1. 1 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

2. 2 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

3. 3 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

4. 4 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

5. 5 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

6. 6 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).

7. 7 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

8. 8 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

9. 9 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?

10. 10 Acknowledgements OSE Paula Gish Rosemary Johann-Liang PMHS Kristin Phucas DRUP Mark Hirsch