Pediatric Advisory Committee Pediatric Advisory Committee March 22, 2006 March 22, 2006 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
33
Embed
Pediatric Advisory Committee March 22, 2006 Psychiatric Adverse Events with Drug Treatments of ADHD Review of Postmarketing Safety Data: Pediatric Population.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
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
Case Narrative Examples – AmphetaminePsychosis or ManiaCase 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 – 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.
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.
Case Narrative Examples – MethylphenidatePsychosis 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.
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 DrugsLabeling for ADDERALL and ADDERALL XR includes: WARNING regarding use of amphetamine in psychotic
Psychosis or Mania Labeling Considerations for Currently Approved DrugsLabeling 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 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 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
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 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
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 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.