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Psychiatric Adverse Events
with Drug Treatments of
ADHD
Review of Postmarketing Safety Data:
Pediatric Population
Kate Gelperin, M.D., M.P.H.
FDA Office of Drug Safety
Division of Drug Risk Evaluation
Pediatric Advisory Committee
March 22, 2006
Points for discussion today:
Methods for case review and analysis
Overview of MedWatch reports:
Signs and/or Symptoms of Psychosis or Mania
Published case reviews
Aggression or Violent Behavior
Suicidality
Clinical implications for product labeling
Summary and conclusions
Pediatric Advisory Committee
March 22, 2006 2
Postmarketing Safety Information from
Manufacturers of ADHD Drugs
Spontaneous or literature reports since January 2000
Four broad categories of psychiatric adverse events:
1. Signs and/or symptoms of psychosis or mania
2. Aggression or violent behavior
3. Suicidal ideation or behavior (suicidality)
4. Miscellaneous serious adverse psychiatric events
This review includes the first three categories only.
High level analysis of patient characteristics and potential
risk factors for psychiatric adverse events completed.
Pediatric Advisory Committee
March 22, 2006 3
Review of FDA AERS Safety Database
In addition, searches of the FDA AERS safety database were
conducted for the same time period.
All identified MedWatch cases were individually assessed by
DDRE Review Team.
Reports were classified into four categories (as described).
Each case could be included under more than one category,
based on judgment of reviewer.
Duplicates, and reports which were considered to be of very
poor quality or highly unlikely to be related to the drug of
interest were excluded from the analysis.
Pediatric Advisory Committee
March 22, 2006 4
Criteria for Assessment of Reports *
Published case reports consistent with a causal association
Temporal association between drug administration and occurrence of
the adverse event
Improvement or resolution of event when the drug was discontinued
(positive dechallenge)
Recurrence when the drug was readministered (positive rechallenge)
Alternative factors that could cause or contribute to the adverse event:
Concomitant medications
Drug abuse
Pre-existing condition with similar signs or symptoms prior to drug
administration
Confirmation by a physician or other health care professional
* Criteria adapted from: Naranjo CA, Busto EM, Sandor P, et al. A method for estimating the probability of
adverse drug reactions. Clin Pharmacol Ther 1981; 30(2):239-245.
Pediatric Advisory Committee
March 22, 2006 5
Demographics and Potential Risk Factors
Age
Sex
Total daily dose
Duration of therapy at time of adverse event
Exacerbation of pre-existing condition?
Psychiatric history other than ADHD?
Seizure disorder?
Drug abuse?
Overdose?
Dechallenge? Rechallenge?
Family history of serious psychiatric illness?
Concomitant medications
Pediatric Advisory Committee
March 22, 2006 6
Psychosis or Mania – Search Terms
Hallucination (any type, including visual, auditory, tactile, mixed, etc)
Delusion (any type including somatic, persecutory, grandeur, reference)
Schizophrenia (any type)
Psychotic disorder
Transient psychosis
Acute psychosis
Paranoia
Childhood psychosis
Schizophreniform disorder
Schizoaffective disorder
Catatonia
Mania
Hypomania
Pediatric Advisory Committee
March 22, 2006 7
Psychosis or Mania
MedWatch Reports Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected Attributes
DRUG Patient Age Sex Other Drug Overdose? Seizure
(Number of non- Psychiatric Abuse? Disorder?
excluded reports) History?
Amphetamine /
1-10 yrs (30%) 61% M 35% Yes 3% Yes 4% Yes 1% Yes
Dextroamphetamine
11-20 yrs (30%) 36% F (36% NR) (32% NR) (29% NR) (49% NR)
(n = 77)
Atomoxetine 1-10 yrs (36%) 70% M 34% Yes 2% Yes 3% Yes 2% Yes
(n = 292) 11-20 yrs (40%) 25% F (64% NR) (74% NR) (43% NR) (95% NR)
Methylphenidate 1-10 yrs (48%) 70% M 24% Yes 3% Yes 6% Yes 1% Yes
(n = 148) 11-20 yrs (26%) 24% F (74% NR) (66% NR) (50% NR) (98% NR)
Modafinil 1-10 yrs (7%) 44% M 60% Yes 12% Yes 14% Yes 5% Yes
(n = 43) 11-20 yrs (9%) 53% F (35% NR) (88% NR) (9% NR) (95% NR)
Pediatric Advisory Committee
March 22, 2006 8
Psychosis or Mania
MedWatch Reports Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected Attributes
Published Positive Positive No Concomitant No Prior Medical
Medical Dechallenge Rechallenge Medications History of Confirmation
DRUG Literature Reported Event from HCP
Reported
Amphetamine /
Dextroamphetamine 12% 58% 3% 71% 87% 47%
(n = 77)
Atomoxetine
(n = 292)
1% 33% 1% 52% 91% 67%
Methylphenidate
(n = 148)
7% 48% 3% 47% 93% 75%
Modafinil
(n = 43)
1% 60% 9% 28% 70% 88%
Pediatric Advisory Committee
March 22, 2006 9
Case Narrative Examples – Amphetamine
Psychosis or Mania
Case report*: A 12 year old female developed hallucinations, agitation, and bizarre
behavior after five weeks of therapy with amphetamine 10 mg daily for the
treatment of attention deficit hyperactivity disorder (inattentive type). There were
no concomitant medications. Medical history included obesity. Family history
included ADHD but no other psychiatric illnesses. Amphetamine was discontinued
and clonazepam 0.25 mg every 6 hours as needed for agitation was initiated. Four
days later, the patient was disoriented and had flight of ideas, tangential thought,
flat affect, psychomotor retardation, and loss of short-term memory. She described
visual hallucinations (disembowelment of her baby brother and bugs crawling on
the walls), command auditory hallucinations, and tactile hallucinations of bugs
crawling under her skin. She displayed waxy flexibility. The patient was admitted
to hospital, and was kept completely medication-free. Her emotional status and
behavior returned to baseline seven days after amphetamines had been stopped. She
had no more hallucinations, and was discharged home on no medications.
* Surles LK, et al. Adderall-induced psychosis in an adolescent. J Am Board Fam Prac 2002; 156:498-500.
Pediatric Advisory Committee
March 22, 2006 10
Case Narrative Examples – Modafinil
Psychosis or Mania
Clintrace #: US008182: A 6 year old male began treatment
with 100 mg day of modafinil for attention deficit disorder.
After one dose, the patient experienced visual hallucinations.
Concomitant medications: None. Modafinil therapy was
discontinued and the symptoms abated.
Pediatric Advisory Committee
March 22, 2006 11
Case Narrative Examples – Atomoxetine
Psychosis or Mania
USA030433792: A physician reported that a 7-year-old female
received atomoxetine 18 mg daily for the treatment of ADHD.
Within hours of taking the first dose, the patient started talking
non-stop, and stated that she was happy. The next morning the
child was still elated. Two hours after taking her second dose
of atomoxetine, the patient started running very fast, stopped
suddenly, and fell to the ground. The patient stated that she
had run into a wall (there was no wall there). The patient slept
a lot that day, and was hallucinating. Atomoxetine was
discontinued. The outcome of the events was not reported.
Pediatric Advisory Committee
March 22, 2006 12
Case Narrative Examples – Methylphenidate
Psychosis or Mania
Case report*: A 12-year-old boy with cerebral palsy, low normal
intelligence, and ADHD, combined subtype, was treated with
methylphenidate 0.3 mg/kg (10 mg) once daily with marked improvement
in attention and hyperactivity. One morning, he was observed crawling on
the floor complaining that roaches were surrounding him. This
phenomenon appeared two hours after ingesting methylphenidate,
continuing for almost two hours, and disappeared without any specific
intervention. Methylphenidate was withdrawn, and there was no
recurrence. However, deterioration in school performance was so dramatic
that rechallenge with methylphenidate was attempted at his previous dose.
Immediate recurrence of hallucinations necessitated stopping
methylphenidate. Three-year follow-up evaluation has been uneventful.
*Gross-Tsur V, Joseph A, Shalev RS. Hallucinations during methylphenidate therapy. Neurology
2004; 63:753-4.
Pediatric Advisory Committee
March 22, 2006 13
Published Case Series - Psychostimulants
Chart review* of all children diagnosed with ADHD in an
outpatient clinic in Canada from January 1989 to March 1995
Over 5 year period:
192 children diagnosed with ADHD
98 children were treated with stimulants
Most received methylphenidate
6 children developed psychotic symptoms during treatment
Average follow-up duration was 1 year 9 months.
Frequency of treated patients developing psychotic side effects
in this chart review was 6%.
*Cherland E and Fitzpatrick R. Psychotic side effects of psychostimulants: A 5-year review.
Can J Psychiatry 1999;44: 811-813.
Pediatric Advisory Committee
March 22, 2006 14
Published Case Series - Atomoxetine
Pooled data* of sequential patients (age 10.5 ± 3.74 years) from outpatient
settings in Colorado and Minnesota
Total 153 sequential patients treated with atomoxetine:
51 children (33%) developed unwanted psychiatric symptoms such as
irritability, aggression, mania or hypomania.
Past history of mood symptoms reported in 80% of these children.
Of these, 10 children developed symptoms severe enough to be
considered mania.
Of these, 3 were admitted to hospital and 3 were incarcerated in juvenile
detention centers.
Frequency of treated patients developing mania in this case series was 7%.
*Henderson TA, Hartman K. Aggression, mania, and hypomania induction associated with Atomoxetine.
Pediatrics 2004;114(3):895-896.
Pediatric Advisory Committee
March 22, 2006 15
Psychosis or Mania with Drugs Currently
Approved for ADHD – Findings
No risk factors were identified which could account for the
majority of reports
Drug abuse reported in < 3% of overall cases
No prior history of similar condition in about 90% of overall cases
Positive rechallenge cases identified (supports causal association)
Many cases with positive dechallenge reported
May not be a rare occurrence based on published case series
Large proportion of cases involve young children
Narratives describing hallucinations in young children often
describe insects, snakes or worms (visual and tactile)
Pediatric Advisory Committee
March 22, 2006 16
Psychosis or Mania
Labeling Considerations for Currently Approved Drugs
Labeling for ADDERALL and ADDERALL XR includes:
WARNING regarding use of amphetamine in psychotic
children.
ADVERSE REACTIONS section describes psychotic
episodes at recommended doses (rare).
DRUG ABUSE AND DEPENDENCE section states that the
most severe manifestation of chronic intoxication is psychosis,
often clinically indistinguishable from schizophrenia.
OVERDOSAGE section states that individual response to
amphetamines varies widely. Toxic symptoms may occur
idiosyncratically at low doses.
Pediatric Advisory Committee
March 22, 2006 17
Psychosis or Mania
Labeling Considerations for Currently Approved Drugs
Labeling for STRATTERA (atomoxetine) includes:
WARNING regarding suicidal ideation.
Under the WARNINGS, a description of symptoms which
have been reported with STRATTERA lists mania, and states
that, although a causal link between the emergence of such
symptoms and the emergences of suicidal impulses has not
been established, there is a concern that such symptoms may
represent precursors to emerging suicidality.
Pediatric Advisory Committee
March 22, 2006 18
Psychosis or Mania
Labeling Considerations for Currently Approved Drugs
Labeling for most brands of methylphenidate (e.g., CONCERTA
and RITALIN) includes:
WARNING for psychosis which states that clinical experience
suggests that in psychotic patients, administration of
methylphenidate may exacerbate symptoms of behavior
disturbance and thought disorder.
Drug Dependence section states that frank psychotic episodes
can occur, especially with parenteral abuse.
ADVERSE REACTIONS section states that toxic psychosis
has been reported.
OVERDOSAGE section describes signs and symptoms of
acute overdosage, which may include hallucinations.
Pediatric Advisory Committee
March 22, 2006 19
Psychosis or Mania
Labeling Considerations
Current approved labeling for drugs with ADHD indication
does not clearly address the risk of drug-induced signs or
symptoms of psychosis or mania (such as hallucinations) in
patients without identifiable risk factors, and occurring at usual
dosages.
Current labeling does not clearly state the importance of
stopping drug therapy in any patient who develops signs
and/or symptoms of psychosis or mania during drug treatment
of ADHD.
Committee will be asked to address labeling issues later today.
Pediatric Advisory Committee
March 22, 2006 20
Aggression or Violent Behavior –
Search Terms
Aggression
Anger
Hostility
Homicidal ideation
Sexual offense
Murder
Imprisonment
Pediatric Advisory Committee
March 22, 2006 21
Aggression or Violent Behavior
MedWatch Reports Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected Attributes
DRUG Patient Age Sex Other Drug Overdose? Seizure
(Number of non- Psychiatric Abuse? Disorder?
excluded reports) History?
Amphetamine /
1-10 yrs (36%) 68% M 43% Yes 4% Yes 4% Yes 4% Yes
Dextroamphetamine
11-20 yrs (32%) 32% F (29% NR) (25% NR) (25% NR) (32% NR)
(n = 28)
Atomoxetine 1-10 yrs (47%) 77% M 31% Yes 1% Yes 5% Yes 3% Yes
(n = 566) 11-20 yrs (34%) 18% F (67% NR) (72% NR) (40% NR) (93% NR)
Methylphenidate 1-10 yrs (45%) 81% M 24% Yes 2% Yes 5% Yes 1% Yes
(n = 110) 11-20 yrs (36%) 16% F (75% NR) (96% NR) (46% NR) (98% NR)
Modafinil 1-10 yrs (13%) 50% M 63% Yes 38% Yes 38% Yes 0% Yes
(n = 8) 11-20 yrs (0%) 50% F (25% NR) (63% NR) (25% NR) (100% NR)
Pediatric Advisory Committee
March 22, 2006 22
Aggression or Violent Behavior
MedWatch Reports Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected Attributes
Published Positive Positive No Concomitant No Prior Medical
Medical Dechallenge Rechallenge Medications History of Confirmation
DRUG Literature Reported Event from HCP
Reported
Amphetamine /
Dextroamphetamine 0 39% 4% 61% 89% 39%
(n = 28)
Atomoxetine
(n = 566)
1% 17% 3% 20% 81% 35%
Methylphenidate
(n = 110)
6% 52% 5% 63% 91% 64%
Modafinil
(n = 8)
0 38% 0 38% 63% 88%
Pediatric Advisory Committee
March 22, 2006 23
Aggression or Violent Behavior with Drugs
Currently Approved for ADHD – Findings
Most cases classified as non-serious, although about 20% of
cases were considered life-threatening or required hospital
admission
Incarceration of juveniles reported in a few cases
Most reports involved children and adolescents
No specific risk factors that could account for most cases were
identified in this analysis:
Drug abuse reported in fewer than 5% of cases
Majority of patients (80 to 90% overall) had no prior history of similar
events reported
Positive rechallenge cases reported
Pediatric Advisory Committee
March 22, 2006 24
Aggression
Labeling Considerations for Currently Approved Drugs
Current labeling for amphetamine / dextroamphetamine and
methylphenidate products does not include information about
drug-induced aggression or violent behavior occurring at usual
prescribed doses.
Current labeling for STRATTERA (atomoxetine) includes a
PRECAUTION regarding aggressive behavior or hostility
based on clinical trial data which recommends that “patients
beginning treatment for ADHD should be monitored for the
appearance of or worsening of aggressive behavior or
hostility.”
Pediatric Advisory Committee
March 22, 2006 25
Suicidality – Search Terms
Depression suicidal
Gun shot wound
Intentional self-injury
Non-accidental overdose
Overdose
Self injurious behavior
Self injurious ideation
Self-mutilation
Suicidal ideation
Suicide attempt
Completed suicide
Pediatric Advisory Committee
March 22, 2006 26
Suicidality
MedWatch Reports Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected Attributes
DRUG Patient Age Sex Other Drug Overdose? Seizure
(Number of non- Psychiatric Abuse? Disorder?
excluded reports) History?
Amphetamine /
1-10 yrs (31%) 66% M 45% Yes 3% Yes 17% Yes 0% Yes
Dextroamphetamine
11-20 yrs (34%) 34% F (45% NR) (38% NR) (28% NR) (34% NR)
(n = 29)
Atomoxetine 1-10 yrs (23%) 69% M 29% Yes 12% Yes 23% Yes 1% Yes
(n = 214) 11-20 yrs (45%) 27% F (70% NR) (66% NR) (42% NR) (93% NR)
Methylphenidate 1-10 yrs (23%) 64% M 29% Yes 9% Yes 25% Yes 0% Yes
(n = 100) 11-20 yrs (42%) 28% F (69% NR) (64% NR) (42% NR) (98% NR)
Modafinil 1-10 yrs (6%) 44% M 72% Yes 33% Yes 33% Yes 11% Yes
(n = 18) 11-20 yrs (6%) 50% F (22% NR) (67% NR) (17% NR) (89% NR)
Pediatric Advisory Committee
March 22, 2006 27
Suicidality
MedWatch Reports Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected Attributes
Published Positive Positive No Concomitant No Prior Medical
Medical Dechallenge Rechallenge Medications History of Confirmation
DRUG Literature Reported Event from HCP
Reported
Amphetamine /
Dextroamphetamine 0 34% 3% 72% 79% 45%
(n = 29)
Atomoxetine
(n = 214)
1% 30% 4% 56% 80% 63%
Methylphenidate
(n = 100)
15% 38% 2% 54% 91% 83%
Modafinil
(n = 18)
0 61% 0 39% 61% 89%
Pediatric Advisory Committee
March 22, 2006 28
Suicidality
Labeling Considerations for Currently Approved Drugs
Current labeling for amphetamine / dextroamphetamine and
methylphenidate products does not include information about
suicidality.
A possible causal association between stimulant therapy of ADHD and
suicidality cannot be ruled out on the basis of this analysis.
Current labeling for STRATTERA (atomoxetine) includes a
BOXED WARNING regarding an increased risk of suicidal
ideation in children.
The results of this review are consistent with an association between
atomoxetine therapy and suicidality in some patients.
Current approved labeling for STRATTERA clearly describes issues
related to suicidality.
Pediatric Advisory Committee
March 22, 2006 29
Summary and Conclusions
Suicidality
Suicidality has been identified as a safety issue for
STRATTERA (atomoxetine), and this information is clearly
conveyed in current labeling.
A causal association between other drug therapies of ADHD
and suicidality cannot be ruled out.
Further evaluation of this issue is recommended.
Clinical expert case review of data obtained for this analysis may yield
insights regarding possible co-occurrence of undesired psychiatric
effects that could contribute to suicidal ideation or behaviors.
Pediatric Advisory Committee
March 22, 2006 30
Summary and Conclusions
Aggression or Violent Behavior
Numerous postmarketing reports of aggression or violent behavior
have been received.
Most reports were in children and adolescents, with a male
predominance.
No specific risk factors which could account for the majority of
cases were identified in this analysis.
These data suggest that some cases of aggression or violent behavior
may be drug induced.
The committee will be asked to discuss any labeling implications
later today.
Pediatric Advisory Committee
March 22, 2006 31
Summary and Conclusions
Psychosis or Mania
Signs and symptoms of psychosis or mania, particularly hallucinations, can
occur in some patients with no identifiable risk factors at usual doses of any
of the drugs currently approved to treat ADHD.
Based on published case series rates, may not be a rare occurrence.
No risk factors were identified which could account for the majority of
reports of psychosis-related events. Drug abuse was reported in fewer than
3% of cases from the FDA AERS analysis.
The predominance in young children of hallucinations, both visual and
tactile, involving insects, snakes and worms deserves further evaluation.
The committee will be asked to discuss labeling implications of these
findings later today.
Pediatric Advisory Committee
March 22, 2006 32
Acknowledgements
We wish to thank:
The manufacturers of drugs discussed today for providing timely and
comprehensive safety data for these analyses.
Colleagues in the Division of Psychiatric Products for guidance in this
review, and in particular, Richardae Araojo and Susan Player, DPP Project
Managers, for coordinating safety data requests and Sponsor responses.
DDRE ADHD Psychiatric Safety Review Team:
Allen Brinker, M.D., M.P.H.
Charlene Flowers, R.Ph.
Kate Gelperin, M.D., M.P.H.
Cindy Kortepeter, Pharm.D.
Andy Mosholder, M.D., M.P.H.
Kate Phelan, R.Ph.
Sonny Saini, Pharm.D.
Joseph Tonning, M.D., R.Ph.
Mary Willy, Ph.D., M.P.H.
Pediatric Advisory Committee
March 22, 2006 33
