# Presentation: 017081

## Update to the Committee:Oxybutynin Central Anticholinergic Effects

**Pediatric Advisory Committee Meeting ****April 11, 2007**
**Andrew D. Mosholder, M.D., M.P.H.**
**Medical Officer**
**Division of Drug Risk Evaluation (DDRE)**

## Background: Oxybutynin

- Anticholinergic tertiary amine
- Approved in U.S. in 1975
- Formulations:
- Tablets (Ditropan, generics)
- Syrup (Ditropan, generics)
- Extended release tablets (Ditropan XL, generics)
- Transdermal patch (Oxytrol)
- Indications:
- bladder instability with neurogenic bladder (Ditropan), overactive bladder (Ditropan XL, Oxytrol)
- Ditropan XL pediatric: patients _>_ 6 y.o. with detrusor overactivity associated with a neurological condition
- Pediatric Exclusivity granted February 8, 2002

## Background: Oxybutynin (cont.)

- June 2003 Pediatric Advisory Committee (PAC)
- Review of pediatric adverse events reports received in the first 13 months following pediatric exclusivity
- Few reports for analysis
- PAC requested additional monitoring
- Follow-up review completed September 2006
- For Nov 2006 PAC
- Noted CNS events reported in 28% (32/114) of pediatric reports vs. 7.6% (99/1286) of adult reports
- Office of Pediatric Therapeutics (OPT) requested in depth analysis of AERS data for CNS events, with comparison of pediatric to adult reports

## Current Oxybutynin Labeling

- _Pediatric labeling:_
- No pediatric labeling for Oxytrol (transdermal)
- Ditropan labeled for pts age >=5 yrs, but dosage specified only > 5 yrs
- Ditropan XL labeled for patients 6+ yrs
- _Precautions:_ may produce drowsiness
- _Adverse Reactions:_ somnolence, insomnia, nervousness, confusion, hallucinations
- _Overdosage:_ CNS excitation

## Use dataSource: Verispan, LLC

- Total 2006 Rx usage: 4,881,000 Rxs1
- (> 1 mil. Pts2)
- Approximately 63% of prescriptions in 2006 were for patients aged 60+ yrs
- Consistently between 2002 and 2006, approximately 4-5% of U.S. prescriptions were for pediatric patients <17 years old
- In 2006, 12% of pediatric prescriptions were off label (i.e., Ditropan XL for < 6 yrs, Ditropan for < 5 yrs, Oxytrol patch for < 17 yrs)

- 1Rx counts- Verispan Vector One National (VONA)2Patient counts- Verispan Total Patient Tracker (TPT)

## AERS search: Methods

- 	AERS searched January 12, 2007 for reports of anticholinergic CNS adverse events in association with oxybutynin since approval, using 52 Preferred Terms (PTs) including *hallucination, sedation, confusional state, agitation, anxiety, amnesia*

## AERS Search: Results

- 347 reports (55 peds, 256 adult, 36 missing age)
- 145/347 reports excluded
- 35 duplicates
- 110 other exclusions
- 202 cases remained
- 180 with age information
- 37 pediatric cases
- 143 adult cases
- 12% of all AERS adverse event reports for oxybutynin involved a CNS adverse event
- 32% of pediatric reports
- 11% of adult reports

## Results: characteristics of oxybutynin AERS pediatric CNS cases (N=37)

- 33/37 reported by HCPs
- Age range: 15 mos -16 yrs,
- Mean: 6.7 yrs
- Median: 6 yrs
- Most common PTs reported:
- hallucinations (n=10)
- agitation (n=5)
- sedation (n=4)
- confusion (n=4)
- amnesia (n=4)
- abnormal dreams (n=4)

## Results: characteristics of oxybutynin AERS pediatric CNS cases (N=37)

- 23/37 positive dechallenge
- 4/37 positive rechallenge
- 6 hospitalizations
- 14/37 with past psychiatric/neurologic history
- 17/37 off-label use (age < 5 yrs, nocturnal enuresis, dose>20mg)

## Examples of case reports

- 4M received single 5 mg dose for enuresis:
- Hallucinations involved snakes, insects, other animals in his room, crawling on him
- 6F with incontinence from injury in auto accident, 2 weeks post dose increase to 10 mg/d:
- Agitation, visual hallucinations of insects, thought hands and feet were bleeding, personality change, fearfulness
- positive dechallenge
- 8F with overactive bladder and urinary frequency, treated with 5mg for <1 month:
- Confusion, hallucinations, mood changes, obsessive thoughts, delusions, disorientation
- positive dechallenge within 3 days
- 4F received oxybutynin 10mg/day for enuresis:
- Visual hallucinations
- Recurred after next dose
- Resolved when oxybutynin discontinued

## Source: Verispan VONA

## Results: Comparison of Pediatric and Adult CNS cases – events reported

- Hallucination
- most common CNS event reported for pediatric patients (27% of cases)
- 2nd most common CNS adverse event in patients aged 60+ yrs (25% of cases)
- reported in 11% of cases in patients 17-59 yrs of age
- Agitation
- Pediatric cases reported agitation about twice as often as adult cases (14% pediatric cases vs. 6% adult cases)
- Sedation
- Adult cases reported sedation > twice as often as pediatric cases (24% adult cases vs. 11% pediatric cases)
- Confusion
- Most commonly reported CNS event for patients aged 60+yrs (30% of cases, vs. 10% of cases in patients less than 60 yrs)

## Conclusions/recommendations

- A significant proportion of all adverse event reports for oxybutynin involve a CNS adverse event. The types of CNS events reported vary by age.
- Current labeling does not explicitly describe the potential for CNS anticholinergic effects, or the age-dependent pattern of CNS effects that have been reported.
- DDRE recommends that the labeling for anticholinergic CNS effects be strengthened.

## Questions

- Does the Committee recommend that oxybutynin labeling include more information for prescribers regarding adverse CNS anticholinergic effects?
- Other comments, suggestions?
- Such as more specific language for pediatric CNS effects?

## Acknowledgements

- Paula Gish, R. Ph, Safety Evaluator, DDRE
- Rosemary Johann-Liang, M.D., Deputy Director, DDRE
- Melissa Truffa, R.Ph, Safety Evaluator Team leader, DDRE
- Mary Willy, Ph.D., M.P.H., Epidemiologist Team Leader, DDRE
- LCDR David Moeny, R.Ph, Drug Use Data Specialist, DSRCS
- Lisa Mathis, MD, Associate Director, Pediatric and Maternal Health Staff
- Gwen L. Zornberg, M.D., Sc.D., Medical Officer, ODE I/DPP
- M. Dianne Murphy, M.D., Director, OPT