Tamsulosin hydrochloride, prolonged release tablet, 400 microgram, Flomaxtra®, November 2008
Public summary document for Tamsulosin Hydrochloride, prolonged release tablet, 400 microgram, Flomaxtra®, November 2008
Page last updated: 24 March 2009
Public Summary Document
Product: Tamsulosin hydrochloride, prolonged
release tablet, 400 microgram, Flomaxtra®
Sponsor: CSL Biotherapies Limited
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission sought a restricted benefit listing for the
treatment of lower urinary tract symptoms (LUTS) due to benign
prostatic hyperplasia (BPH).
2. Background
The PBAC had considered tamsulosin for PBS listing on one previous
occasion. At its March 2008 meeting, the PBAC considered a
submission for tamsulosin seeking an unrestricted benefit for LUTS
associated with BPH. The PBAC rejected the submission because of
high and uncertain cost-effectiveness ratios. (See also Public
Summary Document of March 2008).
Tamsulosin has been available as a private prescription since it
was registered with the TGA in 1999 as a modified release capsule
under the tradename Flomax®. A prolonged release
oral controlled absorption system tablet formulation of tamsulosin
was registered by the TGA on 18 January 2006 under the tradename
Flomaxtra®.
3. Registration Status
This formulation of tamsulosin was approved by the TGA as a line
extension on 18 January 2006 for the relief of LUTS associated with
BPH.
4. Listing Requested and PBAC’s View
Restricted benefit
Lower urinary tract symptoms due to benign prostatic
hyperplasia.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
LUTS due to BPH includes symptoms such as hesitancy, dribbling
after urination, nocturia, frequency and urgency and may culminate
in urinary retention. Tamsulosin is used to relieve LUTS due to
BPH.
6. Comparator
The submission nominated prazosin and placebo as the main
comparators. This was as previously advised by the PBAC.
7. Clinical Trials
No changes had been made to the trial data presented in the
previous submission. (See list of published trials in Public
Summary Document of March 2008).
8. Results of Trials
There was a statistically significant reduction in the
international prostate symptom score (IPSS) following treatment
with tamsulosin compared to placebo (pooled mean difference -2.0,
95 % CI: -2.4, -1.6). However, the clinical significance of this
result was uncertain.
The re-submission did not present an indirect comparison of
tamsulosin versus prazosin although prazosin was presented as a
comparator. During the evaluation a prazosin versus placebo study
(Steven et al 1993) was located which examined the IPSS score,
hence an indirect comparison of tamsulosin versus prazosin in terms
of IPSS score could be performed. The indirect comparison of
tamsulosin versus prazosin estimated a non-significant difference
in the mean difference in IPSS score at 12 weeks (weighted mean
difference =-1.22, 95 % CI: -2.67, 0.23).
Also located during the evaluation were two 12-week studies of
prazosin versus placebo (Chapple et al 1992; 1990) examining
maximal urine flow rate (Qmax), hence an indirect comparison of
tamsulosin versus prazosin using the outcome of Qmax was also
conducted. An indirect comparison of tamsulosin versus prazosin
using the change in Qmax from baseline to 12 weeks as the outcome
demonstrated a statistically significant difference between
tamsulosin and prazosin favouring prazosin weighted mean difference
of -1.56
(95 % CI: -2.94, -0.18).
No new toxicity data were presented in the re-submission. There
were statistically significant increases in treatment related
adverse events for tamsulosin 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 haemodynamics with tamsulosin treatment, but this was
unlikely to be of clinical importance. Intraoperative Floppy Iris
Syndrome (IFIS) had been observed during cataract surgery in some
patients treated with alpha-1 blockers including tamsulosin, and
priapism. This was a rare but serious adverse effect.
The common adverse effects with prazosin were orthostatic
hypotension and dizziness.
9. Clinical Claim
The submission described tamsulosin as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over placebo.
The re-submission implicitly claimed that tamsulosin was
non-inferior to prazosin in accepting the price of prazosin for the
proportion of prazosin patients switching to tamsulosin. The
indirect comparison of tamsulosin versus prazosin performed during
the evaluation demonstrated that tamsulosin was non-inferior to
prazosin in terms of IPSS score, however the possibility that
tamsulosin was inferior to prazosin could not be excluded when
considering the outcome of maximum urine flow rate (Qmax). As noted
for the change in IPSS score, the clinical significance of the
change in Qmax was also uncertain.
10. Economic Analysis
An updated modelled economic evaluation was presented. The proposed
price reduction for tamsulosin was applied in the updated economic
evaluation in the re-submission. The re-submission did not formally
compare the costs and effects of tamsulosin and prazosin in its
modelled economic evaluation.
The structure and all inputs to the model used in the March 2008
submission remained unchanged.
The incremental cost per Quality Adjusted Life Year (QALY) gained
was $45,000 - $75,000, based on the trial duration of 12 weeks. The
incremental cost per QALY gained was $15,000 – $45,000, based
on costs and QALYs over 12 months (assuming the utility differences
at 12 weeks are maintained to 52 weeks).
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be in the
range of 100,000–200,000, while the likely financial cost per
year to the PBS (minus any savings in use of other drugs) was
estimated to be up to $10-30 million ($30–60 million using
prices updated for the 1 August 2008 PBS pharmacy dispensing fees
and mark-ups) in Year 5.
12. Recommendation and Reasons
The PBAC accepted that the resubmission requested listing for a
suitable restricted benefit listing compared to the previous
request for unrestricted listing. The PBAC also confirmed its March
2008 advice that the two main comparators in this population were
placebo for no PBS-subsidised medicine and prazosin, accepted the
projected substitution rates for these two comparators in the
resubmission and noted the related price reduction.
The placebo-controlled randomised trials provided data in relevant
populations. They reported small clinical benefits over placebo (a
meta-analysed mean difference in the International Prostate Symptom
Score (IPSS) of -2.0 (95 % CI: -2.4, -1.6) from baselines of around
19 on a 35-point scale. The PBAC accepted that this difference was
clinically important for patients, but that the nature of the
2-point difference might vary in importance depending on which of
the seven items (e.g. irritation, nocturia, dribbling) were
favourably affected in any single patient. The difference was
sustained over 40 weeks in one trial. The mean difference in total
maximal urine flow rate (Qmax) was also statistically significantly
improved with tamsulosin over placebo, but the clinical importance
of this secondary outcome was more difficult to interpret. The PBAC
noted useful input from both clinicians and patients in
interpreting the evidence on effectiveness. Tamsulosin and prazosin
results were similar for the IPSS across the indirect comparison
involving placebo as the common reference, but these were not
formally analysed to assess non-inferiority. The Qmax results
appeared to have statistically significantly favoured prazosin over
tamsulosin, but the PBAC accepted that this might not be a real
difference due to differences across the compared trials.
Tamsulosin was generally well tolerated with increased risk of
ejaculation problems, priapism and increased risk during cataract
surgery compared to placebo. Prazosin caused more postural
hypotension (important in the prevalent population), headache and
tachycardia.
The PBAC noted the price reduction compared to the previous
submission, but considered that the modelled economic evaluation
resulted in an unacceptably high and uncertain incremental
cost-utility ratio for the requested listing. In particular, the
translation into utilities (a mean incremental QALY gain of 0.0113
per patient per year, which was unchanged from the previous
submission) remained uncertain.
The PBAC noted a substantial private market had developed for
medicines to treat this condition, which was relevant to the
estimate of uptake of any medicine specifically listed on the PBS
for these patients. The PBAC decided not to recommend listing on
the basis of unacceptable and uncertain cost-effectiveness.
Recommendation: Reject
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
CSL is very disappointed with the PBAC’s rejection of this
2nd submission seeking listing of tamsulosin and that
tamsulosin cannot be made available on the PBS for sufferers of
LUTS associated with BPH at this time.
