Long-Term Tolerability of Tolterodine Extended Release in Children 5–11 Years of Age: Results from a 12-Month, Open-Label Study

doi:10.1016/j.eururo.2007.05.002

European Urology

Volume 52, Issue 5, November 2007, Pages 1511-1517

https://doi.org/10.1016/j.eururo.2007.05.002 Get rights and content

Abstract

Objective

To evaluate the long-term tolerability of tolterodine extended release (ER) in children (aged 5–11 yr) with urgency urinary incontinence (UUI).

Methods

This was a multicenter, open-label extension of a 12-wk, double-blind, placebo-controlled study of tolterodine ER. Patients had UUI suggestive of detrusor overactivity (≥1 diurnal incontinence episode per 24 h for ≥5 of 7 d) and ≥6 voids per 24 h at baseline and had completed the 12-wk double-blind study. Patients received tolterodine ER (2 mg once daily) for 12 mo. The primary end points were the incidence and severity of adverse events (AEs) and the incidence and reasons for withdrawals. Visits were scheduled at 3, 6, 9, and 12 mo, and investigators were instructed to report all AEs. At 6 and 12 mo, vital signs were recorded and a physical examination was performed.

Results

A total of 318 patients were enrolled (double-blind tolterodine ER, n = 221; placebo, n = 97). The majority of patients were white (90%), mean ± SD age was 7.6 ± 1.5 yr, and 54% were boys. Forty-nine percent of patients reported ≥1 AE during the study, similar to that observed in the preceding 12-wk study (42%). The most frequent AEs were urinary tract infection (7%), nasopharyngitis (5%), headache (5%), and abdominal pain (4%); 111 (35%) patients withdrew. The most common reasons for withdrawal were lack of efficacy (12%), symptom improvement (8%), and withdrawn consent (6%). Ten patients (3%) withdrew because of AEs.

Conclusion

Long-term treatment with tolterodine ER was well tolerated in children with UUI.

Introduction

Urinary urgency is often caused by detrusor overactivity, a condition characterized by involuntary detrusor contractions during the bladder-filling phase [1]. Urgency appears to be responsible, in part, for the high prevalence of urinary incontinence among children. One study estimated that urgency, with or without urgency urinary incontinence (UUI), affects an estimated 18% of primary school-aged children [2]. Children with urinary symptoms often have low self-esteem [3], [4], and childhood incontinence is associated with adult UUI [5]. Initial treatment for children with UUI typically includes a timed schedule of drinking and voiding, pelvic floor muscle relaxation techniques, biofeedback, and pharmacotherapy as stand-alone therapies or in combination [6]. However, a recent systematic review of randomized controlled trials of treatments for daytime urinary incontinence in children was “unable to identify proof of any intervention that is safe and effective” [6]. More recent studies have demonstrated that the antimuscarinic agents oxybutynin [7], trospium [8], and tolterodine [7], [9], [10], [11] benefit some children with incontinence. In a 12-wk study, Nijman et al [12] examined the efficacy of tolterodine extended release (ER) in children 5–10 yr of age with UUI. Here, we present the results of a 12-mo, open-label extension to evaluate the long-term tolerability profile of tolterodine ER in these patients. To our knowledge, this is the first study to evaluate the long-term tolerability and safety of an antimuscarinic for UUI in a pediatric population.

Section snippets

Study design and patient population

This was an open-label extension of a 12-wk, double-blind, placebo-controlled study of tolterodine ER in children with UUI suggestive of detrusor overactivity [12]. The double-blind and open-label phases of the study were conducted at 47 centers in 11 countries. For the 12-wk double-blind study, eligible children were 5–10 yr of age with ≥1 diurnal incontinence episode per 24 h for ≥5 of 7 d and ≥6 voids per 24 h at baseline. Key exclusion criteria were treatment for detrusor overactivity within

Results

Of the 343 patients (234 tolterodine ER, 109 placebo) who completed the previous double-blind, placebo-controlled trial, 318 (93%; 221 tolterodine ER, 97 placebo) enrolled in the 12-mo open-label study of tolterodine ER. Demographic characteristics at open-label visit 1 (end of double-blind phase) are summarized in Table 1. Countries enrolling the most patients were the United States (26%), Belgium (15%), and Russia (13%) (Table 2). During the study, 111 (35%) patients withdrew; lack of

Discussion

Our findings demonstrate that tolterodine ER is well tolerated in children 5–11 yr of age with UUI who received treatment for 12 mo. Sixty-five percent of patients completed the study, and 3% withdrew because of AEs. The overall frequency of AEs with long-term treatment (49%) was similar to that observed in the preceding 12-wk study (42%). Rates for the most frequently reported AEs, including UTI (7%), nasopharyngitis (5%), and headache (5%), also were similar to those reported in the previous

Conclusion

This open-label study demonstrated that tolterodine ER was well tolerated over a 12-mo period, suggesting a favorable long-term safety profile for use in children with UUI. Because of its large sample size and 12-mo treatment duration, the current study represents a significant contribution to the literature. Similar studies are required to conclusively evaluate the long-term safety and tolerability of other antimuscarinics for children with UUI.

Conflicts of interest

Dr Nijman is a consultant for Novartis and Coloplast. Dr Borgstein was an employee of Pfizer Inc at the time of the study and writing of the manuscript. Dr Ellsworth serves as a consultant and speaker for Novartis and Pfizer. Dr Siggaard has nothing to disclose.

Acknowledgements

The authors would like to acknowledge the editorial assistance of Melinda Ramsey, PhD, from Complete Healthcare Communications, Inc., in the preparation of this manuscript. Editorial support was provided by Pfizer Inc.

This study was sponsored by Pfizer Inc.

References (22)

P. Abrams et al.
The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society
Urology
(2003)
M. Theunis et al.
Self-image and performance in children with nocturnal enuresis
Eur Urol
(2002)
M.P. Fitzgerald et al.
Childhood urinary symptoms predict adult overactive bladder symptoms
J Urol
(2006)
P. Sureshkumar et al.
Treatment of daytime urinary incontinence in children: a systematic review of randomized controlled trials
J Urol
(2003)
Y. Reinberg et al.
Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence
J Urol
(2003)
A. Raes et al.
Retrospective analysis of efficacy and tolerability of tolterodine in children with overactive bladder
Eur Urol
(2004)
R.J. Nijman et al.
Tolterodine treatment for children with symptoms of urinary urge incontinence suggestive of detrusor overactivity: results from 2 randomized, placebo controlled trials
J Urol
(2005)
C.R. Chapple et al.
Muscarinic receptor subtypes and management of the overactive bladder
Urology
(2002)
K. Youdim et al.
Preliminary study of the safety and efficacy of extended-release oxybutynin in children
Urology
(2002)
K.J. Van Arendonk et al.
Frequency of wetting is predictive of response to anticholinergic treatment in children with overactive bladder
Urology
(2006)

M. Kajiwara et al.

Nocturnal enuresis and overactive bladder in children: an epidemiological study

Int J Urol

(2006)

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Pediatric UrologyLong-Term Tolerability of Tolterodine Extended Release in Children 5–11 Years of Age: Results from a 12-Month, Open-Label Study

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study design and patient population

Results

Discussion

Conclusion

Conflicts of interest

Acknowledgements

Urology

Eur Urol

J Urol

J Urol

J Urol

Eur Urol

J Urol

Urology

Urology

Urology

Nocturnal enuresis and overactive bladder in children: an epidemiological study

Int J Urol

Pediatric Urology
Long-Term Tolerability of Tolterodine Extended Release in Children 5–11 Years of Age: Results from a 12-Month, Open-Label Study