1 One Year Post Exclusivity Adverse Event Review as Mandated by the Best Pharmaceuticals for Children Act Presented at the Psychopharmacologic Drugs Advisory Committee & Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee Meeting February 2, 2004 Solomon Iyasu, MD, MPH Hari Cheryl Sachs, MD, FAAP Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2 Best Pharmaceuticals for Children Act (BPCA) Jan 4, 2003 Section 17: Adverse Event (AE) Reporting –review all AEs for one year after granting pediatric exclusivity –report to the Pediatric Advisory Sub-Committee for review

3 Data Source for Drug Adverse Events FDA’s Adverse Event Reporting System (AERS) –spontaneous and voluntary reporting system –electronic database of postmarketing reports of adverse drug reactions –reporters include health care providers, pharmacies, consumers, and pharmaceutical manufacturers

4 Paroxetine Pediatric Psychiatric Adverse Events

5 Background Drug Information Moiety: Paxil ®, Paxil CR ® (paroxetine) Therapeutic Category: Antidepressant Sponsor: GlaxoSmithKline Adult Indications: Major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder –adult dose range: mg/day There are NO approved pediatric indications Original market approval: December 1992 Pediatric exclusivity granted: June 27, 2002

6 Pregnancy Category C Precautions: –Suicide risk inherent in MDD –Suicide risk present in co-morbid conditions –Activation of mania –Seizures –Adverse events with abrupt discontinuation agitation, anxiety, dizziness, sensory disturbance, nausea and sweating Relevant Safety Labeling

7 Drug use trends: paroxetine Second most commonly used SSRI in children. 1 Both pediatric & adult prescriptions have increased steadily between 1999 and Pediatric Diagnosis (off label): depression, anxiety and obsessive-compulsive disorders 2 Pediatric patients account for approximately 3.5 % of total U.S. prescriptions of Paxil ® between Jul 2002 – Jun 2003 (1.1 million). 1,3* 1 IMS Health, National Prescription Audit Plus , On-Line Source Year Aug 1999 – Jul 2003, Data Extracted Aug IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year Jul 2000 – Jun AdvancePCS  Dimension Rx, On-Line *Calculation based on application of proportions of pediatric paroxetine prescriptions in AdvancePCS  to IMS Health, National Prescription Audit Plus  to estimate number of paroxetine prescriptions dispensed nationwide to pediatric population

8 Adverse Events : General Overview (raw counts) Total: over 17,000 adult and pediatric reports (68 % domestic) < 5 % of total are pediatric Top 20 pediatric AEs –similar to those reported in adults –majority labeled –unlabeled events related to maternal exposure Number of pediatric adverse event reports increased in 2002 compared with prior years

9 Raw Counts* of Pediatric Adverse Event Reports by Year (Dec 1992 to Jul 2003) * * includes duplicate reports

10 BBC show “The Secret of Seroxat,” aired October 13, 2002 British government warning issued on June 10, 2003 FDA Talk Paper issued on June 19, 2003 FDA PUBLIC ADVISORY for antidepressants and suicide issued on Oct 27, 2003 Exclusivity Period

11 Pediatric Adverse Events in the One-year Post -exclusivity Period Total unduplicated reports (N= 127) Gender: Female - 61, Male - 59, Unknown - 7 Age: 0-<2 yrs (n=32), 2-5 yrs (n=6), 6-11 yrs (n=33), yrs (n= 55) & unknown (n=1) Outcomes: –10 % of reports were deaths (n = 13) –Approximately 1/3 hospitalizations/ER visit (n= 43)

12 Pediatric Adverse Events by Gender, Age & Exposure to Paroxetine (N=127) Gender: Female Male Unknown Age: 0-2 yrs 2-5yrs 6-11yrs 12-16yrs Unknown Maternal/Breastfeeding (n=33) Direct Pediatric Exposure (n=94)

13 Pediatric Adverse Events: Reasons for Exposure to Paroxetine (N=127) Prenatal Exposure/Breastfeeding (n= 33) Direct Pediatric Exposure (n=94) –Depression/dysthymia - 28 –Anxiety/Panic/PTSD- 15 –ADHD- 2 –OCD- 1 –Multiple Psychiatric diagnosis- 18 –Other- 9 –Unknown - 21

14 Paroxetine: Pediatric Adverse Events Concomitant medications (n =55), exclusively paroxetine (n=5), most unknown (n= 67)Concomitant medications (n =55), exclusively paroxetine (n=5), most unknown (n= 67) Reporters: only 1/3 health professional; 2/3 consumer, media, litigation, etc.Reporters: only 1/3 health professional; 2/3 consumer, media, litigation, etc. Dose range 5-60 mg/day (n=65, excludes maternal/breastfeeding exposure)Dose range 5-60 mg/day (n=65, excludes maternal/breastfeeding exposure)

15 Pediatric Adverse Events: Predominant Events Psychiatric adverse events (68) Discontinuation Syndrome/decrease in dose (7) Maternal exposure (33) Neurologic events (8) Accidental ingestion (2) Other (9)

16 Psychiatric Adverse Events by Labeling Status (n=68 ) Labeled Completed suicide - 9 Suicidal attempts -17 Suicidal ideation - 11 Occurrence of other psychiatric symptoms - 9 Unlabeled Self-injurious behavior - 10 Completed homicide - 4 Aggression/Hostility/ Homicidal ideation - 8

17 Psychiatric Adverse Events (n=68) Demographics: –Gender: 57% Female –Age: 2-5 yrs. (5%), 6-11 yrs. (35%), yrs. (60%) Concomitant medications described in only 24 patients – 20 of the 24 on other psychotherapeutic agent discontinuation or decrease in dose noted in 11 of the 68 patients with psychiatric events

18 Psychiatric Events with Discontinuation or Decrease in Dose Completed suicide (1 out of 9 ) Suicidal attempts (5 out of 17) Homicide (2 out of 4) Aggression/Hostility/Homicidal ideation (3 out of 8)

19 Suicide Attempts (n=17) Diagnosis: Majority MDD, Bipolar Disorder Concomitant medications in approximately one third discontinuation or decrease in dose in approximately one fourth

20 Pediatric Deaths (n=13) 10 deaths involving direct pediatric exposures –9 completed suicides –1 case of Stevens Johnson Syndrome; patient also received valproic acid 3 deaths among patients with prenatal exposure

21 Pediatric Deaths: Completed Suicides (n=9) –Ages years –Gender Female (5) Male (4) –Initial Diagnosis: MDD (5) Explosive Disorder (1) Unknown (3) –Duration of treatment- 14 days to 1 year –Discontinuation or decrease in dose (2) –Concomitant medication (4) –Possible substance abuse (4) –History of prior attempts (3)

22 Factors Contributing to Difficulty in Assessing Causality Patient Factors –severity of illness/ underlying disease –prior history of suicide attempts –concomitant medication –substance abuse Reporting factors –inadequate detail in describing event –timing of event in relationship to medication –ascertainment of reported events –lack of follow-up

23 Limitations of AERS Spontaneous and voluntary system –Underreporting –Reporting bias (media publicity, length of time in market) –Report quality may vary (missing details e.g. concomitant medications) –Cannot estimate true incidence rate of events or exposure risk

24 Closing Observations The psychiatric events described in the adverse event reports may reflect: –underlying disease –drug adverse effect –lack of drug effect Evaluation of controlled trials necessary to sort out

25 Acknowledgements ODS reviews prepared by: Mark Avigan, MD, C. M. Susan Lu, R. Ph Carol Pamer, R. Ph Toni Piazza-Hepp, Pharm.D. Gianna Rigoni, Pharm.D.

26 Citalopram: Pediatric Psychiatric Adverse Events Solomon Iyasu, MD, MPH Hari Cheryl Sachs, MD, FAAP Division of Pediatric Drug Development

27 Citalopram: Background Drug Information Moiety: Celexa ® (citalopram) Therapeutic Category: Antidepressant Sponsor: Forest Pharmaceuticals Adult Indication: Major Depressive Disorder –Adult dose range: mg/day There are NO approved pediatric indications Original market approval: July 17, 1998 Pediatric exclusivity granted: July 9, 2002

28 Relevant Safety Labeling Pregnancy Category C Excreted in human breast milk Precautions: –Suicide risk inherent in depression –Activation of mania/hypomania –Any psychoactive agent may impair intellectual or psychomotor functions –Seizures: introduce citalopram with care

29 Relevant Safety Labeling (cont.) Adverse Reactions –Agitation –Pre marketing reports Frequent: impaired concentration, depression, suicide attempt, confusion Infrequent: aggressive reaction, psychotic reaction, delusion, paranoid reaction, emotional lability, panic reaction

30 Drug use trends: Citalopram 4th most commonly used SSRI in children 1 Both pediatric and adult prescriptions have increased between 1999 and Pediatric patients account for approximately 3.3% (665, 000) of the total U.S. prescriptions of Celexa ® during Jul Jul ,2 Pediatric Diagnosis (off label): depressive disorders, obsessive-compulsive disorder and attention deficit disorder 3 1 IMS Health, National Prescription Audit Plus , On-Line Source Year Aug 1999 – Jul 2003, Data Extracted Aug AdvancePCS  Dimension Rx, On-Line, Jul 2001 – Jun IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year Jul 2000 – Jun 2003 *Calculation based on application of proportions of pediatric citalopram prescriptions in AdvancePCS  to IMS Health, National Prescription Audit Plus  to estimate number of citalopram prescriptions dispensed nationwide to pediatric population

31 Overview of Adverse Event Reports Since Marketing Approval Total: over 6,000 reports (79% domestic) <5 % of total are pediatric Top 20 AE –All adverse events related to in utero exposure were unlabeled –Adverse event reports for children involving direct exposure were generally similar to those reported for adults

32 Pediatric Adverse Events in the One-Year Post-exclusivity Period Total unduplicated reports (n=42) 16 in utero exposures; resulted in unlabeled events and one death 26 children involving direct exposure, 8 unlabeled events, no deaths –16 serious AEs (10 hospitalization, 4 life- threatening, 2 with disability) –dose 5-60 mg/day, median dose 20 mg/day

33 Pediatric Adverse Events by Gender, Age and Exposure GENDER In Utero Exposure (n=16) Direct Exposure (n=26) Female1117 Male29 Unknown30 AGE 0-2 yrs yrs yrs yrs015

34 Pediatric Adverse Events: Reasons for Exposure to Citalopram In utero exposures – 16 Direct Pediatric Exposure – 26 –Depression – 13 –Ingestion of another person’s prescription – 2 –Other – 5 –Unknown - 6

35 Citalopram adverse events- Psychiatric (n= 5) Labeled Cognitive impairment Aggression Agitation, mania, and delusions Suicidality Psychotic reaction Unlabeled Violent/homicidal behavior

36 Citalopram Adverse Events- Psychiatric (cont.) Gender: 4 males, 1 female Age: 6-11 yrs (2), yrs (3) Diagnosis: MDD (4), ODD(1) Concomitant medications – 2 – Prozac®; Keppra®, clonazepam Symptoms resolved when citalopram discontinued - 4

37 Closing observations Few psychiatric events were reported Unable to determine causality due to limitations of AERS FDA will continue monitoring these adverse events in children

38 Acknowledgements ODS reviews prepared by: Mark Avigan, MD Toni Piazza-Hepp, Pharm.D. Kathleen Phelan, R. Ph Gianna Rigoni, Pharm.D.