Pharmacotherapy for Overactive Bladder Rationale for Treatment Choice

Pharmacotherapy for Overactive Bladder Rationale for Treatment Choice
David A. Ginsberg, M.D. Assistant Professor of Urology USC Keck School of Medicine

Overactive Bladder Terminology
OAB = bladder contracting w/o pt’s permission OAB definition per ICS based on symptoms Urgency, with or without urge incontinence, usually with frequency and nocturia In the absence of pathologic or metabolic conditions that might explain these symptoms At the ICS meeting in Seoul Korea in September 2001, a consensus definition of OAB was derived This definition focuses on the symptoms of OAB rather than on urodynamic parameters and is much more clinically useful for physicians, because most do not do urodynamic studies on patients with OAB In addition, it improves communication between physicians and their patients, since the definition includes terms that are much more intuitive and less likely to confuse or even alarm the patient (many patients have been quite bothered with the old term “unstable” bladder) Thus, the new definition encompasses all of the important clinical aspects of OAB, without using terminology that is only interpretable by a specialist in urology ICS = International Continence Society (

Spectrum of Voiding Dysfunction
z Overactive Bladder SUI UUI Mixed (UUI+SUI) Urgency Frequency Nocturia This slide shows the overlap of symptoms for OAB Patients with OAB experience urgency with or without urge incontinence (in fact, only 30% of people with OAB have urge incontinence) Frequency and nocturia are usually associated with urgency; however; these symptoms occurring individually do not constitute a diagnosis of OAB Some women may experience mixed symptoms of stress incontinence and OAB; stress symptoms often resolve with OAB therapy

Prevalence of OAB in adults 40 years of age
OAB Affects 11% to 22% of Adults Older Than 40 Years of Age in Europe, Asia, and the United States Prevalence of OAB in adults 40 years of age Male Female 25 20 15 Prevalence (%) 10 Why should physicians care about OAB? There are several compelling reasons. More patients have OAB than you realize. Overall, 1 out of 6 adults over 40 years of age in Europe has OAB. In France, Germany, Italy, Spain, Sweden, the United Kingdom, Japan, and the United States, the prevalence of OAB ranges from 11% to 22%. 5 France Germany Italy Spain Sweden UK Japan USA Country Milsom I et al. BJU Int. 2001;87: Stewart WF et al. World J Urol. 2003;20: Homma Y et al. ICS Abstract 2003. Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87: Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20: Homma Y, Yamaguchi O, Hayashi K, et al. Nation-wide epidemiologic survey on lower urinary tract symptoms in Japan. Presented at: Annual Meeting of the International Continence Society; October 5-9, 2003; Florence, Italy.

Prevalence of OAB by Age and Gender
Men: 2.4% (Incontinent) 25 Women: 9.3% (Incontinent) Men: 13.6% (Continent) 20 Women: 7.6% (Continent) 15 Prevalence (%) 10 5 <25 25-34 35-44 45-54 55-64 65+ Age (years) 9 In a US national telephone survey (N = 5,204). Stewart WF et al. World J Urol. 2003;20:

Incidence Underreported
“Tip of the iceberg” Increasing incidence in an aging population

Incontinence - Underreported
Less than half with bladder control problems report it to their health care provider WHY? Embarrassment Low expectation for therapy “Normal” part of aging Availability of absorbent products/pads

Impact of Urinary Incontinence on Quality of Life
Physical Limitations or cessation of physical activities Psychological Guilt/depression Loss of self-respect and dignity Fear of: being a burden lack of bladder control urine odor Apathy/denial Sexual Avoidance of sexual contact and intimacy Quality of Life Occupational Absence from work Decreased productivity Psychological—People with OAB often feel guilty about their symptoms, and some become depressed. The embarrassment of leaking or smelling of urine leads to a loss of self-respect and dignity. Social—Overactive bladder sufferers might restrict social activity outside the home for fear of leaking urine or because of the frequent need to use a toilet. Domestic—Some individuals with OAB use disposable pads on the bed during the night or undergarments for incontinence. These items can be costly and are not covered by medical insurance. Occupational—Overactive bladder may lead to decreased productivity in the workplace. Some patients may avoid going to work for fear of leaking urine. Sexual—Women with overactive bladder have reported avoiding dating and sexual intimacy because of overactive bladder symptoms and fear of leaking urine. Physical—Some physical activities like exercising might be limited because of the frequent need to urinate or fear of leaking urine. Social Reduction in social interaction Alteration of travel plans Increased risk of institutionalization of frail older persons Domestic Requirements for specialized underwear, bedding Special precautions with clothing

Falls and Fractures In women over 65 years...
OAB, falls, and fractures are common 19–42% sustain falls Fractures occur in 4–9% of falls Hip fractures associated with a high rate of morbidity and mortality Women with urge incontinence have an increased diurnal and nocturnal voiding Urge incontinence urgency to rush to bathroom Inability of older women to divide attention. Brown, JAGS 48:

Distribution of Disease Among Women Seeking Care for Pelvic Floor Disorders (N = 602)
Urgency/detrusor instability SUI/GSI 90 Pelvic organ prolapse 82 80 Intrinsic sphincter deficiency 77 72 70 67 65 66 65 60 58 56 52 50 51 50 Women Affected (%) 43 40 35 33 34 31 30 30 The reasons women seek care for symptoms of pelvic floor disorders vary by age. According to a study within the Kaiser Permanente Health Care program in Southern California, which evaluated the reasons for pelvic floor disorders among 2070 women seeking care, stress urinary incontinence (SUI) was significantly more common among younger women than older women (78% vs 57%, respectively; P  .05). Detrusor instability urge urinary incontinence (UUI) was more common among older vs younger women (67% vs 56%, respectively; P < .05), as was intrinsic sphincter deficiency (5.7% vs 0%, respectively; P < .05). Symptomatic pelvic organ prolapse occurred with equal frequency in older and younger women. Luber KM, Boero S, Choe JY. The demographics of pelvic floor disorders: current observations and future projections. Am J Obstet Gynecol. 2001;184: 20 10 9 5 6 2 30-39 40-49 50-59 60-69 70-79 80-89 Age Range (Years) GSI = genuine stress incontinence. Luber KM, et al. Am J Obstet Gynecol. 2001;184:

Diagnosis of Overactive Bladder
Most cases of overactive bladder can be diagnosed based on: patient history, symptom assessment physical examination urinalysis Initiation of noninvasive treatment does not require an extensive further workup In most cases, a diagnosis of OAB can be made based on patient history, symptoms assessment, physical examination , and urinalysis These assessments are usually sufficient to initiate noninvasive therapy provided you have ruled out the following: Local pathological factors such as infection, bladder stones, bladder tumor/CIS, interstitial cystitis Metabolic factors such as diabetes or polydipsia Medications that may cause OAB symptoms such as diuretics, narcotics, antidepressants, hypnotics, analgesics, sedatives, OTC sleep aids and cold remedies Other factors such as pregnancy or psychologic issues Reasons to refer to a specialist include: Evidence of difficulty in emptying Recurrent urinary tract infection Hematuria Prostate problems Symptomatic prolapse Unsuccessful prior treatment Unsuccessful prior surgery Planned surgery Radical pelvic surgery

Routine Screening Questions to Consider
Do you frequently limit your fluid intake or map out restrooms when you are away from home? Do you urinate more than 8 times in a 24-hour period? Do you frequently get up 2 or more times at night to go to the bathroom? Do you have uncontrollable urges to urinate, resulting in wetting accidents? Do you use pads to protect your clothes? Are you bothered or concerned about bladder control? The challenge rests with primary care physicians to dispel the fears and misconceptions that keep many patients, especially female patients, from seeking treatment for bladder symptoms. Physicians can detect urinary symptoms in reluctant patients during routine medical examination. Additionally, simple questions (such as those listed on the slide) can be used to elicit information needed for diagnosis.

History How long? How old when started?
How much (volume)? Degree of bother? Characteristics of leakage? Activity related? Day and night, wet pads at night = instability Urgency? Suppressible = probably SUI not suppressible (urge incontinence) = instability Other: fluid intake, UTI’s, pain, hematuria, LE swelling, medications

Medications Influencing LUT Function
Effect Medication Class Alcohol Polyuria, frequency, urgency α-Receptor agonists Urethral constriction and urinary retention (males) α-Receptor antagonists Urethral relaxation ACE inhibitors Cough → SUI Anticholinergics Urinary retention, overflow incontinence, fecal impaction Antidepressants, tricyclic Anticholinergic effect, α-receptor antagonist effect This slide and the next list classes of medications that have been shown to influence LUT function.

Medications Influencing LUT Function (cont)
Medication Class Effect β-Receptor antagonists Urinary retention Calcium channel blockers Urinary retention, fecal impaction Opioids Sedative-hypnotics Sedation, delirium, muscle relaxation Diuretics Polyuria, frequency, urgency Methylxanthines Polyuria, bladder irritation Neuroleptics Anticholinergic effect, sedation

Physical Examination Abdomen Pelvis/perineum Rectal:
Masses: palpable bladder, etc. Pelvis/perineum External genitalia: atrophic vaginitis vaginal Prolapse (assoc. 50% of SUI patients) GYN malignancy, fistula Rectal: tone, masses, teach Kegels during exam prostate Neurological (reflexes, LE’s, sensory, motor)

Conditions Associated With
Physical Examination Rule out possible causes of LUTS Atrophic vaginitis Estrogen deficiency Pelvic floor dysfunction Pelvic organ prolapse Potentially serious pathologic conditions Signs of Hypoestrogenation Conditions Associated With Vaginal Relaxation Prominent caruncle In women, a physical examination can rule out several possible causes of LUTS, including Atrophic vaginitis Estrogen deficiency Pelvic floor dysfunction Prolapse Potentially serious pathologic conditions, such as malignancy Patients with prolapse or other potentially serious conditions should be referred to the appropriate specialist for further evaluation. Cystocele Rectocele Enterocele Uterine prolapse Agglutination of labia minora

Laboratory Tests Urinalysis Appropriate blood work Dipstick Culture
Microscopic examination Look for hematuria, pyuria, bacteriuria, glucosuria, proteinuria Appropriate blood work Glucose Electrolytes Prostate specific antigen (PSA) in men Urinalysis is an essential component of the patient workup and is used to rule out conditions that may be responsible for LUTS. Laboratory testing on blood is also essential. A prostate-specific antigen test should be administered to adequately informed men older than 50 years of age in accordance with the American Urological Association guidelines. Fantl JA, et al. Urinary incontinence in adults: acute and chronic management. Rockville, MD: US Department of Health and Human Services, Agency for Healthcare Policy and Research; AHCPR publication Fantl JA, et al. Agency for Healthcare Policy and Research; 1996. AHCPR publication

Laboratory Tests Rule out possible causes of LUTS
Urinary tract infection (UTI) or sexually transmitted disease (STD) Diabetes mellitus LUT tumor or kidney stones Potentially serious pathologic conditions Specifically, the appropriate laboratory tests should rule out urinary tract infection, sexually transmitted diseases, diabetes, renal disease (including kidney stones), and more serious conditions, such as malignancies. Patients with tumors, kidney stones, or other potentially serious conditions should be referred to the appropriate specialist for further evaluation. Refer to appropriate specialist.

Stress Incontinence, Overactive Bladder, and Mixed Symptoms

Distribution of Urinary Incontinence by Type: United States
Total estimated number of people with urinary incontinence: 17.5 million* Urge 6.9 million Stress 5.1 million Mixed 5.5 million Recent data from the NOBLE Program revealed the prevalence of OAB in the United States. A total of 5.1 million people with incontinence have SUI, 6.9 million have UUI, and 5.5 million have MUI (both SUI and UUI). Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20: *Based on 2000 US Census. Adapted from Stewart WF, et al. World J Urol. 2003;20:

Differentiating OAB With Urge Incontinence From Stress Incontinence
OAB and UUI SUI OAB is associated with involuntary detrusor contractions. Detrusor instability can cause symptoms of urgency of the sudden loss of urine (UUI). Conversely, SUI can be caused by urethral hypermotility; significant displacement of the urethra and bladder neck during exertion and increased abdominal pressure; or urethral sphincter weakness, in which the bladder sphincter cannot generate enough resistance to retain urine during stress maneuvers. In women, urethral sphincter weakness can occur after trauma, hypoestrogenism, aging, or surgical procedures. Fantl JA, et al. Urinary incontinence in adults: acute and chronic management. Rockville, MD: US Department of Health and Human Services, Agency for Healthcare Policy and Research; AHCPR publication Fantl A, et al. Urinary Incontinence in Adults: Acute and Chronic Management. Clinical Practice Guidelines No. 2, 1996 Update. Rockville, MD: Agency for Health Care Policy and Research: March AHCPR publication

Medical History and Physical Examination Symptom Assessment
Differential Diagnosis: Overactive Bladder, Stress Incontinence, and Mixed Symptoms Medical History and Physical Examination Symptom Assessment Symptoms OAB SUI Mixed Symptoms Urgency (strong, sudden desire to void) Yes No Frequency with urgency (> 8 times/24 h) Leaking during physical activity (eg, coughing, sneezing, lifting) Amount of urinary leakage with each episode of incontinence Large (if present) Small Variable Ability to reach the toilet in time following an urge to void Often no Waking to pass urine at night Usually Seldom Maybe This slide demonstrates the findings that differentiate OAB from SUI and patients with mixed symptoms or MUI. Pertinent points include the following: Urgency and frequency are associated with OAB and MUI, but not with SUI SUI and MUI share symptomatology of leakage during physical activity The amount of urinary leakage typically is much greater in OAB than in SUI Patients with OAB rarely have enough time to reach a toilet compared with patients with SUI, but this varies in patients with MUI Nocturia is more closely associated with OAB than with SUI, and may be present in patients with MUI Abrams P, Wein AJ. The Overactive Bladder. A Widespread and Treatable Condition. Stockholm, Sweden: Erik Sparre Medical AB; 1998. Abrams P, Wein AJ. The Overactive Bladder—A Widespread and Treatable Condition

Mixed Incontinence is the Most Bothersome
BOTHER (Quality- of- Life Survey) OAB wet + SUI* 60 OAB wet* 50 40 SUI 30 20 The NOBLE study identified respondents with incontinence based on telephone survey responses. Further investigation (a nested case-controlled study) was conducted on respondents who reported symptoms of OAB. Respondents completed multiple questionnaires (OAB-q, the Medical Outcomes Study [MOS] Short-Form-36 [SF-36], the MOS Sleep Scale, and the Center for Epidemiological Studies—Depression [CES-D] scale) and were categorized according to the primary cause of incontinence: UUI, SUI, or MUI. One hundred seventy-one respondents reported incontinence (UUI: 69; SUI: 62, MUI: 40). Of the respondents, 82.5% were women and the average age was 55.9 years. The findings showed OAB-q subscale scores were significantly worse P < .01) among those with MUI than among those with SUI. In terms of symptom bother, MUI was reported as most bothersome, followed by UUI; respondents with SUI were bothered the least. Coyne KS, Zhou Z, Thompson C, Versi E. The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int. 2003;92: 10 OAB-q Subscale Scores *P  .05 versus SUI. Coyne KS, et al. BJU Int. 2003;92:

Treatment for Overactive Bladder
Pads Behavioral therapy Medications Neuromodulation Surgery

Behavioral Modification
Timed voiding Education/Log Behavioral Modification Pelvic floor exercises Delayed voiding Optional Slide Behavioral modification includes patient education, timed or delayed voiding, pelvic floor exercises, and reinforcement Pelvic floor exercises have been shown to be very useful for women with primarily stress incontinence Diet

Diet Modification Avoid food/beverages irritating to the bladder (coffee, caffeine, etc.) Manage fluid intake Stop evening fluids Avoid constipation

Bladder Training Modify bladder function Methods
bladder diary gradually increase void interval teach coping strategies Strengthen pelvic floor muscles and improving bladder stability Bladder Training Bladder training focuses on modifying bladder function by reviewing the bladder diary; the voiding interval should be increased gradually by to 30-minute intervals based on the voiding pattern, and the patient should be taught bladder coping strategies Bladder training is used primarily for urge incontinence, urgency, and frequency Bladder training can be very effective, but it requires ongoing commitment by the patient

Management of Overactive Bladder
Behavioral therapies1 Pharmacologic therapy Combined pharmacologic and behavioral therapy provides improved outcomes2,3 It has been shown that behavioral therapy alone can improve the symptoms of OAB However, it is often difficult to achieve high compliance with behavioral therapies, and optimal success is dependent on how intense the program is and, in many cases, also requires a high input of caregiver time Studies have shown that the best outcomes are achieved with a combination of pharmacologic and behavioral therapy 1. Mattiasson A. Urology. 2000;55(suppl 5a):12-13. 2. Mattiasson A. Neuro Urodyn. 2001;20: 3. Burgio et al. JAGS. 2000;48:

Burgio, et al 197 women with urge incontinence Modified crossover design Initially on monotherapy of either Behavioral therapy Drug therapy (oxy mg/d) Combined therapy offered after 8 weeks if not content with monotherapy alone Burgio et al. JAGS. 2000;48:

Behavioral therapy 57.5% reduction in incontinence 8 pts crossed over 88.5% reduction in incontinence when meds added (p=0.034) Medical therapy 72.7% reduction in incontinence 27 pts crossed over 84.3% reduction in incontinence when meds added (p=0.001) Conclusion: combining drug & behavioral therapy in a stepped program can produce added benefit for patients with UUI Burgio et al. JAGS. 2000;48:

Pharmacologic Therapy for the Treatment of OAB
Antimuscarinic agents are the mainstay for treating OAB OAB symptoms relieved by inhibition of involuntary bladder contractions increased bladder capacity Treatment can be limited by side effects such as dry mouth, GI effects (eg, constipation), and CNS effects Currently, antimuscarinic agents are the gold standard for the pharmacologic treatment of OAB Antimuscarinic agents inhibit involuntary bladder contractions and increase bladder capacity, thereby relieving the symptoms of OAB, including urgency, frequency, and urge urinary incontinence However, some antimuscarinic agents, particularly the older ones, are associated with typical anticholinergic side effects that may limit treatment

Muscarinic Receptor Distribution
Heart Stomach and esophagus Dyspepsia Iris/ciliary body Lacrimal gland Blurred vision Dry eyes Tachycardia Dizziness Somnolence Impaired memory and cognition CNS Salivary glands Dry mouth Colon Constipation Bladder (detrusor muscle) This is a “build” slide showing the distribution of peripheral cholinergic (ie, muscarinic) receptors throughout the body Muscarinic receptors are located in the CNS, iris and ciliary body, lachrymal gland, salivary glands, heart, gallbladder, stomach, colon, and bladder Agents that are selective for the bladder are preferable over agents that may potentially target other regions of the body Blockade of muscarinic receptors outside the bladder may result in undesired side effects such as dry mouth (the most common side effect), constipation, and CNS side effects (such as dizziness, somnolence, and cognitive impairment), and effects on the stomach and eyes Abrams P, Wein AJ. The Overactive Bladder— A Widespread and Treatable Condition

Ideal Muscarinic Receptor Antagonist
Efficacious inhibits involuntary bladder contractions does not adversely affect volitional detrusor activity Organ selective preferentially affects the bladder over other organs results in minimal side effects and improved tolerability Durable effects improves compliance and/or persistency Provides clinical effectiveness the optimal balance of efficacy, tolerability, and compliance/persistency In broad terms, the ideal muscarinic agent would provide efficacy by inhibiting involuntary bladder contractions, while having no adverse effect on normal bladder contractions be selective for the bladder over other organs innervated by the parasympathetic system have durable effects, ie, have effects that do not diminish over time Clinically, the ideal agent would provide a balance between efficacy, tolerability, and compliance (persistency); together, these factors comprise “clinical effectiveness”

Anticholinergics A Delicate Balance
Efficacy Less frequency Less UUI Increased voided volume Adverse effects Dry mouth Constipation CNS

Antimuscarinic Agents
Oxybutynin (immediate-release and extended release) Propiverine Tolterodine (immediate-release and extended release) Oxybutynin transdermal delivery system Darifenacin Solifenacin Trospium

Tolterodine SR Registration Trial
Van Kerrebroeck P et al. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:

Registration Trial: Van Kerrebroeck et al
Detrol® LA (tolterodine tartrate extended release capsules) Tolterodine SR in the Treatment of OAB: Study Design and Inclusion Criteria Registration Trial: Van Kerrebroeck et al Multicenter (167 sites across North America, Europe, Australia, and New Zealand), randomized, double-blind, active- and placebo-controlled trial in adult patients with symptoms of OAB Adult patients aged 18 or older with symptoms of OAB for >6 months Symptoms of urinary frequency (average of >8 micturitions/24 h) and urge incontinence (>5 incontinence episodes/wk) The inclusion criteria consisted of age and OAB symptomatology requirements. Prior therapy was not considered. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: Van Kerrebroeck P et al. Urology. 2001;57:

Detrol® LA (tolterodine tartrate extended release capsules)
Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Reduction in Incontinence Episodes Registration Trial: Van Kerrebroeck et al Tolterodine SR Tolterodine Placebo –10 –20 –30 Median Change From Baseline (%) –40 –33% –50 *P < 0.01 vs placebo Patients were randomized 1:1:1 to receive double-blind Detrol®, 2 mg twice daily; Detrol® LA, 4 mg once daily; or placebo for 12 weeks. This slide shows the reduction in incontinence episodes after 12 weeks of therapy. Reductions with both Detrol® treatments were significantly greater than with placebo, with Detrol® LA being of significantly greater magnitude than Detrol®. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: This slide to be used in conjunction with the following slide –60 †P < 0.05 vs tolterodine * –60% –70 *† –80 –71% Van Kerrebroeck P et al. Urology. 2001;57:

Detrol® LA (tolterodine tartrate extended release capsules)
Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Reduction in Total Micturitions/24 Hours Registration Trial: Van Kerrebroeck et al Tolterodine SR Tolterodine Placebo –5 –10 Mean Change From Baseline (%) –15 –15% Urinary frequency also was reduced 22% to 25% with both Detrol® formulations, which was significantly greater than with placebo, but there was no significant difference between active treatments. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: *P < vs placebo –20 * –25 * –22% –25% –30 Van Kerrebroeck P et al. Urology. 2001;57:

Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Increase in Mean Volume Voided/Micturition Registration Trial: Van Kerrebroeck et al 30 24% * 25 21% * 20 Change From Baseline (%) 15 10% 10 The mean volume voided also increased significantly with both Detrol® treatments compared with placebo. The difference between active treatments was not significant. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: 5 Tolterodine SR Tolterodine Placebo *P = vs placebo. Van Kerrebroeck P et al. Urology. 2001;57:

Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Reduction in Incontinence Pad Usage Registration Trial: Van Kerrebroeck et al Tolterodine SR Placebo Tolterodine –5 –10 –15 –13% Change From Baseline (%) –20 –25 Incontinence pad usage was reduced 36% with Detrol® LA and Detrol® compared with a 13% reduction with placebo. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: This slide to be used in conjunction with the following slide –30 –35 * * –40 –36% –36% *P < 0.02 vs placebo. Van Kerrebroeck P et al. Urology. 2001;57:

Tolterodine SR in the Treatment of OAB: Incidence of Dry Mouth
Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Incidence of Dry Mouth Registration Trial: Van Kerrebroeck et al The incidence of any dry mouth was: Tolterodine– 30% Tolterodine SR – 23% The rate of dry mouth with tolterodine SR was significantly less than that with tolterodine (P < 0.02) 60 50 *P < 0.02 vs Detrol® 40 30% Patients (%) 30 23%* 20 Detrol® LA was better tolerated than Detrol®. Dry mouth was the most commonly reported side effect for each treatment. Detrol® LA produced a significant 23% reduction in dry mouth in patients compared with Detrol®. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: 8% 10 Tolterodine SR Tolterodine Placebo Van Kerrebroeck P et al. Urology. 2001;57:

Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Incidence of Common Adverse Events Registration Trial: Van Kerrebroeck et al 20 Placebo 18 Tolterodine SR 16 Tolterodine 14 12 Patients (%) 10 8 6.8% 6.3% 5.9% 6 4.3% 4.6% 3.7% This slide shows the incidences of other common anticholinergic adverse events. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: 4 2.8% 2.6% 1.8% 2 Constipation Headache Somnolence Van Kerrebroeck P et al. Urology. 2001;57:

Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Withdrawals Due to Adverse Events Registration Trial: Van Kerrebroeck et al Placebo Tolterodine SR 100 90 Tolterodine 80 70 60 Patients (%) 50 40 The percentage of patients who withdrew from the study early because of adverse events was similar among treatment groups and comparable with placebo. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: This slide to be used in conjunction with the following slide 30 20 5% 5% 6% 10 Withdrawal Van Kerrebroeck P et al. Urology. 2001;57:

Tolterodine SR in the Treatment of OAB: Study Conclusions
Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR in the Treatment of OAB: Study Conclusions Registration Trial: Van Kerrebroeck et al A 12-week multinational study comparing tolterodine SR 4 mg once daily, and tolterodine 2 mg twice daily with placebo in 1,529 patients Compared with placebo, tolterodine SR and tolterodine were significantly more effective in improving: Incontinence episodes/week Total micturitions/24 hours Mean volume voided/micturition Incontinence pad usage/24 hours The registration trial was a 12-week multinational study comparing Detrol® LA 4 mg once daily, and Detrol® 2 mg twice daily, with placebo in 1,529 patients. Compared with placebo, Detrol® LA and Detrol® were significantly more effective in improving: Incontinence episodes/week Total micturitions/24 hours Mean volume voided/micturition Incontinence pad usage/24 hours For the primary efficacy parameter, Detrol® LA was also shown to provide significantly greater improvement compared with Detrol®. In addition, both active treatment groups were associated with positive tolerability and safety profiles. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: Van Kerrebroeck P et al. Urology. 2001;57: Key Messages: Detrol® LA was efficacious in improving all symptoms of OAB Detrol® LA exhibited a positive tolerability and safety profile Detrol® LA was shown to produce significantly better improvements in efficacy and tolerability compared with Detrol®

007 Registration Trial: 12-Month Extension
Kreder K et al. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41:

007 Registration Trial 12-Month Extension: Kreder et al
Detrol® LA (tolterodine tartrate extended release capsules) Study Design 007 Registration Trial 12-Month Extension: Kreder et al 12-Month open-label, uncontrolled, nonrandomized extension (N = 1,337) 759 patients completed 12-month extension Eligibility Those who completed the 12-week double-blind phase Primary end point Safety and tolerability of tolterodine SR 4 mg qd Secondary end points Efficacy Persistency After completion of the phase 3, double-blind, randomized trial of Detrol® LA, a 12-month open-label extension was performed. This extension was not controlled or randomized. The 1,337 patients who completed the 12-week double-blind phase of the trial were eligible to participate in the open-label extension. Of these patients, 1,077 chose to continue tolterodine treatment; 759 completed the 12-month extension. The primary end point was safety and tolerability of Detrol® LA, 4 mg qd, and secondary end points were efficacy and persistency. The majority of the participants were women (82.3%), and the mean age was 60.3 years. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41: Kreder K et al. Eur Urol. 2002;41:

Tolterodine SR: Efficacy Maintained Through 12 Months of Treatment
Detrol® LA (tolterodine tartrate extended release capsules) Detrol® (tolterodine tartrate tablets) Tolterodine SR: Efficacy Maintained Through 12 Months of Treatment 12-Month Extension: Kreder et al 40 25 25.4 20 Urge Incontinence Episodes/Week Micturitions/Week –80 –83.1 –21.3 Volume Voided/ Micturition –20 –18.8 Median Change From Baseline (%) –40 Of the 1,077 patients who chose to remain on Detrol® LA, 1,075 received treatment and were included in the safety population. Of these patients, 759 completed the 12-month extension. Diary data reported indicate that patients who remained on Detrol® LA maintained the level of efficacy achieved at 12 weeks through 1 year of treatment. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41: –60 12 Weeks 12 Months –80 –100 Kreder K et al. Eur Urol. 2002;41:

12-Month Extension: Kreder et al
Detrol® LA (tolterodine tartrate extended release capsules) Tolterodine SR: Exhibited Positive Long-term Safety and Tolerability Profile 12-Month Extension: Kreder et al Adverse Event Patients (%)* Dry mouth 12.9% Constipation 3.3% Headache 2.4% Somnolence 1.0% Dizziness 1.2% The low percentage of adverse events associated with Detrol® LA treatment at 12 weeks was maintained throughout the12-month open- label study. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41: *Incidence of adverse events with onset during the 12-month open-label study period. Kreder K et al. Eur Urol. 2002;41:

12-Month Extension: Kreder et al
Detrol® LA (tolterodine tartrate extended release capsules) Conclusions 12-Month Extension: Kreder et al Efficacy of tolterodine SR was maintained for at least 1 year with continued treatment Improvements from baseline in all micturition variables comparable to those observed in the 12-week double-blind phase Long-term treatment with tolterodine SR was well tolerated 71% of patients completed 12 months of therapy The 12-month open-label extension of the phase 3 trial of Detrol® LA showed that treatment was well tolerated. Efficacy was maintained for at least 1 year with continued Detrol® LA treatment. Improvements from baseline in all micturition variables were comparable to those observed at the completion of the 12-week double-blind phase. Seventy-one percent of patients entering the long-term, open-label phase of the pivotal trial were still on Detrol® LA at 12 months. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41: Kreder K et al. Eur Urol. 2002;41:

Speed of Onset Therapeutic Assessment Trial
STAT Speed of Onset Therapeutic Assessment Trial

Questions How rapidly does medication work?
Does effectiveness increase over time? Is there a difference between patients naïve and non-naïve to prior anticholinergic therapy?

Patients 1138 patients Minimum age of 18 years (range 19-91)
302 men, 836 women 735 naïve, 403 non-naïve Minimum age of 18 years (range 19-91) Diagnosis of OAB Frequency (>8 voids/24 hours) Urgency With or without urge incontinence 911 patients (79.4%) completed the study

Methods Prospective Multicenter 12-weeks duration
Efficacy assessed at 1, 4 & 12 weeks using Micturition diary Patient perception of improvement Physician perception of improvement

Medication Treated with tolterodine extended-release (ER)
4 mg daily for 12 weeks If previously on anticholinergics then had 7-day washout

Reduction in Urge Incontinence Episodes Over Time
Week 1 4 12 –0 –10 Naïve patients –20 Experienced patients –30 Median % Change from Baseline –40 –50 This slide shows the reduction in urge incontinence episodes for naïve and experienced patients at each time point (week 1, week 4, and week 12) There is a substantial reduction from baseline in urge incontinence episodes after only 1 week of treatment in both groups, with further reductions observed at weeks 4 and 12 The reduction in urge incontinence was rapid and significant, and showed a continued benefit over time. These swift results encourage patients to remain on therapy. Median percent reduction from baseline 1 week 4 weeks 12 weeks Naïve patients Experienced patients –60 –70 –80 –90 Intent-to-treat analysis Siami P, et al. Clin Ther. 2002;24:

Reduction in Micturition Frequency Over Time
Week 1 4 12 –0 –5 Naïve patients Experienced patients –10 Median % Change from Baseline –15 This slide shows the reduction in micturition frequency (micturitions/24h) for naïve and experienced patients at each time point (week 1, week 4, and week 12) There is a substantial reduction from baseline in micturition frequency after only 1 week of treatment in both groups, with further reductions observed at weeks 4 and 12 Median percent reduction from baseline 1 week 4 weeks 12 weeks Naïve patients Experienced patients –20 –25 –30 Intent-to-treat analysis Siami P, et al. Clin Ther. 2002;24:

Patients Reporting Positive Treatment Benefit at 1 & 12 Weeks
Percentage of Patients and Physicians Reporting Positive Treatment Benefit at 1 Week Approximately 85% of both naïve and previously treated patients reported benefit from treatment after only 1 week Similarly, physicians independently rated the perception of treatment as beneficial in approximately 85% of patients at 1 week in naïve and experienced patients Yes/little vs. yes/lot vs. none Intent-to-treat analysis

STAT Summary Improvements in efficacy based on patients’ bladder diaries were seen at 1 week, with further improvements noted at 12 weeks Perception of treatment benefit by both patients and physicians was maintained at 12 weeks After only 1 week of treatment, ~85% of patients and physicians reported benefit from treatment half of those patients who reported no treatment benefit at 1 week reported benefit at 12 weeks This slide summarizes the results and conclusions from STAT OAB symptoms, as measured by micturition diary parameters, were improved after 1 week of treatment and showed further improvements throughout the 12-week study; these results are consistent with patient perception of treatment benefit Both patients and physicians had a high perception of treatment benefit with tolterodine ER 4 mg once daily as early as 1 week, which was maintained at 12 weeks Most patients will report treatment benefit within 1 week; those who do not will likely report benefit at 4 or 12 weeks

Efficacy and Tolerability of Tolterodine SR Versus Oxybutynin IR in Japanese and Korean Patients

Efficacy Incontinence episode/wk –78.6% –76.5% –46.4% No. voids/24 h
Change in Mean Voiding Diary End Points Tolterodine SR (n = 239) Tolterodine IR (n = 244) Placebo (n = 122) Incontinence episode/wk –78.6% –76.5% –46.4% No. voids/24 h –2.0 –2.1 –1.1 Significant reduction between treatment and placebo group No significant difference between Detrol® LA and oxybutynin IR Homma Y et al. BJU Int. 2003;92:

Treatment Withdrawal Withdrawals due to dry mouth
Total 102 withdrawals (n = 605) Dry mouth accounted for 9.4% of withdrawals in oxybutynin IR and 0.4% in tolterodine SR Withdrawals due to dry mouth 25 20 15 Patients Discontinued, % Higher incidence of withdrawals reported for oxybutynin IR. This was explained by the higher frequency of withdrawals for adverse events with oxybutynin than with placebo or tolterodine. Other reasons for withdrawal were similar between treatment groups: - lack of efficacy (tolterodine 1.3%, oxybutynin 1.6%, placebo 3.3%) - consent withdrawn - loss to follow-up - protocol violation 10 5 Tolterodine SR Oxybutynin IR Placebo Homma Y et al. BJU Int. 2003;92:

Japanese and Korean Study: Conclusions
Tolterodine SR has similar efficacy but is better tolerated than oxybutynin IR in Japanese and Korean patients with OAB Improved tolerability of tolterodine SR resulted in fewer discontinuations of therapy compared with oxybutynin IR Homma Y et al. BJU Int. 2003;92:

Mixed Incontinence Effectiveness Research Investigating Tolterodine
MERIT Mixed Incontinence Effectiveness Research Investigating Tolterodine

Effect of Tolterodine on Urge-Predominant Mixed Incontinence Episodes
Week 1 8 Tolterodine ER 4 mg qd –10 Placebo –20 –30 Median Change From Baseline (%) –40 –50.5% * –50 Compared with placebo, tolterodine ER significantly reduced the median number of mixed incontinence episodes at weeks 1 and 8 (primary endpoint). This reduction was significantly greater than the reduction with placebo as early as 1 week. Further reductions were apparent at 8 weeks. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology. 2004;64: –60 –77.2% –70 *P < .01 * –80 Intent-to-treat analysis. Khullar V, et al. Urology. 2004;64:

MERIT: Additional Efficacy Endpoints at Week 8
Endpoint Change from baseline, (%) Tolterodine ER 4 mg Placebo P-value Urinary frequency/24h –20.0 –13.8 < .0001 Urgency episodes/24h –37.2 –19.2 Volume voided/micturition +20.5 +9.0 Tolterodine therapy also improved other micturition variables compared with placebo; this included significant reductions in the median change from baseline in urinary frequency episodes per day and urgency episodes per day. Volume voided per micturition significantly increased in tolterodine-treated patients compared with those receiving placebo. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology. 2004;64: Intent-to-treat analysis. Khullar V, et al. Urology. 2004;64:

Patient Assessment of Treatment Benefit After 1 and 8 Weeks
Tolterodine SR 4 mg qd * Placebo 76% 80 70% 70 64% 60 55% 50 % Improved 40 30 This slide shows the percentage of subjects in both groups reporting treatment benefit at 1 and 8 weeks. At week 8, the percentage of subjects reporting treatment benefit was statistically significantly higher in the tolterodine group compared with the placebo group. Note that the percentage of subjects reporting treatment benefit increased from week 1 to week 8 in the tolterodine group (from 70% to 76%), whereas in the placebo group, the percentage of subjects reporting treatment benefit decreased from week 1 to week 8 (from 64% to 55%). Perception of bladder condition and response to treatment were assessed at baseline after 1 and 8 weeks. Patients rated their bladder condition severity using a validated 6-point rating scale (1 = no problems, 2 = very minor problems, 3 = minor problems, 4 = moderate problems, 5 = severe problems, and 6 = many severe problems). Improvement was defined as a decrease of 1 point or more from baseline. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology. 2004;64: *P < .001 20 10 Week 1 Week 8 Intent-to-treat analysis. Khullar V, et al. Urology. 2004;64:

MERIT: Tolerability Tolterodine SR 4 mg Placebo Adverse events 39% 34%
Withdrawal due to adverse events 4.6% 5.6% Dry mouth 19.7% 8.1% Tolterodine was tolerated well and involved fewer withdrawals because of adverse events than placebo. Adverse events were similar between the tolterodine group and the placebo group. The most common adverse event in each treatment group was dry mouth. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology. 2004;64: Khullar V, et al. Urology. 2004;64:

Median Decrease in Incontinence Episodes
Tolterodine: Comparable Efficacy in Urge Predominant Mixed and Urge Incontinence MUI (n = 239) UUI (n = 755) –10 –20 –30 Median Decrease in Incontinence Episodes –40 –50 Compared with baseline, statistically significant reductions in incontinence episodes were observed in patients with MUI or UUI treated with tolterodine. There was no significant difference in tolterodine efficacy in patients with MUI compared with UUI. Kreder KJ, Brubaker L, Mainprize T. Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone. BJU Int. 2003;92: –60 –70 67 –80 75 P = NS Kreder K, et al. BJU Int. 2003;92:

Tolterodine in the Treatment of MUI and UUI: Summary of Results
Pad usage* (%) –40 –50 No pad usage (%) 21 27 Voiding frequency/24 h* (%) –15 –17 < 8 voids/24 h 24 Volume voided* (mL) Nocturia* (%) –33 < 2 episodes nocturia (%) 83 76 Total dryness (%) 39 44 Similarly, with all other voiding diary variables, the differences from baseline were significantly improved with tolterodine, but there was no difference in tolterodine efficacy between patients with MUI or UUI. Therefore, tolterodine was equally efficacious in patients with UUI or MUI. Kreder KJ, Brubaker L, Mainprize T. Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone. BMJ Int. 2003;92: *Significant difference versus baseline, but not between MUI and UUI groups Kreder K, et al. BJU Int. 2003;92:

Tolerability: Clinical Trial Continuation Rates With Tolterodine SR
Clinical Study Study Duration, wk No. Patients Patient Continuation Rate, % Registration Trial 12 507 95 Kreder K et al 52 1077 71 STAT 1138 80 MERIT 8 569 92 Studies indicate that patients taking Detrusitol® SR are likely to continue taking it. The longest Detrusitol SR has been studied was in a 1-year open-label continuation study. In this study, 71% of patients were still taking Detrusitol SR at 1 year. Van Kerrebroeck P et al. Urology. 2001;57: Siami P et al. Clin Ther. 2002;24: Khullar V et al. Urology. 2004;64: Kreder K et al. Eur Urol. 2002;41: Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: Siami P, Seidman LS, Lama D. A multicenter, prospective, open-label study of tolterodine extended-release 4 mg for overactive bladder: the Speed of Onset of Therapeutic Assessment Trial (STAT). Clin Ther. 2002;24: Khullar V, Hill S, Laval K-U, Schiøtz HA, Jonas U, Versi E. Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology. 2004; 64: Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41:

Tolerability: Incidence of Adverse Events* With Tolterodine SR
Body System Adverse Event Placebo, % (n = 507) Tolterodine SR, % (n = 505) Autonomic nervous Dry mouth 8 23 General Headache 5 6 Fatigue 1 2 Central/Peripheral nervous Dizziness Gastrointestinal Constipation 4 Abdominal pain Dyspepsia 3 Vision Xerophthalmia Vision abnormal Psychiatric Somnolence Respiratory Sinusitis Urinary Dysuria As noted in the registration trial, except for dry mouth, adverse events—including those representing other anticholinergic effects—were similar between Detrusitol® SR and placebo. There was no difference from placebo in reported events such as dizziness, constipation, or abnormal vision. In a 6-year safety review, Detrusitol SR had no known association with cardiac events. *Reported by ≥5% of patients in any treatment group or relevant to antimuscarinic therapy during 12 weeks of treatment. Van Kerrebroeck P et al. Urology. 2001;57: Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: Garely AD, Burrows L. Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults. Drug Saf. 2004;27:

Summary OAB is a highly prevalent condition
As our population ages, rates will increase OAB has a large impact on our patient’s quality of life Tolterodine SR is an effective therapy shown to significantly reduce incontinence episodes, reduce urgency and frequency, increase void volume, and reduce pad usage The efficacy of tolterodine SR can be seen as early as 1 week and the effect is maintained with long-term therapy Patients perceive benefit with therapy and improvements in quality of life have been demonstrated

Pharmacotherapy for Overactive Bladder Rationale for Treatment Choice

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Pharmacotherapy for Overactive Bladder Rationale for Treatment Choice

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