Original research

Anticholinergic use in children: Persistence and patterns of therapy

Anne-Sophie Blais, MD; Michelle Bergeron, MD; Geneviève Nadeau, MD; Sophie Ramsay, MD;

Stéphane Bolduc, MD

Université Laval, Quebec City, QC, Canada

Cite as: Can Urol Assoc J 2016;10(3-4):137-40. http://dx.doi.org/10.5489/cuaj.3527

urgency, with or without incontinence and increased void-

ing frequency. These symptoms are especially troublesome

for pediatric patients and their families. Indeed, it is well-

established that OAB affects children’s well-being, limits

everyday activities, and impairs children’s development.

Abstract

Introduction: Overactive bladder (OAB) symptoms are complex

and generally require long-term therapy. Nevertheless, it has been

demonstrated that persistence rates of antimuscarinic drug use are

low in adults. Better understanding of the treatment patterns of

children treated with antimuscarinics could help to improve drug

management. Our objective was to evaluate persistence rates of

patients under 20 years of age on antimuscarinic therapy over a

four-year period.

Methods: Patients having received a ﬁrst-ever antimuscarinic drug

prescription between April 2007 and March 2008 were identi-

ﬁed using IMS Brogan’s Public and Private Drug Plans database.

Canadian drug claims data from Private Drug Plans, Régie de

l’Assurance Maladie du Québec, and Ontario Public Drug Plans

were analyzed retrospectively. Patients were followed for four years

to assess the prescribed drugs, the lines of treatment, and the dura-

tion of each treatment.

Results: Data were available for 374 patients. The most prescribed

drug as a ﬁrst-line therapy was oxybutynin (87.2%), followed by

tolterodine LA (5.9%). Patients reﬁlled their index prescriptions for

an average of 429 days. Solifenacin had the highest mean duration

of index therapy (765 days). The median number of antimuscarin-

ics prescribed was one. At the end of the followup, 44 patients

were still on therapy. Reasons for discontinuation of treatment

were not available.

Conclusions: Overall discontinuation rate of antimuscarinic ther-

apy in children is comparable to what has been reported in adult

patients with OAB. However, children seem to persist on the medi-

cation for a longer duration before adherence rates start declining.

The low rate of persistence highlights the need to identify the rea-

sons for discontinuation of therapy in children in order to obtain

better persistence rates.

Due to the prevalence of OAB and its severe repercussions

on children’s quality of life, novel options for the therapeutic

management of pediatric patients with OAB have emerged

in the last decade and are still a subject of great interest.

Improvement of quality of life and discomfort is the aim of

OAB therapy. Antimuscarinic agents are currently the main-

stay of therapy to achieve these goals. It is well-known that

OAB is a chronic condition that requires long-term treat-

ment. Persistence of antimuscarinic therapy in the treatment

of adults with OAB symptoms has been studied and the high

rate of treatment discontinuation has been well-documented.

A British study from Kelleher et al noted a persistence rate of

8.2% in women with OAB symptoms at six months after ini-

tial prescription. Similarly, Wagg et al showed that 14‒35%

of patients remained on their initial therapy at 12 months.

These ﬁndings have led to the development of strategies to

improve the persistence rates of antimuscarinic therapy.

To our knowledge, the persistence of antimuscarinic ther-

apy in children has never been studied. Better understanding

of the treatment patterns of children treated with antimus-

carinics could potentially improve drug management and

outcomes. Our objective was to evaluate treatment patterns

of patients under 20 years of age on antimuscarinic therapy

over a four-year period.

Methods

Patients under 20 years of age using a prescription for an anti-

cholinergic drug for the ﬁrst time ever between April 2007

and March 2008 were identiﬁed using IMS Brogan’s Public

and Private Drug Plans database. Canadian medical claims

data from Private Drug Plans (PDP), Régie de l’Assurance

Maladie du Québec (RAMQ), and Ontario Public Drug Plans

(OPDP) were analyzed retrospectively. Target drugs were

Introduction

Overactive bladder (OAB) syndrome is the most common

type of voiding dysfunction in children. It is deﬁned by

the International Children’s Continence Society as urinary

® ® ®

oxybutynin (Ditropan ), tolterodine (Detrol , Detrol long

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2016 Canadian Urological Association

137

Bꢀꢁꢂꢃ ꢄt ꢁꢀ.

acting (LA)), trospium (Trosec ), solifenacin (Vesicare ), and

as a ﬁrst-line therapy and both medications were, in fact,

very rarely used. Patients reﬁlled their ﬁrst prescriptions of

antimuscarinics (or index therapy) for an average of 429

days. Solifenacin had the highest mean duration of index

therapy with 765 days (Table 1). Differences were noted in

duration of index therapy based on gender and drug used.

However, when looking at the pooled data from all drugs,

no signiﬁcant differences were noted in mean duration of

index therapy (421 vs. 437 days for males and females,

respectively; p=ns). The mean time for which a patient was

prescribed a second- or third-line therapy was 637 and 566

days, respectively.

The median number of antimuscarinics prescribed was

one. During the four-year followup, 324 (86.6%), 35 (9.4%),

14 (3.7%), and 1 (0.3%) patients had one, two, three, or

four different drugs prescribed, respectively. Interestingly,

the drug initially prescribed affected the number of anti-

muscarinics used during the four-year period. For example,

the majority of patients (55.6%) whose initial prescription

was for tolterodine had a second-line therapy. Table 2 sum-

marizes the total number of drugs used by patients during

the followup according to their index therapy. The most

prescribed drug as a second- or a third-line therapy was

tolterodine LA.

darifenacin (Enablex ). Prior to patients’ inclusion in the

study, any previous use of anticholinergic medications was

determined by a 12-month look-back period; patients who

were not identiﬁed as receiving the anticholinergic drug as

a ﬁrst-line treatment were excluded. Patients were then fol-

lowed in the database for four years. During that time, the

different antimuscarinic drugs they used, the lines of treat-

ment, and the average number of days spent on each medi-

cation were recorded. The lines of therapy were reported by

drug plan, product, age group, and gender. Veriﬁcation was

done three months after each patient’s last claim to ensure

each patient was still active in the database. Patients lost to

followup were excluded from the database.

Discontinuation of drug treatment was deﬁned as stop-

ping the current line of therapy and not switching to another

anticholinergic medication. At the end of the four-year fol-

lowup period, patients were classiﬁed as “no change” if

they had remained on the same line of therapy since the

initiation of the study.

Results

Data were available for 191 males and 183 females for a

total of 374 patients. All patients were under 20 years of

age, with a majority being under 18 years old. The most

prescribed drug as a ﬁrst-line therapy was oxybutynin, fol-

lowed by tolterodine LA, tolterodine, and solifenacin (Table

Three hundred sixteen patients (84.4%) discontinued their

ﬁrst-line therapy and did not switch to another medication

during the followup. At the end of the four-year period, only

44 patients (11.8%) were still using an antimuscarinic agent,

eight of which were still on their index therapy.

). None of the study patients used trospium or darifenacin

Table 1. Mean time on index therapy

Discussion

Mean time (days)

OAB symptoms are complex and generally require long-term

therapy. Despite the impact of these symptoms on patients’

well-being and quality of life, persistence rate of antimus-

carinic treatment was shown to be very low. Many studies

have assessed the persistence rate of antimuscarinic therapy

for lower urinary tract symptoms in adults. Brostrom Hallas

have noted a persistence rate of <50% at six months, >25%

Oxybutynin

172

154

326

444

428

436

Total

Tolterodine

109

539

276

at one year, and <10% at two years and longer. Similarly,

Total

Wagg et al have shown that only 14‒35% of patients remain

Tolterodine LA

on their initial therapy at 12 months. To our knowledge, our

264

342

321

study is the ﬁrst to evaluate persistence rate of antimuscarinic

therapy in the pediatric population. Our results showed a

Total

Solifenacin

—

630

810

765

Table 2. Percentage of patients in regards to number of

drugs prescribed over four years and initial prescription

Total

Number Oxybutynin Tolterodine Tolterodine LA Solifenacin

All anticholinergic drugs

of drugs

n (%)

293 (89.9)

19 (5.8)

13 (4.0)

1 (0.3)

n (%)

8 (44.4)

10 (55.6)

–

n (%)

17 (77.3)

4 (18.2)

1 (4.5)

–

n (%)

6 (75.0)

2 (25.0)

–

191

183

374

421

437

429

Total

F: female; M: male.

–

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aꢅtꢂꢆꢇoꢀꢂꢅꢄꢈꢉꢂꢆꢃ ꢂꢅ ꢆꢇꢂꢀdꢈꢄꢅ

persistence rate of 11.8% at four years. Comparison with

existing adult studies is quite difﬁcult, as our followup is

longer than what has been reported in literature to date.

However, we can advance that younger patients appear

more likely to persist on antimuscarinic therapy than older

patients because our persistence rate at four years is similar

to the reported rates at one or two years of followup in

the adult population. Nonetheless, discontinuation rate still

remains high in children.

ued their treatment because symptoms have resolved during

the four-year period, and not because of side effects or lack

of efﬁcacy. The lack of healthcare data can be explained by

the fact that data were originally collected for a post-market-

ing analysis of persistence. Furthermore, the database made

it impossible to differentiate whether the patients had OAB

symptoms, neurological disorder, enuresia, or other condi-

tions. Nevertheless, the patients assessed in the study were

children with a ﬁrst-ever prescription of antimuscarinics. It

is reasonable to believe that our study included a majority of

patients with OAB, which is a common voiding dysfunction

and indication for antimuscarinics in children. Regarding

patients with neurogenic bladder, they would most likely

represent a very small proportion of our population, as there

can only be a limited number of newly diagnosed children

with a neurological condition per year.

An interesting fact that can be drawn from our results

is that only 13% of all patients assessed in the study were

prescribed a second line of therapy. Since 87% of our

population received oxybutynin as their index therapy, we

can assume that most children were exposed exclusively

to oxybutynin in accordance to the fact that it is the only

antimuscarinic drug currently approved for the pediatric

population. Up-to-date literature on other antimuscarinics,

such as tolterodine, solifenacin, propiverine, and trospium,

and on novel therapies for OAB, such as the β-3 agonist

mirabegron, might encourage physicians and parents to con-

sider other lines of therapy in children presenting with OAB

symptoms.⁷As a result, changes could eventually be seen

in the patterns of therapy and persistence of OAB drugs.

Children who took a second or third line of therapy stayed

on those drugs for a mean time of 637 and 566 days, respec-

tively. Furthermore, 36 of the 50 patients who switched to

another line of therapy were still on antimuscarinics at the

end of the four-year followup period. This could indicate

that children and their physicians are willing to persist on

therapy as long as they ﬁnd a drug that suits their needs and

expectations. Interestingly, our patients’ second-, third-, or

fourth-line therapy was commonly a long-acting antimus-

carinic. In the literature, many studies have assessed the

efﬁcacy and tolerability of immediate- vs. extended-release

formulas. It is easy to assume that the convenience of once-

daily dosing should enhance the patients’ compliance and

persistence to the selected drug treatment. In fact, a prepon-

derance of studies showed an improvement in efﬁcacy and

tolerability with extended-release formulations, especially

with regard to dry mouth, a common adverse effect of anti-

muscarinics.¹⁸^-²³Likewise, some studies reported a greater

Another limitation is the small number of patients in the

tolterodine, tolterodine LA, and solifenacin groups compared

to the oxybutynin group. Therefore, although this study tells

us more about the persistence rate of oxybutynin in the

pediatric population, the data might not be generalizable

to other antimuscarinic medications. Indeed, it is hard to

draw conclusions on persistence rates of tolterodine or soli-

fenacin considering the minimal number of patients having

used these drugs during the course of our study. Moreover,

it is important to remember that solifenacin was listed on

the OPDP formulary for the ﬁrst time in 2011 and that the

initial reports on its use in children were only published in

-17

5,17

2009 and 2010,

which can explain the smaller number

of patients in this cohort.

Conclusion

The overall discontinuation rate of antimuscarinic therapy

in children (88% at four years) seems comparable to what

has been reported in adult patients with OAB. However,

children appear to persist on the medication for a longer

duration before adherence rates start declining. These obser-

vations were mainly based on oxybutynin as a ﬁrst-line ther-

apy. The impact of long-acting formula will need validation

when pediatric usage is approved by federal agencies. The

low rate of persistence highlights the need to identify the

reasons for discontinuation of therapy in children in order

to obtain better persistence rates.

adherence and persistence rate with the once-daily formu-

las.⁵

,24-25

Reinberg et al reported great tolerability and better

efﬁcacy with the extended-release forms of oxybutynin and

tolterodine in children with diurnal urinary incontinence due

to OAB. Although the majority of the previously mentioned

studies concerned adult patients, they represent the only

possible point of comparison to our study due to the current

lack of data on the pediatric population.

Competing interests: Dr. Nadeau has been an Advisory Board member for Allergan, Astellas, AMS,

Ferring, Pꢀzer, and Red Leaf Medical; has been a member of the Speakers Bureau for Allergan,

Astellas, Ferring, Laborie, and Pꢀzer; and has participated in clinical trials for Astellas and Ipsen.

Dr. Bolduc has received Investigator Initiated Research funds from Astellas and Pꢀzer. The remaining

authors declare no competing ꢀnancial or personal interests.

Limitations of this study include the lack of healthcare

data, such as adherence to treatment, severity of symptoms,

and reason for treatment discontinuation. In fact, a signiﬁ-

cant proportion of pediatric patients might have discontin-

Acknowledgement: This study was funded by Astellas Pharma Canada, Inc. Retrospective prescrip-

tion claims data and statistical analyses were provided by IMS Brogan (IMS Health Canada Inc,

CUAJ • March-April 2016 • Volume 10, Issues 3-4

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Kirkland, QC, Canada), Brad Millson (Engagement manager). The statement, ꢀndings, conclusions,

views, and opinions contained and expressed in this article are based in part on data obtained

conclusions, views, and opinions contained and expressed herein are not necessarily those of IMS

Brogan or any afꢀliated or subsidiary entities.

13. Marschall-Kehrel D, Feustel C, Persson de Geeter C, et al. Treatment with propiverine in children suf-

fering from nonneurogenic overactive bladder and urinary incontinence: Results of a randomized,

placebo-controlled, phase 3 clinical trial. Eur Urol 2009;55:729-36. http://dx.doi.org/10.1016/j.

eururo.2008.04.062

4. Kim WJ, Lee DG, Lee SW, et al. Efꢀcacy and safety of propiverine in children with overactive bladder.

Korean J Urol 2012;53:275-9. http://dx.doi.org/10.4111/kju.2012.53.4.275

5. Bolduc S, Moore K, Nadeau G, et al. Prospective, open-label study of solifenacin for overactive bladder in

children. J Urol 2010;184:1668-73. http://dx.doi.org/10.1016/j.juro.2010.03.124

This paper has been peer-reviewed.

16. Nadeau G, Schröder A, Moore K, et al. Long-term use of solifenacin in pediatric patients with overactive

bladder: Extension of a prospective, open-label study. Can Urol Assoc J 2014;8:118-23. http://dx.doi.

org/10.5489/cuaj.1356

7. Hoebeke P, De Pooter J, De Caestecker K, et al. Solifenacin for therapy-resistant overactive bladder. J

Urol 2009;182:2040-4. http://dx.doi.org/10.1016/j.juro.2009.05.100

References

8. Versi E, Apell R, Mobley D, et al. Dry mouth with conventional and controlled-release oxybutynin in

urinary incontinence. The Ditropan XL Study Group. Obstet Gynecol 2000;95:718-21. http://dx.doi.

org/10.1016/S0029-7844(99)00661-4

9. Van Arendonk KJ, Knudson MJ, Austin C, et al. Improved efꢀcacy of extended-release oxybutynin in children

with persistent daytime urinary incontinence converted from regular oxybutynin. Urology 2006;68:862-5.

http://dx.doi.org/10.1016/j.urology.2006.04.034

Franco I. Pediatric overactive bladder syndrome: Pathophysiology and management. Pediatric Drugs

007;9:379-90. http://dx.doi.org/10.2165/00148581-200709060-00005

Nevéus T, Gontard A, Hoebeke P, et al. The standardization of terminology of lower urinary tract function

in children and adolescents: Report from the standardization committee of the International Children’s

Continence Society. J Urol 2006;176:314-24. http://dx.doi.org/10.1016/S0022-5347(06)00305-3

Caldweel HY P, Hodson, E, Craig J, et al. Bedwetting and toileting problems in children. Med J Aust

0. Rovner ES, Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treat -

ment of overactive bladder: A review. Eur Urol 2002;41:6-14. http://dx.doi.org/10.1016/S0302-

005;182:190-5.

838(01)00009-4

Kelleher CJ, Cardozo LD, Khukkar V, et al. A medium-term analysis of the subjective efꢀcacy of treatment

for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol 1997;104:988-93.

http://dx.doi.org/10.1111/j.1471-0528.1997.tb12054.x

1. Van Kerrebroeck P, Kreder K, Jonas U, et al. Tolterodine once-daily: Superior efꢀcacy and tolerability

in the treatment of the overactive bladder. Urology 2001;57:414-21. http://dx.doi.org/10.1016/

S0090-4295(00)01113-4

2. Homma Y, Paick JS, Lee JG, et al. Clinical efꢀcacy and tolerability of extended-release tolterodine

and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: A

randomized, placebo-controlled trial. BJU Int 2003;92:741-7. http://dx.doi.org/10.1046/j.1464-

Wagg A, Compion G, Fahey A, et al. Persistence with prescribed antimuscarinic therapy for overac -

tive bladder: A UK experience. BJU Int 2012;11:1767-74. http://dx.doi.org/10.1111/j.1464-

10X.2012.11023.x

Brostrom S, Hallas J. Persitence of antimuscarinic drug use. Eur J Clin Pharmacol 2009;65:309-14.

http://dx.doi.org/10.1007/s00228-008-0600-9

Bolduc S, Upadhyay J, Payton, J et al. The use of tolterodine in children after oxybutinine failure. BJU Int

10X.2003.04468.x

3. Omotosho T, Chen CCG. Update on tolterodine extended-release for treatment of overactive bladder. Open

Access J Urol 2010;2:185-91. http://dx.doi.org/10.2147/OAJU.S7232

003;91:398-401. http://dx.doi.org/10.1046/j.1464-410X.2003.04085.x

4. D’Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among extended-release

and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care

Spec Pharm 2008;14:291-301. http://dx.doi.org/10.18553/jmcp.2008.14.3.291

5. Shaya FT, Blume S, Gu A, et al. Persistence with overactive bladder pharmacotherapy in a Medicaid

population. Am J Manag Care 2005;11:121-9.

Hjälmås K, Hellström AL, Mogren K, et al. The overactive bladder in children: A potential future indication

for tolterodine. BJU Int 2001;87:569-74. http://dx.doi.org/10.1046/j.1464-410X.2001.00084.x

Munding M, Wessells H, Thornberry B, et al. Use of tolterodine in children with dysfunctional voiding:

An initial report. J Urol 2001;165:926-8. http://dx.doi.org/10.1016/S0022-5347(05)66576-7

0. Reinberg Y, Crocker J, Wolpert J, et al. Therapeutic efꢀcacy of extended release oxybutynin chloride, and

immediate release and long-acting tolterodine tartrate in children with diurnal urinary incontinence. J Urol

6. Ontario Ministry of Health and Long-term Care, Update AC: Ontario Drug Beneꢀt, December 2011, No 41,

http://www.health.gov.on.ca/en/public/programs/drugs/. Accessed August 2013.

003;169:317-9. http://dx.doi.org/10.1016/S0022-5347(05)64115-8

1. Nijman RJ, Borgstein NG, Ellsworth P, et al. Long-term tolerability of tolterodine extended release in

children 5‒11 years of age: Results from a 12-month, open-label study. Eur Urol 2007;52:1511-6.

http://dx.doi.org/10.1016/j.eururo.2007.05.002

2. Lopez Pereira P, Miguelez C, Caffarati J, et al. Trospium chloride for the treatment of detrusor instability

in children. J Urol 2003;170:1978-81. http://dx.doi.org/10.1097/01.ju.0000085667.05190.ad

Correspondence: Dr. Stéphane Bolduc, Université Laval, Quebec City, QC, Canada;

stephane.bolduc@fmed.ulaval.ca

CUAJ • March-April 2016 • Volume 10, Issues 3-4