Overactive Bladder: Improving the
`Efficacy of Anticholinergics by
`Dose Escalation
`
`Scott A. MacDiarmid, MD
`
`
`
`Address
`
`Department of Urology. Wake Forest University School of Medicine.
`Medical Center Boulevard, Winston-Salem, NC ZTIS7, USA.
`E-mail: smacdiar@wfu bmc.edu
`Current Urology Reports 2003, 4:4-46-45 I
`Current Science Inc. ISSN I527-2737
`Copyright © 2003 by Current Science Inc.
`
`Overactive bladder (OAB) affects millions of people in the
`United States and significantly impacts their quality of life.
`New antimuscarinic anticholinergic medications have
`improved the treatment of OAB, offering patients efficacy
`equal to that of immediate-release oxybutynin with fewer
`side effects and an improved dosing schedule. The com-
`monly reported range of reduction of urge incontinence
`episodes is between 46% and 92%. Although patients are
`improving. continence rates are lower and many respond-
`ers continue to leak significantly. The literature supports
`that the efficacy of anticholinergics is enhanced by dose
`escalation, but using higher dosages has not become rou-
`tine in clinical practice. Although dose escalation can be
`implemented with all of the anticholinergics. it is done most
`easily and approved by the US Food and Drug Administra-
`tion with extended-release oxybutynin. This paper critically
`evaluates the pros and cons of dose escalation in the hope
`to improve efficacy in patients with OAB.
`
`nin extended-release (OXY-ER], and oxybutynin transder-
`rnal delivery system (OXY-'l‘DS), ranges between 46% and
`92% [3—6,7°-,8--]. Although most patients respond favor-
`ably to medication. smaller percentages achieve total dry-
`ness.
`
`Clinical studies and standard practice methods suggest
`that a significant number ofpatients who are successfully
`managed by anticholinergic therapy could achieve further
`therapeutic benefit by a number of simple techniques,
`including dose escalation. For years, it has been recognized
`that the efficacy ofanticholinergics is enhanced by the
`addition of behavioral therapy [‘),l0]. Similarly, the litera-
`ture supports that many patients respond more favorably
`to higher dosages of medication, but dose escalation has
`not become routine in clinical practice. The improved ther-
`apeutic impact from dose escalation is especially impor-
`tant to realize with the newer anticholinergics, all of which
`have improved side-effect profiles.
`This article reviews the pharmacologic treatments of
`OAB and critically evaluates the pros, cons, and barriers
`associated with dose escalation. The goal of this paper is to
`educate the reader regarding the potential benefits of
`higher dosages ofantiCholin€1‘giCs
`in hope that this may
`translate into improved therapeutic outcomes in many of
`their patients.
`
`Introduction
`
`Overactive bladder (DAB), a medical condition with syrnp—
`toms of urinary frequency. urgency. and urge incontinence.
`affects more than 17 million people in the United States
`[1]. It is well recognized that OAB has detrimental affects
`on quality oflife and is costly to the American health care
`system [2] and to the individual patient. As a result of new
`and improved pharmacotherapies and increased commu-
`nity and physician awareness and education, millions
`more are receiving affective therapy.
`Clinical practice and the literature support the efficacy
`of anticholinergic medications in the treatment of OAB.
`The reported reduction in urge incontinence episodes with
`the newer anticholinergics, tolterodine immediate-release
`(’l'OL-| R), tolterodine extended-release (’l‘Ol.-ER], oxybuty-
`
`Efficacy Data
`Multiple new and effective antimuscarinic anticholinergic
`medications have emerged for the treatment of DAB and
`urge incontinence. These include 'l'0|.-IR, 'l'0|,-|’.R, OXY-
`l;'R, and OXY-’l‘DS. In general, these new formulations offer
`patients efficacy equivalent to that of immediate-release
`oxybutynin (OXY—lR) with a much improved dosing sched-
`ule and side-effect profile.
`The efficacy and tolerability of immediate-release
`tolterodine, the first drug developed specifically for the
`treatment ofOAl5, has been demonstrated in a number of
`placebo-controlled, randomized clinical trials. A total of
`1120 patients were treated in four multicenter studies and
`subsequently evaluated in a pooled analysis [3 Of the
`1120 patients randomized, 12], 474, 34‘), and 176 patients
`were treated with 1 mg of'[‘OL-IR twice daily, 2 mg of'[‘Ol.-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2091 - 0001
`
`

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`Overactive Bladder: lmproving the Efficacy of Anticholinergics by Dose Escalation 0 MacD1'r1rmid
`
`447
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`IR twice daily, 5 mg of OXY-IR three times daily, and pla-
`cebo, respectively. In three of the studies, tolterodine
`achieved a mean reduction in daily urge incontinence epi-
`sodes of 50%, 56%, and 55%, respectfully, which was not
`statistically superior to placebo. When the data were
`pooled, tolterodine statistically reduced urge incontinence
`compared with placebo and it was better tolerated than
`oxybutynin. In another study, Chancellor at on‘. [4] evalu-
`ated 1022 patients with urge incontinence randomized to
`treatment with 2 mg ofTOL-IR twice daily or placebo.
`Tolterodine reduced urge incontinence from baseline by
`46% versus a 30% reduction with placebo (P = 0.0005).
`Dry mouth was the most commonly reported adverse
`event and occurred in 30% and 8% of the tolterodine and
`
`placebo patients, respectively.
`An extended—release once—daily oral formulation of
`oxybutynin (OXY-I-lR) gained approval by the US Food and
`Drug Administration (FDA) and was introduced into the
`market in 1999. OXY-ER uses a patented, push-pull,
`osmotic delivery system to deliver oxybutynin at a fixed
`rate over 24 hours. In a prospective, randomized, double-
`blind, parallel-group study [5] (referred to as the OBJECT‘
`study), the efficacy and tolerability of 10 mg of OXY-I.-‘R
`was compared with 2 mg ofTOL-IR administered twice
`daily. Of the 378 patients randomized, 276 women and 56
`men completed the study. The reduction in weekly urge
`incontinence episodes in patients treated with OXY-I.-‘R and
`TOL-IR was 76% and 68%, respectively (P = 0.03). Simi-
`larly, oxybutynin was statistically more effective than
`tolterodine in reducing total incontinence: 75% with OXY-
`ER versus 66% with TOL-IR (P = 0.02). Both medications
`were equally well tolerated.
`Tolterodine extended-release, a newer once-daily for-
`mulation of tolterodine, was designed to provide greater
`patient convenience and improved compliance compared
`with the twice—daily formulation. The efficacy and tolera-
`bility of4 mg of'lUL-ER administered daily was compared
`with 2 mg of TOL-JR twice daily in a large double-blind,
`multicenter, placebo—controlled study [6]; 1529 patients
`were randomized to treatment with TOI.-I-ZR (ri = 507),
`'llOL-IR (11 = 514), or placebo (11 = 508). The mean reduc-
`tion in weekly urge incontinence episodes with T0 L-ER
`and TOL—lR was 53% and 46%, respectively (P > 0.05). The
`median reduction in urge incontinence episodes from
`baseline was 71% for TOL-ER, 60% for TOL-IR, and 33%
`for placebo, with the OXY-ER being 18% more effective
`than the immediate—release formulation (P < 0.05). The
`rate of dry mouth was 23% for’l'Ol.-liR, 30% for TOL-IR.
`and 8% for placebo.
`In a randomized, double-blind study (OPERA) [7-0|,
`the efficacy and tolerability of the extended-release formu-
`lations of oxybutynin and tolterodine were compared.
`Four mg ofTOL-ER or 10 mg of OXY-ER were administered
`to 790 women with 21 to 60 urge incontinence episodes
`per week. The mean reduction in weekly urge and total
`incontinence episodes with the two drugs was statistically
`
`similar, ranging from 67% to 72%. The proportion of
`patients who reported total continence was 23% for those
`taking OXY-I.-‘R versus 16.8% with TOL-ER and this differ-
`ence was statistically significant (P = 0.03). The reported
`dry mouth rate was statistically lower in patients treated
`with tolterodine (29.7% vs 22.3%) primarily because ofa
`lower incidence of mild dry mouth. The incidence of mod-
`erate and severe dry mouth and the patient drop—out rate
`because of anticholinergic side effects were similar with
`both medications.
`
`Oxybutynin transdermal delivery system was approved
`by the FDA for the treatment of OAB. The OXY—TDS offers
`several advantages over oral dosing. including twice-weekly
`dosing and the potential for improved patient compliance
`and tolerability. The transdermal delivery system avoids
`the extensive pre—systemic metabolism that occurs with
`oral administration, greatly reducing the formation of the
`metabolite N-desethyloxybutynin. It generally is thought
`that N-desethyloxybutynin is primarily responsible for the
`dry mouth associated with anticholinergics. In a multi-
`center, randomized, placebo—controlled, dose-titration
`study [8--] involving 520 patients, 3.9 mg of OXY-TDS sig-
`nificantly reduced the median number of weekly inconti-
`nence episodes by 19 (61%) versus a 14.5 (50%) reduction
`with placebo (P : 0.0165). Sixteen (13%) of the 123
`patients treated with 3.9 mg achieved complete urinary
`continence. The incidence of dry mouth and constipation
`with 3.‘) mg of OXY-TDS was 9.6% and 0.8%, which was
`equivalent to placebo.
`
`How Good Are We Doing
`with Anticholinergics?
`The data clearly support that the newer oral and transder-
`mal anticholinergic formulations are effective for the treat-
`ment of DAB and achieve significant reductions in urge
`incontinence, but only a percentage of patients reach total
`dryness. Because of this, many patients are dissatisfied with
`treatment and the discontinuation rates in clinical practice
`are seemingly high. Analysis of nationwide prescription
`data tracking a cohort of26,200 patients revealed that less
`than 15% of patients treated with immediate-and
`extended-release tolterodine and oxybutynin refilled their
`prescription at 1 year (data on file at Watson Pharma, lnc.,
`Corona, CA). Although the reason for this is unclear from
`the analysis, it likely is caused by a number of factors
`including lack of efficacy, poor tolerability, poor patient
`selection. and cost. In a separate analysis. many patients
`expressed dissatisfaction with medical therapy. Although
`physicians voiced that side effects likely were the primary
`reason for their dissatisfaction, 29% ofpatients cited lack
`of efficaty (data on file at Ortho-McNeil Pharmaceuticals,
`lnc., Raritan, NJ).
`Unlike the expectations we have regarding anti-inconti-
`nence surgery, OAB always has been viewed as a condition
`that can be helped by medication, but often is not com-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2091 - 0002
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`448
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`Overactive Bladder
`
`pletely controlled or cured. Most urologists recognize that
`anticholinergics are not the panacea and do not address all
`of the pathophysiologic processes involved in patients with
`OAB. For this reason, there has been a natural tendency by
`physicians to accept the patient's initial favorable response
`to therapy, but not to try to be more aggressive, pushing the
`patient closer to achieving dryness. Any degree of leakage
`can adversely affect quality oflife and most patients would
`rather be as dry as possible. as long as side effects and cost
`were kept under control. By making more patients drier,
`perhaps more of them would be satisfied with treatment
`and continue with their therapy.
`
`A Second Look at the Efficacy Data
`When efficacy data are evaluated more closely, it is obvi-
`ous that many patients who respond favorably to anti-
`cholinergics continue to report a significant number of
`leaking episodes. In the OBJECT‘ study [5], the mean
`number of weekly urge and total incontinence episodes
`at baseline in both treatment groups ranged between
`24.1 and 28.6 events. The mean number of urge inconti-
`nence episodes at the end of the study for patients
`treated with OXY-I.-‘R and TOL-IR was 6.1 and 7.8, respec-
`tively. Similarly, patients treated with OXY-liR and TOL-
`IR still reported 7.1 and 9.3 weekly total incontinence
`episodes after 3 months of therapy.
`In the Ol’l£|{A study [700], patients with more severe
`urge or total incontinence were evaluated. The average
`number of weekly urge incontinence episodes decreased
`from 37.1 at baseline to 10.8 for the oxybutynin group and
`from 36.7 to 11.2 for patients treated with tolterodine. The
`decrease from baseline in the mean number of total incon-
`
`tinence episodes was statistically similar with oxybutynin
`(from 43.4 to 12.3) and tolterodine (from 42.4 to 13.8).
`For the sake of discussion, if one evenly distributes the
`number of residual incontinence episodes over each day of
`the week, patients in these two studies continue to leak an
`average of one-and-a-half to two times daily after 3 months
`of therapy. Data regarding the severity of each leaking epi-
`sode are not available. Furthermore, if one excludes the
`
`patients (23% of oxybutynin and 16.8% of tolterodine)
`who achieved total dryness from the 3-month calculations,
`the mean number of weekly (and daily] leaking episodes
`for the patients who are still incontinent at the end of the
`study would increase substantially.
`Greater reductions in urge and total incontinence have
`been reported in patients treated in dose-escalation studies
`with extended-release oxybutynin. In two randomized
`studies, the efficacy and tolerability of OXY-ER were com-
`pared with immediate-release oxybutynin (OXY-lk). 1n the
`first study [11 I], 105 patients with urge or mixed inconti-
`nence (with predominantly an urge component] were ran-
`domized to receive 5 to 30 mg of OXY-I.-‘R once daily or 5
`mg of OXY-IR one to four times daily. Dose titration
`started at 5 mg and the close was increased every 4 to 7 days
`
`until one of three endpoints was achieved: the patient
`reported no urge incontinence during the final 2 days of
`the dosing period, the maximum tolerable dose (defined
`as 5 mg lower than that which resulted in significant side
`effects) was reached, or the maximum allowable dose (30
`mg for OXY-ER and 20 mg for OXY-IR] was administered.
`The mean number of weekly urge incontinence episodes
`decreased from 27.4 to 4.8 and from 23.4 to 3.1 in patients
`treated with 0XY—l-IR and OXY-IR, respectively. Total incon-
`tinence episodes decreased from baseline of29.6 to 6 with
`OXY-ER and from 26.3 to 3.8 with OXY-lR. The mean per-
`cent reduction in weekly urge and total incontinence epi-
`sodes with OXY-[SR was 84% and 82%. respectively. which
`was statistically similar to the immediate-release formula-
`tion. Complete urinary continence was achieved in 41% of
`the OXY-ER patients and 40% of those treated with OXY-
`IR. Dry mouth was reported more often with immediate-
`release oxybutynin (87% vs 68%, P: 0.03].
`In a second dose-titration study [ 12], 226 patients were
`randomized to receive OXY-l_-‘R or OXY-IR. All of the
`
`patients were started on 5 mg daily and the dose was
`increased weekly by 5 mg to a maximum of 20 mg daily or
`when patients reached the most favorable balance between
`efficacy and side effects. 'l‘he mean reduction in weekly
`urge incontinence with OXY-ER and OXY-IR was 83%
`(18.6 to 2.9 episodes) and 76% (19.8 to 4.4 episodes),
`respectively. The mean reduction in total incontinence epi-
`sodes with OXY-ER was 81% versus 75% with OXY-l R.
`
`In both dose-escalation studies, OXY-[ER achieved a >
`
`80% reduction in urge and total incontinence episodes
`and a significant percentage of patients became dry. When
`averaged over a week, the mean number of daily inconti-
`nence episodes was reduced to approximately five to less
`than one accident daily. These results are superior to those
`achieved by the same or by other anticholinergics in other
`series and may be caused by a number of factors.
`Some would argue that this improved efficacy was par-
`tially caused by patient selection. In both studies, all of the
`enrolled patients were known responders to oxybutynin or
`to another anticholinergic medication. Although patient
`selection may be a factor, similar efficacy results have been
`achieved with OXY-ER in a treatment-naive population.
`Gleason at at‘, [13] evaluated 256 patients with urge or
`mixed incontinence treated with increasing dosages of
`OXY-ER from 5 mg once daily up to 30 mg. Seventy-two
`percent of the patients were naive to anticholinergics.
`Patients increased the dosage weekly by 5 mg until conti-
`nence was achieved for 2 days or until a satisfactory bal-
`ance between continence and adverse effects was attained.
`
`The reduction in mean weekly urge and total incontinence
`was 83% and 81%, respectively. A subgroup analysis ofthe
`patients who received previous anticholinergic therapy did
`not demonstrate any differences in efficaqz.
`The consistent superior efficacy demonstrated in these
`studies with OXY-ER was primarily caused by dose escala-
`tion. Patients were asked to increase the dosage until they
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`Patent Owner, UCB Pharma GmbH — Exhibit 2091 - 0003
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`Overactive Bladder: Improving the Efficacy of Anticholinergics by Dose Escalation 0 MacD1'r1rmid
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`449
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`Table I. Maintenance dose chosen with
`dose escalation
`
`Dose, mgld
`
`5
`I0
`I5
`20
`> 20
`
`Data from Anderson et al. [I 1'] and Gleason et al. [12].
`
`Anderson study
`
`Gleason study
`
`Percent (11)
`
`Percent (n)
`
`2:1 (I0)
`l3.0 (5)
`26.| (I2)
`31(4)
`30.4 (I4)
`
`2 I .0 (46)
`30.: (ea)
`I9.6 (43)
`|2.3 (27)
`Ia9on
`
`of ‘)0 patients with OAB and detrusor hyper-reflexia treated
`with immediate-release tolterodine demonstrated a dose-
`
`dependent effect on bladder function. Patients were ran-
`domized to receive 0.5, 1, 2, or 4 mg ofTOL-IR twice daily
`or placebo. Linear regression analysis showed that the
`effect of tolterodine on volume at first contraction and on
`
`maximum cystometric capacity was significantly dose-
`related (I’ = 0.011 and I’ = 0.00‘), respectively). Similarly,
`there was a trend toward an improvement in the micturi-
`tion diary variables and subjective assessment of symp-
`toms with increasing doses of tolterodine. In a study by
`Larsson at al. [17], 31‘) patients with urge incontinence
`were randomized to receive placebo or 0.5. 1. 2. or 4 mg of
`tolterodine twice daily. After 2 weeks of treatment, there
`was a dose-related improvement in micturition diary vari-
`ables, which reached statistical significance for frequency
`and average volume voided. but was not statistically signif-
`icant for the number of urge incontinence episodes. The
`mean increase in postvoid residual urine volume in
`patients taking 4 mg ofTOL-IR twice daily was 163 mL and
`four ofthe five patients who developed urinary retention
`during the study were treated with this higher dosage.
`Although 4 mg is the recommended daily dose for imme-
`diate- and extended-release tolterodine, many physicians
`anecdotally report success stories with 8 mg daily in select
`patients. The author recommends monitoring postvoid
`residual urine volume in patients effectively managed with
`higher dosages of tolterodine.
`Improved efficacy associated with dose-escalation also
`has been demonstrated with OXY-TDS. In a multicenter,
`double-blind study [B00], 520 patients treated with OXY-
`TDS were randomized to 1.3, 2.6, or 3.‘) mg daily. OXY-TDS
`3.9 mg significantly reduced the median number ofweekly
`incontinence episodes by 19 (61%) versus a 14.5 (50%)
`reduction with placebo. The reductions achieved with 1.3
`and 2.6 mg of OXY—TDS were not statistically different from
`placebo. Because of its excellent side-effect profile, OXY-TDS
`may prove to be the ideal delivery system for the administra-
`tion ofhigher dosages. A multicenter, double-blind,
`placebo-controlled. dose-titration study of OXY-TDS is
`underway evaluating its efficacy at higher dosages.
`
`Barriers to Dose Escalation
`
`When patients are given the option to increase the dose of
`their medication to achieve the best balance between effi-
`
`cacy and side effects, they often choose higher dosages
`than 5 anti 10 mg of OXY-liR. In contrast. most prescrip-
`tions in the United States are for 5 or 10 mg. According to
`nationwide prescription data (data on file, Ortho-McNeil
`Pharmaceuticals, Inc., Raritan, NJ), the percentage of5-mg,
`10-mg, and 15-mg prescriptions written by health care pro-
`viders are 41%, 48%, and 11%, respectively. It is estimated
`that only a small percentage of these patients are doubling
`or tripling their 10-mg tablet and taking higher dosages.
`The efficacy of OXY-ER, which was demonstrated in the
`
`achieved the best balance between efficacy and side
`effects. In the series by Gleason er al. [13], although clini-
`cal efficacy was seen across all of the dosages, 48.8% of
`the patients chose a maintenance dose higher than 10 mg
`(Table 1). Ofthe 219 patients included in the efficacy
`analysis, 122 (55.7%) were free of urge incontinence epi-
`sodes at the end of the study. Of these 122 patients, 33
`(27.0%), 39 (32.0%). 22 (18.3%), and 29 (23.8%) were
`on a maintenance dose of 5 mg, 10 mg, 15 mg, and > 15
`mg daily, respectively. Therefore, more than 40% of
`patients who reported no urge incontinence episodes at
`the end of the study were taking more than 10 mg daily.
`In a study by Anderson et al. [110], 46 patients treated
`with OXY-I.-‘R were evaluated. At the end of the study,
`nearly 65% of the patients titrated their OXY-|_-‘R to a
`maintenance dose higher than 10 mg (Table 1). liighteen
`patients (41%) achieved total urinary continence. Eleven
`of the 18 continent patients (61.1%) were taking more
`than 10 mg of OXY-IER.
`Dose escalation of OXY-ER similarly has been shown
`to be effective in patients with neurogenic bladder dys-
`function. In a study by O'Leary er al. [14], 20 patients
`with multiple sclerosis were initiated on 10 mg of OXY-[ER
`and were instructed to increase their dose bi-weekly or
`weekly until satisfaction was achieved or up to a maxi-
`mum dose of 30 mg daily. Thirteen of 20 patients (85%)
`chose a final dose higher than 10 mg. Thirteen patients
`(65%) were taking a daily dose of at least 20 mg at the
`end of study. Four patients (20%) preferred to continue
`taking 30 mg daily. 'l‘he mean number of weekly urge
`incontinence episodes significantly decreased from 1.2 at
`baseline to 0.3 episodes at the end of the study (P :
`0.0046). There was no reported significant increase in
`side effects with increasing dosing. In a second study
`[15], O’l.eary er al. repeated their dose escalation study in
`10 patients with spinal cord injury. All of the patients
`chose a final effective dose higher than 10 mg, with four
`patients taking 30 mg daily. The mean number ofweekly
`urge incontinence episodes significantly decreased from
`13 at baseline to 6 after 3 months of therapy.
`The efficacy of other anticholinergics also has been
`shown to be somewhat dose-dependent. A randomized,
`double-blind, placebo-controlled, multicenter study [16]
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`450
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`Overactive Bladder
`
`previous dose-escalation studies, would have been signifi-
`cantly impaired if patients were limited to the two lowest
`dosages. In the series by Gleason er al. [13], only 58.9% of
`the 122 patients who reported no urge incontinence were
`taking 5 or 10 mg. In the study by Anderson et. al.
`[11 I], of
`the 18 patients who were dry, only seven (38.9%) achieved
`dryness on 5 or 10 mg.
`There appears to be a discrepancy between the doses of
`OXY-I-ZR most com monly prescribed by health care provid-
`ers and those, which in many patients, provide better effi-
`cacy. This discrepancy can be explained by a number of
`factors. Many physicians are well aware of the dose—related
`side effects associated with immediate-release oxybutynin
`and are concerned about the same phenomenon with the
`newer anticholinergics. In the dose-escalation study by
`Anderson at al, [11-], 87% ofpatients treated with OXY—lR
`reported dry mouth (moderate or severe dry mouth in 46%
`of cases] because they increased the dosages up to 20 mg.
`Although it is well recognized that anticholinergic side
`effects are dose-related with all of the anticholinergics, the
`detrimental effects of dose escalation appears to be much
`lower with the newer formulations. In the case of OXY-ER,
`
`this is caused by its patented, push-pull, osmotic delivery
`system, which delivers oxybutynin at a controlled rate
`allowing for once-daily closing and an improved side-effect
`profile. Most of the compound is absorbed in the large
`intestine, minimizing cytochrome P450 metabolism,
`which primarily occurs in the liver and gut wall. This, in
`turn, lowers the formation of the metabolite N-desethylox-
`ybutynin, which is primarily responsible for dry mouth.
`Of the 46 patients in the study by Anderson et all.
`[ 110]
`who were treated with OXY-IER, 25% reported moderate or
`severe dry mouth, which was statistically less than OXY-IR.
`The incidence of moderate or severe dry mouth in those
`treated with 15 and 20 mg of ()XY—IjR was 18% and 22%,
`respectively. In a study by Versi er al. [12], the cumulative
`proportion of patients taking 15 mg of OXY-ER reporting
`moderate or severe dry mouth was 19.4%. Although these
`percentages are not insignificant, the data conversely dem-
`onstrate that approximately 80% of patients treated with
`higher dosages of OXY-ER experienced no or only mild
`dry mouth. In the author's opinion, this acceptable tolera-
`bility results from the reduction in the metabolite N—des—
`ethyloxybutynin and from patient selection. Ifa patient
`can tolerate 10 mg of OXY-ER, the physician likely is
`selecting a patient who can tolerate higher dosages. In
`contrast, every physician has experienced those patients
`who cannot tolerate oxybutynin or other anticholinergics
`even at lower dosages. Why some patients are more sensi-
`tive to anticholinergics is unclear.
`In addition to concerns regarding tolerability, there
`are a number of other factors that likely play a role in
`influencing prescribing habits. Physicians obviously pre-
`scribe the dosage of medication approved by the FDA
`and the dosage that is reported most commonly in the
`literature. In addition to this, marketing and education
`
`largely sponsored by the pharmaceutical industry also
`plays an influential role. In the case of OXY-ER, 5 to 30
`mg is approved by the FDA, but most of the education
`and marketing efforts have been directed toward 5 and
`10 mg of OXY-IER. The" competitive OAB marketplace
`also has been deemed by many as a tolerability market
`versus one that attempts to maximize the efficacy in
`individual patients. This focus on tolerability and safety
`has obvious important merits and is further targeted
`with the recognition that 52% of the total prescriptions
`written are by primary care physicians. With the well-
`recognized time restraints facing most physicians, there
`also has been a tendency to promote a single-dose pill
`or patch. Although all of these factors are legitimate, a
`single dose of any of the anticholinergics will not maxi-
`mize its efficacy in many patients.
`Many well-intended physicians claim that they do not
`push therapy further if the patients are content with their
`response to treatment. Although at first glance this "if the
`patient is happy,
`l'1n happy" approach appears to make
`perfect sense, the author does not endorse it totally. Most
`patients who claim they are pleased with their degree of
`improvement would rather be even drier or reach total dry-
`ness ifpresented with an opportunity to do so.
`Cost obviously is an important factor when consider-
`ing dose escalation. The monthly cost of 15 mg of OXY-ER
`is approximately 10% greater than that of the 5- and 10-mg
`pill and thus should not be considered as a major barrier.
`Iligher dosages of OXY-liR (> 20 mg], OXY-TDS, and
`tolterodine are achieved only by doubling the medication,
`which obviously is more expensive. Many patients are will-
`ing to accept the higher costs if they are significantly better
`or reach total dryness. When analyzing the expense of
`medication for the treatment of OAB, it is especially
`important to consider the direct and indirect costs associ-
`ated with incontinence [2] and the negative impact the
`condition has on quality oflife [18,19].
`
`Dose Flexibility
`Although much has been said about dose escalation, the
`literature also supports that 5 mg of OXY-ER also is effec-
`tive in many patients [11-,12,13]. Why some patients
`respond positively to low dosages of OXY-ER or to lower
`dosages of other anticholinergics is unknown. Treatment
`options for those who are sensitive to anticholinergics
`include 5 mg of ()XY_l_:R and 2 mg of immediate— and
`extended-release tolterodine daily. Because of the excellent
`side-effect profile associated with OXY-TDS, it is less likely
`that lower dosages with this formulation will be necessary.
`Although some have advocated cutting the patch in half,
`there are no data regarding its efficacy and its adherence
`qualities. The integrity of the matrix transdermal delivery
`system is not disrupted by cutting. OXY-ER offers physi-
`cians the greatest flexibility in dosing, allowing them to tai-
`lor their treatment to each individual patient.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2091 - 0005
`
`

`
`Overactive Bladder: Improving the Efficacy of Anticholinergics by Dose Escalation 0 MacDir1rmid
`
`451
`
`10.
`
`Conclusions
`
`More emphasis should be placed on maximizing efficacy
`in patients with OAB. It is clear from the literature and
`from personal experience that many patients can enjoy
`even greater improvements in symptoms and quality of life
`with dose escalation. This is especially the case with OXY-
`ER, which offers physicians the greatest flexibility in dos-
`ing. It is important for us to set our goals high and to take a
`few moments to quantitate our patient's response to ther-
`apy to provide them with the best care possible.
`
`References and Recommended Reading
`Papers of particular interest, published recently, have been
`highlighted as:
`I
`Of importance
`II Of major importance
`
`1.
`
`Thom DH: Overactive bladder: epidemiology and impact on
`quality of life. lhtiertt (Iare 2000:6-14.
`2. Wagner TH, Hu TW: Economic costs of urinary incontinence
`in 1995. Urology 1998, 51:355-361.
`3. Appell RA: Clinical efficacy and safety of tolterodine in the
`treatment of overactive bladder: a pooled analysis. Urology
`I997, 5D:‘J()-‘J6.
`4. Chancellor M, Freedman S, Mitcheson HD, or al.: Tolterodine,
`an effective and well-tolerated treatment for urge inconti-
`nence and other overactive bladder symptoms. Clin Drug
`Invest 2000, 19:83-91.
`('1 :il.: Prospective random-
`Appell RA, Sand 1’, I)mocl1owski R,
`ized, controlled trial of extended-release oxybutynin chloride
`and tolterodine tartrate in the treatment of overactive blad-
`der: results of the OBIECT Study. Mayo Clin Proc
`2001, 76:358-363.
`Van Kerrehroeck I‘, Kreder K, Jonas ll, at ol.: Tolterodine once-
`daily: superior efficacy and tolerability in the treatment of
`the overactive bladder. llmlogy 2001, 57:414-421.
`7." Diokno AC, Appell RA, Sand PK, er al.: Prospective, random-
`ized, double-blind study of the efficacy and tolerability of
`the extended-release formulations of oxybutynin and toltero-
`dine for overactive bladder: results of the OPERA Trial. Mayo
`Cltn Proc 2003, 78:687-695.
`Well-designed head-to-head study of extended-release oxybutynin
`versus tolterodine. The efficacy and tolerahility of each compound
`are compared.
`
`:Jl
`
`f..
`
`8," Dmochowski RR, Davila CW, Zinm-r NR, at nl'.: Eflicacy and
`safety of transdermal oxybutynin in patients with urge and
`mixed urinary incontinence. I Urol 2002, 1t:8:58()-T86.
`The efficacy and tolerability of oxybutynin transdermal delivery
`system is presented. ()XY—'l‘DS has an excellent systemic
`side-effect profile.
`9.
`Burgio KL, Locher ]L, Goode PS: Combined behavioral and
`drug therapy for urge incontinence in older women. IAm
`Ceriatr Soc 2000, 48:370-374.
`Burgio KL, Locher ]L, (Loode P8, or tlf.: Behavioral vs drug treat-
`ment for urge urinary incontinence in older women. [AMA
`1998, 280:l99.'i-2000.
`11 .- Anderson Rll, Mohley D, lilank ll, at al.: Once-daily controlled
`versus immediate-release oxybutynin chloride for urge uri-
`nary incontinence. lllrol 199‘), 161; 1809-1812,
`This paper illustrates the excellent efficacy that can be achieved with
`anticliolinergics by dose escalation.
`12.
`Versi E, Appell R, Mohley D, or ol.: Dry mouth with conven-
`tional and controlled-release oxybutynin in urinary inconti-
`nence. Olrsm Cynrwnl 2000, 95:718-721.
`13. Gleason DM, Susset J, White C, et ol.: Evaluation of a new
`once-daily formulation of oxybutynin for the treatment of
`urinary urge incontinence. Urology 1999, 54:420-423.
`0’Lea1y M, I.-‘rickson JR, Smith Cl’, or al.: Changes in voiding
`patterns in multiple sclerosis patients with controlled-release
`oxybutynin. lm ,‘ MS (Sure 2002, 4: 116-119.
`"I5. O'l.eaIy M, lirickson lR, Smith Cl‘, ct al.: The effect of
`controlled-release oxybutynin on neurogenic bladder func-
`tion in spinal cord injured patients. I Sgrirtril Cont Mail
`2003, 26:159-162.
`Van Kerrebroeck 1’, Amarenco (I, ‘lhuroff ]W, at al'.: Dose-rang-
`ing