Psychiatric Adverse Events with Drug Treatments of ADHD

1
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

2
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

3
Postmarketing Safety Information from
Manufacturers of ADHD Drugs

• Spontaneous or literature reports since January
  2000
• Four broad categories of psychiatric adverse
  events
• Signs and/or symptoms of psychosis or mania
• Aggression or violent behavior
• Suicidal ideation or behavior (suicidality)
• 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.

4
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.

5
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.

6
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

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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

8
Psychosis or Mania MedWatch Reports Received by
FDA January 1, 2000 - June 30, 2005 Percent of
Non-excluded Cases with Selected Attributes
9
Psychosis or Mania MedWatch Reports Received by
FDA January 1, 2000 - June 30, 2005 Percent of
Non-excluded Cases with Selected Attributes
10
Case Narrative Examples AmphetaminePsychosis
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
  156498-500.

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Case Narrative Examples ModafinilPsychosis 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.

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Case Narrative Examples AtomoxetinePsychosis
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.

13
Case Narrative Examples MethylphenidatePsychosi
s 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 63753-4.

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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 199944 811-813.

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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 2004114(3)895-896.

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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 lt 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)

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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.

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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.

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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.

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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.

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Aggression or Violent Behavior Search Terms

• Aggression
• Anger
• Hostility
• Homicidal ideation
• Sexual offense
• Murder
• Imprisonment

22
Aggression or Violent Behavior MedWatch Reports
Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected
Attributes
23
Aggression or Violent Behavior MedWatch Reports
Received by FDA January 1, 2000 - June 30, 2005
Percent of Non-excluded Cases with Selected
Attributes
24
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

25
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.

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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

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Suicidality MedWatch Reports Received by FDA
January 1, 2000 - June 30, 2005 Percent of
Non-excluded Cases with Selected Attributes
28
Suicidality MedWatch Reports Received by FDA
January 1, 2000 - June 30, 2005 Percent of
Non-excluded Cases with Selected Attributes
29
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.

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Summary and ConclusionsSuicidality

• 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.

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Summary and ConclusionsAggression 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.

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Summary and ConclusionsPsychosis 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.

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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.