Case Consults in Overactive Bladder: An Individualized Approach to Management 12:45 p.m. 2:00 p.m. December 2, 2008 Atlanta, GA

Transcription

1 Case Consults in Overactive Bladder: An Individualized Approach to Management 12:45 p.m. 2:00 p.m. December 2, 2008 Atlanta, GA Education Partner:

2 Session 4: Case Consults in Overactive Bladder: An Individualized Approach to Management Learning Objectives Differentiate available agents for the treatment of OAB based on pharmacologic and pharmacokinetic characteristics and the impact these characteristics have on efficacy, safety and tolerability. Implement a treatment plan for OAB that balances efficacy, safety and tolerability to improve treatment persistence and quality-of-life. Faculty Mikel L. Gray, PhD, CUNP, CCCN, FAANP, FAAN Nurse Practitioner Professor, Department of Urology University of Virginia Charlottesville, Virginia Dr Gray is a nurse practitioner and professor in the Department of Urology and School of Nursing at the University of Virginia in Charlottesville. Dr Gray earned his master s degree as a pediatric nurse practitioner from the University of Virginia in 1981, and certificate as a family nurse practitioner in He earned a PhD in lower urinary tract physiology from the University of Florida, in Dr Gray is licensed as a family and pediatric nurse practitioner and holds additional certification as a urologic nurse practitioner. He is editor-in-chief of the Journal of Wound, Ostomy and Continence Nursing and a board member of the Wound, Ostomy and Continence Nurses Society s Center for Clinical Investigation. He has lectured both nationally and internationally on topics related to urologic nursing, wound, ostomy and continence nursing and evidence based practice. A fellow in the American Academy of Nursing, Dr Gray is past president of both the Society of Urologic Nurses and Associates, and Certification Board for Urologic Nurses and Associates. He has received awards for contributions to urologic nursing and to wound, ostomy, and continence nursing and was named as the National Association for Continence Continence Care Champion for WOCN in Gregory T. Bales, MD Associate Professor of Surgery/Urology Director of Female, Reconstrucive and Neurourology University of Chicago Hospitals Chicago, Illinois Dr Bales received his BA degree from Cornell University and his MD degree from Tufts University School of Medicine. He completed his surgery and urology residency at the University of Chicago. Following a fellowship in female and reconstructive urology at the University of Wales in 1996, he joined The University of Chicago Hospital as an Assistant Professor of Surgery/Urology. Dr Bales main areas of interest are reconstructive urology and surgical interventions for male and female incontinence as well as pelvic prolapse. He is an expert in pubovaginal sling surgery for female stress incontinence and artificial urinary sphincters for post-prostatectomy male incontinence. He also specializes in surgery for urethral stricture disease. Dr Bales is the author or co-author of numerous publications on various aspects of urology. Session 4

3 Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Gray has no relationships to disclose. Dr Bales has no relationships to disclose. Content Collaborator Financial Disclosure Statements The content collaborators at Strategic Consultants International have reported the following: Alison L. Howe, managing director; Sarah H. Diffen, associate project director; and Carol Richardson, senior account assistant, have nothing to disclose Drug List Generic botulinum toxin A darifenacin oxybutynin solifenacin tolterodine trospium chloride Trade Botox Enablex Ditropan, Oxytrol VESIcare Detrol Sanctura Suggested Reading List 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(5): Dmochowski RR, Newman DK. Impact of overactive bladder on women in the United States: results of a national survey. Curr Med Res Opin. 2007;23: Klausner AP, Steers WD. Antimuscarinics for the treatment of overactive bladder: a review of central nervous system effects. Curr Urol Rep. 2007;8(6): Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol. 2005;173(2): Marschall-Kehrel D, Roberts RG, Brubaker L. Patient-reported outcomes in overactive bladder: the influence of perception of condition and expectation for treatment benefit. Urology. 2006;68(2 suppl): Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10): Rosenberg MT, Dmochowski RR. Overactive bladder: evaluation and management in primary care. Cleve Clin J Med. 2005;72: 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. Staskin DR. Overactive bladder in the elderly: a guide to pharmacological management. Drugs Aging. 2005;22(12): Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20: Session 4

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5 Case Consults in Overactive Bladder: An Individualized Approach to Management 2 What is Overactive Bladder? Mikel Gray, PhD Professor, Department of Urology University of Virginia Charlottesville, VA 3 4 What is Overactive Bladder (OAB)?...with or without Incontinence OAB is defined as Urgency......usually with Frequency...and Nocturia No infection present or other obvious pathology Abrams P et al. Neurourol Urodyn. 2002;21: Wein AJ et al. Urology. 2002; 60(suppl 5A):7-12 Innervation of the Lower Urinary Tract T11 T12 L1 L2 S2 S3 S4 Spinal cord Sympathetic nerves Parasympathetic nerves Internal sphincter Cholinergic receptors Beta-adrenergic receptors Detrusor muscle Alfa-adrenergic receptors Pelvic floor musculature Somatic (pudendal) External Urethra nerve sphincter Adapted from Chutka DS, et al. Mayo Clin Proc 1996;7: OAB and Common Urinary Disorders Stress incontinence OAB Urinary urge incontinence Urgency Frequency Nocturia Mixed incontinence Adapted from Wein AJ. Am J Manag Care 2000; 6(11 suppl):s559-s564 Urge versus Stress Incontinence Urge incontinence Overwhelming urge to void Associated with frequency and urgency Due to: Detrusor overactivity Onset: Menopause Treatment: Pharmacologic therapy to correct detrusor overactivity (antimuscarinic agents) and bladder training Holroyd-Leduc JM, et al. JAMA 2004;291(8): Groth T, et al. Minerva Med 2007;98(3): Mixed incontinence (30%) Concurrence of both of these symptoms Stress incontinence Sudden involuntary loss of urine with sudden increases in intra-abdominal pressure Associated with exertion, sneezing, coughing Due to: Increased urethral mobility and / or poor intrinsic sphincter function Onset: Reproductive years Treatment: Supplementing urethral continence mechanisms (behavior modifications, surgery) Davila GW, et al. Int J Fertil Womens Med 2004;49(3): Smith PP, et al. CMAJ 2006;175(10):

6 7 How Prevalent is OAB? 8 Prevalence of OAB with Urge Incontinence US national telephone survey (n=5204) Prevalence (%) US national telephone survey (n=5204) Prevalence (%) * Age (years) The prevalence of OAB increases with age Adapted from Stewart WF, et al. World J Urol 2003;20: *p< vs men Age (years) Adapted from Stewart WF, et al. World J Urol 2003;20: Prevalence of OAB versus Other Common Disorders 10 ARS Question? Arthritic symptoms Overactive bladder Chronic sinusitis Heart disease Hay fever / allergic rhinitis Asthma Ulcer Diabetes 33 million Americans How often do you ask your patients about their urinary health? 1. Never 2. Sometimes 3. Often Chronic bronchitis Millions Actual number of patients identified and treated fall short of these figures Patient- and physician-related factors are known barriers to diagnosis and treatment Stewart WF, et al, World J Urol. 2003;20: Always Impact of OAB on Quality-of-life (QoL) Impact of OAB on QoL A US on-line survey assessed the impact of OAB on patients Incontinence is most embarrassing Can affect intimacy OAB impairs QoL Fear of leakage Both wet and dry patients Lifestyle change / coping behavior Bathroom mapping, modifying fluid intake, pad use / dark clothing * Respondents included patients currently being Respondents (%)* treated, lapsed in treatment and never treated (n=898) Adapted from Dmochowski RR, et al. Curr Med Res Opin 2007;23:

7 13 14 Cost of OAB in the US (2000) Costs estimated from the National Overactive BLadder Evaluation (NOBLE) Program Cost of OAB (Billions $) $2.8 billion $3.9 billion Diagnostic Tips: Why OAB Matters 2.5 $1.6 billion $77 million Diagnosis $827 million Indirect costs Routine care Treatment Consequences Hu TW, et al. Urology 2004; 63: Gregory T. Bales, MD Associate Professor Section of Urology University of Chicago Hospitals Chicago, IL 15 Case Scenario 1: New Patient, Long-standing Problem! 16 ARS Question? 45-year-old woman attends her PCP for a routine check up. Despite being summer she is wearing dark pants She says she feels low and very tired she asks if this is a menopause symptom How confident are you in diagnosing and effectively treating patients with overactive bladder? 1. Very confident 2. Confident 3. Not very confident 4. Not at all confident 17 ARS Question? 18 Case Scenario 1: New Patient, Long-standing Problem! Why might you suspect OAB? 1. She wakes 2 3 times during the night 2. She uses the bathroom ~12 times per day 3. She is wearing dark pants in summer 4. She is tired and low Questioning reveals that she wakes 2 3 times a night to use the bathroom; she uses the bathroom ~12 times per day Urinalysis was negative for infection Postvoid residual volume not measured Limited role in neurologically normal female 5. All of the above 3

8 19 Risk Factors for Incontinence That May Also Influence OAB 20 OAB: Medical Complications Use of diuretics and hypnotics Immobility Diabetes Fecal impaction Greater risk of... Lumbar disk disease Risk factors Stroke UTIs Depression Obesity (female) Hysterectomy, vaginal or bladder surgery Multiple vaginal deliveries Urinary tract infections Diminished cognitive status or delirium Rosenberg MT, et al. Cleve Clin J Med 2005;72: Skin infections Falls and fractures Longer hospitalization, poorer health outcomes Darkow J, et al. Pharmacotherapy 2005;25(4):511-9 Brown JS, et al. Am J Manag Care 2000;6(11 Suppl):S Complications of OAB: Falls and Fractures 22 Thoughts of Female Patients Before They Actively Sought Treatment: Results of a US National Survey Type and frequency of incontinent episodes assessed in 6049 women by questionnaire. Follow-up for falls and fractures every 4 months Increased risk in OAB patients (%) Questionnaire statements Agreed / strongly agreed (%)* I thought it was something I had to live with 64 I did not want to take medications 55 I dealt with it by wearing pads 54 I was uncomfortable / embarrassed 51 I did not feel it was enough of a problem to bother with 51 I thought I was too young to have this problem 46 I did not want anyone to know 44 The healthcare provider I saw did not ask me about OAB or urinary health 44 I was not aware anything could be done about it 32 Weekly OAB, UI, frequency and nocturia increase the risk of falls and fractures Early diagnosis and treatment has the potential to prevent / decrease falls and fractures Brown JS et al, J Am Geriatr Soc 2000;48: I was afraid the doctor might recommend surgery 27 *Respondents included patients currently being treated, lapsed in treatment, and never treated (n=685) Adapted from Dmochowski RR, et al. Curr Med Res Opin 2007;23: OAB Patients: Reasons for Seeking Treatment 24 Diagnosis of OAB: History Concerned that.....condition could get worse...leakage / urine loss is a symptom of a more serious condition...condition is not normal...others may smell odor caused by leakage / involuntary urine loss...possibility of an embarrassing accident Tygal S, et al. Urol Clin North Am 2006;33: The first complaint may not be the chief complaint What brings you here today? How are you handling your symptoms? What are the most distressing symptoms? How long have you experienced them? What have you tried to solve your problems? When asking these questions: respect the patient s situation consider a treatment plan aim for patient-centered medicine Do you use absorbent pads to keep from wetting your clothes? Effective questioning is vital Do you avoid places without a restroom? In an unfamiliar place, do you make sure you know where the restroom is? Do you go to the bathroom so often that it interferes with your activities? Do you limit fluid intake when away from home so that you don t need to worry about finding a restroom? Marschall-Kehrel D, et al. Urology 2006;68(Suppl 2A):29-37 Newman DK, et al. Am J Nurs 2002;102:

9 25 Diagnosis of OAB: Additional Probing Questions 26 Differential Diagnostics URGENCY Do you have to rush to the bathroom? Is it a sudden, intense feeling so you have to urinate immediately? FREQUENCY Do you feel that you urinate too often during the day? Do you urinate >8 times a day? Additional questions to diagnose OAB INCONTINENCE When you feel the urge to go to the bathroom, do you have leaks or wetting accidents? NOCTURIA Do you frequently get up 2 or more times during the night to urinate? Does the urge to urinate wake you? Rosenberg MT, et al. Cleve Clin J Med 2005;72: Irwin DE, et al. Eur Urol 2006;50: Newman D, et al. AJN 2002;102:36-46 Presenting symptom OAB Bladder cancer Urinary tract infection Urgency Occasionally Frequency Occasionally Urge incontinence 1/3 of cases Occasionally Occasionally Nocturia Often Rare Often Pain Occasionally Dysuria Occasionally Pyuria Rare Hematuria Usually microscopic Nitti V, et al. Int J Clin Pract. 2005;58: Uncertain diagnosis / inability to develop reasonable management plan Hematuria without infection Lack of response to conservative therapies (e.g., bladder training, pelvic muscle exercises, drug therapy) Red Flags Prostate nodule / enlargement Refer to specialist Abnormal post void residual urinal volume Neurologic condition (e.g., multiple sclerosis, spinal cord lesions) in which a component of neurogenic bladder is suspected History of pelvic surgery Severe (beyond the introitus) pelvic organ prolapse Rosenberg, et al. Cleve Clin J Med. 2007;74(Suppl. 3):S21-S29 Onset Duration Severity Bothersomeness *PSA = Prostatespecific antigen Assessment of OAB Symptoms Medical history Physical exam Laboratory Renal function Blood glucose Urinalysis Urine culture PSA* in ageappropriate men Neurological Gastrointestinal Dietary Previous surgery Obstetric Medications Neurological Pelvic Rectal Mental status Weight / BMI Abdomen Genitalia Additional / optional Voiding diary Post residual volume Cytoscopy Urodynamics Rosenberg, et al. Cleve Clin J Med. 2007;74(Suppl. 3):S21-S Medication May Worsen Symptoms of OAB Diagnosis and Treatment of OAB Sedatives Alcohol, caffeine, diuretics Anticholinergics other than antimuscarinics (e.g., antidepressants) α-agonists β-blockers Calcium channel blockers ACE inhibitors Cholinesterase inhibitors Confusion, secondary incontinence Diuresis Impair detrusor contractility Voiding difficulty Overflow incontinence Increase outlet resistance, voiding difficulty Decrease urethral closure Stress incontinence Reduce bladder smooth muscle contractility Induce cough, stress urinary incontinence Can precipitate urge incontinence Lavelle JP, et al. Am J Med 2006; 119(suppl 3A):37S-40S DeBeau EC. J Urol 2006; 175(3 pt 2):S11-S15 Gill SS, et al. Arch Intern Med 2005;165: More than half of women surveyed who discussed OAB with their PCP waited >1 year before raising the issue many attempted self-management of symptoms 85% of women had to raise the issue with their physician Only 34% of patients diagnosed with OAB receive treatment Dmochowski RR, et al. Curr Med Res Opin 2007;23:65-76 Ricci JA, et al. Clin Ther 2001;23:

10 31 32 Case Scenario 1 Continues She knows the exact location of the restrooms in your practice Often has urgency and sometimes buys pads Rarely incontinent but worries she might be Tailoring Therapy to Meet Individual Needs A diagnosis of OAB and a decision to treat is made Mikel Gray, PhD Professor, Department of Urology University of Virginia Charlottesville, VA 33? 34 ARS Question Specific Aims of Treatment What is your first-line treatment? 1. Antimuscarinic agent For urge incontinence For daytime frequency For urgency 2. Behavioral modifications bladder training 3. Kegel exercises 4. All of the above Eliminate (ideally) incontinence episodes Reduce / eliminate pad use Reduce frequency of bathroom visits Reduce impact on daily activities Improve ability to control need to void Reduce reliance on being near a bathroom Goals of therapy Abrams P, et al. Urology. 2003;61: Non-pharmacological Interventions for OAB 36 Non-pharmacological Interventions for OAB: Behavioral Modifications Bladder control training Voiding habits Bladder diaries Frequent urination leads to detrusor overactivity. The following interventions may be helpful Behavioral modification Pelvic-muscle exercises Identify, isolate, contract, relax Biofeedback Electrical stimulation Surgical procedures Sacral nerve stimulation Botulinum Toxin A Augmentation cystoplasty Borello-France D, et al. Clin Obstet Gynecol, 2004;74:70-82, Gross M, et al. Curr Urol Rep 2002;3: , Rovner ES, et al. Women s Health in Primary Care 2000;3: , Sahai A, et al. Neurourol Urodyn 2005;24:2-12 Bladder control training Learn "timed voiding (by gradually increasing length of time between trips, patients can train bladder to hold more and go less) Bladder diaries Used together incontinence is reduced in 70% female patients <75 years of age Pelvic-muscle exercises Also called Kegel exercises Improvement of urethral resistance and urinary control Primary treatment intervention for stress incontinence (SI) Patients with severe symptoms are refractory to behavioral treatment Burgio KL, J Am Acad Nurse Pract 2004; 16(10 Suppl): 4-7 Burgio KL, Urology 2002; 60(5 Suppl 1): 72-6 Burgio KL, et al. JAMA 1998; 280(23):

11 37 38 Pelvic Floor Muscle (Kegel) Exercises Non-pharmacological Therapy: Reduction of Frequency of Incontinence Episode Reducing stress urinary incontinence (20% cure, 50 70% improvement rate) Aims to prevent sudden falls in urethral pressure by a change in pelvic floor muscle morphology, position, neuromuscular function Leads to a decline in detrusor and increase in urethral pressures and suppression of the micturition reflex Involves: isolation of pelvic floor muscle contraction and elimination of co-activation strategies muscle training of the levator ani automatisation of pelvic floor muscle activity in daily life Di Benedetto, Minerva Ginecol 2004;56(4): Bo K, et al. Urology 2000;55(Suppl 5A):7-11 Shafik A, et al. World J Urol 2003;20(6): Women aged years with urge urinary incontinence or mixed incontinence with urge as predominant pattern 4 sessions (8 weeks) of biofeedback assisted behavioral treatment Oxybutynin mg tid Placebo (n=63) (n=65) (n=62) Biofeedback Oxybutynin Placebo -80 p<0.05 p< Reduction (%) p<0.001 Burgio KL, et al. JAMA 1998;280: Additive Effect of Combining Behavioral and Drug Therapies 40 Location and Role of M 1, M 2, M 3 Muscarinic Receptors Mean reduction in UI (%) 4 sessions (8 weeks) behavioral training followed by behavioral training plus drug therapy (Combined therapy) p<0.05 (n=8) Drug therapy first then behavioral therapy added (Combined therapy) p=0.001 (n=27) Behavioral therapy Drug therapy Burgio KL, et al. J Am Geriatr Soc 2000;48: M 1 M 2 Cerebral cortex Hippocampus Eyes Salivary glands Cardiac muscle Eyes Smooth muscle (bronchus) Hippocampus Hind brain Impacts: Memory, cognitive function Saliva, tear secretion Impacts: Heart rate Tear secretion Bronchodilation M 3 Smooth muscle Impacts: (bladder, bowel) Bladder contraction* Salivary glands Bowel motility Eyes Saliva, tear secretion Brain Visual accommodation *Primary mediators detrusor contractility in the bladder Abrams P, et al. Br J Pharmacol 2006;148(5): Scarpero HM, et al. Curr Urol Rep 2003; 4(6): Treatments for OAB: Antimuscarinic Agents 42 Comparison of Anticholinergic OAB Medications Oxybutynin Affinity* for muscarinic receptor subtypes Tolterodine M 1 M 2 M 3 Normally crosses BBB Structure Trospium Solifenacin Darifenacin Oxybutynin Yes Tertiary amine Tolterodine No Tertiary amine Darifenacin No Tertiary amine Solifenacin ? Tertiary amine Trospium No Quaternary amine *Binding affinity estimates (K Abrams P, et al. BJU Int 2007; 100: i in nm) Napier C, et al. Presented at 32 nd Annual Meeting of the International Continence Society Congress,

12 43 Anticholinergic Medications for OAB: Receptor Affinity 44 Treatment for OAB: Oxybutynin M 3 :M 1 selectivity Oxybutynin Non-selective (M 3 :M 1 =1.5:1) Tolterodine Non-selective (M 3 :M 1 =0.6:1) Darifenacin M 3 (M 3 :M 1 =9:1) Solifenacin Non-selective (M 3 :M 1 =2.5:1) Trospium Non-selective (M 3 :M 1 =1.5:1) Structure Metabolism Selectivity Dosing Tertiary amine Cytochrome P450, P3A4; active metabolite desethyloxybutynin Non-selective 5 mg, 10 mg, 15 mg qd (approved 30 mg qd) Napier C, et al. Neurourol Urodyn 2002; 21(4): Ikeda K, et al. Naunyn Schmiedebergs Arch Pharmacol 2002;366: Diokno AC, et al. Mayo Clin Proc 2003;78: Treatment for OAB: Oxybutynin ER 46 Treatment for OAB: Oxybutynin Transdermal System Efficacy Number of urge incontinence episodes / week Mean change from baseline Safety / tolerability (10 mg) Dry mouth: 29% Constipation: 7% Headache: 6% Blurred vision: 1% CNS adverse events: somnolence: 2% dizziness: 4% *Statistically significant difference from placebo; p value not specified Diokno AC, et al. Mayo Clin Proc 2003;78: Metabolism Dosing Safety / tolerability Active metabolite desethyloxybutynin Transdermal, twice-weekly (delivery rate 3.9 mg/d) Dry mouth: 4.1% Constipation: 3.3% Application site reactions Mild: 7.4% Moderate: 14% Severe: 5% Dmochowski RR, et al. Urology 2003;62: Treatment for OAB: Tolterodine Structure Metabolism Selectivity Dosing *Tested in guinea pig parotid gland Tertiary amine Cytochrome P450 2D6; active metabolite 5-OH-methyl derivative Non-selective, M 1, M 2 and M 3 (8x lower affinity than oxybutynin*) 2 mg, 4 mg qd Rovner ES, et al. BJU Int 2000;62(Suppl 2): Treatment for OAB: Tolterodine Efficacy: Double-blind RCT Safety / tolerability (12 weeks) (2 mg bid) Dry mouth: 35% Constipation: 7% Headache: 7% * CNS adverse events: somnolence: 3% dizziness: 5% CV adverse events: prolongation of QT interval with 2 mg bid and 4 mg bid doses Mean change from baseline RCT = randomized controlled trial *Statistically significant difference from placebo; p value not specified 8

13 49 50 Treatment for OAB: Trospium Chloride Treatment for OAB: Trospium Chloride Structure Quaternary amine Efficacy: Double-blind parallel group RCT (12 weeks) Safety / tolerability (5 mg) Metabolism Excretion Selectivity Dosing Cytochrome P450 70% cleared renally 20% excreted unchanged Non-selective ER 60mg qd ( 1 hour before meals or on empty stomach Mean change from baseline * ** Dry mouth: 20.1% Constipation: 9.6% Headache: 4.2% CV adverse events: no prolongation of QT interval with trospium RCT = randomized controlled trial *p<0.05; **p <0.001 vs placebo Treatment for OAB: Solifenacin Treatment for OAB: Solifenacin Structure Metabolism Half-life Selectivity Dosing Tertiary amine Cytochrome P4503A4; active metabolite 4R-hydroxy solifenacin hrs M 1 :M 3 selective vs M 1 5 mg, 10 mg qd Efficacy: Double-blind parallel group multicenter RCT (12 weeks) ** ** Mean change from baseline *** *** Safety / tolerability (5 mg) Dry mouth: 10.9% Constipation: 5.4% Blurred vision: 3.8% CNS adverse events: dizziness: 1.9% CV adverse events: prolongation of QT interval with 10 mg and 30 mg doses Smulders RA, et al. J Clin Pharmacol 2004;44: RCT = randomized controlled trial; **p 0.01, ***p<0.001 vs placebo Treatment for OAB: Darifenacin Treatment for OAB: Darifenacin Efficacy: Double-blind multicenter RCT (12 weeks) Safety / tolerability (7.5mg) Structure Tertiary amine Dry mouth: 20.2% Metabolism Selectivity Dosing Cytochrome P450 3A4 and 2D6 High affinity for M mg, 15 mg qd * * * * Constipation: 14.8% CNS adverse events: dizziness: 0.9% CV adverse events: no prolongation of QT interval with darifenacin Mean change from baseline RCT= randomized controlled trial; * p 0.05 vs placebo 9

14 55 Treatment for OAB: Effect of Darifenacin on Urgency Multicenter, double-blind, randomized, placebocontrolled study (n=439) 12 weeks of treatment 15 mg/day; percentage change from median baseline Urgency severity decreased by 17%** Urgency episodes decreased by 29%** Micturition frequency decreased by 15%*** **p<0.01, ***p<0.001 vs placebo (Wilcoxon test) Haab F, et al. Eur Urol 2004;45: Dosing of Treatments for OAB Once-daily dosing is preferable for compliance Darifenacin Solifenacin Tolterodine Oxybutynin Trospium chloride 7.5 mg (or 15 mg qd if required) 5 mg (or 10 mg qd if required) 4 mg qd 5 mg bid, tid, qid ER 5, 10, 15 mg qd (up to 30 mg qd) ER 60mg qd Hegde SS. Br J Pharmacol 2006;147 (Suppl 2):S ARS Question Which treatment would you prescribe for our 45-year-old woman?? Oxybutynin 2. Tolteridone Achieving Continence with Acceptable Tolerability 3. Darifenacin 4. Solifenacin 5. Trospium Gregory T. Bales, MD Associate Professor Section of Urology University of Chicago Hospitals Chicago, IL 59 Case Scenario 2: An Older Patient with Ongoing Symptoms 60 Co-morbidities in Elderly Patients with OAB 65-year-old female patient tells you during a routine BP assessment that she had an incontinence episode trying to get to the bathroom Diagnosed comorbid condition (%) OAB sufferers aged over 60 years Several years ago she was prescribed oxybutynin but seldom took them due to dry mouth n=824 McGrother CW, et al. Age Ageing 2006; 35(1): Nitti VW, Rev Urol 2002; 4 Suppl (4): S2-6 10

15 61 Tolerability of OAB Treatments 62 Contraindications of Antimuscarinic Therapy Dry mouth Side-effects of anti-cholinergics Cardiovascular effects Uncontrolled narrow-angle glaucoma Gastric retention Constipation Urinary retention Gastroesophageal reflux Blurred vision Cognitive effects Urinary retention Patients who are at risk of these Klausner AP, et al. Curr Urol Rep 2007; 8(6): Staskin DR, Drugs Aging 2005; 22(12): Hashim H, et al. Drugs 2004; 64(15): Case Scenario 2 (Cont d) 64 What are the Similarities and Differences Between OAB Treatments? After reading the prescribing information, the patient returns concerned that OAB medications cause memory loss and heart problems Her sister has Alzheimer s disease and she doesn t want to go the same way Delivery systems Pharmacokinetics and metabolism Muscarinic receptor selectivity Dosing schedules She is also concerned about her BP medications Efficacy and tolerability Product information safety warnings 65 Comparison of M 3 Selectivity of OAB Agents: Relative Binding Affinity 66 M 3 Receptor Selectivity: Advantages M 3 vs M 1 M 3 vs M 2 Maintained efficacy Less severe dry mouth M 3 is the primary functional receptor in detrusor M 1 and M 3 are evident in salivary glands; M 3 selectivity may result in lower severity than combined antagonism No effects on HR Tachycardia is related to M 2 antagonism Napier C, et al. Presented at 32 nd Annual Meeting of the International Continence Society Congress, 2002 Heading CE, Curr Opin Inves Drugs 2000;3: Fewer cognitive AEs M 1 is involved in cognition Andersson KE. Lancet Neurol. 2004;1:

16 67 Cognitive Performance: Oxybutynin vs Diphenhydramine 68 OAB Medications: CNS Impairment Double-blind placebo-controlled crossover study to assess cognitive function (n=12, years old) with oxybutynin IR 5 mg or oxybutynin IR 10 mg or diphenhydramine 50 mg ; Random regression analysis showed Self-reports: Diary data Surrogate physiological data: EEG, sleep Performance: Cognitive data Case reports & postmarketing surveillance Darifenacin N/A Significant impairment in memory and speed with oxybutynin (7/15 measures) Selective reminding Digit symbol substitution Reaction time Pattern memory Significant cognitive impairment with diphenhydramine (5/15 measures) Digit span Reaction time Continuous performance Procedures (6 visits)- 4 weekly test sessions with acute challenge 90 min after dosing Diphenhydramine used as positive control Katz IR, et al. J Am Geriatr Soc 1998;46:8-13 Solifenacin N/A N/A N/A Trospium Uncertain Tolterodine Uncertain N/A Oxybutynin N/A not available Katz I, et al. J Am Geriatr Soc 1998;46: 8-13 Todorova A, et al, J Clin Pharmacol 2001;41: Cardiac Safety: QT Interval Prolongation QT interval prolongation can cause potential adverse outcomes cardiac syncope and sudden death Torsades de pointes seen in association with congenital prolonged QT syndromes also associated with drug effect in certain instances FDA approval requires post-marketing surveillance to exclude the possibility of fatal arrhythmia Roden DM. N Engl J Med 2004;350: Dmochowski RR, et al. Curr Urol Rep 2005;6: Antimuscarinics: Mean QTcF Increase From Baseline Therapeutic dose 2 4 x therapeutic dose Moxifloxacin (positive control) Darifenacin No increase No increase 7.0 msec Solifenacin 2 (-3,6) msec 8 (4, 13) msec 11, 12 and 16 msec Trospium No increase No increase 6.4 msec Tolterodine Oxybutynin 1.16 (-2.99,5.3) msec Post marketing reports 5.63 (1.48, 9.77) msec 8.9 (4.77, 13.03) msec FDA guidance states that a >5 msec to <20 msec QT prolongation is inconclusive in regards to risk of arrhythmia 71 Treatment with Antimuscarinic Agents for OAB: Summary 72 ARS Question? Fewer cognitive AEs Higher affinity for M 3 receptor subtype results in Fewer visual AEs Which treatment would you prescribe for the 65-year-old woman in our second case study? 1. Oxybutynin 2. Tolteridone 3. Darifenacin Less dry mouth Fewer cardiovascular AEs Choppin E, et al. Br J Pharmacol 2001;132: Dean B, et al. Cur Mol Med 2003;3: Stengel PW, et al. J Pharmacol Exp Ther. 2000;292: Andersson KE. Lancet Neurol. 2004;3: Solifenacin 5. Trospium 12

17 73 Case Scenario Challenge 74 Differentiating OAB From Benign Prostatic Hyperplasia (BPH) What if the patient was male? Storage and / or voiding symptoms are commonly suffered by male patients Treatment of lower urinary tract symptoms most commonly begins by targeting outlet symptoms of BPH Accurate identification of the underlying cause is vital Rosenberg MT, et al. Int J Clin Pract 2007;61: Initial Evaluation for OAB Indications for Referral Physical exam Abdominal exam: Evaluate for tenderness or masses Digital rectal exam: Evaluate rectal tone, prostate size, shape and consistency and detect prostatic implications in symptoms Neurological exam Laboratory tests Urinalysis or microscopic exam: Check for blood, protein, glucose or signs of infection Prostate-specific antigen (PSA) offered to ageappropriate males; refer if abnormal Blood sugar testing suggested Urine cytology (optional) AUA Guideline on the management of benign prostatic hyperplasia 2003 Rosenberg MT, et al. Int J Clin Pract 2007;61: History of recurrent urinary tract infections or other infection Microscopic or gross hematuria Prior genitourinary surgery Elevated prostate-specific antigen Abnormal prostate exam (nodules) Suspicion of neurologic cause of symptoms Findings or suspicion of urinary retention Meatal stenosis History of genitourinary trauma Uncertain diagnosis Pelvic pain Rosenberg MT, et al. Int J Clin Pract 2007;61: OAB Medications in Male Patients Key Questions Covered Muscarinic receptor antagonists What is overactive bladder (OAB)? only therapy currently approved for OAB lower urinary tract symptoms (LUTS) due to OAB How prevalent is OAB? What is the impact of OAB? Concern that antimuscarinics theoretically impair detrusor contractility may cause urinary retention in men Behavioral therapy How does OAB impact on patients quality-of-life? How is OAB diagnosed? What treatments are available for OAB? How do these treatments compare? 13