Long-Term Safety, Tolerability and Ef cacy of Extended-Release Tolterodine in the Treatment of Overactive Bladder

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1 European Urology European Urology 41 (2002) 588±595 Long-Term Safety, Tolerability and Ef cacy of Extended-Release Tolterodine in the Treatment of Overactive Bladder K. Kreder a,*, C. Mayne b, U. Jonas c a Department of Urology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 3120 RCP, Iowa City, IA52242, USA b Department of Obstetrics and Gynaecology, Leicester General Hospital, Leicester, UK c Department of Urology, Hannover Medical School, Hannover, Germany Accepted 12 April 2002 Abstract Background: The objective of the present study was to examine the long-term safety, tolerability and ef cacy of tolterodine extended-release (ER) in patients who had completed 12 weeks' treatment in a randomised, double-blind study comparing tolterodine ER 4 mg once daily (qd), tolterodine immediate-release (IR) 2 mg twice daily and placebo. Methods: Of the 1377 patients completing the 12-week study, a total of 1077 (78%) chose to continue with 12 months' open-label treatment with tolterodine ER 4 mg once daily, irrespective of their previous treatment. Safety was assessed after 3, 6, 9 and 12 months' treatment in the study. Ef cacy was evaluated from micturition diary variables and patients' perception of bladder condition and urgency following 3 and 12 months' treatment. Results: 71% of patients completed the 12-month study. Tolterodine ER was safe and well tolerated. Adverse events of the general (14.5%), autonomic (13.2%), gastrointestinal (11.4%), respiratory (9.8%) and urinary (9.1%) systems were the most frequently reported. Dry mouth was the most common event, occurring in 12.9% of patients, and was generally mild in severity. Other adverse events occurred in less than 5% of patients. There was no increase in the frequency of adverse events with long-term relative to short-term treatment. The ef cacy of tolterodine was maintained over the 12-month treatment period; relative to baseline there were reductions in the number of incontinence episodes per week (median change 83%) and micturitions per 24 hours (median change 21%) and an increase in volume voided (median change 25%) after 12 months' treatment. An improvement in patient perception of their bladder condition was found in 75% of patients completing the study, and 51% had an improvement in patient perception of urgency. Conclusions: Tolterodine ER 4 mg qd displayed a favourable safety, tolerability and ef cacy pro le during 12 months' treatment of patients with overactive bladder. # 2002 Published by Elsevier Science B.V. Keywords: Tolterodine; Overactive bladder; Safety; Tolerability; Ef cacy 1. Introduction Overactive bladder is a chronic condition that is estimated to affect 50 million adults worldwide [1]. Misconceptions about the condition, however, prevent patients from seeking immediate advice and treatment. In fact, for the majority of sufferers, it is not uncommon to experience symptoms for at least 1 year before * Corresponding author. Tel ; Fax: address: karl-kreder@uiowa.edu (K. Kreder). seeking medical advice [2]. Such underreporting of overactive bladder symptoms has recently been con- rmed in a national screening initiative of over 80,000 American adults [3]. The characteristic symptoms of overactive bladderð urgency and frequency with or without urge incontinence [4]Ðarise from uncontrolled detrusor muscle contractions during bladder lling. As contraction of the detrusor muscle is primarily mediated by cholinergic activation of the muscarinic receptors [5], antimuscarinic agents have formed the basis of treatment. Due to the /02/$ ± see front matter # 2002 Published by Elsevier Science B.V. PII: S (02)00177-X

2 K. Kreder et al. / European Urology 41 (2002) 588± chronic nature of overactive bladder, such treatment is frequently long-term. However, tolerability problems, such as dry mouth, gastrointestinal disorders and central nervous system (CNS) effects, which are related to the antimuscarinic properties of these agents, have limited their long-term use [6±8]. Of the available antimuscarinic agents, tolterodine and oxybutynin are the most widely used. The equivalent ef cacy of the immediate-release (IR) formulations of tolterodine (2 mg twice daily) and oxybutynin (5 mg three times daily) is well established [9±11]. However, tolterodine IR is signi cantly better tolerated in terms of the frequency and intensity of dry mouth [9,11] and demonstrates clear differences with regards to the incidence of gastrointestinal disorders [9±11], central and autonomic nervous system effects [11,12] and visual disturbances [10,13]. In fact this favourable tolerability pro le may provide a possible explanation for the high proportion of patients completing longterm tolterodine IR [14,15]. A once-daily (qd), extended-release (ER) formulation of tolterodine has been developed in order to provide maximal convenience for patients. As compliance improves with decreasing dose frequency [16], it was postulated that this increased convenience may further improve compliance rates. It was also postulated that the atter serum pro le of tolterodine ER [17], relative to the IR form, might lead to improved ef cacy and tolerability, this has in fact been con rmed in a recently completed study [18]. Tolterodine ER 4 mg qd, which is pharmacokinetically equivalent to tolterodine IR 2 mg twice daily in terms of the area under the serum concentration time curve, also provides prolonged release of the drug over the entire physiological ph range (Data on le, Pharmacia Corporation), and has demonstrated a signi cant advantage over its IR formulation in terms of ef cacy and tolerability in a 12-week study [18]. The aim of the current study was to investigate the long-term safety, tolerability and ef cacy of tolterodine ER 4 mg qd in a 12-month open-label extension study in patients with overactive bladder. 2. Methods This 12-month, open-label, uncontrolled, non-randomised extension study was conducted at 138 centres in North America (50.2%), Europe (41.3%) and Australia/New Zealand (8.4%). The study was conducted in accordance with the Declaration of Helsinki, local Independent Ethics Committee/Institutional Review Board and Good Clinical Practice guidelines. Patients provided written informed consent prior to entry Patients Patients with overactive bladder completing 12 weeks' treatment in a multinational, randomised, double-blind, active and placebocontrolled trial [18] were allowed to continue with 12 months' open-label treatment with tolterodine ER 4 mg qd, irrespective of treatment received during the double-blind study (tolterodine ER 4 mg qd, tolterodine IR 2 mg twice daily or placebo). No dosage reduction was permitted in either the 12-week double-blind study or the 12-month open-label extension study. The randomised double-blind study enrolled male and female patients aged 18 years with urinary frequency (8 micturitions per 24 hours), urge incontinence (5 incontinence episodes per week) and urgency. Patients were required to have symptoms of overactive bladder for 6 months. Patients were recruited solely on the basis of these symptoms and irrespective of previous treatment and response to prior antimuscarinic therapy. Exclusion criteria included: stress incontinence; total daily urine volume >3 l; contraindications to antimuscarinic treatment; signi cant hepatic or renal disease; symptomatic or recurrent urinary tract infections, interstitial cystitis, hematuria or bladder outlet obstruction; electrostimulation or bladder training; indwelling catheter or intermittent self-catheterization. Pregnant or nursing women, and women of childbearing potential not using reliable contraceptive methods, were excluded. Any treatment for overactive bladder including anticholinergic drugs, drugs that inhibit cytochrome P450 3A4 isoenzymes, or investigational drugs were not permitted. Patients on estrogen therapy that had been started more than 2 months prior to randomisation were able to continue treatment. In order to be included in the present study patients had to have been enrolled correctly (i.e. ful lled the original inclusion/exclusion criteria) and to have completed the double-blind study. Patients were also required to still need and desire treatment Study design This was an open-label, uncontrolled, non-randomised extension study, a schematic representation of which is shown in Fig. 1. Concomitant medication was recorded and monitored throughout the trial. Compliance was assessed by counting returned unused study medication and patients were considered compliant if 75% of medication was taken. Fig. 1. Schematic representation of 12 weeks' randomised treatment and 12 months' open-label treatment protocols.

3 590 K. Kreder et al. / European Urology 41 (2002) 588±595 Patients were contacted by telephone after 1 month and attended the clinic after 3, 6, 9 and 12 months or on withdrawal. Patients were followed up by a clinic visit or telephone contact 1 week after completing 12 months' treatment to monitor any ongoing adverse events Safety and tolerability analysis The primary objective of this study was to assess the safety and tolerability of tolterodine ER 4 mg qd over a 12-month period. Safety was assessed from serious adverse events and laboratory variables. Blood samples were taken at 3 and 12 months during the open-label study (or on withdrawal) in order to assess clinical and hematology variables. Tolerability was assessed from adverse events and withdrawals at 3, 6, 9 and 12 months during the open-label period and at 1-week follow-up. Adverse events were collected from spontaneous patient reports and also solicited from patients by the physician at each visit. An adverse event was de ned as any untoward medical occurrence, regardless of its relationship to treatment, and was classi ed according to intensity: mild (does not interfere with patient's usual function), moderate (interferes to some extent with patient's usual function), or severe (interferes signi cantly with patient's usual function) Ef cacy analysis The secondary objective was to evaluate the ef cacy of tolterodine ER 4 mg qd over the treatment period. For the purposes of this analysis, baseline was de ned as the start of the 12-week randomised study. Ef cacy variables were assessed at 3 and 12 months during the open-label study and included micturition diary variables (mean number of incontinence episodes per week, mean number of micturitions per 24 hours, mean volume voided per micturition) and patients perception of bladder condition and urgency. Micturition diary variables were recorded over a 7-day period preceding the 3- and 12-month visits. The volume voided for each micturition was recorded for at least 2 complete days during this period. Patients rated their perception of bladder condition using a six-point rating scale (0 ˆ no problems; 1 ˆ very minor problems; 2 ˆ minor problems; 3 ˆ moderate problems; 4 ˆ severe problems; 5 ˆ many severe problems) and perception of urgency using a threepoint rating scale (1 ˆ able to nish tasks before going to toilet; 2 ˆ able to hold urine until toilet visit if went immediately; 3 ˆ not able to hold urine). Patients completed the perception of bladder condition and perception of urgency questions in a blinded fashion, i.e. they were not able to review their previous responses Statistical analysis Safety and tolerability were assessed for all patients who entered the 12-month open-label study and received at least one dose of tolterodine ER 4 mg (the `safety population', n ˆ 1075). Adverse events and withdrawals were classi ed by preferred term or reason and summarised using frequency counts. Changes in clinical laboratory values were summarised and shift tables constructed for the changes. Analysis of ef cacy was performed on data from patients who entered andcompleted the 12-month open-label study(the `completer population', n ˆ 759). Ef cacy was also analysed for patients who were initially randomised to tolterodine ER and completed the 12-month study (the `15-month completer population', n ˆ 256). In the completer and 15-month completer populations, missing values were not imputed. For the micturition variables, the percentage change from baseline was calculated for each micturition diary variable, median values are presented because the data was not normally distributed. The Wilcoxon rank-sum test was generated to test the difference in median percentage changes from baseline between the 12-weekrandomisedstudyand3 or12 months of the open-labelstudy. Mean change from baseline and standard deviation were included for informational purposes. Patient perception variables were summarised using percentage of patients improved after treatment. 3. Results 3.1. Patient characteristics Of the 1337 patients completing the 12-week study, a total of 1077 (78%) chose to continue open-label treatment with tolterodine ER (Fig. 1), having previously received either placebo (n ˆ 339, 31.5%), tolterodine IR (n ˆ 370, 34%) or tolterodine ER (n ˆ 368, 34%). Of the 1077 in the study, two did not receive tolterodine therapy and therefore, the safety population comprised 1075 patients. A total of 759 (70.6%) patients completed all 12 months of open-label treatment. Total patient exposure on tolterodine ER was 911 patient years. Baseline characteristics of the safety population are shown in Table 1. The majority of the patients were female and the mean age was 60 years. Over half of the patients had previously received treatment for overactive bladder, of whom 231 (39.1% of those treated) had experienced poor ef cacy. Similar baseline demographic and micturition chart values were observed in the completer population and the 15-month completer population. The main reasons for treatment discontinuation among the 316 (29%) patients in the safety population who failed to complete the 12-month study were adverse events (n ˆ 107, 9.9%), lack of ef cacy (n ˆ 108, 10.0%), withdrawal of consent (n ˆ 46, 4.3%), lost to follow-up (n ˆ 41, 3.8%) or protocol violation (n ˆ 14, 1.3%) Safety and tolerability Tolterodine ER was safe and well tolerated during long-term treatment. The most frequently reported adverse events (i.e. reported in >5% of patients) were disorders of the general (14.5%), autonomic (13.2%), gastrointestinal (11.4%), respiratory (9.8%), urinary (9.1%) and musculo-skeletal (6.0%) systems. There was no evidence of an increase in the incidence of these events with long-term tolterodine treatment. Dry mouth was the most frequent adverse event, which occurred in 12.9% of patients and was generally mild in severity (Fig. 2). In the 12-week study, 23% of tolterodine ER recipients had complained of dry mouth, the majority of which was mild in severity (Fig. 2). In the open-label study, adverse events other than dry mouth occurred in <5% of patients (Table 2).

4 K. Kreder et al. / European Urology 41 (2002) 588± Table 1 Demographic and clinical characteristics of patients at baseline of 12-month open-label study (safety population) Variable Safety population (n ˆ 1075) a Mean age, years (range) 60.3 (19.6±93.2) Gender, male:female (%) 18:82 Medical history (n (%)) Previous treatment for OAB 591 (54.9) Previous treatment for OAB with poor ef cacy b 231 (39.1) Micturition chart variables (n (%)) 8 Micturitions per 24 hours 1041 (96.7) 5 Incontinence episodes per week 1056 (98.1) 200 ml mean volume voided per micturition 1032 (95.8) Abbreviations: ITT, intention to treat; OAB, overactive bladder. a There were 1077 patients in the ITT population. Two patients did not receive any doses of tolterodine ER. b Percentage calculated on number of patients who had received treatment for OAB. Constipation (3.3%) and urinary tract infection (4.1%) were the most frequent gastrointestinal and urinary events, respectively. Xerophthalmia, abnormal vision, dizziness, somnolence, nervousness, abdominal pain, atulence, vomiting and paresthesia had a low incidence (1.3%) in this study. Micturition disorders (e.g. hesitancy, feeling of incomplete emptying, poor stream) were reported by 1.3% of patients and the majority (12/14) were of mild to moderate severity. There were 107 withdrawals due to adverse events. The most common adverse events that occurred singly or in combination with other adverse events and led to withdrawal were as follows: dry mouth (19, 1.8%), headache (9, 0.8%) abdominal pain (9, 0.8%), dizziness (7, 0.7%), urinary tract infection (7, 0.7%), dyspepsia (6, 0.6%) constipation (6, 0.6%), xerophthalmia (5, 0.5%), and micturition disorders (5, 0.5%). All other adverse events leading to discontinuation occurred in less than 0.5% of patients. Serious adverse events were experienced by 79 patients, 12 of whom withdrew from treatment. Serious adverse events were of a wide variety and only four of these events (urinary retention, n ˆ 2; aggravated multiple sclerosis, n ˆ 1; medication error, n ˆ 1) in three patients were considered to be related to tolterodine (all except one had resolved at follow-up). Four deaths occurred during the study, none of which were considered to be related to treatment. There were no clinically relevant changes in laboratory safety parameters Ef cacy The ef cacy of tolterodine ER was maintained during long-term treatment. More than 85% of the patients Fig. 2. Percentage of tolterodine ER patients reporting dry mouth, and maximum intensity reported, during 12 weeks' randomised [18] and 12 months' openlabel treatment.

5 592 K. Kreder et al. / European Urology 41 (2002) 588±595 Table 2 Summary of adverse events reported by >2% of patients (safety population) during 12 months open-label treatment with tolterodine ER 4 mg a Adverse event 12-week randomised study (n ˆ 505) 12-month open-label study (n ˆ 1075) Parasympathetic Dry mouth 118 (23) 139 (12.9) Gastrointestinal Constipation 30 (6) 35 (3.3) Dyspepsia 15 (3) 24 (2.2) Respiratory Upper respiratory tract 14 (3) b 43 (4.0) Infection Bronchitis 2 (0.4%) b 28 (2.6) Urinary Urinary tract infection 16 (3) 44 (4.1) Cystitis 4 (0.8) b 23 (2.1) Nervous system Headache 32 (6) 26 (2.4) Other Back pain 4 (0.8) b 35 (3.3) In uenza-like symptoms 4 (0.8) b 28 (2.6) a Values are numbers (%). Results from the safety population in the 12- week study who received tolterodine ER 4 mg qd are included for comparison purposes [18]. b Data on file. who completed 12 months' treatment were >75% compliant. Compliance in the keeping of micturition diaries was 90%. In the completer population, tolterodine produced signi cant improvements in the number of urge incontinence episodes per week (median change 83%), number of micturitions per 24 hours (median change 21%), and volume voided per micturition (median change 25%) after 12 months of treatment compared with baseline (Table 3). The values were not signi cantly different from those noted after 3 months openlabel treatment or for patients completing 12 weeks' treatment with tolterodine ER in the double-blind study, with the exception of micturition frequency, where a signi cantly greater median percentage change reduction was noted after 3 months' treatment compared to the 12-week double-blind results (Table 3). Patients treated for 12 months perceived their condition to be improved. A total of 75% of patients had an improvement in their bladder condition and 51% had an improvement in their urgency. This level of improvement was more than that reported after 12 weeks' treatment, where 62.5% and 42.7% of patients perceived an improvement in their bladder condition and noted an improvement in their urgency, respectively. The 15-month completer population results were con rmatory of the ef cacy of long-term treatment. After 15 months, tolterodine treatment produced signi cant improvement in the number of urge incontinence episodes per week (median change 85.2%), number of micturitions per 24 hours (median change 21.5%), and volume voided per micturition (median Table 3 Effect of tolterodine on micturition diary variables (completer population) Variable 12-week randomised (n ˆ 429) Open-label study (n ˆ 759) 3 months 12 months Number of incontinence episodes per week Baseline mean (range) 22.5 (0.0±168.0) 21.6 (0.0±168.0) 21.6 (0.0±168.0) Study visit mean (range) 8.9 (0.0±163.0) 8.2 (0.0±125.0) 9.1 (0.0±168.0) Mean change from baseline (S.D.) 13.6 (18.6) 13.4 (19.3) 12.5 (19.9) Median % change from baseline p-value a Number of micturitions per 24 hours Baseline mean (range) 11.0 (2.3±51.3) 10.9 (2.3±48.6) 10.9 (2.3±48.6) Study visit mean (range) 9.0 (2.1±26.0) 8.5 (1.4±31.6) 8.6 (1.2±34.9) Mean change from baseline (S.D.) 2.1 (3.6) 2.4 (3.2) 2.3 (3.4) Median % change from baseline p-value a Volume voided per micturition (ml) Baseline mean (range) (36.2±270.5) (21.2±373.5) (21.2±373.5) Study visit mean (range) (28.8±450.0) (31.3±535.7) (15.0±783.3) Mean change from baseline (S.D.) 40.2 (52.5) 42.9 (55.6) 43.2 (60.3) Median change from baseline (%) p-value a S.D.: standard deviation a Versus median change at 12 weeks.

6 K. Kreder et al. / European Urology 41 (2002) 588± Fig. 3. Effect of tolterodine on micturition variables after 12 weeks' double-blind treatment and 3 and 12 months' open-label treatment in the 15-month completer population. change 27.8%) compared with baseline (Fig. 3). These values were not signi cantly different from those noted after 12 weeks' double-blind treatment or 3 months' open-label treatment in this population (Fig. 3). As with the micturition data, no development of tolerance was noted for patient perception variables. After 12 weeks' double-blind, 3 months' open-label and 12 months' open-label treatment, 69.9%, 77.4% and 73.9% of the 15-month completer patients perceived improvement in their bladder condition, respectively. A total of 46.9%, 52.7% and 54.9% of patients perceived improvement in their urgency at these three time points. 4. Discussion Tolterodine IR is a safe and well tolerated treatment for overactive bladder, with rapid onset of effect as shown urodynamically and with micturition diaries [19±21]. The excellent safety, tolerability and ef cacy of the IR formulation is maintained during long-term treatment as shown in 9- and 12-month open-label extension studies [14,15]. Like the IR formulation, the ER formulation of tolterodine has been shown to be safe and well tolerated and to have an early onset of effect, with patients naõève to pharmacotherapy for overactive bladder experiencing a 62% median reduction in incontinence episodes after 1 week of treatment and patients previously treated on other pharmacological treatments experiencing a 54% reduction during the same timeframe [22]. The present study is the rst to investigate the long-term safety, tolerability and ef cacy of tolterodine ER. The patient population is representative of that seen in clinical practice, with a mean age of 60 years and more than half having previously received treatment for overactive bladder. Patients were recruited into this study irrespective of previous treatment and response to antimuscarinic therapy. As highlighted earlier, compliance has been shown to improve with decreased dosing frequency [16]. In this study, good compliance with tolterodine ER was observed, with 85% of patients 75% compliant. This high compliance, coupled with the ef cacy and favourable tolerability pro le of tolterodine ER, translated into a high proportion of patients remaining on treatment, with 71% of patients completing 12 months' treatment. This high completion rate is superior to that seen with tolterodine IR, where 70 and 62% of patients completed 9 and 12 months of treatment, respectively [14,15]. This result is not overly surprising considering that tolterodine ER has been shown to have superior ef cacy and tolerability to tolterodine IR, with comparable safety [18]. Class effects of muscarinic receptor antagonists include: dry mouth, GI effects (constipation, dyspepsia), changes in visual accommodation, CNS effects (dizziness, somnolence), and urinary retention. In this study, there was no evidence of an increase in the frequency of adverse events with long-term exposure, when the results are compared with those from the 12-week study [18] (Table 2). Dry mouth was seen less frequently (12.9% versus 23%) and with a lower intensity (Fig. 2) compared with the short-term study. Other adverse

7 594 K. Kreder et al. / European Urology 41 (2002) 588±595 events commonly associated with antimuscarinic therapy occurred with a lower frequency in this 12-month study compared with the 12-week study. Abnormal vision, dizziness and somnolence were observed in less than 1.3% of patients in the present study. Acute urinary retention is a safety concern with antimuscarinic medications and potentially this could be more of an issue with an ER formulation of an antimuscarinic agent, with active drug present in the serum for a longer period. However, this was not that case in the present study, where acute urinary retention was reported by 0.19% (2/ 1075) of patientsða nding which is comparable to that reported with long-term tolterodine IR treatment [14,15]. Collectively these ndings support the favourable tolerability pro le of tolterodine ER during longterm treatment. Ef cacy analyses have been reported on completer populations, rather than intent-to-treat (ITT) populations, as this method is more appropriate when estimating an effect in a study with a single arm. If an ITT analysis were used, adjustments would need to be made for those patients who dropped out early. Bringing patient data forward when dropouts occur at different time points would introduce inaccuracies in the data. By analysing the completer populations, we were testing to see if the effect on these patients (and not dropouts) is different from their baseline values. Signi cant improvements in the symptoms of OAB, which were seen in those patients who received tolterodine ER during the 12-week study, were maintained throughout this 12-month open-label study (Table 3). Relative to baseline there were reductions in the number of incontinence episodes per week (median change 83%), reductions in number of micturitions per 24 hours (median change 21%) and an increase in the volume voided (median change 25%) after 12 months' treatment. The ef cacy of tolterodine is therefore, durable and maintained over at least a 12-month period. This point is further illustrated by considering the 15-month completer population, where there was no loss of ef cacy after 15 months' treatment. These ndings are not surprising as ef cacy is maintained during long-term treatment with the IR formulation of tolterodine [14,15]. The view that patients have of their response to therapy is an important outcome with regards to treatment ef cacy. In this study, about three quarters of patients had an improvement in perception of their bladder condition and about half had an improvement in their sense of urgency during long-term treatment with tolterodine. These results are particularly impressive given that 35% of the population had experienced poor ef cacy with previous treatment. This study shows that the favourable safety, tolerability and ef cacy of tolterodine ER 4 mg qd observed following 12 weeks' treatment is maintained over 12 months', and supports its use in the long-term management of overactive bladder. References [1] Wein AJ, Roberts RW. Overactive bladder survey. Evaluates the extent of symptoms in family doctor setting. Fam Urol 2000;5: 7±8. [2] Milsom I, Abrams P, Cardozo L, Roberts RG, ThuÈroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how do we manage them? A population-based prevalence study. BJU Int 2001;87:760±6. [3] Versi E. on behalf of the Study Group. Screening initiative con rms widespread prevalence of overactive bladder in American adults. Int Urogynecol J 2001;12:S13. [4] Abrams P, Wein AJ. The overactive bladder. A widespread and treatable condition. 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