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  • 09/28/11
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  • Key Points Overactive bladder is considered a complex syndrome and often presents with multiple symptoms Urgency alone occurs in 12.6% of individuals, and urge urinary incontinence occurs in 9.1% of individuals Urgency and urge urinary incontinence occur together in 13% of individuals Urgency, urge urinary incontinence, and frequency occur together in 7.0% of individuals Reference Coyne KS, Sexton CC, Vats V, et al. National community prevalence of overactive bladder in the United States stratified by sex and age. Urology. 2011;77:1081-1087. 09/28/11
  • Key Points According to results from the National Overactive Bladder Evaluation (NOBLE) Program, overactive bladder affects over 33 million Americans 1 Overactive bladder is among the most common chronic diseases in the United States 1 In fact, overactive bladder is more common than diabetes mellitus, which affects 8.5 million Americans, and cardiovascular (CV) disease, which affects 7.8 million Americans 2 References Kelleher CJ. Economic and social impact of OAB. Eur Urol Suppl. 2002;1:11-16. Wilper AP, Woolhandler S, Lasser KE, et al. A national study of chronic disease prevalence and access to care in uninsured U.S. adults. Ann Intern Med. 2008;149:170-176. 09/28/11
  • Key Point A number of factors are associated with increased risk of overactive bladder, including Increased age 1 Abnormal metabolic factors 2 Pelvic surgery 3 Pregnancy and vaginal delivery 4 Medications 3 Prostate-related conditions 3,4 References Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol . 2003;20:327-336. Teleman PM, Lidfeldt J, Nerbrand C, et al, for the WHILA study group. Overactive bladder: prevalence, risk factors and relation to stress incontinence in middle-aged women. BJOG . 2004;111:600-604. Rosenberg MT, Newman DK, Tallman CT, et al. Overactive bladder: recognition requires vigilance for symptoms. Cleve Clin J Med . 2007;74(suppl 3):S21-S29. Thüroff JW, Abrams P, Andersson KE, et al. EAU guidelines on urinary incontinence. Eur Urol . 2011;59:387-400. 09/28/11
  • Key Points Comorbidities associated with overactive bladder may increase mortality, morbidity, impair quality of life (QOL) and economic costs These comorbidities include Falls and fractures Urinary tract and skin infections Sleep disturbances Depression Reference Brown JS, McGhan WF, Chokroverty S. Comorbidities associated with overactive bladder. Am J Manag Care . 2000;6(suppl 11):S574-S579. 09/28/11
  • Key Points Overactive bladder often negatively affects QOL Shown here is the percent decrease in the mean SF-36 score by domain for individuals with overactive bladder urge incontinence compared with controls Physical function and emotional role (role of emotional health in ability to carry out daily activities) were most affected at approximately 28% decrease and 25% decrease, respectively Additional Information Other study results indicate that men and women with overactive bladder complain of significantly more frequent sleep disturbances than do individuals without overactive bladder and are significantly more depressed (women more than men) than individuals without overactive bladder (particularly if they have overactive bladder with urge incontinence) Reference Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol . 2003;20:327-336. 09/28/11
  • Key Points Various treatment options are available for individuals who have overactive bladder Pharmacologic therapy includes Antimuscarinic drugs (eg, darifenacin) Drugs acting on membrane channels (eg, calcium antagonists) Antidepressants (eg, duloxetine) Alpha-adrenoreceptor antagonists (eg, alfuzosin) Beta-adrenoreceptor antagonists (eg, terbutaline) Phosphodiesterase type-5 inhibitors (in men) (eg, sildenafil) Cyclo-oxygenase (COX) inhibitors (eg, indomethacin) Hormones (eg, estrogen) Reference Thüroff JW, Abrams P, Andersson KE, et al. EAU guidelines on urinary incontinence. Eur Urol . 2011;59:387-400. 09/28/11
  • Key Points Effective pharmacologic therapy for overactive bladder relies on specificity of inhibition of M 3 (muscarinic) receptor Antimuscarinic agents that target the M 3 receptor block those located on the smooth muscle of the bladder M 1 and M 2 receptor inhibition affects other areas of the body that can result in changes in short-term memory recall and cognitive function, as well as heart rate M 3 receptor specificity allows for targeting of the affected tissue needing therapy Reference Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol . 2006;148:565-578. 09/28/11
  • Key Points Shown here are the various areas of the body where different muscarinic receptors are located As previously mentioned, agents that target the M 1 receptors on the cerebral cortex may have an impact on short-term memory and cognitive functions Agents that target the M 2 receptors on cardiac muscle may impact heart rate Inhibition of M 3 receptors on the smooth muscle of the bladder and bowel may favorably affect urinary bladder function References Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol . 2006;148:565-578. Sarria B, Naline E, Zhang Y, et al. Muscarinic M 2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus. Am J Physiol Lung Cell Mol Physiol. 2002;283:L1125-L1132. 09/28/11
  • Key Points Antimuscarinic agents for the effective treatment of overactive bladder require 1-3 High affinity and specificity for the M 3 receptor High specificity for the receptors on the bladder; important to minimize leaks and accidents and minimize possible side effects of the central nervous system (CNS) and CV system No significant effects on memory have been observed between M 3 -selective antagonists and placebo; however, significant memory deterioration has been demonstrated with less-selective agents 3 References Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol . 2006;148:565-578. Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol . 2005;173:493-498. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. 09/28/11
  • Key Points ENABLEX ® is a selective M 3 receptor antagonist that works by inhibiting the receptors located on the detrusor smooth-muscle cells of the bladder M 3 receptors are also involved in gastrointestinal smooth-muscle contraction, saliva production, and iris sphincter function The relative affinity of ENABLEX ® for M 3 receptors over other muscarinic receptors is shown in the table 1 ENABLEX ® has a 9-fold greater affinity for M 3 receptors than M 1 receptors and a 59-fold greater affinity for M 3 receptors than M 2 receptors 1,2 Compared with the other M 3 receptor antagonists shown here, ENABLEX ® has the highest affinity for M 3 receptors and exhibits more selectivity for M 3 than for M 1 , M 2 , and M 4 receptors This potentially allows for specific targeting of the bladder, while minimizing effects on other organs, which can lead to side effects References Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol . 2006;148:565-578. ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Geriatric Consultant Resources, LLC. Overactive bladder in the elderly. http://www.gcrweb.com/OABdss/comprehensive/comp-02a-muscar.htm. Accessed March 25, 2011. 09/28/11
  • Key Points There is potential for all antimuscarinic agents to cross the blood-brain barrier (BBB); however, less-selective agents such as oxybutynin have been associated with more impairment of cognitive functions 1 Factors that determine the likelihood of BBB crossing include 2 Lipophilicity: more-lipophilic agents favor crossing the BBB Molecular weight: smaller molecules favor crossing the BBB Polarity: less-polar molecules favor crossing the BBB References Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol . 2005;173:493-498. Kay G, Granville L. Antimuscarinic agents: implications and concerns in the management of overactive bladder in the elderly. Clin Ther . 2005;27:127-138. 09/28/11
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  • Key Points Clinical studies have demonstrated that ENABLEX ® is an effective treatment for overactive bladder ENABLEX ® is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency 1 The efficacy of ENABLEX ® is well established in >1000 subjects 1 ENABLEX ® is easy to use, as it has a flexible, once-daily dosing of either 7.5- or 15-mg tablets 1 ENABLEX ® is a selective M 3 inhibitor and thus provides targeted treatment of overactive bladder while potentially minimizing side effects 1-3 ENABLEX ® is well studied (>6000 subjects and up to 2 years) 1 References ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. 09/28/11
  • Key Points Pooled analysis of 3 phase 3, 12-week clinical trials; subjects on 7.5 mg, 15 mg Primary efficacy measure was median change in number of incontinence episodes per week Secondary efficacy measures were Number of significant leaks per week Voiding frequency Bladder capacity Frequency and severity of urgency Number of nocturnal awakenings Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points ENABLEX ® has been shown to be effective in significantly reducing incontinence Data from a pooled analysis of 3 phase 3, 12-week clinical trials showed that ENABLEX ® significantly reduced incontinence by 68% for subjects taking 7.5 mg of ENABLEX ® Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points ENABLEX ® has been shown to be effective in significantly reducing incontinence Data from a pooled analysis of 3 phase 3, 12-week clinical trials showed that ENABLEX ® significantly reduced incontinence episodes by 77% for subjects taking 15 mg of ENABLEX ® Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points ENABLEX ® has also been shown to be effective in significantly reducing the number of urgency episodes 48% of subjects taking 7.5 mg of ENABLEX ® had ≥30% reduction from baseline in urgency episodes at 12 weeks 31% of subjects taking 7.5 mg of ENABLEX ® had ≥50% reduction in urgency episodes Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points ENABLEX ® has also been shown to be effective in significantly reducing the number of urgency episodes 49% of subjects taking 15 mg of ENABLEX ® had ≥30% reduction from baseline in urgency episodes at 12 weeks 34% of subjects taking 15 mg of ENABLEX ® had ≥50% reduction in urgency episodes Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points Treatment-emergent AEs (TEAEs) at 1 year are shown in the table 1,2 The most common TEAEs reported by individuals in all groups were dry mouth and constipation 1,2 Approximately 20% of subjects taking 7.5 mg of ENABLEX ® and 35% of subjects taking 15 mg of ENABLEX ® had dry mouth compared with roughly 8% of patients receiving placebo Approximately 15% and 21% of subjects taking 7.5 mg and 15 mg of ENABLEX ® , respectively, reported constipation compared with 6% of subjects in the placebo group Other common TEAEs included dyspepsia, abdominal pain, nausea, and urinary tract infections References ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points In the pooled analysis, rates of treatment discontinuation were low for individuals in the 7.5-mg and 15-mg treatment groups Discontinuation rates due to constipation and dry mouth were low for all treatment groups. Rates ranged from 0.3% to 1.2% for constipation and 0% to 0.9% for dry mouth Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points 1 This was a multicenter, noncomparative, open-label, 2-year extension study Subjects were recruited from 1 of 2 phase 3, randomized, double-blind pivotal studies in which they received 12 weeks of treatment with darifenacin 3.75 mg, 7.5 mg, or 15 mg or placebo 2,3 In this study, subjects received darifenacin 7.5 mg, irrespective of pivotal study treatment, for the first 2 weeks. Thereafter, they were permitted to increase their dose to 15 mg if additional efficacy was required. Doses could be increased from 7.5 mg to 15 mg or decreased from 15 mg to 7.5 mg, as needed, for the remainder of the extension study (24 months) Primary objective Assess long-term safety and tolerability Secondary objective Evaluate long-term efficacy Efficacy variables Number of incontinence episodes/week Daily frequency of voiding Volume of urine passed/voided Daily frequency and severity of urgency Number of overactive bladder–related nocturnal awakenings/week Number of significant leaks/week References Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. Steers W, Corcos J, Foote J, Kralidis G. An investigation of dose titration with darifenacin, an M 3 -selective receptor antagonist. BJU Int. 2005;95:580-586. Haab F, Stewart L, Dwyer P . Darifenacin, an M 3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol . 2004;45:420-429. 09/28/11
  • Key Points Results from a 2-year extension study are shown here 1, 2 Subjects were enrolled from two, 12-week, phase 3, double-blind, placebo-controlled pivotal trials Over the treatment period of 24 months, subjects achieved a significant reduction in incontinence episodes Compared to baseline, subjects aged ≥65 years had a 63% median reduction in incontinence episodes at the end of 12 weeks and a further decrease to 80% after 3 months This reduction reached a plateau between months 6 and 24, with a median % reduction in incontinence episodes of about 84% References Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. Hill S, Elhilali M, Millard RJ, et al. Long-term darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year, open-label extension study . Curr Med Res Opin . 2007;23:2697-2704. 09/28/11
  • Key Points Results through the 2-year extension study demonstrated low rates of discontinuation from TEAEs, with the 2 most common TEAEs being constipation and dry mouth 1-3 Discontinuation rate due to constipation was 2.4%, and for dry mouth, 1.3% 1 Other commonly reported TEAEs from these studies included dyspepsia and headache 1-3 References 1. Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. 2. Haab F, Stewart L, Dwyer P . Darifenacin, an M 3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol . 2004;45:420-429. 3. Steers W, Corcos J, Foote J, Kralidis G. An investigation of dose titration with darifenacin, an M 3 -selective receptor antagonist. BJU Int. 2005;95:580-586. 09/28/11
  • Key Points 12-week, open-label, single-arm, multicenter study Conducted in ENABLEX ® -naïve subjects who had expressed dissatisfaction (lack of sufficient effect and/or AEs) with prior treatments with either oxybutynin or tolterodine Subjects underwent a 2- to 3-week prescreening/washout period followed by a week during which they were asked to complete a bladder diary for 5 consecutive days to establish baseline symptoms and overactive bladder severity Eligible subjects received darifenacin 7.5 mg QD for the first 2 weeks and were then given the option of up-titration to darifenacin 15 mg QD if additional efficacy was required and treatment was well tolerated (down titration was not permitted) Primary efficacy measured the change in Patient Perception of Bladder Condition (PPBC) score from baseline to end of study Secondary efficacy measures included micturition frequency, urgency, and urge urinary incontinence episodes after 2, 6, and 12 weeks of treatment compared with baseline Reference Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract . 2008;62:1664-1674 . 09/28/11
  • Key Points PPBC scores were subject self-reported from 6 options: No problems, very minor problems, some minor problems, some moderate problems, severe problems, or many severe problems PPBC scores showed that the majority of subjects had “some moderate” problems with bladder control at baseline At 12 weeks, statistically significant improvement was reported for these subjects, as well as patients across the spectrum of severity from “no problems” to “many severe problems” with bladder control Reference Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract . 2008;62:1664-1674 . 09/28/11
  • Key Points This was a multicenter, randomized, double-blind, double-dummy, placebo-controlled, 3-week study The primary end point was the effect on recent (delayed) memory as assessed using the Name-Face Association Test at week 3 Secondary end points included Recall on First-Last Name Association Test Misplaced Objects Test Delayed recall scores at weeks 1 and 2 Effects on immediate memory Visual attention Information processing Psychomotor/reaction time Additional information: First-Last Name Association Test: Subjects are presented with 4 pairs of first and last names and then are asked to recall corresponding first names as each last name is presented. Two separate tests were performed (first and second acquisition) Reference Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. 09/28/11
  • Key Points Change in cognitive function (particularly memory) is a concern for elderly individuals taking antimuscarinic agents, as some of these muscarinic antagonists can cross the BBB In this study, 2 different antimuscarinic agents, darifenacin (ENABLEX ® ) and oxybutynin extended release (ER), were given to subjects ≥60 years of age Oxybutynin binds M 1 and M 3 receptors, whereas ENABLEX ® has higher specificity for M 3 receptors Results of a delayed recall on the First-Last Name Association Test showed that oxybutynin ER resulted in significant impairment vs placebo at weeks 1 and 2. In contrast, no significant differences were observed between ENABLEX ® and placebo at any time point Reference Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. 09/28/11
  • Key Points This was a 7-day, single-center, randomized, parallel-group study in healthy volunteers Subjects received once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) Blood samples were taken pre- and postdose, and plasma concentrations were determined using liquid chromatography and mass spectrometry Standard 12-lead ECGs, including three 10-second lead II rhythm strips, were digitally collected in triplicate pre- and postdose The primary end point measured change from mean baseline in Fridericia-corrected QT interval (QTcF) at T max , based on the ECG recording taken at the time corresponding to each subject’s C max Secondary end points included Mean change from baseline in QT/QTcF Maximum QT interval postdose change from baseline Reference Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. 09/28/11
  • Key Points The majority of patients with overactive bladder will need long-term treatment to manage their disease. Therefore, CV safety is an important concern for many individuals In this 7-day study, patients were given 15 mg ENABLEX ® , 75 mg ENABLEX ® , 400 mg moxifloxacin, or placebo Moxifloxacin, a fluoroquinolone antibacterial agent known to prolong QT interval by 5 to 10 milliseconds, was used as a positive control Results showed that there were no significant changes in the QTcF interval when ENABLEX ® was titrated up to 75 mg, beyond the highest therapeutic dose Note: The QT interval refers to the time period between the Q and T waves on ECG. Reference Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. 09/28/11
  • Key Points Data from clinical studies show that ENABLEX ® has established efficacy and safety showcasing the high specificity for the M 3 receptor 1-7 Efficacy data showed a significant reduction in the number of incontinence and urgency episodes per week from 3 randomized, multicenter, double-blind, 12-week studies 2 and significant improvement in overactive bladder symptoms in subjects who switched from previous overactive bladder therapy 3 Data support the selectivity for the M 3 receptor, 1 with effects comparable to placebo on delayed or immediate recall memory in older subjects 4 and no significant change in QTcF 5 A 2-year extension study demonstrated that ENABLEX ® has a favorable safety, tolerability, and efficacy profile 6 ; in subjects ≥65 years of age, it was well tolerated, with no overall differences in safety or efficacy observed 1,7 References ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract. 2008;62:1664-1674 . Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. Hill S, Elhilali M, Millard RJ, et al. Long-term darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year, open-label extension study. Curr Med Res Opin . 2007;23:2697-2704. 09/28/11
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  • Key Point After considering Amy’s history and treatment options, what would be your next step? 09/28/11
  • Key Points After considering Amy’s history and treatment options, what would be your next step? ENABLEX ® as an Option In clinical studies, ENABLEX ® has demonstrated significant reductions in incontinence and urgency episodes Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points After considering Amy’s history and treatment options, what would be your next step? ENABLEX ® as an Option In clinical studies, ENABLEX ® has demonstrated significant reductions in incontinence and urgency episodes 1 Discontinuation rates from 3 phase 3 studies were minimal 1,2 Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 2. Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. 09/28/11
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  • Key Point After considering George’s medical history, what would be your next step? What would you prescribe? 09/28/11
  • Key Points After considering George’s medical history, what would be your next step? What would you prescribe? ENABLEX ® as an Option Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder Reference Chughtai B, Levin R, De E. Choice of antimuscarinic agents for overactive bladder in the older patient: focus on darifenacin. Clin Interv Aging. 2008;3:503-509. 09/28/11
  • Key Points After considering George’s medical history, what would be your next step? What would you prescribe? ENABLEX ® as an Option Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1 ENABLEX ® demonstrated significant improvements in PPBC scores at week 12 in patients switching from other overactive bladder treatments 2 References Chughtai B, Levin R, De E. Choice of antimuscarinic agents for overactive bladder in the older patient: focus on darifenacin. Clin Interv Aging. 2008;3:503-509. Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract . 2008;62:1664-1674 . 09/28/11
  • Key Points After considering George’s medical history, what would be your next step? What would you prescribe? ENABLEX ® as an Option Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1 ENABLEX ® demonstrated significant improvements in PPBC scores at week 12 in patients switching from other overactive bladder treatments 2 High M 3 specificity with no significant effect on memory 3,4 References Chughtai B, Levin R, De E. Choice of antimuscarinic agents for overactive bladder in the older patient: focus on darifenacin. Clin Interv Aging. 2008;3:503-509. Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract . 2008;62:1664-1674 . Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol . 2005;173:493-498. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. 09/28/11
  • Key Points After considering George’s medical history, what would be your next step? What would you prescribe? ENABLEX ® as an Option Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1 ENABLEX ® demonstrated significant improvements in PPBC scores at week 12 in patients switching from other overactive bladder treatments 2 High M 3 specificity with no significant effect on memory 3,4 ENABLEX ® has demonstrated consistent efficacy and safety in 12-week pivotal studies and a 2-year extension study 5-7 References Chughtai B, Levin R, De E. Choice of antimuscarinic agents for overactive bladder in the older patient: focus on darifenacin. Clin Interv Aging. 2008;3:503-509. Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract . 2008;62:1664-1674 . Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol . 2005;173:493-498. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. Hill S, Elhilali M, Millard RJ, et al. Long-term darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year, open-label extension study . Curr Med Res Opin . 2007;23:2697-2704. Steers W, Corcos J, Foote J, Kralidis G. An investigation of dose titration with darifenacin, an M 3 -selective receptor antagonist. BJU Int. 2005;95:580-586. 09/28/11
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  • Key Points After reviewing Joanne’s history and treatment concerns, what would be your next steps? What would you prescribe that would not adversely affect her memory? This presents as a unique case in that the patient’s symptoms of overactive bladder are now affecting family members 09/28/11
  • Key Points After reviewing Joanne’s history and treatment concerns, what would be your next steps? What would you prescribe that would not adversely affect her memory? This presents as a unique case in that the patient’s symptoms of overactive bladder are now affecting family members ENABLEX ® as an Option As bladder contractions are mediated primarily by M 3 receptors, antimuscarinics with high M 3 specificity are ideal for patients with overactive bladder Reference Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. 09/28/11
  • Key Points After reviewing Joanne’s history and treatment concerns, what would be your next steps? What would you prescribe that would not adversely affect her memory? This presents as a unique case in that the patient’s symptoms of overactive bladder are now affecting family members ENABLEX ® as an Option As bladder contractions are mediated primarily by M 3 receptors, antimuscarinics with high M 3 specificity are ideal for patients with overactive bladder 1 This is particularly important in elderly patients, who are more vulnerable to potential CNS and other safety concerns 2,3 References Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001 Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. 09/28/11
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  • Key Points In conclusion, ENABLEX ® is an effective treatment for patients with overactive bladder. Clinical studies show a significant reduction in the number of incontinence and urgency episodes per week. 1 ENABLEX ® also produces significant improvement in overactive bladder symptoms in patients dissatisfied with previous therapy 2 ENABLEX ® has greater affinity for overactive bladder–specific M 3 receptors than other muscarinic, receptors and study results demonstrate that it targets overactive bladder while minimizing potential CNS- and CV-related side effects 3 A 2-year extension study demonstrated a favorable safety, tolerability, and efficacy profile 4 and showed that, in subjects ≥65 years of age, ENABLEX ® was well tolerated, and no overall differences in safety or efficacy were observed 3,7 No significant effects on delayed or immediate recall memory were noted in older subjects, 6 and no significant changes in QTcF were observed 7 References Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int. 2005;95:993-1001. Zinner N, Kobashi KC, Ebinger U, et al. Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract. 2008;62:1664-1674 . ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Haab F, Corcos J, Siami P, et al. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int. 2006;98:1025-1032. Hill S, Elhilali M, Millard RJ, et al. Long-term darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year, open-label extension study. Curr Med Res Opin . 2007;23:2697-2704. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. Serra DB, Affrime MB, Bedigian MP, et al . QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol . 2005;45:1038-1047. 09/28/11
  • Key Points Case studies provide examples of ENABLEX ® as an effective overactive bladder treatment for a wide range of patients Data support the use of ENABLEX ® as first-line therapy for individuals such as Amy S, who has an active lifestyle; George R, who was previously been prescribed overactive bladder medications that they were dissatisfied with and for older patients, such as Joanne J, who are concerned with safety and AEs on memory Who is your patient, and is ENABLEX ® right for them? 09/28/11
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Transcript

  • 1. ENABLEX ® in the Treatment of Overactive Bladder ENABLEX ® is a registered trademark of Warner Chilcott Company, LLC. ENABLEX ® (darifenacin) extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency
  • 2. Presenter
    • David C. Chaikin, MD, FACS
    • Clinical Assistant Professor of Urology
    • New York-Presbyterian/Weill Cornell Medical Center
    • New York, New York
    • Attending Urologist
    • Morristown Memorial Hospital
  • 3. Table of Contents
  • 4. Overactive Bladder Background: Disease State and Epidemiology
  • 5. Overactive Bladder Is a Complex Syndrome Coyne KS, et al. Urology. 2011; 77:1081-1087. Urgency 12.6% Urge Urinary Incontinence 9.1% Urgency + Frequency 5.2% 1.2% Urgency + Urge Urinary Incontinence 13.1% Urgency + Urge Urinary Incontinence + Frequency 7.0% Prevalence of Overactive Bladder Symptoms in Poll of 2000 Adults Aged ≥40 Years Urge Urinary Incontinence + Frequency
  • 6. Overactive Bladder Affects Over 33 Million Americans
    • According to the National Overactive Bladder Evaluation (NOBLE) Program
    Kelleher CJ. Eur Urol Suppl. 2002;1:11-16. * Overactive bladder dry: ≥4 episodes of urgency during the preceding 4 weeks and either frequency of >8 voids per day or the use of ≥1 coping behaviors to control bladder function. † Overactive bladder wet: same criteria as overactive bladder dry, plus ≥3 episodes of urinary incontinence in the past 4 weeks that could not be explained by stress symptoms. 21.2 million (10.5% of the US adult population) 12.2 million (6.1% of the US adult population) Incontinent (overactive bladder wet † ) Continent (overactive bladder dry * )
  • 7. Overactive Bladder Risk Factors
    • * Include elevated body mass index (BMI) and diabetes.
    • Stewart WF, et al. World J Urol . 2003;20:327-336.
    • Teleman PM, et al. BJOG . 2004;111:600-604.
    • Rosenberg MT, et al. Cleve Clin J Med . 2007;74(suppl 3):S21-S29.
    • Thüroff JW, et al. Eur Urol . 2011;59:387-400.
    Increased Age 1 Abnormal Metabolic Factors 2 * Medications 3 Pregnancy and Vaginal Delivery (Women) 4 Prostate-related Conditions (Men) 3,4 Pelvic Surgery 3
  • 8. Comorbidities Associated With Overactive Bladder Brown JS, et al. Am J Manag Care . 2000;6(suppl 11):S574-S579. Falls and Fractures Depression Sleep Disturbances Urinary Tract and Skin Infections
  • 9. Overactive Bladder Negatively Affects QOL * A standardized questionnaire that measures health-related QOL. Modified from Stewart WF, et al. World J Urol . 2003;20:327-336. Decrease in Mean SF-36 Score (%) QOL Areas of Measure Patients With Overactive Bladder Urge Incontinence Compared With Controls (SF-36)*
  • 10. Treatment Options: Pharmacologic and Non-Pharmacologic Therapies
    • Thüroff JW, et al. Eur Urol . 2011;59:387-400.
    • Yamaguchi O, et al . Int J Urol . 2009;16:126-142.
    * Recommendations for pharmacologic therapy are from the European Association of Urology (EAU) guidelines for incontinence. Non-Pharmacologic (Behavioral Therapy) 2
    • Lifestyle management
    • Limiting excessive water or caffeine intake
    • Bladder training
    • Increasing bladder capacity through lengthening of the voiding interval
    • Physical therapy
    • Pelvic floor exercises
    • Biofeedback therapy
    • Toileting assistance
    • Timed and patterned toileting guidance
    Pharmacologic Therapy 1*
    • Antimuscarinic drugs
    • Drugs acting on membrane channels
    • Antidepressants
    • Alpha-adrenoreceptor antagonists
    • Beta-adrenoreceptor antagonists
    • Phosphodiesterase type-5 inhibitors (in men)
    • Cyclo-oxygenase (COX) inhibitors
    • Hormones
  • 11. M 3 Receptor Selectivity Allows for Targeting of Tissue of Intent Abrams P, et al. Br J Pharmacol . 2006;148:565-578.
  • 12. Targets for Muscarinic Receptor Inhibition
    • Abrams P, et al. Br J Pharmacol . 2006;148:565-578.
    • Sarria B, et al. Am J Physiol Lung Cell Mol Physiol. 2002;283:L1125-L1132 .
    Impacts: Memory, cognitive function, saliva, tear secretion Impacts: Heart rate, tear secretion, bronchodilation Impacts: Bladder contraction,* bowel motility, saliva, tear secretion, visual accommodation Cerebral cortex Hippocampus Eyes Salivary glands Cardiac muscle Eyes Smooth muscle (bronchus) Hippocampus Hind brain Smooth muscle (bladder, bowel) Salivary glands Eyes Brain
  • 13. M 3 -specific Targeted Therapy for Overactive Bladder
    • High affinity for the M 3 receptor 1-3
      • Targets the smooth muscle to minimize leaks
      • and accidents 1
      • Minimizes potential CNS- and CV-related side effects 2,3
    • M 3 -selective antagonists do not significantly affect memory 3
      • Compared with placebo
      • Significant memory deterioration has been demonstrated with less-selective agents, such as oxybutynin
    • Abrams P, et al. Br J Pharmacol . 2006;148:565-578.
    • Lipton RB, et al. J Urol . 2005;173:493-498.
    • Kay G, et al. Eur Urol. 2006;50:317-326.
    CNS=central nervous system; CV=cardiovascular.
  • 14. ENABLEX ® : Muscarinic Receptor Selectivity
    • M 3 receptors are the primary mediators of detrusor contractility in the bladder 1
    • M 3 receptors are also involved in gastrointestinal smooth-muscle contraction, saliva production, and iris sphincter function 1,2
    • NA=not available.
    • Abrams P, et al. Br J Pharmacol . 2006;148:565-578.
    • ENABLEX® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011.
    • Geriatric Consultant Resources LLC. http://www.gcrweb.com/OABdss/comprehensive/comp-02a-muscar.htm. Accessed March 25, 2011.
  • 15. Likelihood of Muscarinic Agents Crossing the BBB
    • Less-selective agents have been associated with more impairment of cognitive function 1
    • Lipton RB, et al. J Urol . 2005;173:493-498.
    • Kay G, et al. Clin Ther. 2005;27:127-138.
    • VESIcare ® [package insert]. Deerfield, IL: Astellas Pharma US, Inc; 2011.
    • Geriatric Consultant Resources, LLC. http://www.gcrweb.com/OABdss/comprehensive/comp-02b-pham.htm. Accessed March 23, 2011.
    BBB= blood-brain barrier. * kDa=kiloDalton.
  • 16. ENABLEX ® as a Treatment Option for Patients With Overactive Bladder Proven Efficacy and Safety by Clinical Trials
  • 17. ENABLEX ® : Prescribing Information
    • ENABLEX ® (darifenacin) extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency
    ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Indication and Usage
  • 18. ENABLEX ® : Prescribing Information
    • ENABLEX ® (darifenacin) extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency
    • ENABLEX ® (darifenacin) extended-release tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. ENABLEX ® is also contraindicated in patients with known hypersensitivity to the drug or any of its ingredients
    ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Indication and Usage Contraindications
  • 19. ENABLEX ® : Prescribing Information
    • ENABLEX ® (darifenacin) extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency
    • ENABLEX ® (darifenacin) extended-release tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. ENABLEX ® is also contraindicated in patients with known hypersensitivity to the drug or any of its ingredients
    ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. Indication and Usage Contraindications ENABLEX ® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention; gastrointestinal obstructive disorders because of the risk of gastric retention; severe constipation, ulcerative colitis, or myasthenia gravis. In patients being treated for narrow-angle glaucoma, ENABLEX ® should be used with caution and only where the potential benefits outweigh the risks. Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin, in some cases, after the first dose. Angioedema associated with upper airway swelling may be life threatening. Patients should be advised to promptly discontinue darifenacin therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.
  • 20.
    • ENABLEX ® has been evaluated in 3 randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies and 1 randomized, double-blind, placebo-controlled, multicenter, dose-titration study
    • In clinical studies, dry mouth and constipation were the most commonly reported adverse events (AEs)
    ENABLEX ® : Prescribing Information ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011.
  • 21. ENABLEX ® : Effective Treatment for Overactive Bladder
    • ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011.
    • Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047.
    • Haab F, et al. BJU Int. 2006;98:1025-1032.
  • 22. ENABLEX ® Pooled Analysis of Phase 3 Studies Chapple C, et al. BJU Int. 2005;95:993-1001. 0 2 6 12 ENABLEX ® 7.5 mg Once Daily (n=337) Placebo Once Daily (n=388) Up to 4 weeks (as needed) Study Visits (weeks) Washout Treatments ENABLEX ® 15 mg Once Daily (n=334) Randomization Primary Efficacy Change in number of incontinence episodes per week Secondary Efficacy Number of significant leaks per week Voiding frequency Bladder capacity Frequency and severity of urgency Number of nocturnal awakenings caused by overactive bladder Subject population similar between treatment arms
      • Symptoms of overactive bladder ≥6 months
    3 Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, Fixed-dose, 12-week Studies
  • 23. 7.5 mg ENABLEX ® Significantly Reduces Incontinence Episodes by ~70% Chapple C, et al. BJU Int. 2005;95:993-1001. * P =.004 vs placebo; data missing for 2 subjects. Treatment Darifenacin 7.5 mg * Placebo Data from a pooled analysis of 3 phase 3, fixed-dose, double-blind, placebo-controlled, parallel-group, 12-week clinical trials (1001, 1002, 1041). A total of 1059 subjects were included in the analysis (darifenacin 7.5 mg: n=337; darifenacin 15 mg: n=334; placebo: n=388). Absolute changes from baseline (last observation carried forward [LOCF]) to Week 12 for subjects on darifenacin: number of weekly incontinence episodes: –8.8 (7.5 mg) and –10.6 (15 mg). n=335 n=271
  • 24. 15 mg ENABLEX ® Significantly Reduces Incontinence Episodes by >75% Chapple C, et al. BJU Int. 2005;95:993-1001. * P <.001 vs placebo; data missing for 4 subjects. Treatment Darifenacin 15 mg * Placebo Data from a pooled analysis of 3 phase 3, fixed-dose, double-blind, placebo-controlled, parallel-group, 12-week clinical trials (1001, 1002, 1041). A total of 1059 subjects were included in the analysis (darifenacin 7.5 mg: n=337; darifenacin 15 mg: n=334; placebo: n=388). Absolute changes from baseline (last observation carried forward [LOCF]) to Week 12 for subjects on darifenacin: number of weekly incontinence episodes: –8.8 (7.5 mg) and –10.6 (15 mg). n=330 n=384
  • 25. 7.5 mg ENABLEX ® Significantly Reduces the Number of Urgency Episodes Chapple C, et al. BJU Int. 2005;95:993-1001. * P <.005 compared with corresponding placebo. 37% 24%
  • 26. 15 mg ENABLEX ® Significantly Reduces the Number of Urgency Episodes Chapple C, et al. BJU Int. 2005;95:993-1001. 39% 23% * P <.01 compared with corresponding placebo. * 49% 34% *
  • 27. ENABLEX ® Is Well-tolerated
    • UTI=urinary tract infection.
    • ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011.
    • Chapple C, et al. BJU Int. 2005;95:993-1001 .
    Treatment-emergent AEs (TEAEs) Over 1 Year 1,2
  • 28. Few Discontinuations Over 12 Weeks Chapple C, et al. BJU Int. 2005;95:993-1001.
  • 29. ENABLEX ® Long-term Efficacy Up to 2 Years Haab F, et al . BJU Int . 2006;98:1025-1032. Subjects recruited from 1 of 2 phase 3, randomized, double-blind, 12-week studies ENABLEX ® 7.5 mg Once Daily 12-week Studies Long-term Study (24 months) ENABLEX ® 15 mg Once Daily ENABLEX ® 7.5 mg for 2 Weeks Study 1 (n=526) ENABLEX ® 3.75, 7.5, 15 mg, and Placebo Study 2 (n=357) ENABLEX ® 7.5, 15 mg, and Placebo Multicenter, Long-term, Noncomparative, Open-label Study Primary Objective Assess long-term safety and tolerability Secondary Objective Evaluate long-term efficacy
  • 30. ENABLEX ® Significantly Reduces Incontinence Episodes Up to 2 Years Treatment Duration (months)
    • Haab F, et al . BJU Int . 2006;98:1025-1032.
    • Hill S, et al. Curr Med Res Opin . 2007;23:2697-2704.
    Results from an open-label, nonrandomized, multicenter, 2-year extension study . Subjects were enrolled from two 12-week, phase 3, double-blind, placebo-controlled pivotal trials 1,2 P <.001 vs pivotal study baseline n=667 n=598 n=541 n=495 n=464
  • 31. Low Discontinuation Rates Through 2 Years
    • Haab F, et al . BJU Int . 2006;98:1025-1032.
    • Haab F, et al. Eur Urol . 2004;45:420-429.
    • Steers W, et al. BJU Int. 2005;95:580-586.
    Most commonly reported TEAEs were similar to pivotal studies and included dry mouth, constipation, dyspepsia, and headache 1-3
  • 32. Efficacy in Subjects on Previous Overactive Bladder Therapy PPBC=Patient Perception of Bladder Condition. Zinner N, et al. Int J Clin Pract. 2008;62:1664-1674 .
    • Subjects were ENABLEX ® -naïve and reported lack of sufficient effect and/or AEs on previous treatments with either oxybutynin or tolterodine
    2-3 weeks Screening/Washout Treatments (optional dose escalation after 2 weeks) Baseline 1 week 10 weeks 2 weeks Primary Efficacy Change in PPBC score from baseline to end of study Secondary Efficacy Micturition frequency Urgency Urge urinary incontinence episodes after 2, 6, and 12 weeks of treatment compared with baseline ENABLEX ® 7.5 mg Once Daily (n=180) ENABLEX ® 15 mg Once Daily (n=302) ENABLEX ® 7.5 mg Once Daily (n=497) Enrollment (n=500) 12-Week, Open-label, Single-arm, Multicenter Study
  • 33. ENABLEX ® Significantly* Improves Patient -reported Bladder Control Zinner N, et al. Int J Clin Pract. 2008;62:1664-1674 . Results of PPBC p <0.0001.
  • 34. ENABLEX ® : Cognitive Function in Older Subjects Kay G, et al . Eur Urol . 2006;50:317-326. 0 1 2 3 Cognitive Function Tests (weeks) Washout Treatments Multicenter, Randomized, Double-blind, Double-dummy, Placebo-controlled, 3-week Study Primary Efficacy Effect on recent (delayed) memory using Name-Face Association Test at Week 3 Secondary Efficacy Recall on First-Last Name Association Test Misplaced Objects Test Delayed recall scores at weeks 1 and 2 Effects on immediate memory Visual attention Information processing Psychomotor/reaction time
  • 35. ENABLEX ® : Memory Sparing * P <.05 vs placebo; † P <.05 vs ENABLEX ® (ANCOVA, adjusted for baseline score, age, and gender). ANCOVA=analysis of covariance. Kay G, et al . Eur Urol . 2006;50:317-326.
    • No significant effects on memory
    ® * † * †
  • 36. ENABLEX ® : Effect on QT Interval QTcF=Fridericia-corrected QT interval. Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047. ENABLEX ® 15 mg Once Daily (n=47) Moxifloxacin 400 mg Once Daily (n=48) Treatment Period (Days 1-6) ENABLEX ® 75 mg Once Daily (n=46) Placebo Run-in (Day –1) Placebo (n=47) 7-Day, Single-center, Randomized, Parallel-group Study in Healthy Subjects Primary Efficacy Change from mean baseline in QTcF at T max Secondary Efficacy Mean change from baseline in QT/QTcF Maximum QT interval postdose change from baseline
  • 37. ENABLEX ® : Minimal Effect on QT Interval
    • No significant changes occurred when ENABLEX ® was given at 75 mg (10 times the starting dose)
    Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047. Change From Baseline in Mean QTcF at T max (ms) Placebo (n=44) – 2.6 ENABLEX ® 15 mg (n=46) – 2.6
  • 38. ENABLEX ® Clinical Trial Data: Established Efficacy and Safety
    • Chapple C, et al. BJU Int. 2005;95:993-1001 .
    • Zinner N, et al. Int J Clin Pract. 2008;62:1664-1674 .
    • ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011.
    • Kay G, et al . Eur Urol . 2006;50:317-326.
    • Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047.
    • Haab F, et al . BJU Int . 2006;98:1025-1032.
    • Hill S, et al. Curr Med Res Opin . 2007;23:2697-2704.
    Efficacy
      • Significant reduction in number of incontinence and urgency episodes per week 1
      • Overactive bladder symptoms significantly improved in subjects who were dissatisfied with prior antimuscarinic therapy 2
    Specificity
      • Strong affinity for M 3 receptors 3
      • No significant effects on delayed or immediate recall memory in older subjects 4
      • No significant change in QTcF 5
    Well Studied
      • 2-year extension study demonstrated a favorable safety, tolerability, and efficacy profile 6,7
      • In subjects ≥65 years of age, ENABLEX ® was well tolerated; no overall differences in safety or efficacy were observed 3,7
  • 39. ENABLEX ® as a Treatment Option for Patients With Overactive Bladder Case Studies
  • 40. Amy S.
    • 52-year-old woman with overactive bladder
    • Active lifestyle
    • Overactive bladder treatment-naive
    Case Study 1 Case studies are illustrative examples and not based on actual patient records.
  • 41. Amy S.
    • 52-year-old, teacher, mother of 4
    • Active lifestyle (skis, golfs)
    • Tried Kegel exercises
    • No other significant medical history
      • Meds: statin, NSAIDs
    • CC: Strong urge to urinate during the day
      • Every 30 minutes
    Medical History
  • 42. Amy S. (cont’d) Medical History
    • No incontinence with coughing, sneezing, laughing, or exercise unless bladder is full
    • Overactive bladder increasingly difficult to control
      • Accidents have hindered activities
    • No history of previous overactive bladder medication use
      • Embarrassed by her overactive bladder symptoms
    • Desires a safe and effective treatment
  • 43. Assessment
    • Amy S. is a 52-year-old woman with an active lifestyle
    • Based on history and symptoms, you agree with the diagnosis of overactive bladder
    • You perform a physical exam and order routine tests to rule out other causes
  • 44. Treatment Plan After considering Amy’s medical history, how would you manage her overactive bladder?
  • 45. Treatment Plan Chapple C, et al. BJU Int. 2005;95:993-1001 .
    • After considering Amy’s medical history, how would you manage her overactive bladder?
    • ENABLEX ® as an Option
    • In clinical studies, ENABLEX ® has demonstrated significant reductions in incontinence and urgency episodes
  • 46. Treatment Plan
    • Chapple C, et al. BJU Int. 2005;95:993-1001 .
    • Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047.
    • After considering Amy’s medical history, how would you manage her overactive bladder?
    • ENABLEX ® as an Option
    • In clinical studies, ENABLEX ® has demonstrated significant reductions in incontinence and urgency episodes 1
    • Discontinuation rates from 3 phase 3 studies were minimal 1,2
  • 47. George R.
    • 69-year-old man
    • Dissatisfied with current overactive bladder therapy
    • Considering changing medication for overactive bladder
    Case Study 2 Case studies are illustrative examples and not based on actual patient records.
  • 48. George R.
    • 69-year-old retired businessman
    • Overactive bladder diagnosed
    • 6 years ago
    • Reluctant to change overactive bladder medication because the first one failed
    • CC: Despite treatment, patient complains of strong and frequent urges to void
    Medical History
  • 49. George R. (cont’d)
    • Medications
      • ACE inhibitor
      • Oral hypoglycemic
    • Concerned that switching treatments may have potential side effects and not provide further symptom relief
    • Seeks an alternative treatment that is safe, effective, and can be used longterm
    Medical History
  • 50. Assessment
    • George R. is a 69-year-old man requesting treatment for his symptoms
    • Based on history and symptoms, you agree with the diagnosis of overactive bladder
    • Perform a physical exam , including prostate exam, and order routine tests, to rule out other causes
  • 51. Treatment Plan After considering George’s medical history and chief complaint of strong and frequent urges to urinate, how would you manage his overactive bladder?
  • 52. Treatment Plan
    • Chughtai B, et al. Clin Interv Aging. 2008;3:503-509.
    • After considering George’s medical history and chief complaint of strong and frequent urges to urinate, how would you manage his overactive bladder?
    • ENABLEX ® as an Option
    • Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1
  • 53. Treatment Plan
    • Chughtai B, et al. Clin Interv Aging. 2008;3:503-509.
    • Zinner N, et al. Int J Clin Pract . 2008;62:1664-1674 .
    • After considering George’s medical history and chief complaint of strong and frequent urges to urinate, how would you manage his overactive bladder?
    • ENABLEX ® as an Option
    • Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1
    • Significant improvements in PPBC scores at week 12 in patients switching from other overactive bladder treatments 2
  • 54. Treatment Plan
    • Chughtai B, et al. Clin Interv Aging. 2008;3:503-509. 2. Zinner N, et al. Int J Clin Pract . 2008;62:1664-1674 . 3. Lipton RB, et al. J Urol . 2005;173:493-498 . 4. Kay G, et al. Eur Urol. 2006;50:317-326.
    • After considering George’s medical history and chief complaint of strong and frequent urges to urinate, how would you manage his overactive bladder?
    • ENABLEX ® as an Option
    • Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1
    • Significant improvements in PPBC scores at week 12 in patients switching from other overactive bladder treatments 2
    • High M 3 specificity with no significant effect on memory 3,4
  • 55. Treatment Plan 1. Chughtai_B, et al. Clin Interventions Aging. 2008; 3:503-509. 2. Zinner N, et al. Int J Clin Pract . 2008;62:1664-1674 . 3. Lipton RB, et al. J Urol . 2005;173:493-498. 4. Kay G, et al. Eur Urol. 2006;50:317-326. 5. Haab F, et al . BJU Int . 2006;98:1025-1032. 6. Hill S, et al. Curr Med Res Opin . 2007;23:2697-2704. 7. Steers W, et al. BJU Int. 2005;95:580-586.
    • After considering George’s medical history and chief complaint of strong and frequent urges to urinate, how would you manage his overactive bladder?
    • ENABLEX ® as an Option
    • Antimuscarinics are currently the treatment of choice in elderly patients with overactive bladder 1
    • Significant improvements in PPBC scores at week 12 in patients switching from other overactive bladder treatments 2
    • High M 3 specificity with no significant effect on memory 3,4
    • Consistent efficacy and safety in 12-week pivotal studies and a 2-year extension study 5-7
  • 56. Joanne J.
    • 78-year-old woman
    • Worried about side effects of overactive bladder treatment
    • History of memory loss
    Case Study 3 Case studies are illustrative examples and not based on actual patient records.
  • 57. Joanne J.
    • 78-year-old retired waitress with dementia
      • Lives with daughter
    • Overactive bladder for >15 years
    • CC: Incontinence limiting her activity
    • Concerned that overactive bladder medications can further compromise her memory
    Medical History
  • 58. Joanne J. (cont’d)
    • Medications:
      • ACE inhibitor
      • Cardioselective beta blocker
      • Antihyperlipidemic
    • Wants to decrease her frequent accidents and subsequent burden on family
    Medical History
  • 59. Assessment
    • Joanne J. is a 78-year-old woman with history of memory loss who presents with her caretaker (daughter) requesting alternative treatment for her overactive bladder symptoms
    • Based on history and symptoms, you agree with the diagnosis of overactive bladder
    • You perform a physical exam and order routine tests, including a urine analysis, to rule out other causes
  • 60. Treatment Plan After reviewing Joanne’s history and treatment concerns, how would you manage her overactive bladder?
  • 61. Treatment Plan
    • Chapple C, et al. BJU Int. 2005;95:993-1001.
    • After reviewing Joanne’s history and treatment concerns, how would you manage her overactive bladder?
    • ENABLEX ® as an Option
    • As bladder contractions are mediated primarily by
    • M 3 receptors, antimuscarinics with high M 3 specificity
    • are ideal for patients with overactive bladder 1
  • 62. Treatment Plan 1. Chapple C, et al. BJU Int. 2005;95:993-1001. 2. Kay G, et al . Eur Urol . 2006;50:317-326. 3. Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047 .
    • After reviewing Joanne’s history and treatment concerns, how would you manage her overactive bladder?
    • ENABLEX ® as an Option
    • As bladder contractions are mediated primarily by
    • M 3 receptors, antimuscarinics with high M 3 specificity
    • are ideal for patients with overactive bladder 1
    • This is particularly important in elderly patients, who are more vulnerable to potential CNS and other safety concerns 2,3
  • 63. ENABLEX ® Treatment in a Wide Range of Patients With Overactive Bladder Summary
  • 64. ENABLEX ® : Effective Treatment for Overactive Bladder Patients 1. Chapple C, et al. BJU Int. 2005;95:993-1001. 2. Zinner N, et al. Int J Clin Pract. 2008;62:1664-1674 . 3. ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011. 4. Kay G, et al . Eur Urol . 2006;50:317-326. 5. Serra DB, et al . J Clin Pharmacol . 2005;45:1038-1047. 6. Haab F, et al . BJU Int. 2006;98:1025-1032. 7. Hill S, et al. Curr Med Res Opin . 2007;23:2697-2704.
  • 65. ENABLEX ® : Overactive Bladder Treatment for a Wide Range of Patients
    • First-line therapy for the active 52-year-old woman
      • Significant reductions in incontinence and urgency episodes
      • Minimal discontinuation rates
    • Treatment for the 69-year-old man who was dissatisfied with
    • previous therapy
      • Significant improvements in PPBC in patients switching from other overactive bladder therapies
      • Consistent efficacy and safety in 12-week pivotal studies and a 2-year
      • extension study
    • Therapy for the 78-year-old woman with safety concerns
      • High M 3 selectivity
      • Low risk of memory deterioration and other AEs
    • Who is your patient?
  • 66. ENABLEX ® : Important Safety Information
    • ENABLEX ® (darifenacin) extended-release tablets is contraindicated in patients with urinary retention, gastric retention or uncontrolled narrow-angle glaucoma, and in patients who are at risk for these conditions. ENABLEX ® is also contraindicated in patients with known hypersensitivity to the drug or any of its ingredients.
    • Daily dose should not exceed 7.5 mg when used with potent CYP3A4 inhibitors or in patients with moderate hepatic impairment. ENABLEX ® is not recommended for patients with severe hepatic impairment.
    • ENABLEX ® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention; gastrointestinal obstructive disorders because of the risk of gastric retention; severe constipation, ulcerative colitis, or myasthenia gravis. In patients being treated for narrow-angle glaucoma, ENABLEX ® should be used with caution and only where the potential benefits outweigh the risks.
    • Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin, in some cases after the first dose. Angioedema associated with upper airway swelling may be life threatening. Patients should be advised to promptly discontinue darifenacin therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.
    • In controlled clinical studies the incidence of the most frequently reported adverse events for ENABLEX ® 7.5 mg or 15 mg and greater than placebo was: 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%); and dry eyes (1.5%, 2.1%, 0.5%).
    • Please see full Prescribing Information for ENABLEX ® at www.enablex.com.
    ENABLEX ® [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2011.
  • 67. SPEAKER TRAINING CERTIFICATION
    • I certify the following: 
    • I completed the Warner Chilcott Product training on Enablex ® and I reviewed the Regulatory Compliance Training slides on the rules and regulations governing speaking on behalf of Warner Chilcott. 
    • I have read and understand the prescribing information for Enablex ® (darifenacin) extended-release tablets. 
    • I understand Enablex ® is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
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  • 68. SPEAKER TRAINING CERTIFICATION
    • I understand the following safety information about Enablex ® :
      • Enablex ® is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients who are at risk for these conditions. Enablex ® is also contraindicated in patients with known hypersensitivity to the drug or any of its ingredients. Daily dose should not exceed 7.5 mg when used with potent CYP3A4 inhibitors or in patients with moderate hepatic impairment. Enablex ® is not recommended for patients with severe hepatic impairment.
      • Enablex ® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention, gastrointestinal obstructive disorders because of the risk of gastric retention, severe constipation, ulcerative colitis, or myasthenia gravis. In patients being treated for narrow-angle glaucoma, Enablex ® should be used with caution and only where the potential benefits outweigh the risks.
      • Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin, in some cases, after the first dose. Angioedema associated with upper airway swelling may be life threatening. Patients should be advised to promptly discontinue darifenacin therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.
      • In controlled clinical studies the incidence of the most frequently reported adverse events for Enablex ® 7.5 mg or 15 mg and greater than placebo was: 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%); and dry eyes (1.5%, 2.1%, 0.5%)
    NEXT
  • 69. SPEAKER TRAINING CERTIFICATION
    • I understand that when presenting information about Enablex® as a speaker for Warner Chilcott, I must only use Warner Chilcott-approved slides and must follow all applicable rules and regulations for speakers.
    • I understand that when presenting information about Enablex® as a speaker for Warner Chilcott, I must present only information contained in the product label or new drug application. If an unsolicited question requires an answer that is off-label, I will briefly answer the question, state that the answer is off-label and derived from my professional experience, and return to the Warner Chilcott-approved presentation and messaging.
    Submit I Agree I Disagree
  • 70. SPEAKER TRAINING CERTIFICATION
    • This concludes the training. Thank you.