DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH

PSYCHOPHARMACOLOGIC DRUGS
ADVISORY COMMITTEE

Monday, March 23, 2006

8:00 a.m.

Hilton Hotel
The Ballrooms
Gaithersburg, MD

PARTICIPANTS

Wayne K. Goodman, M.D., Chair
Cicely Reese, Pharm.D., Executive Secretary

COMMITTEE MEMBERS:

Jorge Armenteros, M.D.
Jean Bronstein, R.N., M.S.
Andrew C. Leon, M.D.
Daniel S. Pine, M.D.
Delbert Robinson, M.D.
Philip Wang, M.D., Dr.P.H.
Barbara Wells, Pharm.D.

TEMPORARY VOTING MEMBERS:

Michael Bigby, M.D.
Deborah Dokken, MPA
Richard Malone, M.D.
Cynthia Pfeffer, M.D.
Marsha Rappley, M.D.

NON-VOTING MEMBER:

Dilip Mehta, M.D., Ph.D.

FDA PARTICIPANTS:

Robert Temple, M.D.
Thomas P. Laughren, M.D.
Paul J. Andreason, M.D.
Glenn Mannheim, M.D.

3
C O N T E N T S
PAGE
Call to Order and Opening Remarks,
Wayne K. Goodman, M.D., Chair 5
Conflict of Interest Statement,
Cicely Reese, Pharm.D.,
Executive Secretary 8
FDA Introductory Remarks,

Thomas P. Laughren, M.D. 11
FDA Presentation:
FDA Clinical Review,

Glenn Mannheim, M.D. 16
Modafinil for Treatment of ADHD,

Paul J. Andreason, M.D. 37
Serious Adverse Cutaneous Reactions to Drugs,

Michael E. Bigby, M.D. 64
Sponsor Presentation:
Introduction,

Victor Raczkowski, M.D. 82
Overview of ADHD,
Joseph Biederman, M.D. 87
Clinical Pharmacology and Efficacy,
Lesley Russell, M.R.C.P. 103
General Safety,
Srdjan Stankovic, M.D. 121
Benefit-Risk Conclusions,
Lesley Russell, M.R.C.P. 163
Questions from the Committee to the
FDA and Sponsor 168

4
C O N T E N T S (Continued)
PAGE
Open Public Hearing 210
Committee Discussion 229
Questions to the Committee 257

P R O C E E D I N G S

Call to Order and Opening Remarks

DR. GOODMAN: We expect a few more people
to join us around the table but I want to make sure
that we start on time. Welcome, everyone, to the
Psychopharmacologic Drugs Advisory Committee, or
the PDAC. We have been asked today by the FDA to
advise them on a new drug application for modafinil
in the treatment of attention deficit hyperactivity
disorder, ADHD. Most of the questions, as will be
articulated by the FDA, concern safety issues.

Yesterday there was a meeting of the
Pediatric Advisory Committee which discussed a
range of safety issues concerning medications used
in the treatment of ADHD, the stimulants as well as
Strattera, and actually some data emerged on
modafinil as well during those discussions. I was
present as an observer during those meetings. I am
glad I was there. Some of the members of the
committee that are here today were also present
yesterday so I think a lot of heavy lifting was
done yesterday on some of these important side

effect issues that will help inform us in our
deliberations today.

My remarks are going to be unusually
brief, in part because my voice is strained. My
voice has not been cooperating for the last few
days. In fact, sometimes I am not sure it is my
voice--I don't know what kind of symptom that would
mean. But we have a backup plan. Danny Pine, when
he comes here, in case my voice fails, he will
become my voice.

I also want to put you on notice that
Cicely Reese may deliver at any moment! I am not
kidding! So, we have plans for her transportation
and replacement should that occur. Please bear
with us under these circumstances.

Now I would just like to go around the
table and ask everyone to introduce themselves.
Let's start from the FDA end.

DR. LAUGHREN: Tom Laughren, from the
Division of Psychiatry Products.

DR. ANDREASON: Paul Andreason, Division
of Psychiatry Products.

DR. MANNHEIM: Glenn Mannheim, Division of
Psychiatry Products.

DR. BIGBY: I am Michael Bigby,
dermatologist from Boston.

DR. RAPPLEY: Marsha Rappley,
Developmental Behavior Pediatrics, Michigan State
University.

DR. WANG: Phil Wang, psychiatrist and
epidemiologist from Harvard Medical School.

DR. REESE: Cicely Reese, executive
secretary.

DR. GOODMAN: Wayne Goodman, chair of this
committee as well as chair of the Department of
Psychiatry, University of Florida.

DR. LEON: I am Andrew Leon, professor of
biostatistics at Cornell Medical School.

DR. ROBINSON: I am Delbert Robinson. I
am a psychiatrist at the Zucker Hillside Hospital
and the Albert Einstein College of Medicine.

DR. PFEFFER: I am Cynthia Pfeffer, child
and adolescent psychiatrist at Weill Medical
College of Cornell University.

DR. ARMENTEROS: Jorge Armenteros, child
and adolescent psychiatrist in Miami, Florida.

DR. WELLS: Barbara Wells, I am dean of
the School of Pharmacy at the University of
Mississippi.

MS. DOKKEN: I am Deborah Dokken. I am
the patient family rep. on the Pediatric Advisory
Committee.

DR. MALONE: I am Richard Malone, a child
psychiatrist from Drexel University College of
Medicine.

DR. MEHTA: Dilip Mehta, retired physician
from the drug industry. I am the industry
representative on the committee.

DR. GOODMAN: Thank you all very much. I
think Daniel Pine will be joining us shortly. I
would now like to turn the microphone over to
Cicely Reese to go over some housekeeping,
particularly the conflict of interest statements.

Conflict of Interest Statement
DR. REESE: The following announcement
addresses the issue of conflict of interest and is

made part of the record to preclude even the
appearance of such at this meeting. Based on the
submitted agenda and all financial interests
reported by the committee's participants, it has
been determined that all interests in firms
regulated by the Center for Drug Evaluation and
Research present no potential for an appearance of
a conflict of interest at this meeting with the
following exceptions:

In accordance with 18 USC, Section
208(b)(30, Dr. Wayne Goodman has been granted a
full waiver for his employer's related contract
with a competitor, funded between $100,001 and
$300,000 per year. His employer also has related
contracts with another competitor, funded for less
than $100,001 per year.

Dr. Andrew Leon has been granted a waiver
under 21 USC, 355(n)(4) for his ownership of stock
in a competitor. This stock is valued from $5,001
to $25,000.

A copy of the waiver statements may be
obtained by submitting a written request to the

agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building.

We would also like to note that Dr. Dilip
Mehta has been invited to participate as an
industry representative, acting on behalf of
regulated industry. Dr. Mehta's role on this
committee is to represent industry interests in
general and not any one particular company. Dr.
Mehta is retired from Pfizer.

In the event that the discussions involve
any other products or firms not already on the
agenda for which the FDA participant has a
financial interest, the participants are aware of
the need to exclude themselves from such
involvement and their exclusion will be noted for
the record.

With respect to all other participants, we
ask in the interest of fairness that they address
any current or previous financial involvement with
any firms whose products they wish to comment upon.
Thank you.

DR. GOODMAN: Dr. Daniel Pine just joined

us so I wonder if you could introduce yourself.

DR. PINE: Danny Pine, Chief of
Developmental Studies, Mood and Anxiety Disorders
Program, National Institute of Mental Health
Intramural Research Program and I am a child and
adolescent psychiatrist.

DR. GOODMAN: In a moment I will turn over
the floor to Dr. Laughren who will give us the
introductory remarks. I think for all of us who
have read through these briefing materials one of
the issues that emerges, that didn't surface during
yesterday's discussions, are questions about
dermatological reactions. I see that we will also
have the benefit of an intensive review of those
issues as well to help us in our decision-making
today. So, Tom, would you please come forward?
Thank you.

FDA Introductory Remarks

DR. LAUGHREN: I would like to welcome
everyone to today's meeting. Before I introduce
the topics for today's meeting I would like to
acknowledge the service of one of your colleagues

on this committee whose term is ending in June, and
that colleague is Wayne Goodman. This has been a
particularly busy time for the committee, as you
know, and Wayne has, of course, been the chair of
the committee for much of this time. Serving on
this committee, again as all of you know, is a very
demanding and sometimes stressful task and I hope
that you all understand how much we appreciate the
help that you give us.

Now, Wayne told me after the September,
2004 meeting on antidepressants and suicidality in
pediatric patients that he didn't have any friends
anymore in the academic and clinical community. I
just want to assure him that he always has friends
here, at FDA.

[Laughter]

So, thank you, Wayne. This is a small
token of our appreciation.

DR. GOODMAN: Thank you very much. I used
to have a voice before I started this!

[Applause]

DR. LAUGHREN: Now, on to the topic for

today's meeting, we are going to focus on NDA
20-717, supplement 19. This is for modafinil in
the treatment of attention deficit hyperactivity
disorder. As you know, modafinil is marketed as
Provigil to improve wakefulness in adults with
excessive sleepiness associated with narcolepsy,
obstructive sleep apnea syndrome and shift work
sleep disorder. It is a Schedule IV drug and the
recommended dose in these disorders in adults is
200 mg.

Now, Cephalon has provided us data in
support of a claim for the safety and the
short-term effectiveness of modafinil in the
treatment of ADHD at a slightly higher dose, at a
dose of 340 mg per day in children less than 30 kg
and 425 mg per day in children greater than 30 kg.
This supplement was submitted in December of 2004
and, as you know, we issued an approvable letter in
October of last year.

Though we did issue an approvable letter,
the letter addressed three concerns that we wanted
to have further addressed. One of those was

serious skin rashes; a second was psychiatric
adverse events; and, finally, there were three
patients with transaminase elevations for which we
wanted additional data.

The sponsor responded to our approvable
letter, in November of last year, and today you
will hear from several FDA staff. You will hear
from the primary reviewer, Glenn Mannheim who, as
you know having seen his review, has recommended
against approving this drug based on his concerns
about rash and several other adverse events.

You will also hear from Dr. Paul Andreason
who will provide some additional comments on
safety. Our presentations are going to focus
entirely on the safety issues because we agree with
the company on efficacy. But you will hear from
the company on efficacy and, as well, you also have
our reviews.

In addition, we have obtained advice on
the dermatologic problems from our own internal
consultants from Dermatology. You have their
reviews, and Dr. Markham Luke, from the Dermatology

Division, is here to address any questions you
might have. In addition, we have Dr. Michael
Bigby, who is the chair of the Dermatology Advisory
Committee, who will be making a presentation on
serious drug-related rashes and he will be
participating in the discussion as well.

Now, I want to be clear that the Division
of Psychiatry Products has not reached a conclusion
yet about this application. We have these concerns
and that is precisely why we are coming to you to
ask for your advice. After you have heard the
findings and the arguments we are going to ask you
to vote on two questions. The first question is
focusing on efficacy questions, whether or not you
believe that the company has demonstrated that this
product is effective in the treatment of ADHD.
Secondly, we will ask you to vote on the question
of whether or not it has been shown to be
acceptably safe in the treatment of this disorder.

In addition, we are going to be asking for
your comments on several other issues related
mostly to rash. First of all, if the drug were to

be approved for this indication we would like your
advice on a risk management plan. We would like
your advice on labeling, particularly for rash.
Finally, we would like your advice on any
postmarketing studies that you think might be
useful to further clarify this problem. I think I
will stop there and Dr. Mannheim will be presenting
his findings. Thank you.

FDA Presentation

FDA Clinical Review

[Slide]

DR. MANNHEIM: As Dr. Laughren explained,
I reviewed the initial submission for modafinil for
this indication. I will review with you today the
information specific to safety.

[Slide]

Here is an outline of what I will be
covering. I will be reviewing a little bit of the
background and history of modafinil; an overview of
the safety database; common adverse events in
Cephalon's clinical trial; other adverse events of
significance; psychiatric adverse events; and, most

importantly, rashes and what I think the potential
public health impact may be. Then I will give you
some closing comments, and I will be followed by
Dr. Andreason.

[Slide]

In 1998 modafinil was approved as a
wakefulness-promoting agent in adults with
excessive daytime sleepiness associated with
narcolepsy. Additional indications were granted by
FDA in 2003 for excessive daytime sleepiness
associated with obstructive sleep apnea/hypopnea
syndrome and shift work sleep disorder.

The important thing that I would like you
to notice from this slide is the dose. The
recommended dosing was 200 mg once a day which,
based on a 65 kg adult, comes to about 2.67 or 2.7
mg/kg. I want you to remember those numbers since
we will come to it in other slides.
Recommendations were to give modafinil, Provigil,
as a single morning dose for narcolepsy or
obstructive sleep apnea or for shift work sleep
disorder one hour prior to the start of the work

shift. No additional benefit was shown for doses

more than 200 mg.

[Slide]

The current application is for use of
modafinil in children and adolescents with ADHD.
Two doses have been proposed by Cephalon. For
children less than 65 lbs or 30 kg, they would be
getting a single daily dose of 340 mg. For
children or adolescents more than 65 lbs or 30 kg,
they would be getting a dose of 425 mg a day.

Now, remember the number 2.6. For the
highest dose in children, on a milligram/kilogram
basis, the children would be getting 21 mg/kg or
about 8 times higher than the adult dose. For
those over 65 lbs or 30 kg the highest dose would
be 5.3 times higher than the adult dose. Cephalon
is recommending that children or adolescents start
the drug at initial doses of 85 mg and slowly
titrate up, based on tolerability, by incremental
steps of 85 mg to the targeted dose of 340 mg or
425 mg a day.

[Slide]

This shows the population which was
studied in the submission. It was children and
adolescents 6-17 years of age with DSM-IV ADHD who
attended a full-time school. These were moderately
to severely ill children. They had minimal
learning difficulties. As it relates to adverse
events, children with psychiatric comorbidities
were excluded. Stimulant non-responders were not
allowed in the trial. Those with abnormal
laboratory or medical conditions one month prior to
the start of the study were also excluded.

[Slide]

There are three studies which are called
the pivotal studies for this. Study 309 and 311
were 2 9-week, double-blind, flexible dose, weekly
titration studies. Study 310 was a 7-week,
double-blind, fixed dose study, followed by a
2-week randomized withdrawal to modafinil or
placebo. Children less than 65 lbs went on 340 mg
a day and those over 65 lbs went on 425 mg a day.

[Slide]

This slide shows the total number of

subjects and doses used in the Phase 3
double-blind, placebo-controlled trial. Of note,
420 subjects were treated with modafinil and 213
subjects were treated with placebo. The important
thing to note here is the numbers 102, 256 or 358.
Children and adolescents only received the proposed
labeled efficacious doses.

[Slide]

This slide comes from Cephalon's briefing
document which was submitted for your consideration
by Cephalon. It summarizes the pediatric trials.
The 420 comes from the Phase 3 double-blind
exposure. The number I want to show here is the
number 933 because this constitutes the core safety
database of this supplemental NDA. This slide
indicates that additional 303 children were exposed
to modafinil in an open-label ongoing Phase 3
trial. About 400 other children for obstructive
sleep apnea and narcolepsy are the legacy studies.

As far as the purposes of this submission,
we are only considering the number 933 since we
don't have an integrated safety database for the

other 689 children and they were not part of this
submission. It certainly would be reassuring if
there were no adverse events in these subjects but
we really don't know at this point.

[Slide]

This slide is a little busy and I
apologize for that. It shows exposure to modafinil
and modafinil metabolites and compares it with what
one sees in clinically used doses in adults with
those proposed for children. What I want to bring
your attention to is the exposure of the modafinil
sulfone as measured by the total exposure area
under the curve. In adults, with an initial dose
of 200 mg, the average area under the curve is 38
or close to 40. Going to the highest child,
receiving 425 mg, the area under the curve of the
sulfone is about 250. This is 6.5 times higher
than the exposure seen in adults. Going to the
lowest dose of children receiving 340 mg, the
average area under the curve is around 630. This
is 16 times higher than that seen in adults with
clinical dosing. This cannot be explained by

differences in dosing on a milligram/kilogram
basis. These are clinically used doses and with
them one sees that the sulfone metabolite is much
higher compared to adults.

[Slide]

Now we are going to look at the adverse
event data.

[Slide]

The incidence of common treatment-emergent
adverse events in the Phase 3 double-blind,
placebo-controlled trial is listed. Of note,
insomnia occurred in 27 percent of subjects on
modafinil and 4 percent of subjects on placebo.
Anorexia occurred in 16 percent of subjects on
modafinil and 3 percent of subjects on placebo.
Perhaps associated with that, there was weight loss
in 4 percent of subjects on modafinil and 1 percent
of subjects on placebo.

[Slide]

Notable psychiatric adverse events include
psychosis in 0.5 percent, as listed here, and
suicidal events in 6 subjects, 0.6 percent. The

suicidal events included 5 ideations; 1 attempt.
None were completed. Yesterday Dr. Mosholder
reported on a pooled analysis of the ADHD trials
and that suicidal behavior was infrequent among the
non-medicated ADHD placebo subjects.

[Slide]

Other clinically significant adverse
events which were noted in this trial consisted of
gastric or duodenal ulcers in 2 subjects. One case
of note was a child who was admitted to the
hospital with a moderate metabolic acidosis who had
an H. pylori infection.

There were 9 cases of syncope in the total
exposure. Of note is a child who, according to the
vignette information, had a 40-minute bradycardia,
hypotensive syncopal episode and one week later an
EKG was performed which showed AV dissociation with
adjunctional rhythm. There were 24 children who
were quoted as having asthma.

Of note is a subject in one of the pivotal
trials, 310, who, 8 days after being started on
modafinil at a dose of 340 mg collapsed at school

during gym, stopped breathing momentarily and was
given an inhaler and began breathing normally.
This was diagnosed as an acute asthma attack and
the child was discontinued from the study on day 9.

There were 3 subjects who had dehydration,
and of note is a subject in the open-label
continuation trial who, on day 147 of treatment,
was admitted to hospital with severe dehydration,
moderate ketoacidosis and hypoglycemia which was
found secondary to a strep. throat.

Sixteen subjects had laboratory evidence
of hepatocellular injury based on transaminases
being greater than 3 times the upper limit of
normal. Of note, there were no cases of jaundice
or liver failure, or no significant bilirubin
elevations.

[Slide]

Now I am going to talk to you about the
rashes but I am not a dermatologist and I am
relying on FDA's dermatologist, Dr. Porres who did
a consult, and someone from FDA from Dermatology is
here to answer some questions.

When you look at all the subjects who were
exposed, rashes were present in 5 percent of all
subjects compared to 4 percent that you saw in the
Phase 3 double-blind, placebo-controlled trial
versus 2 percent in placebo. Only 1 subject
dropped out in the double-blind, placebo-controlled
Phase 3 trial, which was an 8-week, study, because
of a rash.

When you look at all the studies,
including the open-label safety study, 101 subjects
dropped out because of an adverse event, of which
26 percent were noted to have a rash in their
vignettes although it may not have been coded as a
reason for discontinuation. In one-half of these
subjects, or 13 subjects, the rash was coded as a
primary reason for discontinuation. The rashes
varied in spectrum of severity. Eight with rash
also had fever; 2 with rash had elevated liver
function tests, one with a transaminase of 17 times
the upper limit of normal.

[Slide]

I am now going to discuss some of the

serious skin rashes, primarily the erythema
multiforme, Stevens-Johnson which, from my standing
as a pediatric neurologist are usually
hypersensitivity reactions to drugs. There were 2
rashes which were thought to be erythema
multiforme, Stevens-Johnson.

One subject had peeling and blistering
over the entire body, with lips and urinary tract
involvement, in study 311. The drug was stopped
but the rash progressed to involve peeling,
blistering, mucosal involvement over days. In
another subject in study 207 the drug was stopped
but the rash progressed. The child was
hospitalized.

Other rashes of note included a child in
study 207 with vesiculobullous cheeks with severe
lip blisters. In study 312 another subject had a
rash where there is no clear description but the
rash was obviously severe enough that he was
treated with systemic steroids, prednisone and
given Benadryl. The rash recurred when restarted
at 85 mg on day 34. There are two cases of

positive, you know, rechallenge.

[Slide]

Other skin reactions of note--there were
possible allergic events in about 22 of the
subjects out of the total exposure of 933 subjects,
at 2.4 percent. They included hives, urticaria;
facial edema; pruritus; allergic reactions; red
lips; eczema with increased LFTs. There were some
non-allergic events of alopecia, tongue blotches,
Herpes zoster, plantar warts and ringworm.

[Slide]

Now I would like to give some more details
about the index cases here. Case number one was a
young girl with an unremarkable medical history who
had attention deficit disorder. She was started
and then titrated over 2 weeks to a target dose of
either 340 mg or 425 mg a day, but it differs in 2
different vignettes. Two days later, on day 16,
the child developed a fever of almost 102, sore
throat, mild rash which was described as red bumps.
The next day the child was seen in the emergency
room. My understanding is they thought the child

had strep. throat and they gave one dose of
amoxicillin which was subsequently stopped. The
next day, day 18, the modafinil was stopped. Over
the next 4 days the rash worsened and progressed.
There were multiple pruritic areas over the arms
and stomach. On day 22 the rash progressed to
involve the face. On day 23 mucosal involvement
was said to be present in 2 areas. It burned when
the child urinated so there was involvement of the
urethra. The child had swollen and crusty lips.
At some time later--the exact course is uncertain
from the vignettes--there was extensive skin
peeling involving the palms and soles. No new
lesions were said to be present by day 30 and the
event was said to be resolved. By day 31 or day
26--it differs in 2 vignettes--the child was given
1 more dose of modafinil by the mother for unclear
reasons and the itching returned. On day 44 the
child was withdrawn from the study and the vignette
indicates the Stevens-Johnson syndrome resolved but
the erythema multiforme continued.

[Slide]

This case involves a young child with
inattentive deficit disorder who also had Turner's
syndrome and bed-wetting, who was on somatotropin
for the Turner syndrome for 7.5 years prior and
desmopressin for the bed-wetting for 4 months
prior. She was started, titrated on modafinil 200
mg a day for week 1 of the study and then 100 mg a
day for week 2 of the study. By day 4 she
developed fever, abdominal pain and diarrhea. This
lasted for 9 days. By day 14 the child was seen in
the emergency room for pruritic urticaria involving
the face and chest. The drug was stopped. The
child was treated with diphenhydramine. The rash
worsened by day 15. The child was then
hospitalized with a provisional diagnosis of
Stevens-Johnson. The child was seen by a
dermatologist who found no evidence of mucosal
involvement but was diagnosed as a moderate
morbilliform rash. The child was treated with
hydroxyzine. This rash resolved in 1 week. This
case was accepted by Cephalon as being compatible
with Stevens-Johnson syndrome.

[Slide]

Another subject of note is a young boy who
was started on modafinil at 400 mg a day for 2.5
weeks, and on day 14 developed fever and a moderate
rash on the cheeks. The rash progressed. By day
17 there was severe blistering on the lips. The
rash was described as vesiculobullous. On day 19
the modafinil was stopped. The time course of
everything else was not specified in the vignette
and no more information is available. The child
was treated with cephalexin for the rash and
Tylenol with codeine for fever and pain.

[Slide]

Dr. Porres, of the Division of Dermatology
at FDA, reviewed the 21 cases identified in my
initial review and the entire safety database of
this submission. He divided the cases into three
categories, definite cases representing erythema
multiforme, Stevens-Johnson. There are 2 subjects
there or 0.2 percent; subjects who had a history
consistent with early prodromal erythema multiforme
and Stevens-Johnson, there were 3 subjects, 0.32

percent; and then there were 7 additional subjects
who had a history suggestive of prodromal erythema
multiforme, Stevens-Johnson. So, 10 more subjects
plus the 2 subjects, or 12 subjects, so this is a
total of 1.25 percent of subjects with definite and
potential erythema multiforme, Stevens-Johnson.

[Slide]

When one looks at the postmarketing
experience with modafinil, there were 6 reports of
serious skin reactions. All occurred in adults 18
and over. There were 5 biopsy confirmed cases of
erythema multiforme, Stevens-Johnson. Four were
hospitalized and 1 died, but this case was really
confounded by other medications and medical
conditions. There was 1 dermatitis bullous.
Because of the under-reporting, the true number of
cases is probably likely to be greater. But the
take-home message that I would like to say is that
this slide shows that biopsy confirmed
Stevens-Johnson syndrome occurred in adults at
lower exposures than those received by children.

[Slide]

Erythema multiforme or Stevens-Johnson
syndrome is generally thought to be
hypersensitivity reactions to drugs.

[Slide]

One of the cases which was really
interesting involved a child who developed
urticaria, facial edema, fever and a 17-fold
elevation in transaminase between 10-14 days after
starting the drug. The child had a history of
allergy to sulfamethoxazole trimethoprim.
Sulfamethoxazole is a sulfonamide and is one of the
drugs known to cause Stevens-Johnson. It is
structurally similar to modafinil sulfone, which
raises the question of a possible cross-sensitivity
to the sulfone metabolite.

[Slide]

What is the potential public health impact
of these findings? Two recent estimates of the
background rate for erythema multiforme,
Stevens-Johnson was 1-2/million/ year. In this
submission there were 2 subjects with erythema
multiforme and 10 other possible cases of a

significant rash. The total range of risk is

anywhere between 0.2 percent to 1.3 percent.

[Slide]

A recent CDC study estimated that 2.5
million children, ages 4-17, were on ADHD
medication. Now, if we assume that only 10 percent
of these children will try modafinil at some point,
then we ask the next question, how many cases would
result.

[Slide]

We estimated that there would be a range
between 500 and 3,000 cases which will occur based
on the 0.2 percent to the 1.3 percent incidence
among the 10 percent who are switched to modafinil.
Based on the known mortality associated with
erythema multiforme, Stevens-Johnson, we would
expect from 15 to over 400 deaths to occur. We
conclude that even though a crude estimate can only
be made at this time, a potential exists for a
significant number of cases to occur post-approval
since ADHD is so prevalent.

[Slide]

The question is can one label for this?
Can we prevent this? Dr. Le Grenade and her
co-authors at FDA recently published a paper on
Stevens-Johnson syndrome and toxic epidermal
necrolysis in association with selective COX-2
inhibitors. I quote from her and I italicized
certain areas: There is no satisfactory method for
determining who is at greatest risk for developing
drug-associated Stevens-Johnson syndrome and toxic
epidermal necrolysis and hence of preventing it,
short of avoiding drugs altogether. There has been
a single study suggesting that early withdrawal of
the agent at the first sign of illness may improve
the outcome. Although this intuitively makes
sense, this study needs to be replicated. Even if
it is proven correct, its practical application
will be limited because it is very difficult to
identify the very earliest lesion in a timely
manner because of the rapidly progressive nature of
this illness and the non-specific features of its
prodrome.

In the cases observed with modafinil in

this submission in children no deaths occurred.
The rash progressed after the drug was stopped and
the children recovered. It may not be so next
time.

[Slide]

ADHD is a serious condition--I will give
you closing comments--it is a serious condition
which is usually not considered to be associated
with a fatal outcome. Exposure to a sulfone
metabolite is significantly greater, up to 16 times
more in children than in adults. This raises
questions about the relevancy of the adult safety
experiences to pediatric use.

[Slide]

The relationship of this metabolite to
rash is purely speculative but it has structural
similarities to drugs known to cause erythema
multiforme and Stevens-Johnson syndrome which can
be fatal.

The incidence of erythema multiforme,
Stevens-Johnson syndrome observed in these studies
is, at a minimum, hundreds of times the background.

The age ranges of the rashes appear skewed towards
subjects less than 12 years, those having a higher
sulfone exposure. Doses lower than 340 mg have
been shown to limit efficacy, hence, dose reduction
is not a reliable option.

[Slide]

Although some cases with rash got better,
there were 2 positive rechallenges and one case
progressed after discontinuing the drug. One
subject with rash was hospitalized but there was
disagreement about the diagnosis. One child with a
history of reactions to sulfa drugs developed a
hypersensitivity reaction with transaminase
elevation 17 times the upper limit of normal, with
urticaria, fever and facial edema 10 days after
starting modafinil, which raises the hypothesis of
cross-sensitivity with sulfa drugs.

[Slide]

Psychosis and suicidality, although not
standardly significant, were more frequent in
subjects on modafinil than with placebo. Insomnia
was present in 27 percent of subjects on modafinil

versus 4 percent in placebo, and anorexia occurred
in 16 percent of subjects on modafinil versus 3
percent on placebo in the double-blind, Phase 3
trials.

[Slide]

This review was very much a team effort of
my many colleagues at FDA, some of whom I am
blessed to call my friends. Thank you.

DR. GOODMAN: Before you step down, could
you review any cardiovascular effects, effects on
heart rate and blood pressure?

DR. MANNHEIM: Dr. Andreason is going to
do that.

Modafinil for the Treatment of ADHD

DR. ANDREASON: Good morning.

[Slide]

My name is Paul Andreason and I am the
Acting Deputy Director of the Division of
Psychiatry Products. I would like to talk to you
this morning about modafinil in the treatment of
ADHD.

[Slide]

Dr. Mannheim has outlined the concerns
that he has about modafinil in the treatment of
ADHD, and I think what we are faced with as we look
especially at the skin rashes is what I like to
call incongruity of data. I will get into that in
a little bit. I would also like to acknowledge the
Neurology Products Division where the drug
resides--it is kind of its home since it was
approved there first--and the safety team for
helping us out with the background rates for
Stevens-Johnson and looking at the adverse event
reports through the Adverse Event Reporting System
and their epidemiologic expertise.

Glenn did the primary review on the first
submission. June Cai helped out with the review of
the response to the approval letter. In the
Division of Dermatology, I would like to thank Joe
Porres and Markham Luke, who is here with us
today--Markham is here with us today. Joe took
another job and he is not with the Division of
Dermatology right now. Then, in the Division of
Drug Risk Evaluation, I would like to thank Andy

Mosholder and Kate Gelperin who, as part of their
presentation yesterday, did an analysis of the
psychiatric adverse events that are associated with
modafinil use.

[Slide]

Just as a quick review of how we workup
safety problems with drugs or safety profiles of
drugs, I should say, when we look at a drug we look
at deaths, serious adverse events, adverse
dropouts, potentially clinically significant labs,
ECG and vital signs and then we develop information
on comparative common and drug-related adverse
events, all these things from controlled trials.
We also do special searches, especially in this
case with modafinil and many psychiatric
drugs--well, all psychiatric drugs, for psychiatric
adverse events; in this case, for Stevens-Johnson
syndrome and neutropenia because these were things
that kind of popped up; and then the recent
interest in blood pressure, pulse and
cardiovascular adverse events. Then with the
response to the approvable letter we get a safety

update. In that safety update we focus on serious
adverse events and deaths, if they occur. We
develop our profile of the common and drug-related
adverse events from the controlled trial data, as
well as the comparative information on labs, ECGs
and vital signs.

[Slide]

Modafinil is a marketed product and we got
some information from Verispan about the exposure
to modafinil at this point. These are numbers not
in patient-years but in unique patients. At all
ages at this point between the years 2002 to 2005
there were 1,087,000, roughly 1,088,000 exposures
in all ages, and for children ages 0-17 there were
roughly 36,000 exposures.

I kind of want you to keep that in mind
because this is the first piece of what I would
call inconsistent data about rash. It is almost
unheard of to see cases of Stevens-Johnson syndrome
in controlled trial data and here we have at least
nominally 2 cases that have been identified as
such. At that kind of a rate you would expect to

see something in the adverse event reporting data.
Dr. Mannheim said, well, based on these numbers,
these would be the projected number of cases that
we would see after marketing. The piece of
incongruity here is that the drug is already
marketed. We have 36,000 exposures in the age
ranges that were studied, and in the 0-12 group
right around 11,000 and we have no AERS-reported
cases.

Now, one of the cases from the controlled
trial data actually is a duplicate case. It got
reported in AERS but there are no spontaneous
reported cases. So, given that kind of projection,
I would expect to see some cases reported in AERS
and we haven't seen that yet.

[Slide]

This is, again, a review of patient
exposure in the controlled trial database. In the
safety update we did get some information on
serious adverse events and dropouts, as well as
deaths, and Stevens-Johnson syndrome would be
considered in that group. So, as more and more

information comes in, you know, that denominator of
cases reported per amount of exposure changes,
however, even with 2 cases in 1,600 that would
still be a large number.

[Slide]

I think the problem that comes about when
we look at Stevens-Johnson--and we will hear more
from Dr. Bigby in a moment about how that
ascertainment is made--is that in these two cases
one was hospitalized and one was not. Neither of
them were in a burn unit or the ICU and we don't
have biopsy information on those kids.

[Slide]

These are tables that you have already
seen. It reviews the numbers of patients exposed
in the three pivotal trials.

[Slide]

Now, this is a table that shows you the
common adverse event profile. Our usual definition
of common and drug-related is adverse events that
occur at least 5 percent of the time and occur at a
rate that is twice placebo. In italics you will

see that anorexia and insomnia meet that criteria.
There are a couple of other adverse events that are
close but don't quite make that cutoff. This is
the table actually that is proposed in labeling and
is the usual kind of table that we have in
labeling.

[Slide]

Just as a quick overview of the safety
results from the controlled trials, there were no
deaths and, of the adverse events of note, there
were these 2 cases that were identified as either
Stevens-Johnson or erythema multiforme. There were
no new cases of leukopenia in the AERS system
update, and we could see no real signal for
leukopenia in the controlled trial data.

As far as psychiatric events, there were 4
suicide-related adverse events, no completed
suicides. I will talk more about those in a
moment. There were none in the placebo group.

As far as mean blood pressure changes,
modafinil actually showed a slight decrease
compared to placebo in mean blood pressure.

However, the numbers of patients that met the
outlier criteria of systolic blood pressure of
greater than 130 and an increase in greater than 20
mmHg were 9/420 for modafinil and 1/213. With
pulse there was no difference in the mean value
either, and the numbers for outliers are 6/420
versus 2/213. The 6 versus 2 in those 2 groups is,
in my opinion, not terribly different. There was
some weight loss, 0.7 kg weight loss with modafinil
versus 1.0 kg mean weight gain in the placebo
group.

So, did that answer your question about
blood pressure?

DR. GOODMAN: Yes.

DR. ANDREASON: Great!

[Slide]

As far as psychiatric adverse events, this
is drawn from one of Andy Mosholder's slides from
yesterday. These were the comparative numbers with
patient-year exposure, and these are real years.
They are not multiplied. So, with 33 patient-years
exposure in placebo you have no cases of mania or

psychosis or suicide-related adverse events. But
there were 5 cases of aggression, spontaneously
reported aggression. Zero cells are kind of tough
to deal with when you are doing statistical
analysis, but oftentimes you can use a Fisher's
exact test to get at least some idea of whether or
not something is statistically significant. I will
show you that for the suicide-related adverse
events on the next slide.

You will notice that numerically the cases
of aggression are slightly less with modafinil than
they are with placebo. As Dr. Mosholder stated
yesterday, that was not a significant difference
but it is not, by the same token, greater. In the
open-label data it shows that the rates are lower.
That doesn't necessarily mean--well, let me put it
this way, these are patients, once they reach
open-label, who have tolerated the drug and I think
that probably the best comparison for this is the
controlled trial data.

[Slide]

These are the results of the Fisher's

exact test for suicide-related adverse events. You
see here that you have the 4 cases in the modafinil
and that is compared to no suicide-related adverse
events in the 660 in placebo. So, that ends up
with a 2-tail value of p of 0.31 and 1-tailed p of

0.22.
[Slide]
Just to give you kind of a comparison

with, say, Strattera that has received labeling for
suicide-related adverse events, with Strattera
there were 6/1357 versus 0/851. Because of the
increased sample size, those numbers ended up being
statistically significant. There were 5 cases of
ideation and 1 attempt in the FDA defined cases. I
would like to note that Eli Lilly has slightly
different numbers because they had a slightly
different definition of the suicide-related adverse
events. They had 7 versus 1 out of 1357 and 851
respectively. That p value ended up being 0.07.
Traditionally, for safety-related topics we don't
necessarily use a p of 0.05 like we do for
efficacy. We use a p of 0.1. So, using a cutoff

of a p of 0.1, the 0.7 would still be statistically
significant. And, Strattera has a boxed warning.

Now, with the modafinil there are 4/664
versus 0/308. This is not statistically
significant by Fisher's exact and all were cases of
ideation and 3 of the cases actually resolved
without discontinuation of the drug. The sponsor
proposes warning language in labeling as opposed to
boxed language.

[Slide]

As far as the cases of severe rash that
are identified as Stevens-Johnson syndrome, we will
hear more about that, again, from Dr. Bigby, and
Dr. Markham Luke is here today to talk about the
cases individually if people have questions on
those.

The problem that we have with almost any
adverse event report ascertainment, there was no
histopathology with either of these cases. With
Stevens-Johnson syndrome admission to burn units
and ICUs is common. One of the kids was
hospitalized but not in an ICU or burn unit. The

other child was treated as an outpatient. You have
heard about the cases. I can go back to those if
anyone has any questions. Again, there were no
children in the postmarketing Adverse Event
Reporting System, other than the one case that is
the duplicate from the controlled trial.

There were 4 adults in the AERS
postmarketing database, and it turned out that 3
had confirmatory histopathology and the other one
was erythema multiforme without histopathology.
There were no adults with Stevens-Johnson
identified in the adult controlled trial database.

[Slide]

So, what we are left with from this
controlled trial database, along with the
open-label material that goes with it, is 2 serious
cases, one admitted to the hospital, neither to the
ICU or burn unit; none in the placebo group; 10
dropouts due to rash versus no dropouts due to rash
in the placebo group. Spontaneous adverse events
in the controlled trial, about 4 percent for
modafinil versus 1 percent for rash, for all kinds

of rash.

But then, the incongruity here is that
there are no other children with either
Stevens-Johnson syndrome in the postmarketing
adverse event database with about 36,000 kids
exposed. Again, with that kind of exposure and the
projected numbers of cases of SJS, based on 2/933
or even 2/1,600, one would expect to see more in
the Adverse Event Reporting System.

[Slide]

So, just to compare and contrast labeling
with Lamictal that carries a boxed warning for
Stevens-Johnson syndrome, in that boxed warning
there are some fairly hard numbers. For example,
they did a prospective registry study and there was
one death due to Stevens-Johnson syndrome with
Lamictal out of 1983 patients. There was also
information on rates in adults with different kinds
of diagnoses, for example, 8/1000 in children with
Lennox Gasteau and 3/1000 adults. Then in the
bipolar population it was 1.3/1000 adults on
adjunctive therapy for bipolar disorder. So, those

are some fairly hard numbers.

On the modafinil side, the sponsor
proposes warning language and I have listed under
here the points to compare and contrast with
Lamictal. There are no deaths reported. Actually,
on one of the slides that Dr. Mannheim presented,
he said there was one death. That case was a
fellow who came in to the hospital and had a
subarachnoid hemorrhage and was treated with
several drugs, one of which was phenytoin, known to
be associated with Stevens-Johnson syndrome. He
developed Stevens-Johnson syndrome as part of the
course of his hospitalization and apparently was
treated with modafinil prior to that
hospitalization. So, I think that case is terribly
confounded and I wouldn't count that as drug
related, or I don't think we could count that on