Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Urgent Matters in OAB An FAQ Approach to What You Need to Know Dr. Jeffrey M. Spodek, MD, FRCSC Division Head, Urology Rouge Valley Health System Disclosures I have served on Advisory Boards and received Consultant Fees from the following companies: Abbott Actavis Astellas Astra Zeneca Eli Lily GSK Paladin Pfizer Sanofi Triton Disclosure of Commercial Support Potential for conflict(s) of interest: • Dr. Jeffrey M. Spodek has received an honorarium from this event who does not make any products Today’s Program By the end of today’s session, participants will be able to: Utilize key symptoms and patient screeners to recognize male and female OAB patients needing treatment, and identify patients who should be referred to a specialist Differentiate between current treatment options, including antimuscarinics, and be confident in initiation of pharmacotherapy Understand key criteria when individualizing treatment to patient needs LEARNING CHECKPOINT #1 WHAT IS YOUR CURRENT COMFORT LEVEL OF: Identifying patients with OAB needing treatment A Not comfortable at all B Somewhat comfortable C Comfortable D Very comfortable LEARNING CHECKPOINT #2 WHAT IS YOUR CURRENT COMFORT LEVEL OF: Differentiating and initiating antimuscarinics A Not comfortable at all B Somewhat comfortable C Comfortable D Very comfortable LEARNING CHECKPOINT #3 WHAT IS YOUR CURRENT KNOWLEDGE LEVEL OF: Beta-3 receptor agonists and future therapies in OAB management A Not knowledgeable at all B Somewhat knowledgeable C Knowledgeable D Very knowledgeable Your guide to tackling OAB in your office Overactive Bladder Overview Establishing an OAB diagnosis 30 Years of Antimuscarinic Therapy Beta-3 receptor agonists and future therapies in OAB management Wrapping it all up Clinical Definition of OAB “Urgency, with or without urgency incontinence, usually associated with frequency and nocturia” IDENTIFYING THE KEY SYMPTOMS OF OAB: Urgency: Sudden, compelling desire to void that is difficult to defer Urgency Incontinence: Involuntary loss of urine preceded by urgency Frequency: The need to frequently urinate (≥8 micturitions/24 hrs) Nocturia: Waking up ≥ 2 times at night to void Corcos J et al. Can J of Urol. 2006;13(3):3127-3138; Abrams P, et al. Neurourol 2002; 21: 167-178; Wein A et al. J Urol. 2006 Mar;175: :S5-S10; Corcos J, Schick E. Can J of Urology 2004; 11(3):2278-2284. What is Overactive Bladder? OAB Mechanism Wein AJ, Rovner ES. Int J Fertil. 1999;44:56-66. “Urgency” drives OAB symptoms Adapted from Chapple CR et al BJU Int 2005; 95: 335-340 Classifying OAB Dry OAB Wet OAB urgency incontinence Mixed Incontinence Involuntary Considered a leakage associated combination of with urgency stress and urge incontinence urgency, frequency without incontinence Proportion of OAB 38% Wet OAB Stress incontinence is involuntary leakage associated with exertion, effort, sneezing or coughing Corcos J, Schick E. Can J of Urology 2004; 11(3):2278-2284; Kirby M, et al. Int J Clin Pract 2006; 60: 1263–127; Herschorn S, et al. BJU Int. 2008;101(1):52-58.; Irwin D, et al. EPIC Study. European Urology. 2006;50:1306-1314. 62% Dry OAB OAB negatively impacts Canadians Effects more than 1 in 10 Canadians (13.1% of men and 14.7% of women) of Canadian respondents reported symptoms1 Impacts Quality of Life (QoL)2-5 Risk of falls/fractures Economic burden Emotional Occupational Physical Sleep Social Sexual The effect of moderate urinary symptoms on QoL is similar to that of having diabetes, high blood pressure, or cancer6 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63.; 2. Abrams P et al. Am J Manag Care 2000;6:S580–90; 3. Coyne KS et al. J Sex Med 2007;4:656–66; 4. Stewart WF et al. World J Urol 2003;20:327–36; 5. Brown JS et al. J Am Geriatr Soc 2000;48:721–5; 6. Robertson C et al. British Journal of Urology International. 2007;99:347-354. Similar Prevalence of OAB in Men and Women 35 Prevalence (%) 30 25 20 Men Women 15 10 5 0 18-24 25-34 25-44 45-54 55-64 65-74 75+ Age (years) Stewart W et al. Prevalence of OAB in the US: results from the NOBLE program. Poster presented at WHO/ICI; July, 2001; Paris, France. OAB remains largely untreated Treated Untreated Total untreated (men and women) Number of patients: • • (7,244,501) (1,270,892) (543,420) (1,201,365) (755,218) (2,124,705) (1,348,901) 45–54 years 55–64 years ≥ 65 years A large proportion of patients diagnosed with OAB are not taking medication Men with OAB are more frequently untreated than women Helfand et al. Eur Urol 2010;57:586–591 Your guide to tackling OAB in your office Overactive Bladder Overview Establishing an OAB diagnosis 30 Years of Antimuscarinic Therapy Beta-3 receptor agonists and future therapies in OAB management Wrapping it all up ESTABLISHING AN OAB DIAGNOSIS How do I incorporate diagnosis into my practice? What are the most important tests to establish diagnosis? Are there specific considerations for males? How do I differentiate between similar conditions? Which “red flags” require referral to a specialist? Next Module How do I incorporate diagnosis into my practice? OAB: A Secret Condition Do not routinely ask about urinary symptoms Do not always bring up symptoms • May be due to lack of knowledge (considered “a natural part of aging”) • May be due to embarrassment If they do, 84% Welch LC et al. Res Nurs Health 2011;34(6):496-507. approach their primary care physician Simple Questions Start the conversation by asking: 1. Do you have concerns with your bladder? 2. Do you experience frequency and/or urgency? 3. Do you ever lose urine if you do not make it to the bathroom in time? 4. Do you leak when you laugh/cough/squeeze/lift or strain? You can also have your patients complete the sentence “I hate my bladder because…” How do I incorporate diagnosis into my practice? OAB Patient Screener Patients can screen for OAB in the waiting room: How do I incorporate diagnosis into my practice? ESTABLISHING AN OAB DIAGNOSIS How do I incorporate diagnosis into my practice? What are the most important tests to establish diagnosis? Are there specific considerations for males? How do I differentiate between similar conditions? Which “red flags” require referral to a specialist? Next Module Assess Patient History Age (incidence increases with age) Medical history (assess for medications that could cause symptoms) Association with other voiding and storage symptoms Degree of bother/effect on activities of daily life 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63 Prior surgery/ trauma Lifestyle characteristics, including fluid intake Duration and severity of symptoms What are the most important tests to establish diagnosis? Red Flags Smoker with hematuria History of complicated recurrent urinary tract infections Severe symptoms of bladder outlet obstruction Pain related to the bladder Perform Physical Examination Abdominal, pelvic, and perineal examination What are the most important tests to establish diagnosis? Pelvic floor muscle assessment Include digital rectal exam if appropriate Red Flags Bladder/pelvic pain Cough test, if appropriate Use to differentiate stress urinary incontinence 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63 Appropriate Investigations What are the most important tests to establish diagnosis? Standard recommendation: Urinalysis and culture Optional: Post-void residual urine (PVR) PSA, if appropriate Blood tests If applicable co-morbidities are present (diabetes, etc.) Assessment of renal function is not mandatory Red Flags Hematuria (gross or macroscopic) Elevated PVR (>200 cc) (assume palpable bladder) Elevated PSA Complicated positive urine culture 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63 ESTABLISHING AN OAB DIAGNOSIS How do I incorporate diagnosis into my practice? What are the most important tests to establish diagnosis? Are there specific considerations for males? How do I differentiate between similar conditions? Which “red flags” require referral to a specialist? Next Module Differentiating OAB from SUI and MI OAB Stress Urinary Incontinence Mixed Incontinence Urgency (strong, sudden desire to void) Yes No Yes Frequency with Urgency (≥ 8 times/24hrs) Yes No Yes Leaking during physical activity (e.g. coughing, sneezing, lifting) No Yes Yes Amounts of urinary leakage with each episode of incontinence Large (if present) Small Variable Ability to reach the toilet in time following urge to void Often no Yes Variable Nocturia (waking to pass urine at night) Usually Seldom Maybe Symptoms Kirby M, et al. Int J Clin Pract 2006; 60: 1263–127. How do I differentiate between similar conditions? Differential Diagnosis from Related Conditions How do I differentiate between similar conditions? Presenting Symptom* OAB BPH (males) Bladder Cancer UTI Urgency Yes Yes Occasionally Yes Frequency Yes Yes Occasionally Yes Often Yes Rare Often Nocturnal Frequency REMINDER: No OAB IS DEFINED AS No Yes “Urgency, with Weak stream No or without Yes urgency No Straining/hesitancy No Yes No incontinence, usually associated with Elevated PSA frequency No and nocturia” Occasionally No Incomplete emptying No No Occasionally Commonly Pain No No Occasionally Yes Dysuria No No Occasionally Yes Pyuria No No Rare Yes Hematuria No Rare Yes Usually microscopic * Timing of symptom onset usually very different • UTI being acute vs. OAB being chronic Nitti V, Taneja S. Int J Clin Pract. 2005;59:825-830; Nicolle LE Chapter 127, In: Hazzard’s Geriatric Medicine and Gerontology, 2011; Cornett PA, Dea TO. Chapter 39, In: CURRENT Medical Diagnosis & Treatment 2012, 2011; Prostate Cancer Canada Network: Prostate Cancer Symptoms; Prostate Cancer Cnada Network, Non-Cancerous Conditions: Benign Prostatic Hyperplasia. Additional Considerations How do I differentiate between similar conditions? OAB and Interstitial Cystitis Can present with similar symptoms (frequency, urgency, and negative cultures) Key differentiator: Pain Red Flags Smoker with hematuria OAB and Prostate Cancer History of complicated recurrent urinary tract infections Can present with similar symptoms Severe symptoms of bladder outlet obstruction At risk group: older men, abnormal DRE, elevated PSA Bladder/pelvic pain ESTABLISHING AN OAB DIAGNOSIS How do I incorporate diagnosis into my practice? What are the most important tests to establish diagnosis? Are there specific considerations for males? How do I differentiate between similar conditions? Which “red flags” require referral to a specialist? Next Module A Case of Mistaken Identity Sees: a woman who describes LUTS Sees: a man who describes LUTS Dr. thinks: Bladder Dr. thinks: Prostate Dr. treats: with Antimuscarinics Dr. treats: with Alphablockers Are there specific considerations for males? of men with lower urinary tract symptoms do not have bladder outlet obstruction1 Many men may present with primary idiopathic OAB2 1. Chapple C et al. NICE Clinical Guideline. The management of lower urinary tract symptoms in men. May 2010; 2. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63 Lower Urinary Tract Symptoms in Men Storage Symptoms Urgency Frequency Incontinence Nocturia Suggestive of OAB Voiding Symptoms Poor flow Intermittency Straining Hesitancy Terminal dribble Are there specific considerations for males? Post-Micturition Symptoms Post-void dribble Incomplete emptying Suggestive of BOO/BPH However, OAB and BPH frequently co-exist 1. Chapple C et al. NICE Clinical Guideline. The management of lower urinary tract symptoms in men. May 2010; 2. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63 ESTABLISHING AN OAB DIAGNOSIS How do I incorporate diagnosis into my practice? What are the most important tests to establish diagnosis? Are there specific considerations for males? How do I differentiate between similar conditions? Which “red flags” require referral to a specialist? Next Module When referral is necessary: “Red Flags” Consider bladder cancer if: • A smoker who with urgency, frequency, pain, and blood in the urine [painless hematuria (gross or microscopic)] Urine cytology important for patient >40 yrs, smoker, risk factors for bladder cancer, and presence of hematuria Consider prostate cancer if: • Abnormal DRE • Elevated PSA 1. Messing EM, et al. Campbell-Walsh Urology, 9th ed. Philadelphia: Saunders; 2007;2407-2446. 2. Nitti V, Taneja S. Int J Clin Pract. 2005; 59: 825-830. 3. Kelly CE, et al. Rev Urol. 2004;6(Suppl 1): S32–S37.; 4. Ouslander JG. Urology. 2002;60(5 Suppl 1):50-55 When referral is necessary: “Red Flags” Consider post-void residual volume (PVR) if: • Non-mobile elderly • Presence of neurological disease • History suggestive of outflow obstruction Significant hesitancy and straining to void Feeling of incomplete emptying (>200 mL) Previous lower urinary tract surgery • Palpable bladder A large PVR can be associated with UTIs, especially in persons at risk (children or patients with spinal cord injury or diabetes) Very large PVRs (>400 mL) may be associated with an increased risk of renal insufficiency 1. Messing EM, et al. Campbell-Walsh Urology, 9th ed. Philadelphia: Saunders; 2007;2407-2446. 2. Nitti V, Taneja S. Int J Clin Pract. 2005; 59: 825-830. 3. Kelly CE, et al. Rev Urol. 2004;6(Suppl 1): S32–S37.; 4. Ouslander JG. Urology. 2002;60(5 Suppl 1):50-55 ESTABLISHING AN OAB DIAGNOSIS How do I incorporate diagnosis into my practice? What are the most important tests to establish diagnosis? Are there specific considerations for males? How do I differentiate between similar conditions? Which “red flags” require referral to a specialist? Next Module Your guide to tackling OAB in your office Overactive Bladder Overview Establishing an OAB diagnosis 30 Years of Antimuscarinic Therapy Beta-3 receptor agonists and future therapies in OAB management Wrapping it all up Clinician’s OAB Toolbox Oxybutynin Oxybutynin Oxybutynin Oxybutynin Oxybutynin Oxybutynin IR ER CR patch gel 5-HMT Tolterodine IR Tolterodine ER Fesoterodine Solifenacin Darifenacin Trospium chloride 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63 Select agent based on: Patient and physician preference Formulary and private coverage Route and frequency of administration Receptor and organ selectivity Potential side effects Efficacy Provincial Public Drug Coverage (Restricted)* BC AB SK MN ON Darifenacin (Enablex) * Limited Use (Special Authorization/Exception drug status), after generic oxybutynin Fesoterodine (Toviaz) Oxybutynin CR (Uromax) Oxybutynin ER (Ditropan XL) Oxybutynin gel (Gelnique) Oxybutynin transdermal patch (Oxytrol) Solifenacin (Vesicare) Tolterodine ER (Detrol LA) Trospium (Trosec) QC NS NB NF PEI Goals of OAB Treatment Urgency and Frequency Voided volume Urgency incontinence (if applicable) 30 YEARS OF ANTIMUSCARINIC THERAPY What are the options for behavioural therapy? Comparison of efficacy between products? Can antimuscarinics be used in men? Are there pharmacological differences that impact tolerability? What is the efficacy & tolerability in special populations? Next Module Getting Your Patients On Board Patient education is key to optimal treatment outcomes Counseling patients on how to best incorporate strategies into their lives • Adherence to behavioural interventions Optimal treatment outcomes Wyman JF et al. Int J Clin Pract. 2009;63(8):1177-91. What are the options for behavioural therapy? Healthy Bladder Habits Wyman JF et al. Int J Clin Pract. 2009;63(8):1177-91. What are the options for behavioural therapy? Behavioural Modifications Wyman JF et al. Int J Clin Pract. 2009;63(8):1177-91. What are the options for behavioural therapy? 30 YEARS OF ANTIMUSCARINIC THERAPY What are the options for behavioural therapy? Comparison of efficacy between products? Can antimuscarinics be used in men? Are there pharmacological differences that impact tolerability? What is the efficacy & tolerability in special populations? Next Module Therapies Block Muscarinic Receptors in the Bladder Are there pharmacological differences that impact tolerability? M = muscarinic N = nicotinic α = α1 and α2 –adrenergic Β = β3-adrenergic Detrusor muscle (M2 80%; M3 20%; β) Mucosa and submucosa (M2, M3) Bladder neck (α) Pelvic floor (N) Urethra (α) Blocking receptors prevents detrusor contraction Gillenwater JY, Grayhack JT, Howards, SS et al. Adult & Pediatric Urology (4th Edition). Philidelphia, PA: Lippincott Williams & Wilkins. 2002. Muscarinic Receptors are Distributed Throughout the Body M1: Cortex, hippocampus, sympathetic ganglia M2: Hindbrain, heart, smooth muscle M3: Smooth muscle, brain, glands, heart, M4: Basal forebrain, striatum Iris/ciliary body Lacrimal gland Salivary glands Heart Blurred vision Dry eyes Dry mouth Tachycardia Stomach and esophagus Colon Are there pharmacological differences that impact tolerability? Dyspepsia Constipation M5: Substantia nigra Bladder (detrusor muscle) Abrams P., et al. Br J Pharmacol. 2006;148(5):565-578. Sellers DJ, et al. Curr Opin Urol. 2007;17:223-230. Antimuscarinic Agents Differ in Their Receptor and Organ Selectivity Antimuscarinics Agents Are there pharmacological differences that impact tolerability? Oxybutynin Generic Name Darifenacin Fesoterodine Solifenacin succinate Tolterodin e L-tartrate ER Trospium chloride ER CR Transdermal gel Transdermal patch None None None None High Moderate None No No No No Yes No No Bladder Specificity M3 Muscarini c Selectivity Moderate Moderate Yes No Respective Product Monographs; Hashim H et al, Drugs 2004;64(15):1643-1656.; Chapple CR et al. BJU Int. 2006:98(supplement 1);78-87. Are there pharmacological differences that impact tolerability? Commonly Reported Side Effects with Antimuscarinics Dry mouth Constipation Dry eyes Dyspepsia Dizziness Darifenacin (7.5 mg) 20.2% 14.8% 2.1% 2.7% 0.9% Fesoterodine (4 mg) 18.8% 4.2% 1.4% 1.6% n/a Oxybutynin CR (5-20 mg OD) 64.0% 5.1% 2.5% 5.1% 6.4% Oxybutynin ER (5-30 mg OD) 60.8% 13.1% 6.1% 6.8% 6.3% Oxybutynin patch 4.1% 3.3% n/a n/a n/a Oxybutynin gel 6.9% 1.3% n/a n/a 1.5% Solifenacin (5 mg OD) 10.9% 5.4% 0.3% 1.4% 1.9% Tolterodine ER (4 mg OD) 23.4% 5.9% <5% <5% <5% Trospium chloride (20 mg bid) 20.1% 9.6% 1.2% 1.2% n/a Solifenacin succinate is also available in a 10 mg dose. Darifenacin is also available in a 15 mg dose. Fesoterodine is also available in a 8 mg dose. Newer long-acting agents tend to have better tolerability compared to oxybutynin and immediate-release formulations Respective Product Monographs. 30 YEARS OF ANTIMUSCARINIC THERAPY What are the options for behavioural therapy? Comparison of efficacy between products? Can antimuscarinics be used in men? Are there pharmacological differences that impact tolerability? What is the efficacy & tolerability in special populations? Next Module Anticholinergics Effectively Reduce OAB Symptoms Comparison of efficacy between products? Network meta-analysis comparing antimuscarinics in the treatment of OAB Mean reduction in micturitions/24h compared to placebo Solifenacin Oxybutynin Oxybutynin Fesoterodine Trospium Solifenacin Tolterodine Oxybutynin Fesoterodine Oxybutynin 10 mg IR 15 mg IR 10 mg 8 mg chloride 40 mg 5 mg ER 4 mg gel 4 mg ER 15 mg Buser et al. Eur Urol. 2012;62:1040-1060 Anticholinergics Effectively Reduce OAB Symptoms Comparison of efficacy between products? Network meta-analysis comparing antimuscarinics in the treatment of OAB Mean reduction in urgency episodes/24h compared to placebo Solifenacin Oxybutynin Oxybutynin Fesoterodine Trospium Solifenacin Tolterodine Oxybutynin Fesoterodine Oxybutynin 10 mg IR 15 mg IR 10 mg 8 mg chloride 40 mg 5 mg ER 4 mg gel 4 mg ER 15 mg n/a Buser et al. Eur Urol. 2012;62:1040-1060 Anticholinergics Effectively Reduce OAB Symptoms Comparison of efficacy between products? Network meta-analysis comparing antimuscarinics in the treatment of OAB Mean reduction in urgency incontinence episodes/24h compared to placebo Solifenacin Oxybutynin Oxybutynin Fesoterodine Trospium Solifenacin Tolterodine Oxybutynin Fesoterodine Oxybutynin 10 mg IR 15 mg IR 10 mg 8 mg chloride 40 mg 5 mg ER 4 mg gel 4 mg ER 15 mg n/a Buser et al. Eur Urol. 2012;62:1040-1060 Head-to-head studies of antimuscarinics Comparison of efficacy between products? Mean reduction in micturitions/24hrs (primary endpoint) STAR Trial Tolterodine ER vs. Fesoterodine Tolterodine ER vs. Solifenacin Placebo TolterodineFesoterodineFesoterodine ER 4 mg 4 mg 8 mg BL: 12.0 11.5 * 11.6 † 8.7% 11.9 Solifenacin Tolterodine 5/10 mg ER 4 mg 11.78 11.66 † ‡ 9.4% * p=0.001 vs. placebo; † p<0.001 vs. placebo; ‡ p=0.004 (non-inferiority) 1. Chapple C et al Eur Urol 2007;52:1204-12 Corrigendum. Eur Urol 2008;53:1319; 2. Chapple CR et al Eur Urol 2005;48:464-70 30 YEARS OF ANTIMUSCARINIC THERAPY What are the options for behavioural therapy? Comparison of efficacy between products? Can antimuscarinics be used in men? Are there pharmacological differences that impact tolerability? What is the efficacy & tolerability in special populations? Next Module Guidelines advocate the use of antimuscarinics in men Can antimuscarinics be used in men? “Antimuscarinic agents may be used alone as first line therapy when primary idiopathic OAB exists” A significant number of patients will have both BPH and OAB • In these patients, treat with alpha-blockers or 5-alpha-reductase inhibitors of men treated for bladder outlet obstruction have remaining OAB symptoms 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63.. • After 4-6 weeks of alphablockers, if storage symptoms persist an antimuscarinic therapy can be started safely if: o o PVR is low (<200 mL) Qmax is > 5 mL/s Managing Your AUR Concerns Can antimuscarinics be used in men? Assumed increased risk based on what the effect of antimuscarinics may be, but has not been proven scientifically Actual risk of AUR Placebo ~ 1 in 500 patients 0.2 % Antimuscarinics ~ 5.5 in 500 patients Oxybutynin IR 7.5-10mg/day: Only agent that has shown a statistically significant increase in AUR vs. Placebo Incidence with newer agents is ≈ that of placebo 1.1 % 30 YEARS OF ANTIMUSCARINIC THERAPY What are the options for behavioural therapy? Comparison of efficacy between products? Can antimuscarinics be used in men? Are there pharmacological differences that impact tolerability? What is the efficacy & tolerability in special populations? Next Module Antimuscarinic Effects in Elderly Patients Antimuscarinics have the potential to cause CNS impairment: • Memory deficits (patients often unaware of this side effect) • Sleep disruption • Confusion and hallucinations Extent of CNS effects is determined by: • Age related physiology (slower metabolism, drug elimination) • Age related changes in Integrity of BBB • Age related changes in muscarinic receptors • Drug properties that facilitate ability to cross BBB • Drug’s propensity to block M1 receptors in the brain Staskin DR. Drugs Aging. 2005;22(12):1013-1028; Kay GG. Clinical Geriatrics 2007;15(2;suppl 2):1-14; Ouslander JG. Urology. 2002;60(Suppl 5A): 50–55; Kay GG. OBG Management 2007;19(3;suppl):11-14. Agent Characteristics May Impact Potential for Side Effects M1 receptors are the primary subtype involved in cognitive function, with M2 playing a lesser role • M3 receptors are less concentrated in the brain and CNS AMs cause side effects by crossing the BBB and binding to muscarinic receptors in the brain In theory More selective for M3 receptors = May cause less side effects (medications such as solifenacin and darifenacin) Quaternary amine with high polarity and high hydrophilicity, have limited ability to cross the BBB = May cause less CNS side effects (compounds like trospium chloride) Ballert KN and Bales GT. Curr Bladder Dysfunct Rep 2013;8:57-61. 2012 SOGC Recommendations for Antimuscarinic-related CNS Effects Elderly and/or cognitively impaired Oxybutynin Studies are lacking* Fesoterodine Safe to use Trospium Safe to use Solifenacin Safe to use Darifenacin Safe to use *Not necessarily unsafe but safety studies are lacking Specific patient factors may make patients susceptible to CNS events: Increased permeability of the BBB Comorbid diseases predisposing to adverse CNS effects Intake of other drugs with anticholinergic effects Geoffrion R et al. J Obstet Gynaecol Can 2012;34(11):1092-1101 30 YEARS OF ANTIMUSCARINIC THERAPY What are the options for behavioural therapy? Comparison of efficacy between products? Can antimuscarinics be used in men? Are there pharmacological differences that impact tolerability? What is the efficacy & tolerability in special populations? Next Module Your guide to tackling OAB in your office Overactive Bladder Overview Establishing an OAB diagnosis 30 Years of Antimuscarinic Therapy Beta-3 receptor agonists and future therapies in OAB management Wrapping it all up ASK THE AUDIENCE WHAT IS THE MOST IMPORTANT FEATURE OF OAB THERAPY? A Efficacy B Tolerability C Adherence to therapy D Newer therapeutic option E None of the above Levels of Treatment Adherence With Antimuscarinic Treatment 100% On Medication 90% Stopped Medication Patients (%) 80% 70% 60% 50% 40% 30% 20% 10% 0% After 1st Prescription After 3 months Oxybutynin Sexton CC et al. Int J Clin Pract. 2012;65:567–585. A study of patients on antimuscarinics in Quebec shows that over 60% of patients do not refill their prescription and nearly 80% stop using their prescription after 3 months Levels of Treatment Persistence Over 12 Months With Antimuscarinic Treatment After 12 months, less than 35% of patients were still on antimuscarinic treatment Wagg A et al. BJU Int. 2012;110(11):1767-1774. “Real Life” Reasons for Discontinuation of OAB Antimuscarinic Treatment 46% did not work as expected 25% switched to a new medication 23% learned to get by without medication 21% had intolerable side effects Because of bothersome side effects and a lack of compliance, attempts have been made to develop new compounds Percentages do not add to 100 because multiple reasons were allowed Benner JS, Nichol MB, Rovner ES et al. BJU Int. 2010:105(9):1276-1282 Actions of Lower Urinary Treatments Onabotulinumtoxin A • Inhibits ACh release from presynaptic nerve terminal • Prevents stimulation of muscarinic receptors on detrusor muscle Antimuscarinics • Inhibits muscarinic receptors • Prohibits detrusor muscle contraction Onabotulinumtoxin A is now approved for primary idiopathic OAB in Canada Fowler CJ et al. Nature Reviews Urology 2008;(9):453-466; Nitti VW. Rev Urol. 2006;8(4):198-208; Solifenacin Product Monograph, 2011; Tamsulosin Product Monograph, 2012; Mirabegron Product Monograph, 2013. Alpha1-adrenoceptor antagonists • Blockade causes smooth muscle in prostate and bladder neck to relax • Improves urine flow & reduces BPH symptoms Actions of Lower Urinary Treatments Onabotulinumtoxin A • Inhibits ACh release from presynaptic nerve terminal • Prevents stimulation of muscarinic receptors on detrusor muscle Antimuscarinics • Inhibits muscarinic receptors • Prohibits detrusor muscle contraction Beta3-adrenoceptor agonists • Activation causes detrusor muscle relaxation • Increases bladder capacity • Does not interfere with the voiding process Onabotulinumtoxin A is not approved for primary idiopathic OAB in Canada Fowler CJ et al. Nature Reviews Urology 2008;(9):453-466; Nitti VW. Rev Urol. 2006;8(4):198-208; Solifenacin Product Monograph, 2011; Tamsulosin Product Monograph, 2012; Mirabegron Product Monograph, 2013. Alpha1-adrenoceptor antagonists • Blockade causes smooth muscle in prostate and bladder neck to relax • Improves urine flow & reduces BPH symptoms β-3 adrenoceptor (AR) agonists A New OAB Option The first oral OAB treatment with a distinct MoA since the launch of antimuscarinics agents 30 years ago • Mirabegron (Myrbetriq; YM-178; Astellas) is currently approved for use in Canada, the US and Japan Gras J. Drugs of Today. 2012;48(1):25-32.; Sacco E and Bientinesi R. Ther Adv Urol. 2012;4(6):315–324.; Tyagi P, Tyagi V, and Chancellor M. Expert Opin Drug Saf. 2011;10(2):287-294. Hicks A, McCafferty GP, Riedel E et al. J Pharmacol Exp Ther. 2007;323(1):202-209 Mirabegron Efficacy Compared to Antimuscarinics over 12 weeks (178-CL-046) Mean reduction in OAB symptoms compared to placebo Incontinence episodes/ 24hrs Micturitions/ 24hrs Urgency episodes (Grade 3/4)/24hrs † † * ** †† *** Mirabegron demonstrated significant improvements in OAB symptoms, including urgency *p=0.003 vs. placebo; **p<0.001 vs. placebo; ***p=0.005 vs. placebo; † p=0.11(NS) vs. placebo; † †p=0.05 vs. placebo Mirabegron Product Monograph, 2013; Khullar V et al. Eur Urol. 2013;63:283–295 Improvement in OAB parameters maintained over 12 months (178-CL-049) Incontinence † Micturitions † 0.00 Mirabegron 50 mg -0.20 Tolterodine ER 4 mg -0.40 -0.60 -0.80 -1.00 -1.20 -1.40 -1.60 -1.80 Adjusted Mean Change From Baseline Adjusted Mean Change From Baseline 0.00 -2.00 -0.25 Mirabegron 50 mg -0.50 Tolterodine ER 4 mg -0.75 -1.00 -1.25 -1.50 -1.75 -2.00 -2.25 -2.50 -BL 1 3 6 9 -BL 1 12 3 Month 6 9 Month N N Mira 50 mg 478 478 447 409 387 370 Mira 50 mg 789 786 742 684 656 627 Tolterodine 485 485 452 418 387 379 Tolterodine 791 786 735 684 645 623 † Mean ± SE. Chapple CR et al. Eur Urol. 2013;63(2):296-305 12 Mirabegron: Safety Compared to Anticholinergic Treatment (12-weeks) Common TEAEs Any AE Hypertension Nasopharyngitis Dry mouth Headache Influenza Urinary tract infection Constipation Cardiovascular TEAEs QTc prolongation or its sequelae Atrial fibrillation of medical importance Arrhythmia Placebo (%) Mirabegron 50 mg (%) Tolterodine ER 4 mg (%) 43.3% 7.7% 1.6% 2.6% 2.8% 1.6% 1.4% 42.8% 5.9% 2.8% 2.8% 3.7% 2.2% 1.4% 46.7% 8.1% 2.8% 10.1% 3.6% 1.4% 2.0% 1.4% 1.6% 2.0% 0 0 0.4% 0.2% 0.4% 1.0% 1.0% 2.2% 3.2% TEAE = treatment-emergent adverse event; Khullar V et al. Eur Urol. 2013;63:283–295 How β3-adrenoreceptor Agonists Compare to Existing Therapy AEs Comparative efficacy Low incidence of AEs characteristic of antimuscarinic therapy (i.e., dry mouth) Not contraindicated in patients with glaucoma: No difference from placebo for effect on intraocular pressure; Ophthalmological examinations should still be performed as normal Incidence of CNS AE’s did not reach reportable levels in clinical trials and no difference versus placebo Should have no involvement in cognition and memory Attractive option for elderly patients? Chapple CR et al. Eur Urol. 2013;63(2):296-Khullar V et al. Eur Urol. 2013;63:283–295.; Tyagi P et al. (2011) Mirabegron: a safety review. Expert Opin Drug Saf. 10(2):287-294.; Mirabegron Product Monograph, Astellas Pharma Canada, Inc, 2013. Potential for improved patient compliance Your guide to tackling OAB in your office Overactive Bladder Overview Establishing an OAB diagnosis 30 Years of Antimuscarinic Therapy Beta-3 receptor agonists and future therapies in OAB management Wrapping it all up OAB Can Be Tackled in Your Practice Identify OAB patients needing treatment OAB is common and can have a significant impact on patients’ lives Screen for OAB using simple questions on urgency, frequency, & incontinence Treatment can be initiated without referral Selection of an agent can be based on patient and physician preference, formulary and private coverage, route and frequency of administration, receptor and organ selectivity, potential side effect, and efficacy Successful treatment of OAB depends on both efficacy and tolerability of therapy OAB treatment options continue to improve Despite newer formulations, patient adherence to treatment is low β3-adrenoreceptor (AR) agonists represents an effective new oral treatment option with a low incidence of side effects common to antimuscarinics (i.e., dry mouth) LEARNING CHECKPOINT #1 WHAT IS YOUR CURRENT COMFORT LEVEL OF: Identifying patients with OAB needing treatment A Not comfortable at all B Somewhat comfortable C Comfortable D Very comfortable LEARNING CHECKPOINT #2 WHAT IS YOUR CURRENT COMFORT LEVEL OF: Differentiating and initiating antimuscarinics A Not comfortable at all B Somewhat comfortable C Comfortable D Very comfortable LEARNING CHECKPOINT #3 WHAT IS YOUR CURRENT KNOWLEDGE LEVEL OF: Beta-3 receptor agonists and future therapies in OAB management A Not knowledgeable at all B Somewhat knowledgeable C Knowledgeable D Very knowledgeable COMMENTS/QUESTIONS THANK YOU