenarios that could occur where the

17   inappropriate use in the broad stroke terms of this agent

18   over the counter for urticaria might lead to some adverse

19   outcomes.

20                  I think the dilemma that we are facing here

21   is that even if you tried with all the product labeling

22   as has been appropriately proposed, even if you tried



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1    to warn the consumer about all of these different

2    concerns, would the consumer heed these in practice or

3    would actual use be such that there would be just kind

4    of across-the-board use of the products with some of the

5    adverse outcomes that I've discussed.

6                     DR. UDEN:    But those would not be because

7    they are taking antihistamines.              All those examples you

8    cited were because they would have delayed seeking medical

9    care.    They would have been driven to take antihistamines

10   for some reason.

11                    It's just like when you go to see a physician,

12   "Oh, no.       I've got to do it Friday night at midnight,"

13   something happened that they are seeking treatment.               It's

14   not really antihistamines that are causing those issues.

15    It's really them delaying going to therapy.

16                    DR. DYKEWICZ:     Right.      It's not an adverse

17   effect of the medication.          It's that, say we say, the

18   certain amount of comfort level that they may have that

19   they    are     doing   the   appropriate         thing   with     the

20   over-the-counter product might thereby decrease their

21   threshold or change the threshold for seeking appropriate

22   medical intervention.



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1                    DR. UDEN:   I hear that but I don't hear in

2    your examples like when we discussed phenylpropanolamine

3    here and people were dying of -- had a risk of hemorrhagic

4    strokes or dying, I'm not hearing that level of concern

5    of medical catastrophes by delaying a diagnosis.

6                    DR. CANTILENA:     Okay.    Dr. D'Agostino, Dr.

7    Temple, then Dr. Alfano.

8                    DR. D'AGOSTINO:       This is for Dr. Wilkin

9    actually.      I'm trying to figure out one can take the data

10   that we have and say that we can bring it down to acute

11   high situation and feel comfortable with it.              Now, if

12   you go into other fields like analgesics, periodontal

13   fields, and weight reduction, you go after individuals

14   in the study who have serious conditions, headaches five

15   times a week or something like that.

16                   If you establish with the clinical trials

17   that the drug is effective for these individuals, then

18   by extrapolation, or whatever you want to call it, you

19   say that individuals with less severe conditions can,

20   in fact, also take the drug without having to produce

21   new data.

22                   Are we talking about the mechanism of action



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1    that you've described and so forth?       Are we talking about

2    possibly that type of situation that the chronic data

3    and the mechanism which you say is involved here that

4    would allow us to have comfort that, in fact, it can be

5    brought down to acute conditions?

6                   I realize there's some that are triggered

7    by foods and what have you that might be different in

8    terms of the general type of statement for labeling and

9    for these questions we have to face.

10                  DR. WILKIN:    The answer is yes.        I mean,

11   you're saying essentially that if it's acute urticaria

12   and you know it's acute urticaria that it should respond

13   in the same way as patients who have the diagnosis of

14   chronic urticaria or chronic idiopathic urticaria.

15                  I think where the catch comes is is there

16   a greater chance for a patient to make a misdiagnosis

17   of self with short-term kind of urticaria as opposed to

18   something that has been seen by a physician and labeled

19   chronic idiopathic urticaria.       That's where the struggle

20   is on this.

21                  I don't think -- one of your colleagues

22   mentioned that it doesn't seem that the scenarios that



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1    are playing out for the differential of acute urticaria

2    have    things     that     really     would       be    made     worse     by

3    non-sedating H1 antihistamines.                 The whole notion is one

4    of delay.

5                     Many of the things that we're talking about

6    that would be really worrisome and you wouldn't want delay

7    to occur, some of those are going to be things that occur

8    perhaps more often in a medical setting.                 The really world

9    class     anaphylaxis       is    very      often       associated       with

10   parenteral antibiotics, penicillin, cephalosporin.

11                    The radio contrast materials can lead to

12   something that looks very similar and doesn't often have

13   the immune system involved so it's called an anaphylactic

14   kind of reaction.         Really the reactions that occur within

15   seconds are going to be of a medical variety.

16                    There are some that can occur outside the

17   medical        setting.       There      can      be     insect      things,

18   hymenoptera,       stings    that     can       lead    to   very    rapidly

19   developing anaphylaxis.           Many of the patients who have

20   anaphylaxis will actually develop their anaphylaxis over

21   a somewhat more prolonged time period.                   I can't imagine

22   that this would adversely affect a patient to have the



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1    H1 non-sedating antihistamine.

2                      In fact, if they get to the point where they

3    start having some swelling inside the mouth and the throat

4    and they feel they are getting short of breath and they

5    hop into the car and are driving down the road to the

6    emergency room, it might be more beneficial to be on a

7    non-sedating than a sedating antihistamine.          In general,

8    I think it really the things that are chronic idiopathic

9    urticaria they have the same pathophysiologic mechanism.

10                     DR. D'AGOSTINO:     I'm concerned, as everyone

11   else is, with the two wishes of the efficacy and the

12   safety.        The question I was addressing was in some sense

13   the efficacy part that do we have enough data to feel

14   that we don't necessarily need to do more.

15                     I think the delay issue was certainly before

16   as the safety issue but, in some sense, it would be nice

17   if we would not separate them but there is an efficacy

18   issue.     Do we really have to run acute studies?        You can

19   run acute studies.

20                     I would be happy to design a study for you.

21    I'm sure I could do it but do we really need to given

22   the database we have.       Then the second question is about



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1    the delay for the safety implications which you are

2    addressing now.

3                   DR. WILKIN:       I think it comes back to what

4    do we gain from the acute studies versus the resource

5    intensity and what one might actually -- how one can

6    extrapolate.         First of all, of the acute urticaria

7    patients that I most recently saw, and this was at Ohio

8    State University, so we had three sources of urticaria

9    patients.

10                  One would be those who had really severe

11   urticaria that bothered them enough to go to the emergency

12   and they would often be treated at the emergency room

13   before they would send them over to our gun clinic.           They

14   would    get   the    systemic    corticosteroid,   parenteral,

15   diphenhydramine, perhaps some other sorts of things.

16   That was one group.

17                  Then we had the clinic at the campus was on

18   the bus line so we had a lot of indigent patients that

19   would just come to a walk-in setting.          Typically they

20   had urticaria the day before, but you wouldn't see it

21   that morning.

22                  Then the other place we saw patients was out



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1    in one of the tinier suburbs of Columbus, Ohio, Dublin,

2    Ohio.     There we treated diseases of the insured.            They

3    would often go through a family practice doc or an

4    internist before they would come to us.         It was actually

5    rare in my experience, and I've seen a lot of patients

6    who had urticaria, but to actually see urticaria at the

7    time they are coming to the clinic visit so it's a little

8    different.

9                   I mean, those folks come in and they have

10   croup when you're seeing them.            I still think this is

11   a very tough group to study.         Hopefully you find some

12   who have a history of food intolerance and you could

13   recreate an acute episode of urticaria in the laboratory

14   but undiagnosed they would be chronic.          I mean, it gets

15   back to what you mean.

16                  I think the real fundamental piece is that

17   all of the different ideologies that ultimately lead to

18   the weal and to the itch do so by acting on the mass cell.

19    It's the same vesical that's released in every single

20   instance and it leads to the same itching, c-fibers,

21   superficial dermis, and the same kind of weal because

22   that superficial vascularplexis becomes leaky.            I think



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1    it's one common mechanism.

2                   DR. CANTILENA:      Okay.      Thank you.

3                   Dr. Temple, Alfano, Dykewicz.

4                   DR. TEMPLE:       I don't know if this will

5    reassure Ralph or not.     We can't agree to labelling unless

6    we believe there is substantial evidence that the drug

7    is effective for what it's labelled for.               One way or

8    another perhaps by reference to other closely related

9    diseases or whatever, we are going to have to reach that

10   conclusion.

11                  We've asked you what you all think about it

12   and that will help but we have to under law reach that

13   conclusion.     We have no choice.           We'll have to do it.

14   If we can't reach that conclusion without another trial

15   being designed, then somebody is going to have to be smart

16   enough to design another trial.              The question is, and

17   you just heard Jonathan address this, you may not need

18   to do that.    You may know enough already.

19                  DR. D'AGOSTINO:        That is obviously what I

20   was trying to flush out.

21                  DR. TEMPLE:      No.         It's a perfectly good

22   question and we may have mislead you slightly by the



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1    question.      We have to be convinced one way or another

2    that there is something called substantial evidence which

3    means it has to come from well controlled studies and

4    then we'll argue about the applicability of whether it's

5    really the same disease and so on.          Those are things you

6    have to argue about.

7                   I wanted to follow up on one safety matter

8    that Jonathan mentioned also.        I mean, the nightmare here

9    is that somebody is gulled by the availability of this

10   drug when he wasn't gulled by the availability of the

11   sedating antihistamines all these years into delaying

12   treatment for his anaphylactic shock.

13                  I would be curious whether other people

14   agreed with what Jonathan said which I'm going to say

15   was my impression, that other things being equal, even

16   if you're going to the emergency room, you are probably

17   better laying down a little antihistamine base before

18   you do it.     It can't hurt and you won't attach more while

19   you're waiting.     Probably the odds are you will be better

20   off if more people use this if they are about to develop

21   something really nasty.

22                  DR. D'AGOSTINO:      Before that gets responded



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1    to, the question I was -- part of the question I was raising

2    is we do have studies.       There were studies that were done

3    for the Rx.     Is it possible in the appeal to the database

4    that we appeal to those in terms of then an extrapolation?

5                    DR. TEMPLE:    Yeah.    That's what I was trying

6    to say.

7                    DR. D'AGOSTINO:     I just wanted to make sure

8    I understood.

9                    DR. TEMPLE:    There's plainly some judgement

10   involved in whether the situations are close enough for

11   that to be relevant.         We have written documents about

12   how to go with one study or no studies or multiple studies.

13    Those would all have to be part of the consideration

14   and    the     advice   of    experts       figures    into      those

15   considerations.

16                   DR. CANTILENA:     Okay.     There's just a quick

17   comment here from Dr. Sachs and then we'll go back to

18   Alfano, Dykewicz, and then --

19                   DR. SACHS:    Just an important clinical point

20   about anaphylaxis.       The treatment for anaphylaxis is

21   adrenaline or epinephrine.             Giving an antihistamine

22   doesn't actually treat anaphylaxis.            I don't know that



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1    -- I mean, as long as giving the antihistamine didn't

2    delay the seeking of treatment, it wouldn't affect the

3    course but it certainly doesn't really help it.

4                   DR. WOOD:      But it doesn't make it worse.

5                   DR. SACHS:      If it delays the treatment, it

6    makes it worse.      If you look at anaphylaxis studies,

7    particularly in kids where the kids died where the kids

8    that got antihistamine and didn't get epi.

9                   DR. WOOD:        But that was in a hospital

10   setting.

11                  DR. SACHS:      That's part of what led to have

12   epi pens in schools and things like that was to make it

13   more available.    That's just my point.      You need the epi.

14    That's all.

15                  DR. WOOD:     No one is arguing with that.      The

16   issue though is do we -- the real question is do we

17   visualize that people with anaphylaxis because of this

18   drug, because a non-sedating antihistamine is on the

19   market, that people are going to rush down to Walgreens

20   to get themselves a non-sedating antihistamine and,

21   therefore, delay their access to epinephrine which they

22   would not have done with a sedating antihistamines.           That



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1    seems to me fundamentally improbable.

2                   So, I mean, the issue is not does epinephrine

3    -- is epinephrine the treatment for anaphylaxis.           Clearly

4    it is.     The issue though for today's discussion surely

5    is will marketing a non-sedating antihistamine over the

6    counter prevent patients getting epinephrine.              I think

7    the answer to that is no.

8                   DR. CANTILENA:     Okay.      Dr. Alfano and then

9    Dykewicz.

10                  DR. ALFANO:     Yes.        I didn't realize that

11   when I raised my hand the seqway would be so appropriate.

12    I wanted to sort of offer two comments on anaphylaxis.

13    One, at least some bee sting kits include diphenhydramine

14   tablets as a sort of prelude to the more definitive

15   epinephrine treatment as an event unfolds.          At least one

16   manufacturer sort of deemed it appropriate to put together

17   a kit in that fashion.

18                  The second comment relates to the fact that

19   a comment earlier from this morning was suggesting that

20   perhaps there should only be -- if this does go OTC there

21   should only be one put-up.      This becomes, I think, a great

22   debate topic and you could pick either side.



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1                   I kind of come down on the side that a second

2    put-up is advantageous because it makes the product

3    visible and available to individuals who are suffering

4    from CIU in a way that they have access to a non-sedating

5    antihistamine.     It would be the first time, I think, in

6    which a proper label is available for these indications

7    -- for that indication over the counter.

8                   They are going to the counter now and they

9    are acquiring sedating antihistamines and they are not

10   labeled in the fashion that would warn a consumer about

11   the risk of anaphylaxis.     This product conceivably would

12   be the first to be properly labeled.

13                  The third issue is it would be shelved in

14   this skin irritation section where someone who has these

15   chronic conditions would likely see it and pick it up

16   and read it.     The other way it's just going to be in a

17   wrong section of the pharmacy.

18                  DR. CANTILENA:     Okay.    Thank you.

19                  Dr. Dykewicz and then Dr. Szefler.

20                  DR. DYKEWICZ:      Well, several comments on

21   this    specific   issue   about      anaphylaxis,    delay     in

22   treatment, risk for fatality, rapidity of onset.



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1                    First of all, maybe just to return to some

2    comment that were made earlier, it is certainly true that

3    anaphylaxis can occur in medical settings due to use of

4    parenteral      medications,     antibiotics,     radio     contrast

5    media, but what we're looking at really in a nonmedical

6    setting would be the risk of anaphylaxis from foods and

7    potentially      certain     oral     medications,     maybe     even

8    including aspirin and nonsteroidal anti-inflammatory

9    drugs    with    the   pseudo-allergic        reaction    that     was

10   addressed earlier.

11                   It has been found in some studies that food

12   induced anaphylaxis can be more problematic to treat.

13   The reason is that because there is some time delay in

14   the onset of the symptoms and the progression of the

15   symptoms by virtue of the requirement for a need for oral

16   absorption that, in fact, fatal food anaphylaxis can have

17   a slower onset, a slower progression, but still lead to

18   fatality.

19                   If we're getting at the questions that have

20   been raised earlier about whether somebody would run down

21   to the local drug store and because at that point the

22   person is only having hives and they pop a tablet of a



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1    medication which now has over-the-counter indication for

2    hives, there would be the possibility that would, as Dr.

3    Sachs brings up, prolong or delay the patient seeking

4    medical attention and thereby delay the administration

5    of epinephrine and thereby cause a greater risk of

6    fatality.      If you're going to go the whole nine yards,

7    that is a scenario.

8                     The other thing, though, about the kits that

9    are commercially available that do have antihistamines

10   in them, actually it's chlorpheniramine with epinephrine

11   in    a   kit,    it   is    certainly         appropriate    to    use

12   antihistamines in the treatment of anaphylaxis, but that

13   is always viewed as only an adjunct to the primary

14   treatment with epinephrine.

15                    Any type of scenario in which someone would

16   delay receiving epinephrine, whether it's use of an

17   antihistamines with over-the-counter indication or not,

18   that would result in fatality or greater risk thereof.

19                    DR. CANTILENA:      Okay.     Dr. Szefler, then Dr.

20   Joad, then Dr. Davidoff.

21                    DR. SZEFLER:      I guess I just want to clarify

22   a few points.      Because the package inserts change so much



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1    I haven't read every one or do I read every one.                        Let

2    me just get it clear in terms of loratadine.                         It is

3    approved in the package insert for chronic urticaria.

4    Is that right?          The studies that were done were deemed

5    sufficient.

6                      DR.     CHOWDHURY:            Chronic       idiopathic

7    urticaria.

8                      DR. SZEFLER:     Okay.       So the discussion that

9    we're having is not about the indication for the disease.

10    It's about sharing the information and putting it in

11   the product.        I mean, why would you not want to put

12   information in terms of its approval?                I guess may Dr.

13   Ferguson's talk crystallized that for me.

14                     What reason would you not want to put the

15   information in there other than maybe the misinformation

16   about other urticaria?              I mean, it's like sharing

17   information that is reassuring the patient that they have

18   been receiving adequate treatment.

19                     Maybe I just missed that point in the whole

20   review.        I didn't have a package insert on hand but if

21   it's there already, it just seems like it's a logical

22   transfer of information.              It's not new information.



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1    It's a logical transfer of information.

2                   DR. CHOWDHURY:       To answer the question and

3    to address the point here, the studies for loratadine

4    and most other new antihistamines were done on CIU

5    patients.      The application that we reviewed we hadn't

6    had where to get the indication of CIU.                There were no

7    acute      urticaria     or     other        studies      for      these

8    antihistamines.

9                   DR. SZEFLER:      But it is approved for chronic

10   idiopathic so it's already there.              It's not like we're

11   discussing the approval.

12                  DR.     CHOWDHURY:        Already       approved       and

13   marketed with the indication of chronic idiopathic

14   urticaria.

15                  DR. SZEFLER:      Okay.       So my second question

16   is --

17                  DR. GANLEY:       Can I just add something to

18   that?     If you put it into the package insert, you are

19   in essence giving it as an OTC indication.                The company

20   can have an add-on tomorrow for direct consumer labeling

21   for their prescription product to go see your doctor for

22   your    urticaria.       It's   not     that    we're     withholding



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1    information    from   the    public.       All   this   is    public

2    information.    Anyone can go get the package insert.            They

3    are readily available.

4                   DR. SZEFLER:    But the patient still kind of

5    deems the responsibility of treating themself even though

6    it's a medical disease.

7                   DR. GANLEY:    If you start putting uses into

8    a package insert that's labeling.          If it's an OTC product,

9    you are essentially giving it an OTC claim.                  I think

10   that's what the issue is here.       It's not that we're trying

11   to withhold that.

12                  I'm not sure if people -- there is some

13   confusion abut that but if this was not an OTC claim it

14   would still remain a prescription claim.            It's not that

15   the FDA is taking something away from them.

16                  The issue is if allergic rhinitis becomes

17   an OTC claim, should this also become a OTC claim?                 If

18   it doesn't, it remains a prescription claim.               They can

19   still market the product as a prescription product and

20   do their direct-to-consumer advertising.

21                  DR. SZEFLER:     Maybe this gets to the root

22   of a problem and maybe I'm just not clear on payments.



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1     I'm trying to figure out who this benefits and how it

2    might be used to benefit.

3                   Suppose I'm a patient and I go in and I see

4    a physician and I have chronic idiopathic urticaria.

5    I have medical benefits.       The physician feels that the

6    most appropriate drug for me is loratadine and then tells

7    me, "For the next year go out there and purchase it on

8    your own."     I bear the cost.

9                   On the other hand, if it's not on the label,

10   can the physician then say, "Your best drug is loratadine.

11    Because it's not in the label it's a prescription and,

12   therefore, your insurance company should pay for this."

13    Is that what it boils down to?

14                  DR. GANLEY:    I'm not sure we factor that into

15   our decision as to whether this is an appropriate

16   indication for an OTC setting.

17                  DR. SZEFLER:    It is for the patient.

18                  DR. GANLEY:    I understand but this came up

19   at least year's meeting, I think, and we don't factor

20   that into the decision process.            I suspect we could get

21   by with --

22                  DR. SZEFLER:    I guess I would like to factor



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1    it in.

2                   DR. GANLEY:    You're welcome to do that but

3    we don't factor that into our decision.            I think some

4    of the issues, I don't know what individual's co-payment

5    is for prescription products.         Mine is, I think, $15 a

6    month unless I get a three-month prescription.             There's

7    still some co-payment on the side of a consumer in most

8    cases, even if they have a prescription plan.

9                   DR. SZEFLER:    I guess I have to sort out the

10   issues.

11                  DR. GANLEY:    It's what can we factor into

12   that decision and that's generally not been a factor.

13                  DR. CANTILENA:      Dr. Temple, do you have a

14   comment before we go to the next one?

15                  DR. TEMPLE:     Yeah.       I mean, as I'm sure

16   people are aware, there are a number of drugs that are

17   available where the same new molecular entity or the same

18   actimority     (phonetic)     is     available    both      as    an

19   over-the-counter drug and as a prescription drug.

20                  Ibruprofen,     for     example,     remains        as

21   prescription Motrin in doses -- in tablet sizes above

22   200    milligrams.     Nothing       stops   a   physician       from



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1    prescribing it that way in which many people will cover

2    it or telling someone to go get it as an over-the-counter

3    drug in which cases I understand most of the time will

4    not be covered.        We don't deal with that.

5                      But in case you have any doubt about whether

6    most Ibruprofen is used as an over-the-counter drug, try

7    to find the labeling for Motrin in the current PDR.             You

8    won't find any Rx Ibruprofen labelling.           People can do

9    what they want with that.            The question here is only

10   suitability of a particular claim for over-the-counter

11   use.

12                     There are specifications for what makes a

13   drug suitable or a claim suitable for over-the-counter

14   use.    You have to be able to diagnose it, manage it, and

15   so on.         That's why we worry about each of the claims

16   individually.        Before you put it in OTC labeling, you

17   have to believe -- usually we have a way out of that,

18   too -- you have to believe it can be used by the individual

19   that way.

20                     There is such a thing as professional claims

21   for over-the-counter drugs.            Aspirin has professional

22   labeling where you are absolutely positively supposed



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1    to go see the doctor to get your cardiovascular disease

2    prevented.       Does that always happen?          We don't know.

3                     DR. CANTILENA:       Okay.     Dr. Joad and then Dr.

4    Davidoff.

5                     DR. JOAD:   I wanted to speak to the general

6    indication of hives and whether the evidence we have so

7    far about the use of antihistamines in this specific CIU

8    is sufficient for us to approve it or have packaged

9    labeling for acute hives.

10                    I would argue for evidence based medicine

11   on that.       That is a big number of patients in comparison

12   with the CIU patients, No. 1.          Secondly, I think you could

13   make    an     argument   that   is    a      theoretical   one    that

14   antihistamines and CIU are there present all the time

15   occupying those H1 receptors so that they are not

16   available for the release of antihistamines.

17                    Whereas, in acute hives if it's really a

18   single hit one especially, the event will have already

19   happened.       The histamine receptors will be occupied.

20   The secondary effects are already well underway.                     You

21   may not be able to go back with an antihistamine and

22   reverse that.



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1                   There's     no     reason       to    say    I'm    right

2    particularly but if you don't do an evidenced based study

3    of what really happens for acute hives, I don't think

4    you know the answer to that.         I think Dr. Sachs is telling

5    us that primary care physicians are seeing people with

6    acute hives and they could be studied in a primary care

7    setting.

8                   DR. CANTILENA:        Dr. Davidoff.

9                   DR. DAVIDOFF:          Just to stress that last

10   point, I agree.       I think it would be perfectly doable

11   to design an appropriate study for studying acute hives.

12    I actually had a question, though, that had to do with

13   the    presentation    Dr.      Engle    made       about   pharmacist

14   involvement     in     guiding          patients      about       taking

15   over-the-counter drugs.

16                  I think that is a very important point since

17   it does say in the footnote that 61 percent of the

18   respondents    in    one   survey       said   that    they    did    use

19   over-the-counter drugs at one or another type of pharmacy.

20                  That raised a question in my mind as to how

21   often that really -- the pharmacists really get involved

22   in interaction with patients at the time they purchase



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1    over-the-counter drugs.               In the pharmacies I've gone

2    into, most of the antihistamine type preparations are

3    in an open display.            They are not behind the counter.

4                      If     the     person        purchasing       it     wanted

5    information from the pharmacist, they would have to go

6    over to the pharmacist and ask them.                  The pharmacist is

7    usually busy filling prescriptions so it is hard to get

8    their attention.

9                      I actually wondered if there are any data

10   on   how       often   pharmacists       are      actually    asked     about

11   over-the-counter preparations because my suspicion is

12   that it's actually not very often unless the drug is behind

13   the counter.

14                     That led to my second question which is --

15   it expresses my naivety in this, and that is is there

16   any kind of behind-the-counter system in the U.S, formal

17   or otherwise?          I didn't think so.          It certainly doesn't

18   look like there is but I thought maybe there was.                         I do

19   think there are such systems in some other countries.

20   Am I correct?          But not in the U.S.

21                     My first question really is are there any

22   data on how often pharmacists are actually involved in



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1    over-the-counter type purchases?

2                   DR. CANTILENA:      Okay.   The answer to the

3    second question is that there is not that category

4    available in the United States and that I will ask our

5    Drs. of Pharmacy of they would like to respond to your

6    first question.

7                   DR. JOHNSON:    I am not aware of any specific

8    data that describe how often individual seek pharmacy

9    input.     It's been a long time since I worked in a retail

10   setting but I have worked in a retail setting and you

11   do have a fair number of people who come and ask.

12                  Typically it will be in the first time they

13   would use such a product.        Obviously once they've used

14   it and are familiar with it, they are much less likely

15   to come back and ask for that input.          It's clearly a

16   process that is driven by the patient seeking information.

17

18                  There's nothing that forces the patient to

19   see the pharmacist.    I mean, I think there is a fair amount

20   of it and if the labeling on the box -- not on the inside

21   of the carton but on the box suggest that they may want

22   to consult a pharmacist, I think that might increase it.



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1                     I mean, there are a couple -- we do have a

2    few drugs that are, in a sense, behind the counter.

3    Insulin, for example.           In some states there are Schedule

4    V compounds cough products that have codine, for example.

5     In general we don't have that category that some other

6    countries do.

7                     DR.    DAVIDOFF:          Well,    could     I   ask    in

8    connection with that on the last point you made, are there

9    examples of over-the-counter medications that say on the

10   box that you should consult your pharmacist as well as

11   you should see a physician in certain circumstances?

12   Are there any examples of that?             It seems to me that could

13   be very constructive.

14                    DR. WOOD:      Well, there are data from the UK

15   behind the counter prescriptions.                  The data say that

16   almost uniformly no advice is offered.                      The drug is

17   actually behind the counter and the person goes up to

18   the counter, asks for the drug, and it's passed over with

19   no advice being offered.

20                    There    are     also    data     from   this    country

21   offering       advice    on   prescription         medicines      and   the

22   frequency which that happens and there's very little



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1    advice offered on that.    In fact, the majority of patients

2    in surveys don't recognize that when they sign that form,

3    they are signing that they are actually turning down the

4    advice for prescription drugs.             There's actually a lot

5    of data on the advice for prescription drug issues.

6                   DR. UDEN:   But pharmacists are the -- they

7    are there and are available to be consulted with if, in

8    fact, there is -- and labeling might take care of it.

9    I know in TV ads you consult your doctor or your pharmacist

10   but I don't think that there's any OTC labeling which

11   does that.     I won't make my next comment.

12                  DR. CANTILENA:       Are there examples, Dr.

13   Ganley or Dr. Katz?

14                  DR. KATZ:   The new drug facts on labeling

15   actually does have specific headers that will advise a

16   consumer to go seek their physician or healthcare provider

17   or to go ask the pharmacist.       It's very specific and has

18   listed bullet points underneath.

19                  Some may be related to asking for information

20   regarding other concomitant medications or concomitant

21   medical problems that someone may have so they shouldn't

22   take the problem together.         We'll say ask a doctor or



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1    pharmacist in certain headers.                  In others it will say

2    just ask your doctor or healthcare practitioner.

3                      DR. CANTILENA:       Okay.     I think actually what

4    I would like to do now is just take a 15-minute hiatus

5    here from this interesting discussion and have everyone

6    come back in 15 minutes.                We'll clear up any other

7    questions and then we'll go to our questions.                 Thank you.

8                      (Whereupon, at 3:12 p.m. off the record until

9    3:25 p.m.)

10                     DR. CANTILENA:         Before we go ahead with

11   questions, Dr. Monroe has asked to clarify a point on

12   the question on anaphylaxis for the sponsor.

13                     Dr. Monroe.

14                     DR. MONROE:      Thank you.         I'd just like to

15   make a couple of very brief comments on the issue of

16   safety.        The first has to do with anaphylaxis.              I think

17   there     is     consensus     that     it's      a   rare    situation.

18   Antihistamines        are    not      the   treatment        of   choice.

19   Epinephrine, adrenaline is.

20                     An issue was brought up would the approval

21   of an agent like loratadine OTC create a sense of

22   complacency that might cause added delay in the consumer



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1    seeking appropriate care.       I think the best answer I can

2    give is that we've got 10 years of experience in Canada

3    and the UK where this is an OTC medication and there's

4    no indication of increased incidence of complications

5    or deaths related to this condition.       We appreciate it's

6    rare.    It's a serious thing but we don't think that making

7    loratadine OTC would in any way change in a negative

8    fashion the status quo.

9                   I would also just like to say on safety I

10   think that the lack of approval of such an effective and

11   safe agent as loratadine OTC would create the maintenance

12   or the perpetuation of the status quo where most patients

13   who have urticaria, the spectrum of urticaria, that's

14   the vast majority of people with acute and some with

15   chronic who now access the only OTC medicines that they

16   have.

17                  They are accessing sedating antihistamines

18   that are far from safe.           I don't think you should

19   underestimate the potential harm in the perpetuation of

20   those people who right now, and it's the majority of people

21   with hives, access care through a sedating much less safe

22   medication than loratadine.



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1                   I would also say there are subsets of the

2    current population, particularly the elderly, who are

3    taking     these     medicines    and        they   are     more   than

4    antihistamines.       They are anti-colonurgics (phonetic).

5     They affect urinary retention.              They affect glaucoma.

6                   I think if you're looking at patient and

7    consumer safety, the movement of this drug, Claritin,

8    to the OTC scenario, I think, creates a much greater

9    improvement in the safety equation than not doing it.

10                  DR. CANTILENA:       Yes, Dr. Davidoff.

11                  DR.    DAVIDOFF:       Just      a   quick    point    in

12   connection with your first issue.              Absence of evidence

13   is not the same as evidence of absence.              It seems to me

14   that unless someone has specifically gone and looked at

15   the fatal cases of anaphylaxis in over-the-counter

16   countries to see whether or how often the availability

17   of the over-the-counter antihistamine might have, in

18   fact, delayed treatment, I don't think you can say there

19   is any information one way or the other on whether this

20   availability in those countries has delayed treatment

21   and contributed to fatalities?

22                  DR. CANTILENA:       Dr. Uden.



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1                   DR.    UDEN:      I   just      have   to    take   this

2    opportunity to remind us that 11 months ago these drugs

3    weren't safe enough to be OTC and now they are.                    It's

4    quite a reversal.

5                   DR.    CANTILENA:             Thank    you   for    that

6    historical point.

7                   Dr. Clayton, are there any other issues that

8    you wish to clarify from the discussion that was not

9    absolutely clear?      Okay.    I just actually have a question

10   for Dr. Ganley.      As we go through the packet we're looking

11   at in essence a switch application because it's already

12   an approved Rx indication.

13                  I guess are there examples in your files that

14   I'm not familiar with where we have actually accomplished

15   a switch recommendation without an actual use study with

16   the use of the Internet, I guess, as a survey of consumers.

17    Is there anything that you can point to in the files

18   that we have experienced in this area?

19                  DR. GANLEY:      I think there have been.             The

20   vaginal antifungals actually did not have an actual use

21   study but I think there are probably other applications

22   that have never made it to the committee that we haven't



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1    required actual use studies on.

2                   Clearly when the discussion occurred last

3    year -- the committee meeting occurred last year regarding

4    allergic rhinitis, we had actually come out on the

5    positions that we didn't think it would need an actual

6    use study because it's a category of drug that is already

7    available OTC for this indication.         I think there are

8    examples where we don't require that.

9                   I think the issue with the consumer surveys

10   is what kind of -- with that type of study what is the

11   value of that study.   Is that a study that helps you design

12   a better label comprehension study because you understand

13   a population's perceptions of how they should use certain

14   products, or should it be used to improve the design of

15   an actual use study or things like that.

16                  Again, I go back to what the questions in

17   this population they were actually asking.           I didn't

18   really need that study to be convinced that someone who

19   had gone to a physician and had been told they had chronic

20   urticaria and was instructed to use a specific product.

21

22                  They wouldn't do it necessarily correctly



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1    had all these steps in the physician/patient interaction

2    occurred.      You could take many diseases that have

3    intermittent symptoms where this would occur.         Migraine

4    headaches where there is something prescribed to a person

5    and they are told to take it when they have a severe

6    headache because they already know what their migraine

7    is like.

8                   A patient with anginepectoris (phonetic) who

9    is given sublingual nitroglycerin, most of them know when

10   to use that correctly so you don't need to do a study

11   to tell me that someone that has a diagnosis of CIU would

12   be able to use this product.        But that's really not the

13   major issue here.      I think it's how is the general

14   population going to use this product.

15                  The question with the surveys, I think, is

16   this type of study that the committee would like to see

17   come in supporting applications that would limit use to

18   a specific population, or should it be some type of study

19   that is used to -- I think Dr. Davidoff had mentioned

20   earlier we don't know what the general

21   -- how the general population is going to use this.

22                  I may have been better to survey them and



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1    see how they use these products and then try to create

2    a label because clearly I think there are issues in the

3    label comprehension that even the way it was written that

4    the cohorts in the general population and the acute hives

5    population they weren't going to use it as it was labeled.

6     Could that consumer survey have been better used to

7    create a better label?

8                   DR. CANTILENA:       Okay.     Thank you.        Are

9    there any other specific issues that the committee would

10   like to discuss before we go to the questions?          Any other

11   pieces of information?

12                  Dr. Sachs.

13                  DR. SACHS:    The one question I have is what

14   age is this supposed to be approved down to?

15                  DR. CANTILENA:      Dr. Ganley.     Is it 12 and

16   above or six and above?

17                  DR. GANLEY:      I think it was about six years

18   of age.

19                  DR. CANTILENA:     Okay.     Any other questions?

20                  Yes, Dr. Rosenberg.

21                  DR. ROSENBERG:     Just without harping on this

22   just to say one more time that the patient will do one



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1    of three things.      They will either seek medical care and

2    get it at a physicians office, they will buy what is

3    presently available over the counter which is sedating,

4    or they will go to a health food store and go to that

5    sort of thing.     These are the only options.

6                   I turn again to that chart on Tab 7 that shows

7    the   preferred   treatment,      No.       1   choice    of    so   many

8    physicians is corticosteroid.           In the material that we

9    were sent there are these review articles and I've

10   reviewed textbook articles.           Malcolm Grave says use a

11   non-sedating antihistamine once in a while.

12                  Anytime you're on a consensus committee you

13   always have to say something.           Everybody is afraid they

14   are going to be sued unless you make it okay to put

15   everything else in.       What they really say is try the

16   antihistamine.

17                  Then   there's     a   statement          from    another

18   consensus from Europe.       Then there's another authority

19   and a book on urticaria that I've always found the most

20   sensible one.     It's an older book by Dr. Champion from

21   Britain who is one of the original editors of the Rook

22   series of that major textbook.



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1                   He wrote a whole book about urticaria and

2    he concluded that after this and that and trying your

3    best, he said the best thing to do for these people is

4    interdict aspirin and try to find an antihistamine that

5    will give them some relief without putting them to sleep.

6     We have that here now.

7                   I think truly there are hard cases but if

8    the people do this first and then go to the doctor if

9    they didn't get better, then prednisone and so forth is

10   okay, I mean, if they're that sick and maybe they are

11   going to get a workup but they're sure getting an awful

12   -- too much of it now in my opinion.

13                  I see cases.    I mean, I've testified for a

14   plaintiff and a fellow you had urticaria didn't want to

15   miss work so he stopped at the emergency room on the way

16   to work in Honolulu every two weeks for a refill of his

17   dose back.     He had urticaria and he had aseptic narcosis

18   of the hip.

19                  Another patient who has just been referred

20   in because of generalized coccidioidomycosis to our

21   infectious disease fellow.        It was a dermatologist who

22   made the diagnosis and he called me and said, "You don't



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1    want me.       You want our infectious disease guy."

2                     I saw him and I said, "Did that fellow come

3    in from Jonesboro?"      He said, "Yeah."       I said, "Does he

4    have AIDS?"         He said, "No, he doesn't have AIDS.

5    Somebody has been giving him 40 milligrams a day of

6    prednisone."      Thank you.

7                     DR. CANTILENA:     Okay.    Dr. Ganley.

8                     DR. GANLEY:    I think the one thing about if

9    you're talking about the physician survey and the first

10   line therapy, I think you have to -- there's details

11   missing there where you can't really figure out what's

12   going on there unless you ask more questions.

13                    It may be that many of these individuals who

14   come in have already tried multiple antihistamines and

15   they have failed them.         We don't know that.     If you ask

16   follow-up questions to those questions and get the

17   details, that may be the bias of that physician because

18   95 percent of the people who come in with chronic urticaria

19   have already tried diphenhydramine and chlorpheniramine

20   and they just didn't work.

21                    I don't know how much to place on that.               I

22   think the issue that you make that's valid is that we



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1    should be advocating these as first line therapy.               The

2    question is how best to do that.           Is it narrowing this

3    claim down or is it having a more broader claim, for

4    example, if it's to go OTC.

5                   DR. CANTILENA:       Okay.     Thank you.        Any

6    other comments before we move to the questions?               Very

7    good.    What I would like to do then is actually go around.

8     We'll start with question No. 1.           What we'll have you

9    do is indicate your vote, yes or no, and then comment

10   if you would like to comment.          For the first question,

11   "Is urticaria a disease process appropriate for an OTC

12   indication?"

13                  Actually, we can start on that side of the

14   table.     Dr. Alfano, you can comment but, unfortunately,

15   you can't vote.     If you would like to start with your

16   comment if you have one.       If not, then we'll just head

17   around the table with our vote and comment.

18                  DR. ALFANO:      Yes.       I believe it is an

19   appropriate indication.

20                  DR. D'AGOSTINO:      Dr. Dykewicz.

21                  DR. DYKEWICZ:    I'm going to vote no because,

22   at this point in time, I don't believe we have sufficient



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1    use studies to be assured of how this is actually going

2    to be used in practice.

3                   I say this though with kind of a divergent

4    view in my sole, and that is I think we do recognize that

5    there's a problem with the urticaria as it currently

6    exist.     I agree that the de facto use of the currently

7    available over-the-counter antihistamines with their

8    sedating properties is undesirable if it were in an

9    alternative way available for the patient to get a

10   non-sedating antihistamine that would be effective.

11                  I guess my dilemma as I've tried to express

12   during the course of these meetings is what can be done

13   to educate the patients so that they would use these

14   medications most appropriately and minimize risk to them.

15                  It occurs to me that the efforts to provide

16   appropriate labeling on the package might actually be

17   a very good educational thing for the public and if the

18   public were to adhere and to follow the recommendations

19   that are listed on the label, that would be a good thing.

20

21                  I think if anything there is probably both

22   among physicians and among patients an under-recognition



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1    of the potential seriousness of urticaria sometimes being

2    an indication of a serious underlying disease.                  There

3    may be too much of a kind of cavalier approach to it where

4    you just give some antihistamines and don't worry about

5    the full workup of it.

6                     Although I do vote no, I think with some

7    additional use studies, one might be convinced that this,

8    in fact, would be a good thing to have available and,

9    if you will, even give the opportunity to gain greater

10   education for the public.

11                    DR. CANTILENA:         And just as a point of

12   clarification, when you say use studies, you mean actual

13   use studies where they can buy it like in the pharmacy?

14                    DR. DYKEWICZ:       Well, I'm not really clear

15   on whether there would be some type of -- the thing about

16   surveys versus where they would actually be using it,

17   I   think      once   you   actually      would   approve    it    for

18   over-the-counter use once the horse is out of the barn,

19   you probably can't come back very readily with that I

20   would think.

21                    I guess some sort of limited use studies maybe

22   where people would be given the opportunity to obtain



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1    the drug in limited circumstances as part of a study group.

2                   DR. CANTILENA:         Yes.      Actually, those are

3    called actual use studies.           Go ahead.

4                   DR. GANLEY:       Yeah.        I think his answer is

5    then yes, that it could be an OTC indication but you need

6    these types of studies.          I tried to point out earlier

7    if you're answering no, you're coming to the conclusion

8    that this never -- there's nothing that the sponsor could

9    do that could actually convince you that this could be

10   an OTC drug.

11                  If    you   think     this      is   a   possible      OTC

12   indication, it would be a yes and then what kind of data

13   would you be interested in seeing.              If you say no, then

14   that's shutting the door on anyone coming in for this

15   indication.

16                  DR. CANTILENA:        So would you like to amend

17   the wording of the question to be, "Could urticaria be

18   a disease that was appropriate for OTC?"

19                  DR.    GANLEY:         I'll     leave    it    to    your

20   discretion.

21                  DR. CANTILENA:        I think that's what you're

22   asking so why don't we actually amend the question, "Could



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1    urticaria be a disease process appropriate for an OTC

2    indication?"    Your vote, Dr. Dykewicz?

3                   DR. DYKEWICZ:    With all the caveats that I've

4    stated, then I could state yes.

5                   DR. CANTILENA:     Thank you.

6                   Dr. Joad.

7                   DR. JOAD:   I vote also yes, that it could

8    potentially be OTC.        I would recommend that it be

9    broadened to all reasons for urticaria due to the things

10   we mentioned about, that it would be impossible in

11   practical terms limited to chronic idiopathic urticaria.

12

13                  Then the studies I would like to see would

14   be a study that shows people recognize hives versus other

15   important things that could be mistaken for hives in a

16   study of efficacy, an outcome study of efficacy and acute

17   hives and studies in children.

18                  DR. CANTILENA:     Okay.    So we've actually --

19   we've had you cover actually question 1 and 1A.

20                  DR. JOAD:   And 2.

21                  DR. CANTILENA:     I've chosen to ignore that

22   response because it's out of sequence now.       Just kidding.



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1     If we can actually go back to Dr. Dykewicz for 1A and

2    actually what we'll do is if you answer yes for 1, then

3    you can also answer 1A.

4                   DR. DYKEWICZ:     Well, should the indication

5    be for chronic idiopathic urticaria?             Potentially yes

6    with the caveats.     Should it be broader such that it

7    includes acute urticaria hives?            Potentially yes but my

8    caveat to the FDA would be I think it would be much more

9    difficult to gain confidence about the appropriate use

10   of this medication by patients then it would be under

11   the very restrictive provisal of chronic idiopathic

12   urticaria.     I'm saying yes, but hear all my caveats.

13                  DR. CANTILENA:     Okay.      Thank you.

14                  Dr. Szefler.

15                  DR. SZEFLER:    I would vote yes.     I don't know

16   how you do it but I would like to see studies done with

17   acute urticaria.    Again, as I said this morning, I think

18   if people really sat down and thought about it in terms

19   of primary variables and conditions to study it, and I

20   think it's feasible, then I would like to see those put

21   into the package so that it rules out any of these

22   considerations about inappropriate use.



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1                    DR. CANTILENA:        So yes for 1 and yes for 1A?

2                    DR. SZEFLER:         Well, in 1A it's really a

3    desire to see the studies.           I think the implications of

4    the study -- the implications of the question if I said

5    yes to A would mean that I approve it right now for both.

6                    DR. CANTILENA:         Actually, the question is

7    now could it be a process and, if it could, would the

8    indication then -- should the indication be broader to

9    include hives.           Then we'll actually talk about the

10   studies that you would like to see and others would like

11   to see under question No. 2.

12                   Dr. D'Agostino.

13                   DR. D'AGOSTINO:         Yes to both.

14                   DR. CANTILENA:        Dr. Krenzelok.

15                   DR. KRENZELOK:        Yes to No. 1.      We certainly

16   have an established indication.                I don't think we have

17   information to allow us to put the general urticaria

18   statement      on   it    but   I    think      that   post-marketing

19   surveillance of off-label use could provide us with a

20   wonderful opportunity to extend that indication sometime

21   down the line.

22                   DR. CANTILENA:         So yes to 1 and qualified



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1    yes to 1A.

2                     DR. KRENZELOK:     Yes.

3                     DR. CANTILENA:     Dr. D'Agostino.

4                     DR.   D'AGOSTINO:           I   guess     I'm     really

5    confused.       This doesn't sound like a question that's

6    directed to the product so why are we talking about the

7    product?       I mean, it's a question about the indication,

8    isn't it?

9                     DR. GANLEY:   Yeah, it's about the indication

10   because this company isn't the only company that is

11   interested in this claim so if we have to give advice

12   to other companies, it's important for us to understand

13   what we should be telling them, that you need to go for

14   a broader claim or you limit it to chronic urticaria.

15                    Once we get over that hurdle, then looking

16   at the data that Schering-Plough has submitted, does that

17   lead to an indication in the OTC setting or do they need

18   to do other studies?      Should they go after a more broader

19   claim?

20                    So this is the more general question that

21   you have to overcome and it's mainly because we already

22   have gotten inquiries from other companies that have



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1    antihistamines that have an interest in getting this

2    claim.

3                   Dr. Krenzelok's comments, I think, appear

4    to be directed at the company's product and that's really

5    question No. 2 where, you know, what do you think if you

6    vote yes that this could be an OTC claim is it chronic

7    urticaria, is it acute hives.        That's where we need some

8    input.

9                   DR. CANTILENA:     So if I understand you then,

10   really question 1 is in general and question A is product

11   specific.

12                  DR. WOOD:   Question A needs to be qualified

13   because I don't people have a clear understanding of what

14   we're voting for there.      The question A as written must

15   relate to the evidence that's been offered for a specific

16   drug.

17                  Clearly if you vote yes to the stem, then

18   presumably other hives in any subdivision could be

19   potentially approvable to provide data, but having the

20   data has to relate to a product.           The way it's been

21   modified doesn't make much sense unless we modify it

22   again.



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1                   DR. GANLEY:      Well, I guess it depends on what

2    your priors are here, whether you think that this is

3    already being used out there by the population in some

4    respects.

5                   DR. WOOD:     Well, let's read it.          What we've

6    modified it to, as I understood it, was, "Is urticaria

7    a disease process which could be appropriate for an OTC

8    indication."    That was the modified stem.            Right?      Then

9    if yes, should the indication be for chronic idiopathic

10   urticaria or should it be broader to include acute

11   urticaria.

12                  Well, these two subdivisions depend on --

13   are data driven and they are data driven depending on

14   the drug that you've got in front of you so it's not

15   appropriate as written like that.                   That's why the

16   discussion each time raises issues related to the drug.

17                  DR.   CANTILENA:         But   I    heard   a   lot    of

18   discussion actually that said that to have the indication

19   just be CIU is actually confusing to the consumer and

20   it should actually just be hives.                 I thought we were

21   actually addressing that by broadening it.                 I actually

22   sort of see that as a general issue and not product



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1    specific.

2                   Before we give you confusing advice, maybe

3    we should get on the same page.            Dr. Temple.

4                   DR. TEMPLE:      Each of these has multiple

5    variations.     One question you could ask is if you had

6    the data for acute hives, would it be better to label

7    it more broadly.     That's one kind of question.          I don't

8    hear anybody thinking that wouldn't be good

9                   Then there's the question of do you have the

10   data to do that.     There's been a lot of discussion one

11   way or the other.     Some people probably think they have

12   the expert views to contribute to that but maybe not

13   everybody does.      As I said before, in the end we have

14   to conclude that the data exist for that or we can't say

15   yes.     We can't legally say yes.         I don't know if that

16   helps.

17                  DR.   CANTILENA:        Yes,    a   comment,      Dr.

18   Rosenberg.

19                  DR. ROSENBERG:     Can I speak to that?      I think

20   that you were wise to broaden it because that was one

21   of the things that, in fact, did come up and everything

22   comes out more neatly.



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1                   On the other hand, the Schering company is

2    asking for the chronic idiopathic urticaria and brought

3    an exhaustive and complete search of this but not the

4    other.     The reference that I showed sites this as evidence

5    based and had one reference.

6                   I'm not going to be here tomorrow but other

7    on this panel will be here tomorrow.        We've got members

8    of the panel from the Pacific time zone.        I'm sure that

9    one could come up with literature, a search done by an

10   expert informationist that would help everybody by

11   getting up in time tomorrow morning.

12                  DR. CANTILENA:       Yeah, I actually think we

13   are sort of confined to this day on this agenda.        I guess

14   what I would like to suggest, and please, Dr. Ganley and

15   Dr. Temple, if you're comfortable with us going in the

16   generic sense as the overall indication could be.

17                  Are we confusing you, Dr. Titus, in terms

18   of the answer to 1A?      Should we just go one at a time?

19   Overall I think their answer is clear with the following

20   qualifiers.     I think if you're okay, if the FDA contingent

21   nods their head, I guess we will go forward as we are.

22    I didn't say nod off.        I said nod your head.      Are we



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1    okay?

2                   DR. GANLEY:    I think the issue is that we

3    have a claim that's -- you know, I think every prescription

4    product has a claim for chronic idiopathic urticaria.

5    I think Dr. Wood got into the discussion earlier about

6    whether that should just be made a broader claim.

7                   Do we have a comfort level of efficacy or

8    should be segment it to that population and allow

9    companies to either do chronic idiopathic urticaria or

10   they could go after acute hives or they could subsegment

11   it into any other population that they see fit.

12                  I think that's where it was sort of directed

13   at in general terms is that this is the claim on all of

14   the prescription products right now.          To carry it

15   straight over is a choice, too, or should we ask -- should

16   we try not to confuse consumers and have some products

17   labeled for chronic idiopathic urticaria and some labeled

18   for acute hives or hives in general.

19                  We would like to come up with some consensus

20   as what to tell people as to what the label should look

21   like.    It should be similar, I think, potentially across

22   the board unless someone has a differing opinion on that.



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1                   DR.   WOOD:     Could       I   offer    a   solution?

2    Supposing we said that the indication would be hives after

3    you had seen a physician?       Would that deal with the --

4                   DR. TEMPLE:    Can I make a counter?               Maybe

5    this is what Charlie was suggesting.              First cover the

6    question of whether urticarial disease of some sort is

7    suitable for over the counter.         Get that out of the way.

8     Then you can elaborate on what exact claim you like best.

9     Knowing that urticarial disease is suitable for over

10   the counter, the first thing is absolutely critical to

11   us.

12                  DR. CANTILENA:     Okay.

13                  DR. TEMPLE:      The other is a refinement.

14   Alistair's suggestion is certainly one to think about

15   as would a variety.      Again, remember that we're going

16   to have to be satisfied the data support whatever we say

17   or whatever you suggest.

18                  DR. CANTILENA:     Okay.        Just so we're clear

19   on what everyone's intentions were, Dr. Dykewicz, Joad,

20   Szefler, D'Agostino, and Krenzelok voted yes to question

21   1 as modified and yes to question 1A in the general sense,

22   not product specific.



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1                      DR. D'AGOSTINO:      I want to make it clear that

2    I understood 1A to be as it's written and I voted yes

3    on that.        I think that we're talking about if you're

4    trying to make it too segmented, it's not a very useful

5    claim for OTC so I was answering the question as it was

6    originally written.        I believe I understood it correctly.

7                      DR.   CANTILENA:       Okay.    The other four

8    individuals voted yes.          Let's continue.

9                      DR. GANLEY:    Lou, can we just get the answer

10   to No. 1 and then go back and just --

11                     DR. CANTILENA:      Let's do 1 first.

12                     DR. GANLEY:    Don't take a vote on 1A of yes

13   or no.         Just let me put their comments on the record

14   because that's actually more important and we can sort

15   of swift through that.

16                     DR. CANTILENA:      So you want their comments

17   while they're voting?

18                     DR. GANLEY:     It's easier to go through one

19   and just give a yes or no and then go back and get the

20   comments on 1A.

21                     DR. CANTILENA:      So the attempt to expedite

22   things, I guess, didn't work out exactly as planned.



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1    Okay.    The first five have voted yes to one.           Dr. Uden,

2    question 1 as modified.

3                   DR. UDEN:     Yes to 1 and I'll comment on 1A

4    when appropriate.

5                   DR. CANTILENA:       Thank you very much.

6                   Dr. Johnson.

7                   DR. JOHNSON:      Yes.

8                   DR. CANTILENA:       Dr. Lam.

9                   DR. LAM:    Yes.

10                  DR. CANTILENA:       Dr. Davidoff.

11                  DR. DAVIDOFF:       Yes.

12                  DR. CANTILENA:       Dr. Gilliam.

13                  PARTICIPANT:      He's out.

14                  DR. CANTILENA:       Dr. Gilliam will be back.

15                  Dr. Sachs.

16                  DR. SACHS:     Yes.

17                  DR. CANTILENA:       Dr. Wood.

18                  DR. WOOD:     Yes.

19                  DR. CANTILENA:       Dr. Williams.

20                  DR. WILLIAMS:       Yes.

21                  DR. CANTILENA:       Dr. Clapp.

22                  DR. CLAPP:     Yes.



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1                     DR. CANTILENA:       Dr. King.

2                     DR. KING:     Yes.

3                     DR. CANTILENA:       Dr. Rosenberg.

4                     DR. ROSENBERG:       Yes.

5                     DR. CANTILENA:       Thank you.   Let's go back

6    around for question 1A as written if yes for the general

7    condition not product specific, should the indication

8    be for CIU/Hives or should it be broader such that it

9    includes acute urticaria/hives.              We're broadening it

10   beyond CIU.        If I may, Dr. Dykewicz, Joad, Szefler,

11   D'Agostino, and Krenzelok have voted in the affirmative

12   yes.

13                  Dr. Uden, 1A.

14                    DR. UDEN:     Broader, yes.

15                    DR. CANTILENA:        Should it be broader or

16   should it be restricted?

17                    DR. UDEN:     I think it should be broader and

18   I find it real interesting that we are using the product

19   that might be going nonprescription as the battle ground

20   or the proving ground for acute urticaria.             It has not

21   been done with prescription drugs before.

22                    DR. CANTILENA:       Dr. Johnson, should it be



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1    CIU only or should it be broader?

2                   DR. JOHNSON:      My feeling is that it should

3    be broader and there's a couple reasons for that.               One

4    is really sort of reality based, and that is that's how

5    patients are going to use it.          Everybody with urticaria

6    is going to use it.

7                   The second as it relates to data, I mean,

8    I think, you know, in this perfect academic world it might

9    be nice to see data.      But I guess I am comfortable where

10   we are because at present to say these agents are not

11   acceptable for acute urticaria means that we don't believe

12   that all the consensus bodies and experts in dermatology

13   know what they're talking about.

14                  Apparently all of them recommend this as the

15   appropriate therapy and the pathophysiology of the

16   process suggest that is appropriate therapy.              I guess

17   I feel comfortable that the information we have is

18   appropriate for broadening without actual use kind of

19   studies.

20                  DR. CANTILENA:       Dr. Lam.

21                  DR. LAM:    Yes in a general sense.

22                  DR. CANTILENA:      So yes, it should be broader?



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1                   DR. LAM:    Um-hum.

2                   DR. CANTILENA:       Dr. Davidoff.

3                   DR. DAVIDOFF:       Possibly.       I don't want to

4    say an absolute no picking up on Dr. Ganley's concern

5    about what absolute no means.           I don't understand what

6    he means by that because I can't see how a no is ever

7    absolute.      It seems to me there would always be the

8    opportunity to bring back new information that would open

9    the door again but that's another discussion.

10                  The reason I'm hesitating is I'm somewhat

11   impressed with Dr. Dykewicz' comments about concerns

12   about anaphylaxis.      I think it would be feasible to gather

13   information from the other countries that have had OTC

14   non-sedating antihistamines to see -- to look at their

15   cases of fatal anaphylaxis and try to get a direct body

16   of   information   on     whether     or     not   there's   been        a

17   contribution to delay and perhaps to fatality.

18                  It seems to me that the likelihood is that

19   there will either be no evidence that that happens or

20   it will be very, very minimal amount, but at least the

21   decision would have been made with their eyes open instead

22   of doing it in the dark.          As it is now, this would be



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1    a decision, yes, to broaden it but made on the basis of

2    really no input.        I think it's not good for the public

3    health     and    it   makes    everyone       in    this    room     rather

4    vulnerable.

5                      I also think I would wait until there had

6    been some search for the data.             Possibly there are data

7    on management in acute anaphylaxis.                 An exhaustive search

8    would be very helpful.          That could be done fairly quickly.

9

10                     I would also like this information on how

11   often     acute     hives      is,    in   fact,       misdiagnosed        by

12   self-diagnosis.        It seems to me that's information that

13   may not be critical but it would certainly be very, very

14   reassuring to have that information before there was a

15   decision made to broaden the indications.

16                     DR. CANTILENA:       Thank you.

17                     Dr. Sachs, broader or CIU only?

18                     DR. SACHS:         Actually, I also agree with

19   broadening the indication with the caveats that have

20   already been raised.

21                     DR. CANTILENA:       Thank you.

22                     Dr. Wood.



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1                    DR. WOOD:      I would like to see us remove

2    idiopathic     which   I    think      is     meaningless    to   most

3    individuals.      Remembering this is an indication for an

4    over-the-counter drug it needs to be understandable to

5    patients.      I would argue for making it hives, removing

6    urticaria.

7                    If we say the indication is hives after you've

8    seen your doctor and he or she has made that diagnosis,

9    then essentially we avoid the problem of misdiagnosis,

10   at least for the first episode, which is, after all --

11   and it also fits with the indication that the sponsor

12   is seeking.      Secondly, given the time it takes to see

13   a dermatologist, some might have many acute urticaria

14   patients in there anyway.

15                   DR. CANTILENA:       Thank you.

16                   Dr. Williams.

17                   DR. TEMPLE:     Lou, that was actually a do not

18   broaden it.     You want to change the name but you don't

19   want to broaden it.

20                   DR. WOOD:      No.      The indication would be

21   hives.

22                   DR. TEMPLE:      Oh.     Hives after you've seen



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1    your doctor.

2                   DR. WOOD:      Right.

3                   DR. TEMPLE:        I see.        So that's something

4    different.     Okay.

5                   Dr. Williams.

6                   DR. WILLIAMS:        Yes and broader.

7                   DR. CANTILENA:        So the indication should be

8    broader to 1A?

9                   DR. WILLIAMS:        Yes.

10                  DR. CANTILENA:        Thank you.

11                  Dr. King.      Excuse me.         Dr. Clapp.

12                  DR.   CLAPP:        Yes     to   broaden   it   and    my

13   reasoning is for many of the caveats shared previously,

14   but also because of the basic responsibility I think we

15   have to consumers and patients to adequately inform them

16   of appropriate usage of a medication rather than to narrow

17   down the spectrum of using to add further confusion to

18   a medicine that they will likely use anyway.

19                  DR. CANTILENA:        Thank you.

20                  Dr. King.

21                  DR. KING:     Yes, should broaden it.           I would

22   like to see two things happen.                One is I would like to



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1    postmark the surveillance simply to come after the data

2    because I think we need to know how many may have had

3    delay in diagnosis or complications.

4                      There's data out there from the European

5    group and also probably from the occupational health

6    groups.        I think we're just looking in a darkened alley

7    here and we need to find out more in that area so broadening

8    it would get us there with public education.

9                      DR. CANTILENA:     Thank you.

10                     Dr. Rosenberg.

11                     DR. ROSENBERG:     Yes, broader.

12                     DR. CANTILENA:      Broader.    Okay.      My vote

13   was on 1, could it be, yes, and on 1A, broader.                 We're

14   still missing Dr. Gilliam.

15                     Okay.   We'll move on to the second question.

16    Here we are product specific.                We are specifically

17   concerned are there sufficient data to support an OTC

18   switch of loratadine for CIU or a more general urticaria

19   claim.         We're talking specifically about the data we

20   heard about this morning.

21                     What I would like to do here is limit this

22   really just to answer the first part yes or no.              Comment



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1    if you feel strongly but really the second part of the

2    question is where we'll have an opportunity to talk about

3    specific trials if you think they are indicated.

4                   Let's start on this side of the table, please,

5    Dr. Rosenberg answering just the first part of question

6    2.

7                   DR. ROSENBERG:      Yes.

8                   DR. CANTILENA:      Dr. King.

9                   DR. KING:    Yes.

10                  DR. CANTILENA:      Dr. Clapp.

11                  DR. CLAPP:    Yes.

12                  DR. CANTILENA:      Excuse me?

13                  DR. D'AGOSTINO:        The question is an or

14   question, CIU or more general.             What are we responding

15   to?

16                  DR. CANTILENA:      Yes, it's actually an or so

17   it's either/or.

18                  Dr. Ganley, do you want the specific as the

19   indication or just either/or?

20                  DR. GANLEY:      Well, I think it would be

21   helpful rather than just giving yes or no.              There's an

22   over-emphasis on a vote of yes or no and the thoughts



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1    are more important.

2                   I think the dermatologists voted they would

3    like a broader claim and by voting yes here they would

4    be stating that they think the company has provided

5    sufficient information for a broader claim.                 If that's

6    your opinion, that's fine and they don't need to do any

7    other study presumably.

8                   DR. KING:     I was voting for a follow-up study

9    so that's different.

10                  DR.   ROSENBERG:          I     misunderstood.        I'm

11   sorry.

12                  DR. CANTILENA:       I apologize for that.          I was

13   actually using that as written as sort of an either/or.

14    As I understand it now, Dr. Ganley, you would like yes

15   or no and an explanation in terms of the specific

16   indication as proposed versus a more general indication.

17    Is that correct?     Yes or no for the specific switch for

18   CIU.    Yes or no for the general urticaria.

19                  DR. GANLEY:       I think --

20                  DR. CANTILENA:       Is it yes or no for CIU only,

21   yes or no for general urticaria?              We're sort of splitting

22   it into two questions.



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1                   DR. TEMPLE:   You really already answered the

2    first part of that question.         That is, everybody agrees

3    there's enough data for a switch for CIU because --

4                   DR. CANTILENA:     No.      Actually that was just

5    --

6                   DR. TEMPLE:    No.

7                   DR. CANTILENA:       -- as modified could it be

8    an OTC indication.     Now we are product specific in terms

9    of the data presented.

10                  DR. TEMPLE:    Okay.

11                  DR.   CANTILENA:       The    question    would    be

12   basically split into two questions.

13                  DR. TEMPLE:    That's fair.       Fine.

14                  DR. CANTILENA:       Okay.     Let's go ahead and

15   split the question, Dr. Rosenberg.          Are there sufficient

16   data to support an OTC switch of loratadine for CIU?

17                  DR. ROSENBERG:     Yes.

18                  DR. CANTILENA:       Are there sufficient data

19   to support a switch of OTC for a more general urticaria

20   claim?

21                  DR. ROSENBERG:     There may be but we haven't

22   seen it here.



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1                     DR. CANTILENA:       So that would be a no?

2                     DR. ROSENBERG:        That would be a no as we

3    didn't ask for it and they didn't bring it.         Yes, it would

4    be a no as of this minute.

5                     DR. GANLEY:     The answer to question 1 seems

6    like there was a consensus that it should be a broader

7    claim.     I'm not sure that it's relevant then.            The CIU

8    sounds like that's not what people what to have.                  The

9    question really should read if your answer to question

10   is yes, is there sufficient data to support an OT switch

11   of   loratadine     for   a    more   general   urticaria     claim.

12   Everyone has said that they would like a broader claim.

13                    DR. ROSENBERG:       Well, if I'm still voting

14   I would say whether that information -- let's read it

15   exactly.       Are there sufficient data?       Whether there are

16   or are not I don't think as I sit here to vote I don't

17   know if there are or not.

18                    DR. CANTILENA:       But as it is we have amended

19   question 1 to the more generic sense, could CIU be an

20   OTC indication.      Answering in the affirmative there and

21   saying that it should be broader.            Now question 2 --

22                    DR. GANLEY:    Could urticaria be and then you



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1    followed it up by saying should it be --

2                   DR. CANTILENA:       What I specifically said

3    before the vote question 2 is product specific.            It's

4    actually their data and that's why --

5                   DR. GANLEY:   Question 1 was not whether could

6    CIU be a OTC.     It was could urticaria be an OTC claim.

7     Then it was followed up with whether it should be CIU

8    or should it be a broader claim.

9                   DR. CANTILENA:      Right.   But that was not

10   product specific or had anything to do with the data.

11                  DR. GANLEY:     No, but if everyone here is

12   saying that they think it should be a broader claim, then

13   if you answer yes, that they have enough information to

14   switch loratadine for a CIU claim, there's something

15   missing there for me.

16                  DR. TEMPLE:   Charlie, that's true but I think

17   what Lou is saying is now they are asking -- I mean,

18   whatever your preference might be, maybe you really think

19   a broader claim would be a really great thing, but you

20   still have to ask whether there's a basis for it.            The

21   first step in question 2 is to say do they have the data

22   for CIU claim.



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1                   Presumably that's what their studies are in

2    but I guess there's other questions.          Then the next part

3    of that is do they have data for a broader claim.               The

4    committee may say, "I don't know," or "Yes," or send it

5    back to you to think about or a lot of other things.

6    How does that sound?

7                   DR. CANTILENA:           That sounds reasonable.

8    Thank you.

9                   DR. CANTILENA:        Jonca.

10                  DR. BULL:     One other point of clarification

11   here.     Based on the approach you've taken to question

12   1, which is looking broadly at whether or not it's

13   appropriate to have the OTC indication and you're saying

14   yes to the OTC indication, and yes that it should be the

15   broad one.     Is that right?         Is that what we want just

16   in terms of conceptually?

17                  DR. CANTILENA:        Right.

18                  DR. BULL:      Okay.

19                  DR. CANTILENA:        In sort of a generic sense.

20                  DR. BULL:     On No. 2 where you are more product

21   specific it appears that if you -- the question now is

22   on the data to support the general claim because you've



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1    already agreed that you want to see a general claim.

2    Is it mute for the CIU or general claim or are we going

3    back to that?

4                   DR. ROSENBERG:    I think it's what the meaning

5    of "are" are.

6                   DR. CANTILENA:      Let's not get into that.

7    Seriously, I think --

8                   DR. BULL:     I just want to clarify what

9    groundwork you've laid with question 1 for question 2.

10                  DR. CANTILENA:    Question 1 was really in sort

11   of a generic sense.    Now question 2 is product specific.

12    In essence we're saying are there data to support CIU

13   as presented as proposed and are there data to also support

14   the more general claim of urticaria.         We're trying in

15   essence to go -- if you're comfortable extending the data

16   that they presented for CIU as adequate for the more

17   general claim, then the answer to the second question

18   is yes.

19                  DR. GANLEY:    But I think one of the things

20   here is whether we have to make decisions not on a general

21   -- if the committee feels that they -- if they want to

22   see an urticaria claim, they would want to see a broader



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1    claim, then that's the way we should go.               If everyone

2    thinks it could be broader but I would accept CIU, that's

3    a different issue because if you answer that you want

4    a broader claim, then that's what we're going to tell

5    not just this company but other companies.

6                   DR. WOOD:     Charlie, you're getting yourself

7    into a box because if you follow that down the logical

8    path and the committee votes for a CIU as having data

9    and not having data for the other but they want a broad

10   claim, then that's your interpretation but it would be

11   hard to approve.

12                  DR. GANLEY:       Well, no.      I think someone --

13   if you construct, as John has tried to construct, that

14   this and an antihistamine, he's very comfortable and I

15   may be very comfortable with that.            There's no additional

16   efficacy studies to look at acute hives to see whether

17   that's a -- you know, you need to do additional efficacy

18   studies because if we've already established it worked

19   in hives, I don't need efficacy studies.

20                  That being said, then, well, if this is a

21   general claim for hives, what additional information

22   would I want to have?         Is it a labeling comprehension



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1    study or an actual use study?        But to go back and revisit

2    when everyone has come to some understanding that the

3    preference here is whether it should be a broader claim

4    or CIU claim.        The issue then comes for the company.

5    Do they have information to support a broader claim here.

6                   DR.    TEMPLE:     But,      Charlie,   that's    the

7    question.

8                   DR. D'AGOSTINO:      But what if you don't accept

9    our response to 1?       Then you don't want to know about

10   if we were hemmed into CIU in 2 to give a response?

11                  When you have deliberations, you say in the

12   broader claim we don't like at all what the committee

13   said so we're chucking out their response to 1.               We go

14   to 2 and we're only responding to a broader claim so we

15   haven't given you much information.             I think it would

16   be nice for us to do the two pieces.

17                  DR. TEMPLE:      Yeah, but 1 was the statement

18   about what you hoped there were data support.            It wasn't

19   a statement that there were data support.              That comes

20   later.     We understand, I think, because it's going to

21   be used anyway and various other reasons, you would like

22   to see it labeled for urticaria as a more general matter.



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1

2                   But     this    question       was,     as      you're

3    understanding it, are there data that support a claim

4    in CIU only if that were the best we could do, or is there

5    good reason to extrapolate the information from that use

6    to a more general statement about urticaria on which

7    you're going to give a separate opinion.             Part of it may

8    be that we have to go think about that some more.                   We

9    don't know yet.

10                  DR. CANTILENA:         Okay.     So let me just

11   rephrase this.       This was supposed to be the easy part.

12   All right.     We basically agreed to split this question

13   to answer it basically separately for the indications.

14    Are there sufficient data to support an OTC switch of

15   loratadine for CIU?      The first part.

16                  Second part: Are there sufficient data to

17   support an OTC switch of loratadine for a more general

18   urticaria claim?      Product specific, the information that

19   we heard this morning and it's in our packets.

20                  So far we've had Dr. Rosenberg, I believe,

21   vote yes for CIU and no for the more general claim.                 Is

22   that correct?



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1                   DR. ROSENBERG:        Yes.

2                   DR. CANTILENA:        Okay.

3                   Dr. King.

4                   DR. KING:     Same response.      I think in terms

5    of the specific agent they did provide the data.             I don't

6    think the data is here about the general thing.             I would

7    like to see that as a goal.             I think they would come

8    forward with that and it would be coupled with a use study

9    to find out when this is released, if that's true, after

10   the fact.

11                  I think they didn't present the data because

12   they probably weren't thinking they were going to have

13   to do that.    I think this group just haven't seen that

14   data.

15                  DR. CANTILENA:        Okay.    Dr. Clapp.

16                  DR. CLAPP:      Yes for the switch for CIU but

17   no for the general claim.           My concern is based on the

18   efficacy in children.        Although we presume based on what

19   the dermatologists have said that the mechanism for

20   urticaria is the same regardless to the acute versus

21   chronic idiopathic as being the same, I still don't have

22   the sense of certainty that in children the efficacy is



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1    the same in the acute circumstance.        I would like to see

2    some data to confirm that reality.

3                   DR. CANTILENA:     Thank you.

4                   Dr. Williams.

5                   DR. WILLIAMS:     Yes to the first part and no

6    to the second part.        I believe the sponsor should have

7    that type of information in the years of usage that they've

8    had already so I don't think it should be too difficult

9    for them to produce it.

10                  DR. CANTILENA:     Thank you.

11                  Dr. Wood.

12                  DR. WOOD:     Yes to the first part and to the

13   second part I would defer to the FDA looking at the data

14   that I suspect is in the literature to make that decision

15   on the acute.    From what we have from Dr. Rosenberg it

16   sounds like that data is already out there.

17                  DR. CANTILENA:     So based on the information

18   that was presented it would be a no.         But if there was

19   sufficient information available in the file or in the

20   literature, then it would be a yes.

21                  DR.   WOOD:      I'm    precise.      Are     there

22   sufficient data to support an OTC switch for a more general



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1    claim.     The answer to that is I don't know that we can

2    answer that question because we haven't had that data

3    presented.     However, the answer might be yes or no and

4    that's why I'm saying defer it for further review to the

5    FDA.    To say that there are not data I don't think anyone

6    can answer that.

7                   DR. CANTILENA:     Okay.

8                   Dr. Sachs.

9                   DR. SACHS:   I would say yes to the CIU with

10   the one caveat I think the data presented only went down

11   to age 12, and no to the general indication because I

12   think we need the actual use studies as I've said before.

13                  DR. CANTILENA:     Dr. Davidoff.

14                  DR. DAVIDOFF:     I would say yes to the CIU

15   question and to the more general claim, I would say no,

16   that the data at least have not be presented to us here.

17    I think it's not just efficacy data which I think are

18   probably going to be pretty easy to come by.

19                  I would be rather more concerned about safety

20   data.     I think anaphylaxis is essentially not an issue

21   for CIU but it is potentially for acute urticaria.                    I

22   think they are rather different situations and we would



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1    need more information on that.

2                    DR. CANTILENA:       Thank you.

3                    Dr. Lam.

4                    DR. LAM:     Yes to the first one and to the

5    second one, I don't know where there is data out there

6    and, therefore, I can't really make a decision whether

7    it's sufficient or not.

8                    DR. CANTILENA:        So you're voting like Dr.

9    Wood on the second part.

10                   Dr. Johnson.

11                   DR. JOHNSON:      Yes to the CIU and, like many

12   around the table, for the more general clearly the data

13   weren't presented.         They may be out there somewhere.

14   I'm not convinced that further trials are necessary but

15   I think we need more information.

16                   DR. CANTILENA:         Dr. Uden.    Hold on one

17   second.

18                   Dr. Johnson, so you're voting as Dr. Lam and

19   Dr. Wood.      You're not sure about the second part.           It's

20   not a yes or no.

21                   Dr. Uden.

22                   DR. UDEN:     Yes for the first part and the



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1    second part I'm a Wood, Lam, Johnson believer.

2                   DR. CANTILENA:     Dr. Krenzelok.

3                   DR. KRENZELOK:    I vote yes for the first part

4    and my dimpled chad on part 2 will be that I'll vote no

5    until there are more data to change that vote.

6                   DR. CANTILENA:     Thank you.

7                   Dr. D'Agostino.

8                   DR. D'AGOSTINO:       I vote yes on the first

9    part, but I want to emphasize that I was quite serious

10   about the response to question 1.          I don't think that

11   -- I think this is much too narrow.         I think they have

12   the data but it's much too narrow an indication for an

13   OTC.

14                  On the second part I'm going to say no because

15   I haven't seen the data.      The data may be there but I'll

16   say no for the data that I've seen and later we'll talk

17   about is there control clinical trial data on the

18   literature.    There's a lot of data in where it has already

19   been approved for OTC use.

20                  They should be able to collect data there

21   on at least the safety issues and other data sources which

22   would help in terms of whether or not there is enough



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1    data out there for approval.           Right now I haven't seen

2    it so I vote no.

3                   DR. CANTILENA:       Dr. Szefler.

4                   DR. SZEFLER:       I haven't seen the specific

5    data for either indication other than the publications

6    that were included in the material we got so I'm going

7    to say yes to the first part presuming there was adequate

8    data there to get it approved as an Rx indication and

9    defer to the FDA for that decision and it's already been

10   made.

11                  The second category really depends on whether

12   you accept chronic urticaria as a model for urticaria

13   in general.    The FDA had said no to that.           Either there

14   has to be data in the specific disease in terms of acute

15   urticaria or there has to be a reexamination of the

16   similarities    between     chronic      urticaria    and    general

17   urticaria.

18                  I think if they could settle on accepting

19   that as common mechanisms and as this being a palliative

20   drug, then I would go along with extending on current

21   data.     Otherwise there's a need for additional data.

22   It would be essentially exactly what Dr. Wood said.



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1                    DR. CANTILENA:     Dr. Joad.

2                    DR. JOAD:   Yes to the first one and no to

3    the second one.     I do think there needs to be a good solid

4    clinical trial in acute urticaria.          I would also like

5    to add that special emphasis should be done on the product

6    label informing people about what to look for for

7    anaphylaxis and getting emergency help right away.

8                    I think there were some concerns with the

9    sponsors.      Results were there were a lot of the people

10   would talk to their doctor and it was not very clear that

11   they would recognize it as an emergency.        A lot of work

12   on the product label about recognizing anaphylaxis as

13   an emergency.

14                   DR. CANTILENA:     Thank you.

15                   Dr. Dykewicz.

16                   DR. DYKEWICZ:    Yes for CIU.   No for general

17   at this time.

18                   DR. CANTILENA:      Okay.   Comments from Dr.

19   Alfano?

20                   DR. ALFANO:      A couple comments.      One, I

21   guess we see why the sponsor submitted for CIU as the

22   day plays itself out.       Two, I wonder if we would have



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1    voted differently if instead of we asked the question

2    is there sufficient data we ask is there sufficient basis

3    to support a more general claim because we heard some

4    erudite physicians talk about the physiology of this as

5    being the same, and yet there was no data so there could

6    be a semantic witch haunting us as we made these decisions.

7

8                   I guess the final comments would be      you know

9    if we don't move this, then we will deal with the status

10   quo which is less safe products on the market used in

11   the fashion that they are for these conditions anyway

12   without the warning label for anaphylaxis.         I guess the

13   question is will be have left the world a better place.

14                  DR. CANTILENA:     Okay.    Thank you.    My vote

15   is for the first part, yes, and the second part for the

16   general claim, no.

17                  Before we get to the other types of data that

18   are needed for this second part, just an announcement.

19    Dr. Hoff has an emergency phone call at the registration

20   desk outside.     It's just outside the door and to your

21   left is the registration desk if you would take care of

22   that.



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1                   Okay.   Question      No.   2.   Here   I   would

2    actually like not to talk about the label that they

3    proposed specifically, but I would like to advise the

4    sponsor and FDA here what other types of data are needed

5    such as clinical trials for efficacy, safety, label

6    comprehension or actual use.

7                   Since I believe everyone answered in the

8    affirmative for CIU, then we are really just left with

9    those who answered negatively for the more general

10   urticaria claim.

11                  What I would like to do is actually, if you

12   want to, just volunteer what specific kind of studies

13   you would like to see to support the more general claim,

14   I think we would do that as opposed to going around the

15   room we'll just open it up for a minute.         Also, if you

16   voted you don't know or you're not sure because you haven't

17   seen it, you can also comment as well.

18                  Dr. Rosenberg.

19                  DR. ROSENBERG:       I think a conscientious

20   literature search such as used for medianalysis.

21                  DR. CANTILENA:     Thank you.

22                  Dr. Sachs.



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1                     DR. SACHS:      I am sure, as alluded to, that

2    data exist on drug/drug interactions or the absence of

3    them    in     these   products      if   that      would    be   helpful

4    information, the poison control data, and the actual use

5    studies in kids as well as adults if you're going to go

6    down to six.

7                     DR.   CANTILENA:           Other    types    of   study

8    recommendations, Dr. Krenzelok?

9                     DR. KRENZELOK:        I'm sorry.      I was going to

10   make a comment about a label.               Is that okay or do you

11   want to wait on that?

12                    DR. CANTILENA:        If we can cover that on No.

13   3 unless it's a comment about a label comprehension study.

14                    Dr. Wood.

15                    DR. WOOD:     I think without sounding factious

16   we should have studies that actually determine whether

17   people understand chronic idiopathic urticaria better

18   than hives and really focus on what vocabulary people

19   really use.

20                    The other types of data that are needed such

21   as clinical trials for efficacy, etc., I think most of

22   that data is already out there, at least from what Dr.



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1    Rosenberg days.        I think it's just a question of

2    reanalyzing it and resurfacing it.          I'm not sure that

3    we need to leave the impression that major new clinical

4    trials are needed.

5                   DR. CANTILENA:      Dr. D'Agostino.

6                   DR. D'AGOSTINO:         Do we think there are

7    clinical trials on Claritin in acute hives?         I mean, when

8    we say there's data out there, clinical trial data, we're

9    talking about just the whole class of antihistamines that

10   we can extrapolate to this?

11                  DR. WOOD:    I think the answer is we don't

12   know.     We've not had that presented and, therefore, it

13   would be foolish to comment on whether that exist or not,

14   except to say that the dermatologists, Dr. Rosenberg

15   specifically, said there were class A evidence to support

16   use of antihistamines.

17                  DR.    D'AGOSTINO:           The      old       line

18   antihistamines?      These antihistamines?     Just so I'm --

19                  DR. WOOD:    Non-sedating.

20                  DR. ROSENBERG:      Non-sedating antihistamine

21   was given that citation.        I mean, I didn't read the --

22   I didn't do a search for that.



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1                    DR. D'AGOSTINO:       Right.        None of us have.

2                    DR. CANTILENA:     So your question is are there

3    studies that use this drug for acute hives?                 Is that your

4    question?

5                    DR. D'AGOSTINO:        Well, we've -- exactly.

6    We've said CIU was -- we believe the acute part is left

7    hanging.

8                    DR. CANTILENA:         Dr. Clayton, are there

9    studies using loratadine for acute hives?

10                   DR. CLAYTON:     Not that I'm aware of.

11                   DR. CANTILENA:        Okay.         So they are not

12   available.

13                   Any other comments about studies?                     Dr.

14   Davidoff.

15                   DR. DAVIDOFF:      Well, just to get back to the

16   point about studying safety versus studying efficacy.

17   Obviously      studying   safety     is      much    more    difficult,

18   essentially impossible to do in the broad sense in a

19   controlled trial of any manageable size.

20                   I think safety is a big part of the issue

21   here so I would think the kind of data that would be needed

22   for convincing information about safety would include



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1    a variety of possible approaches.

2                   Other people know them better than I, but

3    post-marketing surveillance clearly would be one of them,

4    retrospective looks, better or deeper looks into existing

5    data and so on.      I think that distinction has to be made

6    because I think the efficacy data will not be so difficult

7    to get.

8                   DR. CANTILENA:      Yes, Dr. D'Agostino.

9                   DR. D'AGOSTINO:       Where -- in the countries

10   where this has been approved OTC, do they collect safety

11   data?    Do you feel comfortable there will be safety data

12   from those countries?

13                  DR. CANTILENA:      Dr. Ganley or Katz, Temple?

14                  DR. KATZ:     They do collect safety data but

15   you run into the same problem.

16                  DR. D'AGOSTINO:       Spontaneous.

17                  DR.   KATZ:     That's       right.     Spontaneous

18   reports so that you have no denominator.              As a result,

19   certain countries are better than others at getting data

20   but you're not quite sure when you try to put into

21   perspective what it really means because, again, there's

22   no denominator.



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1                      DR. CANTILENA:     Dr. Temple.

2                      DR. TEMPLE:   We're talking about events that

3    must be unbelievably rare so your denominator is not

4    usually a problem on something like this.                I think you

5    want to know whether there are really any people who didn't

6    go get their anaphylaxis treated because they were using

7    an over-the-counter non-sedating antihistamine.                     Like

8    most spontaneous reporting, the denominator is your whole

9    country.        You can't do better.      You can't do a study of

10   --

11                     DR. D'AGOSTINO:         So if the spontaneous

12   reporting good, then it counts.

13                     DR. TEMPLE:    In the UK it's thought to be

14   pretty good.        In Canada it's thought to be pretty good

15   so those aren't so bad.         You're not going to do a study

16   of 2,000 people and find --

17                     DR. D'AGOSTINO:      No, no.      The question is

18   we're talking about safety data and one possibility is,

19   what do they say, 10 years of history?

20                     DR. TEMPLE:    Sure.        That can be looked at.

21                     DR. WOOD:      But, Bob, you're absolutely

22   right.         These are data that are going to be readily



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1    available.     Anaphylaxis is not something that doesn't

2    get spotted.

3                   DR. TEMPLE:    Yeah.       One of my questions is

4    what kind of anaphylaxis gets reported.             For example,

5    if it doesn't seem to be related to a drug, it probably

6    wouldn't be reported to Medwatch.

7                   DR. WOOD:   No, but it's going to be a death

8    certificate data.

9                   DR. TEMPLE:    I don't think we know yet how

10   good it's going to be but that's what there's going to

11   be.     There's isn't really going to be anything else.

12   You can't do a study of this.         There can't be a lot of

13   them.

14                  DR. JOAD:     That was going to be my point.

15   I'm not sure it would be reported as an adverse drug event

16   because no one would think that the anaphylaxis was due

17   to the antihistamine but it certainly could be related

18   to delay in treatment.

19                  I don't know how you would find that from

20   spontaneous reporting.       I mean, if there's a way to do

21   it, if we approve this, we should try to figure out a

22   way to do it in the future for post-marketing research.



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1                   DR. D'AGOSTINO:       We are saying there's data

2    out there and it doesn't sound like we are offering much

3    by way of what data is and where they can get it.                Am

4    I right?

5                   DR. DYKEWICZ:       If I can ask maybe Dr. Lee

6    with the SAE data that you had discussed earlier with

7    the 12 percent incidence of anaphylaxis of people who

8    had been on loratadine when there is a prior history of

9    urticaria, would that have enough detail in that database

10   to see whether, for instance, there had been, I don't

11   know, some effort to use loratadine during an anaphylic

12   event?

13                  DR. LEE:    Yes.     Some of that data was pretty

14   detailed.      I mean, there are individual case reports.

15   The case report that I mentioned of the Canadian woman

16   who took -- was the only anaphylaxis death in the database.

17

18                  Some of these reports are detailed enough

19   to be able to get a feel as to whether or not the event

20   in some circumstances what the order of -- what happened

21   was, when the drug was taken.            Was it taken after the

22   patient had symptoms.       In some cases not.



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1                   DR. CANTILENA:      Okay.      I think there was a

2    comment over here.     Dr. Uden and then Dr. Davidoff.             Do

3    you still have a comment?

4                   MS. ROHANE:    Excuse me.       Do you need any more

5    information    about   the   cases     on     anaphylaxis   in    the

6    post-marketing safety database?             What I can tell you is

7    that within the entire marketing of loratadine there have

8    been 20 reported with the plain tablet.

9                   Of those 20 four were in patients who took

10   the drug with a CIU diagnosis.              Of the four there was

11   one in Canada who took the drug for acute urticaria.

12   The other 16 were in other diagnoses including allergic

13   rhinitis, sinusitis unspecified.             There's a variety of

14   other things.

15                  DR. SACHS:    But do you have information on

16   whether taking loratadine, for example, delayed their

17   treatment?     That's kind of the question we're asking.

18                  MS. ROHANE:     Well, the issue there is that

19   this all comes from post-marketing safety surveillance.

20    Some cases have very little information and others have

21   much more detail.      It depends on the case.

22                  DR. CANTILENA:      Okay.      Dr. Davidoff.



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1                        DR. DAVIDOFF:        Well, I agree here's detail

2    and you need to look at the detail of the case.                        There's

3    no other way to get the kind of information you'll need

4    because it's not going to be reported as an adverse affect

5    in the usual sense.

6                        DR. CANTILENA:        Dr. Uden.

7                        DR. UDEN:       I haven't heard it explicitly

8    stated in this round but assuming that there's going to

9    be a more general indication and assuming that might be

10   hives, that we do have them redo label comprehension study

11   that adequately represents the diversity of the United

12   States and the literacy of the United States again.                         Make

13   sure that they do something with a new label.

14                       DR. CANTILENA:         I would second that, Dr.

15   Ganley.        I think it's a critical piece of the information

16   package        is   to   make     sure     that     we   are     effectively

17   communicating in the drug label and if you're going to

18   change the drug label now to a more general indication,

19   I think that has to be tested vigorously.                      I would agree

20   with Dr. Uden that subpopulations have to be adequately

21   represented.

22                       Anymore      comments          regarding       additional



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1    studies for the more general claim?

2                   Dr. Wood.

3                   DR. WOOD:   I just want to make a general

4    point, and that is maybe we're all getting tired but we

5    seem to have developed a sort of negative tone about it

6    which I think would be unfortunate because it seems to

7    me that the sponsor came in with an application for CIU

8    and the committee, or the agency, has taken the position

9    that maybe it should be a broadened indication.

10                  Now they are sort of getting attacked for

11   a broader indication they didn't actually ask for in the

12   first place.    I think it's important for us to at least

13   convey to the agency that the sense I get from the

14   committee is there's a broad consensus for a positive

15   view on the CIU indication and this sort of other issue

16   which has been raised is kind of distracting us.        I have

17   a sense of unfair play in some ways on that.

18                  DR. CANTILENA:    Well, I'm not sure if it's

19   unfair or if we are actually anticipating sort of the

20   next move and we're trying to help out on both sides.

21   It was actually our group that I think stimulated the

22   discussion for the more general claim.    I understand your



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1    point and it's well taken.

2                   DR. D'AGOSTINO:         I thought I was following

3    your lead, Dr. Wood, in going to hives and so forth.

4                   DR. WOOD:      I still hives is the right way

5    to go.

6                   DR. D'AGOSTINO:         Can I --

7                   DR. CANTILENA:        Yes.

8                   DR. D'AGOSTINO:        If in the search for data,

9    safety, and efficacy it doesn't materialize, the safety

10   issues sound very profound and maybe there is enough from

11   the company's spontaneous reporting or whatever that they

12   do for adverse events.

13                  What is our sense about the efficacy?                   I

14   mean, how much would be push on the efficacy part if it

15   turns out that the literature isn't convincing enough.

16    Do we feel that they must put together a clinical trial?

17    Is there no extrapolation?

18                  DR. WOOD:     Well, I think if there was no data

19   on the efficacy -- you mean in acute hives?

20                  DR. D'AGOSTINO:         In acute, yes.

21                  DR. WOOD:        Then I would return to the

22   original suggestion I made, that the indication should



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1    be hives that has been diagnosed by a physician which

2    would be compatible with the CIU indication but, it seems

3    to me at least, more understandable to the average patient

4    than over the counter.

5                   DR. CANTILENA:     Yeah.   I think Dr. Temple

6    sort of explained the situation as far as how the agency

7    would have to sort of go by the law if there are no data

8    for that as a specific indication.

9                   DR. D'AGOSTINO:    Well, we said in No. 1 that

10   we think it should be broader and now I'm asking if the

11   broader data is not there, there's one way of getting

12   a good positive response by saying then put after you've

13   seen your physician and that doesn't compel the company

14   and the FDA and the advisory committees that you must

15   have efficacy data and, therefore, you must have a

16   clinical trial.

17                  DR. CANTILENA:     Okay.   Any other comments

18   about additional studies before we answer the last

19   question?

20                  Dr. Sachs.

21                  DR. SACHS:   It was raised.    I just want to

22   make sure you do note about the patient's ability to



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1    recognize hives themselves.        You may roll your eyes but

2    let me just point out that take a TB skin test.              They

3    did a study on whether patients could self-read whether

4    a TB skin test was positive or negative and they could

5    not.

6                   I think you do have to at least look at it,

7    you know, could you distinguish the dangerous things like

8    purpura from hives.    It may not matter if you can't tell

9    a mosquito bite from a hive but purpura from a hive you

10   probably need to know.

11                  DR. CANTILENA:     Okay.    Since we've split up

12   question 2, question 3 basically has to refer to the

13   indication of CIU which everyone answered yes to.              Now

14   as we are referring specifically to CIU, what are your

15   recommendations for appropriate labeling of loratadine

16   with regard to indications, warnings, and directions for

17   CIU because that's what we answered in the affirmative.

18

19                  Just so we are guaranteed to get everyone's

20   input and to keep everybody awake, why don't we start

21   with Dr. Alfano and just go around the table with specific

22   recommendations for CIU.



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1                     DR. ALFANO:      I just urge the sponsor to make

2    sure they have maximized the warning of the consumer for

3    anaphylaxis so they know to seek care.

4                     DR. CANTILENA:        Thank you.

5                     Dr. Dykewicz.

6                     DR. DYKEWICZ:        Well, I'm a little bit torn

7    by the stricture not to go beyond the CIU indication.

8    I think even in a situation where CIU has been diagnosed

9    by a physician, one has to be mindful that there could

10   be evolution to a vasculated process, for instance.

11                    I   think    that    would      be   something     about

12   purpuric       however   that     would     be   found    in    a   label

13   comprehension study or in a use study to indicate that

14   change in skin color at the site or a purple lesion, those

15   would be reasons to seek medical attention or something.

16                    DR. CANTILENA:        Thank you.

17                    Dr. Joad.

18                    DR. JOAD:      For the CIU indication I don't

19   have any additional comments.

20                    DR. CANTILENA:        Dr. Szefler for CIU.

21                    DR. SZEFLER:        I think a clear definition.

22   I think as Dr. Wood mentioned a number of times now, I



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1    don't think the public is aware of what chronic idiopathic

2    urticaria means.     We often just call it chronic hives

3    or recurrent hives.

4                   I think a clear definition with some warnings

5    about when it extends beyond or went to see a physician

6    presumably again would be indicated.          I don't know if

7    package inserts have actual pictures of what a hive looks

8    like but if that could be done, it would be help so they

9    could kind of understand what we're talking about.

10                  DR. CANTILENA:     Dr. D'Agostino.

11                  DR. D'AGOSTINO:      I don't have anything to

12   add.

13                  DR. CANTILENA:     Dr. Krenzelok.

14                  DR. KRENZELOK:    Thank you.   Dr. Wood and Dr.

15   King expressed some very simplistic things about how

16   people in Tennessee perceive words and so on.           I think

17   that is really good.    I think we really need to downplay

18   this chronic urticaria business.

19                  Dr. Ferguson in his presentation emphasized

20   unexplained hives that keep coming back.           Well, there

21   might be a better way to say that but that is actually

22   fairly simplistic and I think we need to present it to



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1    the public that way.

2                   Then Dr. Wilkin in slide 42 had some excellent

3    patient admonitions about when the patient needs to

4    contact a physician.       I think those should really be

5    included on the outside of the package label or inside.

6     Somewhere to warn the patient accordingly.            Thank you.

7                   DR. CANTILENA:        Dr. Joad, did you have

8    something else?

9                   DR. JOAD:   I just to make a comment about

10   the idiopathic or unexplained.             My understanding from

11   the reading is that in 40 percent of the cases we do have

12   an explanation.     It's the IGG against the IGE receptor

13   or the IGE.    I realize historically we haven't known but

14   we do know.    That's a complication, too.          There sounds

15   like there is a disease out there that does have a

16   pathophysiology that explains everything.

17                  DR. CANTILENA:     Dr. Uden.

18                  DR. UDEN:    I have a question.          Maybe the

19   sponsor can answer this.        We handed around one of the

20   suggested labels prior to what our discussion was.               Was

21   there anything -- this isn't related to urticaria.

22                  Was there anything in there about sedation?



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1     They call it non-drowsy.              Was there anything about

2    sedation as one of the side effects?                     I know your

3    advertisements say may cause drowsiness so this is a

4    clarification for me.

5                    DR. CLAYTON:       (Off microphone.)

6                    DR. UDEN:     Because -- well, this is a bigger

7    issue and it's not related to this so maybe I should just

8    shut up.       I mean, the non-sedative antihistamines are

9    less sedative.         I just wanted to know if "may cause

10   drowsiness" is actually in their label even though they

11   call it non-drowsy.

12                   DR. CANTILENA:        It's on the ads.

13                   DR. UDEN:     It's on the ads, you know, "This

14   may cause drowsiness."          I just wanted to have truth in

15   label language and non-drowsy is not truth in labeling.

16                   DR. CANTILENA:        Dr. Johnson.

17                   DR. CLAYTON:       (Off microphone.)

18                   DR. CANTILENA:        Dr. Clayton, could you use

19   a microphone, please?         We're having a hard time hearing.

20                   DR. CLAYTON:         I had given an incomplete

21   thought to Dr. Uden's comment.                    You mentioned the

22   advertising      for    non-sedating           antihistamines.        I'm



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1    talking specifically about loratadine, the advertising

2    just mentioned as the primary side effect but no greater

3    than placebo in the clinical trials.

4                   DR. CANTILENA:      Dr. Johnson.

5                   DR. JOHNSON:    My recommendations are related

6    to the packaging.    I think I have concern about this with

7    a lot of OTC products.     A lot of OTC products are packaged

8    in blister packs.    I suspect what happens is people might

9    read the box when they purchase it.           They go home and

10   open it up and they probably throw away the package insert.

11

12                  They throw away the box, and what they have

13   left is a blister pack which on the back has the name

14   of the drug and the dose.      One thing that I might suggest

15   is that there is consideration to give in to not marketing

16   these in blister packs but in bottles where you could

17   at least put critical warning information and it's always

18   there.

19                  As long as the patient has tablets left they

20   always have the information.         Whereas I think in blister

21   packs in most situations they are going to lose that

22   information as soon as they purchase the product.



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1                         DR. CANTILENA:       Thank you.

2                         Dr. Lam.

3                         DR. LAM:     I like the information that Dr.

4    Wilkin has suggested, although I'm not really sure now

5    we can fit all that information into one tiny label.

6                         DR. CANTILENA:       Okay.     Dr. Davidoff.

7                         DR. DAVIDOFF:         Yes.      I would certainly

8    support        the    emphasis     on   hives      rather   than    chronic

9    idiopathic urticaria, although I don't think it hurts

10   to put the longer term in because some doctors will have

11   used that with their patients.

12                        On the safety issue, even though it's not

13   clear the extent to which anaphylaxis is more common,

14   or if it's more common in CIU, it seems to me that it

15   probably isn't less common in CIU than the rest of the

16   population so you may, in fact, still be at risk to develop

17   anaphylaxis and that does certainly provide a rationale

18   for including information, more specific information on

19   when to recognize something more serious is happening.

20                        DR. CANTILENA:       Dr. Gilliam.

21                        DR. GILLIAM:       Yeah.      Just along this same

22   line.     There was a list that somebody had of 10 points



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1    of when you should consult your physician or provider,

2    the peanut or latex allergy greater than six weeks, skin

3    bruising or skin tone changes, blistering, and so forth.

4     There were 10 of these points and I think they should

5    be in there.

6                   DR. CANTILENA:     On the box or in the package

7    or either?

8                   DR. GILLIAM:     I would say definitely on the

9    box.    We all know that most people don't read the package

10   inserts so definitely on the box

11                  DR. CANTILENA:     Okay.    Thank you.

12                  Dr. Sachs.

13                  DR. SACHS:       I like the idea of having

14   pictures.      Perhaps a do not use type thing.         You guys

15   use a lot of color.     I don't recall if the warnings said

16   anything about alcohol which probably should be and

17   something about the days of treatment.          How are these

18   going to be packaged like a package of seven, package

19   of 21, package of whatever.

20                  I think that would be useful information for

21   the future.     Perhaps a warning to call 911 -- I apologize

22   if I lifted that from anyone over there -- in case of



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1    anaphylaxis or respiratory difficulty.                  Not just a

2    statement to consult your doctor but perhaps call 911.

3                    DR. CANTILENA:        Dr. Wood.

4                    DR. WOOD:     I don't know what I can add except

5    to say you've got to be careful not to overstuff the label

6    with so many warnings that it becomes incomprehensible

7    to the patient.      I think it would be very important in

8    this setting to really try and prioritize what the major

9    issues are and not get it so filled with other things

10   that it becomes actually incomprehensible to a patient

11   which I think we do sometimes.

12                   DR. CANTILENA:        Dr. Williams.

13                   MR. JACKSON:      My concern is to make sure that

14   they read and follow the directions as indicated on the

15   package.       Many of these medications are three times a

16   day or four times a day.          We usually don't have that in

17   the information on the package that this is just a once

18   a day pill.

19                   DR. CANTILENA:        Dr. Clapp.

20                   DR. CLAPP:      Ditto to what has been said.

21                   DR. D'AGOSTINO:         Dr. King.

22                   DR. KING:        I'm concerned, again in the



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1    Tennessee phrase, about how much they are going to be

2    able to comprehend.     I would like to see that there be

3    follow-up studies or preliminary studies on truth in

4    labeling so that we look at and see what you are talking

5    about and do what you're supposed to like once a day or

6    whatever and avoid whatever things you say, you need to

7    go to the physician or whatever.

8                   I don't know about getting 10 indications

9    but I think it's up to the sponsors and the FDA to decide

10   what's going to be the best indication for labeling on

11   the outside of the box to find out if it's going to be

12   used effectively.

13                  DR. CANTILENA:     Dr. Rosenberg.

14                  DR. ROSENBERG:      I think if the indication

15   will be chronic idiopathic urticaria it has to be -- then

16   you have been seen previously by a doctor who told you

17   there was no known cause or he didn't know the cause at

18   that time and it should be treated symptomatically.

19                  I think it relieves the symptoms rather than

20   cures.     That would be one thing.        If it did not have the

21   CIU claim, if, in fact, it were to achieve the broader

22   urticaria claim, then I think we could take out "see your



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1    doctor first."

2                   I would think about it in the same way we

3    think about analgesics for headaches for people who could

4    have a brain tumor or laxatives for people who could have

5    cancer and so forth and have the kind of material that

6    John Clayton mentioned, things to look out for and the

7    kind of statement that if it doesn't get better, go see

8    somebody.

9                   But, in addition, because of the anaphylaxis

10   piece, I think it could have a special box or so that

11   says sometimes like this is a symptom of a very serious

12   condition that can strike suddenly and if you think you're

13   having that, really dial 911.        It is hard to write those

14   things and get them in little boxes but there are

15   specialist at that.

16                  DR. CANTILENA:     Okay.    Thank you.

17                  Dr. Ganley, would you like any additional

18   comments about the labeling for the more general claim

19   or have you had about all the advice you can take for

20   one day?

21                  DR. GANLEY:    I just want to make one final

22   note.    This is the last formal meeting for Dr. Gilliam,



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1    Krenzelok, Sachs, and Dr. Neal who is not here today.

2    We appreciate their efforts over the last years and we

3    may look forward to having you back in the future sometime.

4     Thank you.

5                   DR. CANTILENA:       Yes.    Thank you.       Let's

6    give them a round of applause for their endurance.

7                   Are there any other issues from FDA's side

8    or from the sponsor's side that you would like our

9    streamlined advice about?

10                  DR. D'AGOSTINO:      What time is it tomorrow

11   morning?

12                  DR. CANTILENA:     Tomorrow morning is --

13                  DR. TITUS:   Tomorrow morning starts at 9:00

14   and we are across the room right across the hallway in

15   a smaller room.     If you come in here, you'll be in the

16   wrong meeting.

17                  DR. CANTILENA:    Okay.     So the closed session

18   for the NDAC is tomorrow at 9:00.          Thank you very much

19   everyone.

20                  (Whereupon, at 5:03 p.m. the meeting was

21   adjourned.)

22



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