Reported Manipulation of OxyContin Tablets

1. Reported Manipulation of OxyContin Tablets LCDR Kristina C. Arnwine, PharmD Acting Team Leader Division of Medication Error Prevention Office of Surveillance and Epidemiology

2. Overview • AERS search • Methods of manipulation • Summary

3. Adverse Event Reporting System:Spontaneous Adverse Event Reporting • Voluntary, “spontaneous” reporting • Facilitated by the FDA MedWatch Program • Reports are stored and retrieved via Adverse Event Reporting System (AERS) database

4. AERS Strengths • Includes all U.S. marketed products • Detection of events not seen in clinical trials • Especially good for events with rare background rate, short latency

5. AERS Limitations • Extensive underreporting • Quality of reports is variable • Reporting biases • Actual numerator & denominator not known • Causality of drug-event association often in question

6. AERS Search • Search limited to brand name: • OxyContin • 7300 reports retrieved • Narrative search for terms: • crush, chew, inhale, dissolve, inject, and snort

7. Narrative Search

8. OxyContin Manipulation Reports (n=209)

9. OxyContin Manipulation Reports (cont) • Medication errors (n=22) • healthcare practitioners crushing tablets for ease of administration • labeling includes warnings against crushing or chewing • Abuse (n=187)

10. Methods of Manipulation

11. Summary • Manipulation associated with abuse • Manipulation is not completely representative of all abuse • No discernable trend regarding strength • Consideration should be given to consequences of administration of manipulated tablets of the new formulation • Dissolution of reformulated product in untested solvents • Adverse events related to injection of reformulated product • Postmarketing safety surveillance

12. Acknowledgements CDR Melina N. Griffis, R.Ph. LCDR Cathy A. Miller, M.P.H., B.S.N. Linda Kim-Jung, PharmD Division of Medication Error Prevention Office of Surveillance and Epidemiology

13. Summary of Drug Abuse “Rates” in the United States Catherine Dormitzer, PhD, MPH Division of Epidemiology Office of Surveillance and Epidemiology Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

14. Overview • Background • Methods • Summary of calculations • Conclusions Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

15. Background/Methods • Numerator data • Non-medical Use ED Visits (DAWN) • Past year non-medical use (NSDUH) • Denominator data • Retail prescriptions (Verispan) used as proxy for drug availability • Calculated estimates per 10,000 retail prescriptions Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

16. Limitations • Calculating estimates using data from different sources • Sampling Methodologies • Populations • Data are not linked Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

17. 2004 vs. 2006 Nonmedical-Use ED Visits: Selected Opiates/Opioids, 2004-2006 No significant change *Significant change: * Single- & multi-ingredient formulations Source: National estimates from DAWN, 2004-2006

18. Projected Retail Prescriptions Dispensed for Selected Opioids, 2004-2006Verispan Vector One™: National (VONA). Extracted 3/2008 Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

19. DAWN: ED Visits -- Non-Medical Use per 10,000 Retail Prescriptions 2004 – 2006 * Includes all formulations Source: National estimates from DAWN, 2004-2006; Verispan VONA Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

20. No significant change *Significant change, 2004 vs. 2006 2005 vs. 2006 Nonmedical-Use ED Visits:Oxycodone, ER vs. IR Source: DAWN estimates for the U.S., 2004-2006

21. Projected Retail Prescriptions Dispensed for Oxycodone by Release Type, 2004-2006Verispan Vector One™: National (VONA). Extracted 3/2008 Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

22. DAWN: ED Visits -- Non-Medical Use of per 10,000 Retail Prescriptions, Oxycodone by Release Type, 2004 - 2006 Sources: National estimates from DAWN, 2004-2006; Verispan VONA Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

23. Past Year Indicators of Nonmedical Use of OxyContin®, Ages 12 and Older: 2004-2006 Number in Thousands + Difference between this estimate and the 2006 estimate is statistically significant at the .05 level.

24. NSDUH: Past Year Initiates and Past Year Non-medical Use of Oxycontin per 10,000 Retail Prescriptions: 2004 -2006 Sources: National estimates from NSDUH, 2004-2006; Verispan VONA Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

25. Summary • Non-medical use of pain relievers derived from DAWN and NSDUH provide information on the public burden of non-medical use of opioids. • Prescription data can serve as a proxy for drug availability and provides context for non-medical use. • “Rates” of non-medical use of Oxycodone are considerably higher for extended release versus immediate release Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

26. Conclusions • OxyContin and their generics have higher “rates” of non-medical use than the comparator opioids, hydrocodone, fentanyl and immediate release oxycodone • Although there has been minimal increases in estimated ratios of Oxycontin non-medical use; actual numbers of users are increasing -- an important public health problem. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

27. Questions? Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, May 5, 2008

28. History of OxyContin: Labeling and Risk Management Program Mwango Kashoki, MD, MPH Medical Team Leader Division of Anesthesia, Analgesia, and Rheumatology Products Office of Drug Evaluation II

29. OxyContin: Approval • OxyContin was approved on December 12, 1995. • Launched in 1996 • Approval occurred when: • There was increasing recognition that many patients with pain are inadequately treated • Diversion and abuse of controlled prescription drugs was increasing

30. OxyContin: Initial product labeling • Schedule: CII • Strengths: 10, 20, and 40 mg controlled-release tablets • Clinical trials: • Both cancer and non-cancer pain populations • Arthritis; post-op pain; ambulatory surgery • Use in opioid-naïve patients • Equivalence and open-label studies

31. OxyContin: Initial product labeling • Indication: • “For the management of moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days.”

32. OxyContin: Initial labeling • Warnings; Dosage and Administration: • “OxyContin tablets are to be swallowed whole, and are not to be broken, chewed, or crushed. Swallowing broken, chewed, or crushed OxyContin tablets could lead to the rapid release and absorption of a potentially toxic dose of oxycodone.” • Drug abuse and Dependence: • OxyContin…is a schedule II controlled substance. Oxycodone products are common targets for both drug abusers and drug addicts. Delayed absorption, as provided by OxyContin tablets is believed to reduce the abuse liability of a drug.”

33. OxyContin: supplemental NDAs • 80-mg tablet approved Dec 9, 1996 • Notable changes to the product label: • Description: • 80-mg tablets to be used only in opioid tolerant patients. • Precautions; Dosage and Administration: • OxyContin 80 mg tablets are for use only in opioid tolerant patients requiring daily equivalent dosages of 160 mg or more. … Patients should be instructed against use by individuals other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences.

34. OxyContin: supplemental NDAs • 160 mg tablet approved on Mar 15, 2000 • Notable changes to the product label: • Description: • 80- and 160-mg tablets to be used only in opioid tolerant patients • Precautions; Dosage and Administration: • OxyContin 80 mg and 160 mg tablets are for use only in opioid tolerant patients requiring daily equivalent dosages of 160 mg or more for the 80 mg tablet and 320 mg or more for the 160 mg tablet.

35. 2000: Increased OxyContin availability • Purdue implemented an aggressive marketing campaign: • Primary care providers • Use in non-cancer pain • Musculoskeletal pain; post-operative pain • Use as “first-line” therapy for chronic pain • Physician-directed advertising • Medical journals; conferences; video

36. May 11, 2000: DDMAC Untitled Letter OxyContin promotional material • Press release, flash card, DHCP letters • Misleading efficacy claims: • 160-mg can be used in opioid non-tolerant patients • 160-mg can be used as first-line therapy in patients with long-lasting pain • E.g. arthritis, cancer, injuries, LBP. • “Prompt” onset of drug • Positive effects on quality of life (e.g. sleep, mood) • Lack of fair balance with respect to presentation of risk information • Purdue discontinued these advertising materials.

37. 2000: Initial reports of OxyContin abuse and diversion • Increasing media and state reports of abuse and diversion of OxyContin: • Crushing of tablets • Oral, inhalation, injection administration • Adverse events included addiction, withdrawal and fatalities • Prominently affected areas: • Appalachian states • Kentucky, Virginia, W. Virginia, Pennsylvania • Maine; Ohio • Recreational drug users, teenagers, pain patients

38. OxyContin abuse and diversion: Possible contributing factors • Drug Substance • Recent evidence suggests that oxycodone is more reinforcing than morphine • Product formulation • High oxycodone content • Although it was initially believed that the PK characteristics of a CR formulation would reduce the reinforcing properties, experience has shown that defeat of the CR mechanisms is associated with abuse

39. OxyContin abuse and diversion: Possible contributing factors • Increased drug availability • Increased prescribing of controlled prescription drugs for pain • Medical community more accepting of the use of opioids to treat pain • Purdue’s strong marketing strategy • Product labeling • Warning against crushing may have alerted abusers to a method for misuse • Label language suggesting that OxyContin had lower abuse potential may have impacted product use or prescribing

40. OxyContin abuse and diversion: Initial Agency and company actions • Purdue: • Formed a response team to evaluate problem of abuse/diversion in Maine • Contacted the Agency about the problems (Mar 2001) • Elected to discontinue marketing of the 160 mg tablet • FDA: • Requested additional information regarding OxyContin abuse • Reviewed available data to • Assess for any relationship between OxyContin abuse/misuse and adverse events • Determine prescribing patterns of OxyContin • Met with Purdue to discuss the issues (April 2001)

41. Reconsideration of the OxyContin label • Dec 2000: Purdue submitted a labeling supplement to change the language regarding reduced abuse liability. • In the context of abuse, diversion and adverse events associated with OxyContin, FDA decided to strengthen the wording of the entire label.

42. July 2001: Revised OxyContin label • Addition of a Box Warning • Calls attention to the potential for abuse, misuse and diversion of the product. • Highlights the proper treatment population. • CLINICAL TRIALS section • Restricted to the single adequate and well-controlled clinical study. • INDICATIONS section revised to reflect the appropriate patient population.

43. July 2001: Revised OxyContin label • INDICATIONS: • OxyContin tablets are… indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time. • OxyContin is not intended for intermittent dosing or as a prn analgesic. • OxyContin is not indicated for pain in the immediate post-operative period if the pain is mild or not expected to persist…

44. July 2001: Revised OxyContin label • Expanded WARNINGS section • Warns against breaking, crushing, or chewing the tablets • Highlights the potential for misuse, abuse, and diversion of OxyContin • Specifies the potential adverse events associated with OxyContin misuse and abuse • Deleted: language regarding reduced abuse liability with a CR formulation.

45. OxyContin: Revised labeling and promotional materials • All promotional materials had to be revised based on the product label. • When new risk information is added to the PI, all promotional materials must include this new data within 30 days. • All revised promotional materials must be submitted for (expedited) review within 2 weeks.

46. OxyContin: Risk Management Plan • FDA and Purdue began discussion of the importance and features of an RMP in April 2001. • Ideally, RMP would comprise • Prevention of abuse, misuse and diversion • Clear product labeling • Physician and pharmacist education • Patient education (e.g. Patient Package Insert) • Development of an abuse deterrent formulation • Surveillance, monitoring and feedback • Incidence of drug abuse and misuse • Identification of risk factors • Effectiveness of prevention strategies

47. OxyContin: Risk Management Plan • August 2001: Purdue submitted initial draft RMP • Key features • Education and outreach • Surveillance and monitoring • Drug utilization (IMS Health; NDA Health) • Drug exposure (e.g. prescription monitoring programs) • Drug abuse and misuse • DAWN, NHSDA (now NSDUH), TESS, RADARS • Intervention – when a signal is detected

48. OxyContin: Patient Education • A Patient Package Insert (PPI) was approved in January 2002 • PPI described: • Appropriate therapeutic uses of OxyContin • Proper drug administration • Do not chew, crush, or dissolve the tablet • OxyContin is a desirable drug of abuse • Drug should be stored securely • Risks associated with misuse and abuse

49. OxyContin: Public Discussions January 30 & 31, 2002 • Advisory Committee meeting to discuss: • Opioid analgesic use and development. • Use of opioid analgesics in pediatric patients. • Abuse and misuse of opioid analgesics. • Notable conclusions: • Abuse of opioid analgesics is a considerable public health problem. • However, opioid analgesics are an essential component of pain management. • Any RMP that restricts opioid treatment may prevent their appropriate utilization.

50. Development of an abuse-deterrent OxyContin formulation • After the Advisory Committee meetings, Purdue initiated discussion with the Agency regarding the development of a reformulated OxyContin. • Proposals: • OxyContin/opioid antagonist combinations • Modification of the physiochemical properties • 2003 – 2007: FDA and Purdue met several times to continue discussion of the development a reformulation.