long-term safety, tolerability and efficacy of fesoterodine in subjects with overactive bladder...

Long-Term Safety, Tolerability andEfficacy of Fesoterodine in Subjectswith Overactive Bladder SymptomsStratified by AgePooled Analysis of Two Open-Label Extension Studies

Peter K. Sand,1 John Heesakkers,2 Stephen R. Kraus,3 Martin Carlsson,4 Zhonghong Guan4

and Sandra Berriman4

1 NorthShore University HealthSystem, University of Chicago, Pritzker School of Medicine,

Chicago, IL, USA

2 Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

3 University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

4 Pfizer Inc., New York, NY, USA

Abstract Background: Previous work has demonstrated the efficacy and safety of fes-

oterodine in older and younger subjects with overactive bladder (OAB)

symptoms. The effect of long-term fesoterodine treatment in different age

groups has not been assessed.

Objective: The aim was to determine the impact of age on the safety, toler-

ability and efficacy of long-term treatment with fesoterodine 8mg in subjects

with OAB syndrome.

Methods: This was a pooled analysis of two identically designed open-label

extensions of 12-week, randomized, double-blind, placebo-controlled studies.

The setting was urology and general practice offices. Subjects who partici-

pated in the 12-week, double-blind studies and opted to continue long-term,

open-label treatment with fesoterodine were included. Subjects were initiated

on fesoterodine 8mg/day at open-label baseline. After 1 month, subjects

could elect dose reduction to 4mg/day and subsequent re-escalation to 8mg;

each was permitted once annually. Maximal duration of open-label treatment

ranged from 24 to 36 months. Discontinuations, subject-reported treatment

tolerance, and efficacy (3-day diaries) were assessed at open-label baseline

and months 1, 4, 8, 12 and 24.

Results:A total of 890 subjects were treated (age <45 years, n= 140; 45–64 years,n = 444; 65–74 years, n = 208; ‡75 years, n = 98); 49% continued treatment

for ‡24 months (age <45 years, 43%; 45–64 years, 54%; 65–74 years, 50%;

‡75 years, 37%). Seventy-seven percent of subjects remained on fesoterodine

ORIGINAL RESEARCH ARTICLEDrugs Aging 2012; 29 (2): 119-1311170-229X/12/0002-0119/$49.95/0

ª 2012 Adis Data Information BV. All rights reserved.

8mg throughout treatment; this rate was highest among subjects aged

‡75 years (age <45 years, 72%; 45–64 years, 77%; 65–74 years, 73%; ‡75 years,87%). Approximately 80% of continuing subjects were receiving fesoterodine

8mg at each visit after open-label baseline up to 36 months. No new or un-

expected safety signals were observed in any age group. Most subjects re-

ported ‘good’ or ‘excellent’ treatment tolerance throughout the study (age

<45 years, ‡90%; 45–64 years, ‡93%; 65–74 years, ‡85%; ‡75 years, ‡86%).

Dry mouth, the most commonly reported treatment-emergent adverse event,

was lowest among subjects aged ‡75 years (age <45 years, 31%; 45–64 years,

30%; 65–74 years, 32%; ‡75 years, 26%). Rates of discontinuation due to dry

mouth were low in all age groups. Significant improvements in all diary

variables, including urgency urinary incontinence episodes per 24 hours,

micturitions per 24 hours, urgency episodes per 24 hours, and mean voided

volume per micturition, observed between double-blind baseline and open-

label baseline were sustained or increased during open-label treatment in the

overall population and all age groups.

Conclusions: Long-term fesoterodine (administered primarily as 8mg) was

well tolerated and associated with sustained improvements in OAB symp-

toms, irrespective of age.

Background

Overactive bladder (OAB) is a syndromecharacterized by urinary urgency usually accom-panied by frequency and nocturia, with or with-out urgency urinary incontinence (UUI), thatoccurs in the absence of urinary tract infection orother obvious pathology.[1,2] OAB affects an es-timated 11–16% of men and 11–17% of women,and prevalence estimates increase with advancingage.[3,4]

Both nonpharmacological (e.g. behaviouralinterventions)[5] and pharmacological therapies areused to treat OAB symptoms, with antimuscarinicagents recommended as first-line pharmacologi-cal treatment.[6] Fesoterodine is a nonselective oralantimuscarinic available in 4- and 8-mg once-daily dose formulations. In two phase III fixed-dose trials, fesoterodine 4 and 8mg significantlyimproved micturition frequency, urgency episodesand UUI episodes per 24 hours over a 12-weekperiod compared with placebo in subjects withOAB symptoms,[7,8] and a pooled post hoc anal-ysis showed that the 8-mg dose was significantly

more effective than the 4-mg dose in improv-ing several bladder diary variables, includingUUI episodes.[9] Head-to-head trials and post hocanalyses of fesoterodine versus tolterodine ex-tended release (ER) have shown that fesoterodine8mg is associated with significantly greater im-provements in UUI and other bladder diary var-iables and measures of patient assessments ofsymptom bother, health-related quality of life,urgency and bladder-related problems.[10-12] Theavailability of two doses appears to provide aclinical advantage over tolterodine ER, which hasonly one approved dose (4mg) in most popula-tions of OAB patients.

Because OAB is a chronic condition, long-termpharmacological treatment is often required. How-ever, similar to other chronic conditions, individ-uals with OAB are frequently nonadherent withprescribed treatment.[13] Results of a recent sur-vey study showed that unmet treatment expec-tations (e.g. insufficient clinical response) andtolerability issues were important drivers for in-dividuals electing to discontinue their prescribedOAB medication.[14]

120 Sand et al.

ª 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)

Although the prevalence and severity of OABincrease with age,[3,15] physiological changes andincreased likelihood of taking multiple medica-tions may compromise drug metabolism in olderindividuals.[16,17] Thus, it is important to understandthe impact of age on the efficacy and tolerabilityprofiles of pharmacological treatments for OAB.A pooled post hoc analysis of data from thetwo phase III, 12-week, fixed-dose trials showedthat fesoterodine 4 and 8mg effectively treatedOAB symptoms in subjects aged <75 years, whereasonly the 8-mg dose was effective in subjects aged‡75 years.[18] The present post hoc analysis ex-plores the long-term safety, tolerability and efficacyof once-daily fesoterodine (adjustable between 8and 4mg) beyond the 12 weeks captured in mostOAB trials, by assessing pooled data stratified bysubject age from identically designed open-labelextensions of these two phase III trials.[7,8] This isthe first study to evaluate the effects of long-termantimuscarinic treatment in elderly subjects.

Methods

Subjects and Study Design

This analysis utilized data pooled from theopen-label extensions of two separate 12-week,randomized, double-blind, placebo-controlled,phase III fesoterodine trials.[7,8] Subjects fromboth double-blind trials were eligible for the open-label extension phase if they successfully completedthe 12-week, double-blind treatment period with-out meeting discontinuation criteria and had notexperienced any adverse event (AE) during double-blind treatment that, in the investigator’s opinion,would jeopardize their well-being upon continua-tion of treatment. Exclusion criteria included a re-sidual urine volume >200mL, an absolute correctedQT interval value >500ms or individual increaseof >60ms relative to the double-blind study base-line, onset of illness during the study that requiredtermination of treatment, or an ongoing seriousAE that resulted from double-blind study treat-ment or was of unknown origin.

During both double-blind studies, eligible menand women aged ‡18 years recruited from urol-ogy and general practice offices were randomized

to fesoterodine 4mg, fesoterodine 8mg or place-bo once daily; one study also included a tolter-odine ER active-control arm (4mg once daily).[7]

During the open-label extensions, which were ofidentical design, all subjects were initiated ononce-daily fesoterodine 8mg at the open-labelbaseline study visit. After 1 month, subjects couldelect to lower the dosage to 4mg once daily. Thosechoosing to reduce the dose to 4mg could sub-sequently re-escalate to the original 8-mg dose.Dose reduction and re-escalation were each al-lowed once annually, during scheduled visits, andfollowing discussion with the investigator.

As a result of an administrative delay betweeneach double-blind study and its subsequent open-label extension, participation in these extensionswas not available to all subjects completing dou-ble-blind treatment. One extension study wasconducted at 90 sites in Europe, South Africa,Australia and New Zealand (17 countries total)between July 2004 and July 2007; enrolment ofthe first subject at each study site occurred be-tween July 2004 and February 2005. The otherextension study was conducted at 70 sites in theUS between April 2004 and July 2007; enrolmentof the first subject at each study site occurredbetween April 2004 and January 2005. Accordingto the a priori study design, open-label fesoter-odine treatment was to continue until fesoterodinebecame commercially available, with treatmentnot to exceed 36 months following enrolment;however, both extension studies were operationallyterminated in early 2007, with the last patient visitoccurring in July 2007 for both extension studies.Based on the different dates of subject enrolmentacross study sites, no subject in the multinationalstudy received open-label treatment beyond a32-month period, whereas a subset of subjects inthe US study had the opportunity to receive open-label treatment for a 36-month period. Acrossboth extension studies, all subjects had the op-portunity to receive open-label fesoterodine forat least 24 months before being notified of theoperational study termination at their respectivestudy site.

Extension study protocols were approved bythe appropriate ethics committee at respective studysites, with subjects providing written informed

Long-Term Fesoterodine Treatment for OAB 121


consent before study participation. Both exten-sion studies were conducted in compliance withthe International Conference on HarmonisationGood Clinical Practice guidelines, the Declara-tion of Helsinki, and local regulations.

Outcome Measures

Fesoterodine safety and tolerability were pri-mary study endpoints. Efficacy endpoints (blad-der diary variables) were considered secondarystudy endpoints. All endpoints were evaluated inboth the overall population and individual agesubsets (<45, 45–64, 65–74 and ‡75 years); allage-based analyses were conducted post hoc.

Duration of fesoterodine exposure was assessedthroughout the open-label extension period andwas defined as the total amount of time a subjectreceived fesoterodine. For subjects receiving fes-oterodine 4 or 8mg in the double-blind trial, thefirst dose of fesoterodine corresponded to thedouble-blind study baseline; for subjects receiv-ing placebo or tolterodine ER in the double-blindstudy, the first fesoterodine dose corresponded tothe open-label study baseline. Treatment discon-tinuation rates were assessed through 24 monthsof open-label treatment because all subjects hadthe opportunity to receive open-label fesoterodineup to this time point. Treatment-emergent AEsand treatment-related AEs were assessed through-out the open-label extension period. Laboratoryparameters, residual urine volume, vital signs andelectrocardiogram measurements were assessedat each study visit. Physical, urological and uro-gynaecological examinations were performed atmonths 4, 12 and 16 of the open-label study period,every 8 months thereafter and at the final visit.Subjects rated treatment tolerance on a 4-pointscale (1 = inadequate, 2 =moderate, 3 = good, 4 =excellent) at open-label baseline and months 4, 12and 24 at the beginning of the visit before anyinvasive procedures were performed.

Efficacy was assessed using data from 3-daybladder diaries that were completed at double-blind baseline, open-label baseline and months 1,4, 8, 12 and 24 (a priori evaluation time points).Diary-based endpoints included mean change fromdouble-blind and open-label baseline in UUI epi-

sodes per 24 hours, micturitions per 24 hours,urgency episodes per 24 hours and mean voidedvolume (MVV) per micturition at months 4, 8, 12and 24.

Statistical Analysis

Safety and tolerability were assessed in thepooled safety population, which included sub-jects in both extension studies who received ‡1dose of open-label fesoterodine. Efficacy wasassessed in the pooled full analysis set, which in-cluded subjects from both extension studies re-ceiving ‡1 dose of open-label fesoterodine andhaving ‡1 valid post-baseline efficacy assessment.Subjects who prematurely discontinued the studywere evaluated on the basis of data collected ateach visit attended. Subjects unable to continueopen-label treatment because of operational studysite termination were classified as having ‘oper-ationally completed’ treatment at the last studyvisit attended.

Safety and tolerability endpoints were sum-marized using descriptive statistics. Mean changefrom double-blind and open-label baselines inbladder diary variables were assessed in the over-all population and within individual age subsetsusing a paired t-test. Differences across age sub-sets in mean baseline-adjusted bladder diaryvariable outcomes over the 24-month, open-labelperiod were evaluated with an F-test; a pairedt-test was subsequently used to evaluate differencesbetween individual age subsets. A 5% (two-sided)significance level was used for all inferential testing.UUI analyses included only subjects who recorded‡1 UUI episodes in their 3-day bladder diary atdouble-blind baseline.

Results

Subjects

Of the 1669 subjects who completed the 12-week,randomized, double-blind studies, 890 (53%) weresubsequently enrolled in their respective open-labelextension study (figure 1). The overall mean–SDage in the safety population was 58.4– 13.2 years(table I). Baseline demographic and clinical char-acteristics were generally similar across age subsets

122 Sand et al.


Completed double-blindstudy SP583

(n = 988)

Enrolled in open-labelextension study SP738

(n = 417)

Took ≥1 dose of fesoterodine(pooled safety population, n = 890)

Age group (years):<45 (n = 140)

45−64 (n = 444)65−74 (n = 208)

≥75 (n = 98)

Completed double-blindstudy SP584

(n = 681)

Enrolled in open-labelextension study SP739

(n = 473)

Pooled enrolledpopulation

(n = 890)

Continued treatment for ≥32 months (n = 204)Age group (years):

<45 (n = 23)45−64 (n = 116)65−74 (n = 52)

≥75 (n = 13)

Continued treatment for ≥36 months2 (n = 51)Age group (years):

<45 (n = 9)45−64 (n = 24)65−74 (n = 14)

≥75 (n = 4)

Discontinued treatment (n = 451)• Insufficient response (n = 120)• Withdrawn consent (n = 114)• AE (n = 111)• Lost to follow-up (n = 49)• Noncompliance (n = 14)• Protocol deviation (n = 8)• Other reason (n = 35)

Operationally completed (n = 10)

Discontinued treatment (n = 38)• AE (n = 7)• Withdrawn consent (n = 10)• Insufficient response (n = 3)• Lost to follow-up (n = 7)• Noncompliance (n = 1)• Protocol deviation (n = 1)• Other reason (n = 9)





Took ≥1 dose of fesoterodine and had ≥1efficacy assessment

(pooled efficacy population,1 n = 864)Age group (years):

<45 (n = 134)45−64 (n = 432)65−74 (n = 204)

≥75 (n = 94)


<45 (n = 60)45−64 (n = 238)65−74 (n = 105)

≥75 (n = 36)


<45 (n = 53)45−64 (n = 215)65−74 (n = 94)

≥75 (n = 29)

Fig. 1. Subject disposition. 1 Subjects unable to continue open-label treatment because of operational study site termination were classifiedas having operationally completed treatment at the last study visit attended. 2 Subjects were permitted to receive open-label treatment fora maximum duration of 36 months. AE =adverse event.



(table I), although the proportion of subjectsreporting prior OAB drug therapy or urinary in-continence at open-label baseline increased nu-merically as a function of age.

Safety and Tolerability

Duration of Fesoterodine Exposure

In the overall safety population, the mean –SD total duration of exposure to either fesoter-odine dose across double-blind and open-labeltreatment periods was 21 – 12 months, with 51%of subjects (n = 458) receiving fesoterodine treat-ment for ‡24 months across these treatment peri-ods. During the open-label extension period,subjects received fesoterodine for a mean – SDduration of 20 – 12 months, with 49% of subjectsreceiving fesoterodine treatment for ‡24 months.

Seventy-seven percent of subjects (n = 681) elect-ed to remain on the higher 8-mg fesoterodinedose throughout their respective duration ofopen-label treatment, and approximately 80% ofcontinuing subjects were receiving the 8-mg doseof fesoterodine at each visit after open-label base-line for up to 36 months (table II). Twenty-fourpercent of subjects (n = 209) elected to decreasetheir dose from 8 to 4mg at least once during theopen-label extension period, with 64% of first-time dose reductions (n = 134) occurring withinthe first 60 days of open-label treatment. Twenty-two percent of subjects (n = 46) who elected todecrease their dose to 4mg subsequently electedre-escalation to the 8-mg dose. On average, sub-jects were treated with the higher 8-mg dose for84% of their days on open-label fesoterodinetreatment.

Table I. Open-label baseline demographics and clinical characteristics in the age subsetsa

Characteristic Overall

population

Overall population by subject age (y)

<45 45–64 65–74 ‡75

n 890 140 444 208 98

Age [y; mean –SD] 58.4 – 13.2 37.0 – 6.3 55.6 – 5.4 69.0 –2.8 79.1 –3.5

Sex [n (%)]

Men 185 (20.8) 25 (17.9) 78 (17.6) 57 (27.4) 25 (25.5)

Women 705 (79.2) 115 (82.1) 366 (82.4) 151 (72.6) 73 (74.5)

Race [n (%)]

White 782 (87.9) 114 (81.4) 380 (85.6) 194 (93.3) 94 (95.9)

Black 44 (4.9) 11 (7.9) 28 (6.3) 5 (2.4) 0 (0.0)

Asian 22 (2.5) 6 (4.3) 13 (2.9) 2 (1.0) 1 (1.0)

Other 42 (4.7) 9 (6.4) 23 (5.2) 7 (3.4) 3 (3.1)

Prior drug therapy for OAB [n (%)] 474 (53.3) 51 (36.4) 232 (52.3) 119 (57.2) 72 (73.5)

Urinary incontinence [n (%)] 417 (50.9) 51 (41.1) 204 (49.5) 102 (52.3) 60 (68.2)

Double-blind treatment [n (%)]

Placebo 273 (30.7) 47 (33.6) 138 (31.1) 55 (26.4) 33 (33.7)

Tolterodine ER 4mg/day 103 (11.6) 18 (12.9) 48 (10.8) 26 (12.5) 11 (11.2)

Fesoterodine 4mg/day 260 (29.2) 35 (25.0) 136 (30.6) 67 (32.2) 22 (22.4)

Fesoterodine 8mg/day 254 (28.5) 40 (28.6) 122 (27.5) 60 (28.8) 32 (32.7)

Diary variables [mean]

UUI episodes/24 hb 2.1 1.7 1.9 2.3 3.4

Micturitions/24 h 10.3 9.9 10.3 10.4 11.1

Urgency episodes/24 h 9.6 9.1 9.6 9.7 10.1

MVV/micturition (mL) 181.8 172.3 184.5 179.9 187.1

a Demographic data represent the safety set (all subjects who received ‡1 dose of open-label fesoterodine); clinical data represent the full

analysis set (all subjects who received ‡1 dose of open-label fesoterodine and had ‡1 valid post-baseline efficacy assessment).

b Includes only those with ‡1 UUI episode on open-label baseline diary.

ER = extended release; MVV =mean voided volume; OAB= overactive bladder; UUI =urgency urinary incontinence.

124 Sand et al.


The mean – SD total duration of exposure toeither fesoterodine dose across the double-blindand open-label studies and during the open-labelstudies alone was greatest in subjects aged 45–64 years, followed by subjects aged 65–74 years,<45 years and ‡75 years (table II). Subjects in thehighest age stratum (‡75 years) most frequentlychose to remain on the higher 8-mg dose through-out open-label fesoterodine treatment as comparedwith their younger counterparts. Subjects in thelowest age stratum (<45 years) demonstrated thegreatest propensity for fesoterodine dose reduc-tion to 4mg, whereas subjects in the highest agestratum (‡75 years) were least likely to reduce theirdose to 4mg. Subjects aged 45–64 years were mostlikely to re-escalate to the 8-mg dose after dosereduction. The mean percentage of days subjectsreceived fesoterodine 8mg versus 4mg duringtheir respective treatment period was greatest insubjects aged ‡75 years, followed by those aged45–64 years, 65–74 years and <45 years.

Treatment Discontinuations

Of the 890 subjects in the overall safety pop-ulation, 451 (51%) discontinued treatment beforethe month-24 study visit (figure 1, table III). In-sufficient clinical response (n = 120), withdrawal

of consent (n = 114) and AEs (n = 111) were theprimary reasons for study discontinuation duringthis period.

Adverse Events

During open-label treatment, 679 of the 890subjects in the overall safety population (76%)experienced ‡1 treatment-emergent AE; 437 ofthese subjects experienced ‡1 treatment-relatedAE (table III). The incidence of treatment-relatedAEs was similar across age groups, whereas the in-cidence of treatment-emergent AEs increased nu-merically with age. The most common AEs weredry mouth and constipation, the majority of which(87% for each) were of mild to moderate intensity.

A total of 119 subjects in the overall safety pop-ulation (13%) experienced a treatment-emergentAE during open-label treatment that resulted indiscontinuation of fesoterodine treatment, includ-ing 15 (2%) discontinuations due to dry mouthand 10 (1%) discontinuations due to constipa-tion. Nine (1%) subjects discontinued treatmentdue to symptoms suggestive of urinary retention.However, only one developed acute urinary re-tention; it is not known whether this subject wascatheterized, because he/she was lost to follow-up. The overall frequency of treatment-emergent

Table II. Fesoterodine exposure and dose adjustment in the pooled safety population and age subsets

Overall

population

Overall population by subject age (y)

<45 45–64 65–74 ‡75

n 890 140 444 208 98

Total fesoterodine exposurea [days; mean –SD]

During double-blind and open-label studies 635.9 –371.9 589.0 –371.1 672.4 – 365.8 640.2 –379.6 528.3 –361.4

During open-label study only 586.8 –371.5 543.4 –371.1 622.8 – 363.5 588.4 –382.3 482.3 –364.1

Fesoterodine dose adjustment during open-label

study [n (%)]

Initial fesoterodine 8-mg dose maintained throughout

treatment

681 (76.5) 101 (72.1) 343 (77.3) 152 (73.1) 85 (86.7)

Dose reduction from fesoterodine 8 to 4mg at least

once during treatment

209 (23.5) 39 (27.9) 101 (22.7) 56 (26.9) 13 (13.3)

Subsequent re-escalation of fesoterodine dose from

4 to 8mg at least once during treatmentb46 (22.0) 3 (7.7) 31 (30.7) 10 (17.9) 2 (15.4)

Mean proportion of days subjects received fesoterodine

8mg during respective open-label treatment periods (%)

84.4 78.4 86.1 81.3 91.5

a Fesoterodine 4- or 8-mg once-daily dosing.

b Percentage calculated using a denominator value based on the number of subjects electing to de-escalate from fesoterodine 8 to 4mg

at least once during respective treatment periods.



AEs resulting in study discontinuation generallyincreased numerically with age (10% [n = 14], 10%[n = 44], 17% [n = 35], and 27% [n = 26] in subjectsaged <45, 45–64, 65–74 and ‡75 years, respectively).Only subjects in the age 45–64 and 65–74 yearsstrata experienced treatment-emergent dry mouththat resulted in treatment discontinuation (1%[n = 5] and 3% [n = 6], respectively), whereas sub-jects in the age ‡75 years stratum most frequentlyexperienced cases of treatment-emergent con-stipation (4% [n = 4]) or symptomatic urinary re-tention (5% [n = 5]) that resulted in treatmentdiscontinuation.

Subject-Reported Treatment Tolerance

Treatment tolerance was rated as ‘good’ or‘excellent’ by 93% (n = 819) of subjects at open-label study baseline (figure 2a). High rates of ‘good’or ‘excellent’ treatment tolerance were reportedacross age strata at open-label baseline (‡90%)and at subsequent month 4, 12 and 24 study visits(‡85%) [figure 2b–e].

Other Safety Outcomes

Clinical laboratory results were consistent overtime, with no apparent trends in haematology,blood chemistry or urinalysis during long-termfesoterodine treatment in any age group. Therewas no clinically significant change in residual urinevolume, vital sign and electrocardiogram para-meters, or physical and urological/urogynaecologicalexamination outcomes during the open-label treat-ment period.

Efficacy

Compared with double-blind and open-labelbaseline (table I), there were significant mean im-provements in all bladder diary variables in theoverall efficacy population at all time points dur-ing open-label treatment (p < 0.05). Similar im-provements were observed across the age groups(p < 0.05; figure 3), except for changes versusopen-label baseline in MVV at months 12 and24 among subjects aged <45 years and in UUI

Table III. Treatment-emergent adverse events (AEs), treatment-related AEs and discontinuation rates during the 36-month open-label

fesoterodine treatment period

Overall population Overall population by subject age (y)

<45 45–64 65–74 ‡75

n 890 140 444 208 98

Treatment-emergent AEs [n (%)]

Subjects reporting ‡1 AE 679 (76.3) 93 (66.4) 340 (76.6) 164 (78.8) 82 (83.7)

Most common AEsa

Dry mouth 271 (30.4) 44 (31.4) 135 (30.4) 67 (32.2) 25 (25.5)

Urinary tract infection 134 (15.1) 9 (6.4) 75 (16.9) 31 (14.9) 19 (19.4)

Constipation 66 (7.4) 5 (3.6) 28 (6.3) 16 (7.7) 17 (17.3)

Back pain 39 (4.4) 7 (5.0) 21 (4.7) 8 (3.8) 3 (3.1)

Hypertension 36 (4.0) 2 (1.4) 14 (3.2) 12 (5.8) 8 (8.2)

Treatment-related AEs [n (%)]

Subjects reporting ‡1 AE 437 (49.1) 62 (44.3) 210 (47.3) 117 (56.3) 48 (49.0)

Most common AEsb

Dry mouth 270 (30.3) 44 (31.4) 135 (30.4) 67 (32.2) 24 (24.5)

Constipation 51 (5.7) 4 (2.9) 21 (4.7) 15 (7.2) 11 (11.2)

Urinary tract infection 27 (3.0) 1 (0.7) 11 (2.5) 10 (4.8) 5 (5.1)

Discontinuation rates [n (%)] 509 (57.2) 86 (61.4) 237 (53.4) 116 (55.8) 70 (71.4)

AE 119 (13.4) 14 (10.0) 44 (9.9) 35 (16.8) 26 (26.5)

Lack of efficacy 123 (13.8) 18 (12.9) 53 (11.9) 33 (15.9) 19 (19.4)

a Treatment-emergent AEs reported by ‡4% of subjects in the overall pooled safety population.

b Treatment-related AEs reported by ‡2% of subjects in the overall pooled safety population.

126 Sand et al.


Overall population (all ages)

0

25

50

75

100

OL ba

selin

e

(n =

882)

Mon

th 4

(n =

705)

Mon

th 1

2

(n =

557)

Mon

th 2

4

(n =

425)

39

54

61

36

55

81

41

53

1

40

54

6

Per

cent

age

of s

ubje

cts

Subjects aged <45 years

0

25

50

75

100

OL ba

selin

e

(n =

138)

Mon

th 4

(n =

110)

Mon

th 1

2

(n =

80)

Mon

th 2

4

(n =

59)

40

56

31

40

53

62

44

51

3 3

49

41

10P

erce

ntag

e of

sub

ject

s

Subjects aged 45−64 years

0

25

50

75

100

OL ba

selin

e

(n =

441)

Mon

th 4

(n =

361)

Mon

th 1

2

(n =

295)

Mon

th 2

4

(n =

231)

41

53

52

37

56

61

39

56

5

38

56

5

Per

cent

age

of s

ubje

cts

Subjects aged 65−74 years

0

25

50

75

100

OL ba

selin

e

(n =

206)

Mon

th 4

(n =

162)

Mon

th 1

2

(n =

129)

Mon

th 2

4

(n =

100)

35

55

9 1

30

54

14 1

42

50

8

40

59

1Per

cent

age

of s

ubje

cts

Subjects aged ≥75 years

0

25

50

75

100

OL ba

selin

e

(n =

97)

Mon

th 4

(n =

72)

Mon

th 1

2

(n =

53)

Mon

th 2

4

(n =

35)

38

53

9

39

54

7

47

45

8

37

49

14

Per

cent

age

of s

ubje

cts

a

c

e

d

b

ExcellentGoodModerateInadequate

5

Fig. 2. Subject-reported treatment tolerance in (a) the overall pooled safety population and (b–e) within individual subject age strata of theoverall pooled safety population: (b) age <45 years, (c) 45–64 years, (d) 65–74 years and (e) ‡75 years. OL = open-label.



episodes at month 24 andMVV at months 12 and24 in subjects aged ‡75 years.

Discussion

OAB is a chronic condition that is oftenbothersome[19] and can negatively impact normalsocial, professional, and recreational activities; sex-ual health and function; and relationships withfamily members.[20-22] Results of this post hoc,pooled-data analysis indicate that long-term fes-oterodine treatment was generally well toleratedin all age groups, resulting in no new or unexpectedsafety signals. Approximately 50% of subjects con-tinued open-label fesoterodine treatment for at least24 months.Most subjects (77%) elected to remainon the 8-mg dose for the duration of open-labeltreatment, and approximately 80% of continuingsubjects were receiving the 8-mg dose of fesoter-

odine at each visit after open-label baseline for upto 36 months. Treatment tolerance was high in allage groups, with most subjects reporting at least‘good’ treatment tolerance throughout the study.Dry mouth was the most common treatment-emergent AE; however, few subjects (n = 15 [2%])discontinued treatment due to this AE. Subjectsin all age groups had statistically significant im-provements in UUI episodes, micturitions andurgency episodes per 24 hours and MVV permicturition compared with double-blind baselineat all time points assessed during open-label fes-oterodine treatment. Diary outcomes were alsogenerally significantly improved versus open-labelbaseline in all age groups during open-label fes-oterodine treatment, except for MVV at months12 and 24 among subjects aged <45 years and inUUI episodes at month 24 and MVV at months12 and 24 in subjects aged ‡75 years.

−4

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<45 y45−64 y65−74 y≥75 y

Fig. 3. Mean change in 3-day bladder diary variables from double-blind and open-label study baselines to months 4, 12 and 24 in the agesubsets: (a) urgency urinary incontinence (UUI) episodes per 24 hours; (b) micturitions per 24 hours; (c) urgency episodes per 24 hours; and(d) mean voided volume (MVV) per micturition (mL).

128 Sand et al.


Subjects aged ‡75 years reported the greatestincidence of discontinuations resulting fromtreatment-emergent AEs and lack of efficacy. Thepercentage of subjects who discontinued treat-ment due to a lack of efficacy in the age ‡75 yearsstratum may reflect the greater baseline symptomseverity in these subjects versus their youngercounterparts.[23] Although the incidence of sub-jects experiencing ‡1 treatment-emergent AE in-creased with age, there was no age-based trendobserved for the incidence of subjects experienc-ing ‡1 treatment-related AE – these results sug-gest that age is generally not a determinant offesoterodine-related AEs. One possible exceptionwas constipation, which did increase in incidencewith age. However, most cases of constipationwere of mild to moderate intensity across the dif-ferent age strata and did not result in treatmentdiscontinuation. Multiple epidemiological stud-ies have shown that constipation increases as afunction of age.[24]

Our age-based results are consistent with thefindings of a recent post hoc analysis of data fromthe two phase III double-blind trials from whichthese extension studies originate. It was demon-strated that once-daily fesoterodine 4 and 8mgwereeffective in improving OAB symptoms in subjectsaged <75 years, whereas once-daily fesoterodine8mg was effective in subjects aged ‡75 years.[18]

The analysis also showed that both fesoterodinedoseswere generallywell tolerated across age strata –although dry mouth and constipation occurredmore frequently in subjects aged ‡75 years receiv-ing fesoterodine 8mg (46% and 15%, respectively)versus fesoterodine 4mg (17% and 10%).[18] Ratesof discontinuation resulting from these AEs (£2%)were low and similar between fesoterodine doseswithin this age group.[18] Collectively, these data sug-gest that fesoterodine treatment is generally welltolerated and effective across a wide age range andfor a long period. Long-term higher-dose (8-mg)fesoterodine treatment was well tolerated in el-derly subjects, which is important because of theincreased prevalence of OAB with age.[3]

Dose adjustment is an important componentof antimuscarinic use in clinical practice. Subjectsparticipating in the extension studies analysedhere were allowed to adjust their dose between

8 and 4mg following an initial 1-month period onthe 8-mg dose; 24% (n = 209) elected to make‡1 dose adjustment and 5% (n= 46) elected to make‡2 dose adjustments. These results illustrate thebenefit of havingmultiple doses of an antimuscarinicagent available to help patients with OAB achievea balance between efficacy and tolerability.

These extension studies, conducted for 24–36 months across study sites, are two of the longestantimuscarinic extension studies to date. The max-imum duration of treatment in open-label ex-tension studies of other antimuscarinic drugs is24 months for darifenacin,[25] 40 weeks for soli-fenacin[26] and 12months for tolterodine.[27] Con-sistent with the findings of the present analysis,results from previous extension studies also dem-onstrated long-term tolerability and efficacy ofantimuscarinics.[25-27] Results of our pooled-dataanalysis are also consistent with the two double-blind trials from which they originated[7,8] andother short-term (12-week) studies[28,29] that dem-onstrated the favourable efficacy, safety and tol-erability profiles of fesoterodine treatment insubjects with OAB symptoms. Finally, the age-based stratification data presented herein areconsistent with the results of previous studiesdemonstrating the efficacy, safety and tolerability ofantimuscarinics in elderly subjects.[24,30-34]

Several potential study limitations warrantmentioning. First, both extension studies wereopen-label in design, which introduces the possi-bility of observer bias and prevents analysis of theplacebo effects that frequently occur in OAB,[35]

and the age stratification was conducted post hoc.In addition, only subjects who successfully com-pleted the double-blind studies were eligible forthis analysis – these subjects may have been moremotivated and/or more likely to tolerate or re-spond to long-term fesoterodine treatment. Boththe administrative delay preceding each extensionstudy and the operational termination of eachextension study are potential study limitations.However, operational termination of these studiesdid not impact diary outcomes, considering thatthese evaluations were prespecified during thefirst 24 months of open-label treatment, and allsubjects had the opportunity to continue open-labeltreatment for at least 24 months. Interpretation



of the results may be limited by differences be-tween age strata in population size. Lastly, whiletreatment-emergent and treatment-related AEswere monitored throughout the open-label exten-sion studies, effects on the central nervous system,including effects on cognitive function and mem-ory, were not formally evaluated.

Conclusions

The results of this post hoc, pooled analysisshowed that long-term fesoterodine treatmentwas well tolerated and associated with sustainedimprovements in OAB symptoms across all agegroups, including both younger (aged <45 years)and elderly (aged ‡75 years) subjects. Becausemost subjects, particularly elderly subjects, electedto remain on the higher 8-mg dose throughouttheir respective treatment period, these outcomesprovide strong evidence for the safety, tolerabilityand efficacy of long-term fesoterodine 8-mg treat-ment across multiple age groups. These findingsalso support clinical use of high-dose fesoterodine aspart of a flexible-dose regimen for the managementof OAB symptoms in adult subjects of all ages.

Acknowledgements

Funding for both extension studies was provided bySchwarz BioSciences GmbH and Pfizer Inc. Schwarz Bio-Sciences GmbH participated in the design and conduct of thestudies; Pfizer Inc. was involved in data analysis and manu-script preparation. Editorial assistance was provided by NancySheridan and Colin Mitchell, PhD, from Complete Health-care Communications, Inc., and was funded by Pfizer Inc.

Author’s Contributions:All authors had full access to all ofthe data (including statistical reports and tables) in the studyand take responsibility for the integrity of the data and theaccuracy of the data analysis. All authors participated in studyconcept and design, interpretation of data, drafting, and re-vising the article, and all have given final approval for themanuscript to be published. Other author contributions wereas follows: acquisition of data: P.K.S., S.R.K. and J.H.; sta-tistical analysis: M.C.

Conflicts of Interest: P.K.S. has been an advisor andspeaker for Allergan, Astellas, GlaxoSmithKline, Ortho, Pfizer,Teva and Watson, and has received research grants fromAllergan, Antares, Contura, Bioform, Boston Scientific, Ortho,Pfizer and Watson. J.H. has been an advisor and speaker forAllergan, Astellas, Pfizer and Uroplasty, and has received grantsfrom Astellas, Medtronic, Pfizer and Pohl Boskamp. S.R.K.has been a consultant and lecturer for Pfizer and Laborie andhas received research grants from Pfizer and the National

Institute of Diabetes and Digestive and Kidney Diseases.M.C. and Z.G. are employees of Pfizer. S.B. was an employeeof Pfizer at the time this study was conducted.

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Correspondence: Dr Peter K. Sand, NorthShore UniversityHealthSystem, Evanston Continence Center, University ofChicago, Pritzker School of Medicine, 1000 Central Street,Suite 730, Evanston, IL 60201, USA.E-mail: [email protected]



long-term safety, tolerability and efficacy of fesoterodine in subjects with overactive bladder...

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