1. Update on the Management of Overactive Bladder Challenges in Obstetrics & Gynecology Kuwait, Feb 8, 2017
Dante Pascali MD, FRCS(C)
Urogynecology Division Head
Assistant Professor, University of Ottawa
Canada

2. Disclosures
Consultant for Pfizer, Astellas and Duchesnay.

3. Objectives
To better understand the signs and symptoms of Overactive Bladder (OAB).
To review the various treatment options for OAB.
To evaluate the newer treatment modalities.

4. What Is Overactive Bladder?
Defined by the International Continence Society (ICS) as urgency, with or without urgency incontinence, usually with frequency and nocturia
Definitions of signs and symptoms of OAB
Urgency: a sudden compelling desire to void that is difficult to defer
Urge urinary incontinence (UUI): involuntary leakage of urine accompanied by or immediately preceded by urgency
Urinary frequency: an increase in the number of voids during 24 hours
Nocturia: one or more voids that interrupt a night’s sleep
In 2002, the International Continence Society (ICS) published revised definitions of OAB and other lower urinary tract symptoms. OAB is defined as “urgency with or without urge incontinence, usually with frequency and nocturia, in the absence of proven infection or other obvious pathology”
Urgency is often believed to be the cornerstone symptom of OAB. It is defined as a sudden compelling desire to void that is difficult to defer
Urinary incontinence is defined as any involuntary leakage of urine. Urge urinary incontinence (UUI) is the complaint of involuntary leakage accompanied by or immediately preceded by urgency
Frequency is defined as the number of times a person voids. This can be reported as 24-hour frequency, daytime frequency, and nighttime frequency. The symptom of frequency is usually associated with voiding more than 8 times/24 hrs
Nocturia is defined as 1 or more voids interrrupting a night’s sleep
References:
Abrams P et al. Neurology and Urodynamics. 2002;21:
Abrams P et al. Neurology and Urodynamics. 2002;21:

5. OAB Symptoms Are Prevalent in Both Men and Women and Increase with Age
Data from EPIC study (2005), conducted in
Canada, Italy, Germany, Sweden, and UK
n = 19,165; Overall OAB prevalence = 11.8% 25
Men
Women 20 15
OAB Prevalence (%) 10 5
18-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70+
The EPIC study was the first large-scale, multi-national, population-based, cross-sectional survey to estimate the prevalence of lower urinary tract symptoms using current (2002) International Continence Society (ICS) definitions. This study was conducted between April and December 2005 and included randomly selected men and women ≥18 years of age in Canada, Germany, Italy, Sweden, and the United Kingdom
The prevalence of overactive bladder (OAB) is similar in men and women and increases with age for both sexes. In this study, which included over 19,000 men and women in Europe and Canada, the prevalence of OAB was 10.8% in men and 12.8% in women, or 11.8% overall
In a separate UK study designed to described the natural history of OAB and SUI in women using validated symptom syndrome scores ≥40 with a 3 year follow-up, the severity of OAB increased progressively with age, accelerating after age 60
References:
Irwin DE et al. Eur Urol. 2006;50:
Donaldson MM et al. Neurol Urodyn 2006;25:
Age Group (years)
In a separate, UK study of the natural history of OAB and SUI in women over ≥40 with a 3 year follow-up, the severity of OAB increased progressively with age, accelerating after age 60
OAB = overactive bladder
SUI = stress urinary incontinence
Irwin DE et al. Eur Urol. 2006;50:
Donaldson MM et al. Neurourol Urodyn 2006;25:

6. Normal vs. Overactive Bladder
A normal bladder muscle sends a strong signal to the brain when it’s full
An overactive bladder muscle contracts involuntarily before it’s full
Normal vs. Overactive Bladder
The normal bladder muscle expands like a balloon to hold a cup or two of urine. When the normal bladder is full, nerves in the bladder signal the brain that it is time to go to the bathroom. Once a person reaches the toilet, the brain sends another message to the large bladder muscle called the detrusor. This causes the detrusor to squeeze, or contract, and push the urine out of your bladder. At the same time, the support muscles that surround the urethra (the sphincter muscles) get a message to relax and let the urine through. If the messages or muscles do not function properly, the person may have bladder control problems
Overactive bladder occurs when the large muscle in the bladder, called the detrusor muscle, contracts involuntarily. This causes a person to feel a sudden and sometimes overwhelming urge to urinate, even when the bladder is not full.
References:
Abrams P et al. The Standardisation of Terminology of Lower Urinary Tract Function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:
Abrams P et al. Neurourology Urodyn 2002; 21: 6

7. Quality of Life Consequences of OAB: Impact on Quality of Life
Physical
Limitations or cessation of physical activities
Psychological
Guilt/depression
Loss of self-esteem
Fear of:
Loss of bladder control
Urine odour
Intimacy
Avoidance of sexual contact and intimacy
Occupational
Absence from work
Decreased productivity
Quality of Life
Social
Reduced social interaction
Planning travel around toilet accessibility
Domestic
Requirements for specialized underwear
Precautions with clothing
Tubaro A. Urology. 2004;64(Suppl 6A):2-6. Abrams et al, 2000; Coyne KS et al. Value Health. 2004;7: Irwin DE et al. Eur Urol. 2006a;50: Zorn BH et al. J Urol. 1999;162: Irwin DE et al. BJU Int. 2006b;97: Stewart WF et al. World J Urol. 2003;20: Papanicolaou S et al. BJU Int. 2005;96: Rigby D. Br J Community Nurs. 2005;10:172, Du Moulin MF et al. Res Nurs Health. 2008;31:

8. Patient awareness tool
OAB-V8
Validated 8-question instrument
Patient self-assessment tool
Available in over 15 languages
High sensitivity and specificity
Questions derived from an officially endorsed OAB symptom and quality of life questionnaire (OAB-q)
Explication

9. Behavioural and Lifestyle Approaches
Retraining the bladder to wait longer between bathroom trips
Strengthening the pelvic floor muscles to help stop urine from leaking
Making dietary and lifestyle changes
Absorbent products and devices
Behavioral and Lifestyle Approaches
Often the first approach to treating overactive bladder is conservative lifestyle changes and physical therapy. Your doctor may recommend one or more of the following therapies.
BLADDER RETRAINING - Bladder control can often be improved by “bladder retraining”. Retraining involves making a schedule for bathroom trips. A schedule puts the brain in control of bladder emptying. By changing the schedule over a period of weeks or months, retraining helps to gradually increase the time between trips to the bathroom. Over several weeks or months, the cycle can approach a normal interval of about four hours.
PELVIC FLOOR MUSCLE EXERCISES - These exercises were designed to strengthen the muscles around the bladder and the urethra, called the pelvic floor muscles. Toning them can help support the bladder which, in turn, can decrease frequency and urgency. Pelvic floor muscle exercises are commonly called “Kegel” exercises, after the doctor who developed them.
DIETARY CHANGES - Some dietary changes can help reduce overactive bladder. One strategy includes limiting foods and drinks containing caffeine, which cause the body to lose water. Caffeine is found in chocolate, coffee and tea as well as many soft drinks (which also contain high amounts of sugar). It can help to reduce the intake of foods and drinks containing alcohol or sugar (including artificial sweeteners), which can irritate the bladder. Drinking an adequate amount of liquids, particularly water, and eating foods high in fibre helps alleviate constipation, which can also contribute to urinary incontinence.
ABSORBENT PRODUCTS AND DEVICES - Many absorbent products, including shields, pads, and undergarments, are available for management of urinary incontinence. There are also devices that can be worn internally by women, which support the bladder and improve control. 9

10. Combination Therapy for Overactive Bladder
Percent reductions in incontinence episodes after 8 weeks
Behavioral therapy alone (N = 8)
Drug therapy added
(N = 8)
P-value
57.5%
88.5%
0.034
Drug therapy alone (N = 27)
Behavioral therapy added
(N = 27)
72.7%
84.3%
0.001
Combination Therapy is Most Effective for Overactive Bladder
This slide shows the reduction in incontinence episodes after 8 weeks of drug therapy alone, behavioral therapy alone, or combination therapy
The addition of drug therapy to behavioral therapy, or vice versa, was more effective in reducing incontinence episodes than either therapy alone
Combination therapy is more effective than either therapy alone
Burgio KL et al. J Am Geriatr Soc. 2000;48:

11. Treatment Modalities

12. Distribution of Receptors in the Lower Urinary Tract
M = muscarinic N = nicotinic α = α1 / α2 –adrenergic
β = β3-adrenergic
Detrusor muscle (M2 80%; M3 20%; β)
Mucosa and submucosa (M2, M3)
Bladder neck (α)
The 2 primary functions of the bladder are storage and voiding.
The storage phase, is regulated by activation of the sympathetic nervous system via stimulation of Alpha1 and β3 ARs by norepinephrine (noradreneline).
The voiding phase is regulated by activation of the parasympathetic nervous system via stimulation of M2 and M3 muscarinic receptors by acetylcholine.
Pelvic floor (N)
Urethra (α)
Abrams P, et al. J Pharmacol 2006; 148(5):
Michel MC and Vrydag W. J Pharmacol 2006; Suppl. 2: S88-119

13. Neurologic Innervations and the Micturition Reflex
SYMPATHETIC (Beta)
Located throughout the bladder, more densely populating the dome and less dense in the trigone
NAd
Myrbetriq
(agonist)
Β3-adrenergic
receptor
Antimuscarinics
(antagonist)
PARASYMPATHETIC (Cholinergic)
Located throughout the “body” of the bladder, trigone and bladder neck
(Relaxation)
detrusor smooth
muscle
(Contraction)
ACH
This slide is use to summarize Myrbetriq’s MOA (mechanism of action) in comparison to antimuscarinics.
The control of bladder musculature is achieved by a balance of noradrenergic regulation of smooth muscle relaxation and cholinergic regulation of the detrusor smooth muscle contraction.
We are now going to take a closer look at the role of the β3-AR in the regulation of the detrusor smooth muscle relaxation in the bladder.
M2/M3 muscarinic
receptor
Yamaguchi O, Chapple CR. Neurourol Uro. 2007; 6: Gras J. Drugs of Today. 2012;48(1): Sacco E ,Bientinesi R. Ther Adv Urol. 2012;4(6):315–324. Tyagi P, et al. Expert Opin Drug Saf. 2011; 10(2): Hicks A, et al. J Pharmacol Exp Ther. 2007;323: ; Takeda M, et al. J Pharmacol Sci 2010; 112: ; Fowler CJ et al. Nat Rev Neurosci 2008; 9:

14. Medical Treatment Beta-3 Agonist: Anticholinergics:
Oxybutynin mg PO TID-QID
Tolterodine 1-2mg PO BID
Extended release oxybutynin 5-10mg PO OD
Extended release tolterodine 2-4mg PO OD
Trospium chloride 20mg OD
Darifenacin mg OD
Solifenacin 5-10mg OD
Fesoterodine 4-8mg OD
Gelnique 10% gel 1 pack OD
Oxytrol patch
Tricyclics:
Imipramine 10 – 20 mg PO bid
Beta-3 Agonist:
Mirabegron mg PO OD

15. Common Side Effects of Anticholinergic Medications
Side effects vary from medication to medication, and from person to person. The most common side effects are:
Dry mouth
Nausea
Dizziness
Drowsiness
Increased heart rate
Difficulty urinating
Constipation
Common Side Effects of Anticholinergic Medications
Side effects vary from medication to medication, and from person to person.
Anticholinergics products do not act only at the bladder level but also on other organs where acetylcholine plays a role. This is how they produce side effects called “anticholinergic side effects”. The most common side effects are listed on the slide.
To manage dry mouth, try chewing sugarless gum, sucking on ice chips or sugarless hard candies. For constipation, try increasing the amount of fiber in your diet and getting more exercise.
Your pharmacist may have further suggestions to help manage adverse events.
Reference:
The Canadian Continence Foundation. Overactive Bladder Medications [online]. 15

16. Anticholinergic Agents for Overactive Bladder: Potential Passage Across the BBB
Vasculature
BBB
CNS
Low lipophilicity
Charged
Relatively “bulky” molecular structure +
Tolterodine
DD 01: Active metabolite + + + + + + +
High lipophilicity,
Neutral
Relatively “small” molecular structure +
Oxybutynin
Anticholinergic Agents for Overactive Bladder: Potential Passage Across the BBB
This slide compares three common anticholinergic agents with respect to their propensity to penetrate the blood-brain barrier
Both tolterodine and trospium are charged molecules and are thus less likely to penetrate the blood-brain barrier
Tolterodine also has low lipophilicity and is a relatively bulky molecule
Oxybutynin, in contrast, is neutral, lipophilic, and relatively small and, thus, is more likely to penetrate the blood-brain barrier compared with tolterodine or trospium
Trospium chloride
Highly polar ++ ++ ++ ++ ++ ++ ++ ++ ++
Todorova A et al. J Clin Pharmacol. 2001;41:

17. CNS Penetration Potential
Trospium
5-HMT*
Darifenacin
Tolterodine
Solifenacin
Oxybutynin
Low Penetration
High Penetration
<
<
< =
<
↓Lipophilicity
↑H-Bonding, molecular flexibility
↑P-gp Substrate (influx/efflux)
↓Brain penetration/binding potential (B:P, CSF:free plasma, Kp,free)
*5-HMT – active metabolite of fesoterodine fumarate
Callegari et al. Br J Clin Pharmacol. 2011; 72:2:
Chancellor MB et al. Drugs Aging April; 29(4):

18. Association Between Overactive Bladder and Falls/Fractures
Database study of more than 6,000 women over 4 years
looked for presence, type, and severity of incontinence and related comorbid conditions
weekly urge incontinence was independently associated with an increased risk of falls and fractures of 30%
these associations were independent of other measures of functional status
Association Between Overactive Bladder and Falls/Fractures
Brown et al. used a questionnaire to assess the risk of falls and fractures in women with urinary incontinence.
The goal was to determine if women with urge urinary incontinence (UUI) had a higher risk of falls and fractures
The rationale for assessing women specifically with UUI was that these women have increased diurnal and nocturnal voiding. Additionally, women with UUI often rush to the bathroom to avoid an episode of incontinence. Therefore, urgency in these women may predispose them to an increased risk of falls and fractures.
In their study of 6,049 women with UUI, Brown et al found that weekly or more frequent episodes of urge incontinence were independently associated with a 30% increased risk of falls and fractures
Brown JS et al. J Am Geriatr Soc. 2000;48:

19. Fesoterodine fumarate (TOVIAZ™)
TOVIAZ (fesoterodine fumarate extended-release tablet)
Once-daily antimuscarinic indicated for the treatment of OAB with symptoms of urge urinary incontinence (UUI), urgency, and frequency
Available in two doses: 4 mg and 8 mg once-daily
Safety and tolerability profile demonstrated in 12-week, double-blind studies, and supported by open-label studies (up to 3 years)
Rapidly and extensively converted to its active metabolite, 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine
TOVIAZ (fesoterodine fumarate) is a once-daily antimuscarinic indicated for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and frequency
Two doses of TOVIAZ (4 mg and 8 mg) were shown to be effective in 2 separate Phase 3 studies
[The recommended starting dose of TOVIAZ is 4 mg once-daily. Based upon individual response and tolerability, the dose may be increased to 8 mg-once daily. According to the TOVIAZ Product Monograph, the daily dose of TOVIAZ should not exceed 4 mg in patients with severe renal insufficiency or in patients taking potent CYP3A4 inhibitors. Full dosing recommendations can be found in the TOVIAZ Product Monograph.]
The safety and tolerability profile has been demonstrated in 12-week, double-blind Phase 3 studies and supported by the results of open-label extension studies
Fesoterodine is rapidly and extensively converted to its active metabolite, 5-hydroxymethyl tolterodine, or 5-HMT, which is also the active metabolite of tolterodine. We’ll talk more about 5-HMT on the next slides
References:
TOVIAZ Product Monograph. Pfizer Canada Inc. February 2012.
Chapple C et al. Eur Urol. 2007;52:
Nitti VW et al. J Urol. 2007;178:
TOVIAZ Product Monograph. February 2012.

20. Key Pharmacokinetic Properties of Fesoterodine
5-HMT has a favorable pharmacokinetic profile:
Linear, dose-proportional pharmacokinetics
Terminal half-life is about 7 hours, with no drug accumulation
No food effect
No gender, age, racial differences
No effect of timing of administration (i.e., night vs. day)
No QT prolongation
10X less lipophilic than oxybutynin
In an in vitro model of BBB, permeability was 3-fold lower than that of tolterodine
Phase 1 studies of fesoterodine identified some key additional characteristics of the drug [These studies, in healthy volunteers, used doses of up to 28 mg daily, which was the maximum tolerated dose]
Fesoterodine is rapidly and completely converted to 5-HMT
The pharmacokinetic profile is linear and dose-proportional
Fesoterodine’s terminal half-life is about 7 hours, with no drug accumulation
The drug can be taken with or without food
No differences in pharmacokinetic based on gender or age have been noted; in particular, no dose adjustment is required for elderly patients. No racial differences in pharmacokinetics have been noted between Whites, Blacks, and Asians
There was no effect on QT prolongation as demonstrated by the Thorough QT study
5-HMT was found to be 10X less lipophilic than oxybutynin
In an in vitro model of BBB, permeability was 3-fold lower than that of tolterodine
References:
TOVIAZ Product Monograph. Pfizer Canada Inc. February 2012.
Malhotra B et al. Eur J Clin Pharmacol. 2010;66:
Malhotra B et al. Int J Clin Pharmacol Ther :
Malhotra B et al. Int J Clin Pharmacol Ther 2009;47:
Malhotra B et al. Eur J Clin Pharmacol. 2009;65:
Malhotra B et al. Int J Clin Pharmacol Ther. 2008;46:
Malhotra B et al. Int J Clin Pharmacol Ther 2010;48:
Callegari E et al. Br J Clin Pharmacol 2011;72:
TOVIAZ Product Monograph. February 2012.
Malhotra B et al. Eur J Clin Pharmacol. 2010;66:
Malhotra B et al. Int J Clin Pharmacol Ther :
Malhotra B et al. Int J Clin Pharmacol Ther 2009;47:
Malhotra B et al. Eur J Clin Pharmacol. 2009;65:
Malhotra B et al. Int J Clin Pharmacol Ther. 2008;46:
Callegari E et al. Br J Clin Pharmacol 2011;72:

21. Subject-reported Satisfaction* with Fesoterodine Treatment
12.3%
18.6%
20.2%
16.7%
38.5%
41.6%
36.8%
46.0%
% of subjects
33.3%
34.1%
38.8%
34.3%
15.9%
5.8%
4.2%
2.9%
Among subjects receiving either fesoterodine 4 mg or 8 mg during the double-blind study, 84% reported being satisfied, very satisfied, or extremely satisfied with fesoterodine treatment at the open-label study baseline visit
In the overall population, subject-reported treatment satisfaction was high at Month 4 (94%), and remained high at Months 12 (96%) and 24 (97%)
Reference:
Van Kerrebroeck PEV et al. Int J Clin Pract 2010;64:
(n = 195ǂ)
(n = 361)
(n = 307)
(n = 239)
97% of patients reported being satisfied, very satisfied or extremely satisfied at 24 months
* Subjects rated Treatment Satisfaction on a 4-point scale by completing the statement: ‘My overall satisfaction is…’ (1 = ‘extremely satisfied’, 2 = ‘very satisfied’, 3 = ‘satisfied’, 4 = ‘not satisfied with treatment’).
ǂ Includes only subjects receiving fesoterodine 4 mg or 8 mg during the double-blind study.
Van Kerrebroeck PEV et al. Int J Clin Pract 2010;64:

22. Summary
Fesoterodine is rapidly and extensively converted into 5-HMT
5-HMT has a dose-dependent pharmacokinetic profile
Efficacy demonstrated for fesoterodine 4 & 8 mg
Efficacy was shown to be dose-dependent
Efficacy maintained over 24 months
Superior efficacy demonstrated for fesoterodine 8 mg vs. tolterodine ER 4 mg
Favourable safety profile for fesoterodine 4 & 8 mg
Fesoterodine is superior to placebo in reducing nocturnal urgency episodes1
First antimuscarinic to demonstrate significant efficacy in a study assessing improvement in nocturnal urgency
Fesoterodine is rapidly and extensively converted into 5-HMT independently of the liver
5-HMT has a dose-dependent pharmacokinetic profile
Efficacy demonstrated for fesoterodine 4 & 8 mg
Efficacy was shown to be dose-dependent
Results from the long-term open-label study further demonstrated that significant improvements in OAB symptoms, HRQL and subject- reported bladder problems were observed at the earliest evaluation point and sustained during 24 months of open-label fesoterodine treatment
The head-to-head (FACT 1 and 2) trials demonstrated superior efficacy for fesoterodine 8 mg vs. tolterodine ER 4 mg
Favourable safety profile for fesoterodine 4 & 8 mg
Dry mouth was the most commonly reported AE and most cases were reported to be mild to moderate in intensity
Low discontinuation rates due to dry mouth (<1%)
No clinically or statistically significant effect on cognitive function parameters, including memory, vs. placebo in healthy older adults
No QT prolongation or ECG abnormalities were seen with 28 mg fesoterodine (3.5X the maximum recommended dose)
References:
TOVIAZ Product Monograph. Pfizer Canada Inc. February 2012.
Nitti VW et al. J Urol 2007;178:
Khullar V et al. Urology 2008;
Chapple C et al. Eur Urol 2007;52:
Chapple C et al. BJU Int 2008;102:
Van Kerrebroeck PEV et al. Ing J Clin Pract 2010;64:
Herschorn S et al. BJU Int 2010;105:58-66.
Kaplan SA et al. BJU Int 2011;107:
1. Weiss et al. J Urol (4):

23. Mirabegron Presentation Name 2/8/2018
Presentation Name Slide Call 23
2/8/2018
A distinct mechanism of action since the launch of antimuscarinics agents 30 years ago
Potent and selective β3-AR agonist
Indicated for the treatment of overactive bladder (OAB) with symptoms of urgency, urgency incontinence, and urinary frequency
Takasu T, et al. J Pharmacol Exp Ther 2007; 321: ; Product Monograph of Myrbetriq (March 2013).
Presentation Name

24. Beta Adrenergic Receptor Overview
β1 receptors
β2 receptors
β3 receptors
Location
Heart and Kidneys
Bronchial smooth muscle and Uterine muscle
Detrusor muscle and adipose tissue
Function
Heart: ↑ Heart rate and force of contraction
Kidney: ↑ Renin release
Lungs: Bronchodilation
Uterus: Relaxation
Bladder: Relaxation
Fat: Lipolysis
Clinical relevance
Beta-blockers
i.e. propranolol and metoprolol
Beta-2 agonists
i.e. salbutamol and ritodrine
Beta-3 agonists
i.e. mirabegron and solabegron
Beta-1
Heart: Increase in chronotropy (heart rate)  and inotropy (force of contraction)
Tachycardia results from a Beta 1 mediated increase in the rate of phase 4 depolarization of sinoatrial node pacemaker cells. The inotropic effect is mediated by increased phosphorylation of Ca ++ channels, including calcium channels in the sarcolemma and phospholamban in the sarcoplasmatic reticulum
Increase in AV- node conduction velocity
Beta 1 stimulated increase in Ca entry increases the rate of despolarization of AV node cells.
Kidney: Beta 1 receptors are present mainly on yuxtaglomerular cells, where receptor activation causes renin release.
Beta-2
Bronchial smooth muscle: Beta 2 receptor activation promotes bronchodilation, this physiological property is enhanced by inhaled Beta 2 agonists used in the treatment of asthma and COPD. Some drugs under this category include: salbutamol (albuterol in the US), salmeterol, formoterol and terbutaline.
Uterine contraction: Drugs that bind to Beta 2 receptors (Beta 2 agonists) are used in the treatment of premature labour, this clinical application illustrates how Beta 2 receptors mediate tocolysis on the uterine muscle. Ritodrine is an example of a tocolytic drug.
Beta-3
Bladder detrusor muscle: adrenergic activation of Beta 3 receptors at the bladder promotes relaxation.
Adipose Tissue: Beta 3 receptors promotes lipolysis.
Golan, David E . “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.
Katzung, B. “Basic & Clinical Pharmacology”, 10th Edition. Mc Graw Hill Medical: 2007
Harvey, Richard; Champe, Pamela (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009

25. Presentation Name
Presentation Name Slide Call 25
2/8/2018
Contraindications
Patients with severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg.
Patients who are pregnant or are hypersensitive to this drug or any ingredient in the formulation or component of the container.
Astellas Pharma Canada, Inc. Myrbetriq Product Monograph, 2013.
Presentation Name

26. Summary
Mirabegron is a novel, once-daily, first-in-class β3-adrenoceptor agonist
Improves symptoms associated with OAB by enhancing storage function and bladder capacity
Demonstrated efficacy of Mirabegron was comparable to Detrol LA in both primary and secondary endpoints
Demonstrated placebo-like safety and tolerability profile
Incidents of dry mouth with Mirabegron were similar to placebo
Khullar V, et al. Eur Urol 2013; 63(2): ; Nitti V, et al. J Urol 2013; 189(4): Herschorn S, et al. Urology (accepted 2013), Chapple CR, et al. Eur Urol 2013; 63(2): ; Product Monograph of Myrbetriq (March 2013).

27. Sacral Nerve Stimulation

28. Sacral Nerve Stimulation
Implantation of a programmable stimulator subcutaneously, which delivers low amplitude electrical stimulation via a lead to the sacral nerve, usually accessed via the S3 foramen.
Involves inserting a temporary electrode connected to an external pulse generator for 1-2 weeks.
If the test neuromodulation improves symptoms by 50% or more, a permanent electrode is inserted surgically.
50-90% effective in several studies.
59% of patients at 3 year f/u had greater than 50% improvement in urgency incontinence symptoms1.
1. Siegel et al, Urology, Dec. 2000

29. Percutaneous Tibial Nerve Stimulation

30. Percutaneous Tibial Nerve Stimulation
Less invasive form of neuromodulation to treat OAB.
A fine needle electrode is inserted into the lower, inner aspect of the leg, slightly cephalad to the medial malleolus.
An external pulse generator delivers an adjustable electrical stimulus that travels to the sacral plexus via the tibial nerve.
Initial treatment is weekly for 30 min. for 12 weeks, followed by maintenance every 3 weeks if there is a positive response.

31. Percutaneous Tibial Nerve Stimulation
Peters et al., J. Urology 2009
OrBIT trial compared PTNS to tolterodine 4mg at 12 weeks: 80% vs 55% response1.
Peters et al,. J. Urology 2010
RCT comparing PTNS to sham (SUmiT Trial) Tx at 12 weeks: 55% vs. 21% response2.
Burton et al., Neurourology and Urodynamics 2012
The meta-analysis showed a pooled subjective success rate was 61.4% (95% CI 57.5–71.8) and objective success rate was 60.6% (95% CI 49.2–74.7).

32. Intradetrusor Botox Therapy
Patients randomized in 1:1 ratio:
100 U onabotulinumtoxinA or
Placebo (normal saline)
Administered via:
Rigid or flexible cystoscope
20 intradetrusor injections, sparing trigone
0.5 mL per injection site
Recommended dilution is 100 Units/10 mL with 0.9% non-preserved saline solution
Optional instillation of local anesthesia and/or sedation
Re-treatment permitted:
100 U onabotulinumtoxinA permitted after ≥ 12 weeks
After ≥2 UI episodes over 3 days
Patient request
Nitti VW, et al. J Urol Jun;189(6):
Chapple C et al. Eur Urol Aug;64(2):

33. Significant Decrease in Daily Urinary Incontinence Episodes
~3X reduction from baseline for onabotulintomtoxinA in comparison to placebo
**p < versus placebo
Baseline values
Placebo: 5.39/day
OnabotulinumtoxinA 100 U: 5.49/day
BOTOX® Product Monograph. Allergan Inc. October 10, 2013.

34. Majority of OnabotulinumtoxinA Patients ‘Greatly Improved’ or ‘Improved’
Treatment Benefit Scale; (patient-reported positive response) at weeks 2 and 12:
Greatly improved
Improved
No change
Worsened **
**p < versus placebo
Significantly More OnabotulinumtoxinA Patients Greatly Improved or Improved
BOTOX® Product Monograph. Allergan Inc. October 10, 2013.

35. Summary: OnabotulinumtoxinA for OAB
Significant symptom reduction at week 12
51%
62%
of daily UI episodes
of patients reported a positive treatment response
were reduced
Clinically significant increase in quality of life
Substantial and significant improvements in all measures, including I-QoL* summary score and KHQ† role and social limitations scores
Side Effect Profile
Most common adverse event was UTI, experienced by 26.9% of patients‡
93.5% of patients did not require CIC in a 24-week pivotal trial
* I-QoL = Incontinence quality of life
† KHQ = King’s Health Questionnaire
‡ A urinary tract infection (UTI) was determined by culture results (presence of bacteria 10^5 CFU/mL and presence of leukocytes 5 per HPF), independent of symptoms.
BOTOX® Product Monograph, Allergan Inc., October 10, 2013.
Nitti VW, et al. J Urol Jun;189(6):
Chapple C et al. Eur Urol Aug;64(2):

36. Take Home Message
OAB is a common medical problem that is more prevalent in the older patient population.
Potential cognitive side effects need to be addressed and minimized in the treatment of OAB.
Remember behaviour modification in combination with medical management.
There are several newer treatment modalities for OAB that are effective and well tolerated:
Beta-3 agonist
Neuromodulation
Intravesical Botox injection