Summary of June 2005 PAC-Interim Actions and Landmark Events

1. Summary of June 2005 PAC-Interim Actions and Landmark Events Paul J. Andreason, MD Acting Deputy Director Division of Psychiatry Products Center for Drug Evaluation and Research, FDA

2. June 30, 2005 Concerta Recap At a June 30, 2005 meeting of the Pediatric Advisory Committee, a concern was raised about reports of psychiatric adverse events occurring in patients being treated with various drug products for ADHD. The reports considered at that meeting were for the drug Concerta, but it was acknowledged that similar reports have been made for other ADHD products. Although some psychiatric adverse events are already mentioned in the labeling for various ADHD products, there was general support for the view that labeling may need to be enhanced to better characterize these events. However, there was also agreement that such labeling changes should await a more comprehensive review of psychiatric events for ADHD products. In order to facilitate this more comprehensive review, we are requesting psychiatric adverse event data for various products approved for the treatment of ADHD.

3. It has been a busy 9-months • Canada returned Adderall XR to the market 8/24/2005 (removed 2/6/2005) • Study of all RCT for psychiatric AEs for all treatments was designed and letters were sent to sponsors September 14, 2005-responses due November 1, 2005 • Pemoline removed from market 10/2005 • PDAC Recommends Approving methylphenidate transdermal patch 12/2/2005-Approvable action 12/23/2005 • Request for Labeling Update that warns about use in patients with known CV defects for stimulants 1/25/06 • DSaRM Advisory Committee makes labeling recommendation of Boxed Warning and Med-Guide for “stimulants” 2/9/2006 • Study results of RCTs for psychiatric AEs filed in DFS 3/3/2006 • Adderall XR BPCA Review and presentation of psychiatric AE study-today • 3/23/2006 the PDAC meets to discuss modafinil for ADHD

4. Warning Labeling Updatemethylphenidate and amphetamine productsJanuary 25, 2006 Sudden Death and Pre-existing Structural Cardiac Abnormalities Sudden death has been reported in association with CNS stimulant treatment at usual doses in children with structural cardiac abnormalities. Although some structural cardiac abnormalities alone may carry an increased risk of sudden death, stimulant products generally should not be used in children, adolescents, or adults with known structural cardiac abnormalities

5. Pre-existing Labeling Differences • Differences in section placement • New labeling initiative will combine Warnings and Precautions into one section. • Time of approval (age of drug) reflects the state of FDA requirements and the climate of clinical thought at the time. • Differences in data content • Breadth of program and available data • Age of Drug • Product of Written Request

6. Pre-existing CV Risk Labeling for Methylphenidate and Amphetamine Products and Atomoxetine • Use with caution in patients with • Hypertension • Tachycardia • Cardiovascular/Cerebrovascular Disease • Cardiac Arrhythmia • Monitor blood pressure and pulse • Modest increases in pulse and blood pressure

7. Psychiatric Adverse Eventsby Drug Substance Most Recent- ComparedtoOldest Generally Focuses on Psychosis, Agitation and Anxiety

8. Adderall XR-Dexedrine (amphetamines) • Warnings • Psychosis: Clinical experience suggests that, in psychotic patients, administration of amphetamine may exacerbate symptoms of behavior disturbance and thought disorder. • Drug Abuse and Dependence • The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. • Adverse Events Associated with Discontinuation • Agitation • Table 3 Adverse Events Reported by 5% or More of Adults Receiving ADDERALL XR® with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study* • Agitation 8% 5% • Anxiety 8% 5% • Dizziness 7% 0% • Insomnia 27% 13%

9. Toxicity at Usual Doses • Dexedrine-While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions • Adderall XR- Toxic symptoms may occur idiosyncratically at low doses

10. Adderall XR • OVERDOSAGE • Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses. Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse.

11. Dexedrine • OVERDOSAGE • Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. • In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg. • Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rhabdomyolysis, rapid respiration, hyperpyrexia, confusion, assaultiveness, hallucinations, panic states. • Fatigue and depression usually follow the central stimulation. • Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

12. Psych AE Concerta-Ritalin • Need for Comprehensive Treatment Program • Stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. • Warnings-Psychosis • Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder. • Adverse Events with Other Methylphenidate HCl Products • Toxic psychosis has been reported. • What are the possible side effects of CONCERTA®? • increased blood pressure and psychosis (abnormal thinking or hallucinations). • Talk to your doctor before taking CONCERTA® if you: • Have abnormal thoughts or visions, hear abnormal sounds, or have been diagnosed with psychosis.

13. Concerta-Ritalin Psych AEContinued • Agitation • CONCERTA® is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. • Who should NOT take CONCERTA®? • You should NOT take CONCERTA® if: You have significant anxiety, tension, or agitation since CONCERTA® may make these conditions worse.

14. Ritalin • PRECAUTIONS • Patients with an element of agitation may react adversely; discontinue therapy if necessary.

15. Atomoxetine-Psych AE • Boxed Warning for Suicidal Ideation (also in Warnings and Precautions section and Med Guide) • Warnings-The following symptoms have been reported with STRATTERA: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. • Aggression-Call your doctor if treatment emergent. 0.5% (N=2) discontinued due to aggression/hostility.

16. Nomenclature-Stimulant • Some reported confusion about what was a “stimulant” • Amphetamine and methylphenidate accepted as CNS stimulants • Atomoxetine is marketed as a non-stimulant • Modafinil- “wakefulness-promoting agent” (some but not all properties of stimulants)

17. Amphetamine • Blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron • Increases the release of norepinephrine and dopamine • Dopamine release from reserpine-insensitive cytoplasmic pool • Increases locomotor activity in mice and rats • Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of subjects who have increased the dosage to many times that recommended. • Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. • Schedule II-non-narcotic

18. Methylphenidate • Blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron • Increases the release of norepinephrine and dopamine • Dopamine release from granular reserpine-sensitive vesicular pool • Increases locomotor activity in mice and rats • Chronic abusive use can lead to marked tolerance and dependence with varying degrees of abnormal behavior • Careful supervision is required during withdrawal from abusive use since severe depression may occur. • Schedule II

19. Modafinil • In vitro, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. • Increased locomotor activity in animals • Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine • In a preclinical model, the wakefulness induced by amphetamine, but not modafinil, is antagonized by the dopamine receptor antagonist haloperidol • Modafinil does not reduce cataplexy in narcoleptic canines and has minimal effects on cardiovascular and hemodynamic parameters. • In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants. • Schedule IV

20. Atomoxetine • Selective inhibition of the pre-synaptic norepinephrine transporter (SNRI), as determined in ex vivo uptake and neurotransmitter depletion studies • Does not stimulate release of dopamine or norepinephrine • Does not increase extracellular dopamine • Minimal affinity for either the serotonin or dopamine transporters, or for other neurotransmitter receptors, including alpha-adrenergic, serotonergic, and dopaminergic receptors. • Does not increase locomotor activity in mice and rats • Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine. • There was no evidence of symptom rebound or adverse events suggesting a drug-discontinuation or withdrawal syndrome. • In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine and placebo, atomoxetine was not associated with a pattern of response that suggested stimulant or euphoriant properties. • Not Scheduled