1	Modafinil for the Treatment of ADHD Paul J. Andreason, MD Acting Deputy Director Division of Psychiatry Products Center for Drug Evaluation and Research, FDA
2	Acknowledgments Division of Neurology Products and Safety Team Reviewers- Glenn Mannheim, MD June Cai, MD Division of Dermatology and Dental Products Joseph Porres, MD Markham Luke, MD Division of Drug Risk Evaluation Andy Mosholder, MD Kate Gelperin, MD
3	Safety Work-up Deaths Serious Adverse Events Adverse Dropouts Potentially Clinically Significant Labs/ECG/Vitals Common and Drug Related Adverse Events Special Searches-Psychiatric Adverse Events, SJS, Neutropenia, Blood Pressure-Pulse Safety Update
4	Modafinil-marketed with extensive exposure Verispan, LLC Projected Unique Patients Total Number of Unique Patients That Have Filled Prescriptions at a Retail Pharmacy in the US from 2002-2005.
5	Extent of ADHD Data 2.7.4 Summary of Clinical Safety Page 2-3
6	Phase 2 Exposure 2.7.4 Summary of Clinical Safety-Page-3
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9	Safety Results from Controlled Trials No Deaths Adverse Events of Note SJS/EM: Modafinil N=2; PBO=0 Leukopenia: No new cases in AERS Safety Update Psychiatric Adverse Events SRAE Modafinil N=4; PBO=0 Mean Blood Pressure: Modafinil –slight decrease compared to PBO; 9/420 Modafinil vs 1/213 with BP systolic >130 and increase of >20-mmHG Pulse no mean difference from placebo; 6/420 vs 2/213 outliers >120 bpm and increase of >15 bpm Weight: Modafinil 0.7-Kg loss; PBO 1.0-Kg gain
10	Psychiatric Adverse Events ADHD Children Only A Mosholder Appendix Table D; Page 29 for study sample
11	Fishers Exact Test for Suicide Related Adverse Events 2-tailed p=0.31 1-tailed p=0.22
12	Sponsor Proposes WARNINGS section language Sparlon 4/664 vs. 0/308 Not statistically significant (p=0.22 1-tailed Fisher’s Exact Test) All cases of ideation 3 cases resolved without discontinuation Strattera 6/1357 vs. 0/851 (FDA Criteria) p=0.01 7/1357 vs.1/851 (Lilly Criteria) p=0.07 Statistically significant 5 cases ideation and 1 attempt (FDA defined cases) Boxed Warning
13	Cases of Severe Rash EM/SJS 2 Children in Controlled Trial Database 062338 and 315 (no histopathology) No Children in Post-Marketing AERS 4 Adults in AERS Post-Marketing Database US016653, Triage #202048, Triage # 163459, and US011480 (3 with confirmatory histopathology one the is EM-without histopathology) No Adults in Controlled Trial Database
14	Rash 2 serious (1-admitted to the hospital-not ICU or burn unit)/0 PBO 10 dropouts due to rash/ 0 PBO Spontaneous Adverse Events in Controlled Trials: 4% Modafinil vs. 1% Placebo No other Childhood SJS/EM in Post-Marketing AERS Database with >36K children exposed
15	Verispan, LLC Projected Patients Exposed to Modafinil Total Number of Unique Patients That Have Filled Prescriptions at a Retail Pharmacy in the US from 2002-2005.
16	Labeling Sponsor Proposes WARNINGS section language- no deaths child cases were not severe enough to require burn unit or ICU 2/933 EM/SJS in Sparlon RCT no biopsy confirmation No other child cases in AERS with >36K exposures 3 confirmed adult SJS cases in post-marketing AERS database with >1,050,000 unique adult patients exposed. Lamictal Boxed Warning- SJS death of child in a prospective registry study of 1,983 patients 8/1000 in children; 3/1000 adults; 1.3/1000 in adult adjunctive therapy Bipolar Disorder patients.
17	Questions Has modafinil been shown to be effective for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents? Has modafinil been shown to be acceptably safe in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents? If modafinil were to be considered for approval: What kind of a risk management plan should be implemented with regard to the signal for serious skin rashes with this drug in the ADHD program? How should the concern about serious skin rashes be addressed in product labeling (you have been provided our labeling proposal in the approvable letter and also the sponsor’s currently proposed labeling)? Should there be a requirement for a post-marketing study(ies) to better understand the serious skin rashes, and what type of study(ies) might be considered?