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Abstract

Overactive bladder is a debilitating disorder affecting 16.5% of adults and increasing in prevalence with age. Symptoms, including urgency, urge incontinence and frequency can result from detrusor overactivity with contraction of the bladder mediated primarily by activation of muscarinic M₃ receptors. Antimuscarinic agents are therefore an important approach to treating overactive bladder, but a lack of M₃ receptor subtype selectivity with these agents can generate a range of side effects that limits their effectiveness. This review describes an alternative approach to treating overactive bladder using the selective muscarinic M₃ receptor antagonist darifenacin. The M₃ receptor selectivity of darifenacin improves the symptoms of overactive bladder while reducing the potential for deleterious effects of non-M₃ muscarinic receptor antagonism in the brain or heart. The pharmacology and pharmacokinetics of darifenacin are summarized, and the its clinical efficacy and demonstrated safety profile are described.

Keywords

antimuscarinic agent darifenacin receptor selectivity overactive bladder oxybutynin propiverine solifenacin tolterodine trospium urinary urge incontinence

Overactive bladder (OAB) is a common, debilitating and chronic condition, characterized by symptoms of urgency with or without urge incontinence and usually accompanied by increased frequency of micturition and nocturia [1]. OAB is highly prevalent, affecting approximately 16.5% of adults in Europe and the USA and becomes more common with increasing age, regardless of gender [2,3]. However, OAB with urge incontinence affects more women than men across all age groups (increasing from 2% at <25 years to 19% at 65–74 years), with a steep rise occurring after 44 years of age [3]. OAB, particularly when associated with urge incontinence (OAB wet), represents a considerable social and economic burden. Significant impairment of quality of life across a range of domains, including social, professional, physical, sexual and emotional functioning, has been well documented [4], and costs associated with OAB (wet or dry) have been estimated at $12.6 billion in the USA alone [5].

One of the known causes of symptoms of OAB is detrusor overactivity, with inappropriate contraction of the bladder detrusor muscle during filling [1]. This contraction is mediated primarily by cholinergic activation of muscarinic M₃ receptors in the bladder [6] and antimuscarinic agents have therefore provided the mainstay of treatment for OAB [7]. However, the patient persistency and compliance achieved with some antimuscarinic drugs has been limited by side effects related to indiscriminate blockade of other, non-M₃ muscarinic receptor subtypes, which mediate a range of effects throughout the body [8 –10]. Darifenacin, a novel M₃ selective receptor antagonist (Box 1), therefore offers an alternative approach to the treatment of OAB by targeting the M₃ receptor subtype whilst sparing effects at other sites including the brain and the heart.

Profile of darifenacin

Pharmacology

Darifenacin ((S)-2-[1-(2,3-dihydrobenzofuran-5-yl)ethyl-pyrrolidinyl]-2,2-diphenylacetamide-hydrobromide) is a potent, competitive and reversible muscarinic receptor antagonist with selectivity for the M₃ receptor over other muscarinic receptor subtypes (Box 1) [11,19]. This contrasts with the profile of other antimuscarinic agents such as oxybutynin, tolterodine, propiverine and trospium, which are relatively nonselective for M₃ over M₁ receptors, with similar binding affinity for both subtypes [11,14].

Darifenacin also displays functional selectivity, observed as greater effects on bladder than other tissues, both in vitro (in heart, saphenous vein and submandibular salivary gland) and in vivo (heart rate or salivation) (Box 1) [12,13,15 –18,20]. In two studies using human isolated urinary bladder smooth muscle, darifenacin was a more potent inhibitor of agonist-induced contraction (pA₂ 9.3–9.5) than oxybutynin, propiverine or tolterodine [12,13]. Similarly, in anesthetized dogs, darifenacin inhibited bladder contraction ten times more potently than salivation and exerted no effect on heart rate, showing the greatest functional selectivity among the antimuscarinics tested (including oxybutynin, tolterodine and propiverine) [16]. In another study in rats, darifenacin demonstrated an eightfold selectivity advantage over oxybutynin for the bladder compared with salivation [17].

Box 1.

Pharmacology of darifenacin.

Darifenacin:

A potent, competitive and reversible muscarinic M₃ selective receptor antagonist in vitro

– pK_i 9.1 at human recombinant M₃ receptors [11] - pA2 9.3–9.5 in isolated human bladder [12,13]

Marked in vitro selectivity for the human recombinant M3 receptor relative to other muscarinic receptor subtypes of all overactive bladder antimuscarinics

– Up to 59-fold selectivity for M₃ over other subtypes

Ratio of K_i values (M₃ = 1): M₁ 9.3; M₂ 59.2; M₄ 59.2; M₅ 12.2 [11]

– Selective for M₃ over M₁ as seen by K_i ratios (M₃:M₁) compared with other antimuscarinic agents

Study 1: darifenacin 9.3; tolterodine 0.6; oxybutynin 1.5; propiverine 0.6; trospium 1.5 [11]

Study 2: darifenacin 10.0; oxybutynin 2.0; solifenacin 2.5 [14]

Demonstrates functional selectivity – more potent effects in bladder than in heart, non-bladder smooth muscle or salivary glands in preclinical models

– pA2/pKb in vitro: guinea-pig bladder 8.9; guinea-pig atria 7.2; dog saphenous vein 7.2 [15]

– In vivo inhibition of bladder contraction 8–10 times more potent than inhibition of salivation in dogs [16] or rats [17]

– In vivo doses eliciting maximal inhibition of bladder contraction did not affect heart rate in dogs [16] or minipigs [18]

The functional selectivity of darifenacin may be further influenced by its local tissue concentrations. Unlike other antimuscarinics, darifenacin is reported to be a substrate for the P-glycoprotein efflux pump [21] and is therefore subject to active efflux at the blood–brain barrier. This mechanism, in addition to the physico-chemical properties of darifenacin (positive charge, low–moderate lipophilicity and molecular size), may serve to limit CNS concentrations of darifenacin.

Pharmacokinetics

Darifenacin is rapidly and completely absorbed from the gastrointestinal tract following oral administration, with maximum plasma levels reached approximately 7 h after dosing with the controlled-release formulation [22 –24]. Oral bioavailability of darifenacin (15 and 19% for 7.5 and 15 mg doses, respectively) is limited by extensive first-pass metabolism mediated by cytochrome P450 isoenzymes (CYP3A4 and CYP2D6), but this is saturable after multiple administrations [22 –24]. The pharmacokinetics of darifenacin during multiple-dose administration are unaffected by food [25] and steady-state plasma levels are achieved within 6 days [22]. Following absorption, darifenacin is distributed extensively into body tissues and is 98% plasma protein bound [22,24].

The major circulating metabolites of darifenacin are unlikely to contribute to its clinical effect [22]. Darifenacin is eliminated mainly via the urine (approximately 60%) and the feces (approximately 40%), with only 3% excreted as unchanged parent drug [22,24].

Pharmacokinetic analyses indicate no requirement for dose adjustment for age or gender, for patients with renal insufficiency, or for those with mild hepatic impairment [22,26]. Darifenacin exposure is increased in patients with moderate impairment of hepatic function compared with healthy controls [26] and doses should not exceed 7.5 mg/day in these patients [22]. Individuals with severe hepatic impairment have not been evaluated and darifenacin is therefore not recommended in these patients [22].

Drug–drug interactions

Although darifenacin is metabolized via the cytochrome P450 system, pharmacokinetic analyses have indicated few drug combinations requiring dose modifications. The darifenacin dose should be limited to 7.5 mg/day, or coadministration avoided, with potent CYP3A4 inhibitors such as ketoconazole [23], itraconazole, ritonavir, nelfinavir, clarithromycin and nefazodone, due to the potential for increased darifenacin exposure [22]. However, no dose adjustment is required with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem and verapamil), CYP2D6 inhibitors (e.g., paroxetine, terbinafine and quinidine) or mixed CYP450 inhibitors (e.g., cimetidine) [22].

Darifenacin has shown no significant effect on the pharmacokinetics of a commonly used combined oral contraceptive pill (levonorgestrel 0.15 mg, ethinyloestradiol 0.03 mg) [27] and only minimal interaction with another CYP3A4 substrate, midazolam [22]. However, caution is required for the concomitant administration of darifenacin with a subgroup of CYP2D6 substrates having a narrow therapeutic window, for example, flecainide, thioridazine and tricyclic antidepressants [22]. Similar caution may be required on combination of darifenacin with other antimuscarinic agents to avoid any potentiation of anticholinergic effects.

Other interaction studies have indicated no clinically relevant effects of darifenacin on the pharmacokinetics of warfarin or digoxin (a substrate for P-glycoprotein transport), and no dose adjustment is necessary if routine anticoagulant or digoxin-level monitoring continues [22].

Clinical efficacy of darifenacin

Efficacy in placebo-controlled studies

The efficacy of darifenacin in the treatment of patients with OAB has been demonstrated in randomized, placebo-controlled, double-blind Phase III trials assessing fixed doses of darifenacin (three studies) [22,28,29] or flexible treatment (one study) (Box 2, Table 1) [30].

Table 1.

Summary of pivotal Phase III clinical trials of darifenacin.

Treatment	Number of incontinence episodes/week (primary efficacy end point)				Ref.

	Patients (n)	Median baseline	Median change from baseline	Median difference to placebo
Fixed dose studies
Darifenacin 7.5 mg/day	229	16.3	−9.0	−1.5*	[28]
Darifenacin 15 mg/day	115	17.0	−10.4	−2.1*	[28]
Placebo	164	16.6	−7.6	–	[28]
Darifenacin 7.5 mg/day	108	14	−8.1	−2.8*	[29]
Darifenacin 15 mg/day	107	17.3	−10.4	−4.3*	[29]
Placebo	109	16.1	−5.9	–	[29]
Darifenacin 15 mg/day	112	16.2	−11.4	−2.4*	[22]
Placebo	115	15.5	−9	–	[22]
Darifenacin 7.5 mg/day	335	16	−8.8	−2*	[31]
Placebo (two studies)	271	16.6	−7	–	[31]
Darifenacin 15 mg/day	330	16.9	−10.6	−3.2*	[31]
Placebo (three studies)	384	16.6	−7.5	–	†[31]
Flexible dose study
Darifenacin 7.5/15 mg/day	268	16	−8.2	−1.4*	[30]
Placebo	127	14	−6	–	[30]

p < 0.05 versus placebo, Wilcoxon rank-sum test.

†

Pooled analysis of the same three fixed-dose studies, comparing darifenacin 7.5 mg/day (two studies) and 15 mg/day (three studies) with placebo data from corresponding studies.

Study design and entry criteria for the three fixed-dose studies were almost identical, enabling pooled analysis of data obtained from a total of 1059 patients (85% female) [31]. Darifenacin 7.5 mg and 15 mg/day for 12 weeks were significantly superior to placebo in reducing the median number of incontinence episodes relative to baseline, the primary efficacy end point of these studies (Box 2, Table 1, Table 2). Improvement with darifenacin was apparent within 2 weeks of commencing treatment [22,28] and was paralleled by improvements in urinary frequency, bladder capacity and frequency and severity of urgency compared with placebo (Table 2) [31]. Placebo responses tended to be large, as observed in other OAB trials [32], probably reflecting a bladder training effect due to close patient monitoring and completion of a micturition diary. This was probably enhanced by the use of electronic diaries in the Phase III trials of darifenacin, due to real-time data entry prompting consideration of symptoms [33]. Despite the large placebo response, the effects of treatment were dose-dependent, as shown in a post hoc analysis of two of the Phase III studies which evaluated both of the marketed doses of darifenacin [34].

Table 2.

Efficacy of darifenacin on OAB symptoms: Phase III studies.

	Incontinence episodes/week	Urinary frequency/day	Bladder capacity (mean volume voided; ml)	Frequency of urgency/day	Severity of urgency (100 mm VAS)	Significant leaks#/week
Pooled analysis of fixed dose studies [31]
Darifenacin 7.5 mg/day	−8.8 (−68.4%)**	−1.6 (−16.6%)***	15 (9.6%)**	−2.0 (−29.0)***	−7.8 (−14.2%)***	−4.0 (−77.1%)***
Placebo†	−7.0 (−53.8%)	−0.9 (−9.1%)	8 (4.9%)	−1.0 (−14.3%)	−4.2 (−7.8%)	−2.0 (−47.7%)
Darifenacin	−10.6	−1.9	27 (17.5%)***	−2.3 (−29.0)***	−9.3	−4.8
15 mg/day	(−76.8%)***	(−17.4%)***			(−16.1%)***	(−78.6%)***
Placebo‡	−7.5 (−58.3%)	−1.0 (−9.9%)	6 (3.9%)	−1.2 (−16.7%)	−4.5 (−8.0%)	−2.7 (−55.1%)
Flexible dose study [30]
Darifenacin 7.5/15 mg/day	−8.2 (−62.9%)*	−1.9 (−18.9%)***	19 (10.5%)*	−2.3 (−28.2)***	−9.1 (−16.8%)*	−3.0 (−67.3%)**
Placebo	−6.0 (−48.1%)	−1.0 (−10.0%)	7 (5.4%)	−0.9 (−11.0%)	−3.2 (−5.6%)	−1.8 (−42.9%)

Data shown are median (%) change from baseline to week 12 of treatment.

Incontinence episodes resulting in a change in clothing or pads

†

Data from two studies evaluating darifenacin 7.5 mg versus placebo

‡

Data from three studies evaluating darifenacin 15 mg versus placebo.

p <0.05

p <0.01

***

p <0.001 versus placebo.

OAB: Overactive bladder; VAS: Visual analog scale.

Adapted from [22,30,31].

The effectiveness of darifenacin was further demonstrated by the high proportion of treatment responders, which was significantly superior to placebo across a range of response definitions in the pooled analysis of all three Phase III studies [31]. Notably, approximately one in four patients receiving darifenacin 15 mg/day achieved 7 or more consecutive dry days during the final study period (1 or 2 weeks; p = 0.011 vs placebo). In addition, after 12 weeks' treatment, both darifenacin doses resulted in significantly more patients achieving 3 or more dry days/week compared with placebo [31]. A reduction in the number of incontinence episodes of 90% or greater was attained by 27 and 28% of patients receiving darifenacin 7.5 mg or 15 mg/day, respectively (compared with only 17% in each of the matched placebo groups).

In addition to the fixed-dose studies, the efficacy of darifenacin has been investigated in a Phase III flexible-dosing study (Box 2, Table 1) [22,30]. Patients (n = 395; 84% female) were randomized to darifenacin 7.5 mg/day or placebo for 2 weeks, after which the daily dose could be voluntarily increased to 15 mg/day (or matching placebo) if additional efficacy was desired. Darifenacin reduced the median number of incontinence episodes from baseline to 2 weeks (−42.9%), with further reduction at 12 weeks (−62.9%), significantly more effectively than placebo at both timepoints (−28.6 and −48.1%, respectively; both p < 0.05). Significant improvement was also observed in bladder capacity and symptoms of frequency and urgency (Table 2) [30]. Findings from a subset analysis suggested that patients had selected their optimum dose according to drug sensitivity. Patients who remained on 7.5 mg/day throughout achieved a greater response at 2 weeks than those who opted for the dose increase (49.2 vs 35.7% reduction in number of incontinence episodes). These patients, deemed more sensitive to darifenacin, continued to improve throughout the study. The remaining patients, who appeared less sensitive to darifenacin at 2 weeks, improved after dose escalation to 15 mg/day, such that efficacy outcomes at study completion were similar in the two groups (61.3 and 64.8% reduction in incontinence episodes at 12 weeks in patients continuing on 7.5 mg/day or escalating to 15 mg/day, respectively). These outcomes were mirrored by safety data. These findings highlight the advantage of flexible dosing, such that more sensitive patients can achieve a good initial response to darifenacin 7.5 mg/day and maintain or increase this benefit with continued treatment, while less sensitive patients can receive an increased dose to attain comparable benefit.

Efficacy versus active comparators

Two small, randomized, double-blind, crossover safety studies in patients with OAB have suggested that controlled-release darifenacin 15 mg/day results in efficacy comparable with immediate-release oxybutynin 5 mg three times daily [35,36]. In a study using ambulatory urodynamic monitoring, the improvement in detrusor overactivity with darifenacin was similar to that with oxybutynin [35]. In a second study of 76 patients (93% female), darifenacin significantly improved OAB symptoms similarly to oxybutynin [36].

Box 2.

Summary of pivotal Phase III clinical trials of darifenacin.

The efficacy and safety of darifenacin for overactive bladder (OAB):

– Evaluated in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies [22,28,29], and one randomized double-blind, placebo-controlled, multicenter, 12-week, flexible-dose study [30]

– A pooled analysis has also been conducted of data from the three fixed-dose studies [31]

Patients:

– Eligible patients had experienced symptoms of OAB for >6 months

– >8 micturitions/day

– >1 episode of urinary urgency/day

– >5 episodes of urge urinary incontinence/week

– The majority of patients were white (94%) and female (84%)

– Mean age was 58 years (range 19–93 years), with 33% of the study population aged >65 years

– Previous pharmacotherapy for OAB had been used by 40% of patients

Studies:

– In the three fixed-dose studies, patients entered a 2-week placebo run-in and were then randomized to study medication for 12 weeks

– In the flexible-dose study, patients entered a 2-week placebo run-in and were then randomized to receive darifenacin 7.5 mg/day or matching placebo. After 2 weeks' treatment, the dose of darifenacin could be escalated to 1 5 mg/day if additional efficacy was required by the patient and physician. Thereafter, dose adjustment was not permitted, and efficacy was determined at 12 weeks

– In all studies, efficacy was assessed based on OAB symptoms recorded in electronic diaries

– The primary efficacy end point was the median change from baseline in the number of incontinence episodes/week at 12 weeks

– A summary of results is shown in Table 1.

The effects of darifenacin 15 mg/day have also been compared with immediate-release tolterodine 2 mg twice daily within one of the three pivotal, fixed-dose, placebo-controlled studies [37,38,101]. The median change from baseline in number of incontinence episodes/week at week 12 was similar for darifenacin (−11.4 [83.3%]) and tolterodine (−10.3 [73.7%]), versus −9.0 (70.9%) with placebo (p = 0.049 versus darifenacin) [37,101]. Estimation of treatment differences in incontinence episodes, using a Poisson analysis, found the treatment effect to be significantly greater with darifenacin than tolterodine at all timepoints, (p < 0.05) at week 12 [38].

Long-term efficacy

The efficacy of darifenacin during long-term treatment was assessed in a 2-year open-label, uncontrolled study, which enrolled patients completing one of two 12-week, placebo-controlled, double-blind studies (feeder studies) of darifenacin controlled-release 3.75, 7.5 or 15 mg/day [39]. All patients entering the extension study received darifenacin 7.5 mg/day for 2 weeks. Thereafter, doses were individualized (7.5 or 15 mg/day) as needed. Darifenacin treatment was associated with significant improvements compared with feeder study baseline in the primary efficacy end point, incontinence episodes/week (median decrease from baseline of −84.4% at 2 years; p < 0.001). The improvements seen at the end of the feeder studies were maintained throughout the open-label extension for the primary end point and for all secondary end points (micturitions/day, volume voided, urgency episodes/day, severity of urgency, nocturnal awakenings due to OAB and significant leaks requiring a change in clothes or pads; all p < 0.001 versus feeder study baseline after 2 years' open-label treatment).

Efficacy in patient subpopulations

Older patients

Older patients comprise a considerable proportion of the OAB population, but their treatment can be complicated by the presence of comorbid disorders, comedications and increased vulnerability to adverse events [40]. An analysis of pooled data from the 317 older patients participating in the fixed dose Phase III trials showed that darifenacin was significantly superior to placebo in improving symptoms of OAB in patients aged 65 years or older [41]. Darifenacin significantly reduced the number of incontinence episodes/week (7.5 mg/day −66.7%; 15 mg/day −75.9%) compared with corresponding placebo groups (−34.8% and −44.8%, respectively), accompanied by significant improvements in urinary frequency, urgency episodes and bladder capacity [41]. The magnitude of effect was comparable with that attained in the overall OAB patient population (Box 2, Tables 1 & 2) [31].

Female patients

In an analysis of pooled data from 900 women participating in the three fixed-dose, double-blind, placebo-controlled 12-week trials, darifenacin was significantly superior to placebo in reducing the number of incontinence episodes and urgency episodes (Figure 1) [42]. Darifenacin 7.5 and 15 mg/day also significantly reduced urinary frequency and increased bladder capacity.

Figure 1.

Efficacy of darifenacin in female patients with OAB: pooled analysis of the female cohort from three fixed-dose Phase III studies in patients with OAB.

One of the fixed dose trials compared the efficacy of darifenacin 15 mg/day and tolterodine 2 mg twice-daily with placebo [37]. In the female subset of this study (83.5% of patients), both darifenacin and tolterodine increased bladder capacity (23.4 and 15.3% versus placebo 3.3%, both p < 0.05). Darifenacin also significantly (p < 0.05) reduced the number of incontinence episodes (−78.9% vs tolterodine −74.2%) and urgency episodes (−37.6% vs tolterodine −27.0%) compared with placebo.

Improvement in quality of life

A pooled analysis of quality of life data assessed using the King's health questionnaire (KHQ) in the fixed dose Phase III studies revealed significant improvements with darifenacin treatment [43 –45]. Darifenacin 7.5 and 15 mg/day were both significantly superior to placebo (p ≤ 0.01) in improving severity measures, incontinence impact, emotions and role and social and physical limitations [43]. Furthermore, improvements in KHQ scores with darifenacin treatment exceeded the values considered to be clinically relevant [44] and were significantly correlated with the reductions in incontinence episodes achieved with darifenacin for all domains [45]. Pooled analysis of patient-reported outcomes from the same studies, assessed using a validated questionnaire [46], showed that patients receiving darifenacin 7.5 and 15 mg/day were significantly more satisfied with treatment and were more willing to reuse treatment compared with placebo [47]. Darifenacin-treated patients were up to ten times more likely to prefer darifenacin to previous treatments (which included other drugs, bladder training or no treatment) [47]. Such benefits in patient-reported outcomes are vital for patient compliance and persistency with treatment and, hence, sustained efficacy.

Tolerability & safety of darifenacin

Tolerability and safety data have been assessed in a total of 7257 patients and subjects treated with darifenacin in 95 clinical studies completed up to January 2003 [101], assessing different formulations and indications. Although this review focuses on the OAB population, data in other populations did not suggest any important differences.

Adverse events in placebo-controlled studies

Darifenacin 7.5 or 15 mg/day treatment was well tolerated across the Phase III studies assessed [22,28 –31]. Adverse events were generally mild-to-moderate in severity and usually occurred in the first 2 weeks of treatment [22,28 –31]. In the pooled analysis of fixed-dose studies, adverse events were reported by 54 and 66% of patients receiving darifenacin 7.5 and 15 mg/day, respectively, and 49% of those receiving placebo [31]. Adverse events were typical of the antimuscarinic drug class, with dry mouth and constipation the most commonly reported events, infrequently leading to discontinuation (Table 3) [22,31]. However, constipation during darifenacin treatment was not associated with increased use of interventions such as laxatives, stool softeners or fiber supplements [28 –30,48]. In a pooled analysis of constipation data from the three fixed-dose Phase III trials, constipation was reported by 14.8 and 21.3% of patients treated with darifenacin 7.5 and 15 mg/day, respectively, compared with 6.2% in the placebo group [48]. However, only 4.5% of darifenacin-treated patients (vs 2.3% receiving placebo) had a new requirement for constipation treatments during the studies, suggesting that many cases of self-reported constipation may represent a change in bowel habit rather than constipation according to standard definitions such as the Rome II criteria [49].

Table 3.

Darifenacin tolerability in pooled analysis of three fixed-dose Phase III trials.

Adverse event*	Patients with adverse event (%)

	Darifenacin 7.5 mg /day (n = 337)	Darifenacin 15 mg/day (n = 334)	Placebo (n = 388)
Dry mouth	20.2	35.3	8.2
Constipation	14.8	21.3	6.2
Dyspepsia	2.7	8.4	2.6
Abdominal pain	2.4	3.9	0.5
Nausea	2.7	1.5	1.5
Diarrhea	2.1	0.9	1.8
Urinary tract infection	4.7	4.5	2.6
Dizziness	0.9	2.1	1.3
Asthenia	1.5	2.7	1.3
Dry eyes	1.5	2.1	0.5
Any treatment-related adverse event	37.1	52.1	20.9
Treatment-related discontinuations	1.5	5.1	2.6
Discontinuations for constipation	0.6	1.2	0.3
Discontinuations for dry mouth	0	0.9	0

Data shown are all-causality adverse events reported in >2% patients treated with darifenacin 7.5 or 15 mg/day and more frequently than with placebo.

Adapted from [22,31].

Compared with the pooled fixed-dose studies (Table 3), flexible dosing appeared to be associated with better tolerability, with fewer reports of dry mouth in particular (Table 4) [30]. As expected from the efficacy findings, subset analysis showed that patients who chose to remain on the 7.5 mg/day dose at 2 weeks were more sensitive to darifenacin treatment, reporting dry mouth or constipation at 2 weeks more frequently than the less sensitive patients, in parallel with superior efficacy outcomes. The less sensitive patients who underwent dose escalation to 15 mg/day at 2 weeks achieved outcomes at 12 weeks that were comparable to those of the more sensitive subset, in terms of both efficacy and tolerability [30]. Thus, the flexible dosing regime allowed self-selection of the most appropriate dose for each patient, reducing the total adverse event burden for an equivalent efficacy outcome.

Table 4.

Darifenacin tolerability in a flexible-dose Phase III trial.

Adverse event*	Patients with adverse events (%)

	Darifenacin 7.5 or 15 mg/day (n = 268)	Placebo (n = 127)
Constipation	56 (20.9%)	10 (7.9%)
Dry mouth	50 (18.7%)	11 (8.7%)
Headache	18 (6.7%)	7 (5.5%)
Dyspepsia	12 (4.5%)	2 (1.6%)
Nausea	11 (4.1%)	2 (1.6%)
Urinary tract infection	10 (3.7%)	4 (3.1%)
Accidental injury	8 (3.0%)	4 (3.1%)
Flu syndrome	8 (3.0%)	3 (2.4%)
Any treatment-related adverse event	110 (41.0%)	26 (20.5%)
Treatment-related discontinuations	15 (5.6%)	3 (2.4%)
Discontinuations for constipation	6 (2.2%)	1 (0.8%)
Discontinuations for dry mouth	2 (0.7%)	0 (0%)

Data shown are all-causality adverse events reported in >3% of darifenacin-treated patients and more frequently than with placebo.

Adapted from [22,30].

Adverse events in active comparator studies

In double-blind, crossover studies, adverse events following treatment with either oxybutynin 5 mg three times daily or darifenacin 15 mg/day were mainly mild-to-moderate in severity, but darifenacin was associated with a significantly lower incidence of dry mouth [35,36]. In one study, oxybutynin 5 mg three times daily inhibited salivary flow in patients with detrusor instability more markedly than darifenacin 15 mg/day (−1.55 vs −0.98 ml/min; p < 0.01). This was reflected in the number of reports of dry mouth, which was consistently greater with oxybutynin than darifenacin [35]. The finding is consistent with the greater M₃ binding selectivity of darifenacin in vitro (Box 1), which is expected to result in similar inhibition of salivary gland M₃ receptors, but less inhibition of salivary gland M₁ receptors, compared with oxybutynin. Similarly, in a second study, darifenacin resulted in fewer reports of dry mouth (13 vs 36% with oxybutynin) and associated discontinuations (0 vs 6%), though constipation was more frequent with darifenacin (15 vs 8%, respectively) [36]. There was no difference between treatments in effects on visual nearpoint [35], but blurred vision and dizziness were reported only following oxybutynin (3 and 2% of patients, respectively) [36].

In the fixed-dose Phase III trial comparing darifenacin 15 mg/day, tolterodine 2 mg twice daily and placebo, the most common adverse events were dry mouth (35, 27 and 9.6% of patients, respectively) and constipation (25, 13 and 6.1%, respectively) [37]. These events were well tolerated in both groups, infrequently leading to discontinuation. Constipation-related findings were investigated further in the pooled analysis of three fixed-dose Phase III studies, which included the tolterodine comparator study [48]. This analysis confirmed the low constipation-related discontinuation rates, particularly in the placebo (0.3%) and darifenacin 7.5 mg/day groups (0.6%), compared with tolterodine (1.8%) or darifenacin 15 mg/day (1.2%). Furthermore, initiation of constipation treatments during the study (including laxatives, stool softeners or fiber supplements) was less frequent with darifenacin 7.5 mg/day (3.3%) or placebo (2.7%) than with darifenacin 15 mg/day (5.7%) or tolterodine (6.7%) [47].

Treatment-related cardiovascular or CNS adverse events were also reported in the single comparative Phase III study, and were infrequent with either darifenacin 15 mg/day (1.8% for both types of events) or tolterodine (4% for cardiovascular and 3% for CNS events) [37].

CNS & cardiac safety

Undesirable CNS and cardiovascular adverse events, including somnolence, memory loss and tachycardia, have been reported with existing antimuscarinic therapies for OAB [8,50,51]. Data from randomized clinical trials have shown that darifenacin is not significantly different from placebo with respect to CNS and cardiovascular adverse-event profiles or effects on median heart rate [22].

In addition, several clinical studies have specifically investigated the cognitive and cardiac safety of darifenacin [52 –54]. The effects of darifenacin 7.5 and 15 mg/day on cognitive function and heart rate were compared with placebo and the M₁ selective agent, dicyclomine (20 mg four times daily) in 27 healthy men in a randomized, double-blind, crossover study [52]. Darifenacin and placebo findings were broadly comparable across a battery of computer-based cognitive function tests, electroencephalogram (EEG) activity and heart rate. In contrast, dicyclomine significantly impaired performance in five cognitive assessments, caused significant EEG changes and significantly reduced heart rate and increased heart-rate variability compared with placebo [52]. The lack of adverse effect on cognitive function with darifenacin was confirmed in an additional study of older subjects [53].

A 7-day randomized study assessed the cardiac safety of darifenacin in 179 healthy subjects by measuring the QT/QTc interval, prolongation of which is predictive of a drug's potential to cause ventricular tachyarrhythmia (torsades de pointes) [54]. A positive control, moxifloxacin 400 mg/day, significantly prolonged the QTc interval compared with placebo, whereas darifenacin 15 or 75 mg/day (five times the maximum recommended therapeutic dose) did not, indicating no increased risk of torsades de pointes. Additional QTc data are also available for a total of 964 darifenacin-treated patients included in the overall clinical trial program [101]. This analysis showed QTc prolongation in only 0.4% of patients, identical to the incidence with placebo. In addition, there was no association between change in QTc from baseline and darifenacin-free plasma concentrations up to 26 times the mean exposure seen with the 15 mg/day dose.

In the QT/QTc study in healthy subjects, darifenacin 15 and 75 mg/day demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared with placebo [22]. However, pooled analysis of the Phase II/III clinical studies demonstrated that the change in median heart rate following treatment was no different in patients receiving darifenacin than in patients receiving placebo [22].

Long-term safety

The long-term safety of darifenacin has been investigated in a 2-year open-label study involving patients from two Phase III studies [101,55]. Persistence with therapy over the 2-year study duration was high (66%) [55]; whether this translates into similar persistence rates during everyday use in the general population remains to be determined. The adverse-event profile during long-term exposure to 7.5 or 15 mg/day darifenacin was generally similar to that noted during the Phase III studies, and no new types of adverse events were reported. The incidence of adverse events decreased over time during long-term treatment, which is as expected given that adverse events are usually reported in the first 2 weeks of therapy, and incidences of the most common adverse events were comparable to, or lower than, those observed with placebo in the pooled analysis of Phase III studies. The CNS and cardiovascular safety profile was also maintained with long-term treatment [55].

Adverse events in subpopulations

Older patients

Data from older patients (≥65 years) included in the pooled analysis of fixed-dose Phase III trials have shown that darifenacin is associated with only mild-to-moderate adverse events and very low rates of discontinuation in this population [41]. Adverse event rates were comparable with those for the overall study population (Table 3), with dry mouth occurring in 20.6, 30.9 and 4.5% of older patients receiving darifenacin 7.5, 15 mg/day or placebo, respectively, and constipation noted by 18.6, 23.6 and 6.4% of patients, respectively. Fewer than 3% of older patients withdrew due to these events.

A separate randomized, double-blind, placebo-controlled, crossover study specifically evaluated the effects of darifenacin 7.5 and 15 mg/day on the cognitive function of 129 subjects aged 65 years or over, who had no or mild cognitive impairment [53]. Computer-based cognitive function tests at baseline and after 14 days of treatment showed no significant difference between darifenacin and placebo in memory scanning sensitivity, speed of choice reaction time and word recognition sensitivity (primary end points). Furthermore, there were no clinically relevant changes in alertness, contentment or calmness following darifenacin and, consistent with other reports in the older population [41], darifenacin was well tolerated, indicated by a low incidence of treatment-related adverse events (14.9, 18.5 and 14.5% following darifenacin 7.5, 15 mg/day or placebo, respectively).

Female patients

Pooled analysis of fixed-dose Phase III data from 900 female patients revealed the adverse-event profile of darifenacin to be comparable with the overall study population. The most common adverse events were dry mouth (20, 38 and 9% of patients receiving 7.5, 15 mg/day or placebo, respectively) and constipation (15, 22 and 6%, respectively), and discontinuation due to treatment-related adverse events was low (<4% of patients) [42].

Conclusion

Extensive data from large, randomized, placebo-controlled clinical trials and additional, specialized studies have shown darifenacin 7.5 and 15 mg/day to be efficacious and well tolerated in the treatment of OAB. Efficacy and safety have been demonstrated in female and older patients, and flexible dosing with darifenacin enables treatment to be individualized for optimal benefit. Significant improvement in quality of life with darifenacin indicates that it provides clinical benefit that is meaningful to patients. These findings suggest darifenacin to be a promising new approach for the treatment of OAB.

Future perspective

OAB is currently managed using an integrated approach combining behavioral and pharmacologic methods. Antimuscarinic agents are viewed as the mainstay pharmacologic treatment, but their utility is often limited by tolerability. More recently, concerns have also been raised over the potential impact of antimuscarinics on cognitive or cardiac function, in particular among the more vulnerable population of older patients or those taking multiple medications, for example. Such findings drive the continuing development of antimuscarinic agents and other compounds aimed at novel targets, in an effort to meet patients' healthcare needs more fully.

Approaches adopted in the development of new treatments include improvements to receptor/tissue specificity and selectivity. For novel therapies specific for muscarinic receptors (e.g., darifenacin, solifenacin and fesoterodine), increased selectivity for the M₃ receptor would appear to be beneficial for improving the efficacy–tolerability profile of new agents. Other treatment targets under investigation include CNS transmitter/modulator systems (e.g., norepinephrine, γ-aminobutyric acid [GABA] or dopamine receptors), urothelial signaling mechanisms and afferent nerves. Drugs in development include potassium channel modulators, botulinum toxin injection directly into the bladder wall (possibly to be used when oral antimuscarinic therapy fails), neurokinin (NK1) receptor antagonists and 5-hydroxytryptamine (5-HT)_1a receptor antagonists. However, there has been little progress so far with such agents and antimuscarinics remain the only drug class likely to be available for the next 5 years.

Additional approaches to improving the pharmacologic management of OAB have been to improve the pharmacokinetic profile of existing agents (e.g., via controlled-release matrix formulations to prolong the dosing interval) and/or to alter the mode of administration (e.g., by transdermal application or intravesical instillation). Once-daily oral formulations are rapidly becoming the standard, but the availability of a range of doses to allow individualized therapy for each patient is likely to gain interest. The acceptability for the patient of novel administration routes and their impact on compliance and quality of life remain to be confirmed.

Compliance and persistence with any future treatment requiring long-term administration, as in OAB, is ultimately a reflection of its ability to improve the patient's quality of life and sense of wellbeing, which in turn are dependent on treatment efficacy, tolerability and convenience. Patient-reported outcomes are becoming increasingly important to demonstrate such benefits. In this context, the findings reviewed for darifenacin would appear to be at least as good as those noted with other antimuscarinic agents.

In conclusion, future developments are likely to focus on the continued development of antimuscarinic therapies, including greater variety in dosing and administration routes, and demonstration of long-term benefit with improved quality of life.

Information resources

Proceedings of the British Pharmacological Society Winter Meeting. Liverpool, UK December 14–16 (2004)

www.pa2online.org

(Accessed September 2005)

Proceedings of the Annual Meeting of the International Continence Society.

www.icsoffice.org/publications

(Accessed September 2005)

Disclaimer

François Haab is a consultant for Novartis.

Executive summary

Overactive bladder

Overactive bladder (OAB) is characterized by symptoms of urinary urgency, with or without urge incontinence, usually accompanied by increased frequency of micturition and nocturia.

OAB is a common disorder that increases in prevalence with age and represents a considerable social and economic burden.

Antimuscarinic agents are the mainstay of treatment, but some lack selectivity for the M₃ receptor subtype, which is believed to mediate bladder contraction. Selective antagonism of the muscarinic M₃ receptor therefore offers a more targeted approach to treating OAB.

Profile of darifenacin

Darifenacin is a potent, competitive, reversible muscarinic receptor antagonist with selectivity for the M₃ receptor compared with other muscarinic receptor subtypes in vitro. This profile is accompanied by functional selectivity for bladder tissue in animal studies.

Controlled-release darifenacin can be administered once-daily and requires no dose adjustment for age, gender, renal insufficiency or mild hepatic impairment. Darifenacin is metabolized extensively by cytochrome P450 isoenzymes (CYP3A4 and CYP2D6) but shows a low potential for drug-drug interactions.

Clinical efficacy of darifenacin

Four large, randomized, placebo-controlled trials have demonstrated significant efficacy of darifenacin 7.5 and 1 5 mg/day on the symptoms of OAB; darifenacin resulted in a reduction in the number of incontinence episodes, frequency and urgency, and significant improvement in quality of life. Approximately one in four patients achieves a state approaching freedom from incontinence.

Flexible dosing allows the treatment benefit to be optimized for each patient.

The efficacy of darifenacin appears to be comparable with that of the immediate-release formulations of oxybutynin and tolterodine.

Darifenacin is similarly efficacious in subpopulations of older (>65 years) and female patients.

Tolerability & safety of darifenacin

Darifenacin was well tolerated. Adverse events, commonly dry mouth and constipation, rarely caused discontinuation.

The incidence of dry mouth was lower with darifenacin than the less selective antimuscarinic agent, oxybutynin. Constipation seems to be more frequent with darifenacin than tolterodine, but seems to be equally tolerable, with less frequent requirement for intervention or discontinuation.

The CNS and cardiovascular safety of darifenacin is consistent with its low potential for interaction with M₁ or M₂ receptors and has been confirmed in specific studies. Cognitive function was not impaired following darifenacin, including in older patients, and there was no effect on heart rate or electrocardiogram.

Darifenacin is well tolerated by patient subpopulations (older/female patients) and tolerability was maintained during long-term treatment (up to 15 months), with no new types of adverse events.

Conclusion

Darifenacin is an efficacious and well tolerated treatment option for OAB with a good safety profile. It offers a valuable new approach to providing a significant, individualized benefit for patients.

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Darifenacin for the Treatment of Overactive Bladder

Abstract

Keywords

Profile of darifenacin

Pharmacology

Pharmacokinetics

Drug–drug interactions

Clinical efficacy of darifenacin

Efficacy in placebo-controlled studies

Efficacy versus active comparators

Long-term efficacy

Efficacy in patient subpopulations

Older patients

Female patients

Improvement in quality of life

Tolerability & safety of darifenacin

Adverse events in placebo-controlled studies

Adverse events in active comparator studies

CNS & cardiac safety

Long-term safety

Adverse events in subpopulations

Older patients

Female patients

Conclusion

Future perspective

Information resources

Disclaimer

References