Transcript Slide 1

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