Oxybutynin, transdermal patches, 36 mg (releasing approximately 3.9 mg per 24 hours), Oxytrol®, November 2008
Public summary document for Oxybutynin, transdermal patches, 36mg (releasing approximately 3.9 mg per 24 hours), Oxytrol®, November 2008
Page last updated: 12 March 2009
Public Summary Document
Product: Oxybutynin, transdermal patches, 36 mg
(releasing approximately 3.9 mg per 24 hours),
Sponsor: Hospira Pty Ltd
Date of PBAC Consideration:November 2008
1. Purpose of Application
The submission sought a restricted benefit listing for the
treatment of urge urinary incontinence or urgency due to detrusor
instability as second line therapy in patients who cannot tolerate
oral oxybutynin or propantheline.
At its March 2008 meeting the PBAC rejected an application to list
oxybutynin transdermal patches as a restricted benefit for the
treatment of symptoms of urge urinary incontinence and urgency
because of uncertainty regarding the population that would use the
transdermal patch and the application of the results from the
clinical trials, uncertainty regarding the comparative clinical
effectiveness of the patch, and uncertain cost effectiveness. (See
also Public Summary Document of March 2008).
Oral oxybutynin has been listed on the PBS as a Restricted benefit for detrusor overactivity since 1996.
3. Registration Status
Oxybutynin transdermal patch was TGA registered on 10 May 2007 for
the treatment of overactive bladder with symptoms of urinary
frequency, urgency or incontinence or any combination of these
4. Listing Requested and PBAC’s View
Urge urinary incontinence or urgency due to detrusor instability in a patient who cannot tolerate oral oxybutynin or propantheline.
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Oxybutynin transdermal patch will provide an alternative dosing
option of oxybutynin for the treatment of symptoms of urge urinary
incontinence and urgency due to detrusor instability in patients
unable to tolerate the oral dose form.
The submission nominated placebo as the main comparator. Supportive
comparisons with solifenacin and tolterodine were also included in
the submission. Neither solifenacin or tolterodine are PBS
For PBAC’s view see Recommendation and Reasons.
7. Clinical Trials
No changes were made to the trial data presented in the previous
submission. The re-submission presented two randomised trials
comparing transdermal oxybutynin with placebo in patients with
overactive bladder. The re-submission also presented one randomised
trial comparing transdermal oxybutynin with oral oxybutynin in
patients with overactive bladder in its evaluation of the safety of
TD oxybutynin. However, data presented as supporting evidence in
the previous submission was presented as the key evidence in the
re-submission (Trials 009 and 011).
The trials published at the time of the submission were:
|Trial ID||Publication title||Publication citation|
|Direct randomised trials – key evidence|
|Trial 099009 (Phase III) Dmochowski RR, et al||For The Transdermal Oxybutynin Study Group. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence.||Dmochowski RR, et al. Journal of Urology, 2002, 168 (2): 58-586.|
|Trial 000011 (Phase IIIB) Dmochowski RR, et al||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.||Dmochowski RR, et al. Urology , 2003, 62 (2): 237-242.|
|Direct randomised trials – supportive evidence for safety|
|Trial 096017 (Phase II) Davila GW, et al||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.||Davila GW, et al. Journal of Urology , 2001, 166 (1): 140-145.|
|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).||Sand P, et al. 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||Dmochowski RR, et al. World Journal of Urology, Sep 2005 23 (4): 263-70.|
8. Results of Trials
No new data were presented in the re-submission. The trials
reported small clinical benefits over placebo (in the meta-analysis
of the direct randomised trials, the median change from baseline in
daily urinary incontinence episodes at the end of treatment was
-3.0 for the participants who received transdermal oxybutynin
versus -2.0 for those who received placebo) which were close to
conventional thresholds of statistical significance. Transdermal
oxybutynin and tolterodine results were similar, but these were not
formally analysed to assess non-inferiority. All these trial
results were limited to 12 weeks’ duration.
No new toxicity data were presented in the re-submission. Transdermal oxybutynin was associated with more application site reactions than either placebo or tolterodine. There were more withdrawals over 12 weeks from transdermal oxybutynin (11 %) than from tolterodine (3 %) or from placebo (1 %).
9. Clinical Claim
The submission claimed that TD oxybutynin was more effective than
placebo, but was associated with more adverse events (application
site reactions). The re-submission also claimed that TD oxybutynin
was non-inferior to tolterodine and solifenacin. The claim of
non-inferiority of TD oxybutynin compared with tolterodine was not
well justified due to the uncertainty regarding the clinical
significance of the pre-specified equivalence interval and the
formulation of tolterodine used in Trial 011 differing from those
currently registered for use in Australia. The claim of
non-inferiority of TD oxybutynin compared with solifenacin was also
not well justified due to differences in disease severity of
patients enrolled in the respective trials and that a significantly
greater proportion of patients treated with TD oxybutynin
discontinued treatment compared with those treated with
10. Economic Analysis
An updated modelled economic evaluation was presented. The model
structure was substantially unchanged from the previous submission;
however efficacy estimates were changed to reflect the change in
The results of the primary stepped economic evaluation using the pooled results from Trials 009 and 011 over 12 weeks estimated the incremental cost per extra quality adjusted life year (QALY) gained as < $15,000. Testing the upper and lower confidence intervals (CI) of the relative risk of achieving continence when being treated with TD oxybutynin compared to placebo resulted in a 95% CI for the incremental cost per QALY ranging from TD oxybutynin being dominant (i.e. decreased cost, increased effectiveness - upper 95% CI ) to placebo being dominant (i.e. increased cost, decreased effectiveness - lower 95% CI ).
11. Estimated PBS Usage and Financial Implications
The submission used patient full year equivalents (PFYEs) to
estimate PBS usage at between 10,000 and 50,000 PFYEs in Year 5 of
listing at an estimated financial cost per year to the PBS
(excluding co-payments) minus any savings in use of other drugs of
< $10 million in Year 5.
12. Recommendation and Reasons
The PBAC accepted that the resubmission requested listing for a
more limited patient population than previously, namely to those
patients unable to tolerate oral oxybutynin.
The PBAC confirmed its March 2008 advice that the main comparator in this population was placebo for no PBS-subsidised medicine and that the secondary clinical comparison with tolterodine was informative even though tolterodine was not listed on the PBS.
The PBAC recalled its March 2008 concerns that the key trials submitted did not recruit patients who represented those who would be eligible according to the requested restriction. Specifically, neither trial recruited patients intolerant to oral oxybutynin. Trial 009 recruited a majority of previously untreated patients and Trial 011 recruited patients who had experienced a beneficial response to anticholinergic therapy and then were sufficiently tolerant to this therapy to be stabilised for at least six weeks. This was important because the essential clinical claim of the submission was that switching from oral oxybutynin to transdermal oxybutynin retained superior effectiveness over placebo and similar effectiveness to tolterodine whilst reducing the toxicity that led to intolerance. Trial participants also had moderate to severe disease of many years’ duration, whereas the requested restriction would encompass less severe disease of shorter duration.
The PBAC therefore concluded that the results of these trials would overestimate the extent of effectiveness in the population targeted by the requested restriction. The trials reported small clinical benefits over placebo (in the meta-analysis of the direct randomised trials, the median change from baseline in daily urinary incontinence episodes at the end of treatment was -3.0 for the participants who received transdermal oxybutynin versus -2.0 for those who received placebo) which were close to conventional thresholds of statistical significance. Transdermal oxybutynin and tolterodine results were similar, but these were not formally analysed to assess non-inferiority. All these trial results were limited to 12 weeks’ duration. Longer-term results relied on an assumption that in a symptomatic disease, patients would only persist with therapy if they perceived a sufficient response. There was no basis provided to verify this assumption.
Transdermal oxybutynin was associated with more application site reactions than either placebo or tolterodine. There were more withdrawals over 12 weeks from transdermal oxybutynin (11 %) than from tolterodine (3 %) or from placebo (1 %).
The PBAC considered that the modelled economic evaluation was uncertain. In particular, the translation of achieving complete continence (a secondary outcome of the trials) into utilities was uncertain, both in terms of the transformation to utilities and the impact of assumed discontinuation rates which acted as a surrogate for a loss of effectiveness over time. The expected further waning of effectiveness beyond the 12-month time horizon of the modelled economic evaluation was important given that participants in the key trials were around 60 years of age. The re-analysis of the model with new assumptions about the utility distributions presented in the Pre-PBAC response was not accepted because it was not presented in sufficient detail to allow a clear determination of the appropriateness of this late re-analysis compared with the approach in the resubmission. In addition, while the PBAC noted the argument in the submission that the SF-6D was subject to floor effects, the PBAC did not accept that this was a sufficient basis to reject its general preference of relying on the results of accepted multi-attribute utility instruments reported in the key trials and considered that it would be appropriate to present SF-6D based utility scores in addition to the weights presented in the submission.
The PBAC noted a substantial potential for use of transdermal oxybutynin beyond the requested restriction. The PBAC decided not to recommend listing on the basis of uncertain comparative clinical effectiveness in the population who would be eligible according to the requested restriction and the resulting uncertain cost-effectiveness.
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.