AC car accident injury claim

Document Sample
AC car accident injury claim Powered By Docstoc
					Review of Fentora® and Actiq®
   Adverse Events from the
  Adverse Event Reporting
  System (AERS) Database

                     Yoo Jung Chang, Pharm.D.
                       Lauren Lee, Pharm.D.
                  Division of Adverse Event Analysis II
                 Office of Surveillance and Epidemiology



  Joint meeting of Anesthetic and Life Support Drugs and
  Drug Safety and Risk Management Advisory Committees
  May 6, 2008
                                Outline
• Objectives

• Overview of the Adverse Event Reporting
  System (AERS)

• AERS review of all adverse events
  reported with Fentora since marketing

• AERS review of serious adverse events
  reported with Actiq in 2007

• Summary
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      2
   May 6, 2008
                           Objectives
• Identify unlabeled adverse events or
  other safety concerns, particularly
  with issues of drug diversion, misuse
  and overdose

• Identify trends between Fentora and
  Actiq adverse events

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      3
   May 6, 2008
 AERS: Spontaneous Adverse
      Event Reporting
• Voluntary, “spontaneous” reporting
• Facilitated by the FDA MedWatch
  Program
• Reports are stored and retrieved via
  Adverse Event Reporting System
  (AERS) database


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      4
   May 6, 2008
               AERS Strengths
• Includes all U.S. marketed products
• Detection of events not seen in
  clinical trials
• Especially good for events with rare
  background rate, short latency




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      5
   May 6, 2008
              AERS Limitations
• Extensive underreporting
• Quality of reports is variable
• Reporting biases
• Actual numerator & denominator not
  known
• Causality of drug-event association
  often in question

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      6
    May 6, 2008
 AERS Review of All Adverse
Events Reported with Fentora®




 Joint meeting of Anesthetic and Life Support Drugs and
 Drug Safety and Risk Management Advisory Committees      7
 May 6, 2008
Fentora: AERS Search Criteria
•   Search dates – up to 2/25/08
•   Brand name search only – Fentora
•   All adverse events
•   Foreign and domestic reports




     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      8
     May 6, 2008
        Fentora: Search Results
• 42 cases retrieved from AERS

• 23/42 cases excluded due to the following:
  –   Medication errors with no adverse event (16)
  –   No specific patient information (3)
  –   Adverse event not related to drug per reporter (2)
  –   Product complaint with no adverse event (1)
  –   Report of death from natural causes (1)

• 19/42 cases included in the case series for
  further analysis

      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety and Risk Management Advisory Committees      9
      May 6, 2008
Fentora: Demographics and Indications
  Number of cases                                                   19

  Gender:
   Male                                                             9
   Female                                                           10
  Age (n=16):
   Median                                                       43.5 years
   Range                                                       16 – 73 years
  Indication (n=18):
   Cancer pain                                                    1 (5%)
   Non-cancer pain                                               11 (57%)
   Misc*                                                         6 (32%)
  * Suicidal attempt, abuse, intentional overdose, & accidental exposure
      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety and Risk Management Advisory Committees                      10
      May 6, 2008
Fentora: Dose & Other Opioid Use
Number of cases                                                   19
Daily dose (n=6):
 Median                                                        2000 mcg
 Range                                                       600 – 3200 mcg
Onset (n=6):
 Median                                                     8 days
 Range                                                Same day – 5 months
Opioid tolerance:
 Tolerant                                                       6 (32%)
 Non-tolerant                                                    1 (5%)
 Unspecified                                                    12 (63%)
Concomitant use of other
opioid medications                                                11
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees                       11
    May 6, 2008
Fentora: Outcomes & Report Source
 Number of cases                                              19
 Outcomes:
  Death                                                       5
  Life-threatening                                            1
  Hospitalization                                             1
  Medically significant                                       3
  Unspecified                                                 9
 Year Received
  2007                                                        17
  2008                                                         2
 Report Source
  US                                                          19

     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees           12
     May 6, 2008
                   Fentora: Fatalities
• 5 reports of death

• Causes of death
  – Accidental fentanyl overdose (2)
  – Suicide (1)
  – Underlying metastatic leiomyosarcoma (1)
  – Unknown (1)*

• 4 of 5 reports involved an overdose
*Patient stole Fentora from a spouse and overdosed; he was taken to the ER where he was
diagnosed with acute MI. He left against medical advice and returned home where he later died.

       Joint meeting of Anesthetic and Life Support Drugs and
       Drug Safety and Risk Management Advisory Committees                              13
       May 6, 2008
Fentora: Reported Adverse Events (AE)
System Organ Class                                            Adverse Events
Cardiac disorders (1)                          acute myocardial infarction* (1)
Gastrointestinal disorders (2) retching (1), constipation (1)

General disorders and                          lack of efficacy (6), application site
administration site                            bleeding, bruising, ulcer, pain, or
conditions (14)                                burning (6), flushing (1),
                                               hyperhidrosis (1)

Injury, poisoning, &                           medication errors** (10), intentional
procedural complications                       overdose (2), overdose (2), accidental
(18)                                           overdose (2), intentional drug misuse
                                               (2), accidental exposure (1)
*Unlabeled events underlined; **Included only medication error reports with adverse events
          Joint meeting of Anesthetic and Life Support Drugs and
          Drug Safety and Risk Management Advisory Committees                        14
          May 6, 2008
    Fentora: Reported AE Cont..
System Organ Class                                          Adverse Events
Metabolism & nutritional                       oral intake reduced (1)
disorders (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, &                       respiratory arrest (1) dyspnea (1)
mediastinal disorders (2)
Vascular disorders (1)                         dizziness (1)
       Joint meeting of Anesthetic and Life Support Drugs and
       Drug Safety and Risk Management Advisory Committees                     15
       May 6, 2008
Fentora: Overdose, Misuse, & Suicide
 • Seven cases of overdose and/or misuse

      – Intentional overdose (2)*
      – Accidental overdose (2)
      – Overdose (2)**
      – Intentional misuse (2)

 • Two cases of suicide/suicidal attempt
*1 of 2 intentional overdose cases also reported suicide
** 1 of 2 overdose cases also reported intentional misuse
         Joint meeting of Anesthetic and Life Support Drugs and
         Drug Safety and Risk Management Advisory Committees      16
         May 6, 2008
Fentora: Summary of AERS Review
• 19 adverse event cases

• Extensive off label use; cancer pain (5%)

• 32% were opioid tolerant

• 53% involved medication errors with
  adverse events
  – prescribing/dispensing errors, incorrect route/freq of
    admin by patients, incorrect conversion from Actiq
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      17
   May 6, 2008
Fentora: Summary of AERS Review,
             cont.
• 32% involved overdoses; 11% intentional
  misuse; 11% suicide attempt

• 5 deaths; 4 of which involved overdoses

• Unlabeled adverse events (i.e., acute MI,
  CVA, dysarthria) do not appear to be
  directly related to Fentora
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      18
   May 6, 2008
 AERS Review of Serious* Adverse
   Events Reported with Actiq®
                                        (2007)

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


       Joint meeting of Anesthetic and Life Support Drugs and
       Drug Safety and Risk Management Advisory Committees            19
       May 6, 2008
  Actiq: AERS Search Criteria
• Reports received by the Agency
  between 01/01/07 – 12/31/07
• Brand name search only – Actiq
• Serious adverse events
• US reports




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      20
   May 6, 2008
  Actiq: Indication & Tolerance
 Number of cases                                               61
 Indication (n=57):
  Cancer pain                                                 3 (5%)
  Non-cancer pain                                            31 (51%)
  Misc*                                                      23 (38%)
 Opioid tolerance:
  Tolerant                                                   16 (26%)
  Non-tolerant                                                4 (6%)
  Unspecified                                                41 (67%)
 Concomitant use of other
 opioid medications                                            28
*Suicide, suicidal attempt, intentional misuse & accidental exposure
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees                 21
    May 6, 2008
                    Actiq: Outcomes
Total number of cases                                         61
Outcomes*:
 Death                                                        9
 Life-threatening                                             6
 Hospitalization                                              28
 Disability                                                   2
 Medically significant                                        25
*Cases may have reported more than one outcome.




     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees           22
     May 6, 2008
                  Actiq: Fatalities
• 9 reports of death

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

• 7 of 9 reports involved an overdose

• Of the remaining 2 reports:
   – 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
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees            23
    May 6, 2008
   Actiq: Reported Adverse Events (AE)
 System Organ                                             Adverse Events
 Class
 Cardiac disorders                  tachycardia (4), cardiac arrest* (3), v. fib
 (11)                               (1), v. tachycardia (1)
 Injury, poisoning                  med errors** (18), accidental exposure (8),
 and procedural                     drug toxicity (4), overdose (4), multiple
 complications (42)                 drug overdose accidental (1)
 Nervous system                     convulsion (6), confusion (2),
 disorders (71)                     somnolence (15), coma (7), lethargy (13),
                                    loss of consciousness (3)
 Psychiatric                        agitation (5), anxiety (2), delusion (4),
 disorders (52)                     hallucination (4), irritability (4)
*Unlabeled events underlined; **Included only med error reports with adverse events
            Joint meeting of Anesthetic and Life Support Drugs and
            Drug Safety and Risk Management Advisory Committees                       24
            May 6, 2008
    Actiq: Overdose & Misuse

• 32 cases of overdose and misuse
   –Intentional misuse (16)*
   –Accidental exposure in a child (8)
   –Accidental overdose (6)
   –Undetermined (2)

*Includes cases of suicide, suicidal attempt & abuse
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      25
    May 6, 2008
 Actiq: Summary of AERS Review
• 61 serious adverse event reports in 2007

• Extensive off label use; cancer pain (5%)

• 26% were opioid tolerant

• Overdose & misuse represented 52% of
  cases



   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      26
   May 6, 2008
 Actiq: Summary of AERS Review,
             cont.
• 30% of cases involved medication errors

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

• 9 deaths; 7 of which involved overdoses

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


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      27
    May 6, 2008
             Overall Summary:
          Fentora and Actiq Cases
• Not a direct comparison of Fentora & Actiq

• Extensive off label use in both drugs;
  cancer pain (5%)

• 26 – 32% were opioid tolerant

• 52% of Actiq cases involved overdose &
  misuse; 37% for Fentora
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      28
    May 6, 2008
          Overall Summary:
    Fentora and Actiq Cases, cont.
• 53% of Fentora cases reported medication
  errors, including incorrect conversion from
  Actiq; 30% for Actiq

• Unlabeled adverse events occurred in the
  context of overdoses for Actiq; no positive
  drug-event association for Fentora


     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      29
     May 6, 2008
Fentora Medication Errors



      Kristina C. Arnwine, PharmD
          Acting Team Leader
Division of Medication Error Prevention


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

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




    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      31
    May 6, 2008
                      AERS Search

• Search Conducted March 18, 2008
  – 1 month following DAEA search
  – No MedDRA terms used

• Retrieved 63 cases




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      32
   May 6, 2008
                       AERS Results

Total Number of Cases                                         63

Excluded Cases                                                20
   –intentional overdose
   –adverse events not a result of medication error
   –not enough information to determine if
    medication error occurred
Medication Error Cases                                        43
   –further analyzed for type and causality




     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees           33
     May 6, 2008
  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)


       Joint meeting of Anesthetic and Life Support Drugs and
       Drug Safety and Risk Management Advisory Committees         34
       May 6, 2008
                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

                                                                  1
Accidental exposure

Accidental overdose                                               1


         Joint meeting of Anesthetic and Life Support Drugs and
         Drug Safety and Risk Management Advisory Committees          35
         May 6, 2008
                    Types of Error

• Wrong route of administration (n=10)
  – sublingual vs. buccal
  – attempts to avoid ulceration




  Joint meeting of Anesthetic and Life Support Drugs and
  Drug Safety and Risk Management Advisory Committees      36
  May 6, 2008
             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




     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      37
     May 6, 2008
           Types of Error (cont)

• Improper Patient Selection (n=9)
  – Off-label use (n=7)
      • No other medication error reported
  – Not on concomitant around-the-clock
    opioid therapy (n=2)
      • 1 off-label use
      • 1 labeled use




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      38
   May 6, 2008
                Confusion Between
                 Actiq & Fentora

• 12 cases
  – mcg per mcg conversion between products
  – Improper dose prescribed when converting
    from Actiq to Fentora
  – Improper substitution
• Fentora and Actiq not bioequivalent
  – Insert contains instructions for conversion
  – Warnings in professional insert & carton


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      39
   May 6, 2008
           Types of Error (cont)

• mcg per mcg conversion between
  Actiq and Fentora (n=6)
  – Actiq 800 mcg to Fentora 800 mcg




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      40
   May 6, 2008
            Types of Error (cont)


• Improper dose prescribed when
  converting from Actiq to Fentora (n=4)
  – Actiq 400 mcg to Fentora 200 mcg
  – Correct conversion to Fentora is 100 mcg




    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      41
    May 6, 2008
             Types of Error (cont)

• Improper Substitution (n=2)
  – Pharmacists unaware Fentora and Actiq are not
    bioequivalent
  – Substitution suggested by insurance carrier
    • Lower price of Fentora
  – Fentora dispensed as generic equivalent to Actiq



     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      42
     May 6, 2008
            Types of Error (cont)
• Improper Technique (n=1)
  – Tablet splitting
  – Prescribed ½ of 400 mcg tablet BID

• Accidental Exposure (n=1)
  – Tablet removed from blister
  – Fentora mistaken for aspirin

• Accidental Overdose (n=1)
  – Death
  – Prescribed for back pain
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      43
    May 6, 2008
       Safety Communications

• September 2007
 – Dear Doctor/Healthcare Professional Letter
 – Public Health Advisory
• 22 of 43 errors reported after
  dissemination of communications
 – No event date reported
 – Unable to assess effectiveness of
   communications

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      44
    May 6, 2008
                             Summary

• Medication errors
  – Account for 68% of AERS cases
    • Off-label use (n=35)
    • Labeled use (n=4)
• Knowledge deficit with Actiq and Fentora
• Effectiveness of labeling and Risk
  Minimization Action Plan is questionable

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      45
    May 6, 2008
  Fentora Risk Management:
 Postmarketing Experience and
      Recommendations

               Jeanine Best, MSN, RN, PNP
         Senior Drug Risk Management Analyst
               Division of Risk Management
         Office of Surveillance and Epidemiology




Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees
May 6, 2008
                                 Outline
 Background

 Current RiskMAP
   Overview
   Postmarketing experience
   RiskMAP experience summary

 Additional risk mitigation options

 Conclusions



    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      47
    May 6, 2008
                           Background
Fentora was approved with:
1.    A limited indication where the benefits relative
      to the risks were shown to be acceptable:

      “only for the management of breakthrough pain in patients
      with cancer who are already receiving and who are tolerant to
      around-the-clock opioid therapy for their underlying persistent
      cancer pain”

2.    Medication Guide

3.    A risk minimization action plan (RiskMAP)

 Fentora Label, 2/7/08
      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety and Risk Management Advisory Committees           48
      May 6, 2008
Current Fentora RiskMAP




Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees
May 6, 2008
                                  Goals
1. Fentora should be used only by opioid
   tolerant patients with cancer.

2. Abuse, misuse and diversion of Fentora
   should not occur.

3. Unintended (accidental) exposure to
   Fentora should not occur.


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      50
   May 6, 2008
                      Key Elements
 Labeling

 Education

 Surveillance

 Evaluation/Intervention




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      51
   May 6, 2008
                              Labeling
 Package Insert for HCPs
   Boxed warning emphasizing key safety
    information including
      • use only in opioid tolerant patients with break-through
        cancer pain
      • no use for acute pain
      • dosing and administration instructions
      • conversion instructions
      • no substitution
      • abuse and misuse warnings

 Medication Guide for patients
   Key safety information in consumer-friendly
    language

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees            52
   May 6, 2008
             Labeling - Carton




Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees      53
May 6, 2008
                    Education Plan
 Prescriber education
   Package Insert
   Independent Continuing Medical Education
    (CME) – not product specific

 Patient education
   Medication Guide
   Carton label/blister label

 Pharmacist education
   Package Insert
   Carton label/checklist


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      54
   May 6, 2008
                         Surveillance
 Surveillance Plan

   Spontaneous reporting
   Expedited reporting per regulation with
    reporting of additional events
   Active surveillance for monitoring abuse,
    misuse, and diversion using the following
    systems:
      • The Researched Abuse, Diversion and Addiction-Related
        Surveillance System (RADARS)
      • Toxic Exposure Surveillance System (TESS)
      • Drug Abuse Warning network (DAWN)


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      55
    May 6, 2008
                    Evaluation Plan
 Periodic analysis of surveillance and monitoring
  efforts for signals of abuse, misuse, and
  diversion

 Surveys to evaluate knowledge, attitudes, and
  behavior from education efforts
    physicians
    pharmacists
    patients

 Patient longitudinal drug utilization data
    assessing use in opioid non-tolerant patients


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      56
    May 6, 2008
  RiskMAP Postmarketing
       Experience




Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees
May 6, 2008
      RiskMAP Quarterly Report Information
Quarterly RiskMAP            Non Opioid Tolerant            Non Cancer Diagnosis
Report Data                  (IMS longitudinal              (IMS National Audit Data)
                             database estimates)
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%

       Joint meeting of Anesthetic and Life Support Drugs and
       Drug Safety and Risk Management Advisory Committees                              58
       May 6, 2008
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).


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      59
    May 6, 2008
RiskMAP Quarterly Report Information,
               cont.
 Physician Survey
   no results submitted as of 5th quarterly
    RiskMAP Report


 Pharmacy Survey
   no results submitted as of 5th quarterly
    RiskMAP Report




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      60
   May 6, 2008
RiskMAP Quarterly Report Information,
               cont.
 Patient Survey
    624 patients surveyed to date

    Sponsor reported survey findings including:
       • most patients are aware of key safety information
       • > 33% patients unaware of secure storage to prevent
         theft and diversion
       • ~ 25% patients unaware of need to keep Fentora in the
         original blister package

    Limitations of Survey:
       • survey questions do not address all key safety concerns




    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees          61
    May 6, 2008
       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

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      62
   May 6, 2008
Fentora RiskMAP Experience
         Summary




 Joint meeting of Anesthetic and Life Support Drugs and
 Drug Safety and Risk Management Advisory Committees
 May 6, 2008
Summary of RiskMAP Experience
 Increasing use in opioid non-tolerant patients
    non-tolerant patients at greater risk for life-threatening
     adverse events

 High utilization in non-cancer indications
 Improper use and medication errors account for
   > 2/3 of the reports in the adverse event
  reporting system
    no apparent effect seen from Dear HCP Letters/PHA

 Inadequate information to determine if HCPs and
  patients have an understanding about the safe
  use of Fentora

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees           64
    May 6, 2008
  Comments on RiskMAP Experience

 Current risk minimization tools do not
  appear to achieve RiskMAP goals.

 Expanding the indication will most likely
  amplify and exacerbate the postmarketing
  data trending seen regarding:
   opioid non-tolerant use
   all medication errors
   abuse, diversion, and misuse

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      65
   May 6, 2008
Additional Risk Mitigation Options
 Consider additional risk mitigation
  strategies and the feasibility of these
  strategies

   Prescriber requirements
   Pharmacy/Dispensing requirements
   Additional requirements




    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      66
    May 6, 2008
  Fentora Risk Mitigation Options
Prescriber Requirements

 Mandatory enrollment of prescribers in
  order to prescribe

   Mandatory training or certification

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


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      67
    May 6, 2008
 Fentora Risk Mitigation Options,
              cont.
Pharmacy/Dispensing Requirements

 Mandatory enrollment of pharmacies in order to
  dispense

    Mandatory training or certification
    Acknowledge understanding of dispensing
     requirements
       •   patients must be opioid tolerant
       •   no therapeutic substitution
       •   patient counseling for appropriate use
       •   dispense and instruct patients to read the Medication Guide
       •   prior authorization (if required)


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees                  68
    May 6, 2008
 Fentora Risk Mitigation Options,
              cont.
Pharmacy/Dispensing Requirements, cont.

   Prescription dispensed only with prior
    authorization such as
      • a qualification sticker on the prescription
      • patient registry enrollment




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      69
   May 6, 2008
  Fentora Risk Mitigation Options,
               cont.
Additional Requirements

 Documentation of safe use for patients to
  receive Fentora
   Prescriber/Patient Agreement for
    documentation of safe-use conditions
     • required patient counseling
     • receipt of Medication Guide




    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      70
    May 6, 2008
          Risk Mitigation Options
               Advantages
 Gate keeping for appropriate and/or safe
  use

   may provide evidence and/or documentation of
    safe use conditions

   may assure benefits outweigh the risks in the
    prescribed population where the benefit/risk
    balance is acceptable



   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      71
   May 6, 2008
          Risk Mitigation Options
                Challenges
 More burdensome

 Unintended consequences
   delayed access/no access of product for
    appropriate patients

 Abuse/misuse/diversion will still occur



   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      72
   May 6, 2008
                         Conclusions
 Additional risk mitigation strategies
   may assure benefits outweigh the risks in the
    prescribed population where the benefit/risk
    balance is acceptable
   may not prevent abuse/misuse/diversion,
    especially in non-prescribed individuals

 Expanding the indication even with
  additional risk mitigation strategies
   increases the amount of Fentora in the
    community
   increases risk of abuse/misuse/diversion


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      73
    May 6, 2008
   Regulatory History of Oral
Transmucosal Fentanyl Products


                     Ellen W Fields, M.D., M.P.H
                   Acting Clinical Team Leader
  Division of Anesthesia, Analgesia, and Rheumatology Products




  Joint meeting of Anesthetic and Life Support Drugs and
  Drug Safety and Risk Management Advisory Committees
  May 6, 2008
    Overview of Presentation
• Regulatory history of oral
  transmucosal fentanyl products

• Labeling changes

• Compare the pharmacokinetics of
  Actiq and Fentora

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      75
   May 6, 2008
                   OTFC Products

• Oralet

• Actiq

• Fentora


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      76
   May 6, 2008
                                   Oralet
• Approved in 1993

• Indication: preoperative sedation in children, for
  use only in hospital setting

• Formulation: Raspberry flavored lozenge on a
  stick

• Dosage units: 100, 200, and 400mcg

• Withdrawn in 2001 because of nausea and
  vomiting in opioid-naïve patients


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      77
    May 6, 2008
                                    Actiq
• Approved 1998

• Indication: treatment of breakthrough pain in
  patients with malignancies who are already
  receiving and who are tolerant to opioid therapy
  for their underlying persistent cancer pain

• Formulation: same as Oralet

• Dosage units: 200, 400, 600, 800, 1200, 1600 mcg

• Setting: inpatient and outpatient


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      78
    May 6, 2008
                                     Actiq
• Issues surrounding approval

   – Unique circumstance where population at greatest
     risk of adverse events was not population that
     would benefit from approval

   – Biggest concern was accidental ingestion by
     children

   – Subject of ALSAC meeting September 1997

   – Approved under Subpart H (21CFR§314.20)
      • Restricted distribution
      • Accelerated withdrawal of product if necessary

   – Risk Management Program
      • misuse, abuse and diversion
      • accidental exposure by children
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      79
     May 6, 2008
             Original Actiq Label
• Box Warning
   – Actiq is indicated for the management of
     breakthrough cancer pain in patients with
     malignancies who are receiving and who are
     tolerant to opioid therapy for their underlying
     persistent cancer pain

   – This product must not be used in opioid non-
     tolerant patients

   – Prescribed only by oncologists and pain
     specialists

   – Patients and caregivers must be instructed that
     Actiq contains a medicine in an amount which can
     be fatal to a child……keep all units out of reach of
     children and dispose of units properly
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      80
     May 6, 2008
            Original Actiq Label


• Contraindications:
  – Management of acute or post
    operative pain
  – Use in opioid non-tolerant persons



   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      81
   May 6, 2008
       Actiq Labeling Changes
• June 2002: advising diabetic patients that Actiq
  contains 2 grams of sugar per unit

• September 2004: post-marketing data regarding
  development of dental caries, tooth loss and gum line
  erosion

• September 2005: sugar-free formulation (never
  marketed)

• September 2006: Conversion of patient leaflet (PPI) to
  MedGuide

• February 2007: addition of pharmacokinetic data for
  patients 5-15 years of age
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      82
    May 6, 2008
                                Fentora
• Approved September 2006

• Indication: same as Actiq

• Formulation: effervescent buccal tablet

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

• Setting: inpatient and outpatient

• Risk Management Plan and Medguide part of
  approval

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      83
    May 6, 2008
         Original Fentora Label
• Box Warning
  – Indication for opioid-tolerant cancer
    patients
  – Contraindicated
     • Acute and post operative pain
     • Opioid non-tolerant patients
  – Contains medicine in amount which can
    be fatal to a child
  – Due to higher bioavailability of fentanyl,
    do not convert from other fentanyl
    products on a mcg per mcg basis.

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      84
    May 6, 2008
             Fentora vs. Actiq
           Pharmacokinetic Parameters in Adult Subjects
                Receiving Fentora or Actiq (OTFC)

Pharmacokinetic                             Fentora       Actiq
Parameter (mean)                            400mcg        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
Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees                       85
May 6, 2008
Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees      86
May 6, 2008
                Medication Errors
• 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.


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      87
    May 6, 2008
        Public Health Advisory
• September 2007: Public Health Advisory
  issued for Fentora
   – Off label prescribing to non opioid
     tolerant patients
   – Misunderstanding of dosing
     instructions by both prescribers and
     patients
   – Inappropriate substitution of Fentora for
     Actiq by pharmacists and prescribers

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      88
    May 6, 2008
                Fentora Labeling Changes
                    February 7, 2008
• Box Warning:
   – Warnings strengthened regarding use of
     Fentora in non- opioid tolerant patients
     including patients with migraines,

   – When prescribing, do not convert patients on
     a mcg per mcg basis from Actiq to Fentora

   – When dispensing, do not substitute a Fentora
     prescription for other fentanyl products

   – Special care must be used when dosing
     Fentora. If the BTP episode is not relieved
     after 30 minutes, patients may take only one
     additional dose using the same strength and
     must wait at least four hours before taking
     another dose.
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      89
     May 6, 2008
                             Summary
• There are presently two oral transmucosal
  fentanyl products marketed for the indication of
  the management of breakthrough cancer pain in
  opioid tolerant patients

• Due to the higher bioavailability of Fentora, Actiq
  and Fentora are not interchangeable on a mcg to
  mcg basis

• Despite strong labeling language, a MedGuide,
  and a Risk Management Program, there have
  been medication errors reported to the Agency
  that have resulted in adverse events, including
  death.

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      90
    May 6, 2008
Fentora Abuse Potential in the
 Noncancer Pain Population
              Lori A. Love, M.D., Ph.D.
                   Medical Officer
             Controlled Substance Staff


  Joint meeting of Anesthetic and Life Support Drugs and
  Drug Safety and Risk Management Advisory Committees
  May 6, 2008
     Why the concerns about safety,
      including abuse potential?
• History of fentanyl and abuse
  – Synthesized in late 1950s
  – Introduced as IV anesthetic in 1960s
    (Sublimaze®).
  – Illicit use of pharmaceutical fentanyl first
    identified in the mid-1970s in the medical
    community
  – All pharmaceutical preparations have been
    abused
  – IV, snorting, smoking and sublingual routes
    used and Risk Management Advisory Committees
      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety                                            92
      May 6, 2008
  – Street names: apache, china girl, china white,
    Why the concerns about safety,
     including abuse potential?
• History of fentanyl and abuse
  – High abuse potential
     • Illicitly manufactured for abuse
         – > 12 different fentanyl analogues in U.S. drug
           traffic
         – Recent deaths in several US communities
           attributed to abuse fentanyl-laced heroin
         – One of the precursors was designated as a
           List 1 chemical. DEA is now in the process of
           designating a second chemical as a Schedule
           II immediate precursor
     •Joint Safety and Risk Management Advisory andand
            meeting of of domestic Drugs foreign
        Abuse Anesthetic and Life SupportCommittees
      Drug                                               93
        pharmaceutical products
      May 6, 2008
  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. “
                                                     * www.bluelight.ru
• “i have recently been put on a trial to test the effects of this
         Joint meeting of Anesthetic and Life Support Drugs and
         Drug Safety and Risk Management Advisory Committees      94
  drug for my rheumatoid arthritis, it is wonderful, i get this
         May 6, 2008
  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”
                                                  * www.bluelight.ru
        Joint meeting of Anesthetic and Life Support Drugs and
        Drug Safety and Risk Management Advisory Committees      95
        May 6, 2008
 Fentora phase 3 clinical studies in
          noncancer pain
• Double-blind, placebo-controlled
  studies:
   – Study 3052
   – Study 3041
   – Study 3042
• Open-label, uncontrolled study:
   – Study 3040

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      96
    May 6, 2008
         Protocol-specified entry
•   Inclusion: Takingcriteria the clock opioid and
                     an around
    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
     Joint meeting of Anesthetic patient Drugs and
                                              safety
    compromise and Life SupportCommittees if they
     Drug Safety and Risk Management Advisory        97
     May 6, 2008
    participated in the study
 “Review and Assessment of Risks for
        Abuse and Diversion”
• Reports events of abuse, addiction, and
  overdose in Fentora clinical studies of
  opioid-tolerant patients with chronic
  noncancer pain and break-through pain
• Identified aberrant drug-use behaviors
   – may be precursors or signs for abuse
   – retrospective analysis of clinical
     databases
   – categorized ‘high risk’ behaviors
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      98
    May 6, 2008
   “Review and Assessment of Risks
       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



         Joint meeting of Anesthetic and Life Support Drugs and
         Drug Safety and Risk Management Advisory Committees                           99
         May 6, 2008
   Aberrant drug use behavior
Table 2: Sponsor’s Summary of Patients by Risk Category
                                                 Number of
         Risk Category                            Patients¥              Percent
High risk behaviors*                                    30                  3%
   Abuse/dependence                                      8                 <1%
   Overdose                                             9#                  1%
   Positive urine drug                                  13                  1%
   screen
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 and Life Support Drugs and
       Joint meeting of Anestheticpatient with 2 episodes of overdose
       Drug Safety and Risk Management Advisory Committees                        100
       May 6, 2008
   Aberrant drug use behavior
Table 3: Aberrant Behaviors Identified in > 1% of Patients
         (Identified by Sponsor)
                                                    Number of
             Behavior                                Patients      Percent
Overuse of study drug                                         44     5%
Study drug thefts                                             35     4%
Lost to follow-up                                             33     4%




     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees                  101
     May 6, 2008
     Aberrant drug use behavior
Table 4: Study Drug Thefts during Phase 3 Clinical Trials
         (Identified by Sponsor)
                                  Number of                         Amount of drug
  Study drug theft                  cases                Percent       stolen
    From patients                        35                 4.2%*         ----
        *Number of cases (5) divided by the total 831 patients in studies 3040 & 3052.


• 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


       Joint meeting of Anesthetic and Life Support Drugs and
       Drug Safety and Risk Management Advisory Committees                       102
       May 6, 2008
        Aberrant drug use behavior
Table 5: Study Drug Thefts during Phase 3 Clinical Trials
         (Identified by Sponsor)
                                     Number of                   Amount of drug
    Study drug theft                   cases             Percent    stolen
     From study                              5              ----+              4.3 gm ¥
     center
+There were 69 study centers in study 3040
¥•Calculated from additional information only reported in on 03/21/08, represents > 8000 tablets.
     Thefts from study site provided by the sponsor 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 toand Life SupportCommittees
       Joint meeting of Anesthetic
                                   DEA
       Drug Safety and Risk Management Advisory
                                                Drugs and
                                                                103
          May 6, 2008
                     FDA Comments
• Our review is still ongoing, but we have
  identified additional cases apart from those
  identified by the Sponsor indicative of abuse
  potential
   – Misuse of study
     drug/noncompliance/protocol violations
   – Drug accountability issues
• We are concerned about the lack of criteria on
  how investigators were trained to identify and
  report abuse, misuse, noncompliance and
  diversion cases across the studies and study
  sites
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      104
     May 6, 2008
                        CSS Summary
• The risks of unintentional potentially fatal
  overdose, misuse, abuse or diversion of
  fentanyl and of Fentora in particular, are
  extremely high
   – As demonstrated by instances of
     overdose, misuse, abuse and diversion
     in clinical studies and other
     postmarketing data
      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety and Risk Management Advisory Committees      105
      May 6, 2008
                        CSS Summary
• The clinical study population is not
  representative of potential risks of Fentora
  in the general population
   – highly screened to eliminate ‘high risk’
     patients
   – detection of aberrant drug use behavior
     is uncommon in controlled clinical trials
      • appears to be much more frequent in
        the noncancer population who used
        Fentora long term
      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety and Risk Management Advisory Committees      106
      May 6, 2008
                   CSS Conclusion

Taken together, these findings suggest
that expanded use of this product will
raise serious safety concerns, and will
result in significant abuse and diversion
that further impacts the public health and
safety.


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      107
    May 6, 2008
Fentora (NDA 21-947, S005)
FDA’s Review of Safety and Efficacy

                       Robert B. Shibuya, M.D.
                          Medical Officer
  Division of Anesthesia, Analgesia, and Rheumatology Products




 Joint meeting of Anesthetic and Life Support Drugs and
 Drug Safety and Risk Management Advisory Committees
 May 6, 2008
    Overview of Presentation
• Caveat: Review is in progress, findings
  are preliminary. Discrepancies noted by
  Applicant have been addressed in this
  presentation.
• Proposed new indication
• Implications if indication were approved
• Brief review of Efficacy
• Review of Safety
• Preliminary conclusions regarding Safety
  and Efficacy


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      109
   May 6, 2008
             Proposed indication
• Current indication: “…management of
  breakthrough pain in patients with cancer
  who are already receiving and who are
  tolerant to around-the-clock opioid therapy for
  their underlying persistent cancer pain.”

• Proposed Indication: “… management of
  breakthrough pain in patients who are
  regularly taking around-the-clock opioid
  medicine for their underlying persistent pain”


    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      110
    May 6, 2008
 Implications of increased use if
 this supplement were approved
• Predicted benefits:
  – Insurers responsible for coverage,
    more patients would have access
    to Fentora
• Predicted risks:
  – Larger, less expert prescriber base
  – Increased promotion
  – Wider prescribing => larger
    amounts of drug available for
    misuse/abuse/diversion
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      111
   May 6, 2008
 Implications of increased use if
 this supplement were approved
• FDA estimate of increased use based
  upon the numbers of patients
  theoretically eligible for therapy with
  Fentora in the US
   – Cancer = 1.7 M
   – Non-Cancer = 13.3 M



   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      112
   May 6, 2008
  DAWN: ED Visits -- Non-Medical
 Use per 10,000 Retail Prescriptions
             2004 – 2006

         40

         30
                                                                                  31.4
         20                                                  24.1
                                  22.1                                     17.2
                          13.4                      15.4
         10
                  4.1                         4.5                   5.1
           0
                        2004                      2005                    2006

            Hydrocodone/combinations                Oxycodone/combinations        Fentanyl

Source: National estimates from DAWN, 2004-2006; Verispan VONA
           Joint meeting of Anesthetic and Life Support Drugs and
           Drug Safety and Risk Management Advisory Committees                           113
           May 6, 2008
                                Efficacy
• Study 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

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      114
    May 6, 2008
   Study 3052 – Primary Efficacy
          Endpoint (PEP)




Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees      115
May 6, 2008
        Studies 3041 and 3042
• Short-term studies in opioid tolerant
  patients with neuropathic and
  chronic low back pain.
• Per the applicant, the studies met
  their objectives.




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      116
   May 6, 2008
 Preliminary efficacy conclusion

• Preliminarily, Fentora appears to
  provide analgesia for BTP superior to
  placebo over 12-weeks of therapy.
• No comparative data were collected
  in any studies.




   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      117
   May 6, 2008
                                   Safety
• Evaluation of safety is not straightforward
  for oral transmucosal fentanyl citrate
  (OTFC) products
  – Opioid dosed in the setting of background
    opioid
  – Lack of detail in AE data collection (exact
    timing of onset of AE and timing of Fentora
    dosing)
  – Lack of a control group (crossover design,
    most patients dosed w/ placebo and active on
    the same day)
  – In cancer population, comorbidities associated
    with advanced malignancies, cancer therapies,
    and age

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      118
    May 6, 2008
                                  Safety
• Applicant took a conventional
  approach for a reformulated
  opioid [AEs, labs, vital signs
  (VS), oral cavity exams and
  physical exams (PE)].
• Applicant collected and analyzed
  data pertaining to abuse, misuse,
  diversion.
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      119
   May 6, 2008
               Safety - Exposure
• Applicant pooled data from 3 non-CA
  efficacy studies (3052, 3041, & 3042).
  To supplement these numbers, Study
  3040 conducted.
• Study 3040
  – Eighteen-month, OL study in patients
    with BTP not due to cancer
  – Enrolled 730 patients
      • Approximately 20% were rolled over from Studies
        3041/2.
      • Mean duration of exposure was 292 days.
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      120
   May 6, 2008
                         Safety -Exposure




Source: Summary of Clinical Safety




           Joint meeting of Anesthetic and Life Support Drugs and
           Drug Safety and Risk Management Advisory Committees      121
           May 6, 2008
          FDA’s safety analysis
• With certain caveats, the controlled
  clinical trial data from the cancer
  population is an appropriate comparator
  for certain AEs. Shared characteristics:
      •   Opioid-tolerant adults w/ BTP
      •   Similar clinical trial design and AE capture
      •   Identical dosing paradigm and range
      •   Meets data quality standards for NDA
          submission
  – Dissimilarity
      • Cancer patients would be expected to be more ill;
        therefore, they would be expected to experience
        more AEs.

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      122
   May 6, 2008
               FDA’s safety analysis
• Two-pronged approach
     – Demographics and concomitant
       medications
     – Adverse events in the cancer and non-
       cancer populations
           • Related to abuse/misuse/addiction/
             oversedation and consequences thereof
                  – Serious* AEs (SAEs)
                  – Non-serious AEs
           • Opioid and formulation-related common AEs
*Death, life-threatening, hospitalization or prolongation of hospitalization, persistent or significant
    disability/incapacity, congenital anomaly/birth defect


        Joint meeting of Anesthetic and Life Support Drugs and
        Drug Safety and Risk Management Advisory Committees                                               123
        May 6, 2008
        Demographic Information
Parameter                              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)

        Joint meeting of Anesthetic and Life Support Drugs and
        Drug Safety and Risk Management Advisory Committees                    124
        May 6, 2008
          Concomitant Medication Use*
    Parameter                                          Non-Cancer [n (%)]   Cancer [n (%)]
         N                                                      941              358
Around-the-clock         Mean                               239.7 mg         342.1 mg
opioid dose**
                         Std. Dev                           219.4 mg         407.6 mg
                         Range                             20-2160 mg       24-4800 mg
Other CNS                Benzodiazepines                       43%              38%
depressants
                         Non-benzodiazepine                    21%              16%
                         sleep aids
                         Tricyclic                             14%               7%
                         antidepressants
                         Muscle relaxants                      46%              10%
                         (carisoprodol,
                         cyclobenzaprine, etc.)
                         Gabapentin/pregabalin                 24%              15%
                         Other                                 31%              15%
  *Defined as use for >50% of time-on-trial
  **Morphine equivalents
             Joint meeting of Anesthetic and Life Support Drugs and
             Drug Safety and Risk Management Advisory Committees                         125
             May 6, 2008
   Serious Adverse Events related to
     overdose, misuse, or similar
                                                 Non-cancer         Cancer
                                                 Population        Population
Total N                                             941               358
Accidental overdose                                        8           0
SAE related to drug                                        2           0
dependence/withdrawal/
abuse
SAE possibly related to                                    1           0
oversedation (MVA with
severe CNS and orthopedic
injury where patient was the
driver)
          Joint meeting of Anesthetic and Life Support Drugs and
          Drug Safety and Risk Management Advisory Committees              126
          May 6, 2008
     Non-serious adverse events, moderate or severe in intensity, related to
     CNS depression, psychotropic effects, or respiratory depression,
     duplicates deleted
                                                                          Non-Cancer        Cancer
                                                                            N=941           N=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 caseseach of: Addictive behavior, substance abuse,
*total of case                                                            8*     0.8   0           0
 personality change, six cracked bottom front teeth,
 paranoia, car accident, impaired balance, physical trauma
 *sum of eight discrete cases
                 Joint meeting of Anesthetic and Life Support Drugs and
                 Drug Safety and Risk Management Advisory Committees                         127
                 May 6, 2008
   Non-serious adverse events, moderate or severe in intensity, related to CNS
   depression, psychotropic effects, or respiratory depression, all cases
                                                                    Non-Cancer          Cancer
                                                                      N=941             N=358
 Pooled Term                                                    n       Rate per   n    Rate per 100
                                                                        100 PYR             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                8         1.2      0         0
 abuse, personality change, six cracked bottom front
 teeth, paranoia, car accident, impaired balance,
 physical trauma
*sum of eight discrete cases
             Joint meeting of Anesthetic and Life Support Drugs and
             Drug Safety and Risk Management Advisory Committees                            128
             May 6, 2008
                           Common AEs
        Adverse 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                               15 (6)    12 (10)             116 (12)
complaints




        Joint meeting of Anesthetic and Life Support Drugs and
        Drug Safety and Risk Management Advisory Committees                                  129
        May 6, 2008
Preliminary safety conclusions
• The non-cancer population has an excess incidence
  of serious adverse events related to overdose,
  abuse, misuse, and those consistent with excessive
  CNS depression compared to analogous safety data
  from patients with cancer.
• Depending on the type of analysis conducted, the
  non-serious, moderate to severe adverse events tend
  to show a higher rate of common opioid-related
  adverse events in the cancer population. However,
  the non-cancer database contains rare concerning
  reports related to addiction, substance abuse, etc.,
  not observed in patients with cancer.

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      130
    May 6, 2008
Preliminary safety conclusions
• The higher rates of concomitant CNS
  depressant use in the non-cancer
  population may make medication errors
  more likely.
• The common opioid-related adverse
  event profile is similar between
  populations.


   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      131
   May 6, 2008
     Preliminary Conclusions
• At this point in our review, it appears
  that:
  – The product continues to show efficacy
    over 12-weeks in the non-cancer
    population.
  – Compared to the cancer population, the
    product shows evidence of excess
    abuse-related serious adverse events in
    the non-cancer population which is
    concerning from perspective of the
    public health.

   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      132
   May 6, 2008
Outpatient Drug Utilization Trends
    for Fentora® and Actiq®

              LCDR Kendra C. Worthy, Pharm.D.
                    Drug Utilization Analyst
               Laura Governale, Pharm.D., MBA
            Drug Utilization Analyst Team Leader
                   Division of Epidemiology
           Office of Surveillance and Epidemiology

  Joint meeting of Anesthetic and Life Support Drugs and
  Drug Safety and Risk Management Advisory Committees
  May 6, 2008
                                 Outline
• Settings of use − sales & distribution data:
   – IMS Health, IMS National Sales Perspectives™
     Retail and Non-Retail

• Prescription and patient-level data:
   – Verispan, Vector One™ : National (VONA)
   – Verispan, Vector One™ : Total Patient Tracker
     (TPT)
   – Verispan, Vector One™ : Concurrency
     (VOCON)

• Physician survey data:
   – Verispan, Physician Drug and Diagnosis Audit
     (PDDA)

• Conclusions
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      134
    May 6, 2008
     Sales distribution data
           Year 2007
            IMS Health, IMS National Sales
         Perspectives™ Retail and Non-Retail




Joint meeting of Anesthetic and Life Support Drugs and
Drug Safety and Risk Management Advisory Committees
May 6, 2008
     IMS Health, IMS National Sales
            Perspectives™
•   Measures sales data from
    manufacturers to retail and non-retail
    channels of distribution                              Projected Number of Fentora Tablets (in Thousands)
                                                          Projected Number of Fentora Tablets (in Thousands)
     – Extended Units are the number of                      sold from manufacturer to retail and non-retail
                                                              sold from manufacturer to retail and non-retail
        tablets, capsules, milliliters,                         pharmacies in the U.S. during year 2007
                                                                 pharmacies in the U.S. during year 2007
        ounces, etc. of a product shipped                                  NON-
                                                                           NON-
        in each unit                                                      RETAIL
                                                                          RETAIL
                                                                            8%
                                                                            8%
•   Retail Channels - chain, independent,                                                                                            RETAIL
                                                                                                                                     RETAIL
    mass merchandisers, food stores with                                                                                              92%
                                                                                                                                       92%
    pharmacies, and mail-order
    pharmacies

•   Non-Retail Channels - federal facilities,
    non-federal hospitals, clinics, long-             IMS HEALT H, IMS National Sales Perspective TM, , 2007, Extracted 3-28-2008.
                                                       IMS HEALT H, IMS National Sales Perspective TM2007, Extracted 3-28-2008.
    term care facilities, home health care               Source File: NSPC 2008-226 Fentora Actiq sales 3-28-08 0803acfe.xls
                                                          Source File: NSPC 2008-226 Fentora Actiq sales 3-28-08 0803acfe.xls
    (began 1998), HMOs, miscellaneous
    channels (began 1999; prisons,
    universities, other)

92% Fentora® sales go to retail channels of
distribution during Y2007.
        Joint meeting of Anesthetic and Life Support Drugs and
        Drug Safety and Risk Management Advisory Committees                                                                          136
        May 6, 2008
Prescription and Patient-level Data


     Verispan, Vector One™ : National (VONA)
Verispan, Vector One™ : Total Patient Tracker (TPT)
    Verispan, Vector One™ : Concurrency (VOCON)



   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees
   May 6, 2008
                Verispan, LLC
        Vector One™ : National (VONA)
•   Verispan’s Vector One™ : National (VONA) is a national-level
    projected prescription and patient-centric tracking service. Receives
    over 2.0 billion prescription claims per year, representing over 160
    million unique patients.

•   The number of dispensed prescriptions is obtained from a sample of
    approximately 59,000 pharmacies throughout the U.S., accounting for
    nearly all retail pharmacies and represent nearly half of retail
    prescriptions dispensed nationwide.

•   Retail pharmacies include:
     – national retail chains,
     – mass merchandisers,
     – pharmacy benefits managers and their data systems,
     – provider groups.

•   Data on prescribing specialty and patient age/gender are available as
    well as state level data.


         Joint meeting of Anesthetic and Life Support Drugs and
         Drug Safety and Risk Management Advisory Committees          138
         May 6, 2008
Prescription Data: Total Retail Prescriptions Dispensed For Selected
                     Opioids, Years 1997-2007
    (With Hydrocodone and Oxycodone Combination Products)
                                                   Verispan Vector One™: National (VONA). Extracted 3/2008

                                 140
                                 140

                                 120
                                 120
      Prescriptions (Millions)
      Prescriptions (Millions)


                                                                                                                            Hydrocodone
                                                                                                                            Hydrocodone
                                 100
                                 100
                                                                                                                            Oxycodone
                                                                                                                            Oxycodone
                                 80                                                                                         Fentanyl
                                                                                                                            Fentanyl
                                 80
                                                                                                                            Morphine
                                                                                                                            Morphine
                                 60                                                                                         Methadone
                                                                                                                            Methadone
                                 60
                                                                                                                            Hydromorphone
                                                                                                                            Hydromorphone
                                 40
                                 40

                                 20
                                 20

                                  0
                                  0
                                      7       8        9       0       1       2        3      4       5       6       7
                                    99 7
                                   1199     99 8
                                           1199      99 9
                                                    1199     00 0
                                                            2200     00 1
                                                                    2200     00 2 22003
                                                                            2200     00      00 4
                                                                                            2200     00 5
                                                                                                    2200     00 6
                                                                                                            2200     00 7
                                                                                                                    2200
                                                                               Year
                                                                                Year


• 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
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees                                                                                                   139
     May 6, 2008
                                                                                                    Original File: VONA 2008-223 oxycodone AC 3-5-08.xls
Prescription Data: Total Retail Prescriptions Dispensed for Selected
                     Opioids, Years 1997-2007
          (WITHOUT Hydrocodone Combination Products)
                                             Verispan Vector One™: National (VONA). Extracted 1/2008


                                 8
                                 8
                                 7
                                 7
      Prescriptions (Millions)
      Prescriptions (Millions)



                                 6
                                 6
                                                                                                            Oxycodone (ER)
                                                                                                            Oxycodone (ER)
                                 5
                                 5
                                                                                                            Fentanyl
                                                                                                            Fentanyl
                                 4
                                 4                                                                          Morphine
                                                                                                            Morphine
                                                                                                            Methadone
                                                                                                            Methadone
                                 3
                                 3                                                                          Hydromorphone
                                                                                                            Hydromorphone
                                 2
                                 2
                                 1
                                 1
                                 0
                                 0
                                    7    8    9    0    1    2    3    4    5    6    7
                                  99 7 99 8 99 9 00 0 00 1 00 2 00 3 00 4 00 5 00 6 00 7
                                 1199 1199 1199 2200 2200 2200 2200 2200 2200 2200 2200
                                                              Year
                                                              Year



• Fentanyl products: ~500% growth since Y1997
   – ~891,000 Rx dispensed in Y1997 to 5.5 million
     Rx dispensed in Y2007

     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees                                                                                140
     May 6, 2008
                                                                                       Original File: VONA 2008-223 oxycodone comp AC 3-5-08.xls
Prescription Data: Total Dispensed Prescriptions for Fentanyl
   Products from U.S. Retail Pharmacies, Years 2000-2007
                                     Verispan Vector One™ : National (VONA). Extracted 2/2008
                                              TOTAL MARKET
                                              TOTAL MARKET
                                 6
                                 6             Fentanyl Transdermal
                                                Fentanyl Transdermal
                                               Duragesic
                                                Duragesic
                                              OTFC
                                              OTFC
                                 5
                                 5             Fentora
                                                Fentora
      Prescriptions (Millions)
      Prescriptions (Millions)



                                               Actiq
                                                Actiq
                                               Fentanyl
                                                Fentanyl
                                 4
                                 4             Sublimaze
                                                Sublimaze

                                 3
                                 3

                                 2
                                 2

                                 1
                                 1

                                 0
                                 0
                                      2000
                                       2000       2001
                                                   2001      2002
                                                              2002     2003
                                                                        2003          2004
                                                                                       2004   2005
                                                                                               2005   2006
                                                                                                       2006        2007
                                                                                                                    2007
                                                                               Year
                                                                               Year




 • Fentanyl Transdermal has replaced Duragesic®
   as leading Fentanyl Product

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees                                                                                        141
    May 6, 2008
                                                                                                         Original File: VONA 2008-256 2-8-08 fentanyl.xls
                                     Prescription Data: Total Dispensed Prescriptions for Fentanyl
                                       Products* from U.S. Retail Pharmacies, Years 2000-2007
                                                                   *Excludes Duragesic and Fentanyl Transdermal Products
                                                                  Verispan Vector One™ : National (VONA). Extracted 2/2008



                            400
                             400
                                    OTFC
                                    OTFC               Fentora
                                                        Fentora
                                                                                    357
                                                                                     357                         • Total Rx dispensed Y2007
                            350
                             350                                            324
                                                                             324               313
                                                                                                313                 – Actiq® TRx = 66,000
                                                                                                                    – Fentora® TRx = 91,000
                                     Actiq
                                      Actiq            Fentanyl
                                                        Fentanyl
                            300
                             300
Prescriptions (Thousands)
Prescriptions (Thousands)




                                     Sublimaze
                                      Sublimaze       Total
                                                       Total        250
                                                                     250                                            – OTFC TRx = 188,000
                            250
                             250
                                                                                                      188
                            200
                             200                                                                       188
                                                                                                                 • Between Y2005 and Y2007:
                            150
                             150
                                                        151
                                                         151
                                                                                                                    – ~77% decrease in
                                                                                                        91
                                                                                                         91
                                                                                                                      Actiq® prescriptions
                            100
                             100                                                                          66
                                              64
                                               64                                                          66
                             50
                              50   23
                                    23
                                                                                            31
                                                                                             31
                                                                                              15
                                                                                               15
                                                                                                                 • Between Y2006 and Y2007:
                                                                                                                       – ~500% increase in both
                              00
                                   2000       2001      2002        2003    2004    2005      2006       2007
                                                                                                                         OTFC & Fentora®
                                    2000       2001      2002        2003    2004    2005      2006       2007
                                                                                                                         prescriptions
                                                                        Year
                                                                        Year




                                           Joint meeting of Anesthetic and Life Support Drugs and
                                           Drug Safety and Risk Management Advisory Committees                                                                  142
                                           May 6, 2008
                                                                                                                 Original File: VONA 2008-256 2-8-08 fentanyl.xls
    Cost per Unit of Fentora®, Actiq®, and Oral Transmucosal
       Fentanyl Prescriptions Dispensed from U.S. Retail
                      Pharmacies, Year 2007
                       Verispan Vector One™: National (VONA). Extracted 2/2008


                            $45
                            $45
                            $40
                            $40
                            $35
                            $35
           Cost (Dollars)
           Cost (Dollars)

                            $30
                            $30
                            $25
                            $25
                            $20
                            $20                                            $41.65
                                                                           $41.65
                            $15
                            $15   $26.11
                                  $26.11          $22.77
                                                  $22.77
                            $10
                            $10
                             $5
                             $5
                             $0
                             $0
                                   OTFC
                                   OTFC            Fentora
                                                   Fentora                    Actiq
                                                                              Actiq
                                                  Year 2007
                                                  Year 2007

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

     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees                                                      143
     May 6, 2008
                                                      Original File: VONA 2008-256 Fentora Price 2-8-08.xls
   Projected Number of Prescriptions for Fentora® Dispensed, by
    Physician Specialty, from U.S. Retail Pharmacies, Year 2007
                      Verispan Vector One™: National (VONA). Extracted 2/2008




• Top prescribers for year 2007                          ALL
                                                         ALL
   – Anesthesiology ~31,000                            OTHERS,
                                                       OTHERS,
     Rx (35%)                                            26%
                                                         26%                                             ANES, 35%
                                                                                                         ANES, 35%
   – Physical Medicine and
     Rehabilitation ~19,000 Rx
     (21%)                                        NEURO, 5%
   – GP/FM/DO ~8,000 (9%)                         NEURO, 5%

                                                        IM, 5%
                                                         IM, 5%

                                                            GP/FM/DO,
                                                            GP/FM/DO,
• Oncology specialty (not                                      9%
                                                               9%                              PM&R, 21%
                                                                                               PM&R, 21%
  shown) ranks 14th,
  accounting for approx. 1% of
  Fentora® prescribing in
  Y2007



        Joint meeting of Anesthetic and Life Support Drugs and
        Drug Safety and Risk Management Advisory Committees                                                  144
        May 6, 2008
                                                                  Original File: VONA 2008-256 Fentora MD Spec 2-8-08.xls
                            Projected Number of Patients, by age, receiving a prescription
                              for Fentora®, Actiq®, or Oral Transmucosal Fentanyl from
                                       outpatient retail pharmacies, Year 2007
                                                          Verispan, LLC: Total Patient Tracker, Extracted 2/08



                                                 Patients
                                                                         32,343                        •      Total patients in Y2007
                       35                                                                                      – Actiq® : 15,887 patients
Patients (Thousands)




                                                                                          UNSPEC
                       30
                                                23,035
                                                                                                               – Fentora® : 23,035
                                                                                          66+
                       25                                                                                        patients
                       20
                                                                                          41 - 65              – OTFC: 32,343 patients
                                15,887                                                    26 - 40
                       15
                       10                                                                 17 - 25      •      Majority of patients aged 41-
                                                                                          12 - 16             65 years (66% - 69%)
                        5
                                                                                          6 - 11
                        0                                                                              •      Pediatric patients (0-16
                                Actiq           Fentora                   OTFC            3-5                 years) <1%
                                                                                          0-2
                                                 2007




                                 Joint meeting of Anesthetic and Life Support Drugs and
                                 Drug Safety and Risk Management Advisory Committees                                                                  145
                                 May 6, 2008
                                                                                                   Source File: TPT 2008-226 4-23-08 Fentora Actiq Custom Age Report.xls
    Percentage of Actiq® Prescriptions Switched and the Next
 Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007
                     Verispan Vector One™: National (VONA). Extracted 2/2008



• Most common product                                45%
                                                      45%                                                  OTFC
                                                                                                            OTFC
  dispensed after Actiq®                             40%
                                                      40%
                                                                                                            Hydrocodone/APAP
                                                                                                             Hydrocodone/APAP
  prescription is OTFC                                                                                     Fentanyl Transdermal
                                                                                                            Fentanyl Transdermal
                                                     35%
                                                      35%                                                  Oxycodone w/APAP
                                                                                                            Oxycodone w/APAP

• 4th Q 2006                                         30%
                                                      30%
                                                                                                           Oxycodone ER
                                                                                                            Oxycodone ER
                                                                                                           Fentora
                                                                                                            Fentora
   – 42% of Actiq® Rxs



                                           Percent
                                           Percent
                                                     25%
                                                      25%
     switched to OTFC                                20%
                                                      20%
   – 13% of Actiq® Rxs
                                                     15%
                                                      15%
     switched to Fentora®
                                                     10%
                                                      10%
• 4th Q 2007                                         5%
                                                      5%
   – 14% of Actiq® Rxs                               0%
                                                      0%
     switched to OTFC                                   Dec-06
                                                        Dec-06      Mar-07
                                                                    Mar-07        Jun-07
                                                                                   Jun-07       Sep-07
                                                                                                Sep-07        Dec-07
                                                                                                              Dec-07
   – 3% of Actiq® Rxs                                                             Quarter
                                                                                   Quarter
     switched to Fentora®


      Joint meeting of Anesthetic and Life Support Drugs and
      Drug Safety and Risk Management Advisory Committees                                                         146
      May 6, 2008
                                                            Original File: VONA 2008-256 Actiq Switching 2-7-08.xls
Physician survey data, Year 2007
Indications associated with drug use


        Verispan, Physician Drug and
          Diagnosis Audit (PDDA)


  Joint meeting of Anesthetic and Life Support Drugs and
  Drug Safety and Risk Management Advisory Committees
  May 6, 2008
 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
    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      148
    May 6, 2008
 Verispan, Physician Drug and 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
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      149
     May 6, 2008
        Top diagnoses associated with Actiq® and Fentora® use
          during visits to office-based physicians, Year 2007
                       Verispan, Physician Drug and Diagnosis Audit (PDDA)



                        Cancer           Actiq
                        Related                                                     Fentora
                                                                             Cancer
                         14%                            Other                Related
Other                         Surgical                  37%                   38%
45%                            14%


                       Back                              Back                Surgical
                       27%                                8%                  17%




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

          Joint meeting of Anesthetic and Life Support Drugs and
          Drug Safety and Risk Management Advisory Committees                             150
          May 6, 2008
   Verispan LLC, Vector One™ :
     Concurrency (VOCON)
• Derived from Verispan’s Vector
  One™ database
• Allows users to measure and
  evaluate concurrent drug therapy
  usage in unique patients during a
  selected time period using one of
  four scenarios.
• Nationwide projections are not
  available.
   Joint meeting of Anesthetic and Life Support Drugs and
   Drug Safety and Risk Management Advisory Committees      151
   May 6, 2008
     Verispan LLC, Vector One®:
       Concurrency (VOCON)
• Episode of concurrency:
   – prescription in the Base group (Actiq® or
     Fentora®) overlaps with the days supply for
     a dispensed prescription in the Concurrent
     group (pain market or product within the
     pain market).
• 30 day supply with grace period of 10% =
  36 days
• Fill sequence: Pain market product filled
  before Actiq® or Fentora®

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      152
    May 6, 2008
           Concurrency Analysis –
                  Results
• Y2005: 40% of Actiq® patients were on concurrent therapy
  with a product from the pain market. Y2007: 26%

• Y2007: 59% of Fentora® patients were on concurrent
  therapy with a product from the pain market.

• Higher prevalence of concurrent therapy with products in
  the pain market with Fentora® than Actiq®.

• Fentanyl transdermal, hydrocodone/acetaminophen, and
  oxycodone (immediate release) products were the most
  common concurrent products within the pain market.



     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      153
     May 6, 2008
           Concurrency Analysis -
                Limitations
• VOCON does not capture data from inpatient
  hospitals, oncology clinics, same-day surgery
  centers, or mail order pharmacies.

• True opioid tolerance/non-tolerance cannot
  be determined within the confines of this
  analysis, as a patient could begin opioid
  treatment as an inpatient or in a clinic, and
  continue therapy as an outpatient.

    Joint meeting of Anesthetic and Life Support Drugs and
    Drug Safety and Risk Management Advisory Committees      154
    May 6, 2008
                            Conclusions
• ~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
     Joint meeting of Anesthetic and Life Support Drugs and
     Drug Safety and Risk Management Advisory Committees      155
     May 6, 2008
                         Conclusions
• 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 Committees      156
    May 6, 2008

				
DOCUMENT INFO
Categories:
Tags:
Stats:
views:11
posted:6/17/2012
language:English
pages:156