Urgent Matters in OAB An FAQ Approach to What You Need to Know Dr. Jeffrey M. Spodek, MD, FRCSC...

Urgent Matters in OAB

An FAQ Approach to What You Need to Know

Dr. Jeffrey M. Spodek, MD, FRCSCDivision 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

#1WHAT IS YOUR CURRENT COMFORT LEVEL OF:WHAT IS YOUR CURRENT COMFORT LEVEL OF:

Identifying patients with OAB needing treatment

A Not comfortable at all

Somewhat comfortable

Comfortable

Very comfortable

B

C

D

LEARNING CHECKPOINT


Differentiating and initiating antimuscarinics

Not comfortable at all


Comfortable

Very comfortable

A

B

C

D

LEARNING CHECKPOINT

#3WHAT IS YOUR CURRENT KNOWLEDGE LEVEL OF:WHAT IS YOUR CURRENT KNOWLEDGE LEVEL OF:

Beta-3 receptor agonists and future therapies in OAB management

Not knowledgeable at all

Somewhat knowledgeable

Knowledgeable

Very knowledgeable

A

B

C

D

Overactive Bladder Overview

Your guide to tackling OAB in your officeYour guide to tackling OAB in your office

Establishing an OAB diagnosis

30 Years of Antimuscarinic Therapy


Wrapping it all upWrapping it all up

Clinical Definition of OAB

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

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

“Urgency, with or without urgency incontinence, usually associated with

frequency and nocturia”

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 OABWet OAB

Mixed Incontinence

urgency incontinence

urgency, frequency

without incontinence

Involuntary leakage associated

with urgency

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.

38% 38% Wet OABWet OAB 62% 62%

Dry OABDry OAB

Proportion of OABConsidered a

combination of stress and urge

incontinence

Stress incontinence is involuntary leakage associated with exertion, effort, sneezing or coughing

OAB negatively impacts Canadians

Risk of falls/fractures Economic burden Emotional Occupational Physical

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.

Impacts Quality of Life (QoL)2-5Impacts Quality of Life (QoL)2-5

Effects more than 1 in 10 CanadiansEffects more than 1 in 10 Canadians

Sleep Social Sexual

(13.1% of men and 14.7% of women)

of Canadian respondents reported symptoms1

The effect of moderate urinary symptoms on QoL is similar to that of having diabetes, high blood pressure, or cancer6

Similar Prevalence of OAB in Men and Women

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

45–54 years 55–64 years ≥ 65 years

(1,348,901)Number of patients:

(1,270,892) (543,420) (1,201,365) (755,218) (2,124,705)(7,244,501)

Helfand et al. Eur Urol 2010;57:586–591

Treated

Untreated

Total untreated (men and women)

Treated

Untreated

Total untreated (men and women)

• A large proportion of patients diagnosed with OAB are not taking medication

• Men with OAB are more frequently untreated than women

ESTABLISHING AN OAB DIAGNOSIS

How do I incorporate

diagnosis into my practice?

What are themost 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 ModuleNext Module

OAB: A Secret Condition

Do not always bring up symptoms• May be due to lack of knowledge

(considered “a natural part of aging”)• May be due to embarrassment



Welch LC et al. Res Nurs Health 2011;34(6):496-507.

84%84%If they do,

approach their primary care physician

Do not routinely ask about urinary symptoms

Simple Questions

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…”



Start the conversation by asking:Start the conversation by asking:

OAB Patient ScreenerHow do I

incorporate diagnosis into my

practice?

Patients can screen for OAB in the

waiting room:

Patients can screen for OAB in the

waiting room:








Are there specific




Assess Patient HistoryWhat are the

most importanttests to establish

diagnosis?

Age (incidence increases with age)

Age (incidence increases with age)

Medical history Medical history (assess for medications (assess for medications

that could cause that could cause symptoms) symptoms)

Medical history Medical history (assess for medications (assess for medications

that could cause that could cause symptoms) symptoms)

Duration and severity of symptoms

Duration and severity of symptoms

Degree of Degree of bother/effect bother/effect on activities on activities of daily lifeof daily life

Degree of Degree of bother/effect bother/effect on activities on activities of daily lifeof daily life

Lifestyle characteristics, including fluid

intake

Lifestyle characteristics, including fluid

intake

Association with other

voiding and storage

symptoms

Association with other

voiding and storage

symptoms

Prior surgery/ trauma

Prior surgery/ trauma

1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63

Red FlagsRed FlagsRed FlagsRed Flags Smoker with hematuria

History of complicated recurrent urinary tract infections

Severe symptoms of bladder outlet obstruction

Pain related to the bladder

Perform Physical ExaminationWhat are the


diagnosis?


Red FlagsRed FlagsRed FlagsRed Flags

Bladder/pelvic pain

Cough test, if appropriate

Use to differentiate stress urinary incontinence

Cough test, if appropriate

Use to differentiate stress urinary incontinence

Abdominal, pelvic, Abdominal, pelvic, and perineal and perineal examinationexamination

Include digital rectal exam if Include digital rectal exam if appropriateappropriate

Abdominal, pelvic, Abdominal, pelvic, and perineal and perineal examinationexamination

Include digital rectal exam if Include digital rectal exam if appropriateappropriate

Pelvic floor muscle assessment

Pelvic floor muscle assessment

Appropriate InvestigationsWhat are the


diagnosis?


Red FlagsRed FlagsRed FlagsRed Flags

Hematuria (gross or macroscopic)

Elevated PVR (>200 cc)(assume palpable bladder)

Elevated PSA

Complicated positive urine culture

Standard Standard recommendation: recommendation:

Urinalysis and cultureUrinalysis and culture

Standard Standard recommendation: recommendation:

Urinalysis and cultureUrinalysis and culture

Optional: Post-void residual urine (PVR)PSA, if appropriateBlood tests

If applicable co-morbidities are present (diabetes, etc.)

Assessment of renal function is not mandatory

Optional: Post-void residual urine (PVR)PSA, if appropriateBlood tests

If applicable co-morbidities are present (diabetes, etc.)

Assessment of renal function is not mandatory








Are there specific




Differentiating OAB from SUI and MI

Symptoms OABStress 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

Kirby M, et al. Int J Clin Pract 2006; 60: 1263–127.

How do I differentiate between similar conditions?

REMINDER: OAB IS DEFINED AS“Urgency, with or without urgency

incontinence, usually associated with frequency and nocturia”

Differential Diagnosis from Related Conditions

Presenting Symptom*

OAB BPH (males) Bladder Cancer UTI

Urgency Yes Yes Occasionally Yes

Frequency Yes Yes Occasionally Yes

Nocturnal Frequency Often Yes Rare Often

Incomplete emptying No Yes No No

Weak stream No Yes No No

Straining/hesitancy No Yes No Occasionally

Elevated PSA No Occasionally No 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.

How do I differentiate between similar conditions?

Additional ConsiderationsHow do I

differentiate between similar conditions?

Red FlagsRed FlagsRed FlagsRed Flags Smoker with hematuria

History of complicated recurrent urinary tract infections

Severe symptoms of bladder outlet obstruction

Bladder/pelvic pain

OAB and Interstitial Cystitis

OAB and Prostate Cancer

Can present with similar symptoms (frequency, urgency, and negative cultures)

Key differentiator: Pain

Can present with similar symptoms

At risk group: older men, abnormal DRE, elevated PSA








Are there specific




A Case of Mistaken IdentityAre there specific


of men with lower urinary tract

symptoms do not have bladder outlet

obstruction1

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

Many men may Many men may present with present with

primary idiopathic primary idiopathic OABOAB22

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 Voiding SymptomsPost-Micturition

Symptoms Urgency Frequency Incontinence Nocturia

Poor flow Intermittency Straining Hesitancy Terminal dribble

Post-void dribble Incomplete emptying

Are there specific


Suggestive of OAB Suggestive of BOO/BPH

However, OAB and BPH frequently co-existHowever, 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








Are there specific




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

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

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








Are there specific




Clinician’s OAB Toolbox

Oxybutynin

Oxybutynin IROxybutynin EROxybutynin CROxybutynin patchOxybutynin gel

Oxybutynin

Oxybutynin IROxybutynin EROxybutynin CROxybutynin patchOxybutynin gel

5-HMT5-HMT

Tolterodine IRTolterodine IRTolterodine ERTolterodine ER

FesoterodineFesoterodine

5-HMT5-HMT

Tolterodine IRTolterodine IRTolterodine ERTolterodine ER

FesoterodineFesoterodine

DarifenacinDarifenacinDarifenacinDarifenacinSolifenacinSolifenacinSolifenacinSolifenacin

Trospium chlorideTrospium chloride

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 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

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?

Are there pharmacological differences that

impact tolerability?

Comparison of efficacy between

products?

Can antimuscarinics be used in men?

What is the efficacy & tolerability in

special populations?


Getting Your Patients On BoardWhat are the options for behavioural

therapy?

Counseling patients on how to best incorporate strategies into their lives

• Adherence to behavioural interventions

Optimal treatment outcomes

Patient education is key to optimal treatment outcomes

Patient education is key to optimal treatment outcomes

Wyman JF et al. Int J Clin Pract. 2009;63(8):1177-91.

Healthy Bladder HabitsWhat are the options for behavioural

therapy?


Behavioural ModificationsWhat are the options for behavioural

therapy?




therapy?


products?







Therapies Block Muscarinic Receptors in the Bladder

Gillenwater JY, Grayhack JT, Howards, SS et al. Adult & Pediatric Urology (4th Edition). Philidelphia, PA: Lippincott Williams & Wilkins. 2002.

Mucosa and submucosa (M2, M3)

Bladder neck (α)

Pelvic floor (N)Urethra (α)

Detrusor muscle (M2 80%; M3 20%; β)

M = muscarinicN = nicotinicα = α1 and α2 –adrenergicΒ = β3-adrenergic

Blocking receptors prevents detrusor Blocking receptors prevents detrusor contractioncontraction



Muscarinic Receptors are Distributed Throughout the Body

Heart

Stomach and esophagus

Dyspepsia

Iris/ciliary body

Lacrimal gland

Blurred vision

Dry eyes

Tachycardia

Abrams P., et al. Br J Pharmacol. 2006;148(5):565-578. Sellers DJ, et al. Curr Opin Urol. 2007;17:223-230.

M1: Cortex, hippocampus,sympathetic ganglia

M2: Hindbrain, heart, smooth muscle

M3: Smooth muscle, brain, glands, heart,

M4: Basal forebrain, striatum

M5: Substantia nigraBladder (detrusor muscle)

Colon Constipation

Salivary glands

Dry mouth



Generic Name

Darifenacin Feso-terodine

Oxybutynin

Solifenacin succinate

Tolterodine L-tartrate

ER

Trospium chloride

ER CRTrans-

dermal gel

Trans-dermal patch

Bladder Specificity

Moderate Moderate None None None None High Moderate None

M3 Muscarinic Selectivity

Yes NoNo No No No Yes No 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.

Antimuscarinics AgentsAntimuscarinic Agents Differ in Their Receptor and Organ Selectivity



Commonly Reported Side Effects with Antimuscarinics

Respective Product Monographs.

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.

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)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)Solifenacin (5 mg OD) 10.9% 5.4% 0.3% 1.4% 1.9%

Tolterodine ER (4 mg OD)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

Newer long-acting agents tend to have better tolerability compared to oxybutynin and immediate-release formulations

Newer long-acting agents tend to have better tolerability compared to oxybutynin and immediate-release formulations





therapy?


products?







Anticholinergics Effectively Reduce OAB Symptoms

Buser et al. Eur Urol. 2012;62:1040-1060

Network meta-analysis comparing antimuscarinics in the treatment of OAB

Mean reduction in micturitions/24h compared to placebo

Solifenacin10 mg

OxybutyninIR 15 mg

OxybutyninIR 10 mg

Fesoterodine8 mg

Trospium chloride 40 mg

Solifenacin5 mg

Tolterodine ER 4 mg

Oxybutynin gel

Fesoterodine4 mg

OxybutyninER 15 mg


products?




Mean reduction in urgency episodes/24h compared to placebo

Solifenacin10 mg

OxybutyninIR 15 mg

OxybutyninIR 10 mg

Fesoterodine8 mg


Solifenacin5 mg

Tolterodine ER 4 mg

Oxybutynin gel

Fesoterodine4 mg

OxybutyninER 15 mg

n/a


products?




Mean reduction in urgency incontinence episodes/24h compared to placebo

Solifenacin10 mg

OxybutyninIR 15 mg

OxybutyninIR 10 mg

Fesoterodine8 mg


Solifenacin5 mg

Tolterodine ER 4 mg

Oxybutynin gel

Fesoterodine4 mg

OxybutyninER 15 mg

n/a


products?

Head-to-head studies of antimuscarinics

Solifenacin5/10 mg

Fesoterodine8 mg

Tolterodine ER 4 mg

Fesoterodine4 mg

Tolterodine ER 4 mg

Placebo

Mean reduction in micturitions/24hrs (primary endpoint)

STAR TrialTolterodine ER vs.

Solifenacin

STAR TrialTolterodine ER vs.

SolifenacinTolterodine ER vs.

Fesoterodine

Tolterodine ER vs. Fesoterodine

* 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

Head-to-head studies of antimuscarinics

11.78 11.6611.911.611.512.0BL:

* ††

‡


products?

8.7%9.4%



therapy?


products?







Guidelines advocate the use of antimuscarinics in men

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

“Antimuscarinic agents may be used alone as first line therapy when primary idiopathic

OAB exists”

• After 4-6 weeks of alpha-blockers, if storage symptoms persist an antimuscarinic therapy can be started safely if:o PVR is low (<200 mL)o Qmax is > 5 mL/s

1. Bettez M et al. Can Urol Assoc J 2012;6(5):354-63..

Managing Your AUR Concerns

Assumed increased risk based on what the effect of antimuscarinics may be, but has not been proven scientifically

Actual risk of AUR

Oxybutynin IR 7.5-10mg/day:

Placebo Antimuscarinics

~ 1 in 500 patients 0.2 % ~ 5.5 in 500

patients 1.1 %

Incidence with newer agents is ≈ that of placeboIncidence with newer agents is ≈ that of placebo

Only agent that has shown a statistically significant increase in AUR vs. Placebo




therapy?


products?







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

Ballert KN and Bales GT. Curr Bladder Dysfunct Rep 2013;8:57-61.

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)

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)

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



therapy?


products?







ASK THE

AUDIENCEWHAT IS THE MOST IMPORTANT FEATURE OF OAB THERAPY?

WHAT IS THE MOST IMPORTANT FEATURE OF OAB THERAPY?

Efficacy

Tolerability

Adherence to therapy

Newer therapeutic option

None of the above

A

B

C

D

E

Levels of Treatment Adherence With Antimuscarinic Treatment

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

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

Wagg A et al. BJU Int. 2012;110(11):1767-1774.

After 12 months, less than 35% of patients were still on antimuscarinic treatment

After 12 months, less than 35% of patients were still on antimuscarinic treatment

“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

Benner JS, Nichol MB, Rovner ES et al. BJU Int. 2010:105(9):1276-1282

Percentages do not add to 100 because multiple reasons were allowed

Because of bothersome side effects and a lack of compliance, attempts have been made

to develop new compounds

Because of bothersome side effects and a lack of compliance, attempts have been made

to develop new compounds

Actions of Lower Urinary Treatments

Alpha1-adrenoceptor antagonists•Blockade causes smooth muscle in prostate and bladder neck to relax•Improves urine flow & reduces BPH symptoms

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

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.

Onabotulinumtoxin A is now approved for primary idiopathic OAB in Canada

Actions of Lower Urinary Treatments

Alpha1-adrenoceptor antagonists•Blockade causes smooth muscle in prostate and bladder neck to relax•Improves urine flow & reduces BPH symptoms

Beta3-adrenoceptor agonists•Activation causes detrusor muscle relaxation•Increases bladder capacity•Does not interfere with the voiding process

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 not approved for primary idiopathic OAB in CanadaFowler 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.

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

*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. placeboMirabegron Product Monograph, 2013; Khullar V et al. Eur Urol. 2013;63:283–295

Mirabegron demonstrated significant improvements in OAB symptoms, including urgency

Mirabegron demonstrated significant improvements in OAB symptoms, including urgency

*

**

***

†

†

††

Improvement in OAB parameters maintained over 12 months (178-CL-049)

Chapple CR et al. Eur Urol. 2013;63(2):296-305

-BL 1 3 6 9 12

† Mean ± SE.

N

Mira 50 mg 478 478 447 409 387 370

Tolterodine 485 485 452 418 387 379

N

Mira 50 mg 789 786 742 684 656 627

Tolterodine 791 786 735 684 645 623

Incontinence † Micturitions †

-0.20

-0.40

-0.60

-1.00

-1.20

-1.40

-1.80

-2.00

0.00

-0.80

-1.60

-BL 1 3 6 9 12Month

-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

Tolterodine ER 4 mg

Ad

juste

d M

ean

Ch

an

ge F

rom

B

aselin

e

MonthA

dju

ste

d M

ea

n C

ha

ng

e F

rom

B

as

eli

ne

Mirabegron 50 mg

Tolterodine ER 4 mg

Mirabegron: Safety Compared to Anticholinergic Treatment (12-weeks)

Placebo(%)

Mirabegron 50 mg (%)

Tolterodine ER 4 mg (%)

Common TEAEsAny AE 43.3% 42.8% 46.7%Hypertension 7.7% 5.9% 8.1%Nasopharyngitis 1.6% 2.8% 2.8%Dry mouth 2.6% 2.8% 10.1%Headache 2.8% 3.7% 3.6%Influenza 1.6% 2.2% 1.4%

Urinary tract infection

1.4% 1.4% 2.0%

Constipation 1.4% 1.6% 2.0%Cardiovascular TEAEsQTc prolongation or its sequelae

0 0 0.4%

Atrial fibrillation of medical importance

0.2% 0.4% 1.0%

Arrhythmia 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

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.

AEsAEs

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 placeboShould have no involvement in cognition and memoryAttractive option for elderly patients?

Low incidence of AEs characteristic of antimuscarinic therapy (i.e., dry mouth)

Comparative efficacy

Potential for improved patient compliance

Potential for improved patient compliance

OAB Can Be Tackled in Your Practice

Identify OAB patients needing treatmentIdentify 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 referralTreatment 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 improveOAB 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


Identifying patients with OAB needing treatment



Comfortable

Very comfortable

A

B

C

D

LEARNING CHECKPOINT


Differentiating and initiating antimuscarinics



Comfortable

Very comfortable

A

B

C

D

LEARNING CHECKPOINT

#3WHAT IS YOUR CURRENT KNOWLEDGE LEVEL OF:WHAT IS YOUR CURRENT KNOWLEDGE LEVEL OF:


Not knowledgeable at all

Somewhat knowledgeable

Knowledgeable

Very knowledgeable

A

B

C

D

COMMENTS/QUESTIONS

THANK YOU

Urgent Matters in OAB An FAQ Approach to What You Need to Know Dr. Jeffrey M. Spodek, MD, FRCSC...

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