# Presentation: 557220

## 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**

## 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**

## 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**

## 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**

## 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**

## AERS Limitations

**Extensive underreporting**
**Quality of reports is variable**
**Reporting biases**
**Actual numerator & denominator not known**
**Causality of drug-event association often in question**

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

## Fentora: AERS Search Criteria

**Search dates – up to 2/25/08**
**Brand name search only – Fentora**
**All adverse events **
**Foreign and domestic reports**

## 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**

## Fentora: Demographics and Indications

| Number of cases | 19 |
| --- | --- |
| Gender:
  Male
  Female | 
9
10 |
| Age (n=16):
  Median
  Range | 
43.5 years
16 – 73 years |
| Indication (n=18):
  Cancer pain
  Non-cancer pain
  Misc* | 
1 (5%)
11 (57%)
6 (32%) |

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

## Fentora: Dose & Other Opioid Use

| Number of cases | 19 |
| --- | --- |
| Daily dose (n=6):
  Median 
  Range | 
2000 mcg
600 – 3200 mcg |
| Onset (n=6):
  Median
  Range | 
8 days
Same day – 5 months |
| Opioid tolerance:
  Tolerant
  Non-tolerant
  Unspecified | 
6 (32%)
1 (5%)
12 (63%) |
| Concomitant use of other opioid medications | 
11 |

## Fentora: Outcomes & Report Source

| Number of cases | 19 |
| --- | --- |
| Outcomes:
  Death
  Life-threatening
  Hospitalization
  Medically significant
  Unspecified | 
5
1
1
3
9 |
| Year Received
  2007
  2008 | 
17
2 |
| Report Source
  US | 
19 |

## 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.

## 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 administration site conditions (14) | lack of efficacy (6), application site bleeding, bruising, ulcer, pain, or burning (6), flushing (1), hyperhidrosis (1) |
| Injury, poisoning, & procedural complications (18) | medication errors** (10), intentional overdose (2), overdose (2), accidental overdose (2), intentional drug misuse (2), accidental exposure (1) |

- *Unlabeled events underlined;  **Included only medication error reports with adverse events

## Fentora: Reported AE Cont..

| System Organ Class | Adverse Events |
| --- | --- |
| Metabolism & nutritional disorders (1) | oral intake reduced (1) |
| Nervous system disorders (7) | somnolence (3), loss of consciousnes (2), CVA (1), dysarthria (1) |
| Psychiatric disorders (3) | drug dependence (1), suicidal attempt (1), suicide (1) |
| Renal and urinary disorders (1) | dysuria (1) |
| Respiratory, thoracic, & mediastinal disorders (2) | respiratory arrest (1) dyspnea (1) |
| Vascular disorders (1) | dizziness (1) |

## 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

## 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**

## 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**

## 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).

## 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**

## Actiq: Indication & Tolerance

| Number of cases | 61 |
| --- | --- |
| Indication (n=57):
  Cancer pain
  Non-cancer pain
  Misc* | 
3 (5%)
31 (51%)
23 (38%) |
| Opioid tolerance:
  Tolerant
  Non-tolerant
  Unspecified | 
16 (26%)
4 (6%)
41 (67%) |
| Concomitant use of other opioid medications | 
28 |

- *Suicide, suicidal attempt, intentional misuse & accidental exposure

## Actiq: Outcomes

| Total number of cases | 61 |
| --- | --- |
| Outcomes*:
  Death
  Life-threatening
  Hospitalization
  Disability
  Medically significant | 
9
6
28
2
25 |

- *Cases may have reported more than one outcome.

## Actiq: Fatalities

**9 reports of death**
**Causes of death**
**apnea (1), cardio-respiratory arrest (1), fentanyl toxicity (2), multiple drug overdose (2), unknown (3)**
**7 of 9 reports involved an overdose**
**Of the remaining 2 reports:**
**1****st:**** Fetal death confounded by concomitant use of other medications, one of which was labeled category D**
**2****nd: ****Opioid non-tolerant patient (weaned off of opioids) but restarted Actiq and possibly other opioids**

## Actiq: Reported Adverse Events (AE)

| System Organ Class | Adverse Events |
| --- | --- |
| Cardiac disorders (11) | tachycardia (4), cardiac arrest* (3), v. fib (1), v. tachycardia (1) |
| Injury, poisoning and procedural complications (42) | med errors** (18), accidental exposure (8), drug toxicity (4), overdose (4), multiple drug overdose accidental (1) |
| Nervous system disorders (71) | convulsion (6), confusion (2), somnolence (15), coma (7), lethargy (13), loss of consciousness (3) |
| Psychiatric disorders (52) | agitation (5), anxiety (2), delusion (4), hallucination (4), irritability (4) |

- *Unlabeled events underlined;  **Included only med error reports with adverse events

## Actiq: 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

## 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**

## 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**

## 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**

## 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**

## Fentora Medication Errors

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

## Overview

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

## AERS Search

**Search Conducted March 18, 2008**
**1 month following DAEA search**
**No MedDRA terms used**
**Retrieved 63 cases**

## AERS Results

| Total Number of Cases  | 63 |
| --- | --- |
| Excluded Cases
intentional overdose
adverse events not a result of medication error
not enough information to determine if medication error occurred | 20 |
| Medication Error  Cases
further analyzed for type and causality | 43 |

## 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)**

## Types of Error (n=43)

| Wrong route of administration | 10 |
| --- | --- |
| Improper frequency of administration | 9 |
| Improper patient selection | 9 |
| mcg per mcg conversion between Actiq and Fentora | 6 |
| Improper dose prescribed when converting from Actiq to Fentora | 4 |
| Improper substitution | 2 |
| Improper technique  | 1 |
| Accidental exposure  | 1 |
| Accidental overdose  | 1 |

## Types of Error

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

## 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

## 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

## 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

## Types of Error (cont) 

**mcg per mcg conversion between Actiq and Fentora (n=6)**
- Actiq 800 mcg to Fentora 800 mcg

## 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

## 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

## Types of Error (cont)

**Improper Technique (n=1)**
- Tablet splitting
- Prescribed 1⁄2 of 400 mcg tablet BID
**Accidental Exposure (n=1)**
- Tablet removed from blister
- Fentora mistaken for aspirin
**Accidental Overdose (n=1)**
- Death
- Prescribed for back pain

## Safety 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

## 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**

## 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**

## Outline

**Background**
**Current RiskMAP **
**Overview**
**Postmarketing experience**
**RiskMAP experience summary**
**Additional risk mitigation options**
**Conclusions**

## Background

**Fentora was approved with:**
**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”*** **
**Medication Guide**
**A risk minimization action plan (RiskMAP) **

**Fentora Label, 2/7/08**

## Current Fentora RiskMAP

## Goals

**Fentora should be used only by opioid tolerant patients with cancer.**
**Abuse, misuse and diversion of Fentora should not occur.**
**Unintended (accidental) exposure to Fentora should not occur.**

## Key Elements

**Labeling**
**Education**
**Surveillance**
**Evaluation/Intervention**

## 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**

## Labeling - Carton

## 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**

## 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)

## 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

## RiskMAP Postmarketing Experience

## RiskMAP Quarterly Report Information

| Quarterly RiskMAP Report Data | Non Opioid Tolerant
(IMS longitudinal database estimates) | Non Cancer Diagnosis
(IMS National Audit Data) |
| --- | --- | --- |
| 1st quarter
(9/25/06-12/31/06 | 14.2% | 85.8% |
| 2nd quarter
(1/1/07-3/31/07) | 21.0% | 84.1% |
| 3rd quarter
(4/1/07-6/30/07) | 23.5% | 81.0% |
| 4th quarter
(7/1/07-9/30/07) | 24.1% | 82.8% |
| 5th quarter
(10/1/07-12/31/07) | 28.1% | 82.6% |

## RiskMAP Quarterly Report Information, cont.

**Spontaneous and expedited reports of abuse, misuse and diversion have been received**
**Surveillance system information on abuse, misuse, and diversion**
- RADARS® Signal Detection Systems showed concerning rates, but not definite signals (reported in the 4th Quarterly RiskMAP Report).

## RiskMAP Quarterly Report Information, cont.

**Physician Survey**
**no results submitted as of 5****th****  quarterly RiskMAP Report**
**Pharmacy Survey**
**no results submitted as of 5****th****  quarterly RiskMAP Report**

## 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

## 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**

## Fentora RiskMAP Experience Summary

## 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**

## 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**

## Additional Risk Mitigation Options

**Consider additional risk mitigation strategies and the feasibility of these strategies**
**Prescriber requirements**
**Pharmacy/Dispensing requirements**
**Additional requirements**

## 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

## 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)

## 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

## 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

## 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**

## Risk Mitigation Options Challenges

**More burdensome**
**Unintended consequences**
**delayed access/no access of product for appropriate patients**
**Abuse/misuse/diversion will still occur**

## 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**

## 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**

**Notes:**
Good morning, my name is Ellen Fields, and I am acting clinical team leader in the Division of Anesthesia, Analgesia, and Rheumatology products.

## Overview of Presentation

**Regulatory history of oral transmucosal fentanyl products**
**Labeling changes**
**Compare the pharmacokinetics of Actiq and Fentora**

**Notes:**
Today, I am going to present:
The regulatory history of the oral transmucosal fentanyl products, including important labeling changes that have occurred.
I will also present a comparison of the pharmacokinetic characteristics of Actiq and Fentora that are relevant to the safe conversion of one product to the other.

## OTFC Products

**Oralet**
**Actiq**
**Fentora**

**Notes:**
There have been three approved oral transmucosal fentanyl products: Oralet, Actiq, and Fentora, only two of which remain on the market.

## 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**

**Notes:**
Oralet was approved in 1993 for preoperative sedation in children.  It was intended for use only in a hospital setting. 
 The formulation consisted of a raspberry flavored lozenge on a stick- a lollipop- that was intended to be acceptable to children.  
It was available as 100, 200 and 400mcg dosage units.
Oralet was withdrawn from the market in 2001 because pediatric patients could not tolerate the adverse events of nausea and vomiting that resulted from its use.

## 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**

**Notes:**
Actiq was approved in 1998 for a narrow indication: the treatment of breakthrough pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying cancer pain.
The formulation was the same as Oralet, but the units included higher dosage strengths up to 1600 mcg
Actiq was intended for use in both inpatient and  outpatient settings.

## 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**

**Notes:**
There were a number of important safety issues that came to light during the approval  process for Actiq

Actiq’s approval represented a unique circumstance, where the population at greatest risk for adverse events –opioid naïve patients and children- was not the population that would benefit from the drug’s approval.
Along with the risks common to all high-potency opioids including misuse, abuse, and diversion, an important risk stood out; the accidental or intentional ingestion of the product by children who have mistaken the lollipop formulation for candy.  A single 200 mcg dosage unit contains fentanyl in an amount that can be fatal to a child.
These issues were the subject of an ALSAC meeting in September of 1997.  The committee voted  that there should be a way found to make Actiq available to those patients who would potentially benefit from it, while managing the potential risks to public health. 
Actiq was approved  in 1998 under 21CFR§314.20 (Subpart H) “Approval with restriction to assure safe use” : 
the NDA was approved with restriction for use to the treatment of breakthrough pain associated with malignancy in opioid-tolerant cancer patients , also limiting pharmaceutical marketing detailing  to Oncology and Pain Medicine specialists,  and with the final printed labeling and Risk Management Program as a condition of approval. 
The regulations under which this product was approved also provide for accelerated withdrawal of the product if the Sponsor does not adhere to the agreed upon marketing restrictions. 
A Risk Management program was created to mitigate  misuse, abuse and diversion, and accidental exposure by children

## 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**

**Notes:**
The original Actiq label had a Box warning that contained the following information
the  indication
That the product must not be used in opioid non tolerant patients
That it should be prescribed only by oncologists and pain specialists
And that it must be kept out of reach of children 
and disposed of properly

## Original Actiq Label

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

**Notes:**
Additional information included
Contraindications for
Management of acute or post operative pain
And Use in opioid non-tolerant persons
And instructions for Proper disposal
(Completely used units: throw in trash out of reach of children
Partially used units: run under hot water to dissolve drug matrix)
If cannot run under hot water, temporarily stoe Actiq unit in specially provided child resistant container out of reach of children until proper disposal is possible.
Disposal of unopened Actiq units when no longer needed: drug matrix should be flushed down the toilet

## 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**

**Notes:**
There have been several labeling changes for Actiq since the time of approval.  Those of significance include the addition of a statement advising diabetic patients that Actiq contains two grams of sugar per unit (June 10, 2002); statements added to label based on post-marketing experience regarding the association of Actiq with dental caries, tooth loss, and gum line erosion (September 24, 2004); formulation change to sugar-free (never marketed, September 9, 2005); conversion of patient leaflet (patient package insert) to MedGuide (September 6, 2006); and the addition of pharmacokinetic data for patients 5-15 years of age based on a study carried out in the pediatric population (February 7, 2007). 

## 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**

**Notes:**
Fentora was approved September, 2006 for the same indication: same as Actiq
The formulation is an effervescent buccal tablet with Dosage units ranging  from : 100 to  800 mcg
It was intended for use  in both inpatient and outpatient settings, and 
The Risk Management Plan and Medguide part of approval
The Risk management plan will be presented in detail later this morning.

The Risk Management Plan for Fentora had the following goals:
Use only by opioid tolerant individuals
Prevention of misuse, abuse,and diversion
Prevention of accidental exposure

## 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.**

**Notes:**
The originally approved label had a Box warning that was similar to that of Actiq with the addition of the statement that due to  the higher bioavailability of fentanyl in Fentora, conversion from other fentanyl products should not be done on a mcg per mcg basis.

(1. Indication for opioid-tolerant cancer patients
2. The contraindication for use in 
Acute and post operative pain
And Opioid non-tolerant patients
3. The statement that each dosage unit contains medicine in amount which can be fatal to a child)

## Fentora vs. Actiq

- Source: Fentora Package Insert

**Fentora vs. Actiq**

**Notes:**
At this point, I’m going to compare the pharmacokinetic attributes of Fentora and Actiq
Both Fentora and Actiq deliver fentanyl through the oral mucosa which prevents considerable first-pass metabolism by the intestinal mucosa and the liver via the CYP450-3A4 route
The results from a comparative study showed that the rate (Cmax) and extent (AUC) of fentanyl absorption from Fentora were considerably different from Actiq.
The absolute bioavailability of fentanyl from Actiq in this study was 47%, with 31% of the dose being absorbed via the oral mucosa and 16% via the GI tract.
(numbers are slightly different but comparable in the Actiq label)
The absolute bioavailability of Fentora was approximately 65%, with 50% of the dose being absorbed via the oral mucosa, and the remaining 15% via the GI tract.
Comparing Fentora and Actiq, Fentora delivered approximately 17% more fentanyl via the oral mucosa than Actiq.

## Slide 86

**Notes:**
the initial dosing recommendations for Patients on Actiq converting to Fentora are included in the Fentora label.  
Because of the differences in bioavailability, and intersubject variability, the conversion is very conservative.

## 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.

**Errors included**
**Off-label prescribing to non-opioid tolerant patients**
**Patients prescribed the wrong dose**
**Patients took too many doses **
**Healthcare professionals substituted Fentora for another fentanyl-containing product that is not equal to Fentora.**
** **

**Medication Errors**

**Notes:**

Despite extensive labeling, within the first year of Fentora’s approval, there were prescribing errors associated with adverse events including death. Errors included
Off-label prescribing to non-opioid tolerant patients
patients being prescribed the wrong Fentora dose; 
patients took too many Fentora doses; and 
healthcare professionals substituted Fentora for another fentanyl-containing product that is not equal to Fentora. 

These will be presented in more detail later this morning

## 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**

**Notes:**
In September of  2007, a Public Health Advisory was issued for Fentora that addressed these issues.

The issues addressed in the advisory included
	Off label prescribing to non opioid tolerant patients,
	 misunderstanding of dosing instructions by both prescribers and patients
       inappropriate substitution of Fentora for Actiq by pharmacists and prescribers

## Fentora Labeling 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.**

**Notes:**
The Fentora label and medguide  were  revised on February 7, 2008 in order to reinforce the following safety information
Contraindication of  the 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 Fentora for other fentanyl products
Proper dosing

## 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.  **

**Notes:**
In 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 (~20%), 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.
This concludes my presentation

## Fentora Abuse Potential in the Noncancer Pain Population

**Lori A. Love, M.D., Ph.D.**
**Medical Officer**
**Controlled Substance Staff**

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

**History of fentanyl and abuse**
**Synthesized in late 1950s**
**Introduced as IV anesthetic in 1960s (Sublimaze®). **
**Illicit use of pharmaceutical fentanyl first identified in the mid-1970s in the medical community**
**All pharmaceutical preparations have been abused**
**IV, snorting, smoking and sublingual routes used**
**Street names: ****apache, china girl, china white, dance fever, friend, goodfella, jackpot, murder 8, TNT, etc. **

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

**History of fentanyl and abuse**
**High abuse potential**
**Illicitly manufactured for abuse**
**> 12 different fentanyl analogues in U.S. drug traffic **
**Recent deaths in several US communities attributed to abuse fentanyl-laced heroin**
**One of the precursors was designated as a List 1 chemical. DEA is now in the process of designating a second chemical as a Schedule II immediate precursor **
**Abuse of domestic and foreign pharmaceutical products**

## What Users Are Saying About Fentora*

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

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

## 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**

## Double-blind, placebo-controlled studies: 
Study 3052 
Study 3041 
Study 3042 
Open-label, uncontrolled study: 
Study 3040

**Study 3052 **
**Study 3041 **
**Study 3042 **
**Open-label, uncontrolled study: **
**Study 3040**

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

## Protocol-specified entry criteria

**Inclusion:  ****Taking an  around the clock opioid and managing break-through pain using an opioid**
**Exclusion:**
**To screen out patients who might be at higher risk of abuse or addiction**
**Recent history (within 5 years) or current evidence of alcohol or substance abuse**
**Evidence by urine drug screen of an illicit substance or a medication for which there was no legitimate medical explanation **
**Psychiatric conditions that would compromise patient safety if they participated in the study**

## “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**

## “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 |  |

## Aberrant drug use behavior

| Table 2:  Sponsor’s Summary of Patients by Risk Category |  |  |
| --- | --- | --- |
| 
Risk Category | Number of Patients¥ | 
Percent |
| High risk behaviors* | 30 | 3% |
| Abuse/dependence | 8 | <1% |
| Overdose | 9# | 1% |
| Positive urine drug screen | 13 | 1% |
| Other aberrant behaviors | 126 | 13% |
| None | 785 | 83% |
| ¥ Patients could have more than one aberrant behavior reported
*3 patients also had non-high risk aberrant behaviors
# includes one patient with 2 episodes of overdose |  |  |

## Aberrant drug use behavior

| Table 3: Aberrant Behaviors Identified in > 1% of Patients 
               (Identified by Sponsor) |  |  |
| --- | --- | --- |
| 
Behavior | Number of Patients | 
Percent |
| Overuse of study drug | 44 | 5% |
| Study drug thefts | 35 | 4% |
| Lost to follow-up | 33 | 4% |
|  |  |  |

## Aberrant drug use behavior

**5 patients withdrawn: 4 from study 3040, 1 from 3052**
**30 of 35 thefts perpetrated by those without regular access to study drug**
**20 thefts occurred outside patient’s home**

| Table 4:  Study Drug Thefts during Phase 3 Clinical Trials
                (Identified by Sponsor) |  |  |  |
| --- | --- | --- | --- |
| 
Study drug theft | Number of cases | 
Percent  | Amount of drug stolen |
| From patients | 35 | 4.2%* | ---- |
| *Number of cases (5) divided by the total 831 patients in studies 3040 & 3052. |  |  |  |

## Aberrant drug use behavior

| Table 5:  Study Drug Thefts during Phase 3 Clinical Trials
                (Identified by Sponsor) |  |  |  |
| --- | --- | --- | --- |
| 
Study drug theft | Number of cases | 
Percent  | Amount of drug stolen |
| From study center | 5 | ----+ | 4.3 gm ¥ |
| +There were 69 study centers in study 3040
¥ Calculated from additional information provided by the sponsor on 03/21/08, represents > 8000 tablets.   |  |  |  |

**Thefts from study site only reported in study 3040**
**Study drug stolen:**
**From locked cabinets in 3 thefts**
**Lost in transit from health facility distribution to pharmacy  in 1**
**Unused study drug returned by patient was subsequently missing during drug accountability review**
**All cases reported to DEA**

## 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**

## 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**

## 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**

## 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. **

## 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**

## 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**

## 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”

## 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**

## 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**

## DAWN: ED Visits -- Non-Medical Use per 10,000  Retail Prescriptions 2004 – 2006

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

## 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

## Study 3052 – Primary Efficacy Endpoint (PEP)

## 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.**

## 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.**

## 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**

## 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.**

## 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.**

## Safety -Exposure

**Source:  Summary of Clinical Safety**

## 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.**

## 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**

## 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) |

## Concomitant Medication Use*

| Parameter |  | Non-Cancer [n (%)] | Cancer [n (%)] |
| --- | --- | --- | --- |
| N |  | 941 | 358 |
| Around-the-clock opioid dose** | Mean | 239.7 mg | 342.1 mg |
|  | Std. Dev | 219.4 mg | 407.6 mg |
|  | Range | 20-2160 mg | 24-4800 mg |
| Other CNS depressants | Benzodiazepines | 43% | 38% |
|  | Non-benzodiazepine sleep aids | 21% | 16% |
|  | Tricyclic antidepressants | 14% | 7% |
|  | Muscle relaxants (carisoprodol, cyclobenzaprine, etc.) | 46% | 10% |
|  | Gabapentin/pregabalin | 24% | 15% |
|  | Other | 31% | 15% |

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

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

|  | Non-cancer
 Population | Cancer
 Population |
| --- | --- | --- |
| Total N | 941 | 358 |
| Accidental overdose | 8 | 0 |
| SAE related to drug dependence/withdrawal/
abuse | 2 | 0 |
| SAE possibly related to oversedation (MVA with severe CNS and orthopedic injury where patient was the driver) | 1 | 0 |

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

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

|  | Non-Cancer
N=941 |  | Cancer
N=358 |  |
| --- | --- | --- | --- | --- |
| Pooled Term | n | % | n | % |
| Dizzy | 22 | 2.3 | 1 | 8.0 |
| Lightheaded | 10 | 1.1 | 14 | 3.6 |
| Confusion | 14 | 1.5 | 2 | 2.8 |
| Fall | 19 | 2.0 | 7 | 2.0 |
| Seizures | 0 | 0 | 1 | 0.3 |
| Sedation | 61 | 6.5 | 14 | 3.9 |
| Withdrawal | 12 | 1.3 | 1 | 0.3 |
| Fracture | 17 | 1.8 | 2 | 0.6 |
| Syncope | 4 | 0.4 | 1 | 0.3 |
| Likability of opioid | 7 | 0.7 | 2 | 0.6 |
| One case each of: Addictive behavior, substance abuse, personality change, six cracked bottom front teeth, paranoia, car accident, impaired balance, physical trauma | 8* | 0.8 | 0 | 0 |

- *total of cases

- *sum of eight discrete cases

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

|  | Non-Cancer
N=941 |  | Cancer
N=358 |  |
| --- | --- | --- | --- | --- |
| Pooled Term | n | Rate per 100 PYR | n | Rate per 100 PYR |
| Sedation | 78 | 11.6 | 15 | 11.7 |
| Dizzy | 27 | 4.0 | 42 | 32.8 |
| Lightheaded | 10 | 1.5 | 10 | 7.8 |
| Fall | 20 | 3.0 | 8 | 6.3 |
| Seizures | 0 | 0 | 1 | 0.8 |
| Syncope | 4 | 0.6 | 1 | 0.8 |
| Confusion | 16 | 2.4 | 12 | 9.4 |
| Likability of opioid | 8 | 1.2 | 2 | 1.6 |
| Withdrawal | 12 | 1.8 | 1 | 0.8 |
| Fracture | 23 | 3.4 | 3 | 2.3 |
| One case each of: Addictive behavior, substance abuse, personality change, six cracked bottom front teeth, paranoia, car accident, impaired balance, physical trauma | 8 | 1.2 | 0 | 0 |

- *sum of eight discrete cases

## Common 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 complaints |  | 15 (6) | 12 (10) | 116 (12) |

## 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.

## 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.

## 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.**

## 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**

## Outline

**Settings of use ****− ****sales & distribution data:**
**IMS Health, IMS National Sales Perspectives****TM**** Retail and Non-Retail**
**Prescription and patient-level data:  **
**Verispan, Vector One****TM ****:  National (VONA)**
**Verispan, Vector OneTM :  Total Patient Tracker (TPT)**
**Verispan, Vector OneTM : Concurrency (VOCON)**
**Physician survey data:  **
**Verispan, Physician Drug and Diagnosis Audit (PDDA)**
**Conclusions**

## Sales distribution dataYear 2007

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

## IMS Health, IMS National Sales PerspectivesTM

**Measures sales data from manufacturers to retail and non-retail channels of distribution**
_**Extended Units**_** are the number of tablets, capsules, milliliters, ounces, etc. of a product shipped in each unit**
_**Retail Channels**_** - chain, independent, mass merchandisers, food stores with pharmacies, and mail-order pharmacies**
_**Non-Retail Channels**_** - federal facilities, non-federal hospitals, clinics, long-term care facilities, home health care (began 1998), HMOs, miscellaneous channels (began 1999; prisons, universities, other)**

**92% Fentora****®**** sales go to retail channels of distribution during Y2007.**

## Prescription and Patient-level Data

**Verispan, Vector OneTM :  National (VONA)**
**Verispan, Vector OneTM :  Total Patient Tracker (TPT)**
**Verispan, Vector OneTM : Concurrency (VOCON)**

## Verispan, LLC  Vector OneTM :  National (VONA)

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

## Prescription Data: Total Retail Prescriptions Dispensed For Selected Opioids, Years 1997-2007 (With Hydrocodone and Oxycodone Combination Products) Verispan Vector OneTM: National (VONA).  Extracted 3/2008

**Hydrocodone products #1 among all dispensed prescriptions for past 10 years; nearly 120 million Rx dispensed in Y2007**
**Oxycodone products = 42 million Rx in Y2007**

-                                     Original File: VONA 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 OneTM: National (VONA).  Extracted 1/2008

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

-                                     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 OneTM : National (VONA).  Extracted 2/2008

**Fentanyl Transdermal has replaced Duragesic****®**** as leading Fentanyl Product**

-    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 OneTM : National (VONA).  Extracted 2/2008

**Total Rx dispensed Y2007**
**Actiq****®**** TRx = 66,000**
**Fentora****®**** TRx = 91,000**
**OTFC TRx = 188,000**
**Between Y2005 and Y2007:**
**~77% decrease in Actiq****®**** prescriptions**
**Between Y2006 and Y2007: **
**~500% increase in both OTFC & Fentora****®**** prescriptions**

-                                     Original File: VONA 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 OneTM: National (VONA).  Extracted 2/2008

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

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

## Projected Number of Prescriptions for Fentora® Dispensed, by Physician Specialty, from U.S. Retail Pharmacies, Year 2007Verispan Vector OneTM: National (VONA).  Extracted 2/2008

- Top prescribers for year 2007
- Anesthesiology ~31,000 Rx (35%)
- Physical Medicine and Rehabilitation ~19,000 Rx (21%)
- GP/FM/DO ~8,000 (9%)
- Oncology specialty (not shown) ranks 14th, accounting for approx. 1% of Fentora**®** prescribing in Y2007

-                    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

**Total patients in Y2007**
**Actiq****®**** :  15,887 patients**
**Fentora****®**** :  23,035 patients**
**OTFC:  32,343 patients**
**Majority of patients aged 41-65 years (66% - 69%)**
**Pediatric patients (0-16 years) <1%**

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

## Percentage of Actiq® Prescriptions Switched and the Next Prescription Dispensed by Quarter, 4thQ 2006 through 4thQ 2007 Verispan Vector OneTM: National (VONA).  Extracted 2/2008

**Most common product dispensed after Actiq****®**** prescription is OTFC**
**4th Q 2006**
**42% of Actiq****®**** Rxs switched to OTFC**
**13% of Actiq****®**** Rxs switched to Fentora****®**** **
**4th Q 2007**
**14% of Actiq****®**** Rxs switched to OTFC**
**3% of Actiq****®**** Rxs switched to Fentora****®**

-                    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)**

## 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

- monthly _survey_ that monitors disease states and the physician intended prescribing habits on a national-level
- designed to provide descriptive information on the patterns and treatment of diseases encountered in office-based physician practices in the U.S.
- audit is composed of approximately 3,100 office-based physicians representing 29 specialties across the US

**Verispan, Physician Drug and Diagnosis AuditTM (PDDATM) **

## 
“Drug Uses” – mention of a drug in association with a diagnosis during office-based patient visit

Limitations
Denominator is “visits” - not patients
Sample sizes can be small when use is low, producing unreliable estimates
“Uses” may be duplicated by number of diagnoses and does not necessarily result in prescription

- “Drug Uses” – mention of a drug in association with a diagnosis during office-based patient visit
- Limitations
- Denominator is “visits” - _not patients_
- Sample sizes can be small when use is low, producing unreliable estimates
- “Uses” may be duplicated by number of diagnoses and does not necessarily result in prescription

**Verispan, Physician Drug and Diagnosis AuditTM (PDDATM) **

## Top diagnoses associated with Actiq® and Fentora® use during visits to office-based physicians, Year 2007Verispan, Physician Drug and Diagnosis Audit (PDDA)

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

## Verispan LLC, Vector OneTM : Concurrency (VOCON)

**Derived from Verispan’s Vector OneTM  database**
**Allows users to measure and evaluate concurrent drug therapy usage in unique patients during a selected time period using one of four scenarios.**
**Nationwide projections are not available.**

## Verispan LLC, Vector 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****®**

## 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.**

## 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.

## 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 4****th**** Qtr 2007**
**Sum of total Rx dispensed for Actiq ****®****, Fentora ****®****, OTFC have not caused an increase in the trend**

## 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****®**