joint meeting of anesthetic and life support drugs and drug safety and risk management advisory...

Joint meeting of Anesthetic and Life Support Drugs and Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesMay 6, 2008May 6, 2008

Review of FentoraReview of Fentora®® and Actiq and Actiq®® Adverse Events from the Adverse Events from the Adverse Event Reporting Adverse Event Reporting System (AERS) DatabaseSystem (AERS) Database

Review of FentoraReview of Fentora®® and Actiq and Actiq®® Adverse Events from the Adverse Events from the Adverse Event Reporting Adverse Event Reporting System (AERS) DatabaseSystem (AERS) Database

Yoo Jung Chang, Pharm.D.Lauren Lee, Pharm.D.

Division of Adverse Event Analysis IIOffice of Surveillance and Epidemiology

Yoo Jung Chang, Pharm.D.Lauren Lee, Pharm.D.

Division of Adverse Event Analysis IIOffice of Surveillance and Epidemiology

2Joint meeting of Anesthetic and Life Support Drugs and Joint meeting of Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesMay 6, 2008May 6, 2008

OutlineOutlineOutlineOutline• 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


ObjectivesObjectivesObjectivesObjectives

• 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


AERS: Spontaneous Adverse AERS: Spontaneous Adverse Event ReportingEvent Reporting

AERS: Spontaneous Adverse AERS: Spontaneous Adverse Event ReportingEvent 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


AERS StrengthsAERS StrengthsAERS StrengthsAERS 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


AERS LimitationsAERS LimitationsAERS LimitationsAERS 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


AERS Review of All Adverse AERS Review of All Adverse Events Reported with FentoraEvents Reported with Fentora®®

AERS Review of All Adverse AERS Review of All Adverse Events Reported with FentoraEvents Reported with Fentora®®


Fentora: AERS Search CriteriaFentora: AERS Search CriteriaFentora: AERS Search CriteriaFentora: 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


Fentora: Search ResultsFentora: Search ResultsFentora: Search ResultsFentora: 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


Fentora: Demographics and IndicationsFentora: Demographics and IndicationsFentora: Demographics and IndicationsFentora: Demographics and Indications

Number of cases 19

Gender: Male Female

910

Age (n=16): Median Range

43.5 years16 – 73 years

Indication (n=18): Cancer pain Non-cancer pain Misc*

1 (5%)11 (57%)6 (32%)

* Suicidal attempt, abuse, intentional overdose, & accidental exposure


Fentora: Dose & Other Opioid UseFentora: Dose & Other Opioid UseFentora: Dose & Other Opioid UseFentora: Dose & Other Opioid UseNumber of cases 19

Daily dose (n=6): Median Range

2000 mcg600 – 3200 mcg

Onset (n=6): Median Range

8 daysSame day – 5 months

Opioid tolerance: Tolerant Non-tolerant Unspecified

6 (32%)1 (5%)

12 (63%)

Concomitant use of other opioid medications 11


Fentora: Outcomes & Report SourceFentora: Outcomes & Report SourceFentora: Outcomes & Report SourceFentora: Outcomes & Report Source

Number of cases 19

Outcomes: Death Life-threatening Hospitalization Medically significant Unspecified

51139

Year Received 2007 2008

172

Report Source US 19


Fentora: FatalitiesFentora: FatalitiesFentora: FatalitiesFentora: 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.


Fentora: Reported Adverse Events (AE)Fentora: Reported Adverse Events (AE)Fentora: Reported Adverse Events (AE)Fentora: Reported Adverse Events (AE)

System Organ Class Adverse EventsCardiac 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


Fentora: Reported AE Cont..Fentora: Reported AE Cont..Fentora: Reported AE Cont..Fentora: Reported AE Cont..System Organ Class Adverse EventsMetabolism & 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)


Fentora: Overdose, Misuse, & SuicideFentora: Overdose, Misuse, & SuicideFentora: Overdose, Misuse, & SuicideFentora: 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


Fentora: Summary of AERS ReviewFentora: Summary of AERS ReviewFentora: Summary of AERS ReviewFentora: 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



• 53% involved medication errors with adverse events

– prescribing/dispensing errors, incorrect route/freq of admin by patients, incorrect conversion from Actiq


Fentora: Summary of AERS Review, Fentora: Summary of AERS Review, cont.cont.

Fentora: Summary of AERS Review, Fentora: Summary of AERS Review, cont.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


• Unlabeled adverse events (i.e., acute MI, CVA, dysarthria) do not appear to be directly related to Fentora


AERS Review of Serious* Adverse AERS Review of Serious* Adverse Events Reported with ActiqEvents Reported with Actiq® ®

(2007)(2007)

AERS Review of Serious* Adverse AERS Review of Serious* Adverse Events Reported with ActiqEvents Reported with Actiq® ®

(2007)(2007)

* Serious per regulatory definition includes death, hospitalization or prolongation of hospitalization, life-threatening, disability, congenital anomaly, and other medically important events (CFR 314.80).

* Serious per regulatory definition includes death, hospitalization or prolongation of hospitalization, life-threatening, disability, congenital anomaly, and other medically important events (CFR 314.80).


Actiq: AERS Search CriteriaActiq: AERS Search CriteriaActiq: AERS Search CriteriaActiq: 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


Actiq: Indication & ToleranceActiq: Indication & ToleranceActiq: Indication & ToleranceActiq: Indication & ToleranceNumber of cases 61

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


Actiq: OutcomesActiq: OutcomesActiq: OutcomesActiq: OutcomesTotal number of cases 61

Outcomes*: Death Life-threatening Hospitalization Disability Medically significant

96

282

25*Cases may have reported more than one outcome.


Actiq:Actiq: Fatalities FatalitiesActiq:Actiq: Fatalities Fatalities• 9 reports of death

• Causes of death

– apnea (1), cardio-respiratory arrest (1), fentanyl toxicity (2), multiple drug overdose (2), unknown (3)


• Of the remaining 2 reports:

– 1st: Fetal death confounded by concomitant use of other medications, one of which was labeled category D

– 2nd: 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)


• Of the remaining 2 reports:

– 1st: Fetal death confounded by concomitant use of other medications, one of which was labeled category D

– 2nd: Opioid non-tolerant patient (weaned off of opioids) but restarted Actiq and possibly other opioids


Actiq: Reported Adverse Events (AE)Actiq: Reported Adverse Events (AE)Actiq: Reported Adverse Events (AE)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


Actiq:Actiq: Overdose & Misuse Overdose & MisuseActiq:Actiq: Overdose & Misuse 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


Actiq: Summary of AERS ReviewActiq: Summary of AERS ReviewActiq: Summary of AERS ReviewActiq: Summary of AERS Review

• 61 serious adverse event reports in 2007



• Overdose & misuse represented 52% of cases

• 61 serious adverse event reports in 2007



• Overdose & misuse represented 52% of cases


Actiq: Summary of AERS Review, Actiq: Summary of AERS Review, cont.cont.

Actiq: Summary of AERS Review, Actiq: Summary of AERS Review, cont.cont.

• 30% of cases involved medication errors

– prescribing errors, incorrect route/freq of admin by patients


• 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


• Unlabeled adverse events (i.e., cardiac arrest, ventricular fibrillation & tachycardia, coma, lethargy, loss of consciousness, delusion, and irritability) occurred in the context of overdoses


Overall Summary:Overall Summary:Fentora and Actiq CasesFentora and Actiq Cases

Overall Summary:Overall Summary:Fentora and Actiq CasesFentora 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


Overall Summary:Overall Summary:Fentora and Actiq Cases, cont.Fentora and Actiq Cases, cont.

Overall Summary:Overall Summary:Fentora and Actiq Cases, cont.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


Fentora Medication ErrorsFentora Medication ErrorsFentora Medication ErrorsFentora Medication Errors

Kristina C. Arnwine, PharmDActing Team Leader

Division of Medication Error Prevention

Kristina C. Arnwine, PharmDActing Team Leader

Division of Medication Error Prevention


OverviewOverviewOverviewOverview

• AERS Search• Medication Error Cases• Types of Error• Summary

• AERS Search• Medication Error Cases• Types of Error• Summary


AERS SearchAERS SearchAERS SearchAERS 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


AERS ResultsAERS ResultsAERS ResultsAERS 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


Medication Error Cases (n=43)Medication Error Cases (n=43)Medication Error Cases (n=43)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)


Types of Error (n=43)Types of Error (n=43)Types of Error (n=43)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


Types of ErrorTypes of ErrorTypes of ErrorTypes 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


Types of Error (cont)Types of Error (cont)Types of Error (cont)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



• 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


Confusion Between Confusion Between Actiq & FentoraActiq & Fentora

Confusion Between Confusion Between Actiq & FentoraActiq & 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


Types of Error (cont) Types of Error (cont) Types of Error (cont) 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



• 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



• 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



• 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


Safety CommunicationsSafety CommunicationsSafety CommunicationsSafety 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


SummarySummarySummarySummary

• 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


Fentora Risk Management: Fentora Risk Management: Postmarketing Experience and Postmarketing Experience and

RecommendationsRecommendations

Fentora Risk Management: Fentora Risk Management: Postmarketing Experience and Postmarketing Experience and

RecommendationsRecommendations

Jeanine Best, MSN, RN, PNPSenior Drug Risk Management Analyst

Division of Risk ManagementOffice of Surveillance and Epidemiology

Jeanine Best, MSN, RN, PNPSenior Drug Risk Management Analyst

Division of Risk ManagementOffice of Surveillance and Epidemiology


OutlineOutlineOutlineOutline 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


BackgroundBackgroundBackgroundBackgroundFentora 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, 2/7/08Fentora Label, 2/7/08


Current Fentora RiskMAPCurrent Fentora RiskMAPCurrent Fentora RiskMAPCurrent Fentora RiskMAP


GoalsGoalsGoalsGoals

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.


Key ElementsKey ElementsKey ElementsKey Elements

Labeling

Education

Surveillance

Evaluation/Intervention

Labeling

Education

Surveillance

Evaluation/Intervention


LabelingLabelingLabelingLabeling 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


Labeling - CartonLabeling - CartonLabeling - CartonLabeling - Carton


Education PlanEducation PlanEducation PlanEducation 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


SurveillanceSurveillanceSurveillanceSurveillance 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)


Evaluation PlanEvaluation PlanEvaluation PlanEvaluation 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


RiskMAP Postmarketing RiskMAP Postmarketing ExperienceExperience

RiskMAP Postmarketing RiskMAP Postmarketing ExperienceExperience


RiskMAP Quarterly Report InformationRiskMAP Quarterly Report InformationRiskMAP Quarterly Report InformationRiskMAP Quarterly Report Information

Quarterly RiskMAP Report Data

Non Opioid Tolerant(IMS longitudinal database estimates)

Non Cancer Diagnosis(IMS National Audit Data)

1st quarter(9/25/06-12/31/06

14.2% 85.8%

2nd quarter(1/1/07-3/31/07)

21.0% 84.1%

3rd quarter(4/1/07-6/30/07)

23.5% 81.0%

4th quarter(7/1/07-9/30/07)

24.1% 82.8%

5th quarter(10/1/07-12/31/07)

28.1% 82.6%


RiskMAP Quarterly Report Information, cont.RiskMAP Quarterly Report Information, cont.RiskMAP Quarterly Report Information, cont.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).


RiskMAP Quarterly Report Information, RiskMAP Quarterly Report Information, cont.cont.


Physician Survey no results submitted as of 5th quarterly

RiskMAP Report

Pharmacy Survey no results submitted as of 5th quarterly

RiskMAP Report

Physician Survey no results submitted as of 5th quarterly

RiskMAP Report

Pharmacy Survey no results submitted as of 5th quarterly

RiskMAP Report




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


Postmarketing Actions Postmarketing Actions Postmarketing Actions 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


Fentora RiskMAP Experience Fentora RiskMAP Experience SummarySummary

Fentora RiskMAP Experience Fentora RiskMAP Experience SummarySummary


Summary of RiskMAP ExperienceSummary of RiskMAP ExperienceSummary of RiskMAP ExperienceSummary 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


Comments on RiskMAP ExperienceComments on RiskMAP ExperienceComments on RiskMAP ExperienceComments 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


Additional Risk Mitigation OptionsAdditional Risk Mitigation OptionsAdditional Risk Mitigation OptionsAdditional 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


Fentora Risk Mitigation OptionsFentora Risk Mitigation OptionsFentora Risk Mitigation OptionsFentora 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


Acknowledge understanding of (could include)• appropriate (indicated) use• screening for abuse/misuse/diversion• dosing and administration instructions


Fentora Risk Mitigation Options, Fentora Risk Mitigation Options, cont.cont.


Pharmacy/Dispensing Requirements

Mandatory enrollment of pharmacies in order to dispense


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


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, 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




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


Risk Mitigation Options Risk Mitigation Options AdvantagesAdvantages

Risk Mitigation Options Risk Mitigation Options AdvantagesAdvantages

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



Risk Mitigation Options Risk Mitigation Options ChallengesChallenges

Risk Mitigation Options Risk Mitigation Options ChallengesChallenges

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


ConclusionsConclusionsConclusionsConclusions Additional risk mitigation strategies


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


Regulatory History of Oral Regulatory History of Oral Transmucosal Fentanyl ProductsTransmucosal Fentanyl Products

Regulatory History of Oral Regulatory History of Oral Transmucosal Fentanyl ProductsTransmucosal Fentanyl Products

Ellen W Fields, M.D., M.P.HActing Clinical Team Leader

Division of Anesthesia, Analgesia, and Rheumatology Products

Ellen W Fields, M.D., M.P.HActing Clinical Team Leader



Overview of PresentationOverview of PresentationOverview of PresentationOverview 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


OTFC ProductsOTFC ProductsOTFC ProductsOTFC Products

• Oralet

• Actiq

• Fentora

• Oralet

• Actiq

• Fentora


OraletOraletOraletOralet

• 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


ActiqActiqActiqActiq

• 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



ActiqActiqActiqActiq• 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


Original Actiq LabelOriginal Actiq LabelOriginal Actiq LabelOriginal 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


Original Actiq LabelOriginal Actiq LabelOriginal Actiq LabelOriginal 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


Actiq Labeling ChangesActiq Labeling ChangesActiq Labeling ChangesActiq 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


FentoraFentoraFentoraFentora

• Approved September 2006

• Indication: same as Actiq

• Formulation: effervescent buccal tablet

• Dosage units: 100, 200, 400, 600, and 800 mcg (300mcg approved March 2007)


• 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)


• Risk Management Plan and Medguide part of approval


Original Fentora LabelOriginal Fentora LabelOriginal Fentora LabelOriginal 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.


Pharmacokinetic Parameters in Adult Subjects

Receiving Fentora or Actiq (OTFC)

Pharmacokinetic Parameter (mean)

Fentora 400mcg

Actiq 400mcg*

Absolute Bioavailability

65% ± 20% 47.5% ± 10.5%

Fraction Absorbed Transmucosally 48% ± 31.8% 31% ± 17.3%

Tmax (minute)**

48.8 (20-240) 90.8 (35-240)

Cmax (ng/mL)

1.02 ± 0.42 0.63 ± 0.21

AUC0-tmax (ng.hr/mL)

0.40 ± 0.18 0.14 ± 0.05

Pharmacokinetic Parameters in Adult Subjects

Receiving Fentora or Actiq (OTFC)

Pharmacokinetic Parameter (mean)

Fentora 400mcg

Actiq 400mcg*

Absolute Bioavailability

65% ± 20% 47.5% ± 10.5%

Fraction Absorbed Transmucosally 48% ± 31.8% 31% ± 17.3%

Tmax (minute)**

48.8 (20-240) 90.8 (35-240)

Cmax (ng/mL)

1.02 ± 0.42 0.63 ± 0.21

AUC0-tmax (ng.hr/mL)

0.40 ± 0.18 0.14 ± 0.05

Source: Fentora Package Insert

Fentora vs. ActiqFentora vs. ActiqFentora vs. ActiqFentora vs. Actiq


• 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 ErrorsMedication ErrorsMedication ErrorsMedication Errors


Public Health AdvisoryPublic Health AdvisoryPublic Health AdvisoryPublic 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


Fentora Labeling ChangesFentora Labeling ChangesFebruary 7, 2008February 7, 2008

Fentora Labeling ChangesFentora Labeling ChangesFebruary 7, 2008February 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.


SummarySummarySummarySummary• 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.


Fentora Abuse Potential in the Fentora Abuse Potential in the Noncancer Pain PopulationNoncancer Pain Population

Fentora Abuse Potential in the Fentora Abuse Potential in the Noncancer Pain PopulationNoncancer 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


Why the concerns about safety, Why the concerns about safety, including abuse potential?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.




• 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


What Users Are Saying About Fentora*What Users Are Saying About Fentora*What Users Are Saying About Fentora*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 “

* www.bluelight.ru* www.bluelight.ru


What Users Are Saying About Fentora*What Users Are Saying About Fentora*What Users Are Saying About Fentora*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 website @ 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 website @ 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”

* www.bluelight.ru* www.bluelight.ru


• 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 Fentora phase 3 clinical studies in noncancer painnoncancer pain

Fentora phase 3 clinical studies in Fentora phase 3 clinical studies in noncancer painnoncancer pain


Protocol-specified entry Protocol-specified entry criteriacriteria

Protocol-specified entry Protocol-specified entry criteriacriteria• 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


““Review and Assessment of Risks for Review and Assessment of Risks for Abuse and Diversion”Abuse and Diversion”

““Review and Assessment of Risks for Review and Assessment of Risks for Abuse and Diversion”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


““Review and Assessment of Risks Review and Assessment of Risks for Abuse and Diversion”for Abuse and Diversion”

““Review and Assessment of Risks Review and Assessment of Risks for Abuse and Diversion”for Abuse and Diversion”

Table 1: Types of Aberrant Drug-use Behaviors (Sponsor identified)Abuse/dependence Study drug theft

Overdose Lost to follow-up

Motor vehicle accident Seeking prescriptions from other sources

Fear of addiction Lost study drug

Discharged from practice Overuse of study drug

Positive urine drug screen Acquiring opioids from other medical sources

Unreliability Unapproved use of a medication used for another symptom

Using nonprescribed medication


Aberrant drug use behaviorAberrant drug use behaviorAberrant drug use behaviorAberrant drug use behaviorTable 2: Sponsor’s Summary of Patients by Risk Category

Risk CategoryNumber of Patients¥ Percent

High risk behaviors* 30 3%

Abuse/dependence 8 <1%

Overdose 9# 1%

Positive urine drug screen

13 1%

Other aberrant behaviors 126 13%

None 785 83%¥ 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


Aberrant drug use behaviorAberrant drug use behaviorAberrant drug use behaviorAberrant drug use behavior

Table 3: Aberrant Behaviors Identified in > 1% of Patients (Identified by Sponsor)

BehaviorNumber of

Patients Percent

Overuse of study drug 44 5%

Study drug thefts 35 4%

Lost to follow-up 33 4%


Aberrant drug use behaviorAberrant drug use behaviorAberrant drug use behaviorAberrant drug use behavior

• 5 patients withdrawn: 4 from study 3040, 1 from 3052• 30 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 3052• 30 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)

Study drug theftNumber of

cases Percent Amount of drug

stolen

From patients 35 4.2%* ----

*Number of cases (5) divided by the total 831 patients in studies 3040 & 3052.


Aberrant drug use behaviorAberrant drug use behaviorAberrant drug use behaviorAberrant drug use behaviorTable 5: Study Drug Thefts during Phase 3 Clinical Trials (Identified by Sponsor)

Study drug theftNumber of

cases Percent Amount of drug

stolen

From study center

5 ----+ 4.3 gm ¥

+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


FDA CommentsFDA CommentsFDA CommentsFDA 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


CSS SummaryCSS SummaryCSS SummaryCSS 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


CSS SummaryCSS SummaryCSS SummaryCSS 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


CSS ConclusionCSS ConclusionCSS ConclusionCSS 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.

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.


Fentora (NDA 21-947, S005)Fentora (NDA 21-947, S005)FDA’s Review of Safety and EfficacyFDA’s Review of Safety and Efficacy

Fentora (NDA 21-947, S005)Fentora (NDA 21-947, S005)FDA’s Review of Safety and EfficacyFDA’s Review of Safety and Efficacy

Robert B. Shibuya, M.D.Medical Officer


Robert B. Shibuya, M.D.Medical Officer



Overview of PresentationOverview of PresentationOverview of PresentationOverview 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


Proposed indicationProposed indicationProposed indicationProposed 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”


Implications of increased use if Implications of increased use if this supplement were approvedthis supplement were approvedImplications of increased use if Implications of increased use if this supplement were approvedthis 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


Implications of increased use if Implications of increased use if this supplement were approvedthis supplement were approvedImplications of increased use if Implications of increased use if this supplement were approvedthis 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


DAWN: ED Visits -- Non-Medical DAWN: ED Visits -- Non-Medical Use per 10,000 Retail Prescriptions Use per 10,000 Retail Prescriptions

2004 – 20062004 – 2006

DAWN: ED Visits -- Non-Medical DAWN: ED Visits -- Non-Medical Use per 10,000 Retail Prescriptions Use per 10,000 Retail Prescriptions

2004 – 20062004 – 2006

Source: National estimates from DAWN, 2004-2006; Verispan VONA

4.1

13.422.1

4.5

15.4

24.1

5.1

17.2

31.4

0

10

20

30

40

2004 2005 2006

Hydrocodone/combinations Oxycodone/combinations Fentanyl

4.1

13.422.1

4.5

15.4

24.1

5.1

17.2

31.4

0

10

20

30

40

2004 2005 2006

Hydrocodone/combinations Oxycodone/combinations Fentanyl


EfficacyEfficacyEfficacyEfficacy

• 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 3042- 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 3042- Short-term, R, DB, PC, XO study in OT patients with chronic low back pain


Study 3052 – Primary Efficacy Study 3052 – Primary Efficacy Endpoint (PEP)Endpoint (PEP)

Study 3052 – Primary Efficacy Study 3052 – Primary Efficacy Endpoint (PEP)Endpoint (PEP)


Studies 3041 and 3042Studies 3041 and 3042Studies 3041 and 3042Studies 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.


Preliminary efficacy conclusionPreliminary efficacy conclusionPreliminary efficacy conclusionPreliminary 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.


SafetySafetySafetySafety• 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


SafetySafetySafetySafety

• 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.


Safety - ExposureSafety - ExposureSafety - ExposureSafety - 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.


Safety -ExposureSafety -ExposureSafety -ExposureSafety -Exposure

Source: Summary of Clinical SafetySource: Summary of Clinical Safety


FDA’s safety analysisFDA’s safety analysisFDA’s safety analysisFDA’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.


FDA’s safety analysisFDA’s safety analysisFDA’s safety analysisFDA’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

*Death, life-threatening, hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect


Demographic InformationDemographic InformationDemographic InformationDemographic InformationParameter Non-Cancer** [n (%)] Cancer* [n (%)]

N 941 358

Age (years) Mean 48.7 55.9

Std. Dev 9.86 12.2

Range 20-77 24-95

Race Caucasian 874 (93) 407 (84)

AA 47(5) 29 (6)

Other 20(2) 48 (10)

Sex Male 407 (43) 227 (47)

Female 534 (57) 257 (53)


Concomitant Medication Use*Concomitant Medication Use*Concomitant Medication Use*Concomitant Medication Use*Parameter Non-Cancer [n (%)] Cancer [n (%)]

N 941 358

Around-the-clock opioid dose**

Mean 239.7 mg 342.1 mg

Std. Dev 219.4 mg 407.6 mg

Range 20-2160 mg 24-4800 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

*Defined as use for >50% of time-on-trial**Morphine equivalents


Non-cancer Population

Cancer Population

Total N 941 358Accidental overdose 8 0

SAE related to drug dependence/withdrawal/abuse

2 0

SAE possibly related to oversedation (MVA with severe CNS and orthopedic injury where patient was the driver)

1 0

Serious Adverse Events related to Serious Adverse Events related to overdose, misuse, or similaroverdose, misuse, or similar

Serious Adverse Events related to Serious Adverse Events related to overdose, misuse, or similaroverdose, misuse, or similar


Non-serious adverse events, moderate or severe in intensity, related to CNS depression, psychotropic effects, or respiratory depression, duplicates deleted

Non-CancerN=941

CancerN=358

Pooled Term n % n %

Dizzy 22 2.3 1 8.0

Lightheaded 10 1.1 14 3.6

Confusion 14 1.5 2 2.8

Fall 19 2.0 7 2.0

Seizures 0 0 1 0.3

Sedation 61 6.5 14 3.9

Withdrawal 12 1.3 1 0.3

Fracture 17 1.8 2 0.6

Syncope 4 0.4 1 0.3

Likability of opioid 7 0.7 2 0.6

One case each of: Addictive behavior, substance abuse, personality change, six cracked bottom front teeth, paranoia, car accident, impaired balance, physical trauma

8* 0.8 0 0*total of cases

*sum of eight discrete cases


Non-serious adverse events, moderate or severe in intensity, related to CNS depression, psychotropic effects, or respiratory depression, all cases

Non-serious adverse events, moderate or severe in intensity, related to CNS depression, psychotropic effects, or respiratory depression, all cases

Non-CancerN=941

CancerN=358

Pooled Term n Rate per 100 PYR

n Rate per 100 PYR

Sedation 78 11.6 15 11.7

Dizzy 27 4.0 42 32.8

Lightheaded 10 1.5 10 7.8

Fall 20 3.0 8 6.3

Seizures 0 0 1 0.8

Syncope 4 0.6 1 0.8

Confusion 16 2.4 12 9.4

Likability of opioid 8 1.2 2 1.6

Withdrawal 12 1.8 1 0.8

Fracture 23 3.4 3 2.3

One case each of: Addictive behavior, substance abuse, personality change, six cracked bottom front teeth, paranoia, car accident, impaired balance, physical trauma

8 1.2 0 0

*sum of eight discrete cases


Common AEsCommon AEsCommon AEsCommon AEsAdverse event Cancer* [n (%)] Non-Cancer** [n (%)]

Study 14 15 3039 3040, 3041, 3042, 3052

N 123 232 125 941

Nausea 27 (22) 86 (37) 16 (13) 222 (24)

Vomiting 13 (11) 52 (22) 8 (6) 113 (12)

Constipation 10 (8) 33 (14) 7 (6) 67 (7)

Pruritus 7 (3)

Dizziness 27 (22) 46 (20) 14 (11) 107 (11)

Somnolence 12 (10) 30 (13) 95 (10)

Confusion 15 (6)

Application site complaints

15 (6) 12 (10) 116 (12)


Preliminary safety conclusionsPreliminary safety conclusionsPreliminary safety conclusionsPreliminary 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.


Preliminary safety conclusionsPreliminary safety conclusionsPreliminary safety conclusionsPreliminary 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.


Preliminary ConclusionsPreliminary ConclusionsPreliminary ConclusionsPreliminary 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.


Outpatient Drug Utilization Trends Outpatient Drug Utilization Trends for Fentorafor Fentora®® and Actiq and Actiq®®

Outpatient Drug Utilization Trends Outpatient Drug Utilization Trends for Fentorafor Fentora®® and Actiq and Actiq®®

LCDR Kendra C. Worthy, Pharm.D.Drug Utilization Analyst

Laura Governale, Pharm.D., MBADrug Utilization Analyst Team Leader

Division of EpidemiologyOffice of Surveillance and Epidemiology

LCDR Kendra C. Worthy, Pharm.D.Drug Utilization Analyst

Laura Governale, Pharm.D., MBADrug Utilization Analyst Team Leader

Division of EpidemiologyOffice of Surveillance and Epidemiology


OutlineOutlineOutlineOutline• 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


Sales distribution dataSales distribution dataYear 2007Year 2007

Sales distribution dataSales distribution dataYear 2007Year 2007

IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail

IMS Health, IMS National Sales Perspectives™ Retail and Non-Retail


IMS Health, IMS National Sales IMS Health, IMS National Sales PerspectivesPerspectives™™

IMS Health, IMS National Sales IMS Health, IMS National Sales PerspectivesPerspectives™™

• 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.

Projected Number of Fentora Tablets (in Thousands) sold from manufacturer to retail and non-retail

pharmacies in the U.S. during year 2007

NON-RETAIL

8%RETAIL

92%

IMS HEALTH, IMS National Sales PerspectiveTM, 2007, Extracted 3-28-2008. Source File: NSPC 2008-226 Fentora Actiq sales 3-28-08 0803acfe.xls

Projected Number of Fentora Tablets (in Thousands) sold from manufacturer to retail and non-retail

pharmacies in the U.S. during year 2007

NON-RETAIL

8%RETAIL

92%

IMS HEALTH, IMS National Sales PerspectiveTM, 2007, Extracted 3-28-2008. Source File: NSPC 2008-226 Fentora Actiq sales 3-28-08 0803acfe.xls


Prescription and Patient-level DataPrescription and Patient-level DataPrescription and Patient-level DataPrescription 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)


Verispan, LLC Verispan, LLC Vector One™ : National (VONA)Vector One™ : National (VONA)

Verispan, LLC Verispan, LLC Vector One™ : National (VONA)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.


Prescription Data: Total Retail Prescriptions Dispensed For Selected Prescription Data: Total Retail Prescriptions Dispensed For Selected Opioids, Years 1997-2007 Opioids, Years 1997-2007

(With Hydrocodone and Oxycodone Combination Products) (With Hydrocodone and Oxycodone Combination Products) Verispan Vector One™: National (VONA). Extracted 3/2008Verispan Vector One™: National (VONA). Extracted 3/2008

Prescription Data: Total Retail Prescriptions Dispensed For Selected Prescription Data: Total Retail Prescriptions Dispensed For Selected Opioids, Years 1997-2007 Opioids, Years 1997-2007

(With Hydrocodone and Oxycodone Combination Products) (With Hydrocodone and Oxycodone Combination Products) Verispan Vector One™: National (VONA). Extracted 3/2008Verispan 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

• 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 2008-223 oxycodone AC 3-5-08.xls

0

20

40

60

80

100

120

140

Year

Pre

sc

rip

tio

ns

(M

illio

ns

)

Hydrocodone

Oxycodone

Fentanyl

Morphine

Methadone

Hydromorphone

0

20

40

60

80

100

120

140

Year

Pre

sc

rip

tio

ns

(M

illio

ns

)

Hydrocodone

Oxycodone

Fentanyl

Morphine

Methadone

Hydromorphone


Prescription Data: Total Retail Prescriptions Dispensed for Selected Prescription Data: Total Retail Prescriptions Dispensed for Selected Opioids, Years 1997-2007Opioids, Years 1997-2007

(WITHOUT Hydrocodone Combination Products)(WITHOUT Hydrocodone Combination Products)Verispan Vector One™: National (VONA). Extracted 1/2008Verispan Vector One™: National (VONA). Extracted 1/2008

Prescription Data: Total Retail Prescriptions Dispensed for Selected Prescription Data: Total Retail Prescriptions Dispensed for Selected Opioids, Years 1997-2007Opioids, Years 1997-2007

(WITHOUT Hydrocodone Combination Products)(WITHOUT Hydrocodone Combination Products)Verispan Vector One™: National (VONA). Extracted 1/2008Verispan 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 2008-223 oxycodone comp AC 3-5-08.xls

0

1

2

3

4

5

6

7

8

Year

Pre

sc

rip

tio

ns

(M

illio

ns

)

Oxycodone (ER)

Fentanyl

Morphine

Methadone

Hydromorphone

0

1

2

3

4

5

6

7

8

Year

Pre

sc

rip

tio

ns

(M

illio

ns

)

Oxycodone (ER)

Fentanyl

Morphine

Methadone

Hydromorphone


Prescription Data: Total Dispensed Prescriptions for Fentanyl Prescription Data: Total Dispensed Prescriptions for Fentanyl Products from U.S. Retail Pharmacies, Years 2000-2007Products from U.S. Retail Pharmacies, Years 2000-2007

Verispan Vector One™ : National (VONA). Extracted 2/2008Verispan Vector One™ : National (VONA). Extracted 2/2008

Prescription Data: Total Dispensed Prescriptions for Fentanyl Prescription Data: Total Dispensed Prescriptions for Fentanyl Products from U.S. Retail Pharmacies, Years 2000-2007Products from U.S. Retail Pharmacies, Years 2000-2007

Verispan Vector One™ : National (VONA). Extracted 2/2008Verispan Vector One™ : National (VONA). Extracted 2/2008

• Fentanyl Transdermal has replaced Duragesic® as leading Fentanyl Product

• Fentanyl Transdermal has replaced Duragesic® as leading Fentanyl Product

Original File: VONA 2008-256 2-8-08 fentanyl.xls

0

1

2

3

4

5

6

2000 2001 2002 2003 2004 2005 2006 2007Year

Pre

scri

pti

on

s (

Millio

ns)

TOTAL MARKET

Fentanyl Transdermal

Duragesic

OTFC

Fentora

Actiq

Fentanyl

Sublimaze

0

1

2

3

4

5

6

2000 2001 2002 2003 2004 2005 2006 2007Year

Pre

sc

rip

tio

ns

(M

illi

on

s)

TOTAL MARKET


Duragesic

OTFC

Fentora

Actiq

Fentanyl

Sublimaze


Prescription Data: Total Dispensed Prescriptions for Fentanyl Prescription Data: Total Dispensed Prescriptions for Fentanyl Products* from U.S. Retail Pharmacies, Years 2000-2007Products* from U.S. Retail Pharmacies, Years 2000-2007

*Excludes Duragesic and Fentanyl Transdermal Products*Excludes Duragesic and Fentanyl Transdermal ProductsVerispan Vector One™ : National (VONA). Extracted 2/2008Verispan Vector One™ : National (VONA). Extracted 2/2008

Prescription Data: Total Dispensed Prescriptions for Fentanyl Prescription Data: Total Dispensed Prescriptions for Fentanyl Products* from U.S. Retail Pharmacies, Years 2000-2007Products* from U.S. Retail Pharmacies, Years 2000-2007

*Excludes Duragesic and Fentanyl Transdermal Products*Excludes Duragesic and Fentanyl Transdermal ProductsVerispan Vector One™ : National (VONA). Extracted 2/2008Verispan 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

• 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 2008-256 2-8-08 fentanyl.xls

23

64

151

250

324

357

313

66

188

31

91

15

0

50

100

150

200

250

300

350

400

2000 2001 2002 2003 2004 2005 2006 2007

Year

Pres

crip

tions

(Tho

usan

ds)

OTFC Fentora

Actiq Fentanyl

Sublimaze Total

23

64

151

250

324

357

313

66

188

31

91

15

0

50

100

150

200

250

300

350

400

2000 2001 2002 2003 2004 2005 2006 2007

Year

Pres

crip

tions

(Tho

usan

ds)

OTFC Fentora

Actiq Fentanyl

Sublimaze Total


Cost per Unit of FentoraCost per Unit of Fentora®®, Actiq, Actiq®®, and Oral Transmucosal , and Oral Transmucosal Fentanyl Prescriptions Dispensed from U.S. Retail Fentanyl Prescriptions Dispensed from U.S. Retail

Pharmacies, Year 2007Pharmacies, Year 2007Verispan Vector One™: National (VONA). Extracted 2/2008Verispan Vector One™: National (VONA). Extracted 2/2008

Cost per Unit of FentoraCost per Unit of Fentora®®, Actiq, Actiq®®, and Oral Transmucosal , and Oral Transmucosal Fentanyl Prescriptions Dispensed from U.S. Retail Fentanyl Prescriptions Dispensed from U.S. Retail

Pharmacies, Year 2007Pharmacies, Year 2007Verispan Vector One™: National (VONA). Extracted 2/2008Verispan Vector One™: National (VONA). Extracted 2/2008

• In Y2007, Actiq® has highest cost per unit @ approx. $42• Oral Transmucosal: $26 • Fentora® : $23• Cost per Unit = Retail dollars / Extended Units

• In Y2007, Actiq® has highest cost per unit @ approx. $42• Oral Transmucosal: $26 • Fentora® : $23• Cost per Unit = Retail dollars / Extended Units

Original File: VONA 2008-256 Fentora Price 2-8-08.xls f

$26.11

$41.65

$22.77

$0$5

$10$15$20$25$30$35$40$45

OTFC Fentora Actiq

Year 2007

Co

st

(Do

lla

rs)

$26.11

$41.65

$22.77

$0$5

$10$15$20$25$30$35$40$45

OTFC Fentora Actiq

Year 2007

Co

st

(Do

lla

rs)


Projected Number of Prescriptions for FentoraProjected Number of Prescriptions for Fentora®® Dispensed, by Dispensed, by Physician Specialty, from U.S. Retail Pharmacies, Year 2007Physician Specialty, from U.S. Retail Pharmacies, Year 2007

Verispan Vector One™: National (VONA). Extracted 2/2008Verispan Vector One™: National (VONA). Extracted 2/2008

Projected Number of Prescriptions for FentoraProjected Number of Prescriptions for Fentora®® Dispensed, by Dispensed, by Physician Specialty, from U.S. Retail Pharmacies, Year 2007Physician Specialty, from U.S. Retail Pharmacies, Year 2007


• 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 2008-256 Fentora MD Spec 2-8-08.xls

GP/FM/DO, 9%

ANES, 35%

IM, 5%

NEURO, 5%

ALL OTHERS,

26%

PM&R, 21%

GP/FM/DO, 9%

ANES, 35%

IM, 5%

NEURO, 5%

ALL OTHERS,

26%

PM&R, 21%


Projected Number of Projected Number of PatientsPatients, by age, receiving a prescription , by age, receiving a prescription for Fentorafor Fentora®®, Actiq, Actiq®®, or Oral Transmucosal Fentanyl from , or Oral Transmucosal Fentanyl from

outpatient retail pharmacies, Year 2007outpatient retail pharmacies, Year 2007 Verispan, LLC: Total Patient Tracker, Extracted 2/08Verispan, LLC: Total Patient Tracker, Extracted 2/08

Projected Number of Projected Number of PatientsPatients, by age, receiving a prescription , by age, receiving a prescription for Fentorafor Fentora®®, Actiq, Actiq®®, or Oral Transmucosal Fentanyl from , or Oral Transmucosal Fentanyl from

outpatient retail pharmacies, Year 2007outpatient retail pharmacies, Year 2007 Verispan, LLC: Total Patient Tracker, Extracted 2/08Verispan, 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 41-65 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 41-65 years (66% - 69%)

• Pediatric patients (0-16 years) <1%

Source File: TPT 2008-226 4-23-08 Fentora Actiq Custom Age Report.xls

Patients

15,887

23,035

32,343

0

5

10

15

20

25

30

35

Actiq Fentora OTFC

2007

Patie

nts (T

hous

ands

)

UNSPEC

66+

41 - 65

26 - 40

17 - 25

12 - 16

6 - 11

3 - 5

0 - 2


Percentage of ActiqPercentage of Actiq®® Prescriptions Switched and the Next Prescriptions Switched and the Next Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007


Percentage of ActiqPercentage of Actiq®® Prescriptions Switched and the Next Prescriptions Switched and the Next Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007


• 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®




• Most common product dispensed after Actiq® prescription is OTFC







Original File: VONA 2008-256 Actiq Switching 2-7-08.xls

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Dec-06 Mar-07 Jun-07 Sep-07 Dec-07

Quarter

Perc

ent

OTFC

Hydrocodone/APAP


Oxycodone w/APAP

Oxycodone ER

Fentora

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Dec-06 Mar-07 Jun-07 Sep-07 Dec-07

Quarter

Perc

ent

OTFC

Hydrocodone/APAP


Oxycodone w/APAP

Oxycodone ER

Fentora


Physician survey data, Year 2007 Physician survey data, Year 2007 Indications associated with drug useIndications associated with drug usePhysician survey data, Year 2007 Physician survey data, Year 2007 Indications associated with drug useIndications associated with drug use

Verispan, Physician Drug and Diagnosis Audit (PDDA)

Verispan, Physician Drug and Diagnosis Audit (PDDA)


• 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 Verispan, Physician Drug and Diagnosis Audit™ (PDDA™) Diagnosis Audit™ (PDDA™)



• “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




Top diagnoses associated with ActiqTop diagnoses associated with Actiq®® and Fentora and Fentora®® use use during visits to office-based physicians, Year 2007during visits to office-based physicians, Year 2007

Verispan, Physician Drug and Diagnosis Audit (PDDA)Verispan, Physician Drug and Diagnosis Audit (PDDA)

• For Actiq® and Fentora®, majority of diagnoses are non-cancer related.

• For Actiq® and Fentora®, majority of diagnoses are non-cancer related.

Actiq

Other45%

Surgical14%

Cancer Related

14%

Back27%

FentoraCancer Related

38%

Other37%

Back8%

Surgical17%


Verispan LLC, Vector OneVerispan LLC, Vector One™ ™ : : Concurrency (VOCON)Concurrency (VOCON)

Verispan LLC, Vector OneVerispan LLC, Vector One™ ™ : : Concurrency (VOCON)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.


Verispan LLC, Vector OneVerispan LLC, Vector One®®: : Concurrency (VOCON)Concurrency (VOCON)

Verispan LLC, Vector OneVerispan LLC, Vector One®®: : Concurrency (VOCON)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®


Concurrency Analysis – Concurrency Analysis – ResultsResults

Concurrency Analysis – Concurrency Analysis – ResultsResults

• 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.


Concurrency Analysis - Concurrency Analysis - LimitationsLimitations

Concurrency Analysis - Concurrency Analysis - LimitationsLimitations

• 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.


ConclusionsConclusionsConclusionsConclusions• ~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 4th Qtr 2007

• Sum of total Rx dispensed for Actiq ®, Fentora ®, OTFC have not caused an increase in the trend


ConclusionsConclusionsConclusionsConclusions• 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®

joint meeting of anesthetic and life support drugs and drug safety and risk management advisory...

Documents

actiq adverse events

unlabeled adverse events

drug safety

life support drugs

joint meeting of anesthetic

aers strengths

fentora slide

spontaneous reporting