Self-Study Programme

(internal use only)

Oxybutynin in the management of OAB

The role of oxybutynin in OAB

Oral oxybutynin has been a mainstay in the management of OAB for

many years and provides effective relief of symptoms

However, patients and physicians want a therapy that is more

convenient, has greater efficacy and is better tolerated

Bladix with its innovative delivery of oxybutynin was

developed to provide such a treatment
Self-Study Programme
Oral administration of oxybutynin
Oral drug delivery

Drugs are most often given orally because this route is usually:
the most convenient
the safest
the least expensive

Until recently, oxybutynin was administered orally in the treatment of OAB

Pharmacokinetics of IR oral oxybutynin

After absorption by the small

intestine, IR oral oxybutynin
undergoes first-pass metabolism in
the GI tract and liver

It is then widely distributed in body

tissues by the systemic circulation
and interacts with cholinergic
receptors throughout the body
First-pass metabolism of IR oral oxybutynin

More than 90% of oxybutynin is metabolised into N-DEO; only 6%10% reaches its target
tissues
N-DEO is active and acts at the same cholinergic receptors as oxybutynin
However, N-DEO has a higher affinity for the salivary gland than bladder tissue
Thus, N-DEO is thought to be responsible for the side effect of dry mouth

Rapid absorption and elimination of oxybutynin and N-DEO lead to peak and trough levels
These are a serious drawback to IR oral dosing
Elimination of IR oral oxybutynin

IR oral oxybutynin is rapidly cleared from the body (half-life 2 hours)

Thus, a 5 mg dose of IR oxybutynin has to be taken 24 times/day to be effective
This can be inconvenient for patients

The short half-life and repeated dosing results in variations in the serum
concentrations of oxybutynin and N-DEO

During peak levels, adverse

events are more likely
At minimal levels, serum
concentrations may fall too low
to effectively control symptoms
Limitations of IR oral oxybutynin

First-pass metabolism is extensive

High levels of active metabolites are produced, which are linked to the
incidence of anticholinergic side effects

Multiple dosing is required to maintain therapeutic levels

This results in wide variations in peak and trough levels, which increase side
effects and decrease efficacy
Multiple dosing is also inconvenient for patients

Some drugs interact with certain foods, are destroyed by stomach

acid or may irritate the digestive tract

An alternative method of administration was required to increase

efficacy and decrease the incidence of side effects
 ER oral oxybutynin

ER oral oxybutynin was developed to overcome these limitations

This releases the drug at a controlled rate over a 24-hour dosing period

ER oral oxybutynin was designed to allow once-daily dosing and result in a lower
incidence of anticholinergic side effects
Limitations of ER oral oxybutynin
ER oral oxybutynin still undergoes first-pass metabolism and is converted to
N-DEO before reaching its target tissues

Thus, a method of delivery was

required that would:
Improve bioavailability
Minimise the peaks and
troughs associated with IR
oral administration
Decrease the incidence of
anticholinergic side effects
Be convenient for patients to
use

Transdermal delivery of oxybutynin was the solution

Key points for oral administration of oxybutynin

IR oral oxybutynin:
Undergoes first-pass metabolism to produce large amounts of N-DEO
(linked to anticholinergic side effects)
Requires multiple daily dosing (increasing side effects and decreasing
efficacy)

A greater amount of ER oral oxybutynin reaches the target tissues

intact
However, a substantial amount is still metabolised to N-DEO following
first-pass metabolism
Bladix Self-Study Programme
Transdermal delivery of drugs
Transdermal delivery systems

Transdermal delivery systems allow

prolonged release of a drug onto the
surface of the skin via a patch

The occlusive nature of the patch

means the drug only flows one way

The drug diffuses through the skin

layers into the underlying capillaries
for distribution to the rest of the body
Types of transdermal patches

Liquid reservoir system

The active drug and enhancers are
contained in semisolid, alcoholic gel
A membrane controls the rate of
release from the reservoir
After lengthy storage, large amounts
of drug can be initially released

Matrix-type (most often used today)

The active drug and adhesive are
contained in a polymer matrix
The drug is released at a rate
governed by matrix components (not
a membrane)
The rate of release of the drug
declines slightly over time
Advantages of transdermal delivery systems

First-pass metabolism is avoided:

Results in greater bioavailability
Lower doses of the drug are required to achieve therapeutic levels
Anticholinergic adverse effects caused by active metabolites are reduced

Consistent blood levels are achieved throughout the dosing interval

The dosing frequency can be reduced
Peak serum concentrations are lower, reducing adverse events
Minimum concentrations are higher, maintaining efficacy

Patient convenience and compliance is greater

Bladix Self-Study Programme
The Bladix Patch
Rationale for Bladix

Bladix was designed to:

Deliver the efficacy of oxybutynin
with a greater tolerability than the
oral formulations
Provide a constant supply of
oxybutynin, thus reducing dosing
frequency
Be more convenient

The benefits of Bladix help to

increase patient compliance with
treatment for OAB
The Bladix Patch

An innovative matrix patch that is applied to intact skin to provide continuous,

transdermal delivery of oxybutynin

Composed of three, thin layers:

Flexible backing film
Active matrix adhesive layer
Overlapped release liner
The Bladix Patch

Indicated for the symptomatic treatment of UUI and/or increased urinary frequency
and urgency in OAB

Designed for twice-weekly dosing (3.9 mg/day)

Small and discreet and unlikely to cause disturbance in patients daily activities

Can be adhered to the abdomen, hip or buttock

Pharmacokinetics of Bladix

Upon application of the Bladix patch

to intact skin, oxybutynin is slowly
absorbed from the patch through the
skin and into the bloodstream by
passive diffusion
Levels of oxybutynin following one application

Oxybutynin becomes detectable in

the plasma after about 2 hours

The levels of the drug then increase

over 2436 hours before they reach
a peak
After this time, levels decline
slightly until the patch is removed

Absorption is bioequivalent when

administered to the abdomen,
buttock or hip
Offers flexibility to patients
Reduces application site reactions
Steady-state pharmacokinetics with Bladix

Absorption of oxybutynin does not change over the course of several applications

Blood levels remain consistent over time

As the dose increases, the serum levels increase in a linear fashion

Transdermal dosing of oxybutynin

Transdermal delivery of oxybutynin

results in a smooth plasma
concentration profile compared with
oral dosing

Bladix:
Reduces dosing frequency
Increases efficacy
Decreases the likelihood of
adverse effects
Ratio of N-DEO to oxybutynin after transdermal delivery

Transdermal delivery avoids first-pass metabolism

Thus, oxybutynin does not undergo extensive metabolism to N-DEO

Transdermal dosing produces far lower levels of N-DEO than IR oral oxybutynin

Compared with oxybutynin, the average N-DEO concentration is:

11 times higher after oral administration
1.6 times higher after transdermal administration
Steady-state serum levels of oxybutynin and N-DEO
Immediate Release (IR) * Extended Release (ER) Bladix
OXY OXY OXY
N-DEO N-DEO N-DEO
50

40
Mean plasma conc. (ng/mL)

30

20

10

0
0 12 24 36 48 60 72 84 96
Time (hours)
* Extrapolated concentrations from a single OXY-IR dose = 5 mg/day
R- and S-enantiomers after oral and transdermal delivery

Peak levels of the R-enantiomer and R-N-DEO are much lower following
transdermal delivery

Bladix is likely to result in fewer anticholinergic side effects such as dry mouth
Pharmacokinetics summary
IR oral oxybutynin
Rapidly absorbed from the
digestive tract
Undergoes rapid first-pass
metabolism, resulting in
large amounts of N-DEO
High amounts of the R-
enantiomer produced
Undergoes rapid elimination
from the body (half-life 2 h)
Multiple dosing required,
resulting in peak/trough
concentrations
ER oral oxybutynin
Absorbed from the digestive
tract more slowly than IR
oxybutynin
First-pass metabolism still
occurs, resulting in higher
levels of N-DEO than
oxybutynin
Levels of R-N-DEO higher
than S-N-DEO
Half-life still around 2 hours
Once daily dosing required
(smoother peak/trough
concentrations)
Bladix
Gradually absorbed into the
bloodstream
Enters the bloodstream
directly (much lower
concentrations of
N-DEO)
Much lower levels of
R-enantiomer produced
Apparent half-life 8 h (rate of
absorption eventually equals
rate of elimination)
Serum levels remain fairly
constant, avoiding
peak/trough concentrations
Pharmacokinetic
advantages of Bladix
Lower levels of oxybutynin
required for therapeutic
effect
Consistent blood levels
over the dosing period
Fewer anticholinergic side
effects
Greater efficacy
Reduced dosing frequency
(twice weekly)
Key points for Bladix
Compared with oral oxybutynin, Bladix was developed to :
Be at least as effective
Be more tolerable
Have a better dosing frequency
Offer more convenience

The innovative delivery system of the Bladix patch:

Bypasses first-pass metabolism (resulting in much lower amounts of N-DEO)
Provides an almost constant supply of oxybutynin over the dosing period
(thus avoiding variations in peak/trough levels)

Bladix (3.9 mg/day) results in:

Fewer anticholinergic side effects (comparable to placebo)
Greater maintained efficacy
Reduced dosing frequency (twice weekly)

The Bladix patch is:

Small, discreet and easy to use
Unlikely to cause any disturbance in the daily activities of patients
Bladix Self-Study Programme
Bladix clinical evidence
Clinical evidence for Bladix

Type of study Aim Drugs Parameters assessed

assessed
Davila et al Multicentre, randomised, To compare the short-term Bladix Change in UUI episodes
double-blind, parallel group, (6-week) safety and IR oral Change in urine volume per void
J Urol 2001; dose-titration study (n=76) tolerability of Bladix vs. IR oxybutynin Adverse events
166(1): 140-5 oral oxybutynin and see
whether transdermal
delivery is as effective as
oral delivery in OAB

Dmochowski Two-part, multicentre, To evaluate the efficacy and Bladix Change in UUI episodes
et al randomised study: 12-week, safety of Bladix in patients (1.3, 2.6 or 3.9 Change in urinary frequency and
double-blind, placebo- with moderate to severe mg/day) volume per void
J Urol 2002; controlled period; optional 12- OAB Placebo Incontinence-specific QoL
168: 580-6 week, open-label, dose- Adverse events
titration period (n=520)
Dmochowski Multicentre, randomised, To compare the efficacy Bladix Change in UUI episodes
et al double-blind, double-dummy and safety of Bladix and (3.9 mg/day) Change in urinary frequency and
study (n=361) long-acting, oral tolterodine Tolterodine volume per void
Urology 2003; with placebo (4.0 mg/day) Incontinence-specific QoL
62: 237-42 Matching Overall disease severity
placebos Safety
Study 1. Davila et al 2001

Efficacy:
Bladix significantly reduced the
number of daily incontinence
episodes by 66% (oral oxybutynin,
72%) (p<0.0001)

Safety:
Bladix resulted in a significantly
lower incidence of dry mouth
(38%) (oral oxybutynin, 94%)
(p<0.001)
Bladix was at least as effective as oral
oxybutynin, but was better tolerated,
resulting in significantly fewer
anticholinergic side effects
Study 2. Dmochowski et al 2002

Efficacy:
Bladix reduced the mean number
of weekly incontinence episodes
by 62% (placebo, 50%) (p<0.05)

Bladix reduced the mean daily

urinary frequency by 20% (placebo,
14%) (p<0.05)

Quality of life:
Bladix significantly improved QoL
compared with placebo (p=0.0327) Bladix (3.9 mg/day) significantly
improved the symptoms of OAB,
Safety: increased QoL and resulted in a low
Bladix resulted in a low
incidence of anticholinergic side
incidence of dry mouth (9.6%),
comparable to placebo (8.3%)
effects comparable to placebo
Study 3. Dmochowski et al 2003
Efficacy:
Bladix reduced the median daily
urinary frequency by 17%
(placebo, 8%) (p<0.101)
Bladix reduced the median number
of daily incontinence episodes by
75% (placebo, 50%) (p=0.0137)
Quality of life:
Bladix significantly improved QoL
compared with placebo (p<0.05)
Safety:
Bladix resulted in a low
incidence of anticholinergic side
effects, comparable to placebo
Bladix led to fewer treatment-
related systemic adverse events
than tolterodine
Bladix significantly improved the
symptoms of OAB, improved QoL
and resulted in a low incidence of
anticholinergic side effects
Summary of the clinical evidence for Bladix
Davila et al 2001
Results
Key Bladix is as effective as oral
points oxybutynin at reducing
episodes of urinary
incontinence
Kendera is better tolerated
and results in fewer
anticholinergic side effects,
especially dry mouth
Dmochowski et al 2002
Bladix is effective and safe in
the chronic treatment of OAB
Bladix significantly improves
OAB symptoms and QoL
Bladix is well tolerated and
associated with minimal
anticholinergic side effects
similar to placebo
Dmochowski et al 2003
Twice-weekly application of Bladix is
effective and safe and improves QoL
during chronic treatment of OAB
Efficacy is significantly better than
placebo and comparable to long-
acting, oral tolterodine
Systemic safety is comparable to
placebo, but substantially improved
compared with tolterodine
Bladix Self-Study Programme
Bladix features and benefits
1. Relief of OAB symptoms

Bladix relieves the symptoms of OAB with powerful, sustained efficacy

Clinical studies have clearly demonstrated that in the long-term, Bladix:

Significantly reduces the number of incontinence episodes
Significantly reduces the average daily urinary frequency
Allows a high proportion of patients to achieve total continence

Benefit to doctor: Possibility of reducing the OAB burden

Confidence that Bladix can get the job done
Benefit to patient: Relief as life becomes more normal and less burdened with the
problems associated with OAB
2. Low incidence of anticholinergic side effects

Treatment with Bladix results in a low incidence of anticholinergic side

effects (e.g. dry mouth, constipation, dizziness)
In particular, dry mouth:
Is not statistically significant different to placebo
Has not led to any patients discontinuing treatment during clinical trials
Is negligible because of the innovative transdermal delivery of Bladix

Benefit to doctor: Reduces the worry of prescribing a product that patients will not
stay on because of intolerable side effects
Benefit to patient: Greater satisfaction with treatment, allowing patients to benefit
more from the relief of OAB symptoms
No need to return to doctors to complain about side effects
 3. Improvement in QoL, high patient satisfaction

The powerful clinical efficacy and superior tolerability of Bladix can improve
QoL and lead to high patient satisfaction
No patient has discontinued treatment with Bladix due to dry mouth
92% of Bladix patients complied with treatment
92% of patients chose to continue treatment
Bladix improves quality of life (Global Assessment of Disease State and IIQ)
In a patient satisfaction survey, over 90% of patient expressed satisfaction or
acceptability of the Bladix patch and did not find it bothersome

Benefit to doctor: Offers the satisfaction of providing exactly what the patient wants
Benefit to patient: Ease of use leads to greater satisfaction and compliance with
treatment
4. Easy to use

The unique delivery system of Bladix is easy to use

The majority of patients described the patch as easy to apply

Greater than 90% patch adherence was noted at more than 90% of application site
evaluations; no detachments were observed
A majority of patients indicated that for further treatment of OAB symptoms, they
would prefer to use a transdermal system
The majority of patients found that remembering to reapply the patch was the same
as, or easier than remembering to take a pill once daily

Benefit to doctor: Offers the satisfaction of providing exactly what the patient wants
Benefit to patient: Ease of use leads to greater satisfaction and compliance with
treatment
 Features and benefits of Bladix
Feature
Effective, sustained control of
OAB symptoms
Anticholinergic effects
comparable to placebo
(especially dry mouth)
Efficacy and tolerability proven
in randomised, controlled trials
Unique transdermal delivery
Benefit
Improves the quality of life of OAB patients
Excellent safety profile
Is well tolerated (significantly better than oral
oxybutynin)
Increases compliance with treatment
Reassurance for both patient and physician
Requires lower doses of oxybutynin to achieve
therapeutic levels
Substantially reduces anticholinergic side
effects
 The treatment of choice in OAB

Sustained, effective relief of symptoms

Low incidence of anticholinergic side effects
Improved QoL, high patient satisfaction
Easy to use, innovative delivery system