# Presentation: 843274

## 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

## Topics

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

## Drugs Currently Approved for ADHD

| 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 |

**PRODUCT NAME**

**COMPANY**

**Date of Approval**

**ACTIVE INGREDIENT**

## Drugs Currently Approved for ADHD, continued

| 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 |

**PRODUCT NAME**

**COMPANY**

**Date of Approval**

**ACTIVE INGREDIENT**

## Pending NDAs / sNDAs for ADHD Indication

| Provigil Tablets | Modafinil | Cephalon, Inc. | pending |
| --- | --- | --- | --- |
| Methylphenidate Transdermal system | Methylphenidate | Noven Pharmaceuticals, Inc | pending |

**PRODUCT NAME**

**COMPANY**

**Date of Approval**

**ACTIVE INGREDIENT**

## 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

## 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)

## 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

## 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

## 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

## 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

## 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

## Slide 13

## Slide 14

## Slide 15

## (No completed suicides)

## Slide 17

## 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

## Lilly analysis of suicidal events in atomoxetine double blind 

**clinical trials by age group (indication not limited to ADHD)**

| 
Category of events | Pediatric studies |  | Adult studies |  |
| --- | --- | --- | --- | --- |
|  | 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

## Lilly analysis of aggression in atomoxetine pediatric clinical trials

| Category of event | Frequency in pediatric double blind trials |  |  |
| --- | --- | --- | --- |
|  | 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%) |

## 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 |

## 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

## 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 sponsor’s analysis of atomoxetine

## 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

## 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 |

## 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

## Literature review

- Spear J, Alderton D. Aust N Z J Psychiatry. 2003 Jun;37(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 Jun;2(2):35-8.
- Two children treated with methylphenidate developed toxic hallucinosis.
- Surles LK, May HJ, Garry JP. J Am Board Fam Pract. 2002 Nov-Dec;15(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 24;63(4):753-4.
- Three children treated with low doses of methylphenidate developed visual and tactile hallucinations.

## Literature review, continued

- Cherland E, Fitzpatrick R. Can J Psychiatry. 1999 Oct;44(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 Jan;162(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 Sep;114(3):895-6.
- 10 cases of mania among 153 sequential pediatric outpatients treated with atomoxetine (6.5%).

## 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.*