1. FDA Anesthetic & Life Support Drugs Advisory Committee Sept. 10, 2003 Art Van Zee,MD St. Charles Clinic St. Charles, Va.

2. Susstained-release hydromorphone (Palladone) --Risks vs. benefits discussion

3. Benefits Review sustained release opioids vs. IR opioids

4. IR oxycodone vs CR oxycodone Comparable Efficacy & Safety Hale Clin J Pain 9/99 BACK PAIN Kaplan R J Clin Oncol 10/98 CANCER Stambauugh J.Clin Pharm 5/01 CANCER

5. OxyContin--NDA--1995 MEDICAL OFFICER REVIEW (MOR) Summary of Safety “ The best conclusion is that the efficacy of the CR (oxycodone) is equivalent to the IR, with an adverse event profile that is as good as the IR. I would not allow a ‘better’ claim” --Curtis Wright, MRO

6. OxyContin---NDA---1995 Summary of Efficacy “CR oxycodone appears to be a BID alternative to conventional QID oxycodone. Approval is recommended. Care should be taken to limit competitive promotion. This product has been shown to be as good as current therapy, but has not been shown to have a significant advantage beyond reduction in frequency of dosing.” --Curtis Wright, MRO

7. The Medical Letter— 9/17/01 “OxyContin is a q12h controlled-release formulation of oxycodone that can be used effectively in the treatment of pain due to cancer, and occasionally, other types of chronic pain. There is no evidence that oxycodone offers any advantage over appropriate doses of other opioids, and it appears to have the same potential for addiction as morphine.”

8. CR morphine vs CR oxycodone Comparable in Efficacy and Safety Heiskanen Pain 10/97 CANCER Mucci-LoRusso ’98 CANCER Bruera J. Clin Oncol 10/98 CANCER

9. IR hydromorphone vs CR hydromorphone (Q12hr) Comparable Efficacy and Safety Hayes Cancer 9/94 CANCER Bruera J. Clin Oncol 5/96 CANCER

10. CR oxycodone vs CR hydromorphone (Q12hrs) Comparable Efficacy & Safety Hagen Cancer 4/97 CANCER

11. Summary 1. IR opioids and SR opioids are comparable in efficacy & safety 2. SR preparations appear comparable in efficacy & safety

12. Benefits: ---CONVENIENCE of bid or qd dosing ---Convenience of less pills ---for patients intolerant to other opioid preparations

13. Risks of sustained release hydromorphone 1. of addiction when taken as prescribed-----Unknown 2. of addiction—when used non-medically—recreationally 3. of overdose and death—high potency opioid dosing-- one pill

14. RISKS of CR hydromorphone 1.Brief over-view of the promotion and marketing of OxyContin ---”Aggressive” marketing for chronic non-malignant pain ---Aggressive marketing to primary care physicians

15. OxyContin marketing (cont) -- Trivializing the risk of addiction for chronic non-cancer pain --Use of sophisticated marketing data to target and influence high opioid prescribing docs

17. 1998 2000 Counties hydrocodone OxyContin Tazewell,Va 545% 456% Perry, Ky 415% 559% Logan,WVa 397% 430% % above national average

22. Personal thoughts: 1.Replication of OxyContin problem if “Indications” for use of Palladone, and marketing--- are the same as OxyContin 2. Unrestricted use in cancer 3.Restricted use to a “compassionate use” program in chronic non-cancer pain