DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS
NDA21-645, MT 100, (naproxen sodium
and metoclopramide hydrochloride)
Tablets, Pozen, Inc. for the proposed
indication of acute treatment of migraine
headache with or without aura
Thursday, August 4, 2004
Advisors and Consultants Staff Conference Room
5630 Fishers Lane
Karl Kieburtz, M.D., MPH, Acting Chair
Anuja Patel, MPH, Executive Secretary
Michael D. Hughes, Ph.D.
Carol L. Koski, M.D.
Roger J. Porter, M.D., (Industry Rep, Non-Voting)
Ralph L. Sacco, M.D., M.S.
SPECIAL GOVERNMENT EMPLOYEES (VOTING)
Larry B. Goldstein, M.D.
Lily K. Jung, M.D., MMM (Acting Consumer Rep)
Stanley Fahn, M.D.
Marc E. Lenaerts, M.D.
K. Michael Welch, M.B., Ch.B., FRCP
Sheila Weiss-Smith, Ph.D., FISPE
Mark W. Green, M.D.
FEDERAL GOVERNMENT EMPLOYEE CONSULTANT (Voting)
Dilip V. Jeste, M.D.
Robert Temple, M.D.
Russell Katz, M.D.
Eric Bastings, M.D.
Mary Ross Southworth, Pharm.D.
C O N T E N T S
Call to Order and Opening Remarks:
Karl Kieburtz, M.D., MPH 5
Anuja Patel, MPH
Conflict of Interest Statement:
Mary Ann Killian 7
Overview of Issues:
Russell Katz, M.D. 17
Sponsor Presentation, Pozen Incorporated
Introduction and Summary:
Marshall E. Reese, Ph.D. 24
Overview of Tardive Dyskinesia:
A.H.V. (Tony) Schapira, M.D. 35
Review of MT100 Efficacy:
William James Alexander, M.D., MPH, FACP 61
Potential Role of MT100 in Migraine Therapy:
Balancing Benefits and Risks:
David B. Matchar, M.D., FACP 78
Clinical Considerations on Migraine Treatment:
Stephen D. Silberstein, M.D. 99
FDA Risk/Benefit Considerations:
Eric Bastings, M.D. 108
Overview of Tardive Dyskinesia:
Hyder A. Jinnah, M.D., Ph.D. 127
Post-marketing Review of Movement Disorders
and Neuroleptic Malignant Syndrome Associated
Mary Ross Southworth, Pharm.D. 138
Questions from the Committee to the Sponsor
and to FDA
C O N T E N T S
Open Public Hearing
Cynthia McCormick, M.D. 217
Committee Discussion and Response to FDA
P R O C E E D I N G S
Call to Order and Opening Remarks
DR. KIEBURTZ: Good morning. This is the
Peripheral and Central Nervous System Drugs
Advisory Committee. We here to discuss the New
Drug Application 21-645, proposed trade name of
MT100 Tablets, from Pozen, Incorporated for the
proposed indication of acute treatment of migraine
headache with or without aura.
I would just also take the opportunity to
refer people to the agenda. Incorporated in the
agenda are the questions which are posed to this
committee which will be discussing and voting on
today. We won't be discussing or voting on prior
actions of the FDA including the non-approvable
letter or any issues about a approvability of the
product. That is not our remit or discussion for
So I would hope that the presentations are
focused on what the committee will be discussing
and deliberating about today.
When people speak, please
speak into the
microphone and turn the microphone on. If you are
interested in speaking, raise your hand or you can
turn the microphone on. Anuja, the Executive
Secretary, will keep track and will get to people
who want to speak from the committee.
Just to the committee members, the voting
committee members, please keep in mind that, to
vote, you need to be here. So there is no leaving
of votes. Hopefully, there is no leaving until the
meeting is adjourned which is scheduled to be at 5
o'clock. Please plan your travels accordingly.
In a second, I am going to introduce Mary
Ann Killian. There is a new procedure--I think we
are the inaugural run of it--for disclosure of
conflicts of interest where Mary Ann Killian reads
a statement and then each individual member of the
committee reads their conflict statement. When
that is concluded, Mary Ann has some concluding
remarks and then we will move on with the rest of
The only individual who does report
conflicts of interest is Dr. Porter as
he is the
So Mary Ann Killian, the Program Integrity
Advisor from the Ethics and Integrity Staff.
Conflict of Interest Statement
MS. KILLIAN: Thank you very much. The
FDA is convening today's meeting of the Peripheral
and Central Nervous System Drugs Advisory Committee
under the authority of the Federal Advisory
Committee Act of 1972. The advisory committee
meeting provides transparency into the agency's
With the exception of the industry
representative, all members of the committee are
special government employees or regular federal
employees from other agencies and are subject to
federal conflict-of-interest laws and regulations.
Consequently, in the interest of
transparency and the spirit of disclosure, the
following information on the status of this
advisory committee's compliance with federal ethics
and conflict-of-interest laws covered by but not
limited to those found at 18 U.S.C. 208
U.S.C. 355(n)(4) is being provided to the
participants in today's meeting and to the public.
FDA has determined that members of this
advisory committee are in compliance with the
Federal ethics and conflict-of-interest laws
including but not limited to 18 U.S.C. 208 and 21
U.S.C. 355 (n)(4). Under 18 U.S.C. Section 208,
applicable to all government agencies, and 21
U.S.C. 355(n)(4), applicable to FDA, Congress has
authorized FDA to grant waivers to special
government employees who have limited financial
conflicts when it is determined that the agency's
need for a particular individual's services
outweighs his or her potential financial conflict
Members who are special government
employees at today's meeting, including special
government employees appointed as temporary voting
members, have been screened for potential financial
conflicts of interest of their own as well as those
imputed to them including those of their employer,
spouse, minor child related to the
today's meeting. These interested may include
investments, consulting, expert witness testimony,
patents and royalties, and primary employment.
Today's agenda involves a review of New
Drug Application 21-645, proposed trade MT100
Tablets, proposed for acute treatment of migraine
headache with our without aura sponsored by Pozen,
Inc. MT100 is a combination of two approved drugs,
naproxen sodium, manufactured by the Albemarle
Corporation, and metoclopramide hydrochloride,
manufactured by Cosam S.p.A, a member of the CFM
group. This is a particular matters meeting during
which specific matters related to the NDA will be
Copies of each acknowledgement and
consent-to-disclosure statement signed by each
participant at today's meeting who received a
conflict-of-interest waiver along with this
statement will be available for review at the
registration table during this meeting and will be
included as part of the official meeting
A copy of the written conflict-of-interest
waiver statements may be obtained by submitting a
written request to the agency's Freedom of
Information Office, Room 12A-30, of the Parklawn
At this time, each member will be asked to
state his or her name for the record and announce
whether his or her participation in this meeting is
based on a conflict-of-interest waiver.
Please state your name and whether you
have received a waiver from the agency to
participate in today's meeting. If you have
received a waiver, please describe the details of
the interest or interests for which the waiver has
been granted. If the agency has reviewed your
reported interest and determined that you do not
require a waiver, please indicate that for the
I guess we will start with you.
DR. KIEBURTZ: I will be the exemplar. I
am Dr. Karl Kieburtz. I am a neurologist and on
the faculty of the University of Rochester in
Rochester, New York. Based on the agenda for
today's meeting and the information regarding my
financial and other interests required to be
reported to the agency prior to my participation
today as a committee member, I have not received a
conflict-of-interest waiver to participate in
today's meeting. That means I don't need a waiver.
Next is Dr. Porter.
DR. PORTER: Pass.
DR. KIEBURTZ: If you would just introduce
yourself for the record.
DR. PORTER: Sure. I am Roger Porter. I
am a neurologist twenty years at the NIH, ten years
at Wyeth. I am now a consultant.
DR. HUGHES: I am Michael Hughes. I am
Professor of Biostatistics from Harvard University.
Based on the agenda for today's meeting and the
information regarding my financial and other
interests required to be reported to the agency
prior to my participation today as a committee
member, I have not received a
waiver to participate in today's meeting.
DR. KOSKI: I am Dr. Carol L. Koski. I am
a Professor of Neurology at the University of
Maryland School of Medicine. I have received a
waiver for ownership of stock in two competing
firms. The first is valued between $5,001 and
$25,000. The second is valued between $25,001 and
DR. SACCO: Hi. Ralph Sacco. I am a
Professor of Neurology and Epidemiology and
Director of Stroke and Critical Care at Columbia
University. I have received a waiver for my
service as a consultant for a competing firm. I
also serve on the Data and Safety Monitoring Board
for a competing firm and I receive less than
$10,001 per year from each firm.
DR. GOLDSTEIN: I am Dr. Larry Goldstein.
I am a Professor of Medicine at Duke University and
Director of the Duke Center for Cerebrovascular
Disease. I have received a waiver for consulting
for four competing firms and I receive less than
$10,001 per firm per year from three of
and between $10,001 and $50,000 per year from the
fourth firm. In addition, I serve as a member of
two advisory boards and two steering committees for
competing firms and receive less than $10,001 per
year from each firm.
DR. JUNG: Hi. My name is Lily Jung. I
am a neurologist with the Seattle Neural Science
Institute and Swedish Medical Center. I am also a
Clinical Associate Professor at the University of
Washington. I have received a waiver for ownership
of stock valued from $5,001 to $25,000 in a
DR. FAHN: Good morning. I am Dr. Stanley
Fahn. I am a Professor of Neurology at Columbia
University subspecializing in the field of movement
disorders. I have received a waiver for serving on
steering committees for two competing firms. In
addition, I also serve as a consultant for two
competing firms. I receive less than $10,001 per
year from each firm.
DR. LENAERTS: Good morning. Marc
Lenaerts, Assistant Professor,
Oklahoma, Department of Neurology, a headache
specialist. I have received a waiver for serving
on three speakers bureaus. One is between $10,001
and $50,000, and two are $10,000 or less.
DR. WELCH: Good morning. I am Dr.
Michael Welch. I am a Professor of Neurology at
Rosalind Franklin University of Medicine and
Science. I have received a waiver for serving as a
consultant for two competing firms and I am also an
advisory board member for two competing firms and
serve on the steering committee for a competing
firm. I receive less than $10,001 per year for
DR. SMITH: Good morning. I am Professor
Sheila Weiss Smith. I am an Associate Professor at
the University of Maryland Schools of Pharmacy and
Medicine. I have not received a
conflict-of-interest waiver to participate in
DR. JESTE: Good morning. I am Dr. Dilip
Jeste. I am Professor of Psychiatry and
Neurosciences at the University of
Diego, and the San Diego V.A. Healthcare System. I
have received a waiver for advisory board
activities for a competing firm for which I receive
less than $10,001 per year.
DR. GREEN: I am Dr. Mark Green. I am a
Clinical Professor of Neurology at Columbia
University and Director of the Columbia University
Headache Center. I have received a waiver from my
employer's contracts and grants with three
competing firms. My employer receives less than
$100,000 from one, between $100,001 and $300,000
from a second and more than $300,000 from a third.
MS. KILLIAN: Thank you very much.
Lastly, Dr. Roger Porter is the Industry
Representative on the committee today and he will
be acting on behalf of all related industry.
In the event that the discussions involve
any other products or firms not already on the
agenda for which an FDA participant may have a
financial interest, all meeting participants are
reminded that they are required by 18 U.S.C. 208 to
exclude themselves from such deliberations
announce their exclusion for the record.
Finally, in the interest of public
transparency, with respect to all other
participants, we ask that they publicly disclose,
prior to making any remarks, any current or
previous financial involvement with any firm whose
products they may wish to comment upon.
Thank you very much. This concludes my
DR. KIEBURTZ: Thank you everyone for
doing that. For an inaugural run, I think that
went pretty well.
I would just like to point to the agenda
before letting Dr. Katz begin which is, some people
know, the sponsor will have approximately an hour
and fifteen minutes, up until the 9:45 break, to
give their presentation. We will then break and
then there is a presentation from the FDA.
There will then be the opportunity for the
committee to ask questions about the content of
those presentations to the presenters. Then we
will break for lunch. There will be a public
hearing after that and then a discussion amongst
the committee members after that.
During those discussions, the committee
members may ask questions of the presenters
regarding details of their presentation.
Presenters may not interject or contribute to that
discussion voluntarily, just so people know the
rules of the game here.
If you have questions that arise during
presentations, the FDA's presentation slides are
numbered. You may want to note them. You may want
to note the slides of a presenter so that you can
refer back to them with reference when you pose a
On the FDA side of the table, I would like
to introduce four people. It looks like it flows
from right to left from my sitting. Dr. Robert
Temple, Dr. Rusty Katz, Dr. Bastings and Dr.
Overview of Issues
DR. KATZ: Thanks, Dr. Kieburtz. I want
to be very, very brief. I just have a couple of
points I want to make but, first, I want to add my
welcome to the committee. Thanks for coming.
Particularly we have several new members. I would
like to thank them for agreeing to serve on the
I would also like to thank Dr. Kieburtz
for agreeing to chair the committee. It can be a
tough job. I would also especially like to thank
our invited guests, of whom we have quite a few,
who are experts to help us deal with this
interesting issue. In particular, I would like to
thank Dr. Jinnah who has graciously agreed to
actually be part of the presentations this morning.
So thanks very much to everybody for coming.
As you know, we are here to discuss NDA
16-145 submitted by Pozen for the use of MT100
which, as you have heard and which you know, is a
combination of naproxen and metoclopramide for the
treatment of acute migraine.
Actually, we are asking you today to
address a type of question that is
unusual for the committee to deal with and that is
because many of the questions that we are going to
be asking you to consider are hypothetical in
Those of you who have been on the
committee or have seen previous committee meetings
know that, in a typical case, when we bring you a
new drug application, we would ask you whether or
not the application contains sufficient evidence of
safety or effectiveness in order to support
But, today, as Dr. Kieburtz has already
stated, we are not primarily interested in the
question of whether or not the sponsor submitted
substantial evidence of effectiveness for the
treatment of acute migraine. We have already
decided that they have not done so, in particular
because we are unsure that they have presented
sufficient evidence of effectiveness for the
combination, itself, as a treatment for acute
But, perhaps, more importantly
discussion, we have determined that they have not
demonstrated a contribution of one of the
components to the overall effect of the drug and
that component is metoclopramide. I think we will
have a lot of discussion about that particular
You will, though, of course, hear some
more or less detailed presentations of that
effectiveness data that we have already ruled on in
a sense. You will hear from the company and you
will hear, to some extent, from us as well, from
Dr. Bastings. We would hope that you would
primarily consider those data in the context of
helping to inform your answers to the series of
hypothetical questions that we are going to ask
In particular, we would like you to think
about the previous effectiveness data in the
context of giving us your advice as to whether or
not, if the sponsor does perform an additional
study or additional studies in a particular
population which you will hear about,
not the results--if the results of these new
studies or new study are more or less of the same
magnitude as what has been seen already, whether or
not you would think that would justify approval of
the combination given the potential risks of the
Of course, the potential risks of the
treatment are the underpinnings for the second
serious of hypothetical questions we want to ask
you. Specifically, we are interested to know your
views about the likelihood of occurrence and,
perhaps, even estimates of the frequency of
particular adverse events that we are concerned
about which, as you know, are tardive dyskinesia,
primarily, but, in additional, other tardive
movement disorders and possibly neuroleptic
malignant syndrome associated with the chronic
intermittent use of metoclopramide as it would be
presumably used in the treatment of acute migraine.
This series of questions is hypothetical
because the current data on the risks for these
adverse events associated with
as they are, don't speak directly to the question
of what the frequency of--what they might be when
the drug is given in the regimen that the sponsor
proposes; namely, chronic intermittent use, as is
typical for an acute-migraine treatment.
As difficult as those questions might be
to answer, we would like you to go even further and
venture an opinion about what sort of possible
dosing recommendations, if any, actually could be
adopted that might reduce the risks to an
acceptable level and then ask you to discuss what
you think that possible result and level of risk
might be. So these are all, obviously, questions
for which we do not have adequate data.
That is what makes it difficult. We know
these are difficult questions, but partly because
they are so difficult, and partly because we think
these questions are very important to try to answer
from the perspective of public health, given the
large prevalence of acute migraine in the
population, that is why we have come to you today.
So, again, thank you for
coming. I want
to thank you in advance for all the hard work that
you have done already in reading the documents and
in today's discussion. So thanks again and I look
forward to an interesting and productive meeting.
DR. KIEBURTZ: Thank you, Dr. Katz.
Actually, I realize I was a little remiss
in introducing all of you. Maybe, as we have all
had the chance to introduce ourselves around the
table, Dr. Temple, maybe you could start so that
everyone knows who you all are.
Also, to follow up on Dr. Katz' comments,
just before you do that, Dr. Temple, these are
difficult questions and they are unusual questions.
I hope the committee members feel comfortable
voicing if they are uncertain about that and I will
be happy, as chair, to direct back to the FDA
questions about clarifying as to whether we are
answering the questions they had in mind and
getting clarity that we are providing them the
advice that they are seeking from us because it is
a little bit unusual.
So, if people are a little uncomfortable
about that, that is how we can do that. We can ask
questions of them to be certain we are addressing
the issues at hand.
So, Dr. Temple, please.
DR. TEMPLE: Good morning. I am Bob
Temple. I am the Director of ODE I. That is
office in which the Division of Neurology Products
lives. I have not received a waiver.
DR. KATZ: I am Russ Katz. I am the
Director of the Division of Neurology Products. I,
too, am not allowed to have a conflict of interest.
DR. BASTINGS: I am Eric Bastings. I am a
clinical team leader in the Division of Neurology.
DR. SOUTHWORTH: I am Mary Ross
Southworth, a safety evaluator in the Office of
DR. KIEBURTZ: Next on the agenda is
presentations from the sponsor.
Sponsor Presentation, Pozen, Incorporated
Introduction and Summary
DR. REESE: Good morning and thank you.
Pozen wants to thank the FDA for
assembling the Peripheral and Central Nervous
System Drugs Advisory Committee today to review our
naproxen-metoclopramide combination product called
MT100 for the acute treatment of migraine with and
Let me briefly review an outline of
Pozen's presentation for this morning. Following
my introductory comments, Dr. Schapira, Professor
and Chair of Neurology at the Royal Free and
University College Medical School in London and
Professor of Neurology at Queens Square, will
present an overview of tardive dyskinesia with
Dr. Alexander, Senior Vice President and
Chief Medical Officer at Pozen, will briefly review
the efficacy data for MT100 as contained in our
NDA. Dr. Matchar, Professor of Medicine and
Director of the Center for Clinical Health Policy
Research at Duke University, will discuss
potential role of MT100 in migraine therapy and the
benefit-to-risk ratio of MT100.
Dr. Silberstein, Director of Jefferson
Headache Center in Philadelphia and the current
President of the American Headache Society, will
review clinical considerations in migraine
treatments. Then I will close our presentation of
A bit of history. Pozen filed the IND for
MT100 in 1997 and undertook a preclinical, clinical
and pharmaceutical development program. There were
several discussions in meetings with the FDA over
the next six years which culminated in the
submission of the NDA in July, 2003. Pozen
believed that the totality of the data in the NDA
supported approval of the fixed-combination
product. However, the FDA did not agree with Pozen
and issued a not-approvable letter in May, 2004.
A critical-path meeting was held in late
October, 2004 with the Division Director, Dr. Katz,
and the Office Director, Dr. Temple. As a result
of that meeting, the FDA suggested an
advisory-committee meeting be convened to address
the potential risk of tardive dyskinesia with MT100
before we undertook any additional work.
That brings us to today's meeting which
really revolves around one central question; does
the potential risk of tardive dyskinesia preclude
the ultimate approval of MT100, whether for all
patients or for a readily identifiable group of
patients who receive the maximum benefit.
MT100 is a patented pharmaceutical tablet
formulation which is basically a pill inside a
pill. The core consists of the 500 milligrams of
naproxen sodium that is sprayed with an insulating
coat followed by a spray coating of 16 milligrams
of metoclopramide hydrochloride, which is
equivalent to 13-and-a-half milligrams of
metoclopramide base, then followed by a color coat.
The tablet is designed to release
metoclopramide immediately into the
alleviate the gastroparesis often associated with
migraine following the release of the long-acting
drug, naproxen, after it leaves the stomach.
Please note that the doses of both components are
well below the maximum daily doses approved for
these two products for other indications.
In May, 2004, the FDA issued a
not-approvable letter for MT100 citing both
efficacy and safety concerns. The FDA concluded
that the efficacy data for MT100 provided only
modest benefit over naproxen at 24 hours and that
this benefit, coupled with the possible risk of
metoclopramide-induced tardive dyskinesia, did not
warrant approval of MT100.
The not-approvable letter also stated that
the data submitted in the NDA did not provide a
significant benefit for all of the
migraine-associated symptoms at two hours versus
placebo in two well-controlled studies. The FDA
did agree that one study was considered to have met
all the endpoints necessary for
Therefore, the FDA felt that the potential
risk of developing tardive dyskinesia was not
outweighed by the 4 to 6 percent benefit of the
MT100 over the active control, naproxen, at 24
Now, regarding tardive dyskinesia, the
not-approvable letter states, "The absence of any
detected cases among 300 patients is consistent
with the true rate of TD of about 1 percent, an
unacceptably high risk in the absence of any
advantage of the product."
The FDA's mathematical calculation of 1
percent is derived from the upper limit of the 95
percent confidence interval around zero which we
believe is based on the 300 subjects in the
long-term safety study. Any implication that the
true rate approaches 1 percent is unfounded based
on the available scientific data in the literature,
the spontaneous case reports from the U.S. and the
U.K., national safety databases and our own
clinical-trial experience in treating
patients with MT100.
We feel that the risk of tardive
dyskinesia is very low and, certainly, much less
than 1 percent. While approximately 2700 of these
patients treated only single attacks, our 12-month
safety data that we conducted was actually three
times larger than the FDA had requested.
This study exposed over 1000 subjects to
MT100 for three months, over 600 subjects for 6
months and over 300 subjects for 12 months treating
over 23,000 individual migraine attacks and there
were no reports of tardive dyskinesia in these
Now, metoclopramide had been on the market
for over 20 years when Pozen submitted the NDA and
there were never any concerns raised by the FDA as
far as I am aware regarding tardive dyskinesia
during the development of MT100. Even though we
saw no cases of tardive dyskinesia during the
development program, to be conservative, Pozen
mimicked the current metoclopramide
in Reglan, from the Warnings Section of the
approved label, regarding any possible risk of
The Reglan label states, regarding tardive
dyskinesia, that both the risk of developing the
syndrome and the likelihood that it will become
irreversible are believed to increase with the
duration of treatment and the total cumulative
dose. Less commonly, the syndrome can develop
after a brief treatment period at low doses. In
these cases, the symptoms appear more likely to be
I would like to stress, again, that the
use of MT100 in the migraine population exposes
patients to both a low dose, 16 milligrams, of
metoclopramide hydrochloride and to an episodic use
of about three to six times per month.
Based on the available scientific
evidence, Pozen submits that the risk of tardive
dyskinesia associated with metoclopramide use is
very low and should be even lower with
use of MT100. The therapeutic dose of
metoclopramide hydrochloride, as I said, in MT100
is only 16 milligrams. The data from the long-term
safety study indicates that the expected use of
MT100 is only about four doses per month.
Dr. Schapira will review the spontaneous
national safety databases from both the U.S. and
U.K. and the scientific literature. There have
been very few cases of tardive dyskinesia reported
from the chronic use of metoclopramide as a single
ingredient over the past 40 years and, to our
knowledge, no cases of tardive dyskinesia have been
reported with the episodic use of metoclopramide.
As I said, there were no cases of tardive
dyskinesia seen in our clinical-trial program
either. Therefore, to the best of our knowledge
from the literature, the national safety databases
and experts in the field, the risk of developing
tardive dyskinesia from the episodic use of MT100
should be lower than currently approved
metoclopramide-containing products. Therefore,
Pozen feels its potential risk of
dyskinesia should not preclude the ultimate
approval of MT100.
Since MT100 is a fixed-combination
product, it must also satisfy the FDA combination
policy as shown on this slide which simply states
that, "Two or more drugs may be combined in a
single form when each component makes a
contribution to the claimed effects and the dosage
of each component is such that the combination is
safe and effective for a significant patient
population requiring such concurrent therapy as
defined in the labeling."
We believe MT100 satisfies this policy.
Dr. Alexander will review the efficacy
data for MT100 in a few moments, but I would like
to share a few highlights of what he will show you.
There was a significant improvement in the
primary endpoint of sustained pain response over 24
hours in five of six studies versus placebo or the
pseudoplacebo metoclopramide. One study did not
achieve significance and the p-value was 0.054.
The data from the two component studies
both demonstrate that each component of
metoclopramide makes a significant contribution to
the claimed effects for all patients but an even
greater effect in a significant patient population
experiencing migraine attacks without nausea.
In addition to the primary 24-hour
sustained pain endpoint, the FDA requested that we
evaluate migraine efficacy endpoints at two hours
versus placebo. In all six efficacy studies, MT100
was always significantly better than placebo for
pain at two hours. We also showed improvement over
the associated symptoms of nausea, photophobia and
phonophobia at two hours.
Although these studies were not powered to
show a difference in these secondary symptoms, in
most cases, MT100 was numerically, if not
statistically, superior to placebo.
In conclusion, I believe that the
potential risk of tardive dyskinesia
preclude the ultimate approval of MT100.
Next I would like to introduce Dr.
Schapira, Professor and Chair of Neurology at the
Royal Free and University College Medical School in
London and Professor of Neurology at Queens Square,
who will summarize the available information on
tardive dyskinesia associated with metoclopramide
DR. KIEBURTZ: Dr. Reese, before you--does
anybody have just a quick clarification or--okay.
Overview of Tardive Dyskinesia
DR. SCHAPIRA: Thank you, Dr. Reese, and
thank you, Dr. Kieburtz, and thank you to the
committee for the opportunity to come and speak to
you this morning.
I guess I am coming here wearing two hats.
The first is of a neurologist, a general
neurologist, in the U.K. who, in outpatient clinic,
sees a spectrum of neurological
significant proportion of which, of course,
includes headache and a significant proportion of
that, in turn, includes migraine.
The second hat is that of a neurologist
with a specific interest in movement disorders. So
it is with those two hats, if you wish, that I am
going to cover some specific areas this morning.
The first is to address the issue of why
use metoclopramide in migraine and the second is
specifically to address the risk of tardive
dyskinesias, or TD, with metoclopramide use. I
would like to divide my comments on this into three
areas; the chronic, intermittent and episodic use.
I will come back each of those in turn.
Just to begin with why use metoclopramide
I will cover this only briefly because
others will also comment on this, but we know that
it enhances absorption of orally
analgesics. It is an anti-nauseant and
anti-emetic. A meta-analysis indicates that
parenteral metoclopramide seems to have a specific
anti-migraine activity on its own.
The advantages, if you wish, of
metoclopramide in migraine have actually been used
in the U.K. because we have, for 25 years, actually
had access to three drugs, all of which are
metoclopramide analgesic combinations. The first
is MigraVess. The second is Paramax, and MigraMax.
MigraVess was available between 1980 and 1999 and
was then withdrawn in favor of Migramax because of
the higher dose of aspirin compound in the latter.
All of these three compounds, as I say,
contain 10 milligrams of metoclopramide per dose
and the maximum recommended dose in the U.K. is
three dose per 24 hours, so a 30-milligram-per-day
dose of metoclopramide.
There is no restriction in the U.K. on the
number of times a patient may take this compound
per week, per month, et cetera, so long
as they do
not exceed the three-times-per-day, 24-hour, dose.
I should also point out that, for general use,
metoclopramide has been available in the U.K. since
The use of these metoclopramide-analgesic
combinations in the U.K. have been found useful.
In fact, they have now been incorporated into the
U.K. Guidelines for the management of acute
migraine. The first step is a simple analgesic.
The second step is, then, the
metoclopramide-analgesic combinations given orally
or, if necessary, given by suppository. The third
step is the use of a triptan.
We have found, in clinical practice in the
U.K., that that middle step, that Step 2, is a very
useful practical intermediate step between the use
of simple analgesics and the use of a triptan.
Now, I would like to come on specifically
to address the issues of tardive dyskinesia. In
terms of the use, I will focus first on
use. This I am going to define, really, as the
most frequent, most common, use in the U.S.,
particularly, of Reglan, or metoclopramide, for its
gastrointestinal uses, and also in the U.K. we have
an equivalent drug which we call Maxolon, again
with the same range of uses for gastrointestinal
Let me, first of all, though, before
moving on to the surveillance data, begin with a
view of tardive dyskinesia. There are several
different definitions of tardive dyskinesia, so
what I have tried to draw out is some of the
commonalities between them.
I think we could say that it is a syndrome
consisting of potentially irreversible involuntary
dyskinetic movements which can affect any part of
the body but which predominantly affect the
orolingual-buccal region. It has traditionally
been associated with chronic, and that is 30 days
or more, use of a dopamine antagonist, generally
speaking, at the higher dose ranges of
But some definitions of TD also include
daily use for three months, or daily use for one
month if the patient is 60 years or more, onset
during use or, alternatively, onset with four to
eight weeks of cessation.
The pathogenesis of tardive dyskinesia is
not fully understood but it is thought to include
the development of supersensitivity of the
dopaminergic system. The prognosis of TD, once it
develops, is variable and, again, the precise
handles on this can vary. Two studies, for
instance, quoted in the helpful FDA submission,
suggest that 33 percent of patients may resolve
spontaneously in two years and another 29 percent
over six months.
But, certainly, TD can be irreversible and
can be extremely distressing.
I would like to just now move quickly to
some of the surveillance data that is available on
TD, the first of which, looking at the
between TD and metoclopramide came from
Scandinavia. Between 1977 and 1981, there were
established 11 million doses and they identified 11
cases of TD.
Then the first of two U.K. studies. The
first was a retrospective analysis of the Committee
of Safety of Medicines. This is a yellow-card
system whereby medical practitioners will send in a
yellow card to the CSM when they identify an
adverse drug reaction.
Looking at the years between 1967 and
1982, so about 15 years, of Maxolon only--so this
is looking at the use of, if you will, the Reglan
equivalent in the U.K.--it established 15.9 million
prescriptions over this 15-year period, so just
over 1 million per year. They identified four
cases of TD.
Then there was a prospective study by the
same author looking at a time point in 1986 over a
six-month period where they prospectively looked at
prescriptions, again for Maxolon, the Reglan
equivalent, not for the
combination. So, for this Reglan equivalent, they
identified just over 2-and-a-half thousand
prescriptions or patients who were given
prescriptions and found 25 extrapyramidal events
with 12 dystonias, eight akathisias, five
drug-induced Parkinsonism but no case of tardive
It might be helpful just for me to set in
context the dosage issues of metoclopramide in the
form of Reglan or Maxolon and that suggested for
Reglan, here, I understand, is used at a
recommended dose of 10 to 15 milligrams per day, in
some cases up to 20 milligrams, but the general
recommendation is for 10 to 15, up to four times a
day. So the maximum dose would be 60 milligrams a
day. Then the course of the medication varies
according to the indication it is used for, up to
eight weeks or up to 12 weeks.
If you look at the maximum calculated
recommended exposure for one course, you
just over 5 grams of metoclopramide. But, if you
take a conservative estimate of usage--let's say if
you half that recommended maximum--you would come
out with, let's say, 10 milligrams four times a day
and for eight weeks rather than 12 weeks.
You come out to about 2.24 grams, so that is 45
percent of the maximum recommended dose on that
Just to put this in context, that
half-exposure, if you wish, half of the maximum
recommended exposure, is the equivalent to treat
166 doses of MT100, 166 migraine attacks, or, if a
patient were to take MT100 at its maximum
recommended dose of 6 tablets per month every
month, they could take 2.3 years of MT100.
In fact, the median number of doses per
year of MT100 in the 302 study was 22, so if you
translated this into practical MT100 usage, this
would be the equivalent to seven-and-a-half years
of Reglan at half its maximum recommended dose or
15 years of practical use of MT100 at the maximum
exposure of Reglan in one specific
So that just sets the sort of dosage
issues in context.
I would like to now come to this very
helpful review by Shaffer, Dr. Shaffer, who was--he
and two other colleagues from the FDA and another
from Duke published a paper looking at the U.S.
reporting system for the period 1968 to 2003, so
over 35 years.
Now, just for the 10-year period between
1994 and 2003, they estimated that there were about
42 million scripts for metoclopramide. They
identified in their database 87 cases, 40 of which
made that predetermined definition of TD. But I
will talk about this in a little bit more detail.
This is a 35-year review. Interestingly,
just when they looked at all the scripts for
patients who were given metoclopramide, 62 percent
of those were intended for women and 24 percent,
almost a quarter, were intended for patients who
were age 70 or over. The authors actually didn't
include the use of migraine in their estimations
but I understand from the FDA submission that they
have now calculated that 2 percent of this use was
for migraine and, no doubt, they will address that
issue specifically themselves.
Now, the predetermined definition of TD
that these authors used to identify their cases was
metoclopramide exposure for 30 days or more and
documented involuntary movements or symptoms. As I
say, they identified 87 separate reports but 60 of
these had involuntary movements and 53 had duration
of use of 30 days or more.
In practice, 40 of the 87 met the
predetermined criteria of TD. I note that, in the
FDA submission, their number is 68 and, again, no
doubt, they will address that separately.
Of those that did develop TD, the mean age
was 60 with a range of 11 weeks to 95 years, and 65
percent of the TD patients were women which
corresponds, actually, quite well with the 62
percent women that were given the scripts in the
The mean dose was 33 milligrams per day,
the duration 753 days although, again, the FDA
submission, I note, identifies the median as 180
days. Six of the patients were on anti-psychotics
as well as metoclopramide and 22 of them were
considered to have permanent disability, eight of
whom needed a visit to the emergency department or
hospitalization because of their TD.
I would like to now move from what I have
considered in terms of the Reglan or Maxolon type
usage in the U.K. and the U.S. to the intermittent
or episodic. Here I would like to draw my own
distinction between these.
In my understanding, intermittent
pharmacotherapy is a course of treatment separated
by a period of treatment followed by another course
of that same treatment so, over a prolonged period,
intermittent doses with periods in between without
the medication. I contrast that with episodic PRN
or as in "when required" use such as, for instance,
as used in acute migraine attacks. That is what I
am going to refer to as episodic use.
Let me just remind you that, in the U.K.,
we have, for the last 25 years, had access to these
metoclopramide-analgesic combinations for the
treatment, the episodic treatment, of acute
migraine the dosage of which, in any 24 hours, is
30 milligrams. Looking at the equivalent,
incidently, in MT100, the maximum daily dose is
13.5 milligrams in terms of the base of
metoclopramide which is the equivalent in these
In the U.K., it is estimated almost
100,000 patients receive a total of about 8 million
doses of these combinations per year. In the
five-year period 1999 to 2003, there were estimated
to be a total of 40 million doses. So these are
drugs which are used relatively commonly for the
treatment of acute migraine in the U.K.
Now, the ADROIT database is a physician
database. It records physician-identified and
reported adverse events to a central, now
computerized, database and it records prescriptions
as well as adverse events, so it is particularly
In the period 1964, when metoclopramide
first became available, to 2005, so about a 40-year
period, they were able to collect data on
metoclopramide. But what is, I think, of
particular interest this morning is that this
database is able to discriminate between the
Maxolon-Reglan type use in the U.K. and the use of
metoclopramide-analgesic combinations for acute
migraine. So the database discriminates between
those two uses.
They found almost 3000 adverse-event
reports by any route of which 156 were related to
the acute-migraine metoclopramide-analgesic
combinations of which 69 were neurological over a
period from 1980 to 2005 which is when these
combinations have been available to us.
Just to look at little bit
more closely at
these 69 neurological events over that 25-year
period reported to this database, there were 26
dystonias or oculogyric crises, eight
extrapyramidal disorders not specified, three
dyskinesias which were not classified as TD--they
were reversible after the patient stopped their
medication--one of Parkinsonism, one of akathisia
but no reports of choreiform movements and no
reports over this 25-year period of tardive
There were a collection of other
neurological events; acute extrapyramidal disorders
were numbered 14 and this may well include things
like oculogyric crises, and then a variety of other
neurological features. So that totals a number of
69 none of which were TD.
Just to make a comparison between acute
episodic use of metoclopramide-analgesic
combinations for acute migraine and the other
general use of metoclopramide, I have
the adverse events. You will see that there have
been reports, of course, of a variety of
neurological events including the
dystonia/oculogyric crises with the more chronic
type of metoclopramide use, the sort of
Maxolon-Reglan type use, and 24 cases of tardive
dyskinesia with the non-migraine use of
metoclopramide compared to the zero for the
I would just like to very briefly cover
the MT100 experience; nine phase 3 studies, 3,700
subjects, over 25,000 doses and a study which took
just over a 1,000 patients to follow them up over a
period of up to 12 months.
In the MT100 studies, there were two
patients that experienced acute dystonic reactions
but no patients that experienced tardive
Just looking at the longer-term study,
1,000 patients recruited, 621 were
six months, 329 over 12 months, treating 23,000
migraine attacks. As I mentioned before, the
median number of doses per patient over the 12
months was 22 and the mean number of days between
each dose was almost 10.
So just looking at the--one has to accept
somewhat limited MT100 data. We haven't seen any
cases of TD. But just looking at the U.K. data
where we have got data now for over 25 years, and
there is that period 1999 to 2003 where
specifically, just for that period, they have
estimated 40 million doses, we haven't had any
reports to the ADROIT database of any cases of
tardive dyskinesia over that period.
I would like to summarize. I think we
have to accept that the MT100 experience is
insufficient to exclude a small risk of TD with its
usage. But, moving to the larger U.K. experience,
I think we have had no reports of
and that is use for migraine over 25 years and at a
very conservative estimate, over 100,000 million
This, remember, is using a dosage and a
frequency for these analgesic-metoclopramide
combinations in the U.K. which is greater than that
which is proposed for MT100.
The FDA briefing documents raised some
important topics and I would just like to address
three of those specifically. The first is the
question that they asked, is there sufficient
evidence that the chronic intermittent
administration of metoclopramide does not carry the
same risk of TD as the chronic administration.
I can say that the experience from the
U.K. over the 25 years that we have had them of
these metoclopramide-analgesic preparations, the
answer is yes. Yes; we do have sufficient evidence
that the chronic intermittent administration of
metoclopramide does not carry the same risk of TD
as the chronic administration.
So, if the answer is yes, what is the
maximum number of recommended monthly doses to
avoid the risk of TD? Well, the answer to that is
not known. But I have to come back to the U.K.
experience just to mention that, over the 25 years,
there have been no cases of TD using the
metoclopramide-analgesic combinations at their
recommended dose and schedule which exceeds that
Finally, this is an issue which will be
addressed by other experts specifically and that is
on medication-overuse headache, but the question is
posed, do you believe that, based on the existing
data on medication-overuse headache, there is
evidence that the proportion of patients prescribed
MT100 will likely take a number of monthly doses
higher than that recommended.
Well, I can't answer this question
specifically, of course, but I can only say that if
this does happen, even if it does happen
type of combination, the U.K. data don't indicate
that it should lead to TD.
Thank you very much.
I would like now to pass to Dr. Jim
Alexander who is Pozen's Chief Medical Officer. He
will review the data on the efficacy of MT100 in
DR. KIEBURTZ: Same thing. Anyone have a
point of clarification?
DR. SMITH: Could you go over with me, on
Slide CC-21, the definition of tardive dyskinesia,
please--the definition. My question is, you say
some definitions include the duration of exposure.
When do the definitions include that? In other
words, is that a common use definition?
DR. SCHAPIRA: The definitions vary. As I
say, some definitions, looking at the case studies
that have been published on TD and metoclopramide
have required that the patient has been taking
metoclopramide continuously for two months, others
for three months. Some of the other studies like
the Shaffer review have said that the patient
should be taking it for 30 days or more.
So there is some variation in how people
define the requirement of metoclopramide exposure
before they will associate it with TD.
DR. SMITH: I see. So, if it doesn't meet
the duration of use, it would be dyskinesia, not
TD? Is that correct?
DR. SCHAPIRA: I think that would depend
on the individual study and the interpretation of
the authors. For instance, in the Shaffer paper,
they identified that they would use the definition
of 30 days or more. But they also recognized--for
instance, I think they reported on three juvenile
cases, two infantile and one adolescent case, that
developed tardive dyskinesia, I think the two
infants following an overdose of metoclopramide and
the adolescent also had some other features.
So I think it depends clearly how strictly
you want to define and whether you will comment on
other cases that fall outside your definition.
DR. SMITH: Okay.
DR. KIEBURTZ: Let's hold on that because
we will hear more about definitions. If the
question is about TD definitions--no? Go ahead.
DR. LENAERTS: Dr. Schapira, in sharing
your U.K. experience, what is your estimate of the
prevalence of specifically migrainers either
overusing metoclopramide-analgesic combinations or
staying frequently or constantly at the maximum
recommended dose, because you mention--
DR. KIEBURTZ: Excuse me. I am just going
to stop. If you have a clarification on what he
presented, that is one thing. Additional questions
about something he didn't talk about, not yet.
DR. LENAERTS: Thank you. I will hold.
DR. KIEBURTZ: Just clarifications of the
presented material. Dr. Katz?
DR. KATZ: A couple of questions. On
Slide 22, the second Bateman study, just for
clarification, what the design was. That was a
DR. SCHAPIRA: No; that is a retrospective
The CSM, yellow-card system.
DR. KATZ: The second one is the
yellow-card system. I thought you said it was a
DR. SCHAPIRA: No. I'm sorry. The second
Bateman study that you see on the slide there, the
one published in 1989, that was a prospective
DR. KATZ: Right; I am talking about the
DR. SCHAPIRA: I'm sorry. I thought you
said second on the list.
DR. KATZ: Oh; I'm sorry. The second
Bateman study, the 1989. So that is prospective,
so those patients were followed and their adverse
events were recorded contemporaneous with their
DR. SCHAPIRA: Yes.
DR. KATZ: It was a true prospective--
DR. SCHAPIRA: Yes.
DR. KATZ: Okay. Thanks. One other
question. Slide 28, which looks at the reports of
these events over a 40-year period, do
anything about the temporal pattern of those
reports? In other words, were there more reports
earlier on and then reports started to wane over
time which sort of happens all the time, we think,
with spontaneous reports? Do you know anything
DR. SCHAPIRA: No; I can't comment on
those. I can only say that the system has been in
place, of course, for all of that time. More
recently, over the past years, it has been
computerized. So the ADROIT system is a fairly
responsive system which is linked to primary-care
computers throughout the U.K. But I can't tell you
about the pattern of those over the years.
DR. KATZ: Just one other, if I can,
question. The previous slide, 27, which looks at
the combination, the actual acute-migraine
treatments, do we know the actual doses that people
took? As you say, the maximum dose, I guess, is 30
a day. Do we know? I don't know. Maybe we figure
it out from the numbers, but do we know what people
DR. SCHAPIRA: No; we don't know precisely
how many they took, only how many were prescribed.
As I say, it is estimated as an average of 85 per
person, but that doesn't tell you how many they
took in an individual dose. So I don't have the
data on that.
DR. KATZ: Dr. Fahn?
DR. FAHN: If we can go back to slide 22,
again, for a clarification, the second Bateman
study, the 1989 study, zero cases of TD, do you
know what definition of TD they used to come to
DR. SCHAPIRA: No. They did not specify
their definition of TD.
DR. KIEBURTZ: Dr. Goldstein?
DR. GOLDSTEIN: I am not all that familiar
with your drug-reporting system. Two questions
about it. One is how compulsive is the use of
this? In other words, how often do you think you
are actually getting reports about things that are
The second question related to
it is does
the system allow for validation somehow of these
reports because, especially with primary-care
physicians, it is not clear to me how accurate
these reports may be about particular types of
DR. KIEBURTZ: It is a little evaluative.
It is a good question. Can we hold on it because I
am conscious that the sponsor only has a certain
amount of time to present. I don't want to
infringe on that.
One last question about the second Bateman
study that you have already had questions about.
Was that only new prescriptions?
DR. SCHAPIRA: Yes.
DR. KIEBURTZ: Thank you.
DR. SCHAPIRA: I'm sorry; can I just
clarify. That was the number of prescriptions that
were given during that six-month period. So it
didn't specify whether that was a renewed
prescription for that individual or not.
DR. KIEBURTZ: Oh; I see. Okay. Thank
DR. SCHAPIRA: Thank you. I will now hand
over to Dr. Alexander.
Review of MT100 Efficacy
DR. ALEXANDER: Thank you, Dr. Schapira.
Although the potential risk of tardive
dyskinesia is the primary focus of this meeting,
when Pozen and the FDA discussed the meeting, we
agreed that the committee should have the
opportunity to review data described in the
efficacy of MT100.
My presentation will, therefore, summarize
the results of studies designed to evaluate the
efficacy of MT100 using two different trial designs
which evaluated the acute treatment of single
First, I will show the results from the
phase 3 studies which evaluated MT100 versus
placebo or metoclopramide as a pseudoplacebo.
These studies examined the efficacy of MT100 as a
migraine drug using those endpoints that are
usually required for the approval of new
Secondly, I will review the data from the
two component controlled trials which I will call
the factorial studies. These are the trials that
compared MT100 to its two individual components.
Now, as you have heard, the efficacy of naproxen
sodium as a component of MT100 is really not in
question. So my focus in discussing these data
will be on comparisons between MT100 and naproxen
sodium which directly address the contribution of
metoclopramide as a component of MT100.
The MT100 phase 3 program was quite
extensive and almost 6,000 subjects were enrolled
in six controlled trials treating single migraine
attacks. Four studies directly compared MT100 with
placebo while, in the two factorial studies shown
below, 301 and 304, metoclopramide was considered a
2,355 subjects received single doses of
MT100. Did these studies provide evidence that
MT100 was an effective migraine
drug? Well, Pozen
believes that the data clearly showed this.
This table lists the six studies in the
left-hand column. It is arranged to show the 30
individual different primary and secondary
endpoints in the five columns to the right. Study
306, which is at the top, is the study that was
accepted by the FDA as demonstrating the efficacy
of MT100. The two columns on the far left show the
key pain endpoints--that is, sustained pain
response at 24 hours, which was the primary
endpoint in four studies, and the two-hour pain
response in the second column was a key secondary
endpoint in five studies.
As shown now on the slide, in 11 of 12
comparisons, MT100 was significantly superior to
the comparator for each of these pain endpoints.
In Study 303, which had an unbalanced randomization
with a smaller number of placebo recipients, the
p-value for sustained pain response was 0.054.
But in all six studies, the efficacy of
MT100 over the comparator for the
response, shown in the second column, was
significantly superior. These results provide
clear and compelling evidence that MT100 provides
effective two-hour pain relief, the usual
regulatory endpoint in migraine trials, as well as
providing sustaining pain responses at 24 hours.
I will provide a better definition of
sustained response in a few minutes. I want to
mention the efficacy on the associated symptoms.
Efficacy for the associated symptoms of nausea,
photophobia and phonophobia, are also for a
migraine drug. But, in contrast to pain, these
symptoms are not always present in migraine attacks
and, in fact, none of the Pozen studies were
powered to detect differences for these endpoints
but all were specified as secondary endpoints in
Nevertheless, significant differences in
the incidences of these symptoms were seen among a
number of these studies at two hours after dosing,
as shown now. In additional comparisons, shown in
yellow, the p-values were between 0.05
The p-values, finally, in orange, are above 0.1.
As is reviewed in your briefing document,
by three or four hours after dosing, significant
benefits on all of these associated symptoms were
usually present with MT100 treatment.
So, to summarize, the totality of the
evidence from these six studies clearly shows that
MT100 is an effective acute treatment for migraine.
I will now show the comparisons of MT100
against naproxen sodium. These comparisons, again,
reflect the direct assessments of the contribution
of metoclopramide within MT100 in order to satisfy
the combination drug rule.
The two phase 3 factorial studies were
each performed at sites in the U.S. Subjects were
randomized to treatment with either MT100, naproxen
sodium 500 milligrams, or metoclopramide 16
milligrams, the identical doses of these component
drugs that are contained within MT100.
Subjects treated a single migraine attack
of moderate of severe pain intensity and
assessments were performed at baseline and hourly
for 24 hours. Rescue medication was permitted
after at least two hours had elapsed after dosing.
I would like to take a second and explain
the pain assessments in these trials, the primary
endpoint as well as the secondary endpoints.
Sustained pain response at 24 hours was agreed by
Pozen and the FDA as the appropriate measure to use
to assess the efficacy of MT100 versus each of its
Sustained pain response is a composite
measure of efficacy and is defined as pain relief
at two hours--that is, no pain or only mild
pain--and no relapse or moderate or severe pain and
no need for the use of rescue medication over the
next 22 hours after the two-hour assessment. The
efficacy of this endpoint is judged by how many
subjects meet this definition at 24 hours.
I would like to stop at this point and
explain why Pozen and the FDA agreed that the use
of the two-hour pain response endpoint
would not be
acceptable for the comparison of MT100 with
naproxen sodium. This was because both treatment
are active due to the presence of naproxen in each
drug and should, in fact, produce very similar pain
responses at the time point of two hours after
Two-hour pain response was a secondary
endpoint in these studies and was used to evaluate
MT100 versus metoclopramide as a pseudoplacebo, as
I have previously shown.
In contrast to the sustained pain response
and two-hour response rates which measure the
number of subjects responding, at the bottom of the
slide, you will see three secondary endpoints that
were also evaluated in these trials. These are the
Pain Intensity Difference score, PID, the Sum of
Pain Intensity Difference scores, SPID, and the
TOTPAR scores, or Total Pain Relief scores, over
These are the measurements of how much
pain relief is obtained, not of how many subjects
have a specific pain response at a given
These are the accepted general endpoints for
analgesics within the FDA. They are recognized as
very sensitive for detecting differences between
individual active analgesic drugs.
But let's first look at the agreed primary
endpoint and that was sustained pain response from
these two studies.
Shown here are the data from these studies
with a percent of responders plotted. First, note
that the metoclopramide-alone treatment produced
sustained pain response rates of 19 and 20 percent
which are similar to what might be expected of a
The responses to naproxen sodium alone
were 9 to 10 percent higher than metoclopramide and
the rates were actually 28 percent and 30 percent
in the two trials. These were significant
differences over metoclopramide. The sustained
response rates for MT100 were 6 percent and 4
percent higher than those for naproxen sodium in
these two studies.
I am sure you have noted that Pozen and
the FDA arrived at different p-values for these
comparisons. But both parties agree that the
absolute differences are 4 and 6 percent for this
endpoint. Are these differences confirmed by other
analyses? The secondary endpoints provide support
for these findings.
The mean SPID scores at 24 hours show
significant differences for MT100 versus naproxen
sodium in both studies. So these analyses of a
secondary endpoint, a valid measure of pain relief,
support the findings of the sustained endpoint. I
would also note, and not shown, but the fact that
the differences were significant in the SPID scores
at two hours after dosing in both studies.
A third dataset, the 24-hour TOTPAR
scores, is also supportive with mean TOTPAR scores
at 24 hours for these two studies showing
significant differences between MT100 and naproxen
So these additional analyses, which were
secondary, support and confirm the results seen
with the sustained pain-response endpoint and
substantiate the contribution of metoclopramide to
the effect of MT100.
But, even if this were not the case, there
is a subgroup pseudoplacebo that seems to respond
much better to MT100 than the naproxen sodium.
Now, the reason that we can discuss this subgroup
is the following: at the outset of the phase 3
program, Pozen theorized that metoclopramide might
contribute not only to better pain relief but might
also contribute to the relief of nausea that may
accompany migraine attacks.
For this reason, one of the three
pre-planned analyses that were used in all of the
phase 3 studies include analyses of pain endpoints
within two subgroups of migraine attacks--that is,
those with nausea and those without nausea at the
time of treatment.
These are the results for subjects
migraine attacks were not accompanied by nausea.
This type of migraine attack made up one-third of
the attacks treated in Study 304 and one-half of
the attacks treated in Study 301. The number of
subjects in each study is shown with the figure on
the left being 301, the figure on the right, 304.
In these subgroups of attacks, the
differences between MT100 and naproxen sodium for
sustained pain responses were essentially doubled
to 9 and 10 percent. In this instance, the
differences were highly significant, with p-values
less than 0.01 in both studies. This was seen in
both studies and, therefore, is not likely to be a
Pozen took a further step of providing its
phase 3 data to Drs. Richard Lipton and Ken
Kolodner who conducted independent analyses of
these data and confirmed these findings. The odds
ratios and the significant p-values are provided in
your briefing document in Table 11.
As additional confirmation,
the mean SPID
scores in these subjects with attacks without
nausea also showed significant differences in these
sensitive measures of pain relief for MT100 versus
naproxen sodium at 24 hours. When Pozen met with
the FDA in late 2004 and the data for this subgroup
of attacks were presented to the agency, Pozen was
asked if the same effect was seen for MT100 across
the phase 3 studies.
The answer is definitely yes. Pozen
performed a pooled analysis of phase 3 trial data
and these results were obtained.
These studies were conducted in the same
time period. They all treated subjects with
migraine attacks of moderate to severe intensity
and there were similar entry criteria and
evaluation criteria. The comparators included
placebo, metoclopramide and naproxen sodium.
As you can see, there was a significant
difference only in the treatment with MT100 for the
comparison of the treatment of attacks with and
without nausea, again, highly
So why would these effects be present?
The only plausible explanation is the 16 milligrams
of metoclopramide contained within MT100.
Therefore, the unique contribution of
metoclopramide may be described as counteracting
the gastric stasis associated with migraine,
enhancing the rate of absorption of naproxen,
providing better pain relief in the overall
treatment population and, finally, enabling maximum
benefit to be obtained in migraine attacks without
So where does this leave the efficacy of
MT100? Pozen believes that the data show that
MT100 is an effective migraine treatment, that
MT100 provides an absolute 4 to 6 percent
improvement in sustained pain response over that
for naproxen sodium, that MT100 provides absolute 9
to 10 percent improvements in sustained pain
response over naproxen sodium in migraine attacks
Secondary endpoints, SPID and TOTPAR,
confirm the superiority of MT100 over naproxen
sodium. Finally, the contribution of
metoclopramide to the primary endpoint of sustained
pain response is demonstrated in two studies.
Thank you for your attention.
I would like now to introduce--it is my
privilege now to introduce Dr. David Matchar,
Professor of Medicine at Duke University School of
Medicine. Dr. Matchar is Director of the Duke
Center for Clinical Health Policy Research and,
over the past two decades, he has made significant
contributions in the field of evidence-based
decision making in medical care. In the migraine
area, he has been a member of the U.S. Headache
Consortium and was lead author of the group's
evidence-based guidelines for the treatment of
migraine, a collaboration among eight professional
Dr. Matchar was invited by Pozen to
provide his perspective on the potential
MT100 in the treatment of migraine and his view on
the balance of benefits and risks of this
DR. KIEBURTZ: Just real quickly, any last
clarifying questions? Dr. Welch?
DR. WELCH: The nausea versus the
non-nausea studies. Was that a prospective nausea
DR. ALEXANDER: The studies were both
designed to have a preplanned analysis of the
subgroups of attacks with nausea and without
DR. WELCH: So you didn't look for
DR. ALEXANDER: I'm sorry; I didn't
DR. WELCH: You didn't look for separate
populations. It was all in the same study.
DR. ALEXANDER: Oh; I'm sorry. It was the
same study. It was certainly not randomized
between nausea and no nausea.
DR. WELCH: Did you look at the time from
the start of the pain to the onset of the nausea in
the nausea group?
DR. ALEXANDER: No; we didn't.
DR. KIEBURTZ: Dr. Temple.
DR. TEMPLE: Maybe you will think this is
too much discussion, but when you separated out the
nausea people, my assumption always was you thought
the drug would work better in people that had
nausea, not less.
DR. ALEXANDER: That is exactly right. I
mentioned that--I may not have emphasized it enough
because initially Pozen believed that
metoclopramide would have an anti-nausea effect in
migraine. The thought was, we will look at those
with nausea and those without nausea.
We did that. As it turns out, if there is
an anti-nausea effect, it occurs after two hours--
DR. TEMPLE: No; I don't even mean that.
You have said that the effect on pain is better in
people with nausea.
DR. ALEXANDER: That's correct.
DR. TEMPLE: And you did, as you showed,
have groups with and without nausea separated for
analysis. But what happened was the opposite of
what you expected. Maybe that is not a major
DR. KIEBURTZ: Dr. Koski?
DR. KOSKI: I assume that your patients
within this study had more than one attack of
DR. ALEXANDER: That's not correct. This
was a single-attack study.
DR. KOSKI: It was single attack. Thank
DR. KIEBURTZ: Dr. Goldstein.
DR. GOLDSTEIN: You may also want to defer
this question for later, but the preparations that
you used in these comparator studies, you went
through, or somebody went through, in the beginning
talking about how the MT100 is put together. You
have a core. Then it is sprayed and sprayed again,
and then there is another spraying on top of that.
In these studies, how is the
metoclopramide put together? Was this done with a
blind core that was then sprayed in the same way so
that the pharmacokinetics would be the same?
DR. ALEXANDER: Yes; they were identical
in visual appearance and the placebo--excuse me;
the comparators were identical and the
metoclopramide was around a core, a blank core.
DR. GOLDSTEIN: Thank you.
DR. KIEBURTZ: Dr. Katz, did you have
DR. KATZ: No.
DR. KIEBURTZ: Just to remind the sponsor,
we will stop in half an hour. Just if you want to
think about your presentations, we will be stopping
at ten of the hour.
Potential Role of the MT100 in Migraine Therapy
Balancing Benefits and Risks
DR. MATCHAR: Good morning. I think, in
addition to the introduction that Dr. Alexander
gave me, I would just like to comment that I am
also a principal investigator of the three-city
study of headache management that is funded by the
Agency for Healthcare Research and
Quality and that
is in an effort to link the evidence-based
guidelines that have been developed to actual
clinical practice. So it is in that context that I
will make my remarks this morning.
I guess, also parenthetically, I should
mention that I am the husband of a migrainer and
the father of a migrainer so I guess I have both a
clinical, a research and also a personal interest
in this topic.
My task that I have been asked to fulfil
today is to talk about the clinical trials and the
safety studies in a clinical-practice context. In
thinking about this, three questions really arose
in my mind that I felt were particularly salient.
The first is is there really a role for a
new migraine therapy above and beyond what we have
available. We have seven triptans that are out
there, for example. Do we really need something
The second question is, when we look at
clinical differences in clinical-trial
results of 4
to 6 percent, what, really, does that mean to
patients. Is that something really worth pursuing?
Then the third question is how should we be
thinking about benefit to risk in the particular
scenario of an acute migraine treatment.
So, in talking about these three
questions, or in addressing these three questions,
I am going to follow the following outline which is
first describing just some context of the clinical
burden of migraine, efficacy in clinical trials
focusing on the relationship between the measures
and the meaning those measures might have in a
clinical setting, and a little bit about available
oral treatments including something about adverse
effects of available treatments, and then, finally,
talk a little more about this issue of balancing
benefits and risks and a clinically useful
conceptual framework that I have, I use, and I find
useful in thinking about benefit and risk.
Not to really belabor the obvious to a
group of neurologists about headache,
about pain. The definition from the International
Headache Society places pain as key. It is an
episodic disorder lasting 4 to 72 hours with two of
any of the following pain characteristics;
unilateral location, pulsating quality, moderate or
severe intensity and worsened by movement.
In addition, there are the associated
symptoms which were described earlier, specifically
photophobia and phonophobia together or nausea
and/or vomiting. So that constitutes a definition.
But, again, the key element from a clinical
perspective, and from the diagnostic perspective,
It might go without saying that migraine
is not a homogenous disease. While pain is nearly
always present, what is less consistent is the
presence of associated symptoms. Here the
phonophobia or photophobia, the punch line,
basically, is that most people typically do have
these symptoms whereas, in the case of nausea, most
people typically don't have nausea. So the data
here is only 38 percent reported nausea or vomiting
in more than half of attacks and only 32 percent
reported nausea in all attacks. So that is just,
again, the point. The nausea is not uniformly
present and that migraine really is a syndrome with
a variable syndrome cluster presentation.
The question I am moving on to now is the
issue of the unmet need. I don't know if anyone
cited the statistic of 25 million people in the
United States having migraine. That is based on a
very high-quality epidemiologic study done by
Richard Lipton and colleagues.
Of those 25 million, 53 percent of these
individuals describe a disability, significant
disability, or the need for bed rest. Now, I think
this is going to be described a bit later, but
there needs to be some understanding of the true
magnitude of a migraine for most migrainers. These
are very severe headaches. They are very
disabling. In fact, a day is sliced out of that
In addition to there being a lot of
migrainers and the disability being quite severe,
patients tend not to be satisfied with their
treatment. We will go into that a little bit
later. I will mention--I will expand a bit on the
issue of adverse effects, in particular, but there
is good evidence that patients are not getting
effective care in their early visits, that
physicians are finding it difficult to take the
medications that are available to them and create a
mix that is useful to a large majority of patients.
One of the issues at the bottom here that
is cited, and I realize it is not a FDA concern,
per se, but it certainly is a concern for our
patients, is that the medications available are
very expensive and often interfere with patients'
willingness and ability to take them regularly for
their severe attacks.
What do patients need? What patients
need, effectively, is what they want. What do they
They want pain relief. Again,
this is from
a survey done by Dr. Lipton and colleagues.
Patients surveyed with migraine, they say the most
desirable outcomes in an acute migraine therapy are
rapid onset of pain relief, their freedom from pain
and there is no recurrence of pain. So it is the
notion of a sustained response to pain and
sustained response that goes into the definition of
what patients are asking for from a migraine
Do clinical measures, or do measures used
in clinical trials, address what patients want?
Now, the standard measure that is used in clinical
trials is the ordinal rating system in which pain
is rated 3, 2, 1, 0 from severe to none. It is
important to point out that 3 to 2 is not
especially valuable for patients but going from 2
to 1 is something that patients would clearly
desire and, therefore, the criteria for entry into
clinical studies would be having severe or moderate
pain and the criteria for response is going from
severe or moderate to mild or none.
So the measure that is typically used, the
standard measure that has historically been used,
is pain response rate. It is the proportion of
subjects who achieve mild or pain-free status two
hours after dose when pain was either moderate or
severe at baseline and no rescue medications were
allowed in that period. But it is a two-hour
Let's turn to that other issue about
sustainability of the response. Let's start with
the measure I just mentioned which is a good
measure. It is a two-hour pain relief. It is a
good start. Historically, it is what has been used
as the regulatory endpoint. Triptans, for example,
were approved on the basis of the two-hour
But a better response takes into account
this time-course issue that patients care about.
Sustained pain response at 24 hours includes mild
or no pain at two hours, so it is what the
preceding measure includes, but also
relapse to moderate or severe pain and no use of
rescue medications. This means you get relief.
You continue to have relief.
Again, from a clinical perspective, the
notion that you are not going to have a recurrence
is extremely important because the possibility of
having a recurrence is a very ominous concern for
patients. If you know that there is a good
likelihood that this is going to come back again,
you are not going to be able to experience your day
in a normal way.
This also raises this concern about, well,
is 5 percent more people having this response
really worthwhile. I would suggest, well, if we
were only talking about 5 percent of people, or 5
percent of pain, being better, going from 100 to a
95, or going from 95 to a 90, that would not be
But what we are talking about is 5 percent
more people, so we are talking about people, in
this case, they get relief and they continue to
have relief. Again, this is a point of
differentiation that distinguishes MT100,
At the bottom, I have here what would be
considered the best outcome which would be
sustained pain-free at 24 hours. I think this
constitutes our vision for what we would like to
see in migraine therapy and I think we are moving
towards that as a more standard measure in future
Briefly, on the issue of associated
symptoms, we talked about the three photophobia,
phonophobia and nausea. In clinical trials, these
symptoms tend to be more commonly reported than
they are in community samples of migrainers. But,
again, even in trials, these symptoms are
associated only with a fraction of the patients.
They are recorded as present or absent so
the all-or-none measure is a relatively crude
measure of response to treatment. Again, efficacy
is assessed at two hours which has a concern from a
clinical perspective that some of these
who won't have nausea at the outset will start to
have nausea after and will have nausea two hours,
but then might have it relieved at three hours
after their pain is relieved.
So I think the point here really is that
the measures of associated symptoms--it is not that
associated symptoms aren't important. They are
important. But the measures that tend to be used
and are standard in clinical trials are relatively
crude and more so than the measures used for pain.
So what do we have currently for migraine
therapy that is oral and FDA-approved for migraine
indication? What is currently available includes,
on the left side, the over-the-counters, which are
ibuprofen, which are two products, acetaminophen,
aspirin-caffeine combination. That is one side.
On the other side, and I would say,
actually, far on the right side, are, then the
prescription medications. There are seven triptans
currently FDA-approved for migraine and the point
here is there is a paucity of approved
I don't know any clinicians who would say they are
particularly happy with the variety of medications
that are available.
In light of the fact that most patients
presenting to a doctor have failed over-the-counter
medications for at least their worst headaches,
then there really, truly, is a big gap in what is
available when a patient presents to you. In
effect, the only thing you have available, as a
migraine-specific therapy in this case, is going to
be the triptans.
I will mention in a moment that that is
not always a satisfactory solution for patients.
Unfortunately, what happens clinically, when this
gap is not filled with another more useful
medication, physicians are tending to use--continue
to use--narcotics and barbiturates which are
undesirable for lots of reasons, three of which are
that they have not been studied in clinical trials.
They are not FDA-approved, so that is a concern.
And they, obviously, have undesirable adverse
This clinical impression that there is a
therapeutic gap is supported by empirical evidence.
This is a couple of studies in which, they point
out, in the real world, half of patients will often
delay treatment with prescribed medications. They
will have a prescription in hand and 69 percent of
them will wait and see if the headache is really a
migraine. About half of them will want to take
their medication only if the attack is severe.
This is not the sign of a very healthy
environment, that people have prescriptions and
they are not wanting to take them even though they
are having, in this case, at least moderate to
As a consequence, I would presume, that
four out of five migrainers have expressed an
interest, a specific interest, in trying a novel
product with similar efficacy to what they have in
hand, the prescription they have in hand, but has
fewer adverse effects.
This then turns us to the issue of
bothersome adverse effects. Why don't migrainers
like what we have available?
On the right side, you see the non-triptan
products which include the over-the-counters I
mentioned, nonsteroidals, but also include opioids
and barbiturates. As one would expect, the side
effects are sleepiness, nausea, difficulty
thinking, inability to function, and so on.
Not too dissimilar, even, are the triptans
on the left side. But one syndrome which is
particularly bothersome to many of my patients--I
know it is extremely bothersome to my daughter--is
this chest-pressure phenomenon.
Yes; there are coronary effects of the
triptan. Some patients--and, indeed, it is
contraindicated with patients with coronary-artery
disease--but, for the vast majority of people who
are having these chest-pressure syndromes, they
have no coronary disease. These are not coronary
symptoms. What they are, again, is a bit of
conjecture, but they are extremely
most people who experience them find them
sufficiently disturbing that, even if you try to
convince them endlessly that they are not having
cardiac ischemia, they are frightened and they
won't want to take the medication.
So that is a concern and, as I say, other
symptoms are sufficiently aversive for patients
that they will delay their therapy or not take the
medications prescribed at all.
Now let's turn to the issue of balancing
benefits and risks of acute therapy. To think
about this, I would like you to imagine, first of
all, another scenario entirely. This other
scenario entirely is a stroke-preventive
A stroke-preventive medication might work
and it might not work. How do you know that it
doesn't work? For the most part, you know it
doesn't work because the patient has a stroke.
Okay; you lose. And that is how you know that your
drug is a failure.
Well, we have a very lucky circumstance
with migraine in that migraine lends itself to
tailoring. There are multiple episodic attacks
over many years. You get immediate feedback on the
efficacy of the acute treatment. Tailoring here,
then, is specifically aimed at maximizing the
chance that the therapy will work for a given
The idea, basically, is patients don't
like to take medications that don't work,
especially if they don't have any other effect that
you kind of like. So an opioid you might take even
if it doesn't really--well, not me, personally, or
you, personally, but, certainly, some people will
take them just because they have another effect
that they like.
Consequently, with this tailoring
occurring, the benefit-to-risk margin actually
improves over time for each of our individual
Recognizing that some people don't like
words as much as they like pictures, I have here a
picture that basically raises this concept as the
filter of clinical experience. We start out
basically saying, look, from population studies,
from clinical trials, we realize that not all
patients are going to respond. But we are going to
try it. We are going to treat all these patients
within some set of characteristics.
We have some set of characteristics and,
of course, it wouldn't have been approved if we
hadn't considered the benefit-to-risk to be
acceptable. Now, after some period of time,
patients decide this works under this condition,
this doesn't work under this condition, and they
pick and choose, and what we end up with is
patients taking medications for which they tend to
Consequently, the clinical benefit-to-risk
ratio improves over time and is ultimately
maximized. Again, the point I want to make is that
patients don't take drugs that don't work for the
As suggested earlier, from the experience
in the U.K., as Dr. Schapira mentioned as well as
using the components in the United States, the
notion is that MT100 would fill in this gap that is
currently basically being filled with opioids and
barbiturates which is a bad scenario. The notion,
again, is that, amongst the various options, what
we allow by making this new drug available is to
fill in the gap and to offer an opportunity for
patients to create a mix for themselves that makes
the most sense for them.
Not all patients, certainly, will respond
to this. Those who will respond to it will take
it. The benefit, again, as I mentioned earlier, or
the risks, will only accrue to those people who
So, in summary, I am going to just cover
those three questions real quickly. Is there a
role for a new migraine drug? I believe the answer
is unequivocally yes. Migraine is a common
disorder. Patients have significant unmet needs.
The available oral medications are very limited
and, unfortunately, the gap that exists is now
being filled by undesirable drugs.
The second question is what is the meaning
of the clinical-trial difference, this 4 to 6
percent everyone is talking about. Well, not
quibbling over whether you buy the 4 to 6 percent
statistical significance or not, what does
5 percent mean. Let's just say 5 percent. 5
percent is not 5 percent of pain. It is 5 percent
of people. That is an important point from a
clinical perspective. That is meaningful.
Now, the last point, or the last question,
is what is the meaning of a benefit-to-risk ratio
in clinical practice. I just want to mention again
this concept of tailoring. Migraine treatment
lends itself to tailoring. Patients don't take
drugs that don't work and thus, in clinical
practice, we have the lucky circumstance that
benefit-to-risk ratios can be optimized.
Thank you very much.
DR. KIEBURTZ: Any--Dr. Sacco?.
DR. SACCO: Dr. Matchar, just a
clarification, maybe, on Slide 63 for part of your
talk. I assume most of your talk has been
indicated for acute migraine attacks. You haven't
dealt with any of the FDA-approved medications for
migraine prevention, of which there are some.
DR. MATCHAR: Oh, sure; yes.
DR. SACCO: That would just be a
DR. MATCHAR: Right. These are oral
products for acute indication, acute migraine.
DR. KIEBURTZ: Dr. Lenaerts?
DR. LENAERTS: Thank you. I have a
question regarding Slide 57. Could you confirm the
38 percent of patients reporting nausea and then 32
percent, actually, reporting in all attacks. I
have some other information that says up to 90
percent of people have nausea occurring. So
migrainers have up to 90 percent.
DR. MATCHAR: Right. The point that I am
making here has to do with the patterns,
typical patterns, for patients, not the average for
all migraines. So having nausea is a typical
pattern in a minority of patients. Actually, Dr.
Silberstein did one of these studies and he might
be able to clarify that later.
DR. KIEBURTZ: Dr. Jeste.
DR. JESTE: I have a similar question. If
you look at your Slide 62, you said nausea
incidence is 40 to 70 percent.
DR. MATCHAR: Right; and this is in
clinical trials. So the population you are going
to see in clinical trials is going to be different.
So this says, basically, as a patient enters into
these trials, the presence of nausea is going to be
more likely than it was going to be when you are
asking the question, what is the typical pattern or
cluster of symptoms among migrainers. So, yes;
patients who are in trials will typically have the
symptoms more commonly.
DR. KIEBURTZ: Thank you.
DR. MATCHAR: I am going to turn to Dr.
Dr. Silberstein is actually a colleague
working on one of the clinical trials that I
mentioned earlier and he is the Director of the
Jefferson Headache Center and the Department of
Neurology and is the President of the American
DR. KIEBURTZ: We see your number of
slides in the book, but just so you are--
DR. SILBERSTEIN: I have cut them.
DR. KIEBURTZ: Perfect. Thank you.
Clinical Considerations on Migraine Therapy
DR. SILBERSTEIN: I want to thank
everybody for having us here today. Looking at the
time, I have tried to cut and I will try to talk
I am going to talk a little bit about the
rationale for the use of metoclopramide. I am
going to briefly talk about attacks without nausea.
I am going to spend most of my time talking about
medication-overuse headache of which I
particular interest and then summarize a possible
benefit of MT100.
We learned about metoclopramide and
migraine many years ago from, actually, our
colleagues in London. Marshall Wilkenson and Nat
Blau who run the City of London Migraine Clinic
made it part of their everyday treatment and it got
introduced, like many things do, on the basis of
Many of us continue to use it in the
absence of trials until you saw the evidence today.
It is used to prevent nausea. It enhances the
absorption of nonsteroidals. Many headache experts
continue to use metoclopramide for those reasons.
I think you have seen the evidence to show
that MT100 is more effective than placebo. One can
argue about the statistics, but you see in the
evidence that MT100 is more effective than naproxen
sodium and clearly more effective than
One of issues is its 4 to 6 percent
response, clinically significant. I think, in
part, it depends on how seriously you view migraine
as a disorder. If you had a patient who has had
cancer of the brain and you had a survival rate of
10 percent and you went to 14 percent, nobody would
argue that that is clinically significant. So take
into context what migraine is to the sufferer and
take into context that migraine is often considered
not a serious disorder.
One of the ways of looking at it is to
look at all attacks and look at the absolute and
relative differences. If the 4 to 6 percent really
means in patients getting 14 to 20 percent relative
increase, and if you look at the subset of attacks
without nausea, you are assuming that the data is
correct because the subset analysis was not the
primary endpoint, you are talking about a third
This, to me, is clinically significant.
I would like to spend a little bit of time
talking about the concept of medication-overuse
headache, for that was one of the questions. What
is it? First, many patients have chronic daily
headache which, by definition, means nothing more
than headaches occurring more than 15 days a month.
In the clinic, it is the most common cause
of chronic daily headache. I was fortunate enough
to be the head of the International Headache
Society Classification Committee on Chronic Daily
Headache. The criteria we came up with were the
following: headache has to be there more often
than not greater than or equal to 15 days per
month; regular overuse for more than three months
of acute medication; the headache is actually
developed or worsened coexistent with overuse;
lastly, you stop the overuse medication and the
headache reverts to its previous form.
The next issue is how much medicine.
First, triptans, ergots, opioids or
butalbital-containing analgesics taken
on a regular
basis ten or more days per month. What we don't
mean is ten days in a row. We mean ten days
divided up. Two, other analgesics 15 or more days
a month for a total exposure of 15 or more days a
month. That is the definition of
The next issue is which are the drugs that
are most likely to produce medication-overuse
headache. The first caveat is there are absolutely
no placebo-controlled, well-designed clinical
trials of medication-overuse headache in the world,
yet. High probability based on a series of
anecdotes, opioids or narcotics, ergotamine and
Chris Diener from Germany said the best
thing he ever did was get butalbital-containing
compounds removed from the market in Germany. That
is his legacy.
Caffeine is associated with
medication-overuse headache. Lower probability;
aspirin, acetaminophen, and
triptans. Unlikely and
controversial, other non-steroidals, DHE or
neuroleptics are even associated with
In summary, MT100 in migraine therapy. I
think it could be a primary therapy when simple
analgesics fail. By the time patients come to the
physician, they have failed simple analgesics and,
as Dr. Matchar showed, there is an area in between.
Triptans can't be used, don't work or are overused.
The reason for this is, we believe, that
nonsteroidals and neuroleptics, metoclopramide, in
particular, are unlikely to produce
medication-overuse headache. It is common among
clinicians who are interested in headache--we use
this class of drugs to prevent medication-overuse
headache or to treat medication-overuse headache.
Lastly, we believe it can fill the gap between
simple analgesics and triptans that is now being
filled by opioids and by butalbital-containing
I think it is important to realize the
World Health Organization has said that migraine is
one of the four most disabling disorders know to
mankind and that a patient with a severe migraine
attack has the same degree of disability as
somebody who has quadriparesis, dementia or acute
DR. KIEBURTZ: Thank you.
Any clarification questions? Dr. Temple?
DR. TEMPLE: One of your slides, and a
number of people have shown the same one, was the
attractiveness of oral metoclopramide in migraine.
DR. SILBERSTEIN: Correct.
DR. TEMPLE: Counteracting gastric stasis.
DR. SILBERSTEIN: Correct.
DR. TEMPLE: Treating or preventing
nausea, enhancing absorption of NSAIDs and a lot of
people use it.
DR. SILBERSTEIN: Right.
DR. TEMPLE: I guess what are you saying
about those things? Are you saying that is part of
the evidence? Or what?
DR. SILBERSTEIN: What I am saying is the
following. Until these trials were done, we were
doing this on anecdote. Physicians continue to do
a number of things in the absence of evidence-based
medicine. I think what you have seen today is
evidence-based medicine. I think the questions are
going to be, there are a lot of patterns of
behavior. The pattern of behavior in the United
States today for taking care of most migraine
attacks is to either give a narcotic or opioid or
butalbutal-containing in the absence of scientific
What I am suggesting is this is an
alternative and I think it is the job of this panel
to see whether it is a good or a bad alternative.
DR. TEMPLE: Okay. But you are not
suggesting any of those reasons are the reasons or
DR. SILBERSTEIN: I am suggesting that
this is the anecdotal lure and the basis of why
this compound has been commonly used in
the past in
the absence of good scientific evidence.
DR. TEMPLE: Okay.
DR. KIEBURTZ: Thank you.
We will break now for fifteen minutes. I
will just remind the committee members that our
discussions only happen in public. During the
break, you are not to discuss with other committee
members or, in fact, anybody, the presentations or
your views on things. The point of having a public
meeting is our discussions are public. So, just
avoid that in the interim and we will start at
DR. KIEBURTZ: Why don't we get started.
Dr. Bastings will be our first presenter, the
clinical team leader. We will have, just to
clarify the agenda, about an hour-and-15-minute
presentation from FDA including an invited speaker.
Then we will have time to question, for the
committee to question, both the sponsor and the
Some of the questions I kind of suppressed
earlier about interpretation, context, and so
forth, that is our opportunity to do that.
So, Dr. Bastings, please.
FDA Risk/Benefit Considerations
DR. BASTINGS: Thank you. Good morning.
I will now present you some FDA
risk/benefit considerations for MT100.
As you know, MT100 is a combination of
naproxen sodium 500 milligrams and metoclopramide
hydrochloride 16 milligrams. The proposed
indication is the acute treatment of a migraine
headache with or without aura.
The division issued a not-approvable
action in May, 2004 mostly because the review team
determined that the contribution of both active
drug components to the claimed effects of the
product had not been established.
According to the FDA Combination Policy,
two or more drugs may be combined in a single
dosage form when each component makes a
contribution to claimed effects and the dosage of
each component is such that the combination is safe
and effective for a significant patient population
regarding such concurrent therapy.
To address the Combination Policy
requirements, Pozen conducted two factorial studies
of similar design. These were Study 301 and 304.
In both studies, patients were randomized to MT100,
naproxen or metoclopramide. The primary endpoint
was sustained pain response.
Sustained pain response is defined as a
moderate or severe headache at baseline with mild
or no headache at two hours and no relapse and no
use of rescue medication between two and 24 hours.
This slide shows you the key result of the
two factorial studies. For Study 301, the
sustained response rate for MT100 was 35.6 percent
as compared to 29.8 percent for naproxen. So the
contribution of metoclopramide was 5.8 percent and
this was not a statistically significant difference
according to the prespecified analysis plan.
For Study 304, which was a much larger
study, the sustained response rate for MT100 was
31.8 percent as compared to 27.9 percent for
naproxen. So the contribution of metoclopramide
was 3.9 percent and this was not a statistically
significant difference according to the
prespecified analysis plan.
This slide shows you the two-hour
endpoints in the factorial studies. I must stress
that Pozen was not required to show a contribution
of metoclopramide on these endpoints. However,
these are highly relevant endpoints in migraine
studies. These are the ones typically used to
approve migraine drugs. Since the primary endpoint
did not show a significant contribution of
metoclopramide, it is useful to examine
What you can see on this slide is that, in
both studies, there was no significant difference
between MT100 and naproxen for the two-hour pain
response, the incidence of nausea at two hours, the
incidence of photophobia at two hours and the
incidence of phonophobia at two hours.
As you know, sustained pain response is a
composite endpoint. To better understand the
changes seen with that endpoint, it is useful to
look at the individual components which are the
two-hour pain response and the use of relapse or
So, in Study 301, you can see that the
two-hour response for MT100 was 48.1 percent as
compared to 46.6 percent with naproxen. So the
contribution of metoclopramide at two hours at 1.5
percent. This was not statistically significant.
The use of rescue medication or the
relapse of the headache after a response at two
hours was seen in 12.6 percent of MT100
versus 16.8 percent of naproxen patients. So the
contribution of metoclopramide there was 4.2
percent and this adds up to 5.8 percent of
difference in the sustained response rate.
In Study 304, you can see a contribution
of metoclopramide for the two-hour pain response of
3.1 percent and you see that the difference in the
relapse or rescue-medication use is less than 1
percent. This adds up to 3.9 percent of difference
in the sustained response rate.
Finally, this slide shows the sustained
responses for the associated symptoms. Sustained
responses here are defined in a similar manner as
for sustained pain response. For example,
sustained nausea-free means no nausea at two hours
with no relapse of nausea between two and 24 hours
and not use of rescue medication.
What you can see is that, in both studies,
there was no significant difference between MT100
and naproxen for sustained nausea-free,
photophobia-free, and sustained phonophobia-free.
Pozen met with the division in October,
2004, and, at that time, they presented these
subgroup analyses which suggested a contribution of
metoclopramide in patients with no nausea at
baseline. At that time, the division considered to
accept the prospective replication of these
findings to fulfill the Combination Policy
requirements but we assured Pozen that we would
need to bring this to an advisory meeting because
this is an unusual patient population and we need
to make sure the benefits in that population
outweigh the risk related to metoclopramide.
I will briefly show you these subgroup
analyses that Pozen made. You already know that,
for the combined patient population, there was no
significant difference between MT100 and naproxen
for sustained pain response and for the two-hour
If you look at the patients
who did not
have nausea at baseline, you see about 10 percent
difference between MT100 and naproxen with a low
p-value. But, if you look at the two-hour pain
response, there was no significant difference
between MT100 and naproxen even in that subgroup.
For patients who had nausea at baseline,
you can see that there was less than 1 percent
difference between MT100 and naproxen for sustained
pain response. For the two-hour pain response, the
rate was actually numerically higher for naproxen
but the difference was not statistically
significant with MT100.
Similar findings for Study 304. You know
that, for the combined patient populations, there
was no significant difference for sustained pain
response and two-hour pain response. For patients
with no nausea at baseline, again, there is about a
10 percent difference between MT100 and naproxen.
For the two-hour pain response, there is no
significant difference between MT100 and naproxen
for that subgroup.
For patients with nausea at baseline,
there was about a 1 percent difference between
MT100 and naproxen for sustained pain response and
the two-hour pain response. These differences were
not statistically significant.
I would like to give you some thoughts on
an indication limited to patients with no nausea at
baseline. In a survey of 500 self-reported
migrainers, nausea occurred in more than 90 percent
of these patients and nearly one-third of these
experienced nausea during every attack.
Less than 10 percent of patients
consistently had migraine with no nausea at
baseline which is the indication for which MT100
which is being considered today. In line with that
survey, there was a 45 to 69 percent incidence of
nausea at baseline in the MT100 phase e studies.
Migraine patients, in the majority of
them, may have some attacks with nausea and other
attacks without or nausea may develop
attack. Patients would, therefore, need two
different treatments based on the presence or
absence of nausea or they would treat their attacks
with nausea with a combination product containing
metoclopramide which has no established
contribution for efficacy for the type of attack.
Yet, they would be exposed to the risk of
As you know, our main safety concern is
tardive dyskinesia. Tardive was originally
intended to emphasize a late appearance during
neuroleptic treatment. However, there have been a
number of reports that TD may appear early during
the neuroleptic treatment and there seems to be no
fundamental distinction between cases appearing
early and those appearing late.
In addition, there have been a number of
TD variants described and these include tardive
dystonia, tardive akathisia, tardive myoclonus,
tardive tics, tardive tremor, and it is
unclear how well these different variants have been
captured in the post-marketing reporting systems.
TD is a well-known side effect of
metoclopramide. Its exact incidence remains
unclear. There was no case reported in the MT100
database but the database was too small to detect
rare events such as TD.
The current metoclopramide labeling
includes a warning which I am going to read to you.
"Tardive dyskinesia may develop in patients treated
with metoclopramide. Although the prevalence of
the syndrome appears to be highest among the
elderly, especially elderly women, it is impossible
to predict which patients are likely to develop the
syndrome. Both the risk of developing the syndrome
and the likelihood that it will become reversible
are believed to increase with the duration of
treatment and the total cumulative dose. Less
commonly, the syndrome can develop after relatively
brief treatment periods at low
doses. In these
cases, symptoms appear more likely to be
Because of these safety concerns, the FDA
limited the indication of oral metoclopramide for
short-term therapy for gastroesophageal reflux for
up to 12 weeks and only when conservative treatment
fails for the treatment of diabetic gastroparesis
for up to eight weeks. The recommended dose is 5
to 15 milligrams up to four times a day.
As I mentioned earlier, there have been a
number of cases reported in the literature of the
relatively short durations of treatment, sometimes
as short as one or two weeks. We also asked our
colleagues from the Office of Drug Safety to look
for cases of movement disorders associated to
metoclopramide in the AERS database and you will
hear a presentation with much more detail on that
topic later in the morning.
In that analysis, the first quartile of
duration of treatment for the cases of
TD was 19.5
This slide show you a breakdown of the
treatment duration. You can see that there are
quite a few cases with duration of treatment less
than the 90-day definition which has been used in
some of the earlier studies.
We also asked our colleagues from ODS to
look at the patterns of use of metoclopramide.
Metoclopramide is mostly used for GI indications.
Migraine use, up to now, is quite limited. It is
less than 2 percent. 13 percent of patients
appeared to have received prescriptions for more
than 90 days and 7 percent of patients for more
than 180 days, so exceeding the labeling
Over a three-year period, cumulative
therapy was longer than 90 days for almost 20
percent of patients and greater than 180 days for
over 10 percent of patients, again exceeding the
What about the risk of TD associated with
chronic intermittent use of metoclopramide as has
been proposed in this NDA. This is very difficult
to evaluate for a variety of reasons which include
that there is no current indication for chronic
intermittent use in the United States and that
there is no specific capture of chronic
intermittent use in the AERS database.
Some animal data suggests that the
intermittent use of neuroleptics may be no safer,
or even riskier, than continuous use in an animal
model of TD. In the psychiatric population, the
number of interruptions in chronic treatment--so
this is slightly different from chronic
intermittent but this may be suggestive--the number
of interruptions was the second factor after age in
predicting the occurrence of TD.
Another concern that we have is the
overuse of acute migraine drugs.
Medication-overuse headache was recently
in the IHS classification. There is a subcategory
of analgesic-overuse headache. According to
experts, there is substantial evidence that all
drugs used for the treatment of migraine may cause
medication-overuse headache and the prevalence of
medication-overuse headache in the general
population is around 1 percent.
The IHS also said that the overuse of
symptomatic migraine drugs is the most common cause
of chronic daily headache. We are not that much
worried that MT100 could cause chronic daily
headache. We are just worried that there could be
a similar abuse of the drug as has been seen with
the other approved or non-approved migraine drugs.
So we have the following questions for the
advisory committee. The first one; in a recent
submission to the NDA, Pozen estimated an annual
incidence of TD of up to 0.038 percent for
metoclopramide at a daily dose of 30 to 40
milligrams per day for 72 days per year which
corresponds to up to 380 cases of TD per
patients per year.
Do you think that this is a reasonable
estimate? If MT100 were to carry the same risk,
would such a risk level be acceptable if the only
contribution of metoclopramide is a 5 to 10 percent
improvement on sustained headache relief with no
effect onto our endpoints? Is any risk of TD
acceptable for a migraine population?
Question 1; is there sufficient evidence
that the chronic intermittent administration of
metoclopramide does not carry a risk of TD? Is it
possible to define a maximum recommended number of
monthly doses of MT100 to avoid the risk of tardive
Question 3; do you believe that, based on
the existing data on medication-overuse headache,
there is evidence that a proportion of patients
prescribed MT100 will likely take a number of
monthly doses higher than recommended?
Question 4; all currently approved acute
treatments of migraine are indicated without
restriction regarding the presence of absence of
nausea at baseline. Given that patients may have
nausea at some attacks and no nausea at others,
does an indication limited to the subpopulation of
migraine patients with no nausea at baseline
represent a clinically meaningful and acceptable
The last question; if Pozen shows
prospectively in a new clinical study in migraine
patients with no nausea at baseline a significant
contribution of metoclopramide on sustained
headache pain relief of 5 to 10 percent with no
contribution at two hours and no contribution on
relapse rates or rescue-medication use in the two
to 24 hour period, would the demonstrated benefit
outweigh the risk related to TD? If not, what
additional data or desired primary outcome, or
desired effect on sustained relief, could provide
evidence of safety and efficacy?
Finally, I would like to thank the
following FDA colleagues who have contributed to
this presentation . Thank you for your attention.
DR. KIEBURTZ: Thank you. Same deal. If
there are some clarifying questions. Let me just
point out some things about the questions which Dr.
Bastings has presented. After the public hearing
this afternoon, that will be the time we have to
spend a great deal of time discussing these.
We can clarify points of these questions
at that time rather than at this time because it
will be immediate to our discussion.
I would just add at this point my approach
to this, or our approach to this, should be that
there are some assumptions made in here. We are
not debating whether those assumptions are good
ones or bad ones. The question to us is, if that
was assumed, how would you think. This is what Dr.
Katz referred to earlier in terms of this being
I think we could spend a lot
arguing about whether the assumptions are good ones
or not. I don't think that is the meat of the
matter here. If one assumed those things, then how
would you make decisions about that. I just want
to put that out there.
There are some questions that are asked of
us about estimates and whether those are
reasonable. But, again, much of the clarification
on the questions, I think it would be better to do
at the time we discuss the questions individually
unless you have a burning question about those.
Certainly, they are open to questions about the
rest of Dr. Bastings' presentation.
DR. GREEN: I have a regulatory question
about the Combination Policy. It has to do with
the contribution of each drug and what is
acceptable. Is one drug increasing the
bioavailability of another? How would that be
DR. KIEBURTZ: Dr. Katz or Dr. Bastings?
DR. KATZ: I think the contribution, as
defined in the reg--it is ill-defined in the reg.
It just says "some contribution." So it could be
in any one of a number of clinical areas, safety,
efficacy. But, in and of itself, increasing the
bioavailability probably wouldn't be particularly
helpful unless that resulted in some sort of
clinical advantage; faster onset, or more sustained
onset, or fewer side effects.
So, in and of itself, increasing the
bioavailability in a typical case, at least off the
top of my head, wouldn't be, necessarily,
DR. TEMPLE: But you can imagine cases,
and there have been cases, where inhibiting
metabolism might lead to a more sustained and less
variable blood level. In some sense, what does
carba dopa do? So there could be cases. But, as
Russ says, you would have to weigh the disadvantage
of adding another therapy and, if the alternative
is just tasking 20 percent more, you would probably
find that not worth it.
DR. KIEBURTZ: Okay.
Why don't we go on.
Our next speaker is Dr. Jinnah from Johns Hopkins
Overview of Tardive Dyskinesia
DR. JINNAH: Good morning.
Thanks for the invitation to come and
speak here. I have been asked to give a brief
summary of the clinical condition of tardive
Normally, my presentation on this topic
would be about an hour, but I am going to limit my
comments to ten minutes and, in so doing, I am only
going to be able to touch on the highlights. I am
going to skip a lot of details but I can certainly
answer questions later if necessary.
So, with that, let me just proceed to
review this topic. The term "dyskinesia" refers to
any abnormal movement and the term "tardive" refers
to late or delayed. What I would like to do is
first address the nature of the abnormal movements
and then go on to describe when it
The movements vary quite a bit depending
on different patients. By far the most common
abnormal tardive syndrome is the so-called
buccolingomasticatory syndrome, which is a bit of a
mouthful, but it basically refers to abnormal
movements of the face and tongue. I will show you
an example of this on videotape in just a second.
Less common tardive movement disorder
syndromes include the ones listed there including
tardive dystonia, which refers to mainly twisting
and bending movements, tardive chorea, which
resembles dancing, tardive tourettism which
resembles Tourette syndrome, tardive tremor or
myoclonus which, simply put, are shakes and jerks.
In addition to this group of broader
movement disorders, there are some tardive
syndromes that are not necessarily classified as
abnormal movements but, rather, psychological or
psychiatric manifestations. These include
akathisia, which is a sense of severe restlessness
that prevents people from sitting
includes unusual tardive pain syndromes which have
an unusual anatomical distribution that include the
oral or perineal regions, and, finally, respiratory
irregularities referred to as tardive respiratory
Now, most clinicians will recognize the
most common form here and that is the top one, the
face-and-tongue syndrome. But the less common
forms are far less well appreciated.
Let me show you an example of two of
these, first the most common one. This is a
videotape of a man who has two problems. I hope it
is not too small to see. If you can see his mouth,
it is in constant motion, jaw, lips and tongue. He
came complaining that he had trouble talking, he
had trouble eating and he was biting his tongue.
You can also see his hand. One of his
hands is shaking. He has a tremor that resembles
Parkinson's disease. This man got his condition
after two years of metoclopramide use. He was,
unfortunately, unaware that he was only
be taking the medication for three months and his
doctor was unaware that metoclopramide was on the
list of medications that can cause a tardive
syndrome like this.
Let me show you a second example of the
tardive dystonia. You can see this man's problem
is much more severe and, perhaps, more disabling.
This is an example of dystonia or the
bending-and-twisting syndrome. You can see that he
has great difficulty standing up straight because
of extreme arching of his back and backward bending
of his head and neck.
Here you will see a closer view of the
nature of this problem. He is like this more than
80 percent of his waking hours, standing or seated.
He gets relief only if he lies down. He can only
temporarily bring his head to the midline position
voluntarily and then it just goes back and it is
too much effort to keep straight.
This man got his condition from the use of
a classic neuroleptic agent which is a
source of this problem.
So what exactly causes these syndromes?
It is widely recognized that they are most commonly
caused by the neuroleptics. These are the
dopamine-receptor-blocking agents that Dr. Schapira
alluded to in the initial presentation.
Essentially all classes of neuroleptics will cause
this syndrome although some are less likely to
cause it than others.
These are widely recognized but what is
less well recognized is a much longer list of
agents that also have the potential to cause these
syndromes. On this list include anti-emetics such
as metoclopramide and prochlorperazine. Other
medications used in psychiatry such as
anti-depressants and several others of which I have
provided a partial list here.
So when do these problems actually arise?
They are referred to as tardive syndromes because
they usually require chronic
administration of the
offending drugs. They occur with a wide range of
prevalence according to different studies from less
than 5 percent to more than 50 percent with an
overall average being somewhere in the 20 percent
range of chronically treated patients.
These numbers here were not derived
specifically from metoclopramide use but rather
from all neuroleptics and other drugs capable of
causing tardive syndromes. The incidence is
estimated to be about 5 percent per year during
chronic daily treatment. The treatment duration is
somewhat arguable and varies from report to report
and definition to definition. The most
conservative one is that treatment requires at
least three months of constant therapy.
But, as noted before, there are lots of
cases out there who have developed tardive
syndromes with much shorter durations of action,
sometimes just a few days. We can then ask whether
or not these disorders should be classified as
tardive syndromes or not, but that is generally not
done in most of the epidemiological
There are some known risk factors of
developing this condition. They include older age,
female gender and several other less
well-understood phenomena such as duration of
treatment, the total cumulative dose of treatment,
prior brain injury or other organic problems,
diabetes, mood disorders and others.
How are these treated once they arise? In
general, these recommendations come from psychiatry
where this problem is most prevalent. They refer
to all neuroleptics, not specifically to
metoclopramide. Generally speaking, the
recommendation is to attempt to discontinue the
offending agent if possible.
If it is not possible, or if
discontinuation does not cause resolution of the
syndrome, as it often does not, there are several
other things that are often tried, but there is
very little evidence supporting a beneficial effect
of any of these. Individual patients may respond
somewhat to one or another of the items on this
list, but, by no means, can these be considered
Instead, at least in the psychiatry
literature, the belief for the use of neuroleptics
and related offending medications that can cause
tardive syndromes is that prevention should be one
of the key aspects of treatment.
To prevent the disorder, the general
guidelines are that the neuroleptics should not be
used unless there are no other alternatives. When
they are used, they should be used at the lowest
dose possible. Some even recommend intermittent
withdrawal of the neuroleptic to make sure that
ongoing therapy is still needed. Since this
disorder is quite difficult to treat, prevention is
really quite an important element.
I believe that is all I have here and if
there are any questions, I could take them.
DR. KIEBURTZ: Dr. Jeste.
DR. JESTE: One question. Did you imply
that antidepressants and antibiotics
DR. JINNAH: Causation is difficult to
establish. If you look in the literature, you will
find many cases of tardive dyskinesia reported that
are due to a whole variety of different
medications. The frequency of some of these other
medications--for example, antidepressants or
antibiotics, or I should say the frequency of the
reports, is quite low. We could argue whether or
not the patients who were presented in those
reports really were tardive dyskinesia or not.
I am not passing judgement on the
diagnosis of those. But I think it is generally
well-accepted that tardive dyskinesia does not just
come from neuroleptic medications and that was my
DR. JUNG: Can you clarify what mood
disorders are associated with the development of
DR. JINNAH: There appears to be a slight
epidemiological risk associated with affective and
schizo-affective disorders as opposed
DR. JUNG: So that includes just general
depression which is very prevalent in the
DR. JINNAH: It does.
DR. JUNG: Thank you.
DR. SMITH: When a case comes up where
isn't chronic exposure to a drug, is that typically
categorized, then, as a dyskinesia as opposed to a
DR. JINNAH: It is a very good question.
I think different experts would answer you
differently here. Some people use a very strict
criteria that it has to be at least 30 days or you
call it something else, dyskinesia and acute
abnormal syndrome. Some people are a little bit
less strict in their criteria and say, well, if it
looks and behaves like tardive dyskinesia, then,
perhaps, one week exposure is sufficient. But these
are not generally agreed-upon timetables.
DR. JUNG: You didn't talk about this on
your slides, but could you discuss a
about the kindling phenomenon with intermittent
use, or is this an appropriate time?
DR. KIEBURTZ: Can we hold that one for
the general question session.
DR. SACCO: On Slide 3, I think it is
Slide 3 of yours, can you clarify what you mean
by--it is actually blurred on my
DR. JINNAH: Restlessness is exactly what
that sounds like. These patients report that they
can't sit still. When you watch them, they often
rock in their chair. They stand up. They pace
around. They just can't sit still and they
describe a severe inner sense of restlessness.
DR. SACCO: Thank you.
DR. KIEBURTZ: Just a point of
clarification, a follow up on Dr. Jeste's comment.
Linking exposure to a phenomenon or establishing
causation is a long road. There are various
degrees of that road being established for various
agents in tardive dyskinesia.
But, if I understood you properly, would
you say that it is generally accepted that
metoclopramide, as an agent, can cause tardive
DR. JINNAH: I believe most would agree
DR. KIEBURTZ: Thanks.
Our next speaker is Mary Ross Southworth.
Post-Marketing Review of Movement
Disorders and Neuroleptic Syndrome
Associated with Metoclopramide
DR. SOUTHWORTH: Good morning.
(Slides 1 and 2)
As we have heard this morning, MT100 is a
combination of metoclopramide and naproxen that is
being evaluated for the treatment of acute
migraine. The proposed dosing is an a chronic but
intermittent matter based on episodes of migraine.
The proposed dosing of the drug recommends no more
than six tablets be used per month and more than
one tablet used per single migraine episode.
We were interested in looking
chronic intermittent dosing, whether we could look
in our adverse-event database to see whether we
could elucidate the risks associated with this kind
I think we are pretty clear on the fact
that metoclopramide is well known to cause movement
disorders. In fact, the program labeling is
specific on several movement disorders including
extrapyramidal symptoms, Parkinsonian symptoms,
tardive dyskinesia and neuroleptic malignant
syndrome. The labeling for metoclopramide
recommends a daily dose of 5 to 20 milligrams QID
with a duration of therapy not exceeded 12 weeks.
This slide shows number of prescriptions
dispensed for metoclopramide over about the last
ten years. You can see that it exceeds 7 million
in the year 2004. This jump in number of
prescriptions dispensed in 2000 coincides with the
withdrawal of cisipride from the market.
You have to keep in mind that
represented here are prescriptions dispensed, not
patients. Also keep in mind that, although this
usage data slide only extends for ten years, my
adverse-event review will extend farther than that.
When developing our case series for
metoclopramide-associated movement disorders and
neuroleptic malignant syndrome, we wanted to focus
on several points. First, could we ascertain what
the reversibility of the reaction was, whether it
be treatment with another pharmacologic agent or
withdrawal of the offending drug.
We also were very interested in
associating the dose and duration reported in the
adverse-event reports, themselves, to the proposed
dosing for MT100 which, as you have heard, is in a
chronic intermittent manner. We also wanted to
focus on any associated risk factors that were
apparent in the cases such as concomitant drugs or
concomitant disease states that the patients might
So the purpose of our review is to
characterize the cases of some specific adverse
events that were reported in the adverse-event
reporting system, or the AERS database, that were
associated with metoclopramide.
The AERS database is a computerized
database which contains reports of adverse events
for all U.S. marketed drugs. It contains over 3
million adverse-event reports. The reporting in it
is largely spontaneous meaning that healthcare
providers are not compelled to report adverse
events. However, sponsors, when they become aware
of adverse events through a variety of sources, are
required by regulations to report those to the
Consequently, the source of the reports,
for the most part, come from sponsors. However,
there are a good number that come from healthcare
providers or lay people like consumers, patients,
patient's families or lawyers.
The left side of the screen shows the
adverse events that were specifically searched for
in our database. They included neuroleptic
malignant syndrome, acute dystonia, akathisia,
Parkinsonism and tardive dyskinesia. For each of
these adverse events, we looked at the total number
of case reports with specific focus given to daily
dose of metoclopramide, the duration of treatment,
any risk factors that might be present and the
reversibility of the reaction.
In order to do this, we ran a search of
the database using each of the movement disorders
and NMS as a search term plus metoclopramide. We
classified the cases into movement-disorder
categories based on the diagnosis in the case,
itself. I think it is pretty clear that there is
substantial overlap between some of the reporting
of the different movement disorders and, in order
to keep clarity, we just used the diagnosis that
was used of the case thinking we could capture the
most number of cases that way.
Some points to remember when reviewing our
case series were there could be what could be
considered case misclassification because some
cases might have reported a movement disorder after
several doses of drug but may have caused the
tardive dyskinesia where it could have possibly
been called an acute dystonia. But we used the
diagnosis made in the case.
Another thing to remember is that the way
cases are reported in AERS, we frequently know
dose, duration or frequency of the dose given but
we very rarely know whether the dose was given
continuously or intermittently.
Obviously, because these are labeled
adverse reactions, there is going to be
under-reporting of adverse events and also because
the drug has been on the market for a long time, we
are not going to get a maximum number of reports of
The quality of the reports varied, as you
might expect. There are several data points that
seem to be more inconsistent and some of
included status of recovery. Some cases may not
have reported whether the patient recovered or not,
and also time to that recovery.
This slide shows the number of reports we
retrieved for each of the adverse events we
searched for. There were 37 cases of NMS, 203
cases of acute dystonia, 57 cases of akathisia, 35
cases of Parkinson's and 68 of tardive dyskinesia.
Using those reports, we developed our case
series which I will present to you. The case
series is going to include demographics of the
patients and clinical characteristics including any
information we have on recovery. I am also going
to spend some time talking about cases that
reported continuing symptoms at the time of
reporting. I will present some representative
cases and then focus a little bit on cases
associated with short-term metoclopramide therapy.
The first adverse event that
presented is neuroleptic malignant syndrome. We
had 37 unique cases. The age represented was a
mean of 49. The range of daily dose ranged from
7.5 to 80 milligrams with a mean of 33, mostly I.V.
dosing represented here and mostly G.I.-related
indications which will be very common in the next
few slides. The range of duration of therapy was
from 1 to 196 days with a median of three days.
In these 37 cases, concomitant medications
that were associated with the development of NMS or
NMS-like symptoms was reported in 20 and they
included anti-depressants, anti-emetics and
One thing to remember is that not all
cases reported whether there were concomitant
medications or not, so I have just provided
information on the cases that have.
Drug therapy was used to treat the adverse
event in 18 cases and it largely consisted of what
would be considered standard of care for
neuroleptic malignant syndrome. The symptoms were
reported or resolved in 11 of the cases. The
symptom was reported as continuing in one of the
NMS cases but the symptom that was reported as
continuing was more of a dystonic jaw clenching.
In this series, eight patients died.
To look a little bit closer to the
patients that died, in those eight patients, the
daily dose of metoclopramide ranged from 10 to 40
milligrams with a mean of 32, kind of a mix of oral
and I.V. dosing used, and the duration of therapy
was short and ranged from two days to 15 days.
The first movement disorder, in our view,
is acute dystonia. There were 203 unique cases.
Acute dystonia was reported in a younger population
with a mean age of 32. The range of daily dose was
0.6 to 800 milligrams with a mean of 71 milligrams.
Largely oral dosing reported here. The range of
therapy from one dose to over 2000 days but a short
median duration of therapy of two days.
Again, you see mostly G.I.
treated here although there were a sizeable number
who were getting pre-treatment for chemotherapy
For these 203 acute dystonia cases, there
were 64 cases which reported concomitant
medications that were associated with movement
disorders, mostly anti-depressants and
anti-emetics. Drug therapy was used to treat the
adverse event in 115 cases. For these acute
dystonia cases, 115 cases reported the symptoms as
improved or resolved. But symptoms were reported
as continuing in 12 cases.
In those 12 cases which reported
continuing symptoms, the daily dose ranged from 10
to 40 milligrams with a mean of 25, mostly oral
dosing, and duration of therapy ranged from one day
to over 2000 days with a median of 2.5 days.
We have 57 unique cases of akathisia. The
mean age seen in this case series was
daily dose ranged from 5 to 200 milligrams with a
mean of 42, mostly oral dosing again. Duration of
therapy ranged from one over 2500 days with a
median duration of 17 days. Again, mostly G.I.
For these 57 cases akathisia, concomitant
medications associated with movement disorders was
reported in 23. Drug therapy was used to treat
akathisia in 29 cases. Symptoms were reported as
improved or resolved in 31 cases but symptoms were
reported as continuing in nine cases.
In the nine cases that reported continuing
symptoms, the daily dose ranged from 8.6 to 40
milligrams with a mean of 25 milligrams, mostly
oral dosing. Duration of therapy ranged from 17 to
over 2500 days with a median duration of 119 days.
We reviewed 35 unique cases of
Parkinson's. This was in an older population with
a mean age of 60. Daily dose ranged from 10 to 80
milligrams with a mean dose of 36 milligrams per
day, mostly oral dosing. The duration of therapy
ranged from one to over 1400 days with a median of
In these 35 cases of Parkinson's, there
were 13 cases which reported concomitant
medications that were associated with movement
disorders. Drug therapy was used to treat the
adverse event in 18 cases.
Symptoms were reported as improved or
resolved in 15 of the cases but symptoms were
reported as continuing in eight cases.
In those eight cases that reported
continuing symptoms of Parkinson's, the daily dose
ranged from 20 to 40 milligrams with a mean of 32,
mostly oral dosing, and the duration of therapy
ranged from one day to 203 days with a median
duration of 81.
There were 67 cases of tardive
The mean age was 57. The daily dose ranged from 5
to 80 milligrams with a mean of 35, mostly oral
dosing again. Duration of therapy ranged from one
to over 4700 days with a median of 180 days, again
G.I. indications for the metoclopramide.
25 cases reported that the patient was
taking concomitant medications associated with
movement disorders and drug therapy was used to
treat the adverse event in 19 cases. In 12 of
these cases, symptoms were reported as improved or
resolved. In 20 cases, symptoms were reported as
In those 20 cases with continuing
symptoms, the daily dose ranged from 5 to 80
milligrams with a mean of 53, mostly oral dosing
and a duration of therapy from one to over 4700
days with a median of 165 days.
After we developed our case series, we
wanted to look at a more focused group
cases to see if we could approximate the dosing
seen in the MT100. So we looked at two further
subgroups of our case series. One, we looked at
characteristics of cases that specifically reported
symptoms as continuing at the time of reporting.
Then we also looked at cases with the diagnosis of
tardive dyskinesia that were related to short-term
There were 50 cases out of 400, over 400,
that reported continuing symptoms. They were
represented by eight Parkinson's, 20 tardives, nine
akathisias, 12 acute dystonias and one NMS which
was actually likely a dystonic reaction. A little
over half of the cases with continuing symptoms
reported a duration of therapy of greater than 30
So 15 cases in our series reported
continuing symptoms with a duration of therapy of
less than 31 days. Eight of those cases reported
continuing symptoms with a duration of
less than three days, what we would call very short
durations of therapy. That included one
Parkinsonism case, two tardive cases, four acute
dystonias and one NMS. Most of those eight cases
occurred after at least three doses of
I have a few representative cases to
describe to you. The first one is a 49-year-old
female who received two doses of metoclopramide, 20
milligrams orally, over two days for treatment of
gastric reflux. Concomitant therapy included
cimetidine. On Day 2 of therapy, she developed
dystonic reactions consisting of torticollis and
trismus. Her dystonic reaction was reversed by
diphenhydramine. However, she subsequently
complained of left-sided weakness and temporary
loosing of the teeth.
The second case is a 34-year-old female
with nausea who received metoclopramide, 10
milligrams, orally three times a day for
doses and experienced difficulty breathing,
extremity shaking, head and neck jerking back. She
went to the E.D. where she was treated with
benztropine, after which she started to relax.
However, symptoms still occurred. She was
subsequently treated with lorazepam and paroxetine
which did not completely relieve the symptoms. She
was seen in the E.C. and by neurologists several
times for reactions milder than the first reaction.
Approximately three months later, she still suffers
from head pain, dizziness, tingling, pressure,
fatigue, agitation, involuntary shaking, muscle
spasm and neck pain among other symptoms.
The third case, a 27-year-old male
received three doses of metoclopramide, 10
milligrams orally, over two days for diabetic
gastroparesis. He experienced a dystonic reaction
with psychotic tendencies, agitation and agitation
with suicidal tendencies on the second day of
He was treated in the E.D.
diphenhydramine and lorazepam. Once discharged, he
continued to have symptoms of inability to
concentrate, slowed mental processing, difficulty
focusing, eye strain, vertigo, loss of equilibrium,
fatigue, dizziness and hallucinations.
The second subgroup analysis of our case
series that we did looked at specific cases with
the diagnosis of tardive dyskinesia that were
associated with short-term therapy of
metoclopramide of less than 30 days. What we were
trying to look at here was trying to approximate
what kind of dosing regimen would be seen with
chronic overusers of migraine therapy because there
is a certain population of migrainers who might use
this drug prophylactically in a manner similar to
other migraine therapies.
We chose tardive dyskinesia as our adverse
event because the diagnosis of tardive dyskinesia
infers a long-term or permanent adverse event. We
also noted that about 25 percent of our cases had a
duration of therapy of less than 30
You have seen this slide before, but you
can see that this is the distribution of our cases
based on the duration of therapy of metoclopramide.
The large number are reported with durations of
therapy of less than 90 days, but there is a
significant number with durations of therapy of
less than 30. Actually, there are 15 such cases of
tardive dyskinesia with a duration of therapy of
less than 31 days.
Of these 15 cases, the status of recovery
was not reported in nine of them. Symptoms were
reported as resolved in one case but continuing
symptoms were reported in five of these cases.
Some of the characteristics of these cases include
two out of the five cases reported symptoms as
continuing but improved. Two out of the five cases
reported I.V. dosing and four out of five cases
reported daily doses of 40 milligrams.
The important thing to remember is, again,
we are not really able to discern, because of the
AERS data, whether this was chronic
use of metoclopramide or chronic continuous use of
metoclopramide in these cases.
In fact, we found no cases in AERS that
specifically linked intermittent use of
metoclopramide with any movement disorders. There
are maybe several reasons for this. First, and
probably most likely, is that AERS--the way data is
reported in AERS does not make the distinction
about intermittent dosing so it just wasn't clearly
described in the report.
It could be that intermittent dosing is
not commonly used or the adverse events seen with
intermittent dose are not commonly reported or that
there may be few movement-disorder-related adverse
events with intermittent dosing.
So, in conclusion, most of the reports
that we saw with continuing symptoms of the adverse
event involved long-term therapy of greater than 30
days with the caveat, again, that we didn't know
whether it was intermittent or
There were eight cases which reported
continuing symptoms with very short-term therapy.
There were five cases of tardive dyskinesia that
were associated with therapy of less than 30 days.
Concomitant medications associated with movement
disorders were frequently present in the cases and
there were two out of eight deaths from neuroleptic
malignancy syndrome that occurred after less than
three days of therapy.
DR. KIEBURTZ: Thank you.
Questions or clarifications for our last
DR. KIEBURTZ: Dr. Jeste.
DR. JESTE: In these cases of acute
dystonia and neuroleptic malignant syndrome, some
of the patients have some concomitant therapy as
shown, in these cases, the side effects occur after
DR. MATCHAR: Right; they were temporarily
associated with metoclopramide. Yes.
DR. KIEBURTZ: Dr. Porter.
DR. PORTER: Metoclopramide is not widely
used in the U.S. You didn't spend a lot of time on
the primary diagnosis. I presume that you found no
migraine-related movement disorders in this search.
DR. MATCHAR: There were very, very few
cases that reported adverse events related to
migraine. As you saw from the indications, they
were mostly G.I.-related indications.
DR. KIEBURTZ: Dr. Welch.
DR. WELCH: Were there any different
characteristics of the patients who had the T.D.
after the short-term as opposed to the long-term?
It is almost like a biphasic population response
DR. MATCHAR: No; it was a very
heterogeneous population. There were different
presentations, different durations of therapy, so I
am not really sure whether you could say those that
experienced it earlier had similar characteristics
than those that presented after 90 days of therapy.
DR. KIEBURTZ: Dr. Katz.
DR. KATZ: Just one point of clarification
which I think is true. Maybe you said it and I
missed it, but, obviously, we focused on the
patients with continuing symptoms, at least in
part. As a general matter, I think, for these
reports, and correct me if I am wrong, what we
don't have which would be nice to have in terms of
information about those cases is sort of the
latency between the onset of the event, the
movement disorder, and the time of the report.
So it could be that an event happened on
Day 1 and the report is made on Day 2, in which
case, it might be continuing. But if the report
had been made on Day 47, after the drug had been
discontinued, for example, it might be that they
were discontinued. So I think, as a general
matter, we don't know this duration of continuation
of symptoms because we don't know the link between
when the event happened or stopped and the time of
There were a few cases, I think, where we
do have that but I think, in many cases,
DR. MATCHAR: Right.
DR. KIEBURTZ: Dr. Hughes.
DR. HUGHES: You mentioned under-reporting
in the AERS database, a well-known problem. But
when you have an adverse event which is labeled,
what sort of characterizes the types of adverse
events that might then be reported? We are looking
at a very peculiar set here.
DR. MATCHAR: Probably. There were a lot
of reports from lawyers. I mean, that is one.
Looking at other case series that I have done, it
seemed like there were a lot of reports from
lawyers. But we looked at, actually, quarters of
years, the reports, and there really didn't seem to
be any change, like an increase in reporting after
cisipride came off. It seemed to be fairly steady
so I am not sure that I could say that there was
one specific thing.
DR. KIEBURTZ: Good. Thank you.
Questions from the Committee to the Sponsor and FDA
Now, we have time to ask questions of the
presenters without me suppressing you
about them to
be about clarifications. We have about an hour to
do that. I suggest we start principally with
questions to the sponsor and immediately with those
individuals who I suppressed.
I recall stopping Dr. Goldstein when you
were asking Dr. Schapira a question about the U.K.
reporting database, I believe, and Dr. Lenaerts, I
stopped you in the middle of a question, too, but I
can't remember the context.
DR. LENAERTS: It was in the same context.
DR. KIEBURTZ: Dr. Goldstein, would
you--and you can draw anyone from the sponsor or
from the FDA if you would like to them to repeat or
present material again.
DR. GOLDSTEIN: I guess what I was
actually asking for was clarification about the
validity and accuracy and reporting rates in the
U.K. system, especially now as contrasted to the
last presentation we had from data here in the
United States which is a similar sort of reporting
system, but the numbers seem to be quite different.
DR. SCHAPIRA: Thank you.
reporting system to the Committee of the Safety of
Medicines, the so-called yellow-card system, is a
system by which physicians send in to the CSM
documentation of an adverse event. So it is
physician-led. It is not spontaneous in terms of
including patients. But it is spontaneous in the
sense that physicians have to send in the yellow
Those that do send in yellow cards often
get a response back from the CSM asking for further
clarification if all the relevant information is
not included in the original yellow form that they
As for a proportion of reporting to all
potential cases, of course, I can't comment on
that. I don't know the data. Obviously, that is
not possible to obtain.
DR. GOLDSTEIN: The second part of that
question--it was sort of a two-parter--was, in
terms of validating the conditions that are being
reported, we have this clear problem with
categorizing a lot of these movement
There is this point of definition about how much
exposure is enough exposure to be categorized as a
given type of condition. Are these validated in
any way, or is it just based on individual
DR. SCHAPIRA: It is predominantly based
on physician reporting.
DR. KIEBURTZ: It sounds analogous to what
we heard from Dr. Southworth. Dr. Bastings.
DR. BASTINGS: I have a comment regarding
the U.K. reporting system. We have a fair idea of
the incidence of acute dystonic reactions with
metoclopramide. In the Pozen study, it was 0.05
percent. I find it surprising to see that only 26
cases were reported with migraine product, if you
consider the exposure, to have so few cases and it
suggests that there was a vast under-reporting of
these adverse reactions.
Do you have any comment on that?
DR. SCHAPIRA: This, remember, was the
number of reported cases with migraine preparations
as opposed to those with all
preparations. Do you have the slide number from
which that is taken?
DR. BASTINGS: Yes; it is Slide 31, CC-31.
DR. SCHAPIRA: Just looking at all
metoclopramide preparations, that is to say the
non-migraine ones, there were 478 of those. I
don't know how that compares to the U.S. data.
DR. SOUTHWORTH: There were 203 unique
DR. SCHAPIRA: In the U.S. data.
DR. SOUTHWORTH: Over about the early
'80's to present.
DR. SCHAPIRA: So this is actually twice
the number here in the U.K.
DR. KIEBURTZ: Over a longer period.
DR. SCHAPIRA: Over a period of 64 to 45.
So this is 40 years and the U.S. data was over 35
years, I think. Is that right?
DR. SOUTHWORTH: The earliest reports we
have are from the early '80's.
DR. SCHAPIRA: So about 25 years.
DR. KATZ: I think the point is that we
have a good--an estimate, anyway, from the Pozen
control trials of a particular adverse event
associated with the acute use of the product. It
is 0.05 percent or maybe it is 0.1 percent,
depending--we have seen those numbers vary.
DR. SCHAPIRA: Yes.
DR. KATZ: But, when you look at, for
example, over the 40-year period in the U.K., and
if you look at dystonia with episodic use of the
combination products, which are the migraine
products, there are 26 reports. So I don't know
what the percentage of use that is, but it is
probably less than 0.1 percent.
I think that is the point from the
controlled trials, which are the best way to get an
estimate of these events, you see some finite risk.
It is relatively low but finite that the reporting
rate seems to be, perhaps, orders of magnitudes
less than that, the point being that
under-reporting may be a sizeable--there may be
sizeable under-reporting for these events which are
known to be associated with these
DR. SCHAPIRA: Yes; I agree entirely. It
was just the comparison between the U.S. and the
U.K. reporting system. It seems that there isn't a
difference between them here.
DR. KIEBURTZ: Dr. Hughes, did you have a
DR. HUGHES: A related question. I think
you mentioned there were no cases of tardive
dyskinesia amongst the combination users. I think
you mentioned something like 100 million doses had
been prescribed. That was an estimate.
DR. SCHAPIRA: That was an estimate.
DR. HUGHES: But 24 cases amongst those on
DR. SCHAPIRA: Yes.
DR. HUGHES: Do you have an idea of how
many doses have been prescribed for chronic use? I
am trying to get some sense of--
DR. SCHAPIRA: Right. Of course, I am
going to have to speculate on this, but the
proportion of use of metoclopramide in the U.K. for
migraine as a precaution for all of its
is about 20 to 25 percent of metoclopramide
prescriptions are for migraine, approximately. So
I suppose that one could extrapolate from that.
DR. KIEBURTZ: Dr. Temple.
DR. TEMPLE: Just a comment on reporting
rates and spontaneous reporting systems. We spend
endless hours and months agonizing about this. It
is very clear the rates are different for different
kinds of reactions. There is something called the
Weber curve that was derived mostly from British
data that says reports of any given reaction
decline after the first three years because people
all know about it. It is in the label.
You can easily imagine that people
wouldn't report very much of something like a
dystonic reaction which everybody knows about. You
would hope that they would be more likely to report
TD because it is not as clear that everybody knows
about it. But there is just no way to know these
things and it is a constant source of difficulty.
The other thing that is going on, in the
United States, in the '80s, there were
reports to us a year. You probably have the
number. We are now up over 400,000 a year. So we
have a belief that reporting of all things is going
up. It is very impossible to reach conclusions
that are valid, however.
DR. KIEBURTZ: Dr. Jung.
DR. JUNG: I will pass.
DR. KIEBURTZ: Dr. Fahn.
DR. FAHN: Regarding Slide 31 and then 22,
where there is no tardive dyskinesia being
reported, Slide 22, the Bateman second article
there, the Bateman 1989, the second of the Bateman
articles, fortunately, and I must congratulate the
sponsor because we do have the reprints of these
articles so I was looking at that because that came
as a big surprise where there were zero TD cases.
But, actually, what this survey was is
that they wrote to the physicians who prescribed
the drug Maxolon for migraine--I assume it is all
for migraine--and got the responses back. But they
grouped the responses. They didn't list tardive
dyskinesia as one of the responses. They just said
dystonia-dyskinesias and they grouped all that
together. So they are listed here in your table as
12 dystonias. But a lot of them--and some of these
are older people. It is very likely that a lot of
these were persistent dyskinesias and not just
acute dystonic reactions or something that this
table may imply.
So I just wanted to say that, looking at
this, you can't really clearly say how many--there
was no zero TD cases. So that was one comment.
DR. SCHAPIRA: Yes; they classified
patients as dystonia-dyskinesia which, if you look
back at the first Bateman paper here, they also
used that classification and separated out from
tardive dyskinesia. So, in the first paper they
did, they did clearly separate dystonia-dyskinesia
and tardive dyskinesia. In the dystonia-dyskinesia
they noted that--I think the dyskinesia resolved
and made the comment--and this is with respect to
their paper in 1985--that this was more likely an
acute type reaction.
DR. FAHN: But the other thing on this
table, too, in the second Bateman article, they
have 46 other events. So, perhaps, within that,
there might be TD. That is what I am saying. From
this paper, you can't really say there was no TD
because they specifically failed to talk about TD.
That is the problem.
If I can also make a comment at this time.
The definitions of TD, that is another thing that
can confuse people. If you are going to use the
definition of TD that you have to be on the drug
for 30 days or more or three months, as some
definitions have used, I am not sure any
neurologist used that kind of definition. We
tended to look at tardive dyskinesia as persistent
The name tardive was given because it
wasn't seen until later on after the neuroleptic
drugs had been on the market for a while. That is
when tardive came on. But, with more experience
with this, recognizing what the syndromes are, we
sort of consider, now, tardive dyskinesia really
should have been properly named
dyskinesia, meaning that it lasts longer than 30
It doesn't matter how long they have been
on it for. They can be on it for one day and still
have persistent dyskinesia. To us, that is what we
now refer to as tardive dyskinesia. So we don't
give up the name tardive dyskinesia. We use the
definition differently than what was stated here.
I just wanted to make sure the concern I would
have, as a neurologist, who treats tardive
dyskinesia as meaning persistent dyskinesia, that
these can be irreversible.
When I heard the comment about how
devastating migraine is, and I agree it can
be--severe pains can be very bad for people,
devastating, but so can severe akathisia including
tardive akathisia, I consider that equally as bad.
If you ever induce this for a drug you might not
have needed, then that is a concern for us that we