Oxybutynin, transdermal patches, 36mg (releasing approximately 3.9 mg per 24 hours), Oxytrol, March 2008
Public summary document for Oxybutynin, transdermal patches, 36mg (releasing approximately 3.9 mg per 24 hours), Oxytrol, March 2008
Page last updated: 18 July 2008
Public Summary Document
Product: Oxybutynin, transdermal patches, 36 mg (releasing approximately 3.9 mg per
24 hours), Oxytrol
Sponsor: Hospira Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a Restricted benefit listing for the treatment of symptoms of urge urinary incontinence and urgency.
2. Background
This was the first time oxybutynin transdermal patches had been considered by the PBAC.
3. Registration Status
Oxytrol was TGA registered on the 10 May 2007 for the treatment of overactive bladder with symptoms of urinary frequency, urgency or incontinence or any combination of these symptoms.
4. Listing Requested and PBAC’s View
Restricted benefit
Treatment of symptoms of urge urinary incontinence and urgency.
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Oxytrol is used for the treatment of overactive bladder with symptoms of urinary frequency, urgency or incontinence or any combination of these symptoms.
6. Comparator
7. Clinical Trials
The submission presented one randomised trial comparing transdermal oxybutynin with
oral oxybutynin in patients with overactive bladder. The submission also presented
two randomised trials comparing transdermal oxybutynin with placebo in patients with
overactive bladder.
The trials as published at the time of the submission are presented in the table below.
|
Trial ID |
Publication title |
Publication citation |
|---|---|---|
|
Direct randomised trials |
||
|
Trial 096017 (Phase II) |
A short-term, multicentre, randomised double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. |
Journal of Urology, 2001, 166 (1): 140-145. |
|
Trial 099009 (Phase III) |
For The Transdermal Oxybutynin Study Group. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. |
Journal of Urology, 2002, 168 (2): 58-586. |
|
Trial 000011 (Phase IIIB) |
For The Transdermal Oxybutynin Study Group. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. |
Urology, 2003, 62 (2): 237-242. |
|
Supplementary randomised trial |
||
|
Sand P, et al |
Oxybutynin transdermal system improves the quality of life in adults with overactive bladder: a multicentre, community-based, randomised study (Multicentre assessment of Transdermal Therapy in OAB with oxybutynin - MATRIX). |
BJU International, Apr 2007 99 (4): 836-44. |
|
Meta-analyses of direct randomised trials |
||
|
Dmochowski RR, et al |
Transdermal oxybutynin in the treatment of adults with overactive bladder: combined results of two randomised clinical trials |
World Journal of Urology, Sep 2005 23 (4): 263-70. |
8. Results of Trials
The results of the trials are summarised in the table below:
Proportion of participants achieving complete continence (zero incontinent episodes
per day) at endpoint on all doses of transdermal and oral oxybutynin
|
Trial ID |
TD oxybutynin |
Comparator |
Tolterodine |
Risk Difference |
Relative Risk |
|---|---|---|---|---|---|
|
n/N (%) |
n/N (%) |
n/N (%) |
|||
|
TD oxybutynin versus oral oxybutynin |
|||||
|
017 |
8/37 |
10/35 |
NA |
-6.95% |
0.76 |
|
TD oxybutynin versus placebo |
|||||
|
009 |
18/120 (15.0) |
11/127 |
NA |
6.3% |
1.73 |
|
011 |
47/121 |
26/117 |
47/123 |
16.6% |
1.75 |
|
Pooled 009 & 011: random effects model |
11.0% |
1.74 |
|||
Notes: CI=Confidence Interval, Statistically significant results are bolded.
The results from trial 017 comparing transdermal oxybutynin to oral oxybutynin show
no statistically significant difference in the proportion of patients achieving full
continence.
Trial 017 was a dose titration study and patients were initiated at one of three levels
according to the patient’s prior stable daily oral oxybutynin dose. After two and
four weeks, the dose was increased if patients regarded their side effects as being
absent or mild.
The results show that five of the eight patients achieving full continence received
a transdermal oxybutynin dose that is not TGA-approved (1 on 26 cm2 and 4 on 52 cm2).
The following table summaries the anti-cholinergic adverse events from the Phase II/III
trials:
|
Adverse Event |
TD oxybutynin (double-blind) |
TD placebo |
Oral oxybutynin |
TD oxybutynin (double-blind and open label) |
|---|---|---|---|---|
|
(n=547) |
(n=249) |
(n=38) |
(n=663) |
|
|
Dry mouth |
41 (7.5) |
13 (5.2) |
22 (57.9) |
57 (8.6) |
|
-related |
41 (7.5) |
13 (5.2) |
22 (57.9) |
57 (8.6) |
|
Constipation |
19 (3.5) |
7 (2.8) |
10 (26.3) |
30 (4.5) |
|
-related |
17 (3.1) |
5 (2.0) |
10 (26.3) |
26 (3.9) |
|
Dizziness |
15 (2.7) |
6 (2.4) |
6 (15.8) |
23 (3.5) |
|
-related |
10 (1.8) |
3 (1.2) |
5 (13.2) |
15 (2.3) |
|
Nausea |
18 (3.3) |
8 (3.2) |
7 (18.4) |
25 (3.8) |
|
-related |
10 (1.8) |
3 (1.2) |
6 (15.8) |
14 (2.1) |
|
Somnolence |
6 (1.1) |
1 (0.4) |
6 (15.8) |
8 (1.2) |
|
-related |
6 (1.1) |
1 (0.4) |
6 (15.8) |
8 (1.2) |
|
Palpitations |
4 (0.7) |
0 |
3 (7.9) |
5 (0.8) |
|
-related |
2 (0.4) |
0 |
3 (7.9) |
2 (0.3) |
|
Vision abnormal |
12 (2.2) |
3 (1.2) |
4 (10.5) |
16 (2.4) |
|
-related |
11 (2.0) |
2 (0.8) |
4 (10.5) |
15 (2.3) |
|
Dysuria |
10 (1.8) |
1 (0.4) |
3 (7.9) |
14 (2.1) |
|
-related |
6 (1.1) |
1 (0.4) |
3 (7.9) |
6 (0.9) |
|
Urinary retention |
2 (0.4) |
0 |
1 (2.6) |
2 (0.3) |
|
-related |
2 (0.4) |
0 |
1 (2.6) |
2 (0.3) |
Overall, the safety profile for transdermal oxybutynin appeared favourable compared to placebo. The anticholinergic event profile for transdermal compared to oral oxybutynin also appeared favourable. A greater proportion of patients treated with transdermal oxybutynin (3.9mg/day) experienced an application site adverse event.
9. Clinical Claim
The submission claimed that TD oxybutynin is equivalent to oral oxybutynin in terms
of comparative effectiveness, but has a superior adverse event profile.
The PBAC did not agree with the therapeutic claim in the submission that the transdermal
patch oxybutynin was equivalent to oral oxybutynin in terms of efficacy but with fewer
side effects. The PBAC noted non-inferiority was not shown in Trial 017, with a lower
CI for the difference of -17% when the trial specified non-inferiority at -15%. Additionally,
five of the eight patients achieving full continence on the transdermal patch received
an oxybutynin dose that is not TGA-approved (1 on 26cm2 and 4 on 52cm2). The response
to the transdermal patches may therefore be over-inflated.
10. Economic Analysis
A modelled economic evaluation was presented. The model was a decision tree analysis,
with a single cycle of a one year period. There were four health states used in the
model to which utility values were applied. The key drivers of the model appeared
to be the estimate of effectiveness of TD oxybutynin, the utility values applied to
the health states and a number of cost estimates.
From the primary economic evaluation, the estimated incremental cost per Quality-Adjusted
Life-Year (QALY) gained compared to oral oxybutynin was in the range of $15,000 to
$45,000.
A secondary economic evaluation of transdermal oxybutynin compared to placebo produced
an incremental cost per QALY gained in the range of $15,000 to $45,000.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated to be between $10 and $30 million
in Year 3.
The PBAC considered that these estimates were likely to be underestimated.
12. Recommendation and Reasons
The PBAC noted the differences in pharmacology between the oral and transdermal patches
of oxybutynin. Oral oxybutynin undergoes an extensive first-pass metabolism by the
cytochrome P450 system producing an active metabolite, N-desethyloxybutynin (N-DEO).
N-DEO appears to contribute greatly to the anticholinergic side-effects associated
with the oral administration of oxybutynin (i.e. dry mouth), and it is thought that
the transdermal administration of oxybutynin, which avoids the first-pass (gastrointestinal
and pre-systemic) metabolism, could result in fewer anticholinergic side effects with
similar efficacy by lowering plasma concentrations of N-DEO. On the other hand, the
metabolite N-DEO may contribute to the activity of the drug on the human detrusor
muscle as in vitro studies it has been shown to have similar activity to oxybutynin.
The PBAC acknowledged that, at the hearing, the sponsor was open to the Committee
considering either first-line or second-line listing for the transdermal patch. A
second-line listing, however, did not match the trial populations in the clinical
evidence presented, which were responder populations who were able to sufficiently
tolerate any anticholinergic or other adverse events to enable treatment for at least
a six-week period. The submission did not present sufficient evidence in patients
who failed or were intolerant to oral anticholinergic treatments.
The PBAC also considered that it is unlikely that a patient failing first-line treatment
will not seek further treatment. Therefore, placebo was not considered a sufficient
second line comparator; this part of the requested listing should have also resulted
in a comparison with solifenacin and tolterodine, noting that neither product is PBS-listed.
The PBAC did not agree with the therapeutic claim in the submission that the transdermal
patch oxybutynin was equivalent to oral oxybutynin in terms of efficacy but with fewer
side effects. Non-inferiority was not shown in Trial 017, with a lower CI for the
difference of -17% when the trial specified non-inferiority at -15%. Additionally,
five of the eight patients achieving full continence on the transdermal patch received
an oxybutynin dose that is not TGA-approved (1 on 26cm2 and 4 on 52cm2). The response
to the transdermal patches may therefore be over-inflated.
The PBAC also considered that the lower adverse events (particularly dry mouth) may
be associated with lower effectiveness given the potential for the N-DEO metabolite
to be active on the detrusor muscle. The transdermal patch is also associated with
application site reactions and the PBAC noted that the discontinuation rates between
transdermal patch oxybutynin and oral oxybutynin did not differ.
The Committee noted the price requested for the transdermal patch was considerably
greater that of the oral dose. The economic model used to justify this price was considered
overly complex. The PBAC was of the view that the most important aspect of the model
should be the impact of adverse events on costs and utilities. This aspect was not
clear from the model provided.
The PBAC therefore rejected the submission based on uncertainty regarding the population
that would use the transdermal patch and the application of the results from the clinical
trials, which were made up of responders to oral anticholinergics; uncertainty regarding
the comparative clinical effectiveness of the patch; and uncertain cost effectiveness.
The price advantage over the oral formulation was considered unjustified.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor will be considering its position regarding any future course of action.
