1. 1 One Year Post Exclusivity Adverse Event Review: Fentanyl Transdermal System Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004 ShaAvhrée Buckman, MD, PhD, FAAP Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Background Drug Information Moiety: Duragesic ® (Fentanyl Transdermal System) Therapeutic Category: Opioid Analgesic Sponsor: Johnson and Johnson, ALZA Indications: –Treatment of chronic pain (such as that of malignancy) that: cannot be managed by lesser means such as acetaminophen-opioid combinations, NSAIDs, or PRN dosing with short-acting opioids AND requires continuous opioid administration –Approved for pediatric use in children ≥ 2 years Original Market Approval: August 7, 1990 Pediatric Exclusivity Granted: January 29, 2003

3. 3 Relevant Safety Labeling

4. 4 Selected Additional Safety Labeling Duragesic ® should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain and in the detection and management of hypoventilation including the use of opioid antagonists

5. 5 Drug Use Trends in Outpatient Settings: Fentanyl Transdermal System The total number of prescriptions dispensed for fentanyl transdermal systems in the U.S. have increased by 20% in the past 2 years (2/02 to 1/04), from 4.5 million in 2002 to 5.4 million in 2003. 1 Top three prescribers in 2003 for fentanyl transdermal systems were: internal medicine, family practice, and anesthesiology. Approximately 0.2% of fentanyl transdermal system prescriptions dispensed were written by pediatricians. 1 1 IMS Health, National Prescription Audit Plus , On-Line, Feb 1999 – Jan 2004, Data Extracted March 2004

6. 6 Drug Use Trends in Outpatient and Inpatient Settings: Fentanyl Transdermal System In the outpatient setting, children and adolescents have accounted for very few dispensed fentanyl transdermal system prescriptions over the past two years (2/02-1/04) –4,535 prescriptions (0.1%) (February 2002-January 2003) 1,2* –5,422 prescriptions (0.1%) (February 2003-January 2004) 1,2* In both the outpatient and inpatient settings, adolescents (ages 12-16 years) accounted for over 60% of pediatric fentanyl transdermal system use over the last three years (2/01 to 1/04). 3 1 IMS Health, National Prescription Audit Plus , On-Line, Feb 1999 – Jan 2004, Data Extracted March 2004 2 AdvancePCS™, Dimension Rx, On-Line, Feb 2001 – Jan 2004, Data Extracted March 2004 3 Child Health Corporation of America TM : Pediatric Health Information System (PHIS), Jan 2002 - Jun 2003 *Calculation based on application of proportions of pediatric fentanyl transdermal system prescription claims in AdvancePCS  to total number of prescriptions dispensed in IMS Health, National Prescription Audit Plus  to estimate number of fentanyl transdermal system prescriptions dispensed nationwide to pediatric population.

7. 7 Drug Use Trends in Outpatient and Inpatient Settings: Fentanyl Transdermal Systems In the outpatient setting, the most frequent diagnoses associated with fentanyl transdermal systems in the pediatric, as well as the adult population, were associated with diseases of the musculoskeletal system and connective tissues. In the pediatric population, the most predominant musculoskeletal diagnosis was for spinal stenosis, followed by injuries involving fractured bones. 1 In the inpatient setting, the primary discharge diagnoses most frequently associated with billing of fentanyl transdermal systems during a hospitalization in the pediatric population were for chemotherapy encounters and various blood disorders, including sickle cell disease. 2 1 IMS Health, National Disease and Therapeutic Index™, CD_ROM, Feb 2001 – Jan 2004, Data Extracted Mar 2004 2 Premier Inc., Perspective™, Jan 2002 – Jun 2003, Data Extracted Apr 2004

8. 8 Adverse Event Reports: Fentanyl Transdermal System 01/29/03 - 02/29/04 Total number of reports, all ages: –1917 (1468 U.S.) Pediatric reports: –8 unique cases (7 U.S.) –All with serious outcomes, including 5 deaths –Gender: Female (4), Male (4) –Age: 2-5 years (1), 6-11 years (2), 12-16 years (5)

9. 9 Pediatric Adverse Events in the One- Year Post-Exclusivity Period: Overdose (2) Drug abuser (2) Medication error (2) Coma Convulsions Death Drug level increased Drug withdrawal syndrome Nausea Urinary retention Vomiting Weight decreased Euphoric mood Cardiac arrest (2) Respiratory Arrest (2) Self-medication (2) Loss of consciousness Lung neoplasm Mydriasis Pelvic neoplasm Petechiae Pleural disorder Pulmonary congestion Pulmonary edema Toxicologic test abnormal Endocardial disease Labeled EventsUnlabeled Events Gastrointestinal obstruction Hemorrhage Hallucination Injury Anxious parent, Brain edema

10. 10 Pediatric Adverse Events: Deaths (1 year post-exclusivity period; n=5) 1.8 year old female diagnosed with rhabdomyosarcoma, who died 2 months after being switched from the fentanyl transdermal system to IV morphine (Foreign) 2.9 year old male 2-days post tonsillectomy and adenoidectomy was treated with the fentanyl transdermal system 25  g patch with subsequent respiratory arrest resulting in death. Concomitant meds: Acetaminophen with codeine elixir (US) 3.4 year old female died from cardiac arrest after having fentanyl- transdermal system applied by her grandmother for pain relief. Details unknown (US)

11. 11 Pediatric Adverse Events: Deaths (1 year post-exclusivity period; n=5) 4.16 year old male with history of drug abuse (marijuana, methylphenidate, dextropropoxyphene) reported to have been using the fentanyl transdermal system several days prior to death and was found wearing a 100  g/hr patch (US) 5.16 year old male with history of alcohol and marijuana use died from cardiac arrest after using 100  g/hr patches obtained from another student. He was found wearing a 100  g/hr patch. (US)

12. 12 Non-Fatal Adverse Events (1 year post-exclusivity period; n=3) 1.Euphoria, hallucinations, and weight loss after initiation therapy with the fentanyl transdermal system 2.Withdrawal symptoms from a “loose” patch 3.Respiratory depression after intentional misuse of fentanyl patch

13. 13 1990AdultApproval 2003PediatricExclusivity 4 pediatric deaths 5 pediatric deaths 1 year Post- exclusivity date 3 pediatric deaths 5/15/04 Pediatric Reported Deaths Since Approval Mandatory Reporting Period

14. 14 AERS Pediatric Deaths Outside of the Exclusivity Reporting Period –Accidental exposure –Misuse or Abuse –Off-label use: Post-tonsillectomy and adenoidectomy pain Infectious mononucleosis and sore throat pain Chronic headaches and infectious mononucleosis Acute migraine –Rhabdomyosarcoma

15. 15 Cumulative Pediatric AERS Database Reports for Fentanyl Transdermal System (n=35) Time PeriodTotal Number of Reports Received By FDA Reports By Indication Chronic Pain (deaths) NON-Chronic Pain* (deaths) 8/90 (approval date) - 1/28/03 2419 (1)5 (3) 1/29/03 – 2/29/04 (1 yr post-exclusivity period) 83 (1)5 (4) 3/1/04 – 4/30/0430 (0)3 (3) Totals3522 (2)13 (10) * No indication for chronic pain management identified in report

16. 16 Comments Many of the pediatric adverse events captured occurred in patients who were administered the product for an unlabeled indication (e.g. treatment of acute pain in a non- opioid tolerant patient) Need for additional education regarding proper use of the fentanyl transdermal system to further minimize abuse, misuse, and off-label use