A brief updates on OAB- Over Active Bladder

2. Prevalence of OAB

3. Prevalence of OAB
51% of men and 56% of women age between 40 to 59 experienced the symptoms of OAB….
Can Urol Assoc J. 2017 May; 11(5): E142–E173.

4. Prevalence of OAB
64% of Women with bladder issues still
struggle in SILENCE…
Can Urol Assoc J. 2017 May; 11(5): E142–E173.

5. Impact of Urinary Incontinence on
Quality of Life…
Psychological
• Guilt/depression.
• Loss of self respect & dignity.
• Fear of being a burden/Lack of
bladder control.
Physical
• Limitations or cessation of physical
activities.
QOL
Social
• Reduction in social interaction
• Alteration of travel plans
• Increased risk of institutionalization of
frail older persons
Sexual
• Avoidance of sexual contact and
intimacy.
Occupational
• Absence from work.
• Decreased productivity.
Domestic
• Requirements for Specialized
underwear, Bedding.
• Special precautions with clothing.

6. Overactive bladder - Definition
“Urgency, with or without urge incontinenence, usually with frequency and nocturia…
If there is no infection or proven pathology.
Abrams et al . Neurourol Urodyn 2002:21; 167- 78

7. Overactive bladder
 Nocturia is the complaint that the individual has to wake at night one or more times to void.
 Urgency is the complaint of a sudden compelling desire to pass urine which is difficult to defer.
 Increased daytime frequency is the complaint by the patient who considers that he/she voids
too often by day.
 Urinary incontinence is the complaint of any involuntary leakage of urine.

8. Diagnosis of OAB

9. Diagnosis of Overactive Bladder
 Most cases of overactive bladder can be diagnosed based on:
 Patient history, symptomassessment.
 Physical examination.
 Urinalysis.
 Initiation of noninvasive treatment does not require an extensive further
workup.
 Bladder diary.

10. History
 How long? How old when started?
 How much (volume)? Degree of bother?
 Characteristics of leakage?
 Activity related?
 D a y and night, wet pads at night = instability
 Urgency?
 Suppressible = probably SUI
 not suppressible (urge incontinence) = instability
 Other: fluid intake, UTI’s, pain, hematuria, LE swelling, medications.

11. Differential Diagnosis: Overactive Bladder,
Stress Incontinence, and Mixed Symptoms
Abrams P, Wein AJ. The Overactive Bladder—A Widespread and Treatable Condition. 1998.
Medical History and Physical Examination Symptom Assessment
Symptoms OAB SUI Mixed symptoms
Urgency (strong,sudden desire to void) YES NO YES
Frequency with urgency (> 8 times/24 h) YES NO YES
Leaking during physical activity (eg, coughing, sneezing,
lifting)
NO YES YES
Amount of urinary leakage with each episode of incontinence Large
(if present)
small Variable
Ability to reach the toilet in time following an urge to void Often no YES Variable
Waking to pass urine at night Usually Seldom Maybe

12. Bladder diary
 What is a Bladder Diary?
 A bladder diary is a tool used by you and your healthcare professional to better understand your
OAB symptoms.
 It helps you track and know how much and when you drink liquids, how much and when you
urinate, when you have that “gotta go” feeling, and how much and when you leak urine.
 When is a Bladder Diary used?
 You can use a Bladder Diary before or after visiting with your healthcare professional.
 You may choose to complete a Bladder Diary before you see your healthcare professional for the first
time. Having a Bladder Diary during your first visit can be helpful. You may find it easier to explain
your symptoms and how they are affecting your life. If you don’t keep a Bladder Diary before your
first office visit, your healthcare professional may ask you to start one. It can help them understand
your daily habits and how your bladder is working during a 24-hour period.

13. Bladder diary
 How to complete the diary:
 Begin your diary when you wake up each day. Take notes throughout the day, and continue until you complete 24 hours. For
example, if you wake up at 7 a.m. on the first day of your diary, take notes until 7 a.m. the next day.
 During the day, write down how much liquid you drink. If you do not know exactly how much liquid you are drinking, it’s
important to take a good guess about the number of ounces every time. Most containers will list the number of ounces they
contain. Use these listings to help you make an estimate—for example, an 500ml of juice, 250ml can of soda, or 1L bottle of
water.
 Take note of how much urine you make during the day. If your healthcare professional asks you to keep a Bladder Diary, you
will probably get a special collection device to use. It sits under your toilet seat. It is marked with measurements to let you
know how much urine you make.
 If you are keeping the diary on your own before visiting a healthcare professional, you may want to collect your urine in a
paper cup. Choose a cup that you know holds a certain amount of liquid, such as 500ml.
 It’s best to keep a diary for at least three days.. Copy as many pages of the Bladder Diary you need to complete the three days
or visit UrologyHealth.org/OAB to print out more.
 Don’t forget to bring your completed diary with you to your first office visit.

14. Bladder diary

15. Physical Examination
 Abdomen
 Masses: palpable bladder, etc. Pelvis/perineum
 External genitalia: atrophic vaginitis
 vaginal
 Strenght of PFM
 Prolapse (assoc. 50% of SUI patients
 GYN malignancy, fistula Rectal:
 tone, masses, teach Kegels during exam
 prostate
 Neurological (reflexes, LE’s, sensory, motor)

16. Physical Examination
 Rule out possible causes of LUTS.
 Atrophic vaginitis
 Estrogen deficiency
 Pelvic floor dysfunction
 Pelvic organ prolapse
 Potentially serious pathologic conditions
Signs of Hypoestrogenation
Prominent
caruncle
• Cystocele
• Rectocele
• Enterocele
• Uterine prolapse

17. Fantl JA, et al. Agency for Healthcare Policy and Research; 1996. AHCPR publication 96-0686.
Laboratory Tests
 Urinalysis
 Routine &microscopy
 Culture
 Look for hematuria (Blood in urine) , pyuria (Urine with white blood cells or Pus), bacteriuria (Urine
with Bacteria) , glucosuria (Urine with Glucose), proteinuria (Urine with Protein)
 Appropriate blood work up
 Glucose
 Electrolytes
 Prostate specific antigen (PSA) inmen

18. Laboratory Tests
 Rule out possible causes of LUTS ( Lower Urinary Tract symptoms)
 Urinary tract infection (UTI) or sexuallytransmitted disease (STD)
 Diabetes mellitus (T2DM & T1DM)
 L U T tumor or kidneystones
 Potentially serious pathologicconditions

19. Urodynamic Assessment

20. Urodynamics
Urodynamics :
The diagnostic study of pressure in the bladder, in treating incontinence.
‘A Urodyanamic observation characterized by involuntary detrusor contractions during
the filling phase which may be spontaneous or provoked
Abrams et al, 2002

21. Urodynamics
 Urodynamic evaluation is recommended:
 prior to invasive (Fast progression) treatments.
 after treatment failure.
 Urodynamic studies should only be performed after a full basic urological assessment.

22. Urodynamic classification of OAB
(Flisser et al)
Based on –
 Presence of Detrusar Overactivity
 Patients Awareness
 Ability to abort Type 1- 4.

23. OAB – 1: The patient complains of OAB
symptoms, but no involuntary detrusor
contractions are demonstrated.

24. OAB - 2
There are involuntary detrusor contractions,
but the patient is aware of them and can
voluntarily contract the sphincter, prevent
incontinence, and abort the detrusor
contraction.

25. OAB - 3
•Involuntary detrusor contractionspresent ,
the patient is aware of them and can
voluntarily contract the sphincter and
momentarily prevent incontinence, but the
patient is unable to abort the detrusor
contraction and when the sphincter fatigues,
incontinence ensues .

26. OAB - 4
Involuntary detrusor contractions present , but
the patient is not able to contract the
sphincter voluntarily or abort the detrusor
contraction and simply voids involuntarily

27. Overactive bladder and detrusor over
activity
UI increases

28. Therapy for OAB
1) Behavioral modification/ lifestyle changes
2) Pelvic floor muscle therapy
3) Oral pharmacologic agent
4) Intravesical agent -
1) Capsaicin
2) Resiniferatoxin
3) Botulinum toxin -A
5) Sacral Neuromodulation
6) surgical therapy

29. Conservative management
 Behavioral modification
 Dietary modification
 Bladder training
 Fluid management
 Pelvic floor muscle therapy (PFMT))

30. Management
 OAB – often can not be cured Sympathetic approach
Reasonable expectation
 Goal – minimize effect on quality of life

31. Medications for OAB
 Anticholinergic drugs for OAB
 Beta-3 adrenergic drugs for OAB

32. Anticholinergic drugs for OAB
 The largest class of drugs used to treat OAB is anticholinergic drugs. They work by blocking a chemical in your
body called acetylcholine. This chemical sends a message to your bladder to contract. By blocking this chemical,
these drugs reduce the contractions that cause you to release urine. In studies that compared the drugs, all
anticholinergics worked equally as well in treating OAB.
 Anticholinergics drugs used in OAB management:
 Oxybutynin.
 Tolterodine.
 Trospium.
 Darifenacin.
 Solifenacin.
 Fesoterodine.

33. Beta-3 adrenergic drugs for OAB
 The only drug in this class is mirabegron. It works by relaxing the smooth muscle
in the walls of your bladder. This effect helps your bladder hold more urine.
 This drug is available as a tablet that you take by mouth once per day. It interacts
with several other drugs. Make sure you tell your doctor about all medications
you’re taking.

34. Antispasmodic drugs for OAB |
Antispasmodic drugs
 Flavoxate is the only drug in this class. It’s an oral drug that reduces
bladder spasms.
 This is an older drug. Some studies show that it doesn’t work as well
as newer drugs to treat symptoms of OAB.

35. The new combination approved by USFDA

37. Mirabegron - brief
 Mirabegron is a new drug approved by USFDA in 2012
 Mirabegron is the only OAB treatment in its class that targets the beta-3 pathway to increase
bladder capacity
 Help relax the smooth muscle that surrounds the bladder
 Help the bladder to fill more completely and increase urine storage
 Available strengths are 25mg & 50mg with Once Daily Dosage

38.  Overactive Bladder
 Monotherapy
 Indicated for overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and
urinary frequency
 25 mg PO qDay
 25 mg dose is typically effective within 8 weeks
 May increase to 50 mg PO qDay based on individual efficacy and tolerability
 Combination with muscarinic antagonist
 Indicated in combination with the muscarinic antagonist solifenacin succinate for treatment of OAB with
symptoms of urge urinary incontinence, urgency, and urinary frequency
 Combination regimen: 25 mg PO qDay plus solifenacin succinate 5 mg PO qDay
 May increase mirabegron to 50 mg PO qDay after 4-8 weeks based on individual efficacy and tolerability
Mirabegron - brief

39.  Mechanism of Action
 Beta-3 adrenergic receptor agonist which causes relaxation of the detrusor smooth muscle of the urinary
bladder and increases bladder capacity
 Absorption : Bioavailability: 29% (25-mg), 35% (50-mg), Peak Plasma Time: 3.5 hr
 Peak Plasma Concentration: ~3-fold increase from 50 mg dose to 100 mg dose
 AUC: ~2.5-fold increase from 50 mg dose to 100 mg dose, Steady state: 7 days
 Distribution, Protein Bound: 71%, Vd, steady state: 1670 L
 Metabolism: Via multiple pathways including dealkylation, (direct) glucuronidation, amide hydrolysis, and
minimal oxidative metabolism in vivo by CYP2D6 and CYP3A4, Possible involvement of butylcholinesterase,
uridine diphospho-glucuronosyltransferases (UGT) and alcohol dehydrogenase, Moderate CYP2D6 inhibitor
 Elimination: Half-Life: 50 hr, Total body clearance: 57 L/hr (following IV administration), Excretion: Urine
(55%); feces (34%), Excretion, unchanged: Urine (~25%); feces (0%).
Mirabegron – brief (PKPD)

40. Mirabegron – Administration
 Oral Administration
 May take with or without food
 Swallow whole with water, do not chew, divide, or crush tablet
 Storage
 Extended-release tablets: Store at 25°C (77°F) with excursions permitted from 15-30°C (59-86°F)

41. Solifenacin - brief
 Solifenacin is a new drug approved by USFDA in 2004.
 Solifenacin is the only OAB treatment in its class that targets the Competitive muscarinic-receptor
antagonist.
 Available strengths are 5mg & 10mg with Once Daily Dosage.

42. Solifenacin - Dosing & Uses
 Dosage Forms & Strengths tablet: (5mg &10mg)
 Overactive Bladder
 Indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary
frequency
 Monotherapy: 5 mg PO qDay; may be increased to 10 mg PO qDay
 Combination with beta3 agonists
 Indicated in combination with mirabegron for treatment of OAB with symptoms of urge urinary incontinence, urgency, and
urinary frequency Combination regimen: 5 mg PO qDay in combination with mirabegron 25 mg PO qDay
 Dosing Modifications
 Renal impairment: CrCl <30 mL/min: Not to exceed 5 mg/day
 Hepatic impairment : Moderate: Not to exceed 5 mg/day, Severe (Child-Pugh class C): Not recommended, CYP3A4
inhibitors, Strong CYP3A4 (eg, ketoconazole): Not to exceed 5 mg/day

43. Solifenacin - PKPD
 Pharmacology
 Mechanism of Action : Competitive muscarinic-receptor antagonist
 Absorption
 Bioavailability: 90%
 Peak plasma time: 3-8 hr
 Distribution
 Protein bound: 98%
 Metabolism
 Metabolized in liver, primarily by CYP3A4
 Elimination
 Half-life: 45-68 hr
 Excretion: Urine (69.2%), feces (22.5%)

44.  SYNERGY I:- (No. Patients = 6991, Duration:- 12 weeks) compared
mirabegron/solifenacin combination therapy to solifenacin monotherapies.
 Conclusions :- Combined therapy with solifenacin 5 mg + mirabegron 25 mg and
solifenacin 5 mg + mirabegron 50 mg provided consistent improvements in efficacy
compared with the respective monotherapies across most of the outcome parameters.
Efficacy and safety of combinations of mirabegron and solifenacin
compared with monotherapy and placebo in patients with
overactive bladder (SYNERGY study). BJU Int. 2017 Oct;120(4):562-575

45. Study Design
 This was a multinational, multicentre, randomised, double‐blind, parallel‐group, placebo‐ and
active‐controlled Phase III study (NCT01972841), performed in accordance with the International Conference
on Harmonization, Good Clinical Practice and the Declaration of Helsinki. Independent Review
Board/Independent Ethics Committee‐approved written informed consent was obtained from each patient
before the study. Patients enrolled at sites in the USA also signed a Health Insurance Portability and
Accountability Act (HIPAA) authorisation form.

46. Study Design

47. Study Design
 The study duration was 18 weeks, comprising a single‐blind, 4‐week placebo run‐in, a 12‐week double‐blind treatment
period, and a 2‐week, single‐blind, placebo run‐out period. Patients aged ≥18 years who had had symptoms of wet OAB
(urgency, urinary frequency and UI) for ≥3 months were eligible for screening. In patients with mixed stress UI/UUI, UUI
had to be the predominant factor as evidenced by diary data and determined by the investigator. Those who recorded on
average ≥8 micturitions/24 h, ≥1 urgency episode/24 h (grade 3 or 4 on the Patient Perception of Intensity of Urgency
Scale [PPIUS]/24 h , and ≥3 UI episodes over the 7‐day micturition diary were eligible for randomisation to double‐blind
treatment in a 2:2:1:1:1:1 ratio to daily:
 Solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25) once daily
 Solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50) once daily
 Placebo
 Mirabegron 25 mg OD
 Mirabegron 50 mg OD
 Solifenacin 5 mg OD

48.  SYNERGY II :- (No. Patients = 2084, Duration:- 12 months) compared mirabegron/solifenacin
combination therapy to solifenacin monotherapies.
 Patient summary
 This study investigated the effectiveness and safety of a combination of two different treatments
(mirabegron 50 mg and solifenacin 5 mg) or solifenacin (5 mg or 10 mg) alone in patients aged <65 yr
or ≥65 yr, and <75 yr or ≥75 yr with overactive bladder. Symptoms of overactive bladder, such as the
urgent need to visit the toilet, incontinence, and frequent urination, were improved with all treatments
regardless of the patient’s age, but combination treatment demonstrated the greatest benefit, and was
well tolerated.
 Conclusions :- Mirabegron and solifenacin combination treatment for OAB symptoms was well
tolerated over 12 months and led to efficacy improvements over each monotherapy. This innovative
combination is a treatment option that could become widely used in the clinic.
Long-term Safety and Efficacy of Mirabegron and Solifenacin in Combination
Compared with Monotherapy in Patients with Overactive Bladder: A Randomized,
Multicenter Phase 3 Study (SYNERGY II). Eur Urol Focus. 2017 Dec;3(6):629-638.

49. Design, setting, and participants &
Outcome
Design, setting, and participants
Patients remaining incontinent (≥1 episode during 3-d diary) following 4-wk single-blind daily
solifenacin 5 mg were randomized 1:1:1 to a daily double-blind combination (solifenacin 5 mg and
mirabegron 25 mg, increased to 50 mg at wk 4), solifenacin 5 mg or 10 mg for 12 wk. Four cohorts
stratified by age (<65 yr, ≥65 yr and < 75 yr, ≥75 yr) were investigated.
Outcome measurements and statistical analysis
Efficacy assessments: change from baseline to end of treatment in average daily incontinence (primary)
and micturition frequency (key secondary), number of incontinence episodes during the 3-d diary (key
secondary), and change from baseline in average daily urgency and urgency incontinence episodes.
Safety included treatment-emergent adverse events and vital signs.

50.  BESIDE :- (No. Patients = 2174, Duration:- 12 weeks), mirabegron 50 mg in combination with solifenacin 5 mg was
superior to solifenacin 5 mg alone for relieving symptoms of incontinence and frequent urination.
 PATIENT SUMMARY:
 This study investigated the effectiveness and safety of a combination of two different treatments (mirabegron 50mg
and solifenacin 5mg) or solifenacin (5mg or 10mg) alone in patients aged <65 yr or ≥65 yr, and <75 yr or ≥75 yr
with overactive bladder. Symptoms of overactive bladder, such as the urgent need to visit the toilet, incontinence, and
frequent urination, were improved with all treatments regardless of the patient's age, but combination treatment
demonstrated the greatest benefit, and was well tolerated.
 Conclusions: Efficacy and safety in the overall population is maintained in older
(65 yr) and elderly (75 yr) patients treated with a combination of solifenacin and mirabegron, or solifenacin monotherapy;
irrespective of age, combination was associated with the greatest improvement in overactive bladder symptoms
Treating Overactive Bladder in Older Patients with a
Combination of Mirabegron and Solifenacin: A Prespecified
Analysis from the BESIDE Study. Eur Urol Focus. 2017 Dec;3(6):629-638.

51. DESIGN, SETTING,PARTICIPANTS,
OUTCOME & RESULTS
DESIGN, SETTING, AND PARTICIPANTS:
Patients remaining incontinent (≥1 episode during 3-d diary) following 4-wk single-blind daily solifenacin 5mg were
randomized 1:1:1 to a daily double-blind combination (solifenacin 5mg and mirabegron 25mg, increased to 50mg at wk
4), solifenacin 5mg or 10mg for 12 wk. Four cohorts stratified by age (<65 yr, ≥65 yr and < 75 yr, ≥75 yr) were
investigated.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:
Efficacy assessments: change from baseline to end of treatment in average daily incontinence (primary) and micturition
frequency (key secondary), number of incontinence episodes during the 3-d diary (key secondary), and change from
baseline in average daily urgency and urgency incontinence episodes. Safety included treatment-emergent adverse
events and vital signs.
RESULTS AND LIMITATIONS:
Full analysis set included 2110 patients: 30.9% aged ≥65 yr and 8.9% aged ≥75 yr. At the end of treatment, daily, and 3-
d incontinence daily micturitions, urgency, and urgency incontinence, were improved in each treatment group and age
group; the largest reductions were observed with combination in each age cohort. There were no notable differences in
vital signs or the incidence of treatment-emergent adverse events between treatment and age groups, with the
exception of dry mouth, which was highest with solifenacin10mg.

52. Thank You