Tamsulosin hydrochloride, prolonged release tablet, 400 micrograms, Flomaxtra, March 2008
Public summary document, March 2008
Page last updated: 18 July 2008
Public Summary Documents
Product: Tamsulosin hydrochloride, prolonged release tablet, 400 micrograms, Flomaxtra
Sponsor: CSL Biotherapies
Date of PBAC Consideration: March 2008
1. Purpose of Application
The application sought an unrestricted listing for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
2. Background
This was the first time tamsulosin had been considered by the PBAC.
3. Registration Status
This formulation of tamsulosin was approved by the TGA as a line extension of the old formulation on 18 January 2006 for the relief of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
4. Listing Requested and PBAC’s View
The submission sought an unrestricted listing.
The PBAC considered a restricted benefit listing would be more appropriate.
5. Clinical Place for the Proposed Therapy
Tamsulosin is used to relieve lower urinary tract symptoms associated with benign prostatic hyperplasia.
6. Comparator
7. Clinical Trials
The submission presented nine randomised trials comparing tamsulosin 4 mg with placebo
in men (older than 40 years) with BPH with at least moderate lower urinary tract symptoms
(LUTS), using the International Prostate Symptom Score (IPSS) as the outcome of interest
in all except one of the trials. That trial uses the Boyarski score.
The trials as published are presented in the following table.
|
Trial/First author |
Protocol title/Publication title |
Publication citation |
|---|---|---|
|
617-CL-307 |
Tamsulosin oral controlled absorption system (OCAS) in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): Efficacy and tolerability in a placebo and active comparator controlled phase 3a study. |
European Urology Supplements 4:33-44. |
|
617-CL-303 |
Tamsulosin oral controlled absorption system (OCAS) in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): Efficacy and tolerability in a phase 2b dose-response study. |
European Urology Supplements 4:25-32. |
|
91HAR02 and 91HAR01 |
Tamsulosin, the first prostate-selective alpha 1Aadrenoceptor antagonist. A meta-analysis
of two randomized, placebo-controlled, multicentre studies in patients with benign
prostatic obstruction (symptomatic BPH). |
European Tamsulosin Study Group. European Urology 29:155-167. |
|
92-03A |
Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. |
Tamsulosin Investigator Group. Urology 51:892-900
|
|
93-01 |
A second phase III multicenter placebo controlled study of 2 dosages of modified release
tamsulosin in patients with symptoms of benign prostatic hyperplasia. |
United States 93-01 Study Group. Journal of Urology 160:1701-1706. |
|
Kaplan et al, 2006 |
Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. |
JAMA 296:2319-28 |
|
Djavan et al, 2005 |
The impact of tamsulosin oral controlled absorption system (OCAS) on nocturia and the quality of sleep: Preliminary results of a pilot study. |
European Urology Supplements 4:61-68. |
|
Nordling. 2005 |
Efficacy and safety of two doses (10 and 15 mg) of alfuzosin or tamsulosin (0.4 mg) once daily for treating symptomatic benign prostatic hyperplasia. |
BJU International 95:1006-1012. |
|
Mohanty et al, 2003 |
A double blind placebo controlled study of tamsulosin in the management of benign prostatic hyperplasia in an Indian population. |
Annals of the College of Surgeons of Hong Kong 7:88-93. |
8. Results of Trials
The key results are summarised in the table below.
Results of change in prostate symptom scores from baseline to endpoint in the direct
trials
|
Trial ID |
Tamsulosin |
Placebo |
Mean difference (95% CI) |
||
|---|---|---|---|---|---|
|
End point (SD) |
Change (SD) |
End point (SD) |
Change (SD) |
||
|
International Prostate Symptom Score |
|||||
|
617-CL-307 OCAS |
10.8 (6.2) |
-7.7 (5.8) |
12.4 (6.4) |
-5.8 (5.6) |
-1.9 (-2.8, -1.0) |
|
617-CL-307 MR |
10.6 (5.9) |
-8.0 (5.6) |
12.4 (6.4) |
-5.8 (5.6) |
-2.2 (-3.0, -1.5) |
|
617-CL-303 |
10.4 (5.5) |
-7.6 (5.3) |
11.7 (6.1) |
-6.0 (5.4) |
-1.6 (-2.6, -0.6) |
|
92-03A |
11.5 |
-8.3 (6.3) |
14.1 |
-5.5 (6.3) |
-2.8 (-3.9, -1.7) |
|
93-01 |
12.8 |
-5.1 (6.4) |
15.6 |
-3.6 (5.7) |
-1.5 (-2.6, -0.4) |
|
Djavan 2005 |
10.2 |
-8.0 (5.2) |
12.5 |
-5.6 (4.7) |
-2.4 (-4.2, -0.6) |
|
Nordling 2005 |
10.9 |
-6.5 (6.2) |
13.1 |
-4.6 (5.8) |
-1.9 (-3.3, -0.5) |
|
Mohanty 2003 |
6.9 (4.4) |
-12.6 |
12.7 (4.0) |
-5.8 |
-6.8 |
|
Boyarski score |
|||||
|
6.1 (3.2) |
-3.3 (3.1) |
7.0 (3.4) |
-2.4 (3.2) |
-0.9 (-1.4, -0.4) |
|
|
Pooled analysis (excluding Mohanty 2003 and 91 HAR 02/ 91 HAR 01) |
|||||
|
Pooled relative risk (random effects) |
-2.02 (-2.41, -1.63) |
||||
|
Chi-square for heterogeneity: P= |
0.69 |
||||
Although all the placebo-controlled trials showed a statistically significant improvement
in IPSS, the incremental benefit of approximately 2 points over placebo achieved with
tamsulosin therapy was small, and its clinical importance was considered uncertain.
The PBAC noted the strong placebo response in the clinical trials. A 14.9% change
in symptom score occurred with placebo, and only an extra 5.8% change occurred with
tamsulosin treatment. It also appears that the majority of the clinical benefit is
observed within the first 4 weeks of therapy.
Quality of life data were not discussed in the submission and were difficult to find
in some of the individual study reports. The Pre-Sub Committee response provided additional
information and argued that the majority of results showed a significant benefit for
tamsulosin over placebo. The PBAC noted that, in general, measures of quality of life,
other than the ‘bother’ score tended not to reach statistical significance.
There were statistically significant increases in treatment related adverse events
compared with placebo (RR 1.39 [95% CI 1.09, 1.78]), and the major adverse events
were problems with ejaculation, with statistically significant increases in relative
risk in all trials except one, and a pooled relative risk of 6.79 (95% CI 3.29, 14.00).
There was a small statistically significant effect on hemodynamics with tamsulosin
treatment.
Intraoperative Floppy Iris Syndrome (IFIS) was observed during cataract surgery in
some patients treated with alpha-1 blockers including tamsulosin, and priapism is
a rare but serious adverse effect.
9. Clinical Claim
10. Economic Analysis
The submission presented a trial-based economic evaluation based on direct randomised
trials of tamsulosin (12 weeks duration) and a modelled evaluation representing chronic
therapy (12 months). The type of economic evaluation presented was a cost-utility
analysis. It was a simple model that applied the drug and GP costs and utility associated
with symptom improvement to tamsulosin- and placebo-treated patients. The time horizon
was 12 months.
The trial based incremental cost per Quality-Adjusted Life-Year (QALY) gained as 12
weeks was estimated in the submission to be between $45,000 and $75,000. The modelled
incremental cost per QALY gained over 12 months was estimated in the range of $15,000
to $45,000.
The PBAC noted:
- the simple structure and short time horizon of the model did not allow for costs
and health outcomes associated with treatment-related adverse events, episodes of
acute urinary retention avoided or
- surgery delayed or avoided.
the economic model was sensitive to the assumptions made in the QALY estimates, both
in the methods used to derive the utilities and the extrapolation of utilities past
the duration of the trial data.
For PBAC's views see Recommendations and Reasons.
11. Estimated PBS Usage and Financial Implications
The cost per year to the PBS was estimated in the submission to be in the range of $30 to $60 million in Year 5.
12. Recommendation and Reasons
The PBAC considered that a restricted benefit listing might be more appropriate than
the unrestricted listing proposed in the submission.
The PBAC considered that the choice of placebo as the only comparator in the submission
was not appropriate. Prazosin is the most commonly prescribed therapy for the treatment
of benign prostate hyperplasia (BPH) and the only one currently listed on the PBS,
and is therefore a relevant comparator. The PBAC noted the submission’s argument that
prazosin is not recommended as a treatment for LUTS in management guidelines for BPH.
However, the choice of comparator in submissions to the PBAC is not determined by
whether a therapy is recommended or not by therapeutic guidelines, but by whether
that therapy is the one most likely to be replaced in Australian clinical practice
should tamsulosin be listed on the PBS. According to the definition of the main comparator
in the PBAC guidelines, the therapies most likely to be replaced in clinical practice,
should tamsulosin become available on the PBS, would be prazosin, and in addition,
to account for a proportion of patients who may currently be untreated, placebo.
The submission used symptom scores measured by the International Prostate Symptom
Score (IPSS) and the Boyarski score, as primary outcome, and maximal urinary flow
rate as a secondary outcome. The IPSS consists of 7 items (4 obstructive symptom items
and 3 irritative symptoms items), totalling a maximum of 35 points. A total score
of 0-7 points is suggestive of mild disease, a score of 8-19 moderate disease, and
20-35 severe disease. The PBAC noted that the IPSS is a standard tool to measure LUTS
and is used as a clinical tool as well as a research measure. However, the PBAC was
concerned that no clinically important relationship between the total IPSS, prostate
size, urinary flow and obstruction had been demonstrated. In addition, the natural
history of untreated BPH is variable, making validation problematic.
Although all the placebo-controlled trials showed a statistically significant improvement
in IPSS, the incremental benefit of approximately 2 points over placebo achieved with
tamsulosin therapy was small, and its clinical importance was considered uncertain.
The PBAC noted the strong placebo response in the clinical trials. A 14.9% change
in symptom score occurred with placebo, and only an extra 5.8% change occurred with
tamsulosin treatment. It also appears that the majority of the clinical benefit is
observed within the first 4 weeks of therapy. The PBAC also considered that the extent
of the quality of life gains achieved with tamsulosin therapy were uncertain and mainly
related to “bother” scores.
The PBAC noted the statistically significant increases in treatment related adverse
events compared with placebo, mainly abnormal ejaculation, and intraoperative floppy
iris syndrome in some patients undergoing cataract surgery. Tamsulosin therapy resulted
in small, and unlikely to be clinically important, reduction in blood pressure, and
no statistically significant decrease in heart rate.
The PBAC considered that the trial-based incremental cost-effectiveness ratio of between
$45,000 and $75,000 per extra QALY gained at 12 weeks and modelled incremental cost-effectiveness
ratio of between $15,000 and $45,000 per extra QALY gained over 12 months to be unacceptably
high and uncertain because the results are very sensitive to the utility estimates
used. In addition, the utility estimates did not take into account treatment-related
adverse events. The modelled economic evaluation also assumed that the effect of the
mean change from baseline to endpoint (12 weeks) continues for 12 months. The assumption
was based on trial 92-03B, a 40-week double-blind extension of trial 92-03A, and an
open-label three-year follow-up study of patients enrolled in trials 91 HAR 02/01.
Only limited comparative efficacy data are available from these studies. Of note are
the large discontinuation rates observed in the 3-year open-label study (21% at week
48 and 48% at week 108) which were mainly related to lack of efficacy.
The PBAC also noted the large additional PBS expenditure of between $30 and $60 million
in the first five years should tamsulosin be subsidised.
The PBAC therefore rejected the submission because of unacceptably high and uncertain
cost-effectiveness ratios.
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.
