Darifenacina 5 by Eurostaga Eurostaga

Drugs Aging 2004; 21 (13): 885-892 1170-229X/04/0013-0885/$31.00/0

ADIS DRUG PROFILE

Darifenacin In the Treatment of Overactive Bladder Katherine F. Croom and Gillian M. Keating Adis International Limited, Auckland, New Zealand

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886 2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891 6. Darifenacin: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891

Abstract ▲ Darifenacin is a selective muscarinic M3-receptor antagonist that has been evaluated in clinical trials in patients with overactive bladder syndrome (OAB) using a controlled-release formulation. ▲ In multicentre, randomised, double-blind trials in patients with OAB, darifenacin 7.5 or 15mg once daily for 12 weeks significantly reduced the frequency of urinary incontinence, frequency of micturition and frequency and severity of urgency versus placebo. A significant difference from placebo was apparent 2 weeks after starting treatment. At a dosage of 30mg once daily, darifenacin significantly prolonged warning time compared with placebo. ▲ Darifenacin 15mg once daily for 2 weeks was as effective as oxybutynin 5mg three times daily at reducing the frequency of urinary incontinence and frequency and severity of urgency in patients with OAB. ▲ Darifenacin was generally well tolerated in clinical trials. The most common adverse events were dry mouth and constipation. CNS tolerability appeared to be similar to that of placebo. ▲ Darifenacin had no adverse effect on cognitive function in healthy elderly volunteers.

Features and properties of controlled-release (CR) darifenacin (Enablex®, Emselex®) Indication Overactive bladder syndrome Mechanism of action Muscarinic M3-receptor antagonist Dosage and administration Usual dosage in clinical trials

7.5 or 15 mg/day

Route of administration

Oral

Frequency

Once daily

Pharmacokinetic profile of CR darifenacin (steady state for 7.5 and 15mg once daily) Time to peak plasma concentration

≈7h

Area under plasma concentration-time curve (7.5 and 15mg)

34 and 82 ng • h/mL

Bioavailability (7.5 and 15mg)

15% and 19%

Elimination half-life (population 3.12h analysis) Adverse events Most common

Dry mouth, constipation

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H N O

NH2

Darifenacin

Overactive bladder syndrome (OAB) is a symptom complex involving urinary urgency, with or without urge incontinence, generally accompanied by frequency and nocturia.[1] It is a common problem, more so with increasing age,[2,3] with an overall prevalence of at least 16% in adults in the US and Europe.[2,3] Anticholinergic (antimuscarinic) drugs are the mainstay of pharmacotherapy for OAB;[4] however, currently available drugs are not specific for the bladder and cause adverse effects such as dry mouth, constipation, blurred vision or cognitive impairment.[4] Recently, receptor-selective agents have been developed to try and improve the tolerability of therapy. One such drug is darifenacin (Enablex®, Emselex®)1, a muscarinic receptor antagonist that is selective for the M3 receptor subtype.[5-9] M3 receptors are found predominantly in smooth muscle and exocrine glands; the urinary bladder contains both M3 and M2 receptors, with the former having the main role in detrusor contraction.[4] A controlled-release oral formulation of darifenacin has been evaluated in clinical trials. This article summarises the pharmacology, efficacy and tolerability profile of darifenacin in patients with OAB. 1. Pharmacodynamic Profile Darifenacin is a selective muscarinic M3-receptor antagonist.[5-9] Relevant data from human studies and animal models are discussed in this section. Six studies[8,10-14] were reported in full, the remainder as abstracts. 1

● In vitro, darifenacin showed higher binding affinity for the muscarinic M3 receptor than for other subtypes,[6,8,9,13] and greater antagonistic activity in smooth muscle in which contraction is mediated by M3 receptors than that in which contraction is mediated by M1, M2 or M4 receptors.[5,15,16] In human bladder tissue, the apparent antagonist potency of darifenacin was 8.72 and 8.40–9.34 in models using acetylcholine-[17] and carbachol-induced[14,18] muscle contraction (compared with 9.32 and 9.26–9.50 for atropine, a non-selective muscarinic receptor antagonist).

In cystometry studies in rats[19] and minipigs,[20] both intravenous darifenacin (0.1–3.0 mg/kg in rats; 1–10 mg/kg in minipigs) and intravenous oxybutynin (a nonselective muscarinic receptor antagonist and an antispasmodic) [0.1–3.0 mg/kg in rats; 10–60 mg/kg in minipigs] caused dose-related decreases in micturition parameters, including peak micturition pressure. However, the dose required to reduce peak micturition pressure by 50% was up to 14-fold lower for darifenacin than oxybutynin (0.089 vs 0.83 mg/kg in rats, p < 0.05;[19] 3 vs 43 mg/kg in minipigs; statistical analysis not reported[20]). ● Despite responses in both tissues being largely mediated by M3 receptors, darifenacin showed selectivity for bladder over salivary gland in vitro,[11,12,15] and functional selectivity for bladder over salivary gland in one study in patients with detrusor instability,[21] and some,[19,22,23] but not all,[10,12] in vivo animal studies. The latter finding is possibly as a result of the involvement of other receptor subtypes in salivary secretion, as suggested by the residual oral lubrication observed in pilocarpine-treated M3 knockout mice.[24] ● In healthy male volunteers, darifenacin 7.5 and 15mg once daily for 7 days produced only minor changes in EEG activity, and had similar effects to placebo on cognitive function tests (mediated by M1 receptors) and heart rate (M2).[25] ● Darifenacin also had no adverse effect on cognitive function in elderly male and female volunteers ●

The use of trade names is for product identification purposes only and does not imply endorsement.

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(n = 129; aged 65–84 years) in a randomised, double-blind, placebo-controlled, 3-period crossover study.[26] There was no significant difference between controlled-release darifenacin 7.5 or 15mg once daily for 2 weeks and placebo for memory scanning sensitivity, choice reaction time or word recognition sensitivity (primary endpoints), nor for simple reaction time, digit vigilance task speed and accuracy, memory scanning speed or word recognition speed (secondary endpoints).[26] 2. Pharmacokinetic Profile Population pharmacokinetics for darifenacin (intravenous and oral, dose range 0.6–45mg) and its hydroxylated metabolite were modelled using data from 292 healthy volunteers and 45 patients with OAB;[27] this section focuses on the controlled-release oral formulation where possible. An assessment of the effect of cytochrome P450 (CYP) isoenzyme 2D6 genotype on pharmacokinetics was also included, given that darifenacin is metabolised by this isoenzyme. Steady-state pharmacokinetics of oral darifenacin 5mg three times daily in six healthy male volunteers are discussed where appropriate.[28] ● In the population analysis, median area under the plasma concentration-time curve at steady state for the controlled-release formulation of oral darifenacin 7.5 and 15mg once daily was estimated to be 34 and 82 ng • h/mL, respectively.[27] Time to peak plasma concentration was ≈7 hours.[29] ● The bioavailability of darifenacin in a typical Caucasian male CYP2D6 homozygote-extensive metaboliser (hom-EM, the more common genotype) was 15% and 19% after administration of controlled-release oral darifenacin 7.5 and 15mg.[27] CYP2D6 heterozygote-extensive metabolisers and poor metabolisers had 40% and 90% higher exposure than hom-EM.[27] Bioavailability was 56% lower in Japanese than non-Japanese people.[27] ● Darifenacin was highly bound to plasma proteins (98%),[28] and the volume of distribution at steady state for a typical CYP2D6 hom-EM was 163.4L.[27] ● Darifenacin was extensively metabolised by three main routes: monohydroxylation (probably involving CYP3A4 and CYP2D6[27]), oxidative open© 2004 Adis Data Information BV. All rights reserved.

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ing of the dihydrobenzfuran ring and N-dealkylation.[28] The hydroxylated metabolite was 50-fold less potent than the parent drug.[30] Excretion of darifenacin was rapid, with 77% of the total dose being recovered within 48 hours.[28] Approximately 44% of a dose was recovered from the faeces and 58% from the urine, in both cases predominantly as metabolites.[28] ● Darifenacin clearance was 40.2 L/h for a typical male CYP2D6 hom-EM.[27] Clearance was 31% lower in females than males.[27] The terminal elimination half-life of darifenacin was 3.12 hours in CYP2D6 hom-EM and 3.83 hours in poor metabolisers.[27] ● Pharmacokinetic analyses have indicated a trend for decreased clearance with advancing age (19% per decade, based on patients aged 60–89 years), and a 4.7-fold increase in exposure in the presence of moderate hepatic impairment, but no effect on pharmacokinetics for mild hepatic impairment or varying degrees of renal impairment.[29] ● Coadministration of the CYP3A4 inhibitors ketoconazole and erythromycin increased darifenacin bioavailability to approximately 100%.[27] Ketoconazole decreased darifenacin clearance by 67.5%, whereas erythromycin had no effect on this parameter. 3. Therapeutic Efficacy The clinical efficacy of oral controlled-release darifenacin has been evaluated in several multicentre, randomised, double-blind, parallel-group, placebo-controlled studies in adults with OAB (n = 561,[31] n = 439,[32] n = 395[33] and n = 72[34]). A further two randomised, double-blind studies included an active comparator, oxybutynin, (one also reported data for a placebo group[35]) and used a crossover design (n = 76[35] and n = 40[21]). All except the largest trial[31] are available only as abstracts. A pooled analysis based on three placebocontrolled phase III trials (including two of the studies mentioned above[31,32] and a third trial not published separately; total n ≥1049) has been reported in a number of abstracts,[36-39] including one Drugs Aging 2004; 21 (13)

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focusing on a subset of 317 elderly patients (aged ≥65 years).[40] Generally patients had had symptoms of OAB for ≥6 months, and were experiencing four or more episodes of urge incontinence per week, frequency with a mean of eight or more voids per 24 hours, and urgency at least once daily.[31,35,37] Where reported, ≥84% of patients were female, and the overall age range was 19–89 years.[31-33,35,36] Patients were generally excluded if they had clinically significant stress incontinence or bladder outlet obstruction or intended to start bladder retraining during the study period.[31,36] Where necessary patients went through a 2-week washout period before entering a 2-week placebo run-in phase.[31,32,34-36] The double-blind treatment phase lasted 1,[21] 2[34,35] or 12 weeks. [31-33,36] All except one[33] of the placebo-controlled trials evaluated fixed dosages of darifenacin, most commonly 7.5 and 15mg once daily.[31,32] In the fully published study,[31] patients were also randomised to receive darifenacin 3.75mg once daily; however, results pertaining to this treatment arm are not discussed. In the dose-titration study,[33] the initial dosage of 7.5mg once daily could be increased to 15mg once daily after 2 weeks if necessary. Data on 30mg once daily were reported for one placebo-controlled study.[34] In the active comparator trials, patients received darifenacin 15[21,35] or 30mg[21] once daily or oxybutynin 5mg three times daily. Symptoms were recorded using electronic[31-34,36] or paper[35] diaries. Where specified, the primary endpoint in most trials was change from baseline in the number of incontinence episodes per week,[31,33,36] but for one study it was change in warning time (time from first sensation of urgency to voiding).[34] Another study used ambulatory urodynamic monitoring to assess duration of detrusor overactivity.[21] Secondary variables generally reflected urinary frequency and urgency,[31-33,35,36] and also included nocturia.[31,32] Severity of urgency was assessed using visual analogue scales, commonly with 0 = mild and 100 = severe.[31,33,36] Where reported, efficacy analysis populations included © 2004 Adis Data Information BV. All rights reserved.

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randomised patients who took at least one dose of medication and had a post-baseline assessment for at least one efficacy endpoint.[31,35]

Comparisons with Placebo

Incontinence

Darifenacin 7.5 and 15mg once daily for 12 weeks significantly reduced the frequency of urinary incontinence in adults with OAB compared with placebo (p ≤ 0.05), with median percent reductions from baseline of 68–69% and 73–77% vs 46–56%.[31,32] The results for the largest trial (and the only one reported in full) are shown in figure 1.[31] The results of the pooled analysis were consistent with trials reported individually.[36] A significant difference from placebo (p < 0.05) was apparent 2 weeks after starting treatment in several studies.[31,32,35] Improvements in elderly patients were similar in magnitude to those seen in the overall population.[40] ● In the pooled analysis, more than two-thirds of patients treated with darifenacin 7.5 or 15mg once daily for 12 weeks experienced ≥50% reduction in the number of incontinence episodes per week (compared with just over half of placebo recipients, p < 0.005), and more than one-quarter achieved a reduction of ≥90% (vs one-sixth of the placebo group, p < 0.005).[37] In the same analysis, significantly more patients treated with darifenacin 7.5 or 15mg once daily than placebo had 3 dry days per week (p ≤ 0.001); 24% of recipients of darifenacin 15mg once daily experienced 7 consecutive dry days compared with 16% of the placebo group (p = 0.011).[37] ● In patients who did not have an adequate response to darifenacin 7.5mg once daily after 2 weeks, increasing the dosage to 15mg once daily for the next 10 weeks led to a similar overall improvement in the frequency of incontinence to that seen in patients who responded to 7.5mg once daily (median reduction 64.8% vs 61.3%).[33] In this study, for all darifenacin recipients combined the median reduction was 63% versus 48% for placebo (p < 0.05). ●

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DAR 7.5

889

DAR 15

Median % change from baseline

−10

−20

−30

cebo (p < 0.03) in one[32] of two studies[31,32] that reported results for this symptom. ● After 2 weeks’ treatment, the improvement in median warning time was longer by 4.3 minutes with darifenacin 30mg once daily than with placebo (p = 0.004), and significantly more patients treated with darifenacin than with placebo had prolongation of the minimum warning time by ≥30% (53% vs 31%, p = 0.015).[34]

−40

Health-Related Quality of Life and Patient Satisfaction

−50

−60

−70

In the pooled analysis, both darifenacin 7.5 and 15mg once daily significantly improved a number of measures of health-related quality of life (QOL) compared with placebo, as assessed using the OABspecific King’s Health Questionnaire.[38] Differences were significant (p ≤ 0.01 vs placebo) for incontinence impact, severity measures, emotions and role, social and physical limitations, but not for personal relationships, sleep and energy or general health.[38] Significantly more patients treated with darifenacin 7.5 or 15mg once daily were satisfied with their treatment and willing to re-use the treatment compared with placebo recipients (p ≤ 0.002 for both doses).[39] ●

** *

−80 Fig. 1. Efficacy of controlled-release darifenacin in overactive bladder syndrome. Median percent change from baseline for number of incontinence episodes per week (primary endpoint) is shown. Data are from a multicentre, randomised, double-blind trial of 12 weeks’ treatment with oral darifenacin 7.5 (DAR 7.5; n = 229) and 15mg (DAR 15; n = 115) once daily or matching placebo (PL; n = 164).[31] * p = 0.017, ** p = 0.01 vs PL.

Other Symptoms of Overactive Bladder Syndrome

Darifenacin 7.5 or 15mg (including 7.5 titrated to 15mg) once daily improved urgency and frequency compared with placebo in patients with OAB,[31,33,36] including those aged ≥65 years.[40] Specifically, darifenacin significantly improved micturition frequency, bladder capacity (mean volume voided), frequency of urgency and severity of urgency (p ≤ 0.05 vs placebo for all parameters in all reported analyses).[31,33,36,40] Results for the largest study are shown in figure 2; changes were significantly greater than with placebo from 2 weeks after starting therapy (p ≤ 0.001), except for bladder capacity.[31] ●

● Where reported, the number of incontinence episodes leading to a change of pad or clothing was also significantly reduced with darifenacin versus placebo (p < 0.002).[31,36] Nocturnal awakening due to OAB was significantly reduced compared with pla-

Comparison with Oxybutynin ● Based on one of the small crossover studies, 2 weeks’ treatment with darifenacin 15mg once daily was as effective as oxybutynin 5mg three times daily at reducing the frequency of urinary incontinence and the frequency and severity of urgency.[35] The mean number of weekly incontinence episodes during week 2 was similar in the darifenacin and oxybutynin groups, and both were significantly more effective than placebo (10.93 and 9.45 vs 14.64, p < 0.05 for both active groups vs placebo). ● The mean number of urgency episodes per day during week 2 was 7.95, 8.12 and 8.71 and the mean severity of urgency was rated as 1.93, 1.89 and 2.03 for darifenacin, oxybutynin and placebo (p < 0.05 for both active groups vs placebo for both parameters; the rating scale for urgency severity was 1 = mild, 2 = moderate, 3 = severe).[35] There was no

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Darifenacin 7.5mg Darifenacin 15mg Placebo

*** Frequency of urgency/day

*** Severity of urgency/day

*** Micturition frequency/day

***

* Volume voided/micturition

***

Incontinence-related pad or clothing change/week

Nocturnal awakenings due to OAB/week −90

−80

−70

−60

−50

−40

−30

−20

−10

Median % change from baseline Fig. 2. Efficacy of controlled-release darifenacin in overactive bladder syndrome (OAB) [secondary endpoints]. Median percent change from baseline for micturition frequency per day, bladder capacity (volume voided per micturition), frequency of urgency per day, severity of urgency, number of incontinence episodes resulting in a change of clothing or pads per week and number of nocturnal awakenings due to OAB per week. Data are from a multicentre, randomised, double-blind trial of 12 weeks’ treatment with darifenacin 7.5 (n = 229) and 15mg (n = 115) once daily or matching placebo (n = 164).[31] * p < 0.05, ** p ≤ 0.005, *** p ≤ 0.001 vs placebo.

significant difference between any of the three groups for the number of micturitions per day.[35] ● The second crossover study demonstrated that darifenacin 15 or 30mg once daily and oxybutynin 5mg three times daily produced similar effects on the duration of detrusor overactivity after a short, 7-day, period of treatment.[21] 4. Tolerability Tolerability data on darifenacin 7.5 or 15mg once daily are available from several of the studies and pooled analyses discussed in section 3.[21,31,33,35,36,40,41] Another pooled analysis of placebo-controlled trials specifically evaluated CNS-related adverse events;[42] this analysis also included data from a group of patients who received tolterodine 2mg twice daily in one of the studies. All © 2004 Adis Data Information BV. All rights reserved.

tolerability data were reported in abstracts except for one study.[31] Darifenacin was generally well tolerated,[31,36] including by patients aged ≥65 years.[26,40] The majority of adverse events were of mild or moderate severity.[31,40,41] ●

● The most common adverse events regardless of age were dry mouth (19% vs 31% vs 9% for darifenacin 7.5 and 15mg once daily and placebo in the study published in full[31]) and constipation (14% vs 14% vs 7% in the same study[31]).[31,33,36,40,41] However, the rate of discontinuation due to these events was low (none for dry mouth and 0.9% vs 0.6% of darifenacin- and placebo-treated patients for constipation, in the fully published trial[31]).[31,40] In the crossover studies, darifenacin recipients had a significantly lower incidence of dry mouth than oxybutynin recipients (13% vs 36%, p < 0.05)[35] or

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Darifenacin: Adis Drug Profile

significantly less of a reduction in salivary flow (p = 0.0002 for darifenacin 15mg once daily).[21] ● The cardiovascular tolerability profile of darifenacin was reported to be similar to that of placebo.[31,33,36,41] In the study reported in full, one patient with a prior history of atrioventricular block who was treated with darifenacin 7.5mg, experienced second-degree block.[31] ● Nervous system, including CNS, tolerability was similar for darifenacin and placebo[31,33,36,41,42] or tolterodine 2mg twice daily.[42] There were no reports of blurred vision with darifenacin in the largest phase III study[31] or a comparison with oxybutynin, whereas the incidence was 3% for oxybutynin.[35] The most common CNS adverse events with darifenacin were dizziness and somnolence (≤2% of patients in the pooled analysis).[42] See section 1 for effects on cognitive function in healthy volunteers. 5. Dosage and Administration Formal prescribing recommendations for darifenacin are not yet available. In phase III trials in patients with OAB, darifenacin was administered as oral controlled-release tablets at dosages ranging from 3.75 to 30mg once daily.[31,32,36] The proposed market dosages are 7.5 and 15mg once daily.[43] 6. Darifenacin: Current Status Darifenacin has been granted an approvable letter by the US FDA for the treatment of OAB and has also received a positive opinion from the European Commission’s regulatory advisory board.[44] It has shown clinical efficacy in several large, well controlled trials in this indication and was generally well tolerated. References 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-Committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167-78 2. Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001; 87: 760-6

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3. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003; 20: 327-36 4. Andersson K-E. Antimuscarinics for treatment of overactive bladder. Lancet Neurology 2004; 3 (1): 46-53 5. Wallis RM, Burges RA, Cross PE, et al. Darifenacin, a selective muscarinic M-3 antagonist [abstract]. Pharmacol Res 1995; 31 Suppl.: 54 6. Nunn PA, Greengrass PM, Newgreen DT, et al. The binding profile on the novel muscarinic receptor antagonist darifenacin against the five cloned human muscarinic receptors expressed in CHO cells [abstract no. 130P]. Br J Pharmacol 1996 Apr; 117 Suppl. 7. Eglen RM, Pulido-Rios MT, Webber AP, et al. Characterization of the interaction of darifenacin at muscarinic receptor subtypes in vitro [abstract no. 35P]. Br J Pharmacol 1996 Jul; 118 Suppl. 8. Smith CM, Wallis RM. Characterisation of [3H]-darifenacin as a novel radioligand for the study of muscarinic M3 receptors. J Recept Signal Transduct Res 1997; 17 (1-3): 177-84 9. Napier C, Gupta P. Darifenacin is selective for the human recombinant M3 receptor subtype [abstract no. 445]. 32nd Annual Meeting of the International Continence Society; 2002 Aug 27-30; Heidelberg [online]. Available from URL: http:// www.icsoffice.org/publications [Accessed 2004 Sep 1] 10. Gillberg PG, Sundquist S, Nilvebrant L. Comparison of the in vitro and in vivo profiles of tolterodine with those of subtypeselective muscarinic receptor antagonists. Eur J Pharmacol 1998 May 22; 349 (2-3): 285-92 11. Nelson CP, Gupta P, Napier CM, et al. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea-pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther 2004 May 12 12. Ohtake A, Ukai M, Hatanaka T, et al. In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats. Eur J Pharmacol 2004 May 25; 492 (2-3): 243-50 13. Wallis RM, Napier CM. Muscarinic antagonists in development for disorders of smooth muscle function. Life Sci 1999; 64 (6-7): 395-401 14. Miyamae K, Yoshida M, Murakami S, et al. Pharmacological effects of darifenacin on human isolated urinary bladder. Pharmacology 2003 Dec; 69 (4): 205-11 15. Newgreen DT, Naylor AM. Comparison of the functional muscarinic receptor selectivity of darifenacin with tolterodine and oxybutinin [abstract no. 107P]. Br J Pharmacol 1996 Apr; 117 Suppl. 16. Alexandrou A, Claringbold A, Harris J, et al. Darifenacin has a low affinity for muscarinic M1 receptors in dog saphenous vein confirming its M3 selectivity [abstract no. 458]. Eur Urol Suppl 2003; 1: 117 17. Newgreen DT, Naylor AM. Characterisation of functional muscarinic receptors in human bladder [abstract no. 45P]. Br J Pharmacol 1996 Oct; 119 Suppl. 18. Chua CB, Harriss DR, Marsh KA, et al. Effect of darifenacin on muscarinic responses in normal and unstable human detrusor smooth muscle cells. Neurourol Urodyn 1997; 16: 355-6 19. Williamson IJR, Newgreen DT, Naylor AM. The effects of darifenacin and oxybutynin on bladder function and salivation in the conscious rat [abstract no. 205P]. Br J Pharmacol 1997 Mar; 120 Suppl.

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20. Davies CL, Dodd MG, Merner PA, et al. In vivo bladder selectivity of the novel muscarinic antagonist, darifenacin, in the conscious minipig [abstract no. 202P]. Br J Pharmacol 1996 Apr; 117 Suppl. 21. Mundy AR, Abrams P, Chapple CR, et al. Darifenacin, the first selective M3 antagonist for overactive bladder: comparison with oxybutynin on ambulatory urodynamic monitoring and salivary flow [abstract no. 221]. 31st Annual Meeting of the International Continence Society; 2001 Sep 17-21; Seoul [online]. Available from URL: http://www.icsoffice.org/publications [Accessed 2004 Aug 31] 22. Gupta P, Anderson C, Carter A, et al. In vivo bladder selectivity of darifenacin, a new M3 antimuscarinic agent, in the anesthetised dog [abstract no. 515]. Eur Urol 2002; 1 Suppl 1: 131 23. Newgreen DT, Anderson CWP, Carter TJ, et al. Darifenacin: a novel bladder-selective muscarinic antagonist for the treatment of urge incontinence [abstract no. 1156]. J Urol 1996 May; 155 Suppl.: 600A 24. Matsui M, Motomura D, Karasawa H, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000 Aug 15; 97 (17): 9579-84 25. Kay G. The M3 selective receptor antagonist darifenacin has no clinically relevant effect on cognition and cardiac function [abstract no. 65]. Prog Urol 2004; 14 Suppl. 3: 22 26. Wesnes K, Lipton R, Kolodner K, et al. Darifenacin, an M3 selective receptor antagonist for the treatment of overactive bladder, does not affect cognitive function in elderly volunteers [abstract no. 513]. 19th Congress of the European Society of Urology; 2004 Mar 24-27; Vienna [online]. Available from URL: http://www.uroweb.org [Accessed 2004 Jun 18] 27. Kerbusch T, Wahlby U, Milligan PA, et al. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br J Clin Pharmacol 2003 Dec; 56 (6): 639-52 28. Beaumont KC, Cussans NJ, Nichols DJ, et al. Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man. Xenobiotica 1998 Jan; 28 (1): 63-75 29. Data on file. Novartis Pharma AG, 2004 Aug 26

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34. Cardozo L, Dixon A. Darifenacin prolongs median and minimum warning time associated with urinary urgency [abstract]. Obstet Gynecol 2004 Apr; 103 (4 Suppl.): 130 35. Zinner N, Tuttle J, Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist, compared with oxybutynin in the treatment of patients with overactive bladder [abstract no. 378]. Joint Meeting of the International Continence Society and the International Urogynecological Assocation; 2004 Aug 23-27; Paris [online]. Available from URL: http://www.icsoffice.org [Accessed 2004 Jul 2] 36. Chapple CR. Darifenacin is well tolerated and provides significant improvement in the symptoms of overactive bladder: a pooled analysis of phase III studies [abstract no. 487]. J Urol 2004 Apr; 171 (4 Suppl.): 130 37. Abrams P, Foot J, Lheritier K, et al. Responder rates, a better way to express drug efficacy: data from darifenacin pooled phase III studies [abstract no. 389]. Joint Meeting of the International Continence Society and the International Urogynecological Assocation; 2004 Aug 23-27; Paris [online]. Available from URL: http://www.icsoffice.org [Accessed 2004 Jul 2] 38. Chapple C, Kelleher C, Perrault L. Darifenacin, an M3 selective receptor antagonist, improves quality of life in patients with overactive bladder [abstract no. 67]. Prog Urol 2004; 14 Suppl. 3: 22 39. Glavind K, Perrault L. Patient satisfaction, preference and willingness to reuse darifenacin in the treatment of overactive bladder [abstract no. UP-14.17]. 27th Congress of the Soci´et´e International d’Urologie; 2004 Oct 3-7; Honolulu [online]. Available from URL: http://www.siu2004.com [Accessed 2004 Sep 30] 40. Foote JE. Darifenacin, an M3 selective receptor antagonist (M3SRA), is effective and well tolerated in elderly patients with overactive bladder [abstract no. P321]. J Am Geriatr Soc 2004 Apr; 52 (4 Suppl.): 126-7 41. Hill S. The effects of darifenacin on the reduction of incontinence episodes in patients with overactive bladder [abstract no. 610]. J Pelvic Med Surg 2004; 10 Suppl. 1

30. Kerbusch T, Milligan PA, Karlsson MO. Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic-pharmacodynamic data. Br J Clin Pharmacol 2004 Feb; 57 (2): 170-80

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31. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated oncedaily treatment for overactive bladder. Eur Urol 2004 Apr; 45 (4): 420-9; discussion 429

43. Novartis. Darifenacin increases warning time for OAB sufferers. Media release 2003 Oct 10 [online]. Available from URL: http://www.novartis.com [Accessed 2004 Jun 15]

32. Khullar V. Darifenacin, an M3 selective receptor antagonist, reduces the frequency of nocturnal awakening, an important symptom of overactive bladder [abstract no. 491]. J Urol 2004 Apr; 171 (4 Suppl.): 131

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Correspondence: Katherine F. Croom, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, New Zealand. E-mail: demail@adis.co.nz

Drugs Aging 2004; 21 (13)