# Presentation: 067412

## Update to Post-Exclusivity Pediatric Adverse Event Review:Oxybutynin Pediatric Advisory Committee Meeting November 16, 2006

**Lisa Mathis, MD, Associate Director**
**Pediatric and Maternal Health Staff****Office of New Drugs**
**Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information 

**Drug: ** Ditropan® (oxybutynin)
**Therapeutic Category:  **Antispasmodic
**Sponsor: **Johnson and Johnson
**Original Market Approval: **July 16, 1975
**Pediatric Exclusivity Granted: **February 8, 2002
**Mechanism of action: **Anticholiniergic

## Background Drug Information

**Indication:**
- Adults: symptoms of bladder irritability associated with voiding in patients with uninhibited neurogenic bladder (urgency, frequency, urinary leakage, urge incontinence, dysuria)
- Children: _>_5 years and XL in _>_6 years for detrusor muscle over-activity in association with a neurological condition (e.g.. Spina bifida).
**Pediatric Dosage:**
- 5 mg twice daily with maximum 5 mg three times daily

## Oxybutynin: Pediatric Labeling Changes

- Ditropan
- Additional information on dose and PK parameters
- Precautions section of label updated
- Ditropan XL
- Safety and effectiveness established down to 6 years of age

## Oxybutynin : Pediatric Adverse Events

- 5 unduplicated reports during the one year post exclusivity period (2/8/02-3/19/03)
- Too few reports to make an assessment
- 10 additional unduplicated reports during the subsequent three year period (3/19/03-8/30/06)
- Total since exclusivity granted: 13 serious, no deaths

## Oxybutynin: Pediatric Adverse Events

- 13 reports considered serious
- Most common were in patients treated for nocturnal enuresis (unapproved indication)
- 7 confounded by other drugs/underlying conditions or did not contain enough information to make a causality assessment
- 6 remaining serious cases
- extrapyramidal reaction (unlabeled) in a 10 year old boy
- 5 remaining serious cases were labeled events that may be due to anticholinergic  effects of oxybutynin, particularly anticholinergic CNS excitation (hallucinations, irritability, insomnia).

## Oxybutynin: Pediatric CNS Excitation

- (32/114) in pediatric patients vs. (99/1286) in adult reports using preferred terms
- Preferred Terms indicative of CNS excitation:
-    Abnormal dreams; hallucination; panic reaction; aggression; hallucination, visual; psychomotor hyperactivity; agitation; initial insomnia; restlessness; anger; insomnia, sleep disorder; anxiety; irritability; sleep terror; attention deficit/hyperactivity disorder; middle insomnia; sleep walking; emotional disorder; nervousness; tremor; excitability; panic attack

## Oxybutynin: Pediatric CNS Excitation

- May or may not indicate increased sensitivity to anticholinergic effect of this drug in pediatric patients
- Anticholinergics may cross the blood-brain barrier in pediatric patients more easily
- Cholinesterase levels virtually the same for pediatric patients and adult patients
- Patients had other underlying neurologic conditions and on other psychoactive drugs

## Summary: Oxybutynin

- No safety signal identified: few reports, single cases, confounded or insufficient information
- The FDA recommends routine monitoring of oxybutynin for AEs in all populations
- Does the Advisory Committee concur?

## Acknowledgements

- _OSE_
- Paula Gish
- Rosemary Johann-Liang
- _PMHS_
- Kristin Phucas

- _DRUP_
- Mark Hirsch