# Presentation: 796846

## One Year Post-Exclusivity Adverse Event Review:TolterodinePediatric Advisory Committee Meeting June 29, 2005

**Lawrence Grylack, MD****Medical Officer**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information

**Drugs:** Detrol® and Detrol® LA
- Tolterodine tartrate is the active ingredient in both drugs.
**Therapeutic category:** Muscarinic receptor antagonist
**Sponsor:** Pfizer
**Indication:** Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency
**Original Market Approval**: March 25, 1998 for Detrol® and December 22, 2000 for Detrol LA®
**Pediatric Exclusivity granted: **January 5, 2004

## Drug Use Trends in Children

- Almost all pediatric (1-16 years) use for both drugs was in out-patient setting; estimated pediatric prescriptions during 2004: Detrol®**14,448**,** **Detrol LA® **53,976 **1
**1.4%** of all Detrol® and **0.8%** of all Detrol LA® claims during 2/04-1/05 were for children.1
- Detrol® usage **decreased by 33%** and Detrol LA® usage **increased by 50%** in children from 2/02-1/03 period to 2/04-1/05 period. Detrol LA® prescription claims were 4 times greater than Detrol® during post-exclusivity period.1
- Pediatric hospital discharges accounted for **≤ ****0.2%** of all discharges in which a tolterodine product was mentioned from 7/03-6/04 .2

- 1Caremark Dimension RXTM, Feb 2002 - Jan 2005, Data extracted Mar 2005
- 2 Premier Inc., Jul 2003 - Jun 2004, Data extracted Apr 2005

## Pediatric Exclusivity Studies

- Three pharmacokinetic (PK), pharmacodynamic (PD) [urodynamic] and safety studies
- One clinical efficacy, PK and safety study in patients with overactive bladder

## PK, PD and Safety Studies in Neurologically Impaired Patients 

**Three 12-week, open-label, dose escalation studies**:
- 1 month-4 year olds (n=19) received 0.03, 0.06, 0.12 mg/kg/d   Detrol®  immediate-release syrup
- 5-10 year olds (n=15) received  0.03, 0.06, 0.12 mg/kg/d  Detrol® immediate-release syrup
- 11-15 year olds (n=11) received 2, 4, 6 mg/day Detrol LA® capsules
- Of patients in all studies, 78% had myelomeningocoele; others had spinal cord injury or anomaly
-  Urodynamic data inconsistent within and across trials
-  Lack of dose-response trends across studies

## Phase 3 Efficacy, PK and Safety Studies in Neurologically Intact Patients 

**Two multi-center randomized, placebo-controlled, blinded studies of tolterodine extended –release capsules,  2 mg/day for 12 weeks for the indication: treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency **
**       ****-    5-10 year olds, 235 treated with drug, 107 with placebo**
**5-10 year olds, 251 treated with drug, 117 with placebo **
**Detrol LA****®   ****dose was chosen after comparison of the PK of tolterodine and DD01 (the active metabolite) in children, 5 to 10 years, with adults**
**Primary efficacy endpoints for both studies were change from baseline in number of weekly incontinence episodes during waking hours after 12 weeks of treatment**
**No significant difference in outcome between Detrol LA****®**** and placebo **
**Label states that efficacy in children not demonstrated**

## Integrated Review of Safety  from Pediatric  Studies 

**Database from pediatric exclusivity studies and other pediatric studies conducted by Sponsor**
**     ****-  ****917 unique patients exposed to tolterodine**
**No deaths**
**24 Serious Adverse Events (SAEs) in 20 patients including 4 lower UTIs; 4 with pyelonephritis (one in  placebo group)**
**18 patients manifested aggressive and/or abnormal behavior, categorized as non-serious AEs**
**Excess of UTIs and abnormal behavior in tolterodine- treated patients compared to placebo are included in Detrol LA****®**** label**

## Summary of Labeling Changes Resulting from Exclusivity Studies

**Detrol ****LA****®****:**
**Efficacy not demonstrated **
**PK: Dose-plasma concentration relationship linear; parent/metabolite ratios differed according to enzyme metabolizer status**
**Percentage of UTIs in 5-10 year olds higher with Detrol LA****®**** (6.6%) compared to placebo (4.5%)**
**Aggressive, abnormal and hyperactive behavior and attention disorders higher with Detrol LA****®**** (2.9%) compared with placebo (0.9%) **

## Pediatric Adverse Events for Detrol® and Detrol LA®: One-Year Post-Exclusivity Period 

**No AE reports received**

## Pediatric Adverse Event Reports after Marketing Approval for Detrol® (03/25/1998) and Detrol LA® (12/22/2000) through 02/05/2005

-  **31 reports* (25 U.S.); **
**   ****29 unduplicated reports**
** ****25 Detrol****®****, 4 Detrol LA****®**
** ****Positive de-challenge in 15 patients; positive **
**    ****re-challenge in one patient**
*** Raw counts include duplicates**

## Categories of Pediatric Adverse Event Reports for Detrol® and Detrol LA®(N=29) 

**Anti-cholinergic events (9 reports): **_**confusion**_**, lethargy, urine retention, **_**overheating**_**, constipation, **_**flushing**_**, dry mouth, blurry vision**
**CNS stimulation (8 reports): aggression*, hyperactivity*, **_**irritability**_**, **_**insomnia**_
**Anti-cholinergic plus CNS stimulation (2 reports)**
**UTI (2 reports)**
**Medication error (3 reports)**
**Other (5 reports)**

*** Unlabeled in Detrol****® **** label**
_**Underlined**_** = Unlabeled events in Detrol ****®**** and Detrol LA****®**** labels**

## Pediatric Adverse Event Reports forDetrol® and Detrol LA®:Marketing Approval through 02/05/2005

**In 18 reports, the outcome was reported as**
**     ****serious.**
**Upon careful review of the 18 reports****, ****there were:**
** ****0 deaths**
** ****5 hospitalizations **
** ****1 disability **
** ****2 older than 16 years  (85 and 16.5 years old)**
** ****10 non-serious**

## Pediatric Adverse Event Reports forDetrol® and Detrol LA® with Serious Outcomes since Market Approval

**6 reports with serious outcomes:**
**Hospitalizations **
**One patient with breathing difficulty, nocturnal laryngitis and cough; resolved after tolterodine was discontinued; possibly related to drug; **
**One patient with transient blindness; event continued after drug was discontinued**
**One patient developed heart block, dizziness and chest pain; also on azathioprine; heart block resolved upon stopping tolterodine**
**One patient with exfoliative skin rash; positive culture for HSV**
**One patient developed convulsions**
**Disability**
**Hyperactivity**

## Request for Labeling Revision Issued for Detrol®

**Sponsor has been requested by FDA to incorporate safety information that already exists in Detrol LA****®**** label into Detrol****®**** label in Pediatric Use section**
** ****Increased incidence of UTIs and abnormal **
**    ****behavior in tolterodine-treated patients **
**    ****compared with placebo**
**Pediatric efficacy not demonstrated**

## Conclusion

**This completes the one-year post-exclusivity AE monitoring as mandated by BPCA.**
**FDA recommends routine monitoring of AEs for this drug in all populations.**
**Does the Advisory Committee  concur?**** **

## Acknowledgments

_**ODS**_                                  _**DRUP**_
- Paula Gish                         Lisa Soule
- Mark Avigan                     George Benson
- Kendra Worthy                 Daniel Shames
- Gerald Dal Pan		      Jean Makie