Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Review of Fentora® and Actiq® Adverse Events from the Adverse Event Reporting System (AERS) Database Yoo Jung Chang, Pharm.D. Lauren Lee, Pharm.D. Division of Adverse Event Analysis II Office of Surveillance and Epidemiology Yoo Jung Chang, Pharm.D. Lauren Lee, Pharm.D. Division of Adverse Event Analysis II Office of Surveillance and Epidemiology

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, OutlineOutline Objectives Overview of the Adverse Event Reporting System (AERS) AERS review of all adverse events reported with Fentora since marketing AERS review of serious adverse events reported with Actiq in 2007 Summary Objectives Overview of the Adverse Event Reporting System (AERS) AERS review of all adverse events reported with Fentora since marketing AERS review of serious adverse events reported with Actiq in 2007 Summary

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, ObjectivesObjectives Identify unlabeled adverse events or other safety concerns, particularly with issues of drug diversion, misuse and overdose Identify trends between Fentora and Actiq adverse events Identify unlabeled adverse events or other safety concerns, particularly with issues of drug diversion, misuse and overdose Identify trends between Fentora and Actiq adverse events

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, AERS: 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 Voluntary, “spontaneous” reporting Facilitated by the FDA MedWatch Program Reports are stored and retrieved via Adverse Event Reporting System (AERS) database

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 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

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 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

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, AERS Review of All Adverse Events Reported with Fentora ®

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: AERS Search Criteria Search dates – up to 2/25/08 Brand name search only – Fentora All adverse events Foreign and domestic reports Search dates – up to 2/25/08 Brand name search only – Fentora All adverse events Foreign and domestic reports

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Search Results 42 cases retrieved from AERS 23/42 cases excluded due to the following: –Medication errors with no adverse event (16) –No specific patient information (3) –Adverse event not related to drug per reporter (2) –Product complaint with no adverse event (1) –Report of death from natural causes (1) 19/42 cases included in the case series for further analysis 42 cases retrieved from AERS 23/42 cases excluded due to the following: –Medication errors with no adverse event (16) –No specific patient information (3) –Adverse event not related to drug per reporter (2) –Product complaint with no adverse event (1) –Report of death from natural causes (1) 19/42 cases included in the case series for further analysis

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Demographics and Indications Number of cases19 Gender: Male Female 9 10 Age (n=16): Median Range 43.5 years 16 – 73 years Indication (n=18): Cancer pain Non-cancer pain Misc* 1 (5%) 11 (57%) 6 (32%) * Suicidal attempt, abuse, intentional overdose, & accidental exposure

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Dose & Other Opioid Use Number of cases19 Daily dose (n=6): Median Range 2000 mcg 600 – 3200 mcg Onset (n=6): Median Range 8 days Same day – 5 months Opioid tolerance: Tolerant Non-tolerant Unspecified 6 (32%) 1 (5%) 12 (63%) Concomitant use of other opioid medications 11

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Outcomes & Report Source Number of cases19 Outcomes: Death Life-threatening Hospitalization Medically significant Unspecified Year Received Report Source US19

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Fatalities 5 reports of death Causes of death –Accidental fentanyl overdose (2) –Suicide (1) –Underlying metastatic leiomyosarcoma (1) –Unknown (1)* 4 of 5 reports involved an overdose 5 reports of death Causes of death –Accidental fentanyl overdose (2) –Suicide (1) –Underlying metastatic leiomyosarcoma (1) –Unknown (1)* 4 of 5 reports involved an overdose *Patient stole Fentora from a spouse and overdosed; he was taken to the ER where he was diagnosed with acute MI. He left against medical advice and returned home where he later died.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Reported Adverse Events (AE) System Organ ClassAdverse Events Cardiac disorders (1)acute myocardial infarction* (1) Gastrointestinal disorders (2)retching (1), constipation (1) General disorders and administration site conditions (14) lack of efficacy (6), application site bleeding, bruising, ulcer, pain, or burning (6), flushing (1), hyperhidrosis (1) Injury, poisoning, & procedural complications (18) medication errors** (10), intentional overdose (2), overdose (2), accidental overdose (2), intentional drug misuse (2), accidental exposure (1) *Unlabeled events underlined; **Included only medication error reports with adverse events

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Reported AE Cont.. System Organ ClassAdverse Events Metabolism & nutritional disorders (1) oral intake reduced (1) Nervous system disorders (7)somnolence (3), loss of consciousnes (2), CVA (1), dysarthria (1) Psychiatric disorders (3)drug dependence (1), suicidal attempt (1), suicide (1) Renal and urinary disorders (1)dysuria (1) Respiratory, thoracic, & mediastinal disorders (2) respiratory arrest (1) dyspnea (1) Vascular disorders (1)dizziness (1)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Overdose, Misuse, & Suicide Seven cases of overdose and/or misuse –Intentional overdose (2)* –Accidental overdose (2) –Overdose (2)** –Intentional misuse (2) Two cases of suicide/suicidal attempt Seven cases of overdose and/or misuse –Intentional overdose (2)* –Accidental overdose (2) –Overdose (2)** –Intentional misuse (2) Two cases of suicide/suicidal attempt *1 of 2 intentional overdose cases also reported suicide ** 1 of 2 overdose cases also reported intentional misuse

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Summary of AERS Review 19 adverse event cases Extensive off label use; cancer pain (5%) 32% were opioid tolerant 53% involved medication errors with adverse events –prescribing/dispensing errors, incorrect route/freq of admin by patients, incorrect conversion from Actiq 19 adverse event cases Extensive off label use; cancer pain (5%) 32% were opioid tolerant 53% involved medication errors with adverse events –prescribing/dispensing errors, incorrect route/freq of admin by patients, incorrect conversion from Actiq

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora: Summary of AERS Review, cont. 32% involved overdoses; 11% intentional misuse; 11% suicide attempt 5 deaths; 4 of which involved overdoses Unlabeled adverse events (i.e., acute MI, CVA, dysarthria) do not appear to be directly related to Fentora 32% involved overdoses; 11% intentional misuse; 11% suicide attempt 5 deaths; 4 of which involved overdoses Unlabeled adverse events (i.e., acute MI, CVA, dysarthria) do not appear to be directly related to Fentora

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, AERS Review of Serious* Adverse Events Reported with Actiq ® (2007) * Serious per regulatory definition includes death, hospitalization or prolongation of hospitalization, life-threatening, disability, congenital anomaly, and other medically important events (CFR ).

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: AERS Search Criteria Reports received by the Agency between 01/01/07 – 12/31/07 Brand name search only – Actiq Serious adverse events US reports Reports received by the Agency between 01/01/07 – 12/31/07 Brand name search only – Actiq Serious adverse events US reports

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Indication & Tolerance Number of cases61 Indication (n=57): Cancer pain Non-cancer pain Misc* 3 (5%) 31 (51%) 23 (38%) Opioid tolerance: Tolerant Non-tolerant Unspecified 16 (26%) 4 (6%) 41 (67%) Concomitant use of other opioid medications 28 *Suicide, suicidal attempt, intentional misuse & accidental exposure

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Outcomes Total number of cases61 Outcomes*: Death Life-threatening Hospitalization Disability Medically significant *Cases may have reported more than one outcome.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Fatalities 9 reports of death Causes of death –apnea (1), cardio-respiratory arrest (1), fentanyl toxicity (2), multiple drug overdose (2), unknown (3) 7 of 9 reports involved an overdose Of the remaining 2 reports: –1 st: Fetal death confounded by concomitant use of other medications, one of which was labeled category D –2 nd: Opioid non-tolerant patient (weaned off of opioids) but restarted Actiq and possibly other opioids 9 reports of death Causes of death –apnea (1), cardio-respiratory arrest (1), fentanyl toxicity (2), multiple drug overdose (2), unknown (3) 7 of 9 reports involved an overdose Of the remaining 2 reports: –1 st: Fetal death confounded by concomitant use of other medications, one of which was labeled category D –2 nd: Opioid non-tolerant patient (weaned off of opioids) but restarted Actiq and possibly other opioids

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Reported Adverse Events (AE) System Organ Class Adverse Events Cardiac disorders (11) tachycardia (4), cardiac arrest* (3), v. fib (1), v. tachycardia (1) Injury, poisoning and procedural complications (42) med errors** (18), accidental exposure (8), drug toxicity (4), overdose (4), multiple drug overdose accidental (1) Nervous system disorders (71) convulsion (6), confusion (2), somnolence (15), coma (7), lethargy (13), loss of consciousness (3) Psychiatric disorders (52) agitation (5), anxiety (2), delusion (4), hallucination (4), irritability (4) *Unlabeled events underlined; **Included only med error reports with adverse events

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Overdose & Misuse 32 cases of overdose and misuse –Intentional misuse (16)* –Accidental exposure in a child (8) –Accidental overdose (6) –Undetermined (2) 32 cases of overdose and misuse –Intentional misuse (16)* –Accidental exposure in a child (8) –Accidental overdose (6) –Undetermined (2) *Includes cases of suicide, suicidal attempt & abuse

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Summary of AERS Review 61 serious adverse event reports in 2007 Extensive off label use; cancer pain (5%) 26% were opioid tolerant Overdose & misuse represented 52% of cases 61 serious adverse event reports in 2007 Extensive off label use; cancer pain (5%) 26% were opioid tolerant Overdose & misuse represented 52% of cases

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq: Summary of AERS Review, cont. 30% of cases involved medication errors –prescribing errors, incorrect route/freq of admin by patients 9 deaths; 7 of which involved overdoses Unlabeled adverse events (i.e., cardiac arrest, ventricular fibrillation & tachycardia, coma, lethargy, loss of consciousness, delusion, and irritability) occurred in the context of overdoses 30% of cases involved medication errors –prescribing errors, incorrect route/freq of admin by patients 9 deaths; 7 of which involved overdoses Unlabeled adverse events (i.e., cardiac arrest, ventricular fibrillation & tachycardia, coma, lethargy, loss of consciousness, delusion, and irritability) occurred in the context of overdoses

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Overall Summary: Fentora and Actiq Cases Not a direct comparison of Fentora & Actiq Extensive off label use in both drugs; cancer pain (5%) 26 – 32% were opioid tolerant 52% of Actiq cases involved overdose & misuse; 37% for Fentora Not a direct comparison of Fentora & Actiq Extensive off label use in both drugs; cancer pain (5%) 26 – 32% were opioid tolerant 52% of Actiq cases involved overdose & misuse; 37% for Fentora

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Overall Summary: Fentora and Actiq Cases, cont. 53% of Fentora cases reported medication errors, including incorrect conversion from Actiq; 30% for Actiq Unlabeled adverse events occurred in the context of overdoses for Actiq; no positive drug-event association for Fentora 53% of Fentora cases reported medication errors, including incorrect conversion from Actiq; 30% for Actiq Unlabeled adverse events occurred in the context of overdoses for Actiq; no positive drug-event association for Fentora

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Fentora Medication Errors Kristina C. Arnwine, PharmD Acting Team Leader Division of Medication Error Prevention Kristina C. Arnwine, PharmD Acting Team Leader Division of Medication Error Prevention

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, OverviewOverview AERS Search Medication Error Cases Types of Error Summary AERS Search Medication Error Cases Types of Error Summary

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, AERS Search Search Conducted March 18, 2008 –1 month following DAEA search –No MedDRA terms used Retrieved 63 cases Search Conducted March 18, 2008 –1 month following DAEA search –No MedDRA terms used Retrieved 63 cases

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, AERS Results Total Number of Cases 63 Excluded Cases –intentional overdose –adverse events not a result of medication error –not enough information to determine if medication error occurred 20 Medication Error Cases –further analyzed for type and causality 43

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Medication Error Cases (n=43) Off-label Use (n=35) –Accounts for 81% of errors reported –Chronic/non-cancer pain –Migraines –Back pain –shoulder pain, neck pain, mandibular jaw pain, reflex sympathetic dystrophy, Guillain Barre syndrome, pain from automobile accident, pain from gunshot wound Labeled Use (n=4) –breakthrough cancer pain Unspecified indication (n=4) Off-label Use (n=35) –Accounts for 81% of errors reported –Chronic/non-cancer pain –Migraines –Back pain –shoulder pain, neck pain, mandibular jaw pain, reflex sympathetic dystrophy, Guillain Barre syndrome, pain from automobile accident, pain from gunshot wound Labeled Use (n=4) –breakthrough cancer pain Unspecified indication (n=4)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (n=43) Wrong route of administration 10 Improper frequency of administration 9 Improper patient selection 9 mcg per mcg conversion between Actiq and Fentora 6 Improper dose prescribed when converting from Actiq to Fentora 4 Improper substitution 2 Improper technique 1 Accidental exposure 1 Accidental overdose 1

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error Wrong route of administration (n=10) –sublingual vs. buccal –attempts to avoid ulceration Wrong route of administration (n=10) –sublingual vs. buccal –attempts to avoid ulceration

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (cont) Improper frequency of administration (n=9) –more frequent than every 4 hours resulted in patient death –more than 4 times daily –regularly scheduled BID, QD Improper frequency of administration (n=9) –more frequent than every 4 hours resulted in patient death –more than 4 times daily –regularly scheduled BID, QD

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (cont) Improper Patient Selection (n=9) –Off-label use (n=7) No other medication error reported –Not on concomitant around-the-clock opioid therapy (n=2) 1 off-label use 1 labeled use Improper Patient Selection (n=9) –Off-label use (n=7) No other medication error reported –Not on concomitant around-the-clock opioid therapy (n=2) 1 off-label use 1 labeled use

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Confusion Between Actiq & Fentora 12 cases –mcg per mcg conversion between products –Improper dose prescribed when converting from Actiq to Fentora –Improper substitution Fentora and Actiq not bioequivalent –Insert contains instructions for conversion –Warnings in professional insert & carton 12 cases –mcg per mcg conversion between products –Improper dose prescribed when converting from Actiq to Fentora –Improper substitution Fentora and Actiq not bioequivalent –Insert contains instructions for conversion –Warnings in professional insert & carton

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (cont) mcg per mcg conversion between Actiq and Fentora (n=6) –Actiq 800 mcg to Fentora 800 mcg mcg per mcg conversion between Actiq and Fentora (n=6) –Actiq 800 mcg to Fentora 800 mcg

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (cont) Improper dose prescribed when converting from Actiq to Fentora (n=4) –Actiq 400 mcg to Fentora 200 mcg –Correct conversion to Fentora is 100 mcg Improper dose prescribed when converting from Actiq to Fentora (n=4) –Actiq 400 mcg to Fentora 200 mcg –Correct conversion to Fentora is 100 mcg

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (cont) Improper Substitution (n=2) –Pharmacists unaware Fentora and Actiq are not bioequivalent –Substitution suggested by insurance carrier Lower price of Fentora –Fentora dispensed as generic equivalent to Actiq Improper Substitution (n=2) –Pharmacists unaware Fentora and Actiq are not bioequivalent –Substitution suggested by insurance carrier Lower price of Fentora –Fentora dispensed as generic equivalent to Actiq

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Types of Error (cont) Improper Technique (n=1) –Tablet splitting –Prescribed ½ of 400 mcg tablet BID Accidental Exposure (n=1) –Tablet removed from blister –Fentora mistaken for aspirin Accidental Overdose (n=1) –Death –Prescribed for back pain Improper Technique (n=1) –Tablet splitting –Prescribed ½ of 400 mcg tablet BID Accidental Exposure (n=1) –Tablet removed from blister –Fentora mistaken for aspirin Accidental Overdose (n=1) –Death –Prescribed for back pain

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Safety Communications September 2007 –Dear Doctor/Healthcare Professional Letter –Public Health Advisory 22 of 43 errors reported after dissemination of communications –No event date reported –Unable to assess effectiveness of communications September 2007 –Dear Doctor/Healthcare Professional Letter –Public Health Advisory 22 of 43 errors reported after dissemination of communications –No event date reported –Unable to assess effectiveness of communications

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, SummarySummary Medication errors –Account for 68% of AERS cases Off-label use (n=35) Labeled use (n=4) Knowledge deficit with Actiq and Fentora Effectiveness of labeling and Risk Minimization Action Plan is questionable Medication errors –Account for 68% of AERS cases Off-label use (n=35) Labeled use (n=4) Knowledge deficit with Actiq and Fentora Effectiveness of labeling and Risk Minimization Action Plan is questionable

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Fentora Risk Management: Postmarketing Experience and Recommendations Jeanine Best, MSN, RN, PNP Senior Drug Risk Management Analyst Division of Risk Management Office of Surveillance and Epidemiology Jeanine Best, MSN, RN, PNP Senior Drug Risk Management Analyst Division of Risk Management Office of Surveillance and Epidemiology

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, OutlineOutline  Background  Current RiskMAP  Overview  Postmarketing experience  RiskMAP experience summary  Additional risk mitigation options  Conclusions  Background  Current RiskMAP  Overview  Postmarketing experience  RiskMAP experience summary  Additional risk mitigation options  Conclusions

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, BackgroundBackground Fentora was approved with: 1.A limited indication where the benefits relative to the risks were shown to be acceptable: “only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain” 2.Medication Guide 3.A risk minimization action plan (RiskMAP) Fentora was approved with: 1.A limited indication where the benefits relative to the risks were shown to be acceptable: “only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain” 2.Medication Guide 3.A risk minimization action plan (RiskMAP) Fentora Label, 2/7/08

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Current Fentora RiskMAP

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, GoalsGoals 1.Fentora should be used only by opioid tolerant patients with cancer. 2.Abuse, misuse and diversion of Fentora should not occur. 3.Unintended (accidental) exposure to Fentora should not occur. 1.Fentora should be used only by opioid tolerant patients with cancer. 2.Abuse, misuse and diversion of Fentora should not occur. 3.Unintended (accidental) exposure to Fentora should not occur.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Key Elements  Labeling  Education  Surveillance  Evaluation/Intervention  Labeling  Education  Surveillance  Evaluation/Intervention

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, LabelingLabeling  Package Insert for HCPs  Boxed warning emphasizing key safety information including use only in opioid tolerant patients with break-through cancer pain no use for acute pain dosing and administration instructions conversion instructions no substitution abuse and misuse warnings  Medication Guide for patients  Key safety information in consumer-friendly language  Package Insert for HCPs  Boxed warning emphasizing key safety information including use only in opioid tolerant patients with break-through cancer pain no use for acute pain dosing and administration instructions conversion instructions no substitution abuse and misuse warnings  Medication Guide for patients  Key safety information in consumer-friendly language

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Labeling - Carton

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Education Plan  Prescriber education  Package Insert  Independent Continuing Medical Education (CME) – not product specific  Patient education  Medication Guide  Carton label/blister label  Pharmacist education  Package Insert  Carton label/checklist  Prescriber education  Package Insert  Independent Continuing Medical Education (CME) – not product specific  Patient education  Medication Guide  Carton label/blister label  Pharmacist education  Package Insert  Carton label/checklist

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, SurveillanceSurveillance  Surveillance Plan  Spontaneous reporting  Expedited reporting per regulation with reporting of additional events  Active surveillance for monitoring abuse, misuse, and diversion using the following systems: The Researched Abuse, Diversion and Addiction-Related Surveillance System (RADARS) Toxic Exposure Surveillance System (TESS) Drug Abuse Warning network (DAWN)  Surveillance Plan  Spontaneous reporting  Expedited reporting per regulation with reporting of additional events  Active surveillance for monitoring abuse, misuse, and diversion using the following systems: The Researched Abuse, Diversion and Addiction-Related Surveillance System (RADARS) Toxic Exposure Surveillance System (TESS) Drug Abuse Warning network (DAWN)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Evaluation Plan  Periodic analysis of surveillance and monitoring efforts for signals of abuse, misuse, and diversion  Surveys to evaluate knowledge, attitudes, and behavior from education efforts  physicians  pharmacists  patients  Patient longitudinal drug utilization data  assessing use in opioid non-tolerant patients  Periodic analysis of surveillance and monitoring efforts for signals of abuse, misuse, and diversion  Surveys to evaluate knowledge, attitudes, and behavior from education efforts  physicians  pharmacists  patients  Patient longitudinal drug utilization data  assessing use in opioid non-tolerant patients

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 RiskMAP Postmarketing Experience

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, RiskMAP Quarterly Report Information Quarterly RiskMAP Report Data Non Opioid Tolerant (IMS longitudinal database estimates) Non Cancer Diagnosis (IMS National Audit Data) 1 st quarter (9/25/06-12/31/ %85.8% 2 nd quarter (1/1/07-3/31/07) 21.0%84.1% 3 rd quarter (4/1/07-6/30/07) 23.5%81.0% 4 th quarter (7/1/07-9/30/07) 24.1%82.8% 5 th quarter (10/1/07-12/31/07) 28.1%82.6%

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, RiskMAP Quarterly Report Information, cont.  Spontaneous and expedited reports of abuse, misuse and diversion have been received  Surveillance system information on abuse, misuse, and diversion  RADARS ® Signal Detection Systems showed concerning rates, but not definite signals (reported in the 4th Quarterly RiskMAP Report).  Spontaneous and expedited reports of abuse, misuse and diversion have been received  Surveillance system information on abuse, misuse, and diversion  RADARS ® Signal Detection Systems showed concerning rates, but not definite signals (reported in the 4th Quarterly RiskMAP Report).

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, RiskMAP Quarterly Report Information, cont.  Physician Survey  no results submitted as of 5 th quarterly RiskMAP Report  Pharmacy Survey  no results submitted as of 5 th quarterly RiskMAP Report  Physician Survey  no results submitted as of 5 th quarterly RiskMAP Report  Pharmacy Survey  no results submitted as of 5 th quarterly RiskMAP Report

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, RiskMAP Quarterly Report Information, cont.  Patient Survey  624 patients surveyed to date  Sponsor reported survey findings including: most patients are aware of key safety information > 33% patients unaware of secure storage to prevent theft and diversion ~ 25% patients unaware of need to keep Fentora in the original blister package  Limitations of Survey: survey questions do not address all key safety concerns  Patient Survey  624 patients surveyed to date  Sponsor reported survey findings including: most patients are aware of key safety information > 33% patients unaware of secure storage to prevent theft and diversion ~ 25% patients unaware of need to keep Fentora in the original blister package  Limitations of Survey: survey questions do not address all key safety concerns

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Postmarketing Actions  Dear Doctor and Dear Healthcare Professional Letters – 9/10/07  FDA Public Health Advisory – 9/26/07  Revised Labeling (enhancement of key safety information) – approved 2/7/08  RiskMAP revisions (under review)  debit card  Dear Doctor and Dear Healthcare Professional Letters – 9/10/07  FDA Public Health Advisory – 9/26/07  Revised Labeling (enhancement of key safety information) – approved 2/7/08  RiskMAP revisions (under review)  debit card

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Fentora RiskMAP Experience Summary

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Summary of RiskMAP Experience  Increasing use in opioid non-tolerant patients  non-tolerant patients at greater risk for life-threatening adverse events  High utilization in non-cancer indications  Improper use and medication errors account for > 2/3 of the reports in the adverse event reporting system  no apparent effect seen from Dear HCP Letters/PHA  Inadequate information to determine if HCPs and patients have an understanding about the safe use of Fentora  Increasing use in opioid non-tolerant patients  non-tolerant patients at greater risk for life-threatening adverse events  High utilization in non-cancer indications  Improper use and medication errors account for > 2/3 of the reports in the adverse event reporting system  no apparent effect seen from Dear HCP Letters/PHA  Inadequate information to determine if HCPs and patients have an understanding about the safe use of Fentora

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Comments on RiskMAP Experience  Current risk minimization tools do not appear to achieve RiskMAP goals.  Expanding the indication will most likely amplify and exacerbate the postmarketing data trending seen regarding:  opioid non-tolerant use  all medication errors  abuse, diversion, and misuse  Current risk minimization tools do not appear to achieve RiskMAP goals.  Expanding the indication will most likely amplify and exacerbate the postmarketing data trending seen regarding:  opioid non-tolerant use  all medication errors  abuse, diversion, and misuse

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Additional Risk Mitigation Options  Consider additional risk mitigation strategies and the feasibility of these strategies  Prescriber requirements  Pharmacy/Dispensing requirements  Additional requirements  Consider additional risk mitigation strategies and the feasibility of these strategies  Prescriber requirements  Pharmacy/Dispensing requirements  Additional requirements

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora Risk Mitigation Options Prescriber Requirements  Mandatory enrollment of prescribers in order to prescribe  Mandatory training or certification  Acknowledge understanding of (could include) appropriate (indicated) use screening for abuse/misuse/diversion dosing and administration instructions Prescriber Requirements  Mandatory enrollment of prescribers in order to prescribe  Mandatory training or certification  Acknowledge understanding of (could include) appropriate (indicated) use screening for abuse/misuse/diversion dosing and administration instructions

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora Risk Mitigation Options, cont. Pharmacy/Dispensing Requirements  Mandatory enrollment of pharmacies in order to dispense  Mandatory training or certification  Acknowledge understanding of dispensing requirements patients must be opioid tolerant no therapeutic substitution patient counseling for appropriate use dispense and instruct patients to read the Medication Guide prior authorization (if required) Pharmacy/Dispensing Requirements  Mandatory enrollment of pharmacies in order to dispense  Mandatory training or certification  Acknowledge understanding of dispensing requirements patients must be opioid tolerant no therapeutic substitution patient counseling for appropriate use dispense and instruct patients to read the Medication Guide prior authorization (if required)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora Risk Mitigation Options, cont. Pharmacy/Dispensing Requirements, cont.  Prescription dispensed only with prior authorization such as a qualification sticker on the prescription patient registry enrollment Pharmacy/Dispensing Requirements, cont.  Prescription dispensed only with prior authorization such as a qualification sticker on the prescription patient registry enrollment

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora Risk Mitigation Options, cont. Additional Requirements  Documentation of safe use for patients to receive Fentora  Prescriber/Patient Agreement for documentation of safe-use conditions required patient counseling receipt of Medication Guide Additional Requirements  Documentation of safe use for patients to receive Fentora  Prescriber/Patient Agreement for documentation of safe-use conditions required patient counseling receipt of Medication Guide

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Risk Mitigation Options Advantages  Gate keeping for appropriate and/or safe use  may provide evidence and/or documentation of safe use conditions  may assure benefits outweigh the risks in the prescribed population where the benefit/risk balance is acceptable  Gate keeping for appropriate and/or safe use  may provide evidence and/or documentation of safe use conditions  may assure benefits outweigh the risks in the prescribed population where the benefit/risk balance is acceptable

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Risk Mitigation Options Challenges  More burdensome  Unintended consequences  delayed access/no access of product for appropriate patients  Abuse/misuse/diversion will still occur  More burdensome  Unintended consequences  delayed access/no access of product for appropriate patients  Abuse/misuse/diversion will still occur

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, ConclusionsConclusions  Additional risk mitigation strategies  may assure benefits outweigh the risks in the prescribed population where the benefit/risk balance is acceptable  may not prevent abuse/misuse/diversion, especially in non-prescribed individuals  Expanding the indication even with additional risk mitigation strategies  increases the amount of Fentora in the community  increases risk of abuse/misuse/diversion  Additional risk mitigation strategies  may assure benefits outweigh the risks in the prescribed population where the benefit/risk balance is acceptable  may not prevent abuse/misuse/diversion, especially in non-prescribed individuals  Expanding the indication even with additional risk mitigation strategies  increases the amount of Fentora in the community  increases risk of abuse/misuse/diversion

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Regulatory History of Oral Transmucosal Fentanyl Products Ellen W Fields, M.D., M.P.H Acting Clinical Team Leader Division of Anesthesia, Analgesia, and Rheumatology Products Ellen W Fields, M.D., M.P.H Acting Clinical Team Leader Division of Anesthesia, Analgesia, and Rheumatology Products

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Overview of Presentation Regulatory history of oral transmucosal fentanyl products Labeling changes Compare the pharmacokinetics of Actiq and Fentora Regulatory history of oral transmucosal fentanyl products Labeling changes Compare the pharmacokinetics of Actiq and Fentora

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, OTFC Products Oralet Actiq Fentora Oralet Actiq Fentora

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, OraletOralet Approved in 1993 Indication: preoperative sedation in children, for use only in hospital setting Formulation: Raspberry flavored lozenge on a stick Dosage units: 100, 200, and 400mcg Withdrawn in 2001 because of nausea and vomiting in opioid-naïve patients Approved in 1993 Indication: preoperative sedation in children, for use only in hospital setting Formulation: Raspberry flavored lozenge on a stick Dosage units: 100, 200, and 400mcg Withdrawn in 2001 because of nausea and vomiting in opioid-naïve patients

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, ActiqActiq Approved 1998 Indication: treatment of breakthrough pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain Formulation: same as Oralet Dosage units: 200, 400, 600, 800, 1200, 1600 mcg Setting: inpatient and outpatient Approved 1998 Indication: treatment of breakthrough pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain Formulation: same as Oralet Dosage units: 200, 400, 600, 800, 1200, 1600 mcg Setting: inpatient and outpatient

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, ActiqActiq Issues surrounding approval –Unique circumstance where population at greatest risk of adverse events was not population that would benefit from approval –Biggest concern was accidental ingestion by children –Subject of ALSAC meeting September 1997 –Approved under Subpart H (21CFR§314.20) Restricted distribution Accelerated withdrawal of product if necessary –Risk Management Program misuse, abuse and diversion accidental exposure by children Issues surrounding approval –Unique circumstance where population at greatest risk of adverse events was not population that would benefit from approval –Biggest concern was accidental ingestion by children –Subject of ALSAC meeting September 1997 –Approved under Subpart H (21CFR§314.20) Restricted distribution Accelerated withdrawal of product if necessary –Risk Management Program misuse, abuse and diversion accidental exposure by children

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Original Actiq Label Box Warning –Actiq is indicated for the management of breakthrough cancer pain in patients with malignancies who are receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain –This product must not be used in opioid non- tolerant patients –Prescribed only by oncologists and pain specialists –Patients and caregivers must be instructed that Actiq contains a medicine in an amount which can be fatal to a child……keep all units out of reach of children and dispose of units properly Box Warning –Actiq is indicated for the management of breakthrough cancer pain in patients with malignancies who are receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain –This product must not be used in opioid non- tolerant patients –Prescribed only by oncologists and pain specialists –Patients and caregivers must be instructed that Actiq contains a medicine in an amount which can be fatal to a child……keep all units out of reach of children and dispose of units properly

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Original Actiq Label Contraindications: –Management of acute or post operative pain –Use in opioid non-tolerant persons Contraindications: –Management of acute or post operative pain –Use in opioid non-tolerant persons

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Actiq Labeling Changes June 2002: advising diabetic patients that Actiq contains 2 grams of sugar per unit September 2004: post-marketing data regarding development of dental caries, tooth loss and gum line erosion September 2005: sugar-free formulation (never marketed) September 2006: Conversion of patient leaflet (PPI) to MedGuide February 2007: addition of pharmacokinetic data for patients 5-15 years of age June 2002: advising diabetic patients that Actiq contains 2 grams of sugar per unit September 2004: post-marketing data regarding development of dental caries, tooth loss and gum line erosion September 2005: sugar-free formulation (never marketed) September 2006: Conversion of patient leaflet (PPI) to MedGuide February 2007: addition of pharmacokinetic data for patients 5-15 years of age

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, FentoraFentora Approved September 2006 Indication: same as Actiq Formulation: effervescent buccal tablet Dosage units: 100, 200, 400, 600, and 800 mcg (300mcg approved March 2007) Setting: inpatient and outpatient Risk Management Plan and Medguide part of approval Approved September 2006 Indication: same as Actiq Formulation: effervescent buccal tablet Dosage units: 100, 200, 400, 600, and 800 mcg (300mcg approved March 2007) Setting: inpatient and outpatient Risk Management Plan and Medguide part of approval

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Original Fentora Label Box Warning –Indication for opioid-tolerant cancer patients –Contraindicated Acute and post operative pain Opioid non-tolerant patients –Contains medicine in amount which can be fatal to a child –Due to higher bioavailability of fentanyl, do not convert from other fentanyl products on a mcg per mcg basis. Box Warning –Indication for opioid-tolerant cancer patients –Contraindicated Acute and post operative pain Opioid non-tolerant patients –Contains medicine in amount which can be fatal to a child –Due to higher bioavailability of fentanyl, do not convert from other fentanyl products on a mcg per mcg basis.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Source: Fentora Package Insert Fentora vs. Actiq

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6,

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Within first year of approval, there were medication errors associated with adverse events, including death. Errors included –Off-label prescribing to non-opioid tolerant patients –Patients prescribed the wrong dose –Patients took too many doses –Healthcare professionals substituted Fentora for another fentanyl-containing product that is not equal to Fentora. Within first year of approval, there were medication errors associated with adverse events, including death. Errors included –Off-label prescribing to non-opioid tolerant patients –Patients prescribed the wrong dose –Patients took too many doses –Healthcare professionals substituted Fentora for another fentanyl-containing product that is not equal to Fentora. Medication Errors

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Public Health Advisory September 2007: Public Health Advisory issued for Fentora –Off label prescribing to non opioid tolerant patients –Misunderstanding of dosing instructions by both prescribers and patients –Inappropriate substitution of Fentora for Actiq by pharmacists and prescribers September 2007: Public Health Advisory issued for Fentora –Off label prescribing to non opioid tolerant patients –Misunderstanding of dosing instructions by both prescribers and patients –Inappropriate substitution of Fentora for Actiq by pharmacists and prescribers

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Fentora Labeling Changes February 7, 2008 Box Warning: –Warnings strengthened regarding use of Fentora in non- opioid tolerant patients including patients with migraines, –When prescribing, do not convert patients on a mcg per mcg basis from Actiq to Fentora –When dispensing, do not substitute a Fentora prescription for other fentanyl products –Special care must be used when dosing Fentora. If the BTP episode is not relieved after 30 minutes, patients may take only one additional dose using the same strength and must wait at least four hours before taking another dose. Box Warning: –Warnings strengthened regarding use of Fentora in non- opioid tolerant patients including patients with migraines, –When prescribing, do not convert patients on a mcg per mcg basis from Actiq to Fentora –When dispensing, do not substitute a Fentora prescription for other fentanyl products –Special care must be used when dosing Fentora. If the BTP episode is not relieved after 30 minutes, patients may take only one additional dose using the same strength and must wait at least four hours before taking another dose.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, SummarySummary There are presently two oral transmucosal fentanyl products marketed for the indication of the management of breakthrough cancer pain in opioid tolerant patients Due to the higher bioavailability of Fentora, Actiq and Fentora are not interchangeable on a mcg to mcg basis Despite strong labeling language, a MedGuide, and a Risk Management Program, there have been medication errors reported to the Agency that have resulted in adverse events, including death. There are presently two oral transmucosal fentanyl products marketed for the indication of the management of breakthrough cancer pain in opioid tolerant patients Due to the higher bioavailability of Fentora, Actiq and Fentora are not interchangeable on a mcg to mcg basis Despite strong labeling language, a MedGuide, and a Risk Management Program, there have been medication errors reported to the Agency that have resulted in adverse events, including death.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Fentora Abuse Potential in the Noncancer Pain Population Lori A. Love, M.D., Ph.D. Medical Officer Controlled Substance Staff Lori A. Love, M.D., Ph.D. Medical Officer Controlled Substance Staff

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Why the concerns about safety, including abuse potential? History of fentanyl and abuse –Synthesized in late 1950s –Introduced as IV anesthetic in 1960s (Sublimaze®). –Illicit use of pharmaceutical fentanyl first identified in the mid-1970s in the medical community –All pharmaceutical preparations have been abused –IV, snorting, smoking and sublingual routes used –Street names: apache, china girl, china white, dance fever, friend, goodfella, jackpot, murder 8, TNT, etc. History of fentanyl and abuse –Synthesized in late 1950s –Introduced as IV anesthetic in 1960s (Sublimaze®). –Illicit use of pharmaceutical fentanyl first identified in the mid-1970s in the medical community –All pharmaceutical preparations have been abused –IV, snorting, smoking and sublingual routes used –Street names: apache, china girl, china white, dance fever, friend, goodfella, jackpot, murder 8, TNT, etc.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Why the concerns about safety, including abuse potential? History of fentanyl and abuse –High abuse potential Illicitly manufactured for abuse –> 12 different fentanyl analogues in U.S. drug traffic –Recent deaths in several US communities attributed to abuse fentanyl-laced heroin –One of the precursors was designated as a List 1 chemical. DEA is now in the process of designating a second chemical as a Schedule II immediate precursor Abuse of domestic and foreign pharmaceutical products History of fentanyl and abuse –High abuse potential Illicitly manufactured for abuse –> 12 different fentanyl analogues in U.S. drug traffic –Recent deaths in several US communities attributed to abuse fentanyl-laced heroin –One of the precursors was designated as a List 1 chemical. DEA is now in the process of designating a second chemical as a Schedule II immediate precursor Abuse of domestic and foreign pharmaceutical products

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, What Users Are Saying About Fentora* From a patient in Phase 3 study: –“ive been fentora, oxycontin, methadone, oxymorphone, actiq, ms, hydro and imho fentora is the most euphoric. granted, its short lived, but by far the most potent. [i take 80mg of done, 240mg of oxy and the fentora still hits me hard. [all legit scripts for legit pain and from one pm doc]” –“Ive been on Fentora for a couple of years, since the drug study, im still on them, they are verrrrrrry expensive. im the on the 800mcg and each one cost about 45 bucks a piece. my insurance wont cover them because they are indicated for cancer break thru pain, but they have a patient assistant program that will let you have them for back pain if your doc will prescribe them. I get 90 each month at no cost. “ “i have recently been put on a trial to test the effects of this drug for my rheumatoid arthritis, it is wonderful, i get this along with oxycontin and the fentora just blows it out of the water “ From a patient in Phase 3 study: –“ive been fentora, oxycontin, methadone, oxymorphone, actiq, ms, hydro and imho fentora is the most euphoric. granted, its short lived, but by far the most potent. [i take 80mg of done, 240mg of oxy and the fentora still hits me hard. [all legit scripts for legit pain and from one pm doc]” –“Ive been on Fentora for a couple of years, since the drug study, im still on them, they are verrrrrrry expensive. im the on the 800mcg and each one cost about 45 bucks a piece. my insurance wont cover them because they are indicated for cancer break thru pain, but they have a patient assistant program that will let you have them for back pain if your doc will prescribe them. I get 90 each month at no cost. “ “i have recently been put on a trial to test the effects of this drug for my rheumatoid arthritis, it is wonderful, i get this along with oxycontin and the fentora just blows it out of the water “ *

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, What Users Are Saying About Fentora* “Wow, imagine the possibilities... some drugkid looking thru sick grandma's medicine cabinet and sees round "3" pills... D00D!!! CODEEN!!!!!!! several thousand mcg of fent later...” “I was able to get 800mcg of fentora for the ppax program for free. It is much better then the actiq do to the higher bioavalibility. I whould say that the 800 fentora is equal to 2200mcg of the actiq. go to the ppax fill out the paperwork. You may get it for free and it also depends on your doctors dosage. The whole process is very legit.” “As was said before, it's fentanyl in an orally dissolving tablet form. The main thing that you cannot forget is the sheer potency of fentanyl. As such, you need to be careful when taking it in order to avoid the risk of dangerous respiratory depression. However, all things considered, fentanyl is really enjoyable stuff, IMO “ “a strong CNS depressent with euphoric and analgesic properties” “Wow, imagine the possibilities... some drugkid looking thru sick grandma's medicine cabinet and sees round "3" pills... D00D!!! CODEEN!!!!!!! several thousand mcg of fent later...” “I was able to get 800mcg of fentora for the ppax program for free. It is much better then the actiq do to the higher bioavalibility. I whould say that the 800 fentora is equal to 2200mcg of the actiq. go to the ppax fill out the paperwork. You may get it for free and it also depends on your doctors dosage. The whole process is very legit.” “As was said before, it's fentanyl in an orally dissolving tablet form. The main thing that you cannot forget is the sheer potency of fentanyl. As such, you need to be careful when taking it in order to avoid the risk of dangerous respiratory depression. However, all things considered, fentanyl is really enjoyable stuff, IMO “ “a strong CNS depressent with euphoric and analgesic properties” *

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Double-blind, placebo-controlled studies: –Study 3052 –Study 3041 –Study 3042 Open-label, uncontrolled study: –Study 3040 Double-blind, placebo-controlled studies: –Study 3052 –Study 3041 –Study 3042 Open-label, uncontrolled study: –Study 3040 Fentora phase 3 clinical studies in noncancer pain

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Protocol-specified entry criteria Inclusion: Taking an around the clock opioid and managing break-through pain using an opioid Exclusion: –To screen out patients who might be at higher risk of abuse or addiction Recent history (within 5 years) or current evidence of alcohol or substance abuse Evidence by urine drug screen of an illicit substance or a medication for which there was no legitimate medical explanation –Psychiatric conditions that would compromise patient safety if they participated in the study Inclusion: Taking an around the clock opioid and managing break-through pain using an opioid Exclusion: –To screen out patients who might be at higher risk of abuse or addiction Recent history (within 5 years) or current evidence of alcohol or substance abuse Evidence by urine drug screen of an illicit substance or a medication for which there was no legitimate medical explanation –Psychiatric conditions that would compromise patient safety if they participated in the study

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, “Review and Assessment of Risks for Abuse and Diversion” Reports events of abuse, addiction, and overdose in Fentora clinical studies of opioid-tolerant patients with chronic noncancer pain and break-through pain Identified aberrant drug-use behaviors –may be precursors or signs for abuse –retrospective analysis of clinical databases –categorized ‘high risk’ behaviors Reports events of abuse, addiction, and overdose in Fentora clinical studies of opioid-tolerant patients with chronic noncancer pain and break-through pain Identified aberrant drug-use behaviors –may be precursors or signs for abuse –retrospective analysis of clinical databases –categorized ‘high risk’ behaviors

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, “Review and Assessment of Risks for Abuse and Diversion” Table 1: Types of Aberrant Drug-use Behaviors (Sponsor identified) Abuse/dependenceStudy drug theft OverdoseLost to follow-up Motor vehicle accidentSeeking prescriptions from other sources Fear of addictionLost study drug Discharged from practiceOveruse of study drug Positive urine drug screenAcquiring opioids from other medical sources UnreliabilityUnapproved use of a medication used for another symptom Using nonprescribed medication

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Aberrant drug use behavior Table 2: Sponsor’s Summary of Patients by Risk Category Risk Category Number of Patients ¥ Percent High risk behaviors * 303% Abuse/dependence 8<1% Overdose 9#9# 1% Positive urine drug screen 131% Other aberrant behaviors12613% None78583% ¥ Patients could have more than one aberrant behavior reported *3 patients also had non-high risk aberrant behaviors # includes one patient with 2 episodes of overdose

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Aberrant drug use behavior Table 3: Aberrant Behaviors Identified in > 1% of Patients (Identified by Sponsor) Behavior Number of Patients Percent Overuse of study drug445% Study drug thefts354% Lost to follow-up334%

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Aberrant drug use behavior 5 patients withdrawn: 4 from study 3040, 1 from of 35 thefts perpetrated by those without regular access to study drug 20 thefts occurred outside patient’s home 5 patients withdrawn: 4 from study 3040, 1 from of 35 thefts perpetrated by those without regular access to study drug 20 thefts occurred outside patient’s home Table 4: Study Drug Thefts during Phase 3 Clinical Trials (Identified by Sponsor) Amount of drug stolen Percent Number of cases Study drug theft %*35 From patients *Number of cases (5) divided by the total 831 patients in studies 3040 & 3052.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Aberrant drug use behavior Table 5: Study Drug Thefts during Phase 3 Clinical Trials (Identified by Sponsor) Amount of drug stolen Percent Number of cases Study drug theft 4.3 gm ¥ From study center + There were 69 study centers in study 3040 ¥ Calculated from additional information provided by the sponsor on 03/21/08, represents > 8000 tablets. Thefts from study site only reported in study 3040 Study drug stolen: –From locked cabinets in 3 thefts –Lost in transit from health facility distribution to pharmacy in 1 –Unused study drug returned by patient was subsequently missing during drug accountability review All cases reported to DEA Thefts from study site only reported in study 3040 Study drug stolen: –From locked cabinets in 3 thefts –Lost in transit from health facility distribution to pharmacy in 1 –Unused study drug returned by patient was subsequently missing during drug accountability review All cases reported to DEA

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, FDA Comments Our review is still ongoing, but we have identified additional cases apart from those identified by the Sponsor indicative of abuse potential –Misuse of study drug/noncompliance/protocol violations –Drug accountability issues We are concerned about the lack of criteria on how investigators were trained to identify and report abuse, misuse, noncompliance and diversion cases across the studies and study sites Our review is still ongoing, but we have identified additional cases apart from those identified by the Sponsor indicative of abuse potential –Misuse of study drug/noncompliance/protocol violations –Drug accountability issues We are concerned about the lack of criteria on how investigators were trained to identify and report abuse, misuse, noncompliance and diversion cases across the studies and study sites

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, CSS Summary The risks of unintentional potentially fatal overdose, misuse, abuse or diversion of fentanyl and of Fentora in particular, are extremely high –As demonstrated by instances of overdose, misuse, abuse and diversion in clinical studies and other postmarketing data The risks of unintentional potentially fatal overdose, misuse, abuse or diversion of fentanyl and of Fentora in particular, are extremely high –As demonstrated by instances of overdose, misuse, abuse and diversion in clinical studies and other postmarketing data

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, CSS Summary The clinical study population is not representative of potential risks of Fentora in the general population –highly screened to eliminate ‘high risk’ patients –detection of aberrant drug use behavior is uncommon in controlled clinical trials appears to be much more frequent in the noncancer population who used Fentora long term The clinical study population is not representative of potential risks of Fentora in the general population –highly screened to eliminate ‘high risk’ patients –detection of aberrant drug use behavior is uncommon in controlled clinical trials appears to be much more frequent in the noncancer population who used Fentora long term

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, CSS Conclusion Taken together, these findings suggest that expanded use of this product will raise serious safety concerns, and will result in significant abuse and diversion that further impacts the public health and safety.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Fentora (NDA , S005) FDA’s Review of Safety and Efficacy Robert B. Shibuya, M.D. Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products Robert B. Shibuya, M.D. Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Overview of Presentation Caveat: Review is in progress, findings are preliminary. Discrepancies noted by Applicant have been addressed in this presentation. Proposed new indication Implications if indication were approved Brief review of Efficacy Review of Safety Preliminary conclusions regarding Safety and Efficacy Caveat: Review is in progress, findings are preliminary. Discrepancies noted by Applicant have been addressed in this presentation. Proposed new indication Implications if indication were approved Brief review of Efficacy Review of Safety Preliminary conclusions regarding Safety and Efficacy

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Proposed indication Current indication: “…management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.” Proposed Indication: “… management of breakthrough pain in patients who are regularly taking around-the-clock opioid medicine for their underlying persistent pain” Current indication: “…management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.” Proposed Indication: “… management of breakthrough pain in patients who are regularly taking around-the-clock opioid medicine for their underlying persistent pain”

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Implications of increased use if this supplement were approved Predicted benefits: –Insurers responsible for coverage, more patients would have access to Fentora Predicted risks: –Larger, less expert prescriber base –Increased promotion –Wider prescribing => larger amounts of drug available for misuse/abuse/diversion Predicted benefits: –Insurers responsible for coverage, more patients would have access to Fentora Predicted risks: –Larger, less expert prescriber base –Increased promotion –Wider prescribing => larger amounts of drug available for misuse/abuse/diversion

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Implications of increased use if this supplement were approved FDA estimate of increased use based upon the numbers of patients theoretically eligible for therapy with Fentora in the US –Cancer = 1.7 M –Non-Cancer = 13.3 M FDA estimate of increased use based upon the numbers of patients theoretically eligible for therapy with Fentora in the US –Cancer = 1.7 M –Non-Cancer = 13.3 M

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, DAWN: ED Visits -- Non-Medical Use per 10,000 Retail Prescriptions 2004 – 2006 Source: National estimates from DAWN, ; Verispan VONA

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, EfficacyEfficacy Study 3052Study 3052 – 12-week study of unconventional design in opioid-tolerant (OT) non-cancer patients with breakthrough pain (BTP) Study 3041 – Short-term, Randomized (R), Double-Blind (DB), Placebo-Controlled (PC), Crossover (XO) study in OT patients with neuropathic pain Study Short-term, R, DB, PC, XO study in OT patients with chronic low back pain Study 3052Study 3052 – 12-week study of unconventional design in opioid-tolerant (OT) non-cancer patients with breakthrough pain (BTP) Study 3041 – Short-term, Randomized (R), Double-Blind (DB), Placebo-Controlled (PC), Crossover (XO) study in OT patients with neuropathic pain Study Short-term, R, DB, PC, XO study in OT patients with chronic low back pain

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Study 3052 – Primary Efficacy Endpoint (PEP)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Studies 3041 and 3042 Short-term studies in opioid tolerant patients with neuropathic and chronic low back pain. Per the applicant, the studies met their objectives. Short-term studies in opioid tolerant patients with neuropathic and chronic low back pain. Per the applicant, the studies met their objectives.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Preliminary efficacy conclusion Preliminarily, Fentora appears to provide analgesia for BTP superior to placebo over 12-weeks of therapy. No comparative data were collected in any studies. Preliminarily, Fentora appears to provide analgesia for BTP superior to placebo over 12-weeks of therapy. No comparative data were collected in any studies.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, SafetySafety Evaluation of safety is not straightforward for oral transmucosal fentanyl citrate (OTFC) products –Opioid dosed in the setting of background opioid –Lack of detail in AE data collection (exact timing of onset of AE and timing of Fentora dosing) –Lack of a control group (crossover design, most patients dosed w/ placebo and active on the same day) –In cancer population, comorbidities associated with advanced malignancies, cancer therapies, and age Evaluation of safety is not straightforward for oral transmucosal fentanyl citrate (OTFC) products –Opioid dosed in the setting of background opioid –Lack of detail in AE data collection (exact timing of onset of AE and timing of Fentora dosing) –Lack of a control group (crossover design, most patients dosed w/ placebo and active on the same day) –In cancer population, comorbidities associated with advanced malignancies, cancer therapies, and age

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, SafetySafety Applicant took a conventional approach for a reformulated opioid [AEs, labs, vital signs (VS), oral cavity exams and physical exams (PE)]. Applicant collected and analyzed data pertaining to abuse, misuse, diversion. Applicant took a conventional approach for a reformulated opioid [AEs, labs, vital signs (VS), oral cavity exams and physical exams (PE)]. Applicant collected and analyzed data pertaining to abuse, misuse, diversion.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Safety - Exposure Applicant pooled data from 3 non-CA efficacy studies (3052, 3041, & 3042). To supplement these numbers, Study 3040 conducted. Study 3040 –Eighteen-month, OL study in patients with BTP not due to cancer –Enrolled 730 patients Approximately 20% were rolled over from Studies 3041/2. Mean duration of exposure was 292 days. Applicant pooled data from 3 non-CA efficacy studies (3052, 3041, & 3042). To supplement these numbers, Study 3040 conducted. Study 3040 –Eighteen-month, OL study in patients with BTP not due to cancer –Enrolled 730 patients Approximately 20% were rolled over from Studies 3041/2. Mean duration of exposure was 292 days.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Safety -Exposure Source: Summary of Clinical Safety

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, FDA’s safety analysis With certain caveats, the controlled clinical trial data from the cancer population is an appropriate comparator for certain AEs. Shared characteristics: Opioid-tolerant adults w/ BTP Similar clinical trial design and AE capture Identical dosing paradigm and range Meets data quality standards for NDA submission –Dissimilarity Cancer patients would be expected to be more ill; therefore, they would be expected to experience more AEs. With certain caveats, the controlled clinical trial data from the cancer population is an appropriate comparator for certain AEs. Shared characteristics: Opioid-tolerant adults w/ BTP Similar clinical trial design and AE capture Identical dosing paradigm and range Meets data quality standards for NDA submission –Dissimilarity Cancer patients would be expected to be more ill; therefore, they would be expected to experience more AEs.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, FDA’s safety analysis Two-pronged approach –Demographics and concomitant medications –Adverse events in the cancer and non- cancer populations Related to abuse/misuse/addiction/ oversedation and consequences thereof –Serious* AEs (SAEs) –Non-serious AEs Opioid and formulation-related common AEs Two-pronged approach –Demographics and concomitant medications –Adverse events in the cancer and non- cancer populations Related to abuse/misuse/addiction/ oversedation and consequences thereof –Serious* AEs (SAEs) –Non-serious AEs Opioid and formulation-related common AEs *Death, life-threatening, hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Demographic Information ParameterNon-Cancer** [n (%)]Cancer* [n (%)] N Age (years)Mean Std. Dev Range RaceCaucasian874 (93)407 (84) AA47(5)29 (6) Other20(2)48 (10) SexMale407 (43)227 (47) Female534 (57)257 (53)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Concomitant Medication Use* ParameterNon-Cancer [n (%)]Cancer [n (%)] N Around-the-clock opioid dose** Mean mg342.1 mg Std. Dev mg407.6 mg Range mg mg Other CNS depressants Benzodiazepines 43%38% Non-benzodiazepine sleep aids 21%16% Tricyclic antidepressants 14%7% Muscle relaxants (carisoprodol, cyclobenzaprine, etc.) 46%10% Gabapentin/pregabalin 24%15% Other 31%15% *Defined as use for >50% of time-on-trial **Morphine equivalents

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Non-cancer Population Cancer Population Total N Accidental overdose 80 SAE related to drug dependence/withdrawal/ abuse 20 SAE possibly related to oversedation (MVA with severe CNS and orthopedic injury where patient was the driver) 10 Serious Adverse Events related to overdose, misuse, or similar

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Non-serious adverse events, moderate or severe in intensity, related to CNS depression, psychotropic effects, or respiratory depression, duplicates deleted Non-Cancer N=941 Cancer N=358 Pooled Termn%n% Dizzy Lightheaded Confusion Fall Seizures Sedation Withdrawal Fracture Syncope Likability of opioid One case each of: Addictive behavior, substance abuse, personality change, six cracked bottom front teeth, paranoia, car accident, impaired balance, physical trauma 8*0.800 *total of cases *sum of eight discrete cases

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Non-serious adverse events, moderate or severe in intensity, related to CNS depression, psychotropic effects, or respiratory depression, all cases Non-Cancer N=941 Cancer N=358 Pooled TermnRate per 100 PYR n Sedation Dizzy Lightheaded Fall Seizures Syncope Confusion Likability of opioid Withdrawal Fracture One case each of: Addictive behavior, substance abuse, personality change, six cracked bottom front teeth, paranoia, car accident, impaired balance, physical trauma *sum of eight discrete cases

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Common AEs Adverse eventCancer* [n (%)]Non-Cancer** [n (%)] Study , 3041, 3042, 3052 N Nausea27 (22)86 (37)16 (13)222 (24) Vomiting13 (11)52 (22)8 (6)113 (12) Constipation10 (8)33 (14)7 (6)67 (7) Pruritus7 (3) Dizziness27 (22)46 (20)14 (11)107 (11) Somnolence12 (10)30 (13)95 (10) Confusion15 (6) Application site complaints 15 (6)12 (10)116 (12)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Preliminary safety conclusions The non-cancer population has an excess incidence of serious adverse events related to overdose, abuse, misuse, and those consistent with excessive CNS depression compared to analogous safety data from patients with cancer. Depending on the type of analysis conducted, the non-serious, moderate to severe adverse events tend to show a higher rate of common opioid-related adverse events in the cancer population. However, the non-cancer database contains rare concerning reports related to addiction, substance abuse, etc., not observed in patients with cancer. The non-cancer population has an excess incidence of serious adverse events related to overdose, abuse, misuse, and those consistent with excessive CNS depression compared to analogous safety data from patients with cancer. Depending on the type of analysis conducted, the non-serious, moderate to severe adverse events tend to show a higher rate of common opioid-related adverse events in the cancer population. However, the non-cancer database contains rare concerning reports related to addiction, substance abuse, etc., not observed in patients with cancer.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Preliminary safety conclusions The higher rates of concomitant CNS depressant use in the non-cancer population may make medication errors more likely. The common opioid-related adverse event profile is similar between populations. The higher rates of concomitant CNS depressant use in the non-cancer population may make medication errors more likely. The common opioid-related adverse event profile is similar between populations.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Preliminary Conclusions At this point in our review, it appears that: –The product continues to show efficacy over 12-weeks in the non-cancer population. –Compared to the cancer population, the product shows evidence of excess abuse-related serious adverse events in the non-cancer population which is concerning from perspective of the public health. At this point in our review, it appears that: –The product continues to show efficacy over 12-weeks in the non-cancer population. –Compared to the cancer population, the product shows evidence of excess abuse-related serious adverse events in the non-cancer population which is concerning from perspective of the public health.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Outpatient Drug Utilization Trends for Fentora ® and Actiq ® LCDR Kendra C. Worthy, Pharm.D. Drug Utilization Analyst Laura Governale, Pharm.D., MBA Drug Utilization Analyst Team Leader Division of Epidemiology Office of Surveillance and Epidemiology LCDR Kendra C. Worthy, Pharm.D. Drug Utilization Analyst Laura Governale, Pharm.D., MBA Drug Utilization Analyst Team Leader Division of Epidemiology Office of Surveillance and Epidemiology

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, OutlineOutline Settings of use − sales & distribution data: –IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail Prescription and patient-level data: –Verispan, Vector One ™ : National (VONA) –Verispan, Vector One™ : Total Patient Tracker (TPT) –Verispan, Vector One™ : Concurrency (VOCON) Physician survey data: –Verispan, Physician Drug and Diagnosis Audit (PDDA) Conclusions Settings of use − sales & distribution data: –IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail Prescription and patient-level data: –Verispan, Vector One ™ : National (VONA) –Verispan, Vector One™ : Total Patient Tracker (TPT) –Verispan, Vector One™ : Concurrency (VOCON) Physician survey data: –Verispan, Physician Drug and Diagnosis Audit (PDDA) Conclusions

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Sales distribution data Year 2007 IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 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) 92% Fentora ® sales go to retail channels of distribution during Y2007.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Prescription and Patient-level Data Verispan, Vector One™ : National (VONA) Verispan, Vector One™ : Total Patient Tracker (TPT) Verispan, Vector One™ : Concurrency (VOCON) Verispan, Vector One™ : National (VONA) Verispan, Vector One™ : Total Patient Tracker (TPT) Verispan, Vector One™ : Concurrency (VOCON)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 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.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Prescription Data: Total Retail Prescriptions Dispensed For Selected Opioids, Years (With Hydrocodone and Oxycodone Combination Products) Verispan Vector One™: National (VONA). Extracted 3/2008 Hydrocodone products #1 among all dispensed prescriptions for past 10 years; nearly 120 million Rx dispensed in Y2007 Oxycodone products = 42 million Rx in Y2007 Original File: VONA oxycodone AC xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Prescription Data: Total Retail Prescriptions Dispensed for Selected Opioids, Years (WITHOUT Hydrocodone Combination Products) Verispan Vector One™: National (VONA). Extracted 1/2008 Fentanyl products: ~500% growth since Y1997 –~891,000 Rx dispensed in Y1997 to 5.5 million Rx dispensed in Y2007 Fentanyl products: ~500% growth since Y1997 –~891,000 Rx dispensed in Y1997 to 5.5 million Rx dispensed in Y2007 Original File: VONA oxycodone comp AC xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Prescription Data: Total Dispensed Prescriptions for Fentanyl Products from U.S. Retail Pharmacies, Years Verispan Vector One™ : National (VONA). Extracted 2/2008 Fentanyl Transdermal has replaced Duragesic ® as leading Fentanyl Product Original File: VONA fentanyl.xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Prescription Data: Total Dispensed Prescriptions for Fentanyl Products* from U.S. Retail Pharmacies, Years *Excludes Duragesic and Fentanyl Transdermal Products Verispan Vector One™ : National (VONA). Extracted 2/2008 Total Rx dispensed Y2007 –Actiq ® TRx = 66,000 –Fentora ® TRx = 91,000 –OTFC TRx = 188,000 Between Y2005 and Y2007: –~77% decrease in Actiq ® prescriptions Between Y2006 and Y2007: –~500% increase in both OTFC & Fentora ® prescriptions Original File: VONA fentanyl.xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Cost per Unit of Fentora ®, Actiq ®, and Oral Transmucosal Fentanyl Prescriptions Dispensed from U.S. Retail Pharmacies, Year 2007 Verispan Vector One™: National (VONA). Extracted 2/2008 In Y2007, Actiq ® has highest cost per approx. $42 Oral Transmucosal: $26 Fentora ® : $23 Cost per Unit = Retail dollars / Extended Units In Y2007, Actiq ® has highest cost per approx. $42 Oral Transmucosal: $26 Fentora ® : $23 Cost per Unit = Retail dollars / Extended Units Original File: VONA Fentora Price xls f

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Projected Number of Prescriptions for Fentora ® Dispensed, by Physician Specialty, from U.S. Retail Pharmacies, Year 2007 Verispan Vector One™: National (VONA). Extracted 2/2008 Top prescribers for year 2007 –Anesthesiology ~31,000 Rx (35%) –Physical Medicine and Rehabilitation ~19,000 Rx (21%) –GP/FM/DO ~8,000 (9%) Oncology specialty (not shown) ranks 14th, accounting for approx. 1% of Fentora ® prescribing in Y2007 Top prescribers for year 2007 –Anesthesiology ~31,000 Rx (35%) –Physical Medicine and Rehabilitation ~19,000 Rx (21%) –GP/FM/DO ~8,000 (9%) Oncology specialty (not shown) ranks 14th, accounting for approx. 1% of Fentora ® prescribing in Y2007 Original File: VONA Fentora MD Spec xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Projected Number of Patients, by age, receiving a prescription for Fentora ®, Actiq ®, or Oral Transmucosal Fentanyl from outpatient retail pharmacies, Year 2007 Verispan, LLC: Total Patient Tracker, Extracted 2/08 Total patients in Y2007 –Actiq ® : 15,887 patients –Fentora ® : 23,035 patients –OTFC: 32,343 patients Majority of patients aged years (66% - 69%) Pediatric patients (0-16 years) <1% Total patients in Y2007 –Actiq ® : 15,887 patients –Fentora ® : 23,035 patients –OTFC: 32,343 patients Majority of patients aged years (66% - 69%) Pediatric patients (0-16 years) <1% Source File: TPT Fentora Actiq Custom Age Report.xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Percentage of Actiq ® Prescriptions Switched and the Next Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007 Verispan Vector One™: National (VONA). Extracted 2/2008 Most common product dispensed after Actiq ® prescription is OTFC 4th Q 2006 –42% of Actiq ® Rxs switched to OTFC –13% of Actiq ® Rxs switched to Fentora ® 4th Q 2007 –14% of Actiq ® Rxs switched to OTFC –3% of Actiq ® Rxs switched to Fentora ® Most common product dispensed after Actiq ® prescription is OTFC 4th Q 2006 –42% of Actiq ® Rxs switched to OTFC –13% of Actiq ® Rxs switched to Fentora ® 4th Q 2007 –14% of Actiq ® Rxs switched to OTFC –3% of Actiq ® Rxs switched to Fentora ® Original File: VONA Actiq Switching xls

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, 2008 Physician survey data, Year 2007 Indications associated with drug use Verispan, Physician Drug and Diagnosis Audit (PDDA)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Office-based physician survey data –monthly survey that monitors disease states and the physician intended prescribing habits on a national-level –designed to provide descriptive information on the patterns and treatment of diseases encountered in office-based physician practices in the U.S. –audit is composed of approximately 3,100 office-based physicians representing 29 specialties across the US Office-based physician survey data –monthly survey that monitors disease states and the physician intended prescribing habits on a national-level –designed to provide descriptive information on the patterns and treatment of diseases encountered in office-based physician practices in the U.S. –audit is composed of approximately 3,100 office-based physicians representing 29 specialties across the US Verispan, Physician Drug and Diagnosis Audit™ (PDDA™)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, “Drug Uses” – mention of a drug in association with a diagnosis during office-based patient visit Limitations –Denominator is “visits” - not patients –Sample sizes can be small when use is low, producing unreliable estimates –“Uses” may be duplicated by number of diagnoses and does not necessarily result in prescription “Drug Uses” – mention of a drug in association with a diagnosis during office-based patient visit Limitations –Denominator is “visits” - not patients –Sample sizes can be small when use is low, producing unreliable estimates –“Uses” may be duplicated by number of diagnoses and does not necessarily result in prescription Verispan, Physician Drug and Diagnosis Audit™ (PDDA™)

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Top diagnoses associated with Actiq ® and Fentora ® use during visits to office-based physicians, Year 2007 Verispan, Physician Drug and Diagnosis Audit (PDDA) For Actiq ® and Fentora ®, majority of diagnoses are non-cancer related.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Verispan LLC, Vector One ™ : Concurrency (VOCON) Derived from Verispan’s Vector One™ database Allows users to measure and evaluate concurrent drug therapy usage in unique patients during a selected time period using one of four scenarios. Nationwide projections are not available. Derived from Verispan’s Vector One™ database Allows users to measure and evaluate concurrent drug therapy usage in unique patients during a selected time period using one of four scenarios. Nationwide projections are not available.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Verispan LLC, Vector One ® : Concurrency (VOCON) Episode of concurrency: –prescription in the Base group (Actiq ® or Fentora ® ) overlaps with the days supply for a dispensed prescription in the Concurrent group (pain market or product within the pain market). 30 day supply with grace period of 10% = 36 days Fill sequence: Pain market product filled before Actiq ® or Fentora ® Episode of concurrency: –prescription in the Base group (Actiq ® or Fentora ® ) overlaps with the days supply for a dispensed prescription in the Concurrent group (pain market or product within the pain market). 30 day supply with grace period of 10% = 36 days Fill sequence: Pain market product filled before Actiq ® or Fentora ®

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Concurrency Analysis – Results Y2005: 40% of Actiq ® patients were on concurrent therapy with a product from the pain market. Y2007: 26% Y2007: 59% of Fentora ® patients were on concurrent therapy with a product from the pain market. Higher prevalence of concurrent therapy with products in the pain market with Fentora ® than Actiq ®. Fentanyl transdermal, hydrocodone/acetaminophen, and oxycodone (immediate release) products were the most common concurrent products within the pain market. Y2005: 40% of Actiq ® patients were on concurrent therapy with a product from the pain market. Y2007: 26% Y2007: 59% of Fentora ® patients were on concurrent therapy with a product from the pain market. Higher prevalence of concurrent therapy with products in the pain market with Fentora ® than Actiq ®. Fentanyl transdermal, hydrocodone/acetaminophen, and oxycodone (immediate release) products were the most common concurrent products within the pain market.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, Concurrency Analysis - Limitations VOCON does not capture data from inpatient hospitals, oncology clinics, same-day surgery centers, or mail order pharmacies. True opioid tolerance/non-tolerance cannot be determined within the confines of this analysis, as a patient could begin opioid treatment as an inpatient or in a clinic, and continue therapy as an outpatient. VOCON does not capture data from inpatient hospitals, oncology clinics, same-day surgery centers, or mail order pharmacies. True opioid tolerance/non-tolerance cannot be determined within the confines of this analysis, as a patient could begin opioid treatment as an inpatient or in a clinic, and continue therapy as an outpatient.

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, ConclusionsConclusions ~92% of Fentora ® sales go to retail channels of distribution ~500% increase in Fentora ® prescriptions from 14,620 Rx dispensed in Y2006 to 90,751 Rx dispensed in Y2007 Total patients in Y2007 –Actiq ® : 15,887 patients –Fentora ® : 23,035 patients –OTFC: 32,343 patients ~3.3% of Actiq ® Rxs switched to Fentora ® during 4 th Qtr 2007 Sum of total Rx dispensed for Actiq ®, Fentora ®, OTFC have not caused an increase in the trend ~92% of Fentora ® sales go to retail channels of distribution ~500% increase in Fentora ® prescriptions from 14,620 Rx dispensed in Y2006 to 90,751 Rx dispensed in Y2007 Total patients in Y2007 –Actiq ® : 15,887 patients –Fentora ® : 23,035 patients –OTFC: 32,343 patients ~3.3% of Actiq ® Rxs switched to Fentora ® during 4 th Qtr 2007 Sum of total Rx dispensed for Actiq ®, Fentora ®, OTFC have not caused an increase in the trend

Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees May 6, ConclusionsConclusions In Y2007: Actiq ® has highest cost per unit ($43) –Oral Transmucosal: $26; Fentora ® : $23 Anesthesiology specialty account for 35% of Fentora ® Rx in 2007, followed by Physical Medicine and Rehabilitation specialty with 21% –Oncology specialty 14th in 2007 with ~1% of prescriptions Majority of uses associated with non-cancer indications in office-based practices Higher prevalence of concurrent therapy with products in the pain market with Fentora ® than Actiq ® In Y2007: Actiq ® has highest cost per unit ($43) –Oral Transmucosal: $26; Fentora ® : $23 Anesthesiology specialty account for 35% of Fentora ® Rx in 2007, followed by Physical Medicine and Rehabilitation specialty with 21% –Oncology specialty 14th in 2007 with ~1% of prescriptions Majority of uses associated with non-cancer indications in office-based practices Higher prevalence of concurrent therapy with products in the pain market with Fentora ® than Actiq ®