Urgent Matters in OAB An FAQ Approach to What You Need to Know

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 This slide must be visually presented to the audience AND verbalized by the speaker.

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

A B C D 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

WHAT IS YOUR CURRENT COMFORT LEVEL OF: Differentiating and initiating antimuscarinics A Not comfortable at all B Somewhat comfortable C Comfortable D Very comfortable

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

Overactive Bladder Overview
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): ; Abrams P, et al. Neurourol 2002; 21: ; Wein A et al. J Urol Mar;175: :S5-S10; Corcos J, Schick E. Can J of Urology 2004; 11(3):

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:

Involuntary leakage associated with urgency
Classifying OAB Wet OAB Dry OAB urgency, frequency without incontinence urgency incontinence Mixed Incontinence Involuntary leakage associated with urgency Considered a combination of stress and urge incontinence Proportion of OAB 38% Wet OAB 62% Dry OAB Stress incontinence is involuntary leakage associated with exertion, effort, sneezing or coughing Corcos J, Schick E. Can J of Urology 2004; 11(3): ; 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:

OAB negatively impacts Canadians
Effects more than 1 in 10 Canadians 13.9% of Canadian respondents reported symptoms1 (13.1% of men and 14.7% of women) Impacts Quality of Life (QoL)2-5 Risk of falls/fractures Economic burden Emotional Occupational Physical Sleep Social Sexual According to the SOGC 2012 Guidelines, up to 67% of women with OAB report a negative effect on daily living.1 Significant comorbidities associated with OAB include depression, falls and fractures, and increased admissions to hospitals and nursing homes2-4 References: Milsom I et al Br J Urol Int 2001;87(9):760-6. Zorn BH et al J Urol 1999;162:82-4 Brown JS et al J Am Fer Soc 2000;48(7)721-5. Thorn DH et al Age Ageing 19997;26(5) 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): ; 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:

Similar Prevalence of OAB in Men and Women
Prevalence of Overactive Bladder in the US The results of the National Overactive BLadder Evaluation (NOBLE) Program indicate that the overall prevalence of symptoms of overactive bladder is 16.6%, and that the prevalence of overactive bladder is similar between men (16.0%) and women (16.9%) Consistent with other epidemiologic studies, the incidence increases with age in both men and women The prevalence appears to increase with advancing age. 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
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? How do I differentiate between similar conditions? Are there specific considerations for males? Which “red flags” require referral to a specialist? Next Module

OAB: A Secret Condition
How do I incorporate diagnosis into my practice? 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 84% If they do, approach their primary care physician Welch LC et al. Res Nurs Health 2011;34(6):

How do I incorporate diagnosis into my practice?
Simple Questions How do I incorporate diagnosis into my practice? Start the conversation by asking: Do you have concerns with your bladder? Do you experience frequency and/or urgency? Do you ever lose urine if you do not make it to the bathroom in time? 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 How do I incorporate diagnosis into my practice? Patients can screen for OAB in the waiting room: Notes to Facilitator: As OAB is diagnosed according to symptoms and is largely based on patient history, the URGENCY test is a quick and simple introductory questionnaire used to determine if your patients are suffering from OAB symptoms A misconception is that there is no time in an office visit to screen for OAB, however, implementing this quick and easy patient screener can efficiently and effectively identify whether a patient in your practice is experiencing OAB symptoms and requires further investigation

Assess Patient History
What are the most important tests to establish diagnosis? Age (incidence increases with age) Prior surgery/ trauma Medical history (assess for medications that could cause symptoms) Association with other voiding and storage symptoms Lifestyle characteristics, including fluid intake Red Flags Smoker with hematuria History of complicated recurrent urinary tract infections Severe symptoms of bladder outlet obstruction Pain related to the bladder Duration and severity of symptoms Degree of bother/effect on activities of daily life 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63

Perform Physical Examination
What are the most important tests to establish diagnosis? Pelvic floor muscle assessment Abdominal, pelvic, and perineal examination Include digital rectal exam if appropriate Red Flags Bladder/pelvic pain Pelvic floor muscle assessment: Kegel exercises are often combined with biofeedback techniques to teach the proper exercise methods and to make sure the exercises are working. Biofeedback allows you to see, feel, or hear when an exercise is being done correctly. This can be done by placing a finger in your vagina or anus to feel it contract when the pelvic muscles are exercised. More elaborate devices can also be used that measure the pressure of the bladder and abdominal muscles or provide a measurement of the pressure within the vagina. Another exercise technique involves using a weighted cone that is inserted into the vagina. You must contract the pelvic muscles to prevent the cone from dropping out of the vagina. A set of cones identical in size and shape but of increasing weight are provided. As treatment progresses, heavier cones are used that require stronger contractions to keep them in place. Ref: 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

Differentiating OAB from SUI and MI
How do I differentiate between similar conditions? Symptoms OAB Stress Urinary Incontinence Mixed Incontinence Urgency (strong, sudden desire to void) Yes No Frequency with Urgency (≥ 8 times/24hrs) Leaking during physical activity (e.g. coughing, sneezing, lifting) 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 Nocturia (waking to pass urine at night) Usually Seldom Maybe Notes to Facilitator: OAB overlaps with many LUT dysfunction symptoms, with patients demonstrating varying degrees depending on the underlying condition Majority of patients suffering from OAB are classified as experience urgency and frequency but not urinary incontinence (synonymous with “OAB dry” (this is in line with current opinion regarding the importance of urgency as the driving force behind the other OAB components, frequency, nocturia, and incontinence) Stress urinary incontinence , which involves failure of the urethra and pelvic floor to withstand pressure created by such stressors as sneezing or laughing, does not fall within the OAB syndrome; however, patients can suffer from urinary incontinence and/or urgency with mixed symptoms (urgency and stress) Stress urinary incontinence accompanied by urgency but not urge urinary incontinence constitutes “mixed symptomatology” Kirby M, et al. Int J Clin Pract 2006; 60: 1263–127. 26

Differential Diagnosis from Related Conditions
How do I differentiate between similar conditions? Presenting Symptom* OAB BPH (males) Bladder Cancer UTI Urgency Yes Occasionally Frequency Nocturnal Frequency Often Rare Incomplete emptying No Weak stream Straining/hesitancy Elevated PSA Commonly Pain Dysuria Pyuria Hematuria Usually microscopic REMINDER: OAB IS DEFINED AS “Urgency, with or without urgency incontinence, usually associated with frequency and nocturia” NOTE: SLIDE IS ANIMATED. OAB definition will appear PRIOR to table Notes to Facilitator: For patients presenting with irritative bladder symptoms but no associated pain, and who also have a history of unconfirmed UTI and a gradual rather than acute onset of symptoms, OAB is a high probability diagnosis. UTIs may also occur in individuals with OAB. These patients usually present with an exacerbation of their OAB symptoms and dysuria. It is also important to note that a positive culture, or the presence of bacteria on microscopic examination, without pyuria does not represent bacterial cystitis and is not usually a cause of OAB symptoms. * Timing of symptom onset usually very different UTI being acute vs. OAB being chronic Nitti V, Taneja S. Int J Clin Pract. 2005;59: ; 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 History of complicated recurrent urinary tract infections Severe symptoms of bladder outlet obstruction Bladder/pelvic pain OAB and Prostate Cancer Can present with similar symptoms At risk group: older men, abnormal DRE, elevated PSA

A Case of Mistaken Identity
Are there specific considerations for males? Sees: a woman who describes LUTS Dr. thinks: Bladder Dr. treats: with Anti- muscarinics Sees: a man who describes LUTS Dr. thinks: Prostate Dr. treats: with Alpha- blockers ~50% 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
Are there specific considerations for males? Storage Symptoms Voiding Symptoms Post-Micturition Symptoms Urgency Frequency Incontinence Nocturia Poor flow Intermittency Straining Hesitancy Terminal dribble Post-void dribble Incomplete emptying Suggestive of OAB 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

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; Nitti V, Taneja S. Int J Clin Pract. 2005; 59: 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; Nitti V, Taneja S. Int J Clin Pract. 2005; 59: Kelly CE, et al. Rev Urol. 2004;6(Suppl 1): S32–S37.; 4. Ouslander JG. Urology. 2002;60(5 Suppl 1):50-55

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 IR Oxybutynin ER Oxybutynin CR Oxybutynin patch Oxybutynin gel 5-HMT Tolterodine IR Tolterodine ER Fesoterodine 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 Solifenacin Darifenacin Trospium chloride 1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63

Provincial Public Drug Coverage (Restricted)*
BC AB SK MN ON QC NS NB NF PEI Darifenacin (Enablex) Fesoterodine (Toviaz) Oxybutynin CR (Uromax) Oxybutynin ER (Ditropan XL) Oxybutynin gel (Gelnique) Oxybutynin transdermal patch (Oxytrol) Solifenacin (Vesicare) Tolterodine ER (Detrol LA) Trospium (Trosec) * Limited Use (Special Authorization/Exception drug status), after generic oxybutynin 38

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? Are there pharmacological differences that impact tolerability? Can antimuscarinics be used in men? What is the efficacy & tolerability in special populations? Next Module

Getting Your Patients On Board
What are the options for behavioural therapy? 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):

Healthy Bladder Habits
What are the options for behavioural therapy? Wyman JF et al. Int J Clin Pract. 2009;63(8):

Behavioural Modifications
What are the options for behavioural therapy? Wyman JF et al. Int J Clin Pract. 2009;63(8):

Therapies Block Muscarinic Receptors in the Bladder
Are there pharmacological differences that impact tolerability? Therapies Block Muscarinic Receptors in the Bladder 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) Speaker will have to be able to describe the mechanisms of what takes place for both sympathetic and parasympathetic system at these receptors. 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

Muscarinic Receptors are Distributed Throughout the Body
Are there pharmacological differences that impact tolerability? Heart Stomach and esophagus Dyspepsia Iris/ciliary body Lacrimal gland Blurred vision Dry eyes Tachycardia M1: Cortex, hippocampus, sympathetic ganglia M2: Hindbrain, heart, smooth muscle M3: Smooth muscle, brain, glands, heart, M4: Basal forebrain, striatum M5: Substantia nigra Salivary glands Dry mouth Colon Constipation Bladder (detrusor muscle) Abrams P., et al. Br J Pharmacol. 2006;148(5): Sellers DJ, et al. Curr Opin Urol. 2007;17:

Antimuscarinic Agents Differ in Their Receptor and Organ Selectivity
Are there pharmacological differences that impact tolerability? Antimuscarinics Agents Generic Name Darifenacin Feso-terodine Oxybutynin Solifenacin succinate Tolterodine L-tartrate ER Trospium chloride ER CR Trans-dermal gel Trans-dermal patch Bladder Specificity Moderate None High M3 Muscarinic Selectivity Yes No Notes to Facilitator: This slide lists the anticholinergic drugs that are in current clinical use These drugs can be divided into agents that block, to some extent, all cholinergic receptors; drugs that selectively block a particular subtype of cholinergic receptor; and/or drugs that specifically target the bladder or have more systemic mechanism of action Anticholinergics oxybutynin, tolterodine and trospium work through the non-selective inhibition of acetylcholine on muscarinic receptors in smooth muscle throughout the body Solifenacin and darifenacin, two new agents for OAB, have a stronger affinity for the M3 receptor compared to other anticholinergic agents and therefore have comparable efficacy but a proposed lower side effect profile Respective Product Monographs; Hashim H et al, Drugs 2004;64(15): ; Chapple CR et al. BJU Int. 2006:98(supplement 1);78-87. 47

Commonly Reported Side Effects with Antimuscarinics
Are there pharmacological differences that impact tolerability? 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% 6.4% Oxybutynin ER (5-30 mg OD) 60.8% 13.1% 6.1% 6.8% 6.3% Oxybutynin patch 4.1% 3.3% Oxybutynin gel 6.9% 1.3% 1.5% Solifenacin (5 mg OD) 10.9% 5.4% 0.3% 1.9% Tolterodine ER (4 mg OD) 23.4% 5.9% <5% Trospium chloride (20 mg bid) 20.1% 9.6% 1.2% 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. 48 48

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 10 mg Oxybutynin IR 15 mg Oxybutynin IR 10 mg Fesoterodine 8 mg Trospium chloride 40 mg Solifenacin 5 mg Tolterodine ER 4 mg Oxybutynin gel Fesoterodine 4 mg Oxybutynin ER 15 mg Buser et al. Eur Urol. 2012;62:

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 10 mg Oxybutynin IR 15 mg Oxybutynin IR 10 mg Fesoterodine 8 mg Trospium chloride 40 mg Solifenacin 5 mg Tolterodine ER 4 mg Oxybutynin gel Fesoterodine 4 mg Oxybutynin ER 15 mg n/a Buser et al. Eur Urol. 2012;62:

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 10 mg Oxybutynin IR 15 mg Oxybutynin IR 10 mg Fesoterodine 8 mg Trospium chloride 40 mg Solifenacin 5 mg Tolterodine ER 4 mg Oxybutynin gel Fesoterodine 4 mg Oxybutynin ER 15 mg n/a Buser et al. Eur Urol. 2012;62:

Head-to-head studies of antimuscarinics
Comparison of efficacy between products? Mean reduction in micturitions/24hrs (primary endpoint) STAR Trial Tolterodine ER vs. Solifenacin Tolterodine ER vs. Fesoterodine Placebo Tolterodine ER 4 mg Fesoterodine 4 mg Fesoterodine 8 mg Solifenacin 5/10 mg Tolterodine ER 4 mg BL: 12.0 11.5 11.6 11.9 11.78 11.66 * † † 8.7% ‡ 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: Corrigendum. Eur Urol 2008;53:1319; 2. Chapple CR et al Eur Urol 2005;48:464-70

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 After 4-6 weeks of alpha-blockers, if storage symptoms persist an antimuscarinic therapy can be started safely if: PVR is low (<200 mL) Qmax is > 5 mL/s 65% of men treated for bladder outlet obstruction have remaining OAB symptoms 1. Bettez M et al. Can Urol Assoc J 2012;6(5):

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 Oxybutynin IR mg/day: Placebo Antimuscarinics ~ 1 in 500 patients 0.2 % ~ 5.5 in 500 patients 1.1 % Only agent that has shown a statistically significant increase in AUR vs. Placebo Incidence with newer agents is ≈ that of placebo

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 Notes to Facilitator: To determine whether a drug will have adverse effects on cognition, 3 factors must be considered: How readily will the agent cross the BBB? Does the patient have an intact BBB? (3) To what extent does the agent block the M1 receptor subtype? Staskin DR. Drugs Aging. 2005;22(12): ; 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. 58

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 Solifenacin Darifenacin *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):

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

A B C D E ASK THE AUDIENCE Efficacy Tolerability Adherence to therapy
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
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 In Quebec 61% of oxybutynin and 63% of flavoxate patients did not refill after their first prescription 78% and 83% respectively stopped using their prescription after 3 months Abstract Rates of treatment discontinuation for OAB treatment are consistently high. This study systematically reviewed persistence and adherence data in patients with OAB treated with anticholinergic therapy. Results from 12-week clinical trials showed high rates of discontinuation, ranging from 4% to 31% and 5% to 20% in treatment and placebo groups, respectively. Unsurprisingly, rates of discontinuation found in medical claims studies were substantially higher, with 43% to 83% of patients discontinuing medication within the first 30 days and rates continuing to rise over time. Findings from medical claims studies also suggest that over half of patients never refill their initial prescription and that adherence levels tend to be low, with mean/median medication possession ratio (MPR) values ranging from 0.30 to 0.83. The low levels of persistence and adherence documented in this review reveal cause for concern about the balance between the efficacy and tolerability of anticholinergic agents. Strategies should be identified to increase persistence and adherence. New agents and non-pharmacologic alternatives with good efficacy and minimal side effects should be explored. Oxybutynin Sexton CC et al. Int J Clin Pract. 2012;65:567–585.

Levels of Treatment Persistence Over 12 Months With Antimuscarinic Treatment
Abstract - Patients aged 60 years and above were more likely to persist with prescribed oral antimuscarinic drugs than younger patients (40-59 years). - Solifenacin was consistently associated with the highest rate of persistence compared with the other antimuscarinics included in the study Objectives: To describe the level of persistence for patients receiving antimuscarinics for overactive bladder (OAB) over a 12-month period based on real prescription data from the UK. To investigate patterns of persistence with oral antimuscarinic drugs prescribed for OAB, across different age groups. Patients and methods: UK prescription data from a longitudinal patient database were analysed retrospectively to assess persistence with darifenacin, flavoxate, oxybutynin (extended release [ER] and immediate release [IR]), propiverine, solifenacin, tolterodine (ER/IR) and trospium. Data were extracted from the medical records of >1,200,000 registered patients via general practice software, and anonymized prescription data were collated for all eligible patients with documented OAB (n = 4833). Data were collected on patients who started treatment between January 2007 and December 2007 and were collected up to December 2008, to allow each patient a full 12-month potential treatment period. Failure of persistence was declared after a gap of at least 1.5 times the length of the period of the most recent prescription. The analysis included only patients who were new to a course of treatment (i.e. who had not been prescribed that particular treatment or dosage for at least 6 months before the study period). Results: The number of patients prescribed each antimuscarinic drug varied from 23 for darifenacin to 1758 for tolterodine ER. The longest mean persistence was reported for solifenacin (187 days versus days for the other treatments). At 3 months, the proportions of patients still on their original treatment were: solifenacin 58%, darifenacin 52%, tolterodine ER 47%, propiverine 47%, tolterodine IR 46%, oxybutynin ER 44%, trospium 42%, oxybutynin IR 40%, flavoxate 28%. At 12 months, the proportions of patients still on their original treatment were: solifenacin 35%, tolterodine ER 28%, propiverine 27%, oxybutynin ER 26%, trospium 26%, tolterodine IR 24%, oxybutynin IR 22%, darifenacin 17%, flavoxate 14%. In a sub-analysis stratified by age, patients aged ≥ 60 years were more likely to persist with prescribed therapy over the 12-month period than those aged <60 years. Conclusions: Twelve months after the initial prescription, persistence rates with pharmacotherapy in the context of OAB are generally low. Solifenacin was associated with higher levels of persistence compared with other prescribed antimuscarinic agents. Older people are more likely than younger patients to persist with prescribed therapy. Further studies are required to understand this finding and why patients are more likely to persist with one drug rather than another. After 12 months, less than 35% of patients were still on antimuscarinic treatment Wagg A et al. BJU Int. 2012;110(11):

46% did not work as expected 25% switched to a new medication
“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 Survey of people in the USA on antimuscarinic therapy Based on 1322 phase 2 respondents who discontinued OAB medication CONCLUSIONS: Expectations about treatment efficacy and side-effects are the most important considerations in discontinuing OAB medications for most patients. Interventions to promote realistic expectations about treatment efficacy and side-effects might enhance adherence. 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):

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 Alpha1-adrenoceptor antagonists Blockade causes smooth muscle in prostate and bladder neck to relax Improves urine flow & reduces BPH symptoms Onabotulinumtoxin A is now approved for primary idiopathic OAB in Canada Fowler CJ et al. Nature Reviews Urology 2008;(9): ; Nitti VW. Rev Urol. 2006;8(4): ; Solifenacin Product Monograph, 2011; Tamsulosin Product Monograph, 2012; Mirabegron Product Monograph, 2013.

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 Alpha1-adrenoceptor antagonists Blockade causes smooth muscle in prostate and bladder neck to relax Improves urine flow & reduces BPH symptoms Onabotulinumtoxin A is not approved for primary idiopathic OAB in Canada Fowler CJ et al. Nature Reviews Urology 2008;(9): ; Nitti VW. Rev Urol. 2006;8(4): ; Solifenacin Product Monograph, 2011; Tamsulosin Product Monograph, 2012; Mirabegron Product Monograph, 2013.

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): Hicks A, McCafferty GP, Riedel E et al. J Pharmacol Exp Ther. 2007;323(1):

Mean reduction in OAB symptoms compared to placebo
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 † -0.20 -0.40 -0.60 -1.00 -1.20 -1.40 -1.80 -2.00 0.00 -0.80 -1.60 -2.25 -1.00 -2.00 0.00 -0.25 -0.50 -0.75 -1.25 -1.50 -1.75 -2.50 Mirabegron 50 mg Mirabegron 50 mg Tolterodine ER 4 mg Tolterodine ER 4 mg Adjusted Mean Change From Baseline Adjusted Mean Change From Baseline Results: A total of 812, 820, and 812 patients received mirabegron 50mg, mirabegron 100mg, and tolterodine ER 4 mg, respectively. Baseline demographic and OAB characteristics were similar across groups. TEAEs were reported in 59.7%, 61.3%, and 62.6% of patients, respectively; most were mild or moderate. Serious TEAEs were reported in 5.2%, 6.2%, and 5.4% of patients, respectively. The most common TEAEs were similar across groups. Dry mouth was reported by 2.8%, 2.3%, and 8.6% of patients, respectively. Adjusted mean changes from baseline to final visit in morning systolic blood pressure were 0.2, 0.4, and -0.5mm Hg for mirabegron 50mg, 100mg, and tolterodine ER 4 mg, respectively. Mirabegron and the active control, tolterodine, improved key OAB symptoms from the first measured time point of 4 wk, and efficacy was maintained throughout the 12-mo treatment period. The study was not placebo controlled, which was a limitation. Conclusion: The safety and tolerability of mirabegron was established over 1 yr, with sustained efficacy observed over this treatment period. -BL 1 3 6 9 12 -BL 1 3 6 9 12 Month Month N Mira 50 mg Tolterodine N Mira 50 mg Tolterodine † Mean ± SE. Chapple CR et al. Eur Urol. 2013;63(2):

Mirabegron: Safety Compared to Anticholinergic Treatment (12-weeks)
Placebo (%) Mirabegron 50 mg Tolterodine ER 4 mg (%) Common TEAEs Any AE 43.3% 42.8% 46.7% Hypertension 7.7% 5.9% 8.1% Nasopharyngitis 1.6% 2.8% Dry mouth 2.6% 10.1% Headache 3.7% 3.6% Influenza 2.2% 1.4% Urinary tract infection 2.0% Constipation Cardiovascular TEAEs QTc prolongation or its sequelae 0.4% Atrial fibrillation of medical importance 0.2% 1.0% Arrhythmia 3.2% Abstract (Khuller, 2013) Background: Mirabegron, a β(3)-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB). Objective: To assess the efficacy and tolerability of mirabegron versus placebo Design: Multicenter randomised double-blind, parallel-group placebo- and tolterodine-controlled phase 3 trial conducted in 27 countries in Europe and Australia in patients ≥ 18 yr of age with symptoms of OAB for ≥ 3 mo. Intervention: After a 2-wk single-blind placebo run-in period, patients were randomised to receive placebo, mirabegron 50mg, mirabegron 100mg, or tolterodine extended release 4 mg orally once daily for 12 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients completed a micturition diary and quality-of-life (QoL) assessments. Co-primary efficacy end points were change from baseline to final visit in the mean number of incontinence episodes and micturitions per 24h. The primary comparison was between mirabegron and placebo with a secondary comparison between tolterodine and placebo. Safety parameters included adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, and postvoid residual volume. Results: A total of 1978 patients were randomised and received the study drug. Mirabegron 50-mg and 100-mg groups demonstrated statistically significant improvements (adjusted mean change from baseline [95% confidence intervals]) at the final visit in the number of incontinence episodes per 24h (-1.57 [-1.79 to -1.35] and [-1.68 to -1.23], respectively, vs placebo [-1.39 to -0.95]) and number of micturitions per 24h (-1.93 [-2.15 to -1.72] and [-1.99 to -1.56], respectively, vs placebo [-1.55 to -1.12]; p<0.05 for all comparisons). Statistically significant improvements were also observed in other key efficacy end points and QoL outcomes. The incidence of treatment-emergent AEs was similar across treatment groups. The main limitation of this study was the short (12-wk) duration of treatment. CONCLUSIONS: Mirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability. TRIAL IDENTIFICATION: This study is registered at ClinicalTrials.gov, identifier NCT TEAE = treatment-emergent adverse event; Khullar V et al. Eur Urol. 2013;63:283–295

How β3-adrenoreceptor Agonists Compare to Existing Therapy
 Comparative efficacy AEs Low incidence of AEs characteristic of antimuscarinic therapy (i.e., dry mouth) Potential for improved patient compliance 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? Improved incidence of side effects hallmark of antimuscarinic drugs i.e. Dry mouth: 2.8 % vs. 2.4% vs. 8.6% for Mirabegron 50 mg, 100 mg and Tolterodine ER 4 mg respectively May translate into better adherence Does not block muscarinic receptors in brain, known to be involved 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): ; Mirabegron Product Monograph, Astellas Pharma Canada, Inc, 2013.

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)

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

WHAT IS YOUR CURRENT COMFORT LEVEL OF: Differentiating and initiating antimuscarinics A Not comfortable at all B Somewhat comfortable C Comfortable D Very comfortable

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

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Urgent Matters in OAB An FAQ Approach to What You Need to Know

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