# Presentation: 659945

## 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

## 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

## 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.

## 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.

## 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.

## 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

## 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

## Psychosis or Mania MedWatch Reports Received by FDA  January 1, 2000 - June 30, 2005 Percent of Non-excluded Cases with Selected Attributes

| DRUG
(Number of non-excluded reports) | Patient Age | Sex 
 | Other Psychiatric History? | Drug 
Abuse?
 | Overdose? | Seizure Disorder? |
| --- | --- | --- | --- | --- | --- | --- |
| Amphetamine / Dextroamphetamine
(n = 77) | 1-10 yrs (30%)
11-20 yrs (30%) | 61% M
36% F | 35% Yes
(36% NR) | 3% Yes
(32% NR) | 4% Yes
(29% NR) | 1% Yes
(49% NR) |
| Atomoxetine
(n = 292) | 1-10 yrs (36%)
11-20 yrs (40%) | 70% M
25% F | 34% Yes
(64% NR) | 2% Yes
(74% NR) | 3% Yes
(43% NR) | 2% Yes
(95% NR) |
| Methylphenidate
(n = 148) | 1-10 yrs (48%)
11-20 yrs (26%) | 70% M
24% F | 24% Yes
(74% NR) | 3% Yes
(66% NR) | 6% Yes
(50% NR) | 1% Yes
(98% NR) |
| Modafinil
(n = 43) | 1-10 yrs (7%)
11-20 yrs (9%) | 44% M
53% F | 60% Yes
(35% NR) | 12% Yes
(88% NR) | 14% Yes
(9% NR) | 5% Yes
(95% NR) |

## Psychosis or Mania MedWatch Reports Received by FDA  January 1, 2000 - June 30, 2005 Percent of Non-excluded Cases with Selected Attributes

| DRUG | Published Medical Literature | Positive Dechallenge | Positive Rechallenge | No Concomitant Medications Reported
 | No Prior History of Event Reported | Medical Confirmation from HCP |
| --- | --- | --- | --- | --- | --- | --- |
| Amphetamine / Dextroamphetamine
(n = 77) | 12% | 58% | 3% | 71% | 87% | 47% |
| 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% |

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## 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)

## 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.

## 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.

## 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.

## 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.

## Aggression or Violent Behavior – Search Terms

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

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

| DRUG
(Number of non-excluded reports) | Patient Age | Sex 
 | Other Psychiatric History? | Drug 
Abuse?
 | Overdose? | Seizure Disorder? |
| --- | --- | --- | --- | --- | --- | --- |
| Amphetamine / Dextroamphetamine
(n = 28) | 1-10 yrs (36%)
11-20 yrs (32%) | 68% M
32% F | 43% Yes
(29% NR) | 4% Yes
(25% NR) | 4% Yes
(25% NR) | 4% Yes
(32% NR) |
| Atomoxetine
(n = 566) | 1-10 yrs (47%)
11-20 yrs (34%) | 77% M
18% F | 31% Yes
(67% NR) | 1% Yes
(72% NR) | 5% Yes
(40% NR) | 3% Yes
(93% NR) |
| Methylphenidate
(n = 110) | 1-10 yrs (45%)
11-20 yrs (36%) | 81% M
16% F | 24% Yes
(75% NR) | 2% Yes
(96% NR) | 5% Yes
(46% NR) | 1% Yes
(98% NR) |
| Modafinil
(n = 8) | 1-10 yrs (13%)
11-20 yrs (0%) | 50% M
50% F | 63% Yes
(25% NR) | 38% Yes
(63% NR) | 38% Yes
(25% NR) | 0% Yes
(100% NR) |

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

| DRUG | Published Medical Literature | Positive Dechallenge | Positive Rechallenge | No Concomitant Medications Reported
 | No Prior History of Event Reported | Medical Confirmation from HCP |
| --- | --- | --- | --- | --- | --- | --- |
| Amphetamine / Dextroamphetamine
(n = 28) | 0 | 39% | 4% | 61% | 89% | 39% |
| 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% |

## 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

## 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.”

## 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

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

| DRUG
(Number of non-excluded reports) | Patient Age | Sex 
 | Other Psychiatric History? | Drug 
Abuse?
 | Overdose? | Seizure Disorder? |
| --- | --- | --- | --- | --- | --- | --- |
| Amphetamine / Dextroamphetamine
(n = 29) | 1-10 yrs (31%)
11-20 yrs (34%) | 66% M
34% F | 45% Yes
(45% NR) | 3% Yes
(38% NR) | 17% Yes
(28% NR) | 0% Yes
(34% NR) |
| Atomoxetine
(n = 214) | 1-10 yrs (23%)
11-20 yrs (45%) | 69% M
27% F | 29% Yes
(70% NR) | 12% Yes
(66% NR) | 23% Yes
(42% NR) | 1% Yes
(93% NR) |
| Methylphenidate
(n = 100) | 1-10 yrs (23%)
11-20 yrs (42%) | 64% M
28% F | 29% Yes
(69% NR) | 9% Yes
(64% NR) | 25% Yes
(42% NR) | 0% Yes
(98% NR) |
| Modafinil
(n = 18) | 1-10 yrs (6%)
11-20 yrs (6%) | 44% M
50% F | 72% Yes
(22% NR) | 33% Yes
(67% NR) | 33% Yes
(17% NR) | 11% Yes
(89% NR) |

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

| DRUG | Published Medical Literature | Positive Dechallenge | Positive Rechallenge | No Concomitant Medications Reported
 | No Prior History of Event Reported | Medical Confirmation from HCP |
| --- | --- | --- | --- | --- | --- | --- |
| Amphetamine / Dextroamphetamine
(n = 29) | 0 | 34% | 3% | 72% | 79% | 45% |
| 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% |

## 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.

## 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.

## 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.

## 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.

## 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.