Update On OAB

1
Update On OAB

• Joon Chul Kim
• The Catholic University of Korea

2
Overactive Bladder Syndrome ICS Definition

• Urgency, with or without urge incontinence,
  usually with frequency and nocturia
• Absence of pathologic or metabolic conditions
  that might explain these symptoms
• Urgency - Sudden, compelling desire to pass urine
  that is difficult to defer

Abrams P et al. Urology. 20036137-49.
3
Desire to Void (Urge to Void) and Normal
Micturition Process
Void
Urge Intensity
Bladder Volume ()
100 cc
300 500 cc
Time

• Urge A physiological desire to void
• Gradual onset
• Increases as a function of bladder volume
• Can usually be deferred with appropriate
  strategies

Chapple CR et al. BJU Int. 2004 94738-744.
4
Urgency Micturition Process in OAB
Urgency
Desire to Void
Bladder Volume ()
Intensity
Void(voluntary and/orinvoluntary)
Time
Chapple CR et al. BJU Int. 2004 94738-744.
5
Urgency Drives the Other Symptoms of OAB
Urgency
1
Incontinence
Nocturia
Increased Frequency and Reduced Intervoid
Interval
2
2
1
Reduced Volume Voided per Micturition

1. Proven direct effect
2. Effect correlated with urgency but inconsistent
   due to multifactorial etiology of the symptom

Chapple CR et al. BJU Int. 2004 94738-744.
6
Prevalence of OAB by Gender in Korea
The Overall Prevalence of OAB in Korea was 12.2
(10.0 Men and 14.3 Women)
25
Men
Women
20
For population 40 years of age, OAB 14.9
(male 11.2 female 18.4) Estimation of people
with OAB in Korea
5,951,437
15
Prevalence,
10
5
0
Korea
7
Prevalence of OAB by Gender in Korea
Total
Men
Women
30
25
20
15
Prevalence of OAB,
10
5
0
gt70
18-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
Age Group, years
8
OAB Initiating Treatment

• If there is no significant abnormality of
  physical exam, urine analysis and PVR, treatment
  for OAB can be initiated without further workup
• In some cases where abnormalities are found,
  treatment can be initiated, but abnormality must
  be worked up (e.g. hematuria)
• UDS in select patients

9
Antimuscarinics 2008 in Korea

• Oxybutynin IR BID-TID
• Oxybutynin ER QD
• Tolterodine IR/ER BID / QD
• Trospium BID / QD
• Solifenacin QD

10
Whats The Difference??

• Efficacy
• No great differences
• Dose dependent
• Tolerability
• Safety
• Clinical Effectiveness different for different
  patients depending on expectations

11
Differences Among Anticholinergics

• Metabolism
• Hepatic
• Renal
• Pharmacokinetics
• Delivery system
• Bioavailability
• Receptor selectivity
• Chemical structure
• Permeability
• Dose titration
• 50-60 of patients will choose higher dose

Produce a number of clinically measurable and
theoretical differences
12
Why is Efficacy So Hard to Measure in the OAB
Population

• Different patients have different
• Primary bother symptoms
• Expectations from treatment
• Different studies have different populations

13
Efficacy of Antimuscarinic Agents vs Placebo
Frequency Drug Frequency Placebo Ratio UUI Drug UUI Placebo Ratio
Tolterodine ER (4 mg) 1 -22 -15 1.47 -71 -33 2.15
Oxybutynin ER (10 mg) NA NA NA NA NA NA
Oxybutynin TDS (3.9 mg)2 -18 -8.7 2.07 -75 -50 1.5
Trospium (20 mg BID) 3 Trospium (20 mg BID) 4 -18.1 -20.5 -8.4 -13.5 2.15 1.52 -59 -63 -44 -43 1.34 1.47
Solifenacin (5 mg) 5 Solifenacin (5 mg) 6 -19.6 -17 -12.8 -8 1.53 2.12 -62.7 -65 -42.5 -40 1.48 1.63
Solifenacin (10 mg) 5 Solifenacin (10 mg) 6 -21.9 -20 -12.8 -8 1.71 2.5 -57.1 -63 -42.5 -40 1.34 1.58
Darifenacin (7.5 mg) 7 -16.6 -9.1 1.82 -68.4 -53.8 1.27
Darifenacin (15 mg) 7 -17.4 -9.9 1.76 -76.8 -58.3 1.31
Median change for baseline Mean change
from baseline.
14
Side Effects Dry Mouth Incidence

• Drug Placebo
• Oxybutynin ER 10mg 28.1-29.7 n.a.
• Tolterodine ER 4mg 23 8
• Oxybutynin TDS 9.6 8.3
• Solifenicin 5 mg 14 4.9
• Solifenicin 10 mg 21.3 4.9
• Darifenicin 7.5 mg 18.8 13.2
• Darifenicin 15 mg 31.3 13.2

Ratio 2.9 1.2 2.9 4.3 1.4 2.4
15
Side Effects Constipation Incidence

• Drug Placebo
• Oxybutynin ER 10mg 6.4-7.0 n.a.
• Tolterodine ER 4mg 6 4
• Oxybutynin TDS lt2 lt2
• Solifenicin 5mg 7.2 1.9
• Solifenicin 10 mg 7.8 1.9
• Darifenicin 7.5mg 14.8 6.7
• Darifenicin 15mg 21.3 6.7

Ratio 1.5 1 3.8 4.1 2.2 3.2
16
Urgency Defining Symptom of OAB

• How is it measured?
• Yes/no
• Degree
• VAS, IUSS, UPS
• Warning time
• OAB voids
• Recent studies have shown positive effects on
  antimuscarinics on urgency
• Darifenicin and solifenicin using yes/no scales
• Tolterodine and trospium using fixed scales
• Darifenicin using a VAS

17
Reduction in Urgency Episodes/24 hrs
Episodes
Mean baseline 6.15 6.03 End of study
mean 2.24 3.30
4
63.6
3
Mean change from baseline to endpoint
45.3
2
1
0
Plt0.0001
Flexible dosing with solifenacin 5 or 10mg.
Patients were allowed to dose increase at wk 4
and increase/decrease at wk 8
Serels S et al. Urology 2006 68 (suppl 5a) 73
MP-04.11
18
Improvement in IUSS Score Baseline to End of
Study

Lower IUSS score indicates reduced urgency
IUSS score
100
3 Severe
90
2 Moderate
80
1 Mild
70
0 None
60
Percent
50
40
30
20
10
0.3
0.3
0
Baseline
End of Study
Baseline
End of Study
Solifenacin
Placebo
Serels S et al. Urology 2006 68 (suppl 5a)73
MP-04.11
19
Improvement in Urgency Perception Score Baseline
to End of Study
1 Usually not able to hold urine 2 Usually
able to hold urine until I reach the toilet if I
go immediately 3 Usually able to finish what I
am doing before going to the bathroom
100
15.2
15.1
90
80
70
60
68.4
73.2
Percent
50
40
30
20
10
16.4
11.7
0
Baseline
End of Study
Baseline
End of Study
Solifenacin
Placebo
Higher UPS score indicates reduced urgency
Serels S et al. Urology 2006 68 (suppl 5a)73
MP-04.11
20
Tolterodine LA Nighttime Dosing Reduced 24-Hour
Frequency
Study 037
Placebo (n421)
Tolterodine LA (n429)
Total
OAB
Normal
0
-10
9.4
11.5
14.7
12.3
-20
18.1
18.6
Median Reduction inMicturitions,
-30
-40
P.0068
-50
P.1571
P.0012
-60
P.0225
Micturition episodes defined as Urgency score
of 15 on urgency scale Urgency score of 12 on
urgency scale Urgency score of 35 on urgency
scale
Rackley et al. Urology. 200667731-736.
21
Individual AgentsAdvantages and Drawbacks
22
Oxybutynin - ER

• Advantages
• Widest range of dose titration
• Only compound approved for high dose
  administration
• Drawbacks
• Effects on cognitive function

23
Tolterodine

• Advantages
• Long safety record
• Number 1 prescribed drug
• New CNS data favorable
• Data on male OAB
• Drawbacks
• Lack of titration
• Mild increase in QT interval at super
  therapeutic doses

24
Trospium

• Drawbacks
• BID dosing
• No dose titration
• Slight increase
• in heart rate

• Advantages
• No hepatic metabolism
• Less drug-drug interactions
• Less crossing of blood-brain barrier
• ? Clinical correlation at this time
• Higher urine concentration
• ? Clinical meaning

25
Solifenicin

• Advantages
• Dose titration
• Relatively low dry mouth incidence
• Drawbacks
• Mild increase in QT interval at super therapeutic
  doses

26
Antimuscarinics Summary

• Efficacy among antimuscarinic agents is similar
• There are several different advantages (some
  theoretical) which may influence drug choice in a
  particular patient
• Expect in cases of high dose antimuscarinics,
  decisions are more likely to revolve around
  tolerability and safety (or perceived safety)

27
Male LUTS Can Be Associated With the Bladder, the
Prostate, or Both
Bladder Condition OAB
Prostate Condition BPH
Urgency, with or without urgency incontinence,
usually with frequency and nocturia
Term used and reserved for the typical
histological pattern that defines the disease
Pharmacologic Therapy for OAB Antimuscarinics
Pharmacologic Therapy for BPH alpha-Blockers 5-A
RIs
BPH benign prostatic hyperplasia OAB
overactive bladder 5-ARI 5-alpha-reductase
inhibitor.
Abrams P et al. Urology. 20036137-49.
28
Timing of combination treatment

• Primary vs. Add-on
• Many patients with BPH and OAB have benefit
• from alpha blocker only
• Initially treated with an alpha blocker
• Anticholinergics is added in patients who
  report
• partial response to the alpha blocker but
  still
• have persistent OAB symptoms

29
In Men With OAB, Treatment With Tolterodine Was
Not Associated With Increased Incidence of AUR
Subanalyses of Male Patients With OAB in
Tolterodine ER Studies
Withdrawal Because of Symptoms Suggestive of Urinary Retention, (n/N) AUR,
Registration study (N 163) Tolterodine ER Placebo 1.3 (1/77) 0.0 (0/86) 0.0 0.0
Studies 037 and 041 (N 745) Tolterodine ER Placebo 0.8 (3/371) 0.5 (2/374) 0.0 0.0
IMPACT study (N 155) Tolterodine ER 1.3 (2/155) 0.0
Roehrborn CG et al. BJU Int. 2006971003-1006. Ab
rams P et al. J Urol. 2006175999-1004. Elinoff
V et al. Intl J Clin Pract. 200660745-751.
Tolterodine ER 4 mg/d. Open-label study.
30
TIMES Study Urinary Retention Summary
Placebo (n 220) Tolterodine ER (n 216) Tamsulosin (n 215) Tolterodine ER/Tamsulosin (n 225)
Reported urinary AEs 4 4 0 2
Urinary retention 3 2 0 2
Urinary flow decreased 1 2 0 0
Discontinued dueto AE 2 1 0 1
Catheterisation necessary (AUR) 0 1 0 1
Kaplan SA et al. JAMA. 20062962319-2328.
31
Concerns about the risk of AUR

• Several recent clinical trials have refuted
• But, given the exclusion criteria should be
  considered
• Exclusion criteria for PVR in clinical trials
• - greater than 30-40 of maximum capacity
• - or 50-200ml

32
Concerns about the risk of AUR

• Post-void residual volume should be measured to
  exclude baseline urinary retention
• The safety in patients with baseline urinary
  retention is not known

33
Recommendation
Low PVR lt40 of functional capacity
Jaffe WI, Te AE, Current Urology Reports 2005
34
Summary OAB in Men

• Available data suggests that antimuscarinics are
  safe in men with OAB BOO, but PVR should be
  considered
• Optimal way to use alpha blockers needs to be
  sorted out
• It should be evaluated which patient benefit from
  adding of antimuscarinics initially in real life
  practice