# Presentation: 382746

## 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**

## 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****	****    **

## 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

## Paroxetine  Pediatric Psychiatric Adverse Events 

## 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: 20-60 mg/day**
**There are NO approved pediatric indications**
**Original market approval: December 1992**
**Pediatric exclusivity granted: June 27,  2002**

**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**

## Drug use trends: paroxetine

**Second most commonly used  SSRI in children.****1**** **
**Both pediatric & adult prescriptions have increased steadily between 1999 and 2003. ****1***** ***
**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 2003
- 	2IMS Health, National Disease and Therapeutic Index, CD-Rom, Source 3 Year Jul 2000 – Jun 2003***  ***
***	*****3**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

## Adverse Events 1992-2003:  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**

## Raw Counts* of Pediatric Adverse Event Reports by Year (Dec 1992 to Jul 2003)

- * **includes duplicate reports**

## BBC show “The Secret of Seroxat,”    

**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

## 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),**
**	**** ****12-16 yrs (n= 55) & unknown (n=1) **
_**Outcomes**_**: **
**10 % of reports were deaths (n = 13)**
**Approximately 1/3 hospitalizations/ER visit      (n= 43)**

## 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) |
| --- |
| 7 |
| 19 |
| 7 |
| 32 |
| 0 |
| 0 |
| 0 |
| 1 |

| Direct Pediatric Exposure
(n=94) |
| --- |
| 54 |
| 40 |
| 0 |
| 0 |
| 6 |
| 33 |
| 55 |
| 0 |

## 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**

## Paroxetine:  Pediatric Adverse Events

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

## 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)**

## 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**

## Psychiatric Adverse Events (n=68)

- Demographics:
- Gender: 57% Female
- Age: 2-5 yrs. (5%), 6-11 yrs. (35%), 12-16 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

## 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)**

## Suicide Attempts(n=17)

**Diagnosis:  Majority MDD, Bipolar Disorder**
**Concomitant medications in approximately one third**
**discontinuation or decrease in dose in approximately one fourth**

## 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

## Pediatric Deaths: Completed Suicides (n=9)

**Ages 12-16 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)**

## 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

## 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

## 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

## 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.

## Citalopram:  Pediatric Psychiatric Adverse Events

**Solomon Iyasu, MD, MPH**
**Hari Cheryl Sachs, MD, FAAP**
**Division of Pediatric Drug Development**

## Citalopram:  Background Drug Information 

**Moiety: Celexa****®**** (****citalopram)**
**Therapeutic Category: Antidepressant**
**Sponsor: Forest Pharmaceuticals**
**Adult Indication: Major Depressive Disorder **
**Adult dose range: 20-40 mg/day**
**There are NO approved pediatric indications**
**Original market approval:  July 17, 1998**
**Pediatric exclusivity granted:  July 9, 2002**

## 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**

## 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**

## Drug use trends: Citalopram

**4th most commonly used SSRI in children****1**
**Both pediatric and adult prescriptions have increased between 1999 and 2003****1**** **
**Pediatric patients account for approximately 3.3% (665, 000) of the total U.S. prescriptions of  Celexa****®**** during Jul 2002- Jul 2003****1,2**
**Pediatric Diagnosis (off label): depressive disorders, obsessive-compulsive disorder and attention deficit disorder****3**
- 1IMS Health, National Prescription Audit *Plus*, On-Line Source Year Aug 1999 – Jul 2003, Data Extracted Aug 2003
- 2AdvancePCS Dimension Rx, On-Line, Jul 2001 – Jun 2003
- 3IMS 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

## 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**

## 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**

## Pediatric Adverse Events byGender, Age and Exposure

| GENDER | In Utero Exposure (n=16)
 | Direct Exposure (n=26) |
| --- | --- | --- |
|   Female | 11 | 17 |
|   Male | 2 | 9 |
|   Unknown | 3 | 0 |
| AGE |  |  |
|   0-2 yrs | 15 | 1 |
|   2-5 yrs | 1 | 1 |
|   6-11 yrs | 0 | 9 |
|   12-16 yrs | 0 | 15 |

## 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**

## Citalopram adverse events- Psychiatric (n= 5)

_**Labeled**_
**Cognitive impairment**
**Aggression**
**Agitation, mania, and delusions**
**Suicidality**
**Psychotic reaction**

_**Unlabeled **_
**Violent/homicidal behavior **

## Citalopram Adverse Events- Psychiatric (cont.)

**Gender: 4 males, 1 female**
**Age: 6-11 yrs (2), 11-16 yrs (3)**
**Diagnosis: MDD (4), ODD(1)**
**Concomitant medications – 2**
** ****Prozac®; Keppra®, clonazepam**
**Symptoms resolved when citalopram discontinued - 4**

## 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**

## Acknowledgements

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