Pharmacologic Treatments in Attention Deficit Hyperactivity Disorder Draft Update 4 Report October 2011

2. Key Questions Evidence on Effectiveness and Efficacy What is the evidence that pharmacologic treatments for ADHD improve effectiveness outcomes? What is the comparative efficacy between any included pharmacologic treatment, stimulants and nonstimulants, and immediate-release vs. intermediate-release vs. long-acting formulations, for ADHD? Tolerability, Serious Adverse Events, Misuse and Diversion What is the evidence of comparative tolerability of different pharmacologic treatments, between stimulants and nonstimulants, and between immediate-release vs. intermediate-release vs. long-acting formulations, for ADHD? What is the evidence of serious or long-term adverse events associated with use of drugs for ADHD? What is the evidence that drugs for ADHD impact the risk of misuse or illicit diversion in patients with no history of misuse or diversion? Evidence in Subgroups of Patients 2

3. 3 Included drugs

4. Methods Electronic searches Through June 2011 Pharmaceutical company submissions Shire US (guanfacine and lisdexamfetamine) UCB (methylphenidate CD) Shionogi (clonidine) Ortho-McNeil Janssen (methylphenidate OROS) 4

5. Key Question 1. Benefits 5

6. Key Question 1. Benefits (cont.) 6

7. Key Question 1. Benefits (cont.) 7

8. Key Question 1. Benefits (cont.) 8 LixDex: PCT trials: and superior to placebo on SKAMP-DS, as well as on ADHD rating scale IV mean changes. LixDex: PCT trials: and superior to placebo on SKAMP-DS, as well as on ADHD rating scale IV mean changes.

9. 9 Key Question 1. Benefits (cont.)

10. 10 Key Question 1. Benefits (cont.)

11. 11 Key Question 1. Benefits (cont.)

12. 12 Key Question 1. Benefits (cont.)

13. Key Question 2. Harms: short-term trial evidence 13

14. Key Question 2. Harms: short-term trial evidence (cont.) 14

15. 15 Key Question 2. Harms: short-term trial evidence (cont.)

16. Key Question 2. Harms: short-term trial evidence (cont.) 16

17. Key Question 2. Harms: short-term trial evidence (cont.) 17

18. Key Question 2. Long-term safety: death 18

19. Key Question 2. Long-term safety: cardiovascular 19

20. Key Question 2. Long-term safety: growth 20

21. Key Question 2. Abuse/misuse/diversion 21

22. Key Question 3. Subgroups 22

23. Key Question 3. Subgroups 23

24. Key Question 3. Subgroups: common comorbidities 24

25. Key Question 3. Subgroups: common comorbidities (cont.) 25

26. Key Question 3. Subgroups: common comorbidities (cont.) 26

27. Conclusions: Children Evidence in children and adolescents on the comparative effectiveness of drugs to treat ADHD was insufficient. Evidence on the comparative efficacy in children and adolescents was moderate to low strength and indicated very few differences among the drugs in improving symptoms or in adverse event rates. Sustained-release formulations of stimulants showed benefit over comparators at specific times of day depending on the pharmacokinetics of the specific formulation, but overall differences were not found. Atomoxetine was not found superior to some extended-release stimulant products, and resulted in higher rates of vomiting and somnolence and similar rates of nausea and anorexia, but lower rates of insomnia than stimulants. Extended-release formulations of clonidine and guanfacine had no comparative evidence to date. Immediate-release clonidine was similar to immediate-release methylphenidate. 27

28. Conclusions: Adults Evidence in adults on the comparative effectiveness of drugs to treat ADHD was insufficient. Evidence on comparative efficacy in adults was low-strength and found no significant differences between switching to methylphenidate OROS compared with continuing with immediate-release methylphenidate or between immediate-release guanfacine�or modafinil compared with immediate-release dextroamphetamine. Evidence was insufficient to assess the comparability of adverse events between switching to methylphenidate OROS or continuing with immediate-release methylphenidate. Low-strength evidence found no significant differences in adverse events between immediate-release guanfacine�or modafinil compared with immediate-release dextroamphetamine. 28

29. Conclusions: Harms and Subgroups Evidence on the risk of serious harms or in important subgroups of patients with ADHD (e.g. comorbid anxiety) was primarily noncomparative. Atomoxetine had increased risk of suicidal behavior compared with placebo, but estimates of the magnitude of risk were not precise. Immediate-release methylphenidate may have increased risk for sudden death, but evidence was conflicting and insufficient to make conclusions. Cerebrovascular events in adults did not differ between stimulants and atomoxetine. Dextroamphetamine immediate-release caused more inhibition of growth than other stimulants. The difference was influenced by dose and resolved after 2 years of treatment. Atomoxetine caused similar inhibition of weight gain up to 5 years. Evidence on abuse, misuse, and diversion was limited, but suggested that stimulant use was not associated with increased risk of substance use. Misuse and diversion rates varied by age and were highest among college students. Rates of diversion were highest with amphetamine-based products but similar among methylphenidate products. 29