Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 2008 Reported Manipulation of OxyContin Tablets LCDR Kristina C. Arnwine, PharmD Acting Team Leader Division of Medication Error Prevention Office of Surveillance and Epidemiology LCDR Kristina C. Arnwine, PharmD Acting Team Leader Division of Medication Error Prevention Office of Surveillance and Epidemiology

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OverviewOverview AERS search Methods of manipulation Summary AERS search Methods of manipulation Summary

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Voluntary, “spontaneous” reporting Facilitated by the FDA MedWatch Program Reports are stored and retrieved via Adverse Event Reporting System (AERS) database Voluntary, “spontaneous” reporting Facilitated by the FDA MedWatch Program Reports are stored and retrieved via Adverse Event Reporting System (AERS) database Adverse Event Reporting System : Spontaneous Adverse Event Reporting

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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 Includes all U.S. marketed products Detection of events not seen in clinical trials Especially good for events with rare background rate, short latency

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 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 Extensive underreporting Quality of reports is variable Reporting biases Actual numerator & denominator not known Causality of drug-event association often in question

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, AERS Search Search limited to brand name: –OxyContin 7300 reports retrieved Narrative search for terms: –crush, chew, inhale, dissolve, inject, and snort Search limited to brand name: –OxyContin 7300 reports retrieved Narrative search for terms: –crush, chew, inhale, dissolve, inject, and snort

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Narrative Search Total number of reports evaluated380 Reports excluded –did not involve manipulation of OxyContin 171 Reports further evaluated –to determine method of manipulation 209

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin Manipulation Reports (n=209) Strengths involved 10 mg13 20 mg11 40 mg27 60 mg and 160 mg No longer marketed 5 80 mg25 No strength reported128

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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) Medication errors (n=22) –healthcare practitioners crushing tablets for ease of administration –labeling includes warnings against crushing or chewing Abuse (n=187)

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Methods of Manipulation Methods of preparation crush90 chew16 cut2 grind2 melt2 crack1 dissolve1 Methods of administration inject69 snort26

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, SummarySummary 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, AcknowledgementsAcknowledgements 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 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

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

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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Background/MethodsBackground/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 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

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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Nonmedical-Use ED Visits: Selected Opiates/Opioids, Source: National estimates from DAWN, * Single- & multi-ingredient formulations No significant change*Significant change: 2004 vs. 2006

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

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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Nonmedical-Use ED Visits: Oxycodone, ER vs. IR Source: DAWN estimates for the U.S., No significant change*Significant change, 2004 vs vs. 2006

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

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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Past Year Indicators of Nonmedical Use of OxyContin ®, Ages 12 and Older: Number in Thousands + Difference between this estimate and the 2006 estimate is statistically significant at the.05 level.

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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, SummarySummary 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, ConclusionsConclusions 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. 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

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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 2008 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 Mwango Kashoki, MD, MPH Medical Team Leader Division of Anesthesia, Analgesia, and Rheumatology Products Office of Drug Evaluation II

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin: Approval OxyContin was approved on December 12, –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 OxyContin was approved on December 12, –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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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.” Indication: –“For the management of moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days.”

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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.” 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.”

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, : 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, : 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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) 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)

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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… 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…

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin: Risk Management Plan FDA and Purdue began discussion of the importance and features of an RMP in April 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 FDA and Purdue began discussion of the importance and features of an RMP in April 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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 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

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 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. 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.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, January 17, 2003: DDMAC Warning Letter OxyContin promotional material Print ads in medical journals Issues: –Minimization of serious safety risks No presentation of information in the Box Warning –Overstatement of the safety profile No mention of serious, potentially fatal risks –Promotion for a broader range of patients No information on limitations of the indicated use Purdue ceased dissemination of the ads. Print ads in medical journals Issues: –Minimization of serious safety risks No presentation of information in the Box Warning –Overstatement of the safety profile No mention of serious, potentially fatal risks –Promotion for a broader range of patients No information on limitations of the indicated use Purdue ceased dissemination of the ads.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin Promotional Materials: Other DDMAC Untitled letters Misleading claims regarding treatment population Incomplete information regarding limitations for OxyContin use Misleading efficacy claims –Implied greater efficacy than IR oxycodone –Implied/unsubstantiated beneficial effects on life and function Minimization of risk –Minimization of potentially fatal effects of OxyContin and adverse effects in opioid naïve patients Misleading dosage and administration claims Misleading claims regarding treatment population Incomplete information regarding limitations for OxyContin use Misleading efficacy claims –Implied greater efficacy than IR oxycodone –Implied/unsubstantiated beneficial effects on life and function Minimization of risk –Minimization of potentially fatal effects of OxyContin and adverse effects in opioid naïve patients Misleading dosage and administration claims

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin: Public Discussions September 9 & 10, 2003 Advisory Committee meeting to discuss: –RMPs for opiate analgesic drug products Particular attention to modified-release products –Abuse liability of and RMP for Palladone (controlled-released hydromorphone) Key conclusions: RMP should include - –Appropriate prescriber education –Surveillance of misuse, abuse, diversion –Assessment of the source(s) of diverted drugs –Assessment of the RMP’s impact on opioid prescribing practices Advisory Committee meeting to discuss: –RMPs for opiate analgesic drug products Particular attention to modified-release products –Abuse liability of and RMP for Palladone (controlled-released hydromorphone) Key conclusions: RMP should include - –Appropriate prescriber education –Surveillance of misuse, abuse, diversion –Assessment of the source(s) of diverted drugs –Assessment of the RMP’s impact on opioid prescribing practices

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, : Approval of generic controlled-release oxycodone Endo Pharmaceuticals Inc. –10 mg, 20 mg, 40 mg, and 80 mg tablets Teva Pharmaceuticals USA –80 mg tablet Impax Laboratories Inc. –80 mg tablet All generic controlled-release oxycodone formulations had an RMP. Endo Pharmaceuticals Inc. –10 mg, 20 mg, 40 mg, and 80 mg tablets Teva Pharmaceuticals USA –80 mg tablet Impax Laboratories Inc. –80 mg tablet All generic controlled-release oxycodone formulations had an RMP.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin Patent Litigation (1999) Purdue filed patent infringement actions against generic companies: –Endo Pharmaceuticals, Inc. –Boehringer Ingelheim GmbH –Teva Pharmaceuticals, Inc. –Impax Laboratories, Inc. (1999) Purdue filed patent infringement actions against generic companies: –Endo Pharmaceuticals, Inc. –Boehringer Ingelheim GmbH –Teva Pharmaceuticals, Inc. –Impax Laboratories, Inc.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin Patent Litigation Initial judgments in favor of defendants –January 5, 2004: District Court: Endo infringed, but the patents were invalid due to inequitable conduct. –Purdue enjoined from enforcing patents Summary judgment issued in favor of Teva, Impax, and Boehringer –June 7, 2005 Decision affirmed by Federal Circuit Initial judgments in favor of defendants –January 5, 2004: District Court: Endo infringed, but the patents were invalid due to inequitable conduct. –Purdue enjoined from enforcing patents Summary judgment issued in favor of Teva, Impax, and Boehringer –June 7, 2005 Decision affirmed by Federal Circuit

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Patent Litigation: Final outcomes Federal Circuit withdrew its affirmance and vacated the District Court decision –February 1, 2006 –Endo case remanded back to District Court Purdue settled its suits with the generic companies –October 16, 2006 District Court judgment on Endo case: Patents are enforceable –January 7, 2007 Final settlement agreement: – Generics would be marketed for only a limited time after the settlement. Federal Circuit withdrew its affirmance and vacated the District Court decision –February 1, 2006 –Endo case remanded back to District Court Purdue settled its suits with the generic companies –October 16, 2006 District Court judgment on Endo case: Patents are enforceable –January 7, 2007 Final settlement agreement: – Generics would be marketed for only a limited time after the settlement.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Generic CR oxycodone products: Current Status Approved but discontinued: –Teva and Impax products Initial approval rescinded; currently in tentative approval status: –Endo product Marketed: –Watson’s generic version of Purdue’s OxyContin –Watson is Purdue’s authorized distributor of generic OxyContin 10, 20, 40, and 80 mg strengths Approved but discontinued: –Teva and Impax products Initial approval rescinded; currently in tentative approval status: –Endo product Marketed: –Watson’s generic version of Purdue’s OxyContin –Watson is Purdue’s authorized distributor of generic OxyContin 10, 20, 40, and 80 mg strengths

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin: Other Key Events Approval of additional OxyContin strengths –Sep 18, 2006 –15, 30, and 60, mg tablets Purdue and 3 executives pleaded guilty charges of misleading the public about the risks of OxyContin –Settlement: May 10, 2007 –$634.5 million to be paid in fines –Case was regarding promotional activities that occurred prior to mid-2001 Approval of additional OxyContin strengths –Sep 18, 2006 –15, 30, and 60, mg tablets Purdue and 3 executives pleaded guilty charges of misleading the public about the risks of OxyContin –Settlement: May 10, 2007 –$634.5 million to be paid in fines –Case was regarding promotional activities that occurred prior to mid-2001

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin Tamper Resistant (OTR) Reformulation Purdue submitted an NDA for its reformulated OxyContin product last year. Reformulated strengths: 10, 15, 20, 30, and 40 mg –No reformulated 80-mg strength New formulation is intended to be resistant to physical and chemical manipulation: –Crushing/milling –Crushing/milling and extraction with solvents Manipulation testing was done based on known methods of abuse –Drug preparation and routes of administration Purdue submitted an NDA for its reformulated OxyContin product last year. Reformulated strengths: 10, 15, 20, 30, and 40 mg –No reformulated 80-mg strength New formulation is intended to be resistant to physical and chemical manipulation: –Crushing/milling –Crushing/milling and extraction with solvents Manipulation testing was done based on known methods of abuse –Drug preparation and routes of administration

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin Reformulation: Proposed Labeling and Risk Management Package insert: –Description of the effects of physical manipulations on the drug product. Risk management program: –Additional surveillance: OxyContin abuse after approval of reformulation Abuse techniques and consequences –“old” OxyContin formulation vs. reformulation Package insert: –Description of the effects of physical manipulations on the drug product. Risk management program: –Additional surveillance: OxyContin abuse after approval of reformulation Abuse techniques and consequences –“old” OxyContin formulation vs. reformulation

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OxyContin: Current status Over the years, FDA and Purdue have negotiated numerous revisions to strengthen the product labeling and the RMP. However, multiple indices show that abuse and diversion of OxyContin continue to be significant public health issues. Availability of a CR oxycodone product with reduced abuse liability is desirable. –Impact on abuse prevalence and patterns in unknown. Over the years, FDA and Purdue have negotiated numerous revisions to strengthen the product labeling and the RMP. However, multiple indices show that abuse and diversion of OxyContin continue to be significant public health issues. Availability of a CR oxycodone product with reduced abuse liability is desirable. –Impact on abuse prevalence and patterns in unknown.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 2008 Outpatient Drug Utilization Trends for Oxycodone Products LCDR Kendra Worthy, Pharm.D. Drug Utilization Analyst Laura Governale, Pharm.D., MBA Drug Utilization Analyst Team Leader Division of Epidemiology Office of Surveillance and Epidemiology May 5, 2008 LCDR Kendra Worthy, Pharm.D. Drug Utilization Analyst Laura Governale, Pharm.D., MBA Drug Utilization Analyst Team Leader Division of Epidemiology Office of Surveillance and Epidemiology May 5, 2008

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, OutlineOutline Sales distribution data: IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail Prescription data: Verispan, Vector One ® : National (VONA)* –Opioid market –State level data –Prescriber specialty Patient-level data: Verispan, Vector One ® : National (VONA)* and Verispan, Vector One ® : Total Patient Tracker (TPT)* –Age distribution Conclusions Sales distribution data: IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail Prescription data: Verispan, Vector One ® : National (VONA)* –Opioid market –State level data –Prescriber specialty Patient-level data: Verispan, Vector One ® : National (VONA)* and Verispan, Vector One ® : Total Patient Tracker (TPT)* –Age distribution Conclusions * Does not include data from mail order pharmacies, outpatient clinics, long term care facilites, or same day surgery centers.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 2008 Sales distribution data Year 2007 IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, IMS Health, IMS National Sales Perspectives™ Measures sales data from manufacturers to retail and non-retail channels of distribution –Extended Units are the number of tablets, capsules, milliliters, ounces, etc. of a product shipped in each unit Retail Channels - chain, independent, mass merchandisers, food stores with pharmacies, and mail- order pharmacies Non-Retail Channels - federal facilities, non-federal hospitals, clinics, long-term care facilities, home health care (began 1998), HMOs, miscellaneous channels (began 1999; prisons, universities, other) Measures sales data from manufacturers to retail and non-retail channels of distribution –Extended Units are the number of tablets, capsules, milliliters, ounces, etc. of a product shipped in each unit Retail Channels - chain, independent, mass merchandisers, food stores with pharmacies, and mail- order pharmacies Non-Retail Channels - federal facilities, non-federal hospitals, clinics, long-term care facilities, home health care (began 1998), HMOs, miscellaneous channels (began 1999; prisons, universities, other)

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected number of OxyContin® and Oxycodone ER Tablets (in thousands) sold from the manufacturer to retail and non-retail pharmacies in the U.S., Year 2007 Retail pharmacy distribution, 87% Non-retail pharmacy distribution, 13% IMS HEALTH, IMS National Sales Perspective TM, 2007, Extracted Source File: NSPC Oxycontin oxyc.xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, 2008 Prescription and Patient-level Data Verispan, Vector One ® : National (VONA) Verispan, Vector One ® : Total Patient Tracker (TPT) Verispan, Vector One ® : National (VONA) Verispan, Vector One ® : Total Patient Tracker (TPT)

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Verispan, LLC Vector One ® : National (VONA) Verispan’s Vector One ® : National (VONA) is a national-level projected prescription and patient-centric tracking service. –Receives over 2.0 billion prescription claims per year, representing over 160 million unique patients. The number of dispensed prescriptions is obtained from a sample of approximately 59,000 pharmacies throughout the U.S., accounting for nearly all retail pharmacies and represent nearly half of retail prescriptions dispensed nationwide. Retail pharmacies include: –national retail chains, –mass merchandisers, –pharmacy benefits managers and their data systems, –provider groups. Data on prescribing specialty and patient age/gender are available as well as state level data. Verispan’s Vector One ® : National (VONA) is a national-level projected prescription and patient-centric tracking service. –Receives over 2.0 billion prescription claims per year, representing over 160 million unique patients. The number of dispensed prescriptions is obtained from a sample of approximately 59,000 pharmacies throughout the U.S., accounting for nearly all retail pharmacies and represent nearly half of retail prescriptions dispensed nationwide. Retail pharmacies include: –national retail chains, –mass merchandisers, –pharmacy benefits managers and their data systems, –provider groups. Data on prescribing specialty and patient age/gender are available as well as state level data.

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Retail Prescriptions Dispensed For Selected Opioids, Years (With Hydrocodone and Oxycodone Combination Products) Verispan Vector One™: National (VONA). Extracted 3/2008 Hydrocodone #1 dispensed prescription product of all dispensed prescriptions for the past 10 years Oxycodone products nearly 42 million dispensed prescriptions during year 2007 Hydrocodone #1 dispensed prescription product of all dispensed prescriptions for the past 10 years Oxycodone products nearly 42 million dispensed prescriptions during year 2007 Original File: VONA oxycodone comp AC xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Retail Prescriptions Dispensed for Selected Opioids, Years (WITHOUT Hydrocodone Combination Products) Verispan Vector One™: National (VONA). Extracted 1/2008 Extended release oxycodone products: ~7.5 million retail Rx in Y2007 (5.5 million oxycodone ER, 2 million OxyContin ® ) Fentanyl & Morphine tied for 3rd: ~5.5 million retail Rx in Y2007 Extended release oxycodone products: ~7.5 million retail Rx in Y2007 (5.5 million oxycodone ER, 2 million OxyContin ® ) Fentanyl & Morphine tied for 3rd: ~5.5 million retail Rx in Y2007 Original File: VONA oxycodone AC xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Retail Prescriptions Dispensed for Oxycodone, Years (Immediate Release vs. Extended Release Formulations) Verispan Vector One™: National (VONA). Extracted 2/2008 Extended-release market relatively constant at 6-8 million dispensed prescriptions for last 7 years Immediate-release market increasing Extended-release market relatively constant at 6-8 million dispensed prescriptions for last 7 years Immediate-release market increasing Original File: VONA oxycodone xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Retail Prescriptions Dispensed for Extended Release Oxycodone Products, Year 2007 Verispan Vector One™: National (VONA). Extracted 4/2008 Highest ER Oxycodone volume in: FL (604,000), CA (515,000), PA (428,000), OH 389,000), NY (311,000), NJ (268,000)

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Retail Prescriptions Dispensed for Extended Release Oxycodone by Company, Years Verispan Vector One™: National (VONA). Extracted 2/2008 TEVA brand lead market in Y2007, accounting for 37% of all oxycodone extended release market. Purdue was second with 27% of market share. TEVA brand lead market in Y2007, accounting for 37% of all oxycodone extended release market. Purdue was second with 27% of market share. Original File: VONA oxycodone xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Number of OxyContin ® and All Generic Oxycodone ER Prescriptions, by strength, Dispensed from U.S. Retail Pharmacies, Years Verispan Vector One™: National (VONA). Extracted 4/2008 ~89% decreaseOxyContin~89% decrease in OxyContin ® Rxs (from 6.6 million to 6.1 million prescriptions) between years 2003 and ~330% decrease (from 6.1 million to 1.4 million prescriptions) between years 2004 and 2006 with the introduction of Oxycodone ER Oxycodone ER prescription volume peaked at 5.5 million prescriptions in Y2006. ~89% decreaseOxyContin~89% decrease in OxyContin ® Rxs (from 6.6 million to 6.1 million prescriptions) between years 2003 and ~330% decrease (from 6.1 million to 1.4 million prescriptions) between years 2004 and 2006 with the introduction of Oxycodone ER Oxycodone ER prescription volume peaked at 5.5 million prescriptions in Y2006. Original File: VONA oxycodone er strgth.xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Retail Prescriptions Dispensed for Extended Release Oxycodone Prescriptions, by strength, Years Verispan Vector One™: National (VONA). Extracted 4/ mg leading strength since 1998: 2.4 million Rx in Y mg second since Y2002: 2.3 million Rx in Y mg and 80 mg: 1.4 million Rx in Y mg leading strength since 1998: 2.4 million Rx in Y mg second since Y2002: 2.3 million Rx in Y mg and 80 mg: 1.4 million Rx in Y2007 Original File: VONA oxycodone er strgth.xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Number of OxyContin ® and All Generic Oxycodone ER Prescriptions, by Physician Specialty, Dispensed from U.S. Retail Pharmacies, Years Verispan Vector One™: National (VONA). Extracted 4/2008 Leading prescribers in Y2007: General Practice* 2.1 million Rx (28%), Internal Medicine 1.3 million Rx (18%), Anesthesiology 843,000 Rx (11%) *Family Medicine, Osteopathic Medicine, General Practice

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, Projected Number of Prescriptions and Unique Patients, by age, receiving a prescription for OxyContin ® and Oxycodone ER from outpatient retail pharmacies, Year 2007 Verispan Vector One®: National (VONA), Data Extracted 4/08 Verispan, LLC: Total Patient Tracker, Extracted 3/08 Oxycodone ER products (brand and generic combined): 1.5 million patients –Oxycodone ER: 1.3 million patients –OxyContin ® : 400,000 patients Majority of prescriptions dispensed to year age group. Pediatric patients (0-16 years) account for <1%. Oxycodone ER products (brand and generic combined): 1.5 million patients –Oxycodone ER: 1.3 million patients –OxyContin ® : 400,000 patients Majority of prescriptions dispensed to year age group. Pediatric patients (0-16 years) account for <1%. Original File: VONA oxycodone er age.xls

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, ConclusionsConclusions Hydrocodone products #1 dispensed prescription product –~119 million Rx in 2007 Oxycodone products (ER & IR combined) 2 nd among opioids –~42.2 million Rx in 2007 and 14.7 million patients Oxycodone ER products –Oxycodone ER: 5.5 million Rx and 1.3 million patients –OxyContin ® : 2 million Rx and 400,000 patients Highest ER Oxycodone Rx volume in FL, CA, PA, OH, NY, NJ TEVA brand lead market share of ER Oxycodone Rx in Y2007 (37%) –Purdue: 27% –Watson: 18% Leading prescribers in Y2007: General Practitioners (28%), Internal Medicine (18%), Anesthesiologists (11%) ER Oxycodone Rxs most commonly dispensed to patients aged years Hydrocodone products #1 dispensed prescription product –~119 million Rx in 2007 Oxycodone products (ER & IR combined) 2 nd among opioids –~42.2 million Rx in 2007 and 14.7 million patients Oxycodone ER products –Oxycodone ER: 5.5 million Rx and 1.3 million patients –OxyContin ® : 2 million Rx and 400,000 patients Highest ER Oxycodone Rx volume in FL, CA, PA, OH, NY, NJ TEVA brand lead market share of ER Oxycodone Rx in Y2007 (37%) –Purdue: 27% –Watson: 18% Leading prescribers in Y2007: General Practitioners (28%), Internal Medicine (18%), Anesthesiologists (11%) ER Oxycodone Rxs most commonly dispensed to patients aged years

Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 5, AcknowledgementAcknowledgement Mara McAdams Epidemiology and Policy Fellow Office of Surveillance and Epidemiology Mara McAdams Epidemiology and Policy Fellow Office of Surveillance and Epidemiology