1. Remoxy In Vivo Abuse Resistance Studies Ping Ji, PhD Senior Clinical Pharmacologist Office of Clinical Pharmacology Center of Drug Evaluation and Research Food and Drug Administration Ping Ji, PhD Senior Clinical Pharmacologist Office of Clinical Pharmacology Center of Drug Evaluation and Research Food and Drug Administration

2. 2 In Vivo Abuse Resistance Studies Physical Disruption Study Mastication (chewing) Study Buccal Absorption Study Physical Disruption Study Mastication (chewing) Study Buccal Absorption Study

3. 3 Dose Dumping For opioids, Cmax is a critical pharmacokinetic parameter For the assessment of dose dumping, it is important to examine data from both individual and group mean basis For opioids, Cmax is a critical pharmacokinetic parameter For the assessment of dose dumping, it is important to examine data from both individual and group mean basis

4. 4 Cumulative Frequency Analysis In a data set, the ‘more than’ cumulative frequency of a value x is the total number of observations that are more than or equal to x Frequency counts can be measured in terms of absolute numbers or relative numbers (e.g., proportions or percentages) In a data set, the ‘more than’ cumulative frequency of a value x is the total number of observations that are more than or equal to x Frequency counts can be measured in terms of absolute numbers or relative numbers (e.g., proportions or percentages)

5. 5 Physical Disruption Study –Treatment A: Remoxy 40 mg capsule (whole) –Treatment B: Remoxy 40 mg capsule (crushed, extracted with solvent) –Treatment C: OxyContin 40 mg tablet (whole) –Treatment D: OxyContin 40 mg tablet (crushed, extracted with solvent) –Treatment E: Oxycodone oral solution 40 mg –Treatment A: Remoxy 40 mg capsule (whole) –Treatment B: Remoxy 40 mg capsule (crushed, extracted with solvent) –Treatment C: OxyContin 40 mg tablet (whole) –Treatment D: OxyContin 40 mg tablet (crushed, extracted with solvent) –Treatment E: Oxycodone oral solution 40 mg

6. 6 Physical Disruption Study Physical Disruption Study Mean Oxycodone Plasma Concentration-Time Profiles

7. 7 Physical Disruption Study Remoxy OxyContin Mean Oxycodone Plasma Concentration-Time Profiles Statistical Comparison

8. 8 Physical Disruption Study Physical Disruption Study Mean Oxycodone Plasma Concentration-Time Profiles Statistical Comparison

9. 9 Physical Disruption Study Physical Disruption Study Cumulative Frequency Plots

10. 10 Physical Disruption Study Conclusion The extended-release characteristics appeared to be compromised when Remoxy was subjected crushing and extraction with a solvent

11. 11 Mastication Study Mastication Study –Treatment A: Remoxy 40 mg capsule (whole) –Treatment B: Remoxy 40 mg capsule masticated rigorously and then swallowed –Treatment C: Oxycondone oral solution 40 mg

12. 12 Mean Oxycodone Plasma Concentration-Time Profiles Mastication Study Mastication Study Statistical Comparison

13. 13 Cumulative Frequency Plots Mastication Study Mastication Study

14. 14 Mastication Study Conclusion The extended-release characteristics appeared to be compromised when Remoxy was subjected to mastication

15. 15 Buccal Absorption Study Buccal Absorption Study –Treatment A: Remoxy 40 mg capsule (whole) –Treatment B: Remoxy 40 mg capsule held in the buccal cavity and then swallowed –Treatment C: Oxycodone oral solution 40 mg

16. 16 Buccal Absorption Study Mean Oxycodone Plasma Concentration-Time Profiles Statistical Comparison

17. 17 Cumulative Frequency Plots Buccal Absorption Study Buccal Absorption Study

18. 18 Buccal Absorption Study Conclusion The extended-release characteristics appeared to be compromised when Remoxy was subjected to buccal absorption

19. 19 Overall Summary The extended-release characteristics appeared to be compromised when Remoxy was subjected to crushing and extraction with ethanol, mastication, and buccal absorption