Psychiatric Adverse Events in Attention Deficit Hyperactivity Disorder (ADHD) Clinical Trials

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Psychiatric Adverse Events in Attention Deficit
Hyperactivity Disorder (ADHD) Clinical Trials

• Andrew D. Mosholder, M.D., M.P.H.
• FDA Division of Drug Risk Evaluation

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Topics

• Background on FDA analyses of neuropsychiatric
  adverse events with ADHD medications
• Clinical trial data on these events
• Literature review

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Drugs Currently Approved for ADHD
ACTIVE INGREDIENT
PRODUCT NAME
COMPANY
Date of Approval
Adderall Tablets Amphetamine Shire Pharmaceuticals, Inc. 1/19/1960 Re-established approval on 2/13/1996
Adderall XR Extended-Release Capsules Amphetamine Shire Pharmaceuticals, Inc. 10/11/2001
Concerta Extended-Release Tablets Methylphenidate McNeil Consumer and Specialty Pharmaceuticals 8/11/2000
Ritalin Tablets Methylphenidate Novartis Pharmaceuticals Corporation 12/5/1955
Ritalin LA Extended-Release Capsules Methylphenidate Novartis Pharmaceuticals Corporation 6/5/2002
Ritalin SR Sustained-Release Tablets Methylphenidate Novartis Pharmaceuticals Corporation 3/30/1982
Strattera Capsules Atomoxetine HCL Eli Lilly Company 11/26/2002
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Drugs Currently Approved for ADHD, continued
ACTIVE INGREDIENT
PRODUCT NAME
COMPANY
Date of Approval
Focalin Tablets Dexmethylphenidate Novartis Pharmaceuticals Corporation 11/13/2001
Focalin XR Extended-Release Capsules Dexmethylphenidate Novartis Pharmaceuticals Corporation 5/26/05
Metadate CD Extended-Release Capsules Methylphenidate UCB Pharma, Inc. 4/3/2001
Dexedrine Dextroamphetamine GlaxoSmithKline 8/2/1976
Methylin Chewable Tablets Methylphenidate Tyco Healthcare/ Mallinckrodt 4/15/2003 (has not been marketed)
Methylin Oral Solution Methylphenidate Tyco Healthcare/ Mallinckrodt 12/19/2002
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Pending NDAs / sNDAs for ADHD Indication
ACTIVE INGREDIENT
PRODUCT NAME
COMPANY
Date of Approval
Provigil Tablets Modafinil Cephalon, Inc. pending
Methylphenidate Transdermal system Methylphenidate Noven Pharmaceuticals, Inc pending
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Background

• BPCA review of Concerta, and a comparable review
  of other methylphenidate products, identified
  psychiatric adverse events as a possible concern.
  
• The review concluded that labeling regarding
  psychiatric adverse events could be improved.
• The Pediatric Advisory Committee in June 2005
  recommended that psychiatric adverse events with
  all ADHD drugs should be examined, so that drug
  labeling could be updated and made consistent
  between products.
• Accordingly, the FDA Division of Drug Risk
  Evaluation undertook a review of clinical trial
  and postmarketing data on psychiatric adverse
  events associated with ADHD drugs

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Information Requests to Sponsors

• Information pertaining to selected psychiatric
  adverse events was requested from the
  manufacturers of products approved or with
  pending applications for the treatment of ADHD
• Postmarketing data
• Clinical trial data
• Sponsors were asked to provide information
  regarding four broad categories of psychiatric
  adverse events
• 1) signs and/or symptoms of psychosis or mania
• 2) suicidal ideation and behavior
• 3) aggression and violent behavior and,
• 4) miscellaneous serious adverse psychiatric
  events (will not be discussed today)

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Information Requests to Sponsors, continued

• For the postmarketing data analysis, information
  on reports received since January 1, 2000 was
  requested
• The analysis of the postmarketing data will be
  presented separately
• This presentation will describe the findings from
  the clinical trial data

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Purpose of Clinical Trial Analysis

• To characterize the adverse psychiatric events
  observed in ADHD clinical trials, with emphasis
  on three categories of events
• Psychosis/Mania
• Suicidal events
• Aggression
• To determine rates of these events by pooling
  clinical trial data
• By development program
• For all oral methylphenidate products

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Methods

• Information requests sent to sponsors of ADHD
  drug products
• Sponsors were asked to
• perform a text string search of their clinical
  trial databases for selected terms
• search both preferred terms and investigator
  verbatim terms
• Include events from these categories
• psychosis/mania
• suicidal events
• aggression
• miscellaneous

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Methods, continued

• Sponsors were asked to
• enumerate clinical trial events according to drug
  exposure, age group, gender, trial
• provide brief clinical descriptions of adverse
  events identified
• provide descriptions of each clinical trial in
  the analysis
• All sponsors responded data reviewed and
  aggregated

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Results

• Data obtained on 8 ADHD products
• Approved products by active ingredient
• Methylphenidate Concerta, Metadate CD, Ritalin
  LA
• Atomoxetine (Strattera)
• Amphetamine (Adderall XR)
• D-methylphenidate (Focalin/Focalin XR)
• Pending applications
• Methylphenidate transdermal system (MTS)
• Modafinil (Provigil)
• Adult data will not be covered in this slide
  presentation
• See written report in briefing package

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(No completed suicides)
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Pooled placebo data from all pediatric double
blind ADHD trials, selected drugs

• N 3990
• Pt yrs 425.11
• Predominantly males, pre-adolescents
• Rates of events per 100 pt yrs of placebo
  exposure in pediatric ADHD trials
• Psychosis/mania 0
• Suicidal events 0.9
• Aggression events 7.1

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Lilly analysis of suicidal events in atomoxetine
double blind clinical trials by age group
(indication not limited to ADHD)
Category of events Pediatric studies Pediatric studies Adult studies Adult studies
Category of events Atomoxetine (n 1357) Placebo (n 851) Atomoxetine (n 1718) Placebo (n 1072)
Suicidal events, FDA definition 6 (0.4) 0 15 (0.9) 10 (0.9)
Suicidal events, Lilly definition 7 (0.5) 1 (0.1) 11 (0.6) 8 (0.7)
p-value versus placebo 0.01 p-value
versus placebo 0.07
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Lilly analysis of aggression in atomoxetine
pediatric clinical trials
Category of event Frequency in pediatric double blind trials Frequency in pediatric double blind trials Frequency in pediatric double blind trials
Category of event Atomoxetine (n 1308) Placebo (n 806) Methylphenidate active control (n 472)
Aggression and hostility, Lilly definition 21 (1.6) 9 (1.1) 4 (0.8)
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Data from open label pediatric exposure
Drug N Patient -years Psychosis/ mania events Suicidal events Aggression events Psychosis /mania Events per 100 pt-yrs Suicidal Events per 100 pt-yrs Aggression Events per 100 pt-yrs
Concerta OL 2688 1322.04 8 6 52 0.6 0.5 3.9
Metadate CD OL 322 19.55 0 0 6 0.0 0.0 30.7
MTS OL 617 341.97 6 1 7 1.8 0.3 2.0
Modafinil OL 799 369.35 2 0 14 0.5 0.0 3.8
Adderall XR OL 4233 1280.80 9 8 150 0.7 0.6 11.7
Atomoxetine OL 4669 4546.74 12 44 191 0.3 1.0 4.2
Ritalin LA OL 125 25.95 0 1 0 0.0 3.9 0.0
d-MPH OL 570 302.87 2 1 11 0.7 0.3 3.6
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Limitations of these data

• Small sample sizes, short durations of treatment
• Small number of events
• Possible lack of consistency across trials with
  respect to ascertainment and reporting of these
  adverse events by investigators
• Possibility of misclassification of cases
• Was there adequate sensitivity and specificity of
  case definition?
• Only one sponsor (Lilly, atomoxetine) adjudicated
  events

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Conclusions and Comments Pediatric ADHD trials

• Frequency of aggression events
• Higher with MTS, Ritalin LA, and atomoxetine than
  with placebo
• Little evidence from double blind trials that
  these drugs reduce events (modafinil only drug
  with numerically lower rate versus placebo)
• Frequency of suicidal events
• Higher with modafinil and atomoxetine than with
  placebo
• Statistically significant in sponsors analysis
  of atomoxetine

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Conclusions and Comments Pediatric ADHD trials,
continued

• Psychosis/mania events
• Only observed with active drug treatments in
  double blind trials
• 13 with active drug
• 0 with placebo
• Observed with all compounds in open label
  treatment
• 0.3 of oral methylphenidate patients
• 0.3 of atomoxetine patients
• 0.3 of modafinil patients
• 0.2 of amphetamine patients
• 1.0 of methylphenidate transdermal patch
  patients

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Examples Psychosis/Mania events
Age Sex Drug Treatment Dose (mg/day) at time of event Duration (days) Event Serious (y/n) Comments
8 M Modafinil 300 19 Hospitalized for treatment of psychosis (command auditory hallucinations, suicidal ideation) Y Unknown to investigators, child had previous history of similar symptoms
10 M Adderall XR 10 8 Hallucinations N Drug was discontinued
8 M MTS 25 cm2 15 Hallucinations, manic reaction, depersonalization N Drug was discontinued
9 M Atomoxetine 0.5 mg/kg 212 Psychotic disorder, bizarre behavior, delusions, hallucinations, hospitalized Y No previous history of such episodes
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Conclusions and Comments Pediatric ADHD trials,
continued

• Many clinical trials were of short duration
• Many clinical trials enrolled subjects previously
  known to respond to drugs in the class
• These factors limit the utility of these trials
  for determining the drug products safety
  profiles

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Literature review

• Spear J, Alderton D. Aust N Z J Psychiatry. 2003
  Jun37(3)383
• 6 patients (18 age) treated with d-amphetamine
  were admitted for psychosis to same public
  psychiatric hospital over 3 months
• Young JG. J Dev Behav Pediatr. 1981
  Jun2(2)35-8.
• Two children treated with methylphenidate
  developed toxic hallucinosis.
• Surles LK, May HJ, Garry JP. J Am Board Fam
  Pract. 2002 Nov-Dec15(6)498-500.
• 13-year old female developed characteristic
  amphetamine psychosis while being treated with
  Adderall
• Gross-Tsur V, Joseph A, Shalev RS. Neurology.
  2004 Aug 2463(4)753-4.
• Three children treated with low doses of
  methylphenidate developed visual and tactile
  hallucinations.

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Literature review, continued

• Cherland E, Fitzpatrick R. Can J Psychiatry. 1999
  Oct44(8)811-3
• Chart review of 98 child outpatients diagnosed
  with ADHD and treated with stimulants. 6/98 (6)
  developed psychotic symptoms.
• Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Am J
  Psychiatry. 2005 Jan162(1)58-64.,
• Placebo controlled, 4-week crossover trial of
  amphetamine plus divalproex sodium in pediatric
  ADHD with comorbid bipolar disorder. None of 30
  subjects had worsening of mania with amphetamine
  while receiving divalproex sodium.
• Henderson TA, Hartman K. Pediatrics. 2004
  Sep114(3)895-6.
• 10 cases of mania among 153 sequential pediatric
  outpatients treated with atomoxetine (6.5).

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Acknowledgements

• Sponsors who provided their clinical trial data
• At FDA
• Division of Psychiatry Products
• Thomas Laughren, M.D.
• Susan Player, MS, APRN, BC
• Chardae Araojo, Pharm.D.
• Division of Neurology Products Judith Racoosin,
  M.D., M.P.H.
• Division of Surveillance, Research and
  Communication Support Tarek Hammad, M.D., Ph.D.,
  M.Sc., M.S.
• Division of Drug Risk Evaluation Kate Gelperin,
  M.D., M.P.H.