ELEVIE
`
`Life Sciences 63 (2001) 2549-2556
`
`Life Sciences
`
`Clinical experiences with tolterodine
`
`Lisbeth Nilvebrant
`
`Biavemia Life Science Corrsultamts C/0 Ni1vebra'r1t Pharma Corrsulting/I B, Lii1.sj{1'na‘.svc'1'gen 11,
`SE—167 32 Bmmma, Sweden
`
`Abstract
`
`Tolterodine is the first muscarinic receptor antagonist that has been specifically developed for the
`treatment of overactive bladder. The objectives in the discovery program were to design a potent mus-
`carinic receptor antagonist that is equipotent to oxybutynin in the bladder, but less potent in salivary
`glands. with the aim of improving tolerability (less dry mouth) in patients with overactive bladder.
`Tolterodine is non—selective with respect to the muscarinic M1—M5 receptor subtypes, but has a greater
`effect on the bladder than on salivary glands in vivo, in both animals and humans. Clinical results
`show that the efficacy and safety of tolterodine in overactive bladder is equal to that ofoxybutynin,
`but that tolterodine is significantly better tolerated by the patients.
`2001 Elsevier Science Inc. All
`rights reserved.
`
`Key-wara’s.' Urinary bladder: Urge incontinence: Dry mouth: Selectivity: Human
`
`Introduction
`
`Overactive bladder is a chronic and debilitating urological condition (characterised by the
`symptoms of frequency and urgency, with or without urge incontinence) which has a pro-
`found effect on the quality oflife and activities ofdaily living for the patients [1]. Muscarinic
`receptor antagonists are routinely used in the treatment of overactive bladder and the efficacy
`and safety of oxybutynin (e. g. Ditropan“) in this condition have been well documented [2,3].
`However, at least 50% of patients treated with oxybutynin experience dry mouth [2], which
`often results in discontinuation of treatment [24]. Tolterodine is the first muscarinic receptor
`antagonist that has been specifically developed for the treatment of overactive bladder.
`Pharmacological data from functional in vitm and radioligand binding studies show that
`tolterodine is equipotent to oxybutynin in the urinary bladder, whereas the afiinity of toltero-
`dine is 8-fold lower than that of oxybutynin in salivary glands [5,6]. Tolterodine shows a se-
`lectivity for the bladder over salivary glands in the anaesthetised cat, while oxybutynin and
`
`* Corresponding author. Tel.: +46 3 704 3097; fax: +46 3 704 3097.
`E-mail address: lisbeth.nilvebrzmtéfibioventia.com (L. Nilvebrzmt)
`
`0024-3205/01/S — see front matter (if) 2001 Elsevier Science Inc. All rights reserved.
`PII: S0024-3205(01)01051-7
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0001
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`L. Niih-'6/Jram /Lift’ Sciences 68 (2001) 2549-2556
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`other M3-selective antagonists show the opposite selectivity in this model [5,6]. The selectiv-
`ity of tolterodine in vivo is not due to muscarinic receptor subtype selectivity, since tolterod-
`ine is non—selective with respect to the M.—M5 receptor subtypes [5,6]. This tissue—selectivity
`can probably also not be attributed to secondary actions in smooth muscles, because screen-
`ing of >50 receptors and other targets, showed that tolterodine exhibits significant affinity
`only at muscarinic receptors [Nilvebrant, unpublished data].
`Bladder function is complex, and several muscarinic receptor subtypes may be involved.
`Data on tolterodine and oxybutynin (M3/M, selective) and other antagonists, indicate that
`both M3 and M3 receptors may be important for bladder Contraction in viva [5,6]. This is
`supported by results from other studies on bladder contraction in vitro and in viva [7]. It has
`further been found that prejunctional excitatory M. receptors might be important in bladder
`function [8]. The pharmacological profile of tolterodine has been reported and reviewed
`elsewhere [5,6 and refs. therein]. This paper will concentrate on the clinical experience
`with tolterodine. The documentation of tolterodine in patients represents the largest clinical
`development program that has been undertaken for any drug in the treatment of overactive
`bladder [9].
`
`Early clinical studies with tolterodine
`
`Clinical plmrse I .s‘tudies in liearlthy volunteers
`
`The first phase 1 study with tolterodine (0.2—l2.8mg_) showed that the effect on the bladder
`was more marked and long—lasting than the effect on salivation. After l2.8mg, volunteers re-
`ported micturition difficulties up to 16h post-dose [10]. The effects oftolterodine (6.4mg) on
`the bladder were objectively measured by cystometry in another study. The pharmacological
`effect on the bladder was immediate and sustained (>5h post-dose), while the effect on sali-
`vation was apparent only around the peak serum concentration (l—2h post-dose) [ll]. This
`indicated that the effect on the bladder might be dose—limiting. A twice daily (bid) dosage
`regimen was therefore selected for the phase II dose—finding studies in patients [6,l2].
`
`Metabolism— extensive and poor nretcil;oli.s'e:~.s'
`
`Tolterodine is extensively metabolised in the liver, mainly via cytochrome P450 2D6
`(CYP ZD6) to the 5—hydroxymethyl derivative (5-1-1M, labcode DD 0l_)[6]. The pharmacolog-
`ical profile of this metabolite is almost identical to that of tolterodine and 5-HM contributes
`to the therapeutic effect [6]. Some individuals (about 7% of Caucasians) lack the CYP 2D6
`enzyme (poor metabolisers) and can not form 5—HM_. but get higher serum levels of tolterod-
`ine [12]. A concentration—effect relationship has been demonstrated between the sum of un-
`bound serum concentrations (tolterodine+ 5—HM) and clinical effects on the bladder (phase II
`data) [12]. Clinically effective serum concentrations are comparable to the KifKB—values de-
`termined for tolterodine and 5—HM at bladder muscarinic receptors. It was concluded that
`5—HM is responsible for the clinical effect in extensive metabolisers, whereas the clinical ef-
`fect in poor metabolisers is due to tolterodine. The efficacy, safety and tolerability were simi-
`lar in poor and extensive metabolisers. The same dose of tolterodine can therefore be used, ir-
`respective of metabolic phenotype [6,l2].
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0002
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`2551
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`A.
`
`B.
`
`300
`
`I Residual Urine
`
`,_
`39
`0
`.E
`T:
`E
`E
`
`E
`cu
`
`5
`
`O MieIuritionsl24 hours
`
`O Incontinence episodesI24 hours
`
`
`
`,. 250
`E3.
`0
`.5 200
`E
`E 150
`E
`
`.5.’
`in
`
`100
`
`5 59
`
`0
`
`Placebo 0.5 mg
`bid
`
`1 mg
`bid
`
`2 mg
`bid
`
`4 mg
`bid
`
`Placebo 0.5_mg
`bld
`
`1 mg
`bld
`
`2 mg
`bid
`
`4 mg
`bld
`
`Fig. 1. Efficacy results in phase II. Panel /\ shows the dose-dependent decrease in number of micturitions and
`incontinence episodes/24h after 2 weeks of treatment with tolterodine. Panel B shows the increase in residual
`urine after 2 weeks of tolterodine treatment.
`
`Clirrirra/p/1cz.s‘e H .s‘tudie.s' in pat‘iem‘.s' with a,'etru.s'0r mstabi/ity
`or de1‘ru.s‘0r hyperre exia
`
`Tolterodine 0.5. 1. 2 and 4mg bid and placebo (2 weeks) were compared in 4 phase II
`studies (319 patients). A pooled analysis of urodynamie variables indicated that tolterodine
`4mg was the most effective dose [12]. A dose—dependent effect was also seen on number of
`micturitions/24h and number of incontinence episodes/24h, but 4mg tolterodine did not have
`a greater effect than 2mg on these symptoms (Fig.1). This was attributed to the dramatic in-
`crease in residual volumes in the 4mg group (Fig.1). Apparently, tolterodine 4mg interfered
`with the normal bladder function, resulting in incomplete emptying and decreased functional
`bladder capacity. There were 4 Cases of urinary retention in the 4mg group [12]. Tolterodine
`1 and 2mg bid were therefore selected for evaluation in the phase lll program.
`
`Clinical phase III studies
`
`The phase lll program for tolterodine Comprised 8 double blind, randomised studies in 15
`Countries and involved 2080 patients. Four of the 8 studies were 4 weeks in treatment dura-
`tion and compared tolterodine l and 2mg bid versus placebo. The other 4 studies were l2
`week treatment duration studies. Two of these compared tolterodine (2mg bid) to oxybutynin
`(Smg tid —i.e., three times daily) and placebo, one study compared tolterodine (2mg bid)
`to oxybutynin (Smg tid) and one study compared tolterodine (1 and 2 mg bid) to placebo.
`Micturition diaries were used for measurement of efficacy in all studies, with numbers of
`mieturition/24h as the primary cnd—point. Eflieaey was measured also by urodynamics in one
`of the studies comparing tolterodine 1 and 2mg to placebo during 4 weeks [13]. Several reports
`of individual phase III studies have been published and reviewed [3,9,l4 and refs. therein].
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0003
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`2552
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`A.
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`0.0
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`-0.5
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`L. Nihsehram /Lift’ Sciences 68 (2001) 2549-2556
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`Micturttionsl24 h
`
`Incontinence
`episodesf24 h
`
`B.
`
`100
`90
`
`i an
`5
`--
`70
`3
`50
`E
`2‘
`so
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`0
`40
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`,
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`t
`
`El Placebo
`|:| Tnllarodlne 2 mg and
`I Oxyhulynln 5 mg lld
`-No.05 vs placebo
`
`Fig. 2. Ellieaey and tolerability oflollerodiiie 2mg bid. oxybutynin Sing lid and placebo, alter 12 weeks ol'lrcz11-
`ment (phase III results). Panel A shows the decrease in the number of incontinence episodes and micturitions/24h.
`Panel B shows the incidence of dry mouth (none, mild. moderate. or severe) for the different treatment regimens
`used in phase III.
`
`Placebo
`
`Toflarodina Oxybutynln
`2 mg bid
`5 mg Ild
`
`Efficmy
`
`Tolterodine l and 2mg bid were both superior to placebo in efficacy, although the differ-
`ence between tolterodine l and 2mg was not always clear—cut, as measured by micturition di-
`ary variables [9,l4]. However, the study with urodynamie evaluation showed a dose—effect
`relationship and that only the effect of tolterodine 2mg (not lmg) was significant [13]. The
`greater effect of tolterodine 2mg over lmg was further manifested in the subjective assess-
`ment of patients perception of improvement of their bladder condition [3,9].
`In each of the comparative 12 week studies, tolterodine 2mg bid was shown to be equiva-
`lent to oxybutynin 5mg tid with regards to eflieaey on micturition and number of inconti-
`nence episodes. A pooled analysis of data showed that both tolterodine and oxybutynin are
`significantly more effective than placebo (Fig 2), although a statistical significance was not
`achieved for all efiicacy variables in each individual study [9,l4]. As compared to base—line
`values, the number of micturitions/24h decreased by 20% for both tolterodine and oxybuty—
`nin. The number of incontinence episodes/24h decreased by 40—60% and the mean volume
`voided per micturition increased by l8—28%. Patients overall subjective perception of im-
`provement of their bladder condition was also similar for tolterodine and oxybutynin [3,9].
`Interestingly, the compliance was higher in the tolterodine than in the oxybutynin group [9].
`
`Safety and Iolerability
`
`Tolterodine 2mg bid was equal to both placebo and oxybutynin 5mg tid, with respect to
`general safety and there were no cardiovascular safety concerns in the studies of tolterodine
`[3,9,l4]. Except for dry mouth, tolterodine did not differ from placebo in the incidence of
`classical antimuscarinic side-effects, while oxybutynin had a higher incidence of side-effects
`related to the gastro—intestinal tract [9,] 4]. Dry mouth was the most commonly reported ad-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0004
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`2553
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`verse event for all groups: placebo (16%), tolterodine (40%) and oxybutynin (78%). How-
`ever, it was classified as moderate to severe by 60% of patients on oxybutynin, as compared to
`only 17% for tolterodine and 6% for placebo (Fi g 2). Withdrawals from the studies because of
`side—effects were significantly less frequent in tolterodine (8%) and placebo (5%) patients,
`than in the oxybutynin group (20%). Similarly, 32% of patients treated with oxybutynin re-
`quired a dose—reduction, as compared to only 9% in the tolterodine and 4% in the placebo
`group [9]. Tolterodine was thus significantly better tolerated than oxybutynin in these studies.
`
`Lrmg—term re,s'u:'r,s'
`
`The efiicacy and tolerability of tolterodine have been confirmed in long—term open—label
`studies of 9-12 months duration. Thus, for example, 512 of 815 (63%) patients completed
`treatment for 12 months with maintained efiicacy and only 3% of patients withdrew because
`of dry mouth [3,14]. Similar results were reported for 854 patients offered to enter a 9-month
`treatment period [3]. The use of antimuscarinic agents in overactive bladder (primarily oxy-
`butynin) has previously been disappointing because the compliance among patients has been
`low [2] and in more than 80% of the patients resulted in discontinuation of treatment within
`6 months, due to side—eifects, primarily dry mouth [4].
`
`General comments and considerations regarding clinical trials
`in overactive bladder
`
`Overactive bladder is a difficult condition for clinical trials because objective urodynamic
`findings do not always correlate well with the subjective symptoms of the patient. Urody—
`namies was therefore used for evaluation of efficacy in only one of the phase 111 studies,
`while micturition diaries were used in all studies to measure the meaningful patient variables.
`Frequency of micturition/24h was the primary end—point, whereas numbers of incontinence
`episodes/24h and mean volume voided per micturition were secondary end—points. This is
`important. with respect to the outcome of the individual phase III studies because, although
`all patients had symptoms of an overactive bladder, all of them were not incontinent. There-
`fore, the individual phase III studies on tolterodine were not powered to measure statistically
`significant decreases in incontinence episodes [9].
`This is illustrated by a later, large study comparing tolterodine 2mg bid (n=514) to placebo
`(n=508) for 12 weeks, in which the number of incontinence episodes was used as primary
`end-point. Thus, tolterodine 2rng bid significantly decreased the number of incontinence epi-
`sodes (46%) and the number of micturitions (15%), while the mean volume voided increased
`by 21% [15]. Overall, these results were very similar to those of the phase 111 studies and
`showed statistically significant changes as compared both to base—line values and placebo,
`for all efficacy variables. Interestingly, this study also attempted to measure the effect on ur-
`gency, a symptom that probably is more bothersome and relevant to the patient, than frequent
`micturitions per se. The results showed a decreased sensation of urgency in 40% of tolterod-
`ine patients vs. 26% on placebo and this was accompanied by a 36% decrease in the number
`of pads used in the tolterodine group vs. a 13% decrease in the placebo group [15].
`Similarly, the placebo effect was fairly high in all tolterodine studies and this was not un-
`expected, because the frequent use of micturition diaries to measure subjective effects intro-
`
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`dueed an element of bladder training into these studies. Bladder training is indeed important
`in the management of patients with overactive bladder and it is certainly effective in the short
`term, although it also affects the placebo response in clinical trials of drugs [9,l5].
`Another important point is the dose of oxybutynin used in the comparative phase III
`studies (Smg tid). This is the recommended dose, but it is well known that many patients can-
`not tolerate this dose of oxybutynin. In clinical practise it is therefore common to use a lower
`dose or dose—titration [3,l4]. However, in order not to underestimate the eflicacy of oxybuty-
`nin, the recommended dose was used, but with a possibility to reduce the dose in case of in-
`tolerable side-effects. A comparative study using tolterodine 2mg bid, but a lower dose of
`oxybutynin (2.5mg, increasing to 5mg bid, with a possibility to revert to the lower dose) in
`patients D50 years was therefore done[l4]. The results confinned that the two drugs are
`equally effective, whereas tolterodine still has a superior tolerability profile—even in compari-
`son to a lower than recommended dose of 5mg tid for oxybutynin [3,l4].
`In the 12 week phase III studies, where efficacy was measured by micturition diaries, it was
`noticed that it took about 5-8 weeks of treatment before the effect of both tolterodine and oxy-
`butynin reached a maximum [9]. This may seem surprising, since a direct effect on the bladder
`is objectively demonstrable after a single dose of tolterodine [1 1]. However, micturition diaries
`do not refiect the direct pharmacological effect on the bladder and it takes time before the pa-
`tients learn to trust their medication and change their habits (e. g. scheduled voiding and fluid
`intake) [9,l5]. Thus, it is important to note that the mean volume voided per micturition actu-
`ally increases already before any change can be noted in the number of micturitions or inconti-
`nence episodes and that this reflects the pharmacological effect (increased bladder capacity) [12].
`
`Tolterodine in elderly
`
`The prevalence of overactive bladder increases with age and it is therefore important to
`demonstrate safety in this population, particularly since it is well known that e. g. oxybutynin
`may have a negative impact on cognitive function [16]. It has been shown that neither the ef-
`ficacy, nor the safety of tolterodine seems to differ between patients aged <65 and those >65
`years of age [14]. Tolterodine is >30 times less lipophilie than oxybutynin and 5-HM is an-
`other 12 times less lipophilie than tolterodine—i.e.,>350 times less lipophilie than oxybuty-
`nin. Thus, given the fact that the unbound serum concentration of 5—HM is 10 times greater
`than that of tolterodine, treatment with tolterodine would be expected to have a lower risk of
`a potential negative impact on cognitive function, than treatment with oxybutynin [17]. This is
`supported by tissue—distribution data in the mouse (after oral treatment with "‘C—tolterodine)
`which clearly show that the distribution of tolterodine and its metabolites into the central ner-
`vous system is very low [17] and by a recent study using quantitative EEG for measurements
`of potential effects of tolterodine, oxybutynin and placebo on the central nervous system. In
`this study, oxybutynin was shown to have significant effects on the EEG pattern, while
`tolterodine did not show any effects [18].
`
`Tolterodine in children
`
`Tolterodine is not yet licensed for use in children, but one open-label 3 month study in 22
`children has been published [19]. This study included 12 children who had previously not re-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0006
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`2555
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`ceived drug treatment and 10 who were switched from oral or intravesical oxybutynin to
`treatment with tolterodine. The tolterodine dose used was 0.1 mg/kg/day (0.5—4mg/day). The
`results showed that tolterodine is equally effective, but better tolerated, as compared to oxy-
`butynin in children with detrusor hyperrefiexia [19]. Only one patient experienced a moder-
`ate, transient side—efi"ect during tolterodine treatment. The dose used was higher than that rec-
`ommended in adults (2mg bid—i.e., 0.06—0.07mg/kg/day). Moreover, pharmacokinetics in
`children is not the same as in adults and other studies indicate that children get a higher expo-
`sure. Thus, ling bid might be the optimal dose for children [data on file, Pharmacia]. There-
`fore, tolterodine should not be used in children until more documentation is available.
`
`ToIterodine— once daily formulation
`
`A new once daily (qd) formulation of tolterodine 4mg has recently been developed and
`studied vs. placebo in a clinical study of 12 weeks duration [20]. Tolterodine qd was signifi-
`cantly superior to placebo with respect to the number of incontinence episodes and other
`micturition diary variables. For example, incontinence episodes decreased by 71% and num-
`ber of micturitions by 17%, while the volume voided per micturition increased by 24“/o—i.e.,
`the results with tolterodine 4mg qd are comparable to those reported for tolterodine 2mg bid.
`More patients on placebo (6.5%) withdrew from treatment due to adverse events, than in the
`tolterodine qd group (5.3%). Dry mouth was reported by 23% in the tolterodine qd group and
`by 8% in the placebo group [20]. Thus, the tolerability of tolterodine may have been some-
`what improved in this qd formulation, although a qd dosing might not be optimal for all pa-
`tients with an overactive bladder.
`
`Conclusion
`
`The clinical results with tolterodine vs. oxybutynin confirm the preclinical studies—in
`which tolterodine showed a selectivity for the urinary bladder over salivary glands in viva,
`whereas oxybutynin exhibited the reversed selectivity profile. Thus, tolterodine is equipotent
`to oxybutynin, with respect to the efficacy on overactive bladder symptoms in patients, but
`tolterodine shows a significantly better tolerability with respect to dry mouth and compliance.
`
`References
`
`l. Lenderking WR, Nackley JF, Anderson RB, Testa MA. A review of the quality—of—life aspects ol‘ urinary in-
`continence. Pharmaeoeeonomies l096;9:l 1-23.
`2. Yarker YE, Goa KL. Fitton A. Oxybutynin. A review of its pharmacodynamic and pharmacokinetic proper-
`ties, and its therapeutic use in detrusor instability. Drugs & Ageing l995;6(3):243—62.
`3. Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 2000;55 (SA,
`Suppl):33—46.
`4. Kelleher C.], Cardozo LD, Khullar V, Salvatore S. A medium term analysis ofthe subjective efficacy oftreat-
`ment for women with detrusor instability and low bladder compliance. British Journal of Obstetrics and
`Gynaecology l997;l04:988—93.
`5. Nilvebrant L, Hallen B, Larsson G. Tolterodine— a new bladder selective muscarinic receptor antagonist:
`Preclinical pharmacological and clinical data. Life Sciences l997';60(l3/14):] 129-36.
`6. Nilvebrant L. The mechanism of action of tolterodine. Reviews in Contemporary Pharmacotherapy
`2000;l l(l):l3—27.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0007
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`
`2556
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`L. Niit-‘Hiram /Life Sciences 68 (2001) 2549-2556
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`7. Hegdc SS. Chopin A. Bonhaas D, Biaud S. Loeb M. Moy TM, Loary D. Eglcn RM. Functional role MM;
`and M} muscarinic receptors in the urinary bladder of rats in virro and in viva. British Journal of Pharmacol-
`ogy 1997; l20:l409—l8.
`8. Somogyi GT, dc Groat WC. Function, signal transduction mechanisms and plasticity of prcsynaptic muscar—
`inie receptors in the urinary bladder. Life Sciences l999;(i4 ((1/7):4l 1-19.
`9. Appell RA. Clinical efficacy and safety oftolterodine in the treatment of overactive bladder: a pooled analy-
`sis. Urology l997;50 (6A, Suppl.):90—6.
`l0. B1'ynne N, Stahl MMS, Hallen B, Edlund PO, Palmer L, Hoglund P, (iabrielsson J. Pharmacokinetics and
`pharmacodynamics oftolterodine in man: a new drug for the treatment of urinary bladder overactivity. Inter-
`national Journal ofClinical Pharmacology and Therapeutics l997:35(7):287—95.
`l l. Stahl MMS, Ekstrfiin B, SparfB, Mattiasson A, Andersson K-11‘. Urodynamic and other effects of tolterodine:
`a novel antimuscarinic drug for the treatment of dctrusor overactivity. Ncurourology and Urodynamics
`l995;l4((i):647—55.
`l2. Larsson G, Hallen B. Nilvebrant L. Tolterodine in the treatment of overactive bladder: analysis of the pooled
`phase II efficacy and safety data. Urology l999;53(5):990—5.
`l3. Jonas U, Holher K, Madersbacher H, Holmdahl TH—and the participants of the international study group. Ef-
`ficacy and safety of two doses oftolterodine vs. placebo in patients with detrusor overaetivity and symptoms
`of frequency. urge incontinence and urgency: urodynamic evaluation. World Joumal of Urology l997:l5:
`144-51.
`
`14. Malone-Lee JG. The etficacy, tolerability and safety profile ol‘tolterodine in the treatment ot‘ove1'active/un-
`stable bladder. Reviews in Contemporary Pharmacotherapy 2000;] l(l):29—42.
`15. Chancellor M, Freedman S. Mitcheson HD. Antoci J, Priinus G. Wein A. Tolterodine, an effective and well
`tolerated treatment for urge incontinence and other overactive bladder symptoms. Clinical Drug lnvestigation
`2000;l9(2):83—9l.
`16. Kat: IR. Sands LP. Bilker W, DiFilippo S. Boyce /\. D’/\ngelo K. Identification of medications that cause
`cognitive impairment in older people: the case of oxybutynin. Journal of the American Geriatrics Society
`l998;46(l):6—l3.
`l7. Nilvebrant L, Piihltnan I, d’Argy R. Tissue distribution olitolterodine and its metabolites; low penetration into
`the central nervous system. European Urology 2000;37(Suppl 2):84 (Abstract 333).
`18. Dimpfel W, Todorova A, Vonderheid B. Electrophysiological evaluation of potential adverse effects of
`tolterodine, oxybutynin and trospium chloride on the central nervous system. Neurourology and Urodynam—
`ics 2000; 19 (4):487—8 (Abstract 94).
`l9. Goessel C. Sauter T. Michael T. Bergé B. Staehler M. Miller K. Efficacy and tolerahility of tolterodine in
`children with detrusor hyperreflexia. Urology 2000: 55(3):4l4—l8.
`20. Van Kerrebroeck PEVA (on behalf of the tolterodine study group). Significant decreases in perception of ur-
`gency and urge incontinence episodes with once-daily tolterodine treatment in patients with overactive blad-
`der. Neurourology and Urodynamics 2000: l9(4):493—4 (Abstract 89).
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`Patent Owner, UCB Pharma GmbH — Exhibit 2040 - 0008