Pediatric Advisory Committee April 11, 2007 1 Update to the Committee: Oxybutynin Central Anticholinergic Effects Pediatric Advisory Committee Meeting.

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Presentation transcript:

Pediatric Advisory Committee April 11, 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)

Pediatric Advisory Committee April 11, 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

Pediatric Advisory Committee April 11, 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

Pediatric Advisory Committee April 11, 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

Pediatric Advisory Committee April 11, Use data Source: Verispan, LLC Total 2006 Rx usage: 4,881,000 Rxs 1 (> 1 mil. Pts 2 ) 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) 2 Patient counts- Verispan Total Patient Tracker (TPT)

Pediatric Advisory Committee April 11, 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

Pediatric Advisory Committee April 11, 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

Pediatric Advisory Committee April 11, 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)

Pediatric Advisory Committee April 11, 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 20mg)

Pediatric Advisory Committee April 11, 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

Pediatric Advisory Committee April 11, Source: Verispan VONA

Pediatric Advisory Committee April 11, 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 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)

Pediatric Advisory Committee April 11, 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.

Pediatric Advisory Committee April 11, 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?

Pediatric Advisory Committee April 11, 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