Current Pharmacologic Treatment of Lower Urinary Tract Symptoms

Abstract

Disorders of micturition may be divided into disturbances of the storage function of the bladder and disturbances of the emptying function. The main symptoms of disturbances of storage function are frequency, urgency with or without incontinence often with nocturia and is defined as the overactive bladder syndrome (OABs). Overactivity of the bladder may lead to urgency incontinence and incompetence of the urethral closure mechanism to stress incontinence. There are many drugs available for treating OABs, but their efficacy as judged from controlled clinical trials is often limited and there are few drugs that have an efficacy and adverse effect profile sufficient for approval and clinical use. Currently used generally approved drugs target the cholinergic (muscarinic acetylcholine receptors—antimuscarinics) and adrenergic systems (β3-adrenoceptors—β3-adrenoceptor agonists). Bladder contraction in man is mediated by stimulation of muscarinic receptors, and antimuscarinic drugs have been shown to have effect on OABs; however, treatment is often unsatisfactory due to fading of effect and systemic adverse effects. β₃-Adrenoceptor agonists seem to have a similar efficacy as antimuscarinics, but fewer adverse effects. The aim of drug treatment of stress incontinence is to increase outflow resistance. Although there is only a limited possibility of improving the condition with drugs, beneficial effects can be obtained in some patients by use of duloxetine.

Appendix

Antimuscarinics with “Specific” Action

Below data on the different antimuscarinics are presented. These drugs are assumed to block only muscarinic receptors (motivating the term “specific”). The amount of information for the individual drugs varies, and so does the degree of details from the different studies presented. However, the information has been chosen to give a reasonable efficacy and adverse effect profile of each individual drug.

Atropine Sulfate

Atropine (dl-hyoscyamine) is rarely used for treatment of OABs/DO because of its systemic side effects, which preclude its use as an oral treatment. However, in patients with neurogenic DO, intravesical atropine may be effective for increasing bladder capacity without causing any systemic adverse effects, as shown in open pilot trials [212, 253, 260, 264, 314]. It appears that intravesical atropine may be as effective as intravesical oxybutynin in patients with neurogenic DO [264].

The pharmacologically active antimuscarinic component of atropine is l-hyoscyamine. Although still used, few clinical studies are available to evaluate the antimuscarinic activity of l-hyoscyamine sulfate [571]. For assessment, see Table 13.1.

Darifenacin Hydrobromide

Darifenacin is a tertiary amine with moderate lipophilicity, well absorbed from the gastrointestinal tract after oral administration, and extensively metabolized in the liver by the cytochrome P450 isoforms CYP3A4 and CYP2D6, the latter saturating within the therapeutic range [704]. UK-148,993, UK-73,689, and UK-88862 are the three main circulating darifenacin metabolites of which only UK-148,993 is said to have significant antimuscarinic activity. However, available information suggests that various metabolites of darifenacin contribute little to its clinical effects [549]. The metabolism of darifenacin by CYP3A4 suggests that co-administration of a potent inhibitor of this enzyme (e.g., ketoconazole) may lead to an increase in the circulating concentration of darifenacin [441].

Darifenacin is a relatively selective muscarinic M₃ receptor antagonist. In vitro, it is selective for human cloned muscarinic M₃ receptors relative to M₁, M₂, M₄, or M₅ receptors. Theoretically, drugs with selectivity for the M₃ receptor can be expected to have clinical efficacy in OABs/DO with reduction of the adverse events related to the blockade of other muscarinic receptor subtypes [27]. However, the clinical efficacy and adverse effects of a drug are dependent not only on its profile of receptor affinity, but also on its pharmacokinetics, and on the importance of muscarinic receptors for a given organ function.

Darifenacin has been developed as a controlled-release formulation, which allows once-daily dosing. Recommended dosages are 7.5 and 15 mg/day. The clinical effectiveness of the drug has been documented in several RCTs [6, 122, 138, 140, 148, 150, 152, 154, 161, 163, 248, 274, 338, 339, 361, 721, 848; for reviews, see 153, 162, 334, 594, 844]. Haab et al. [339] reported a multicenter, double-blind, placebo-controlled, parallel-group study which enrolled 561 patients (19−88 years; 85 % female) with OAB symptoms for more than 6 months and included some patients with prior exposure to antimuscarinic agents. After washout and a 2-week placebo run-in, patients were randomized (1:4:2:3) to once-daily oral darifenacin controlled-release tablets: 3.75 mg (n = 53), 7.5 mg (n = 229), or 15 mg (n = 115) or matching placebo (n = 164) for 12 weeks. Patients recorded daily incontinence episodes, micturition frequency, bladder capacity (MVV), frequency of urgency, severity of urgency, incontinence episodes resulting in change of clothing or pads and nocturnal awakenings due to OABs using an electronic diary during weeks 2, 6, and 12 (directly preceding clinic visits). Tolerability data were evaluated from adverse event reports. Darifenacin 7.5 and 15 mg had a rapid onset of effect, with significant improvement compared with placebo being seen for most parameters at the first clinic visit (week 2). Darifenacin 7.5 mg and 15 mg, respectively, were significantly superior to placebo for (median) improvements in micturition frequency (7.5 mg: −1.6; 15 mg: −1.7; placebo −0.8), frequency of urgency per day (−2.0; −2.0; −0.9) and number of incontinence episodes leading to a change in clothing or pads (−4.0; −4.7; −2.0). There was no significant reduction in nocturnal awakenings due to OABs. The most common adverse events were mild-to-moderate dry mouth and constipation with a CNS and cardiac safety profile comparable to placebo. No patients withdrew from the study as a result of dry mouth and discontinuation related to constipation was rare (0.6 % placebo vs. 0.9 % darifenacin).

In a dose titration study on 395 OABs patients, darifenacin, allowing individualized dosing (7.5 or 15 mg), was found to be effective and well-tolerated [721]. A 2-year open label extension study of these investigations (i.e., [339, 721]) confirmed a favorable efficacy, tolerability, and safety profile [338].

A review of the pooled darifenacin data from the three phase III, multicenter, double-blind clinical trials in patients with OABs was reported by Chapple et al. [152, 154, 161]. After a 4-week washout/run-in period, 1,059 adults (85 % female) with symptoms of OAB (urgency incontinence, urgency, and frequency) for at least 6 months were randomized to once-daily oral treatment with darifenacin: 7.5 mg (n = 337) or 15 mg (n = 334) or matching placebo (n = 388) for 12 weeks. Efficacy was evaluated using electronic patient diaries that recorded incontinence episodes (including those resulting in a change of clothing or pads), frequency and severity of urgency, micturition frequency, and bladder capacity (volume voided). Safety was evaluated by analysis of treatment-related adverse events, withdrawal rates, and laboratory tests. Relative to baseline, 12 weeks of treatment with darifenacin resulted in a dose-related significant reduction in median number of incontinence episodes per week (7.5 mg, −8.8 [−68.4 %; placebo −54 %, P < 004]; 15 mg, −10.6 [−76.8 %; placebo 58 %, p < 0.001]). Significant decreases in the frequency and severity of urgency, micturition frequency, and number of incontinence episodes resulting in a change of clothing or pads were also apparent, along with an increase in bladder capacity. Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth and constipation, although together these resulted in few discontinuations (darifenacin 7.5 mg 0.6 % of patients; darifenacin 15 mg 2.1 %; placebo 0.3 %). The incidences of CNS and cardiovascular adverse events were comparable to placebo. The results were confirmed in other RCTs, including also a pooled analysis of three phase III studies in older patients (≥65 years), showing that darifenacin (7.5 and 15 mg) had an excellent efficacy, tolerability, and safety profile [274, 361, 849].

The time-to-effect with darifenacin was analyzed in a pooled analysis of efficacy and safety data from 1,059 patients participating in three double-blind 12-week studies [447]. Darifenacin significantly improved all OAB symptoms as early as 6–8 days.

One of the most noticeable clinical effects of antimuscarinics is their ability to reduce urgency and allow patients to postpone micturition. A study was conducted to assess the effect of darifenacin, on the “warning time” associated with urinary urgency. Warning time was defined as the time from the first sensation of urgency to the time of voluntary micturition or incontinence. This was a multicenter, randomized, double-blind, placebo-controlled study consisting of 2 weeks’ washout, 2 weeks’ medication-free run-in, and a 2-week treatment phase [122]. Warning time was defined as the time from the first sensation of urgency to voluntary micturition or incontinence and was recorded via an electronic event recorder at baseline (visit 3) and study end (visit 4) during a 6-h clinic-based monitoring period, with the subject instructed to delay micturition for as long as possible. During each monitoring period, up to three urgency-void cycles were recorded. Of the 72 subjects who entered the study, 67 had warning time data recorded at both baseline and study end and were included in the primary efficacy analysis (32 on darifenacin, 35 on placebo). Darifenacin treatment resulted in a significant (p < 0.004) increase in mean warning time with a median increase of 4.3 min compared with placebo (darifenacin group from 4.4 to 1.8 min; placebo from 7.0 to −1.0 min). Overall, 47 % of darifenacin-treated subjects compared with 20 % receiving placebo achieved a 30 % increase in mean warning time. There were methodological problems associated with this study; it utilized a dose of 30 mg (higher than the dose recommended for clinical use), the treatment period was short, it was conducted in a clinical-centered environment, the methodology carried with it a significant potential training effect, and the placebo group had higher baseline values than the treatment group. In another warning time study [848] on 445 OABs patients, darifenacin treatment (15 mg) resulted in numerical increases in warning time; however, these were not significant compared to placebo.

Further studies have demonstrated that darifenacin treatment is associated with clinically relevant improvements on health-related quality of life (HRQoL) in patients with OABs [6], and such improvements were sustained as shown in a 2-year extension study [248]. It was shown that neither the positive effects on micturition variables, nor on HRQoL produced by darifenacin (7.5 and 15 mg) were further enhanced by a behavioral modification program including timed voiding, dietary modifications, and Kegel exercises [138, 140].

Since darifenacin is a substrate for the P-glycoprotein drug efflux transporter [142, 555], which is present both in the blood–brain and blood-ocular barriers, several clinical studies have been devoted to investigate possible effect of darifenacin on cognition. Neither in healthy volunteers (19–44 years) and healthy subjects (≥60 years), nor in volunteers 65 years or older could any effect of darifenacin (3.75–15 mg daily) be demonstrated, compared to placebo [142, 432–434, 491].

To study whether darifenacin had any effect on QT/QTc intervals, Serra et al. [688] performed a 7-day, randomized, parallel-group study (n = 188) in healthy volunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily. No significant increase in QTcF interval could be demonstrated compared with placebo. Mean changes from baseline at pharmacokinetic T _max vs. placebo were −0.4 and −2.2 ms in the darifenacin 15 mg and 75 mg groups, respectively, compared with +11.6 ms in the moxifloxacin group (P < 0.01). The conclusion was that darifenacin does not prolong the QT/QTc interval.

Darifenacin 15 mg/day given to healthy volunteers did not change heart rate significantly compared to placebo [604].

Assessment. Darifenacin has a well-documented beneficial effect in OABs/DO (Table 13.1), and tolerability and safety seem acceptable.

Fesoterodine Fumarate

Fesoterodine functions as an orally active prodrug that is converted to the active metabolite 5-hydroxymethyltolterodine (5-HMT) by non-specific esterases [511, 548]. This compound, which is chemically identical to the 5-hydroxy metabolite of tolterodine, is a non-subtype selective muscarinic receptor antagonist [577]. All of the effects of fesoterodine in man are thought to be mediated via 5-HMT, since the parent compound remains undetectable upon oral dosing. 5-HMT is metabolized in the liver, but a significant part of 5-HMT is excreted renally without additional metabolism. Since the renal clearance of 5-HMT is about 250 mL/min, with >15 % of the administered fesoterodine dose excreted as unchanged 5-HM, this raises the possibility that 5-HMT also could work from the luminal side of the bladder [548]. The bioavailability of fesoterodine, averaging 52 %, was independent of food intake and the drug may be taken with or without a meal [514]. Peak plasma concentration of 5-HMT is reached at 5 h following oral administration and has a half-life of 7–9 h [513]. The suggested starting dose, 4 mg/day, can be used in patients with moderately impaired renal or hepatic function due to the combination of renal excretion and hepatic metabolism of 5-HMT [207, 510].

The clinical efficacy and tolerability of fesoterodine have been documented in several RCTs [148, 150, 163, 226, 232, 233, 357, 421, 425, 586, 588; see 216]. In a multicenter, double-blind, double-dummy RCT with tolterodine ER, 1,132 patients were enrolled and received treatment [148, 150, 163]. The trial showed that both the 4 and 8 mg doses of fesoterodine were effective in improving symptoms of OAB, with the 8 mg dose having a greater effect at the expense of a higher rate of dry mouth. There appeared to be little difference between fesoterodine 4 mg and tolterodine ER. Only one subject from the fesoterodine 8 mg group and one subject from the tolterodine ER group withdrew from the study due to dry mouth. The dose–response relationship was confirmed in another study that pooled data from two phase III RCTs [448]. Fesoterodine 8 mg performed better than the 4 mg dose in improving urgency and urge UI as recorded by 3-day bladder diary, offering the possibility of dose titration.

A head-to-head placebo controlled trial has been completed comparing fesoterodine 8 mg to tolterodine-extended release 4 mg and placebo [357]. The study randomized 1,590 patients to assess the primary outcome of reduced urgency incontinence episodes at 12 weeks. Fesoterodine produced statistically significant improvements in urgency incontinence episodes, complete dry rates (64.0 % vs. 57.2 %, p = 0.015), mean voided volume per void (+32.9 mL vs. +23.5 mL, p = 0.005), and in patients’ assessments of bladder-related problems as measured by OABs questionnaire (except sleep domain), Patient Perception of Bladder Condition (40 % vs. 33 % with >2 point improvement, p < 0.001), and Urgency Perception Scale (46 % vs. 40 % with improvement, p = 0.014) compared with tolterodine. The clinical significance of these statistically significant findings is questionable as there was no difference between agents with respect to number of micturitions, urgency episodes, and frequency-urgency sum per 24 h. The improved efficacy of fesoterodine came at the cost of greater dry mouth (27.8 % vs. 16.4 %), headache (5.6 % vs. 3.4 %), constipation (5.4 % vs. 4.1 %), and withdrawal rates (6 % vs. 4 %). Nonetheless, this first head-to-head trial comparing two drugs in class supports the use of fesoterodine 8 mg for additional benefit over tolterodine ER 4 mg.

Wyndaele et al. [821] reported the first flexible-dose open-label fesoterodine trial, which was conducted at 80 different centers worldwide and comprised 516 participants (men and women) >18 years who self-reported OAB symptoms for at least 3 months before screening and had been treated with either tolterodine or tolterodine ER within 2 years without symptom improvement. Approximately 50 % opted for dose escalation to 8 mg at week 4. Significant improvements from baseline to week 12 were observed in micturitions, urgency urinary incontinence episodes, micturition-related urgency episodes, and severe micturition-related urgency episodes per 24 h. Significant improvements from baseline were observed in QoL parameters. Dry mouth (23 %) and constipation (5 %) were the most common adverse events; no safety issues were identified.

The largest double-blind, double-dummy, flexible-dose fesoterodine RCT, which was conducted at 210 different centers with a total of 2,417 patients enrolled, was performed by Kaplan et al. [421]. All patients were healthy, >18 years of age, and self-reported OAB symptoms for at least 3 months. The 960 patients who received fesoterodine 8 mg showed significantly greater mean improvements at week 12 in most efficacy parameters (diary variables) than those receiving either tolterodine ER or placebo; UUI and urgency episodes, micturition frequency, and MVV. No statistically significant changes were shown in reduction of nocturnal micturitions compared with the tolterodine group, whereas when comparing the mean changes in nighttime micturition with the placebo group a significant difference was found. This phase III study confirmed the superiority of fesoterodine 8 mg over tolterodine ER 4 mg for improving UUI and urgency episodes and 24-h micturitions but not for MVV and nocturia. In another RCT of flexible-dose fesoterodine, Dmchowski et al. reported statistically significant improvements at week 12 in the mean number of micturition per 24 h and in both UUI and urgency episodes. Between groups, difference in nocturnal micturition was not statistically significant.

Nitti et al. [588] determined whether the presence of DO in patients with OABs and urgency urinary incontinence was a predictor of the response to treatment with fesoterodine in a phase 2 randomized, multicenter, placebo-controlled trial. They concluded that regardless of the presence of DO, the response to fesoterodine treatment was dose-proportional and associated with significant improvements in OAB symptoms, indicating that the response to OABs pharmacotherapy in patients with UUI was independent of the urodynamic diagnosis of DO.

Kelleher et al. [439] evaluated the effect of fesoterodine on HRQoL in patients with OAB syndrome. Pooled data from two randomized placebo-controlled phase III studies [148, 150, 163, 586] were analyzed. Eligible patients were randomized to placebo or fesoterodine 4 or 8 mg for 12 weeks; one trial also included tolterodine-extended release (tolterodine-ER) 4 mg. By the end of treatment, all active-treatment groups had significantly improved HRQoL compared with those on placebo. In a post hoc analysis of data pooled from these studies, significant improvements in all KHQ domains, ICIQ-SF scores, and bladder-related problems were observed at months 12 and 24 compared to open label baseline [438]. The authors concluded that treatment satisfaction was high throughout the open-label treatment regardless of gender and age.

Malhotra et al. [515] performed a thorough QT study to investigate the effects of fesoterodine on cardiac repolarization in a parallel-group study. Subjects were randomly assigned to receive double-blind fesoterodine 4 mg, fesoterodine 28 mg, or placebo or open-label moxifloxacin 400 mg (positive control) for 3 days. ECGs were obtained on Days −1 (baseline), 1, and 3. The primary analysis was the time-averaged changes from baseline for Fridericia’s-corrected QT interval (QTcF) on Day 3. Among 261 subjects randomized to fesoterodine 4 mg (n = 64), fesoterodine 28 mg (n = 68), placebo (n = 65), or moxifloxacin 400 mg (n = 64), 256 completed the trial. The results indicated that fesoterodine is not associated with QTc prolongation or other ECG abnormalities at either therapeutic or supratherapeutic doses.

Assessment. Fesoterodine has a well-documented beneficial effect in OABs (Table 13.1), and the adverse event profile seems acceptable.

Imidafenacin

Imidafenacin (KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide) is an antagonist for the muscarinic ACh receptor with higher affinities for M₃ and M₁ receptors than for the M₂ receptor. Metabolites of imidafenacin (M-2, M-4, and M-9) had low affinities for muscarinic ACh receptor subtypes [458]. The drug blocks pre- as well as postjunctional muscarinic receptors and was shown to block both detrusor contractions and acetylcholine release [570]. The receptor-binding affinity of imidafenacin in vitro was found to be significantly lower in the bladder than submaxillary gland or colon [823], and in rats orally administered imidafenacin distributes predominantly to the bladder and exerts more selective and longer-lasting effect here than on other tissues. Whether this can be translated to the human situation has to be established before claims of clinical bladder selectivity can be made.

Imidafenacin is well absorbed from the gastrointestinal tract and its absolute bioavailability in human is 57.8 % [601, 602]. It is rapidly absorbed with maximum plasma concentration occurring 1–3 h after oral administration [602]. Metabolites in the plasma are produced mainly by first-pass effects. The major enzymes responsible for the metabolism of the drug are CYP3A4 and UGT1A4. The oxidative metabolism is reduced by concomitant administration of CYP3A4 inhibitors. In contrast, imidafenacin and its metabolites have no inhibitory effect on the CYP-mediated metabolism of concomitant drugs [418].

Kitagawa et al. [455] reported that the subjective efficacy of imidafenacin was observed from 3 days after the commencement of administration and that mean total overactive bladder symptom score (OABSS) decreased gradually during 2 weeks after administration.

A randomized, double-blind, placebo-controlled phase II dose-finding study in Japanese OABs patients was performed to evaluate the efficacy, safety/tolerability, and dose–response relationship of imidafenacin [371]. Overall, 401 patients were enrolled and randomized for treatment with 0.1 mg of imidafenacin/day (99 patients), 0.2 mg of imidafenacin/day (100), 0.5 mg of imidafenacin/day (101), or a placebo (101). After 12 weeks of treatment, the number of incontinence episodes was reduced in a dose-dependent manner, and a significant difference between the imidafenacin treatment and the placebo was observed (P < 0.0001). Compared with the placebo, imidafenacin caused significant reductions in urgency incontinence, voiding frequency, and urinary urgency, and a significant increase in the urine volume voided per micturition. Imidafenacin was also well tolerated. The incidence of dry mouth in the imidafenacin groups increased dose-dependently. Even though the percentage of patients receiving 0.5 mg/day who discontinued treatment due to dry mouth was high (8.9 %), the percentages in the 0.1 and 0.2 mg/day groups (1.0 % and 0.0 %, respectively) were comparable with that in the placebo group (0.0 %).

A randomized, double-blind, placebo- and propiverine-controlled trial of 781 Japanese patients with OAB symptoms was conducted by Homma et al. [370]. They were randomized to imidafenacin (324), propiverine (310), or a placebo (147). After 12 weeks of treatment, a significantly larger reduction in the mean number of incontinence episodes was observed in the imidafenacin group than in the placebo group (P < 0.0001). The non-inferiority of imidafenacin compared with propiverine was confirmed for the reduction in using incontinence episodes (P = 0.0014, non-inferiority margin: 14.5 %). Imidafenacin was well tolerated. The incidence of adverse events with imidafenacin was significantly lower than with propiverine (P = 0.0101). Dry mouth, the most common adverse event, was significantly more common in the propiverine group than in the imidafenacin group. There were no significant increases in either the imidafenacin or placebo group in the mean QTc interval, whereas there was a significant increase in the mean QTc interval in the propiverine group (P < 0.0001). However, there were no clinical arrhythmia and clinical arrhythmic events in any of the treatment groups.

The long-term safety, tolerability, and efficacy of imidafenacin were studied in Japanese OABs patients [370], of whom 478 received treatment and 376 completed a 52-week program. Imidafenacin was well tolerated, the most common adverse event being a dry mouth (40.2 % of the patients). Long-term treatment did not produce an increase in the frequency of adverse events compared with short-term treatment. A significant efficacy of the drug was observed from week 4 through week 52. After 52 weeks, imidafenacin produced mean changes from baseline in the number of incontinence episodes (−83.51 %), urgency incontinence episodes (−84.21 %), voiding frequency (−2.35 micturitions/day), urgency episodes (−70.53 %), and volume voided per micturition (28.99 mL). There were also significant reductions from baseline in all domains of the King’s Health Questionnaire. Imidafenacin had no significant effects on the corrected QT interval, vital signs, results from laboratory tests, or post-void residual volume.

A 52-week prospective, open randomized comparative study to evaluate the efficacy and tolerability of imidafenacin (0.2 mg/day) and solifenacin (5 mg/day) was conducted in a total of 41 Japanese patients with untreated OABs [842]. They were randomly assigned to imidafenacin and solifenacin groups. There was no difference in OABSS and KHQ scores between the two groups, but the severity and incidence of adverse events caused by the drugs showed increased differences between the groups with time. The severity of dry mouth and the incidence of constipation were significantly lower in the imidafenacin group (P = 0.0092 and P = 0.0013, respectively). An important limitation of this study is the low number of patients. Only 25 patients (17 males, 8 females) were available for long-term analysis.

Assessment. Imidafenacin seems to be effective and to have an acceptable tolerability. However, the documentation is relatively scarce and the drug is not yet available in the Western countries.

Propantheline Bromide

Propantheline is a quaternary ammonium compound, non-selective for muscarinic receptor subtypes, which has a low (5–10 %) and individually varying biological availability. It is metabolized (metabolites inactive) and has a short half-life (less than 2 h) [82]. It is usually given in a dose of 15–30 mg four times daily, but to obtain an optimal effect, individual titration of the dose is necessary, and often higher dosages are required. Using this approach in 26 patients with detrusor overactivity contractions [94] in an open study obtained a complete clinical response in all patients but one, who did not tolerate more than propantheline 15 mg four times daily. The range of dosages varied from 7.5 to 60 mg four times daily. In contrast, Thüroff et al. [760] comparing the effects of oxybutynin 5 mg three times daily, propantheline 15 mg three times daily, and placebo in a randomized, double-blind, multicenter trial on the treatment of frequency, urgency, and incontinence related to DO (154 patients) found no differences between the placebo and propantheline groups. In another randomized comparative trial with crossover design (23 women with idiopathic DO), and with dose titration, Holmes et al. [368] found no differences in efficacy between oxybutynin and propantheline. Controlled randomized trials (n = 6) reviewed by Thüroff et al. [761] confirmed a positive, but varying, response to the drug.

Assessment. Although the effect of propantheline on OABs/DO has not been well documented in controlled trials satisfying standards of today, it can be considered effective, and may, in individually titrated doses, be clinically useful (Table 13.1). No new studies on the use of this drug for treatment of OABs/DO seem to have been performed during the last decade.

Solifenacin Succinate

Solifenacin succinate (YM905) is a tertiary amine and well absorbed from the gastrointestinal tract (absolute bioavailability 90 %). The mean terminal half-life is 45–68 h [465, 710, 711]. It undergoes significant hepatic metabolism involving the cytochrome P450 enzyme system (CYP3A4). In subjects who received a single oral dose of 10 mg solifenacin on day 7 of a 20-day regimen of ketoconazole administration (200 mg), C _max and AUC_0-inf were increased by only approximately 40 % and 56 %, respectively [737]. Solifenacin has a modest selectivity for M3 over M2 (and M1) receptors [2]. Supporting an effect on sensory function by solifenacin, 15 women with DO receiving 10 mg/day of the drug showed an increase in the area under the bladder-volume sensation curve [501]. Solifenacin also increased maximum bladder capacity, a finding in agreement with other studies [374, 751].

Two large-scale phase 2 trials with parallel designs, comprising men and women, were performed [146, 708]. The first dose-ranging study evaluated solifenacin 2.5, 5, 10, and 20 mg and tolterodine (2 mg twice daily) in a multinational placebo-controlled study of 225 patients with urodynamically confirmed DO [146]. Patients received treatment for 4 weeks followed by 2 weeks of follow-up. Inclusion criteria for this and subsequent phase 3 studies of patients with OABs included at least 8 micturitions/24 h and either one episode of incontinence or one episode of urgency daily as recorded in 3-day micturition diaries. Micturition frequency, the primary efficacy variable, was statistically significantly reduced in patients taking solifenacin 5 mg (−2.21), 10 mg (−2.47), and 20 mg (−2.75), but not in patients receiving placebo (−1.03) or tolterodine (−1.79). This effect was rapid with most of the effect observed at the earliest assessment visit, 2 weeks after treatment initiation. In addition, there were numerically greater reductions in episodes of urgency and incontinence when compared with placebo. Study discontinuations due to adverse events were similar across treatment groups, albeit highest in the 20-mg solifenacin group. As the 5 and 10 mg doses caused lower rates of dry mouth than tolterodine, and superior efficacy outcomes relative to placebo, these dosing strengths were selected for further evaluation in large-scale phase 3 studies.

The second dose-ranging study of solifenacin 2.5–20 mg was carried out in the United States (USA) [708]. This trial included 261 evaluable men and women receiving solifenacin or placebo for 4 weeks followed by a 2-week follow-up period. Micturition frequency was statistically significantly reduced relative to placebo in patients receiving 10 and 20 mg solifenacin. The number of micturitions per 24 h showed reductions by day 7 and continued to decrease through day 28; day 7 was the earliest time point tested in solifenacin trials and these findings demonstrate efficacy as early as 1 week. The 5, 10, and 20 mg dosing groups experienced statistically significant increases in volume voided; the 10 mg solifenacin dose was associated with statistically significant reductions in episodes of incontinence.

In one of the early RCTs, a total of 1,077 patients were randomized to 5 mg solifenacin, 10 mg solifenacin, tolterodine (2 mg twice daily), or placebo [160]. It should be noted that this study was powered only to compare active treatments to placebo. Compared with placebo (−8 %), mean micturitions/24 h were significantly reduced with solifenacin 10 mg (−20 %), solifenacin 5 mg (−17 %), and tolterodine (−15 %). Solifenacin was well tolerated, with few patients discontinuing treatment. Incidences of dry mouth were 4.9 % with placebo, 14.0 % with solifenacin 5 mg, 21.3 % with solifenacin 10 mg, and 18.6 % with tolterodine 2 mg twice daily.

Cardozo et al. [124, 125] randomized 911 patients to 12-week once daily treatment with solifenacin 5 mg, solifenacin 10 mg or placebo. The primary efficacy variable was change from baseline to study endpoint in mean number of micturitions per 24 h. Secondary efficacy variables included changes from baseline in mean number of urgency, nocturia, and incontinence episodes per 24 h, and MVV per micturition. Compared with changes obtained with placebo (−1.6), the number of micturitions per 24 h was statistically significantly decreased with solifenacin 5 mg (−2.37) and 10 mg (−2.81). A statistically significant decrease was observed in the number of all incontinence episodes with both solifenacin doses (5 mg: −1.63, 61 %; 10 mg: −1.57, 52 %), but not with placebo (−1.25, 28 %). Of patients reporting incontinence at baseline, 50 % achieved continence after treatment with solifenacin (based on a 3-day micturition diary, placebo responses not given). Episodes of nocturia were statistically significantly decreased in patients treated with solifenacin 10 mg vs. placebo. Episodes of urgency and MVV per micturition were statistically significantly reduced with solifenacin 5 and 10 mg. Treatment with solifenacin was well tolerated. Dry mouth, mostly mild in severity, was reported in 7.7 % of patients receiving solifenacin 5 mg and 23 % receiving solifenacin 10 mg (vs. 2.3 % with placebo). A 40-week follow-up of these studies (i.e., [124, 125, 160]) demonstrated that the favorable profile, both in terms of efficacy and tolerability, was maintained over the study period [337].

The STAR trial [148, 150, 152, 154, 161, 163] was a prospective, double-blind, double-dummy, two-arm, parallel-group, 12-week study which was conducted to compare the efficacy and safety of solifenacin 5 or 10 mg and TOLT-ER 4 mg once daily in OABs patients. The primary effect variable was micturition frequency. After 4 weeks of treatment patients had the option to request a dose increase, but were dummied throughout as approved product labeling only allowed an increase for those on solifenacin. The results showed that solifenacin, with a flexible dosing regimen, was “non-inferior” to tolterodine concerning the primary effect variable, micturition frequency. However, solifenacin showed significant greater efficacy to tolterodine in decreasing urgency episodes (−2.85 vs. −2.42), incontinence (−1.60 vs. −0.83), urgency incontinence (−1.42 vs. −0.83), and pad usage (−1.72 vs. −1.19). More solifenacin-treated patients became continent by study endpoint (59 vs. 49 %) and reported improvements in perception of bladder condition (−1.51 vs. −1.33) assessments. However, this was accompanied by an adverse event incidence which was greater with solifenacin than with tolterodine. Dry mouth and constipation (mild + moderate + severe) were the most common (solifenacin 30 and 6.4 %, tolterodine 23 and 2.5 %). The majority of side effects were mild to moderate in nature, and discontinuations were comparable and low (5.9 and 7.3 %) in both groups.

Luo et al. (2012) performed a systematic review and meta-analysis of solifenacin RCTs and provided a comprehensive assessment regarding the efficacy and safety of the drug. Their results which largely confirmed what could be deduced from previously published information indicated that solifenacin could significantly decrease the number of urgency episodes per 24 h, micturitions per 24 h, incontinence episodes per 24 h, nighttime micturitions per 24 h, and UUI episodes per 24 h and improve volume voided per micturitions compared with the placebo or tolterodine treatment.

A number of studies and reviews have further documented the effects of solifenacin [120, 147, 148, 150, 159, 163, 519, see also 153, 162, 503, 594, 687, 765, 785], including men with OABs without bladder outlet obstruction [421]. In a pooled analysis of four RCTs, Abrams and Swift [8] demonstrated positive effects on urgency, frequency, and nocturia symptoms in OABs dry patients. In an analysis of four phase III clinical trials, Brubaker and FitzGerald [105] confirmed a significant effect of solifenacin 5 and 10 mg on nocturia in patients with OABs (reductions of nocturia episodes with 5 mg: −0.6, p < 0.025; with 10 mg: −0.6, p < 0.001vs. placebo: −0,4) but without nocturnal polyuria. A positive impact on nocturia and sleep quality in patients with OABs treated with solifenacin has also been reported in other studies [742, 831]. Kelleher et al. [437] and Staskin and Te [720] presented data showing efficacy in patients with mixed incontinence.

A pooled analysis of four studies confirmed the efficacy and tolerability of solifenacin 5 and 10 mg in elderly (≥65 years) patients and also showed a high level of persistence in a 40-week extension trial [797]. Post hoc analysis of two 12-week, open label, flexible-dosing studies on 2,645 patients over 65 years of age with OABs revealed that solifenacin was associated with improvements in measures assessing patients’ perception of their bladder problems, symptom bother, and aspects of health-related quality of life [117]. Solifenacin was equally well tolerated in younger (<65 years) and older (>65 years) patients [356]. An exploratory pilot study with single doses of solifenacin 10 mg to 12 elderly volunteers suggested no clear propensity to impair cognitive functions [815].

Improvement of QoL by solifenacin treatment has been documented in several studies [294, 436]. In 30 patients with multiple sclerosis, van Rey and Heesakkers [783] improved OAB symptoms as well as neurogenic disease-specific QoL measures.

Information on solifenacin treatment in children is scarce. In a prospective open label study in 72 children (27 with neurogenic bladders) Bolduc et al. [98] improved urodynamic capacity and improved continence. Chart review of 138 children with therapy-resistant OABs treated with solifenacin increased mean voided volume and improved continence [365].

In female volunteers, aged 19–79 years, the effect of 10 and 30 mg solifenacin on the QT interval was evaluated at the time of peak solifenacin plasma concentration in a multi-dose, randomized, double-blind, placebo, and positive-controlled (moxifloxacin 400 mg) trial. The QT interval prolonging effect appeared greater for the 30 mg (8 ms, 4, 13: 90%CI) compared to the 10 mg (2 ms, −3, 6) dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

Michel et al. [551] studied cardiovascular safety and overall tolerability of solifenacin in routine clinical use in a 12-week, open-label, post-marketing surveillance study. They concluded that “in real-life conditions, i.e., with inclusion of large numbers of patients with cardiovascular co-morbidities and taking comedications, therapeutically effective doses of solifenacin did not increase heart rate or blood pressure.”

Assessment. Solifenacin has a well-documented beneficial effect in OABs/DO (Table 13.1), and the adverse event profile seems acceptable.

Tolterodine Tartrate

Tolterodine is a tertiary amine, rapidly absorbed, and extensively metabolized by the cytochrome P450 system (CYP 2D6). The major active 5-hydroxymethyl metabolite (5-HMT) has a similar pharmacological profile as the mother compound [579] and significantly contributes to the therapeutic effect of tolterodine [106, 107]. Both tolterodine and 5-HMT have plasma half-lifes of 2–3 h, but the effects on the bladder seem to be more long-lasting than could be expected from the pharmacokinetic data. Urinary excretion of tolterodine accounted for <1–2.4 % of the dose; 5–14 % of 5-HMT is eliminated in the urine [107]. Whether or not the total antimuscarinic activity of unchanged tolterodine and 5-HMT excreted in urine is sufficient to exert any effect on the mucosal signaling mechanisms has not been established. However, the preliminary studies by Kim et al. [450] and Chuang et al. [171] do not support such an effect.

The relatively low lipophilicity of tolterodine and even lesser one of 5-HMT implies limited propensity to penetrate into the CNS, which may explain a low incidence of cognitive side effects [174, 362, 668]. However, tolterodine may disturb sleep in subjects unable to form the even less lipophilic 5-HMT due to a low activity of CYP 2D6 [219].

Tolterodine has no selectivity for muscarinic receptor subtypes, but is claimed to have functional selectivity for the bladder over the salivary glands [578, 713]. In healthy volunteers, orally given tolterodine in a high dose (6.4 mg) had a powerful inhibitory effect on micturition and also reduced stimulated salivation 1 h after administration of the drug [713]. However, 5 h after administration, the effects on the urinary bladder were maintained, whereas no significant effects on salivation could be demonstrated.

Animal experiments have suggested that antimuscarinics may affect signaling from the bladder [33]. Cirfirming data in humans were found by Vijaya et al. [791]. In a randomized, placebo-controlled study, they evaluated the effect of tolterodine on urethral and bladder afferent nerves in women with DO in comparison to placebo, by studying the changes in the current perception threshold (CPT). They found a significantly increased CPT value at 5 (described as urgency) and 250 Hz upon both urethral and bladder stimulation after 1 week of treatment. When compared with placebo, women taking tolterodine had significantly increased bladder CPT values at 5 Hz (P-value <0.05).

Tolterodine is available as immediate-release (TOLT-IR; 1 or 2 mg; twice daily dosing) and extended-release (TOLT-ER) forms (2 or 4 mg; once daily dosing). The ER form seems to have advantages over the IR form in terms of both efficacy and tolerability [781].

Several randomized, double-blind, placebo-controlled studies on patients with OABs/DO (both idiopathic and neurogenic DO) have documented a significant reduction in micturition frequency and number of incontinence episodes [174, 362, 668]. Comparative RCTs such as the OBJECT (Overactive Bladder: Judging Effective Control and Treatment) and the OPERA (Overactive Bladder; Performance of Extended Release Agents) studies have further supported its effectiveness.

The OBJECT trial compared oxybutynin ER (OXY-ER) 10 mg once daily with TOLT-IR 2 mg twice daily [62] in a 12-week randomized, double-blind, parallel-group study including 378 patients with OABs. Participants had between 7 and 50 episodes of urgency incontinence per week and 10 or more voids in 24 h. The outcome measures were the number of episodes of urgency incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. At the end of the study, OXY-ER was found to be significantly more effective than TOLT-IR in each of the main outcome measures adjusted for baseline (see also below: oxybutynin chloride). Dry mouth, the most common adverse event, was reported by 33 % and 28 % of participants taking OXY-ER and TOLT-IR, respectively. Rates of CNS and other adverse events were low and similar in both groups. The authors concluded that OXY-ER was more effective than TOLT-IR and that the rates of dry mouth and other adverse events were similar in both treatment groups.

In the OPERA study [224], OXY-ER at 10 mg/day or TOLT-ER at 4 mg/day were given for 12 weeks to women with 21–60 urgency incontinence episodes per week and an average of 10 or more voids per 24 h. Episodes of incontinence episodes (primary endpoint), total (urgency and non-urgency) incontinence, and micturition were recorded in seven 24-h urinary diaries at baseline and at weeks 2, 4, 8, and 12 and compared. Adverse events were also evaluated. Improvements in weekly urgency incontinence episodes were similar for the 790 women who received OXY-ER (n = 391) or TOLT-ER (n = 399). OXY-ER was significantly more effective than TOLT-ER in reducing micturition frequency, and 23.0 % of women taking OXY-ER reported no episodes of urinary incontinence compared with 16.8 % of women taking TOLT-ER. Dry mouth, usually mild, was more common with OXY-ER. Adverse events were generally mild and occurred at low rates, with both groups having similar discontinuation of treatment due to adverse events. The conclusions were that reductions in weekly urgency incontinence and total incontinence episodes were similar with the two drugs. Dry mouth was more common with OXY-ER, but tolerability was otherwise comparable, including adverse events involving the CNS.

In the ACET (Antimuscarinic Clinical Effectiveness Trial) [736] study, which consisted of two trials, patients with OABs were randomized to 8 weeks of open-label treatment with either 2 or 4 mg of once-daily TOLT-ER (study one) and to 5 or 10 mg of OXY-ER (study two). A total of 1,289 patients were included. Fewer patients prematurely withdrew from the trial in the TOLT-ER 4 mg group (12 %) than either the OXY-ER 5 mg (19 %) or OXY-ER 10 mg groups (21 %). More patients in the OXY-ER 10 mg group than the TOLT-ER 4 mg group withdrew because of poor tolerability (13 % vs. 6 %). After 8 weeks, 70 % of patients in the TOLT-ER 4 mg group perceived an improved bladder condition, compared with 60 % in the TOLT-ER 2 mg group, 59 % in the OXY-ER 5 mg group, and 60 % in the OXY-ER 10 mg group. Dry mouth was dose-dependent with both agents, although differences between doses reached statistical significance only in the oxybutynin trial (OXY-ER 5 mg vs. OXY-ER 10 mg; p = 0.05). Patients treated with TOLT-ER 4 mg reported a significantly lower severity of dry mouth compared with OXY-ER 10 mg. The conclusion that the findings suggest improved clinical efficacy of TOLT-ER (4 mg) than of OXY-ER (10 mg) is weakened by the open label design of the study.

Zinner et al. [847] evaluated the efficacy, safety, and tolerability of TOLT-ER in older (≥65) and younger (<65) OABs patients, in a 12-week RCT including 1,015 patients with urgency incontinence and urinary frequency. Patients were randomized to treatment with TOLT-ER 4 mg once daily (n = 507) or placebo (n = 508) for 12 weeks. Efficacy, measured with micturition charts (incontinence episodes, micturitions, volume voided per micturition) and subjective patient assessments, safety, and tolerability endpoints, was evaluated, relative to placebo. Compared with placebo, significant improvements in micturition chart variables with TOLT-ER showed no age-related differences. Dry mouth (of any severity) was the most common adverse event in both the TOLT-ER and placebo treatment arms, irrespective of age (<65: ER 22.7 %, placebo 8.1 %; ≥65: ER 24.3 %, placebo 7.2 %). A few patients (<2 %) experienced severe dry mouth. No CNS (cognitive functions were not specifically studied), visual, cardiac (per ECG), or laboratory safety concerns were noted in this study. Withdrawal rates due to adverse events on TOLT-ER 4 mg QD were comparable in the two age cohorts (<65: 5.5 %; ≥65: 5.1 %).

The central symptom in the OAB syndrome is urgency. Freeman et al. [284] presented a secondary analysis of a double-blind, placebo-controlled study evaluating the effect of once-daily TOLT-ER on urinary urgency in patients with OABs. Patients with urinary frequency (8 or more micturitions per 24 h) and urgency incontinence (5 or more episodes per week) were randomized to oral treatment with TOLT-ER 4 mg once daily (n = 398) or placebo (n = 374) for 12 weeks. Efficacy was assessed by use of patient perception evaluations. Of patients treated with TOLT-ER, 44 % reported improved urgency symptoms (compared with 32 % for placebo), and 62 % reported improved bladder symptoms (placebo, 48 %). The proportion of patients unable to hold urine upon experiencing urgency was decreased by 58 % with TOLT-ER, compared with 32 % with placebo (P < 0.001).

In the Improvement in Patients: Assessing symptomatic Control with Tolterodine ER (IMPACT) study [255], the efficacy of TOLT-ER for patients’ most bothersome OAB symptom was investigated in an open label, primary care setting. Patients with OAB symptoms for ≥3 months received TOLT-ER (4 mg once daily) for 12 weeks. By week 12, there were significant reductions in patients’ most bothersome symptom: incontinence, urgency episodes, nocturnal and daytime frequency. The most common adverse events were dry mouth (10 %) and constipation (4 %), and it was concluded that in primary care practice, bothersome OAB symptoms can be effectively and safely treated with TOLT-ER, even in patients with comorbid conditions.

Various aspects of the efficacy and tolerability of tolterodine have been further documented in a number of RCTs [87, 167, 190, 225, 228, 647, 651; see further: 153, 162, 594]. Importantly, the QTc effects of tolterodine were determined in a crossover-designed QT study of recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo. No subject receiving tolterodine exceeded the clinically relevant thresholds of 500 ms absolute QTc or 60 ms change from baseline, and it was concluded that tolterodine does not have a clinically significant effect on QT interval [512].

Olshansky et al. [604] compared the effects on heart rate of TOLT-ER 4 mg/day with those of darifenacin 15 mg/day in healthy volunteers. They found that tolterodine, but not darifenacin, significantly increased mean heart rate per 24 h. The proportion of subjects with an increase >5 beats/min was significantly greater in those receiving TOLT-ER (25 % than with darifenacin (8.9 %)).

Hsiao et al. [374] compared the urodynamic effects, therapeutic efficacy, and safety of solifenacin (5 mg) vs. tolterodine ER (4 mg) treatment in women with the OAB syndrome. Both solifenacin and tolterodine had similar urodynamic effects, therapeutic efficacy and adverse events; however, tolterodine had a greater effect in increasing heart rate than solifenacin.

In a prospective, open study, Song et al. [712]compared the effects of bladder training and/or tolterodine as first-line treatment in female patients with OABs. One hundred and thirty-nine female patients with OABs were randomized to treatment with bladder training (BT), tolterodine (2 mg twice daily) or both for 12 weeks. All treatments were efficacious; however, combination therapy was the most effective. Mattiasson et al. [534] compared the efficacy of tolterodine 2 mg twice daily plus simplified bladder training (BT) with tolterodine alone in patients with OABs in a multicenter single-blind study. At the end of the study the median percentage reduction in voiding frequency was greater with tolterodine + BT than with tolterodine alone (33 % vs. 25 %; p < 0.001), while the median percentage increase in volume voided per void was 31 % with tolterodine + BT and 20 % with tolterodine alone (p < 0.001). There was a median of 81 % fewer incontinence episodes than at baseline with tolterodine alone, which was not significantly different from that with tolterodine + BT (−87 %). It was concluded that the effectiveness of tolterodine 2 mg twice daily can be augmented by a simplified BT regimen. However, Millard et al. [553] investigated whether the combination of tolterodine plus a simple pelvic floor muscle exercise program would provide improved treatment benefits compared with tolterodine alone in 480 patients with OABs. Tolterodine therapy for 24 weeks resulted in significant improvement in urgency, frequency, and incontinence; however, no additional benefit was demonstrated for a simple pelvic floor muscle exercise program. In a 16-week, multicenter, open label study tolterodine-extended release plus behavioral intervention resulted in high treatment satisfaction and improved bladder diary variables in patients who had previously been treated and were dissatisfied with tolterodine or other antimuscarinics [457].

Abrams et al. [5] studied the safety and tolerability of tolterodine for the treatment of OAB symptoms in men with BOO. They found that tolterodine did not adversely affect urinary function in these men. Urinary flow rate was unaltered, and there was no evidence of clinically meaningful changes in voiding pressure and PVR or urinary retention. It was suggested that antimuscarinics can be safely administered in men with BOO. Lee et al. [483] reviewed the safety and efficacy of antimuscarinic agents in treating men with BOO and OABs and emphasized their safety and efficacy. They also concluded that combination therapy of antimuscarinic and α1-AR antagonists improves the symptoms effectively without increasing the incidence of AUR.

The beneficial effect of TOLT-ER in men with BPE and LUTS, including OABs, has been well documented. Both as monotherapy, but in particularly in combination with α₁-adenoceptor (AR) antagonist, TOLT-ER was found effective [367, 423, 424, 426, 644, 645, 651, 652]. This effect was obtained irrespective of prostate size and was not associated with increased incidence of AUR [644, 645]. A large, 26-week, multicenter, randomized, double-blind, placebo-controlled, three-period crossover study enrolled women aged ≥18 years who were diagnosed with OABs and reported ≥8 micturitions/24 h and ≥4 urgency episodes/week on 5-day bladder diary at baseline [520]. Subjects were randomized to 1 of 10 treatment sequences and received three of five treatments, each for 4 weeks with 4-week washout periods: standard-dose pregabalin/tolterodine ER (150 mg twice daily [BID]/4 mg once daily [QD], n = 102), pregabalin alone (150 mg BID, n = 105), tolterodine ER alone (4 mg QD, n = 104), low-dose pregabalin/tolterodine ER (75 mg BID/2 mg QD, n = 105), and placebo (n = 103). Subjects completed 5-day diaries at the end of treatment and washout periods. The primary endpoint was change from baseline to week 4 in mean voided volume (MVV) per micturition. Baseline-adjusted changes in MVV were significantly greater after treatment with standard-dose pregabalin/tolterodine ER (39.5 mL) vs. tolterodine ER alone (15.5 mL; P < 0.0001), and with pregabalin alone (27.4 mL) vs. tolterodine ER alone (P = 0.005) and placebo (11.9 mL; P = 0.0006). Treatments were generally well tolerated; discontinuation rates due to adverse events were 4 %, 2 %, 5 %, 0 %, and 1 % with standard- and low-dose pregabalin/tolterodine ER, pregabalin, tolterodine ER, and placebo, respectively. (See further section on “Combinations”]).

Assessment. Both the IR and ER forms of tolterodine have a well-documented effect in OABs/DO (Table 13.1) and are well tolerated.

Trospium Chloride

Trospium is a quaternary ammonium compound with a biological availability less than 10 % [240, 292]. The drug has a plasma half-life of approximately 20 h and is mainly (60 % of the dose absorbed) eliminated unchanged in the urine. The concentration obtained in urine seems to be enough to affect the mucosal signaling system in a rat model [452]. Whether or not it contributes to the clinical efficacy of the drug remains to be established.

Trospium is not metabolized by the cytochrome P450 enzyme system [81, 240]. It is expected to cross the blood–brain to a limited extent since it is a substrate for the drug-efflux transporter P-glycoprotein, which restricts its entry into the brain [716]. This was demonstrated by Staskin et al. [716], showing that trospium chloride levels in CSF samples were undetectable on Day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values. Clinically, trospium seems to have no negative cognitive effects [142, 292, 716, 764, 816].

Trospium has no selectivity for muscarinic receptor subtypes. In isolated detrusor muscle, it was more potent than oxybutynin and tolterodine to antagonize carbachol-induced contractions [776].

Several RCTs have documented positive effects of trospium both in neurogenic [507, 545, 725] and non-neurogenic DO [16, 121, 235, 341, 407, 653, 719, 846]. In a placebo-controlled, double-blind study on patients with neurogenic DO [725], the drug was given twice daily in a dose of 20 mg over a 3-week period. It increased maximum cystometric capacity, decreased maximal detrusor pressure, and increased compliance in the treatment group, whereas no effects were noted in the placebo group. Side effects were few and comparable in both groups. In another RCT including patients with spinal cord injuries and neurogenic DO, trospium and oxybutynin were equieffective; however, trospium seemed to have fewer side effects [507].

The effect of trospium in urgency incontinence has been documented in several RCTs. Allousi et al. [16] compared the effects of the drug with those of placebo in 309 patients in a urodynamic study of 3-week duration. Trospium 20 mg was given twice daily. Significant increases were noted in volume at first involuntary contraction and in maximum bladder capacity. Cardozo et al. [121] investigated 208 patients with DO, who were treated with trospium 20 mg twice daily for 2 weeks. Also in this study, significant increases were found in mean volume at first unstable contraction (from 233 to 299 mL; placebo 254–255 mL) and in maximum bladder capacity (from 329 to 356 mL; placebo 345–335 mL) in the trospium-treated group. Trospium was well tolerated with similar frequency of adverse effects as in the placebo group. Jünemann and Al-Shukri [407] compared trospium 20 mg twice daily with tolterodine 2 mg twice daily in a placebo-controlled double-blind study on 232 patients with urodynamically proven DO, urgency incontinence without demonstrable DO, or mixed incontinence. Trospium reduced the frequency of micturition, which was the primary endpoint, more than tolterodine and placebo, and also reduced the number of incontinence episodes more than the comparators. Dry mouth was comparable in the trospium and tolterodine groups (7 and 9 %, respectively).

Halaska et al. [341] studied the tolerability and efficacy of trospium chloride in doses of 20 mg twice daily for long-term therapy in patients with urgency syndrome. The trial comprised a total of 358 patients with urgency syndrome or urgency incontinence. After randomization in the ratio of 3:1, participants were treated continuously for 52 weeks with either trospium chloride (20 mg twice daily) or oxybutynin (5 mg twice daily). Urodynamic measurements were performed at the beginning, and at 26 and 52 weeks to determine the maximal cystometric bladder capacity. Analysis of the micturition diary clearly indicated a reduction of the micturition frequency, incontinence frequency, and a reduction of the number of urgency episodes in both treatment groups. Mean maximum cystometric bladder capacity increased during treatment with trospium chloride by 92 mL after 26 weeks and 115 mL after 52 weeks (P = 0.001). Further comparison with oxybutynin did not reveal any statistically significant differences in urodynamic variables between the drugs. Adverse events occurred in 65 % of the patients treated with trospium and 77 % of those treated with oxybutynin. The main symptom encountered in both treatment groups was dryness of the mouth. An overall assessment for each of the drugs revealed a comparable efficacy level and a better benefit-risk ratio for trospium than for oxybutynin due to better tolerability.

Zinner et al. [846] treated 523 patients with symptoms associated with OABs and urgency incontinence with 20 mg trospium twice daily or placebo in a 12-week, multicenter, parallel, double-blind, placebo-controlled trial. Dual primary endpoints were change in average number of toilet voids and change in urgency incontinent episodes per 24 h. Secondary efficacy variables were change in average of volume per void, voiding urgency severity, urinations during day and night, time to onset of action, and change in Incontinence Impact Questionnaire. By week 12, trospium significantly decreased average frequency of toilet voids per 24 h (−2.37) and urgency incontinent episodes 59 % compared to placebo (−1.29; 44 %). It significantly increased average volume per void (32 mL; placebo: 7.7) mL and decreased average urgency severity and daytime frequency. All effects occurred by week 1 and all were sustained throughout the study. Nocturnal frequency decreased significantly by week 4 (−0.43; placebo: 0.17) and Incontinence Impact Questionnaire scores improved at week 12. Trospium was well tolerated. The most common side effects were dry mouth (21.8 %; placebo 6.5 %), constipation (9.5 %; placebo 3.8 %), and headache (6.5 %; placebo 4.6 %). In a large US multicenter trial with the same design, and including 658 patients with OABs, Rudy et al. [653] confirmed the data by Zinner et al. [846], both with respect to efficacy and adverse effects.

Dose escalation seems to improve therapeutic efficacy. In a 12-week, randomized, double-blind, phase IIIb study including 1,658 patients with urinary frequency plus urgency incontinence received trospium chloride 15 mg TID (n = 828) or 2.5 mg oxybutynin hydrochloride TID (n = 830). After 4 weeks, daily doses were doubled and not readjusted in 29.2 % (242/828) of patients in the trospium group, and in 23.3 % (193/830) in the oxybuytnin group, until the end of treatment. At study end, there were no relevant differences between the “dose adjustment” subgroups and the respective “no dose adjustment” subgroups (trospium: P = 0.249; oxybutynin: P = 0.349). After dose escalation, worsening of dry mouth was higher in both dose-adjusted subgroups compared to the respective “no dose adjustment” subgroups (P < 0.001). Worsening of dry mouth was lower in the trospium groups than in the oxybutynin groups [97].

An extended release formulation of trospium allowing once daily dosing has been introduced [700] and its effects tested in controlled trials [141, 235, 504, 671, 672, 719, 845]. These studies demonstrated similar efficacy as found with previous formulations, but include experiences in, e.g., elderly patients (>75 years), obese patients, and in patients who use multiple concomitant medications. The most frequent side effects were dry mouth (12.9 %; placebo 4.6) and constipation (7.5 %; placebo 1.8) [235].

Intravesical application of trospium may be an interesting alternative. Fröhlich et al. [288] performed a randomized, single-blind, placebo-controlled, mono-centre clinical trial in 84 patients with urgency or urgency incontinence. Compared to placebo, intravesical trospium produced a significant increase in maximum bladder capacity and a decrease of detrusor pressure accompanied by an increase of residual urine. There was an improvement in uninhibited bladder contractions. No adverse events were reported. Interestingly, intravesical trospium does not seem to be absorbed [800], thus offering an opportunity for treatment with minimal systemic antimuscuscarinic effects.

Assessment. Trospium has a well-documented effect in OABs/DO, and tolerability and safety seem acceptable (Table 13.1).

Antimuscarinics with “Mixed” Action

Some drugs used for treatment of the OABs/DO have been shown to have more than one mechanism of action. They all have a more or less pronounced antimuscarinic effect and, in addition, an often poorly defined “direct” action on bladder muscle. For several of these drugs, the antimuscarinic effects can be demonstrated at much lower drug concentrations than the direct action, which may involve blockade of voltage-operated Ca²⁺ channels. Most probably, the clinical effects of these drugs can be explained mainly by an antimuscarinic action. Among the drugs with mixed actions was terodiline, which was withdrawn from the market because it was suspected to cause polymorphic ventricular tachycardia (torsade de pointes) in some patients [185, 723].

Oxybutynin Chloride

Oxybutynin is a tertiary amine that is well absorbed and undergoes extensive upper gastrointestinal and first-pass hepatic metabolism via the cytochrome P-450 system (CYP3A4) into multiple metabolites. The primary metabolite, N-desethyloxybutynin (DEO), has pharmacological properties similar to the parent compound [799], but occurs in much higher concentrations after oral administration [377]. It has been implicated as the major cause of the troublesome side effect of dry mouth associated with the administration of oxybutynin. It seems reasonable to assume that the effect of oral oxybutynin to a large extent is exerted by the metabolite. The occurrence of an active metabolite may also explain the lack of correlation between plasma concentration of oxybutynin itself and side effects in geriatric patients reported by Ouslander et al. [607]. The plasma half-life of the oxybutynin is approximately 2 h, but with wide interindividual variation [242, 377].

Oxybutynin has several pharmacological effects in vitro, some of which seem difficult to relate to its effectiveness in the treatment of DO. It has both an antimuscarinic and a direct muscle relaxant effect, and in addition, local anesthetic actions. The latter effect may be of importance when the drug is administered intravesically, but probably plays no role when it is given orally. In vitro, oxybutynin was 500 times weaker as a smooth muscle relaxant than as an antimuscarinic agent [411]. Most probably, when given systemically, oxybutynin acts mainly as an antimuscarinic drug. Oxybutynin has a high affinity for muscarinic receptors in human bladder tissue and effectively blocks carbachol-induced contractions [581, 799]. The drug was shown to have slightly higher affinity for muscarinic M₁ and M₃ receptors than for M₂ receptors [580, 592], but the clinical significance of this is unclear.

The immediate release (IR) form of oxybutynin (OXY-IR) is recognized for its efficacy and most of the newer anti-muscarinic agents have been compared to it once efficacy over placebo has been determined. In general, the new formulations of oxybutynin and other antimuscarinic agents offer patients efficacy roughly equivalent to that of OXY-IR, and the advantage of the newer formulations lies in improved dosing schedules and side effect profile [62, 224, 227]. An extended release oxybutynin (OXY-ER) once daily oral formulation and an oxybutynin transdermal delivery system (OXY-TDS) are available. OXY-TDS offers a twice-weekly dosing regimen and the potential for improved patient compliance and tolerability. Some of the available formulations of oybutynin were overviewed by McCrery and Appell [538].

Immediate-release oxybutynin (OXY-IR). Several controlled studies have shown that OXY-IR is effective in controlling DO, including neurogenic DO [38, 827]. The recommended oral dose of the IR form is 5 mg three times daily or four times daily, even if lower doses have been used. Thüroff et al. [761] summarized 15 randomized controlled studies on a total of 476 patients treated with oxybutynin. The mean decrease in incontinence was recorded as 52 % and the mean reduction in frequency per 24 h was 33 % (data on placebo not presented). The overall “subjective improvement” rate was reported as 74 % (range 61–100 %). The mean percent of patients reporting an adverse effect was 70 (range 17–93 %). Oxybutynin, 7.5–15 mg/day, significantly improved quality of life of patients suffering from overactive bladder in a large open multicenter trial. In this study, patients’ compliance was 97 % and side effects, mainly dry mouth, were reported by only 8 % of the patients [20]. In nursing home residents (n = 75), Ouslander et al. [608] found that oxybutynin did not add to the clinical effectiveness of prompted voiding in a placebo-controlled, double-blind, cross-over trial. On the other hand, in another controlled trial in elderly subjects (n = 57), oxybutynin with bladder training was found to be superior to bladder training alone [741].

Several open studies in patients with spinal cord injuries have suggested that oxybutynin, given orally or intravesically, can be of therapeutic benefit [449, 740].

The therapeutic effect of OXY-IR on DO is associated with a high incidence of side effects (up to 80 % with oral administration). These are typically antimuscarinic in nature (dry mouth, constipation, drowsiness, blurred vision) and are often dose-limiting [73, 239, 404, 405]. The effects on the ECG of oxybutynin were studied in elderly patients with urinary incontinence (Hussain et al., 1998); no changes were found. It cannot be excluded that the commonly recommended dose 5 mg × 3 is unnecessarily high in some patients, and that a starting dose of 2.5 mg × 2 with following dose-titration would reduce the number of adverse effects [20].

Extended release oxybutynin (OXY-ER). This formulation was developed to decrease liver metabolite formation of DEO with the presumption that it would result in decreased side effects, especially dry mouth, and improve patient compliance with remaining on oxybutynin therapy (see [65]). The formulation utilizes an osmotic system to release the drug at a controlled rate over 24 h distally primarily into the large intestine where absorption is not subject to first-pass metabolism in the liver. This reduction in metabolism is meant to improve the rate of dry mouth complaints when compared to OXY-IR. DEO is still formed through the hepatic cytochrome P-450 enzymes, but clinical trials have indeed demonstrated improved dry mouth rates compared with OXY-IR [61]. Salivary output studies have also been interesting. Two hours after administration of OXY-IR or TOLT-IR, salivary production decreased markedly and then gradually returned to normal. With OXY-ER, however, salivary output was maintained at predose levels throughout the day [135].

The effects of OXY-ER have been well documented [695]. In the OBJECT study [62], the efficacy and tolerability of 10 mg OXY-ER was compared to a twice daily 2 mg dose of TOLT-IR. OXY-ER was statistically more effective than the TOLT-IR in weekly urgency incontinence episodes (OXY-ER from 25.6 to 6.1 %; TOLT-IR 24.1 to 7.8), total incontinence (OXY-ER from 28.6 to 7.1 %; TOLT-IR 27.0 to 9.3), and frequency (OXY-ER from 91.8 to 67.1 %; TOLT-IR 91.6 to 71.5) and both medications were equally well tolerated. The basic study was repeated as the OPERA study [224] with the difference that this study was a direct comparison of the two extended-release forms, OXY-ER (10 mg) and TOLT-ER (4 mg), and the results were quite different. In this study there was no significant difference in efficacy for the primary endpoint of urgency incontinence; however, TOLT-ER had a statistically lower incidence of dry mouth. OXY-ER was only statistically better at 10 mg than TOLT-ER 4 mg in the reduction of the rate of urinary frequency. These studies made it clear that in comparative studies IR entities of one drug should no longer be compared with ER entities of the other.

Greater reductions in urgency and total incontinence have been reported in patients treated in dose-escalation studies with OXY-ER. In two randomized studies, the efficacy and tolerability of OXY-ER were compared with OXY-IR. In the 1999 study [23], 105 patients with urgency or mixed incontinence were randomized to receive 5–30 mg OXY-ER once daily or 5 mg of OXY-IR 1–4 times/day. Dose titrations began at 5 mg and the dose was increased every 4–7 days until one of three endpoints was achieved. These were (1) the patient reported no urgency incontinence during the final 2 days of the dosing period; (2) the maximum tolerable dose was reached; the maximum allowable dose (30 mg for OXY-ER or 20 mg for OXY-IR) was reached. The mean percentage reduction in weekly urgency and total incontinence episodes was statistically similar between OXY-ER and OXY-IR, but dry mouth was reported statistically more often with OXY-IR. In the 2000 study [789], 226 patients were randomized between OXY-ER and OXY-IR with weekly increments of 5 mg daily up to 20 mg daily. As in the 1999 study, OXY-ER again achieved a >80 % reduction in urgency and total incontinence episodes and a significant percentage of patients became dry. A negative aspect of these studies is that there were no naïve patients included, as all patients were known responders to oxybutynin. Similar efficacy results have been achieved, however, with OXY-ER in a treatment-naïve population [313].

In an RCT comparing different daily doses of oxybutynin (5, 10 and 15 mg), Corcos et al. [187] found a significant dose–response relationship for both urgency incontinence episodes and dry mouth. The greatest satisfaction was with 15 mg oxybutynin/day.

In a multicenter, prospective, observational, flexible-dosing Korean study, Yoo et al. [832] investigate the prescription pattern and dose distribution of OXY-ER in patients with the OAB syndrome in actual clinical practice. The dosage for each patient was adjusted after discussions of efficacy and tolerability between doctor and patient, over a 12-week treatment period. Efficacy was measured by administering the Primary OAB Symptom Questionnaire (POSQ) before and after treatment. Patients were also administered; the patient perception of treatment benefit (PPTB) questionnaire is at the end of the study. Of the 809 patients enrolled, 590 (73.2 %) continued to take study medication for 12 weeks. Most patients were prescribed 5–10 mg/day oxybutynin ER as both starting and maintenance doses, with a dose escalation rate of only 14.9 %. All OAB symptoms evaluated by the POSQ were improved; 94.1 % of patients reported benefits from treatment and 89.3 % were satisfied.

Transdermal oxybutynin (OXY-TDS). Transdermal delivery also alters oxybutynin metabolism reducing DEO production to an even greater extent than OXY-ER. A study [201] comparing OXY-TDS with OXY-IR demonstrated a statistically equivalent reduction in daily incontinent episodes (from 7.3 to 2.3: 66 % for OXY-TDS, and 7.4 to 2.6: 72 % for OXY-IR), but much less dry mouth (38 % for OXY-TDS and 94 % for OXY-IR). In another study [227] the 3.9-mg daily dose patch significantly (vs. placebo) reduced the mean number of daily incontinence episodes (from 4.7 to 1.9; placebo from 5.0 to 2.9), while reducing average daily urinary frequency confirmed by an increased average voided volume (from 165 to 198 mL; placebo from 175 to 182 mL). Furthermore, dry mouth rate was similar to placebo (7 % vs. 8.3 %). In a third study [229, 234] OXY-TDS was compared not only to placebo but to TOLT-ER. Both drugs equivalently and significantly reduced daily incontinence episodes and increased the average voided volume, but TOLT-ER was associated with a significantly higher rate of antimuscarinic adverse events. The primary adverse event for OXY-TDS was application site reaction pruritis in 14 % and erythema in 8.3 % with nearly 9 % feeling that the reactions were severe enough to withdraw from the study, despite the lack of systemic problems.

The pharmacokinetics and adverse effect dynamics of OXY-TDS (3.9 mg/day) and OXY-ER (10 mg/day) were compared in healthy subjects in a randomized, 2-way crossover study [61]. Multiple blood and saliva samples were collected and pharmacokinetic parameters and total salivary output were assessed. OXY-TDS administration resulted in greater systemic availability and minimal metabolism to DEO compared to OXY-ER which resulted in greater salivary output in OXY-TDS patients and less dry mouth symptomatology than when taking OXY-ER.

Dmochowski et al. [231] analyzing the combined results of two RCTs concluded that transdermal oxybutynin was shown to be efficacious and well tolerated. The most common systemic side effect was dry mouth (7.0 % vs. placebo 5.3 %). Application site erythema occurred in 7 % and pruritus in 16.1 %. Also Cartwright and Cardozo [129], reviewing published and presented data, concluded that transdermal oxybutynin has a good balance between efficacy and tolerability with a rate of systemic antimuscarinic side effects lower that with oral antimuscarinics—however, this benefit was offset by the rate of local skin reaction. The reviews of Sahai et al. [663] and Staskin and Salvatore [718] largely confirmed these conclusions, which also have been supported by further studies [130].

Oxybutynin topical gel. Given the efficacy and tolerability of the transdermal application, limited only by skin site reactions, a gel formulation was developed. Oxybutynin topical gel (OTG) was approved by the US FDA in January 2009. OTG is applied once daily to the abdomen, thigh, shoulder, or upper arm area [715]. The 1 g application dose delivers approximately 4 mg of drug to the circulation with stable plasma concentrations and a “favorable” DEO metabolite: oxybutynin ratio believed to minimizing antimuscarinic side effects [717]. In a multicenter RCT, 789 patients (89 % women) with urgency-predominant incontinence were assigned to OTG or placebo once daily for 12 weeks [715]. The mean number of urgency episodes, as recorded by 3-day voiding diary, was reduced by 3.0 episodes/day vs. 2.5 in the placebo arm (P < 0.0001). Urinary frequency decreased by 2.7 episodes/day and voided volume increased by 21 mL (vs. 2.0 episodes (P = 0.0017) and 3.8 mL (P = 0.0018), respectively, in the placebo group). Dry mouth was reported in 6.9 % of the treatment group vs. 2.8 % of the placebo group. Skin reaction at the application site was reported in 5.4 % of the treatment group vs. 1.0 % in the placebo arm. It was felt that improved skin tolerability of the gel over the OXY transdermal patch delivery system was secondary to lack of adhesive and skin occlusion. The gel dries rapidly upon application and leaves no residue; person-to-person transference via skin contact is largely eliminated if clothing is worn over the application site [230]. The evolution of the transdermal gel allows greater patient tolerability and improved compliance. This was confirmed by Sand et al. [669, 670] showing that in 704 women with OABs, OTG significantly reduced the number (mean ± standard deviation) of daily incontinence episodes (OTG, −3.0 ± 2.8 episodes; placebo, −2.5 ± 3.0 episodes), reduced urinary frequency, increased voided volume, and improved select health-related quality-of-life domains vs. placebo. Dry mouth was the only drug-related adverse event significantly more common with OTG (7.4 %) than with placebo (2.8 %).

Other administration forms. Rectal administration [180] was reported to have fewer adverse effects than the conventional tablets.

Administered intravesically, oxybutynin has in several studies been demonstrated to increase bladder capacity and produce clinical improvement with few side effects, both in neurogenic and in other types of DO, and both in children and adults [264, 298, 335, 499], although adverse effects may occur [428, 611].

Effects on cognition. Several studies have documented the possibility that oxybutynin may have negative effects on cognitive functions, particularly in the elderly population but also in children (see, e.g., [432, 433, 456]). This factor should be taken into consideration when prescribing the drug.

Assessment. Oxybutynin has a well-documented efficacy in the treatment of OABsDO (Table 13.1). Despite the adverse effect profile, it is still an established therapeutic option.

Propiverine Hydrochloride

Several aspects of the preclinical, pharmacokinetic, and clinical effects of propiverine have been reviewed by Madersbacher and Mürz [506]. The drug is rapidly absorbed (t _max 2 h), but has a high first pass metabolism, and its biological availability is about 50 %. Propiverine is an inducer of hepatic cytochrome P450 enzymes in rats in doses about 100-times above the therapeutic doses in man [801]. Several active metabolites are formed which quantitatively and qualitatively differ from the mother compound [347, 568, 733, 820, 843]. Most probably these metabolites contribute to the clinical effects of the drug, but their individual contributions have not been clarified [549]. The half-life of propiverine itself is about 11–14 h. An extended release preparation was shown to be effective [409, 535]. Oral absorption of propiverine is site-dependent and influenced by dosage form and circadiantime-dependent elimination processes [535].

Propiverine has combined antimuscarinic and calcium antagonistic actions [343, 766]. The importance of the calcium antagonistic component for the drug’s clinical effects has not been established. Propiverine has no selectivity for muscarinic receptor subtypes. The effects of propiverine on cardiac ion channels and action potentials were investigated by Christ et al. [170]. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native I(Kr) current in ventricular myocytes of guinea pig. However, action potential duration was not prolonged in guinea-pig and human ventricular tissue, and the investigators concluded that their results did not provide evidence for an enhanced cardiovascular safety risk with the drug.

Propiverine has been shown to have beneficial effects in patients with DO in several investigations. Thüroff et al. [761] collected nine randomized studies on a total of 230 patients and found a 17 % reduction in micturitions per 24 h, a 64 mL increase in bladder capacity, and a 77 % (range 33–80 %) subjective improvement. Side effects were found in 14 % (range 8–42 %). In patients with neurogenic DO, controlled clinical trials have demonstrated propiverine’s superiority over placebo [726]. Propiverine also increased bladder capacity and decreased maximum detrusor contractions. Controlled trials comparing propiverine, flavoxate, and placebo [807], and propiverine, oxybutynin and placebo [505, 808] have confirmed the efficacy of propiverine and suggested that the drug may have equal efficacy and fewer side effects than oxybutynin. In a comparative RCT including 131 patients with neurogenic DO, propiverine and oxybutynin were compared [727]. The drugs were found to be equally effective in increasing bladder capacity and lowering bladder pressure. Propiverine caused a significantly lower frequency of dry mouth than oxybutynin.

Also in children and adolescents with neurogenic DO, propiverine was found to be effective [328, 680], with a low incidence rate of adverse events: <1.5 % [328]. A randomized, double-blind, placebo-controlled trial with parallel-group design in children aged 5–10 year was performed by Marschall-Kehrel et al. [524]. Of 171 randomized children, 87 were treated with propiverine and 84 with placebo. Decrease in voiding frequency per day was the primary efficacy parameter; secondary endpoints included voided volume and incontinence episodes. There was a significant decrease in voiding frequency episodes for propiverine vs. placebo. Superiority could also be demonstrated for voided volume and incontinence episodes per day. Propiverine was well-tolerated: 23 % of side effects were reported for propiverine and 20 % for placebo.

In a randomized, double-blind, multicenter clinical trial, patients with idiopathic DO were treated with 15 mg propiverine twice daily or 2 mg TOLT-IR twice daily over a period of 28 days [408]. The maximum cystometric capacity was determined at baseline and after 4 weeks of therapy. The difference of both values was used as the primary endpoint. Secondary endpoints were voided volume per micturition, evaluation of efficacy (by the investigator), tolerability, post-void residual urine, and quality of life. It was found that the mean maximum cystometric capacity increased significantly (p < 0.01) in both groups. The volume at first urgency and the frequency/volume chart parameters also showed relevant improvements during treatment. The most common adverse event, dry mouth, occurred in 20 patients in the propiverine group and in 19 patients in the tolterodine group. The scores for the quality of life improved comparably in both groups.

Madersbacher et al. [505] compared the tolerability and efficacy of propiverine (15 mg three times daily) oxybutynin (5 mg twice daily) and placebo in 366 patients with urgency and urgency incontinence in a randomized, double-blind placebo-controlled clinical trial. Urodynamic efficacy of propiverine was judged similar to that of oxybutynin, but the incidence of dry mouth and the severity of dry mouth were judged less with propiverine than with oxybutynin. Dorschner et al. [241] investigated in a double-blind, multicenter, placebo-controlled, randomized study the efficacy and cardiac safety of propiverine in 98 elderly patients (mean age 68 years), suffering from urgency, urgency incontinence, or mixed urgency-stress incontinence. After a 2-week placebo run-in period, the patients received propiverine (15 mg three times daily) or placebo (three times daily) for 4 weeks. Propiverine caused a significant reduction of the micturition frequency (from 8.7 to 6.5) and a significant decrease in episodes of incontinence (from 0.9 to 0.3 per day). The incidence of adverse events was very low (2 % dryness of the mouth under propiverine—2 out of 49 patients). Resting and ambulatory ECGs indicated no significant changes. The cardiac safety of propiverine was further studied by Donath et al. [236] in two comprehensively designed mono-centric ECG studies (including 24 healthy females, followed by a second study on 24 male patients with CHD and a pathological Pardee-Q-wave in the ECG). Both studies were placebo-controlled and compared the effects of single (30 mg s.i.d.) and multiple dosing (15 mg TID) of propiverine hydrochloride in a crossover design over 6 and 13 days, respectively. They were performed to investigate the influence of propiverine hydrochloride and its main metabolite propiverine-N-oxide on cardiac function with regard to QTc prolongation, QTc dispersion, and T-wave shape. No negative effects on cardiac safety could be demonstrated.

Abrams et al. [3] compared the effects of propiverine and oxybutynin on ambulatory urodynamic monitoring (AUM) parameters, safety, and tolerability in OABs patients. Patients (n = 77) received two of the following treatments during two 2-week periods: propiverine 20 mg once daily, propiverine 15 mg three times daily, oxybutynin 5 mg three times daily, and placebo. They found that oxybutynin 15 mg was more effective than propiverine 20 mg in reducing symptomatic and asymptomatic involuntary detrusor contractions in ambulatory patients. Oxybutynin had a higher rate of dry mouth, and propiverine had a more pronounced effect on gastrointestinal, cardiovascular, and visual function.

Yamaguchi et al. [824] performed a multicenter, 12-week, double-blind phase III trial in Japanese men and women with OABs (1,593 patients were randomized and 1,584 were treated), comparing solifenacin 5 or 10 mg, propiverine 20 mg, and placebo. Changes at endpoint in number of voids/24 h, urgency, incontinence, urgency incontinence and nocturia episodes, volume voided/void, restoration of continence and quality of life (QoL) were examined. It was found that at endpoint, there were greater reductions in mean (SD) voids/24 h with all drug regimens than with placebo. All active treatments improved the volume voided and QoL vs. placebo; solifenacin 10 mg reduced nocturia episodes and significantly improved urgency episodes and volume voided vs. propiverine 20 mg, and solifenacin 5 mg caused less dry mouth. Solifenacin 10 mg caused more dry mouth and constipation than propiverine 20 mg. Wada et al. [793] performed a prospective nonrandomized crossover study of female OABs patients, assigned alternately to treatment with propiverine (20 mg) for 8 weeks then solifenacin (5 mg) for 8 weeks or solifenacin for 8 weeks then propiverine for 8 weeks. At baseline, eighth week and 16th week symptoms were assessed using OABSS. Of the 121 patients enrolled, 83 were analyzed. Both drugs were effective. Urgency was further improved after switching from propiverine to solifenacin, but not after switching from solifenacin to propiverine. Solifenacin was better tolerated than propiverine.

In another multicenter, prospective, parallel, double-blind, placebo-controlled trial, Lee et al. [482] studied the effects of 30 mg propiverine/day in 264 OABs patients (mean age 52.2 years), 221 of whom had efficacy data available from baseline and at least one on-treatment visit with >75 compliance. The study was focused on improving urgency. Overall, among patients treated with propiverine, 39 % rated their treatment as providing “much benefit,” compared with 15 % in the placebo group. Adverse events reported by 32 (22.5 %) and 10 (12.7 %) patients in the propiverine and placebo group were all tolerable.

Masumori et al. [530] examined prospectively the efficacy and safety of propiverine in patients with OABs who poorly responded to previous treatment with solifenacin, tolterodine, or imidafenacin. Of 73 patients enrolled (29 males and 44 females, median age 71 years), 52 completed the protocol treatment. The OABSS was significantly improved by propiverine treatment. The scores of OAB symptoms (nighttime frequency, urgency and urge incontinence) except daytime frequency also improved significantly. No increase in PVR was observed. The most frequent adverse event was dry mouth (13.7 %), followed by constipation (6.8 %).

In a non-controlled study in patients with wet OABs the efficacy of propiverine on symptoms and quality of life was confirmed [463].

Assessment. Propiverine has a documented beneficial effect in the treatment of OABs/DO (Table 13.1) and seems to have an acceptable side effect profile.

Flavoxate Hydrochloride

Flavoxate is often discussed as a drug with mixed actions; however, its main mechanism of action may not be antimuscarinic. Flavoxate is well absorbed, and oral bioavailability appeared to be close to 100 % [334]. The drug is extensively metabolized and plasma half-life was found to be 3.5 h [692]. Its main metabolite (3-methylflavone-8-carboxylic acid, MFCA) has been shown to have low pharmacological activity [111, 132]. The main mechanism of flavoxate’s effect on smooth muscle has not been established. The drug has been found to possess a moderate calcium antagonistic activity, to have the ability to inhibit PDE, and to have local anesthetic properties; no antimuscarinic effect was found [333]. Uckert et al. [776], on the other hand, found that in strips of human bladder, the potency of flavoxate to reverse contraction induced by muscarinic receptor stimulation and by electrical field stimulation was comparable, It has been suggested that pertussis toxin-sensitive G-proteins in the brain are involved in the flavoxate-induced suppression of the micturition reflex, since intracerebroventricularly or intrathecally administered flavoxate abolished isovolumetric rhythmic bladder contractions in anesthetized rats [603].

The clinical effects of flavoxate in patients with DO and frequency, urgency, and incontinence have been studied in both open and controlled investigations, but with varying rates of success [654]. Stanton [714] compared emepronium bromide and flavoxate in a double-blind, cross-over study of patients with detrusor overactivity and reported improvement rates of 83 % and 66 % after flavoxate or emepronium bromide, respectively, both administered as 200 mg three times daily. In another double-blind, cross-over study comparing flavoxate 1,200 mg/day with that of oxybutynin 15 mg daily in 41 women with idiopathic motor or sensory urgency, and utilizing both clinical and urodynamic criteria, Milani et al. [552] found both drugs effective. No difference in efficacy was found between them, but flavoxate had fewer and milder side effects. Other investigators, comparing the effects of flavoxate with those of placebo, have not been able to show any beneficial effect of flavoxate at dosages up to 400 mg three times daily [104, 157, 198]. In general, few side effects have been reported during treatment with flavoxate. On the other hand, its efficacy, compared to other therapeutic alternatives, is not well documented (Table 13.1).

Assessment. No RCTs seem to have been performed with flavoxate during the last decade. The scarcity of documented clinical efficacy should be considered before using the drug.