Once-Daily, Extended-Release Formulations of Antimuscarinic Agents in the Treatment of Overactive Bladder: A Review

European Urology

European Urology 41 (2002) 6±14

Once-Daily, Extended-Release Formulations of Antimuscarinic Agents in the Treatment of Overactive Bladder: A Review Eric S. Rovner, Alan J. Wein* Division of Urology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, PA 19104, USA Accepted 10 July 2001

Abstract Overactive bladder (OAB) is a chronic condition that often requires long-term treatment to maintain control of symptoms. A range of therapeutic options are available; however, antimuscarinic agents form the mainstay of treatment. Of these agents, tolterodine and oxybutynin are the most widely used. It is well documented that the immediate-release (IR) formulations of these agents have equivalent ef®cacy in relieving OAB symptoms. However, tolterodine demonstrates a more favorable tolerability pro®le, particularly in terms of the frequency and severity of dry mouth. Due to the development of novel drug delivery systems, extended-release (ER) formulations of both oxybutynin and tolterodine are now available, permitting once-daily dosing. The convenience of once-daily dosing of antimuscarinic agents would be expected to improve patient compliance and further relieve the symptoms of OAB. Clinical studies with the ER formulations of tolterodine and oxybutynin demonstrate potential clinical advantages over their respective IR forms in terms of either ef®cacy or tolerability or both, although the therapeutic index of tolterodine ER appears to show a greater advantage over its IR counterpart compared with oxybutynin ER and its IR form. Importantly, the two ER agents have not been compared directly in a head-to-head clinical study. Overall, available clinical data suggest that the newly developed ER formulation of tolterodine represents a signi®cant therapeutic advancement in the treatment of OAB. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Overactive bladder; Micturition; Muscarinic antagonist; Oxybutynin; Oxybutynin ER; Tolterodine; Tolterodine ER; Tolerability; Dry mouth

1. Introduction Overactive bladder (OAB) is one of the most common causes of bladder control problems. It arises due to uncontrolled spontaneous activity of the detrusor muscle during bladder ®lling, leading to symptoms of urinary urgency and increased frequency of micturition, with or without urge incontinence. It is underreported by those who suffer from the condition [1], and data on the true prevalence are only now emerging [2±4]. Extrapolation of results from the largest study to investigate population-based prevalence rates indicates that OAB affects over 22 million people in the six *

Corresponding author. Tel. ‡1-215-662-6755; Fax: ‡1-215-662-3955. E-mail address: [email protected] (A.J. Wein).

European countries studied [5]. In the US, it is estimated that at least 17 million individuals are affected [6]. Based on these ®gures, OAB is more common than diabetes mellitus and of similar prevalence to asthma or chronic bronchitis [6]. Although its prevalence increases with age [7], the occurrence of OAB is not normal at any age. The symptoms of OAB have a profoundly negative effect on the lives of affected individuals [8,9]. Frequency is the most common symptom, followed by urgency and urge incontinence. In fact the unpredictable nature of the symptoms of frequency and/or urgency have a substantial impact on quality of life similar to that of incontinence [10]. Moreover, the ®nancial implications of OAB, and bladder control problems in general, are considerable. From a societal

0302-2838/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 2 - 2 8 3 8 ( 0 1 ) 0 0 0 0 9 - 4

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perspective, for example, the cost of urinary incontinence for individuals aged 65 years or older in the US was estimated at US$ 26.3 billion in 1995 [11]. Of this, US$ 11.4 billion was for routine costs, such as use of pads, reusable briefs, laundry and catheterization. Despite the disturbing nature of OAB, many sufferers do not seek help for urinary symptoms because of embarrassment or the belief that they are a normal part of aging [12]. This is most unfortunate since effective treatments are readily available. Treatment options range from behavioral therapies (bladder drill or retraining) to surgical interventions [13], although a very effective form of treatment is pharmacotherapy with antimuscarinic agents such as oxybutynin and tolterodine [14±16]. Despite proven ef®cacy in OAB, however, such agents have limitations. The aim of this review is to discuss these limitations and to consider the appropriate application of new oncedaily, extended-release (ER) formulations of tolterodine and oxybutynin in the treatment of OAB. 2. Limitations of current antimuscarinics Of the antimuscarinic agents currently available for the treatment of OAB, oxybutynin and tolterodine are the most commonly used. Oxybutynin was originally developed for the treatment of gastrointestinal hypermotility, but has been widely used for the treatment of OAB for over 25 years, a practice based on its well documented clinical ef®cacy [17,18]. Tolterodine is a more recent addition to the antimuscarinic armamentarium, and was the ®rst agent of this class to be speci®cally developed to treat OAB [19]. Tolterodine is highly effective in the treatment of OAB, signi®cantly reducing the number of incontinence episodes and frequency of micturition, with a concomitant increase in mean voided volume [20,21]. However, treatment with the intermediate-release (IR) form of antimuscarinic agents may have certain limitations. These limitations can be considered in terms of tolerability or dosing regimen issues, both of which may signi®cantly impair patient compliance and therefore overall ef®cacy. 2.1. Tolerability Historically, the major limitation of treatment with antimuscarinic agents has been a high incidence of side effects. Indeed, side effects can be so bothersome that they result in early discontinuation of therapy in a large number of patients [22±24]. The most frequent antimuscarinic side effects include dry mouth, gastrointestinal disorders, central nervous system (CNS)

7

effects and visual disturbances [18]. In particular, dry mouth can occur in up to 80% of patients receiving oxybutynin IR [18,25]. Inhibition of salivation may have serious rami®cations including a predisposition to oral infections and dental caries, since saliva plays an important role in oral health due to its antimicrobial properties [26]. Saliva is also important for mastication and swallowing processes [27], and it has been suggested that in some elderly patients druginduced dry mouth may contribute to malnutrition [28]. Tolterodine shows a greater selectivity for bladder smooth muscle than salivary glands in vivo, whereas oxybutynin displays the opposite organ selectivity [19]. This `bladder selective' pro®le of tolterodine suggests that it should be associated with a lower incidence of dry mouth, a fact that has been con®rmed in controlled clinical studies. Indeed, a number of randomized, double-blind, placebo-controlled studies have demonstrated that the IR formulations of tolterodine (2 mg twice-daily) and oxybutynin (5 mg three times daily) are equivalent in terms of ef®cacy but that tolterodine is better tolerated, particularly with respect to the frequency and intensity of dry mouth [25,29,30]. Notably, the adverse effects of both of these agents, as well as all antimuscarinic agents in general, may increase in a dose-dependent fashion such that dose titration may be necessary to balance ef®cacy and side effects [31,32]. However, this appears to be more problematic with oxybutynin than tolterodine, the latter of which does not require dosage titration and appears to have a good balance of ef®cacy and tolerability at its recommended dose of 2 mg twice-daily. Aside from the salivary glands, tolterodine has also shown favorable selectivity for the bladder over other tissues that contain muscarinic receptors. Thus, while gastrointestinal disorders such as constipation are common with oxybutynin IR and may even contribute to urinary symptoms in some patients [33], tolterodine IR has a similar gastrointestinal tolerability pro®le to placebo [25]. Muscarinic receptors are also widespread in the CNS and antimuscarinic agents therefore have the potential to cause cognitive impairment, which is of particular concern in the elderly. Tolterodine IR appears to be without signi®cant adverse CNS effects, as measured by quantitative-topographical electroencephalogram [34]. This may be explained at least in part by its low lipophilicity and consequently poor CNS penetration. In contrast to tolterodine, signi®cant cognitive impairment has been reported with oxybutynin [35]. Visual disturbances are also common during treatment

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with oxybutynin IR [18], but are less pronounced with tolterodine IR [36]. Overall, patient tolerability represents an important issue with the administration of antimuscarinic agents. This limitation appears to be somewhat more problematic with oxybutynin IR as compared with tolterodine IR. Tolterodine IR seems to possess a more favorable balance of tolerability and ef®cacy, which may explain the high rates of compliance observed with this agent during long-term therapy [37]. 2.2. Dosing schedule Although it is generally accepted that polypharmacy is the central factor in poor compliance with medical regimens, it has been suggested that multiple daily dosing (poly-dosing) is more problematic [38]. This is particularly relevant for the elderly, who frequently take many concomitant medications [39], often with different administration schedules. Research into polydosing in other chronic diseases, such as hypertension, has shown that compliance is signi®cantly impaired as the prescribed dose frequency increases [40]. This suggests the potential for poor compliance with the IR formulations of antimuscarinics, which require multiple daily dosing due to their short elimination half-lives [41,42]. Oxybutynin IR may be administered up to four times daily, while tolterodine IR requires twice-daily administration. With respect to tolterodine, twice-daily administration does not appear to present a signi®cant barrier to compliance during long-term therapy [43]. However, in a recent retrospective analysis of a US pharmacy claims database, less than one-third of patients continued treatment with IR formulations of tolterodine and oxybutynin for 6 months [44]. While such ®ndings are in accordance with the earlier results of Kelleher et al. [23], there is a discrepancy with results of open, longterm studies with tolterodine in which approximately two-thirds of patients continued treatment for 9±12 months [37]. One possible explanation is that patients who volunteer to participate in clinical research, as was the case in the open, long-term studies with tolterodine, tend to be more compliant [45]. Therefore, in routine clinical practice, long-term compliance may still be problematic for existing IR formulations of antimuscarinics when there is a requirement for multiple daily dosing. Of course, dosing schedule is not the only factor in¯uencing compliance. Moreover, compliance is in¯uenced by a combination of factors including ef®cacy and tolerability, as well as convenient dosing, and so an ideal agent would address all of these factors.

3. The role of ER formulations for once-daily treatment of OAB The poor tolerability and/or the need for frequent daily dosing with current antimuscarinic IR formulations has led to the search for new treatment approaches. Alternative drug delivery systems, in terms of the development of ER formulations for once-daily administration, is one such approach to improve not only dosing, but potentially also affecting tolerability and ef®cacy. Indeed, given the established link between prescribed dose frequency and compliance [40], such formulations can be expected to maximize convenience and thereby improve compliance. This is of direct relevance to patients with OAB, a chronic condition often requiring satisfactory adherence to long-term therapy. Moreover, the pharmacokinetic pro®le of such ER formulations should lessen the `peak-and-trough' serum concentrations seen following multiple daily dosing with IR formulations. A lowering of peak drug levels may be associated with a reduction in dose-related adverse effects [46], such as dry mouth. ER formulations of oxybutynin and tolterodine are now available and their pro®les and role in the oncedaily treatment of OAB are discussed below. 3.1. Oxybutynin ER An ER formulation of oxybutynin was introduced in the US during early 1999. It uses an established osmotic system (OROS1) that delivers a controlled amount of drug over a 24 h period following oral administration [47]. The tablet consists of two layers, one of which contains the drug and the other an osmotically active polymeric component, also known as the `push' compartment (Fig. 1) [47]. In the gastrointestinal tract, water enters the tablet through a semipermeable, rate-controlling membrane to form a suspension of the drug. The polymeric component in the push layer subsequently expands and forces the suspension out through a laser-drilled hole, known as the delivery ori®ce, thereby ensuring constant drug delivery as the dosage form passes through the gastrointestinal tract. The multiple-dose pharmacokinetic pro®le of oxybutynin ER (15 mg once-daily) has been compared with that of oxybutynin IR (5 mg three times a day), in a randomized, open-label, crossover study in 13 healthy volunteers [48]. As expected, the mean peak plasma concentrations were lower, and the mean steady-state plasma concentrations of oxybutynin and the main active metabolite (N-desethyloxybutynin) were less variable for the ER formulation compared with the IR tablet. The resulting area under the curve

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Fig. 1. Cross-section of the OROS1 extended-release delivery system for oxybutynin (adapted from [46]).

was the same for oxybutynin ER in comparison to oxybutynin IR. Overall, the two formulations demonstrated similar ef®cacy in three controlled clinical studies [32,49,50]. In a study of 105 patients, the mean number of urge incontinence episodes per week was reduced by 84% with oxybutynin ER and 88% with the IR formulation [32]. Although the ef®cacy data are impressive, these comparative studies of oxybutynin ER have some signi®cant design issues, which limit their applicability to the normal population with OAB symptoms. Firstly, all patients included in the study populations were known responders to, and many had previously tolerated, antimuscarinic medication. This `enriched' population would be expected to have a very high response rate to therapy. Thus, the ef®cacy data from the trials with respect to reduction in incontinence episodes, pad usage and urinary frequency are not representative of normal in clinical practice. These studies may therefore provide a `best case' scenario for response rate and any other conclusions may be

somewhat speculative. Secondly, results from these studies were analyzed on a `completer' basis, which assesses the response rate in only those patients who completed the study. Interestingly, analysis of the intent-to-treat population of this study [32] revealed that oxybutynin ER was not equivalent to oxybutynin IR on incontinence and oxybutynin IR was signi®cantly more effective than the ER formulation on reducing micturition frequency [51]. On the basis of its pharmacokinetic pro®le, oxybutynin ER was anticipated to be associated with improved tolerability in comparative clinical trials with oxybutynin IR. However, comparisons of the incidence of the most frequently observed adverse event, dry mouth, between the two formulations of oxybutynin show inconsistent results. In the study by Anderson et al. [32], for example, there was a signi®cantly lower rate of dry mouth (any severity) with oxybutynin ER compared with IR (68 versus 87%; P ˆ 0:04). A larger study in 226 patients, however, showed no signi®cant difference in the incidence of dry mouth between the

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two formulations [49]. Furthermore, in the Anderson study the incidences of somnolence (IR 40%; ER 38%), dizziness (IR 38%; ER 28%) and constipation (IR 31%; ER 30%) were not statistically different between the two formulations of oxybutynin [32]. The US Food and Drug Administration concluded that the ef®cacy of oxybutynin ER was superior to placebo and equivalent to that of the IR formulation in one study, but that a claim of improved tolerability versus oxybutynin IR with respect to dry mouth was not supported by the data [51]. Despite equivalent ef®cacy to the IR formulation together with improved patient convenience from once-daily dosing, no conclusion can be reached in terms of a tolerability advantage of oxybutynin ER. 3.2. Tolterodine ER Tolterodine ER has recently been launched as a oncedaily ER capsule for the treatment of OAB. The oncedaily formulation utilizes a unique drug delivery system containing soluble microspheres (Fig. 2). As the outer layer of the microsphere dissolves, the drug is slowly released, providing consistent delivery over 24 h. The ER delivery release mechanism allows for smooth serum concentrations of tolterodine. The multiple-dose pharmacokinetic pro®le of tolterodine ER (4 mg oncedaily) has been compared with that of tolterodine IR

(2 mg twice a day), in a randomized, open-label, crossover study in 19 healthy volunteers [52]. For tolterodine ER, the maximum observed serum concentration for active moiety was about 75% that of tolterodine IR, and the minimum observed serum concentration was about 150% higher. However, the area under the curve of ER 4 mg once-daily tolterodine is equivalent to that of tolterodine IR 2 mg twice-daily. These results led the authors to speculate that the reduced peak concentrations and elimination of the troughs of the ER formulation might lead to better tolerability and ef®cacy, respectively. In another study it was shown that the pharmacokinetic pro®le of tolterodine ER is not affected by food (i.e. gastric pH) [53]. The ef®cacy and tolerability of tolterodine ER has been evaluated in a multicenter, double-blind, randomized, placebo-controlled study in 1529 OAB patients, the largest such study ever conducted [54]. The study population included both treatment-naõÈve patients (50%) and those who had received prior treatment for OAB symptoms, often without success. Ef®cacy was analyzed on an intention-to-treat basis (all patients who participated in the study were analyzed). A signi®cant clinical advantage in terms of ef®cacy and tolerability was demonstrated for tolterodine ER relative to the IR formulation. There was a 71% median reduction in urge incontinence episodes with tolterodine ER compared

Fig. 2. Cross-section of the microsphere extended-release delivery system for tolterodine. Each capsule contains many hundreds of microspheres. The broad arrows indicate inflow of water, followed by outflow of water and drug across the polymer and overcoat layers.

E.S. Rovner, A.J. Wein / European Urology 41 (2002) 6±14

with a 60% reduction with tolterodine IR. Indeed, tolterodine ER was 18% more effective than tolterodine IR (P < 0:05). The incidence of dry mouth was 23% for tolterodine ER versus 30% for tolterodine IR. The overall rate of dry mouth was 23% lower with tolterodine ER than with the IR formulation (P < 0:02). The incidences of constipation (ER 7%; IR 6%), dizziness (ER 2%; IR 2%) and somnolence (ER 3%; IR 3%) were similar between treatment groups and comparable with placebo. Therefore, unlike the studies comparing oxybutynin ER and IR formulations, this study suggests an improved therapeutic index and a clinical advantage of tolterodine ER over the IR formulation of the drug in terms of ef®cacy and tolerability, in addition to its obvious bene®t of a convenient once-daily preparation. 3.3. Comparing efficacy and tolerability profiles A comparison of the ef®cacy and tolerability pro®les of oxybutynin ER and tolterodine ER is of clinical interest. To date, however, there have been no clinical head-to-head studies of these ER formulations, and direct comparison of previous studies is complicated by differences in enrolled patient populations and methodologies. Nevertheless, both tolterodine IR and oxybutynin ER have been compared to oxybutynin IR. Oxybutynin ER was shown to have equivalent ef®cacy to oxybutynin IR. Tolterodine IR and oxybutynin IR have also demonstrated equivalent ef®cacy. Tolterodine ER has not yet been directly compared to any of

11

the oxybutynin formulations in a clinical study, but has been shown to be 18% more effective than tolterodine IR using urge incontinence as an outcome indicator [54]. An attempt at a comparison of the ef®cacy of the ER formulations of tolterodine and oxybutynin can be made by correcting for the placebo response, which is frequently seen in clinical trials of patients with OAB [55]. When such an adjustment is made, as expected, the clinical ef®cacy of the ER formulations of oxybutynin and tolterodine are similar in terms of reduction in urge incontinence episodes. Indeed, the ef®cacy ratio of active to placebo for oxybutynin ER is 1.8 (active 90%, placebo 49%) [56] and is 2.2 (active 71%, placebo 33%) for tolterodine ER [54]. One study has been completed that compared oxybutynin ER with tolterodine IR [57]. Of 378 patients enrolled, 332 completed the 12 weeks study. Compared to baseline, weekly urge incontinence episodes per week were reduced (25.6±6.1 versus 24.1±7.8, oxybutynin ER and tolterodine IR groups, respectively) as was urinary frequency (91.8±67.1 versus 91.6±71.5 episodes per week, oxybutynin ER versus tolterodine IR groups, respectively). Although there was a statistically signi®cant difference between the two drugs favoring oxybutynin in both of these outcome parameters, the overall clinical signi®cance of these differences (for example, a difference of 1.7 urge incontinent episodes per week) is unclear. Furthermore, like the other oxybutynin ER controlled studies [32,49,50],

Table 1 Comparison of adverse event profiles in patients receiving once-daily, extended-release formulations of antimuscarinic agents for the treatment of overactive bladder [32,50,54,56±58]a Body system/adverse event Gastrointestinal (%) Dry mouth Constipation Diarrhea Nausea Dyspepsia

(DetrolTM LA tolterodine 4 mg per day; n ˆ 505)

Ditropan1 XL (oxybutynin 5±30 mg per day; n ˆ 429)b

23.4 5.9 2.0 1.4 3.0

60.8 13.1 9.1 8.9 6.8

Nervous (%) Somnolence Dizziness Special senses Blurred vision Dry eyes

2.8 2.2

11.9 6.3

1.2 3.4

7.7 6.1

General (%) Headache Asthenia Pain

6.3 0.4 1.2

9.8 6.8 6.8

a b

Only adverse events reported by 6% of patients treated with either agent are shown. Pooled analysis of safety data from three controlled studies and one open-label study.

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E.S. Rovner, A.J. Wein / European Urology 41 (2002) 6±14

there are some signi®cant design issues. Firstly, results were analyzed on a completer basis, which assesses the response rate in only those patients who completed the study. Secondly, statistical methods employed for analysis of the data appear questionable in that they employed parametric analysis when the assumption of normality was unclear. Adverse events including overall dry mouth (28.1 versus 33.2%, for oxybutynin ER versus tolterodine IR, respectively) and constipation (7 versus 6.2%, for oxybutynin ER versus tolterodine IR, respectively) were not signi®cantly different between the two groups. These results were surprising, considering the large discrepancy for oxybutynin ER between this study and previous trials where dry mouth occurred at a 59±68% incidence and constipation occurred at a 13±30% incidence [32,58]. Due to the fact that a head-to-head study has not been performed between tolterodine ER and oxybutynin ER makes tolerability comparisons dif®cult. One choice is to compare the adverse event pro®les of the two medications. Using this approach, the tolerability pro®le of tolterodine ER is superior to oxybutynin ER. When a pooled analysis of adverse events from relevant clinical studies is performed (see Table 1), there is an overall lower frequency of dry mouth (23 versus 61%), constipation (6 versus 13%), somnolence (3 versus 12%) and blurred vision (1 versus 8%) with tolterodine ER versus oxybutynin ER [54,56]. One pharmacological study has been conducted which compared tolterodine ER and oxybutynin ER [59]. A double-blind, randomized, four-way crossover study compared oxybutynin ER 5, 15 and 25 mg versus tolterodine ER 6 mg. Oxybutynin ER treatment resulted

in a linear dose-dependent increase in bladder capacity and a linear dose-dependent decrease in salivation. Tolterodine ER 6 mg had the same effect on bladder capacity as a 20 mg dosage of oxybutynin ER and the same effect on salivation as a 10 mg dosage of oxybutynin ER, thus highlighting the bladder selectivity of tolterodine ER compared to oxybutynin ER. The results of this trial are consistent with data reported in previous individual clinical studies of tolterodine ER and oxybutynin ER. 4. Conclusions Antimuscarinic agents remain the mainstay of treatment for OAB. However, the utility of some of these agents is limited due to tolerability concerns and/or multiple daily dosage regimens. This can lead to problems with long-term compliance and may, in some patients, preclude optimal management of this chronic condition. The development of ER dosage forms has changed pharmacological management of OAB and promises to improve the long-term management in terms of tolerability and, to some degree, ef®cacy. Oxybutynin ER has demonstrated similar ef®cacy to the IR formulation without conclusive evidence of improvement in tolerability. Once-daily antimuscarinic therapy with tolterodine ER, however, provides signi®cant clinical ef®cacy and tolerability advantages over the current tolterodine IR formulation. Thus, current ®ndings suggest that the ER formulation of tolterodine has a superior pro®le to other agents currently being prescribed.

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Editorial Comment Christopher R. Chapple Sheffield, UK

This is a very timely manuscript from leading worker in this ®eld. It is clearly established that drug tolerability can be improved by the delayed-release formulation which is more convenient for the patient and also as a consequence of the improved pharmaco-kinetic pro®le

[58] Gleason DM, Susset J, White C, Munoz DR, Sand PK. Evaluation of a new once-daily formulation of oxybutynin for the treatment of urinary urge incontinence. Ditropan1 XL study group. Urology 1999;54:420±3. [59] Chapple C. Tolterodine once-daily: Selectivity for the bladder over effects on salivation compared to Ditropan1 XL. J Urol 2001;165:253.

which lessens ``peak and through'' see sawing thereby improves tolerability and ef®cacy. The two most commonly used anti-cholinergics in the treatment of the overactive bladder namely oxybutinin and tolterodine have both recently been reformulated as an extended release preparation and it is therefore very helpful to have this critical review of the existing data relating to these agents in the context of the contemporary clinical management of this important clinical condition.