Tapentadol, tablet, 50 mg, 100 mg, 150 mg, 200 mg and 250 mg (as hydrochloride) (sustained release), Palexia SR®
Page last updated: 01 July 2011
Public Summary Document
Product: Tapentadol, tablet, 50 mg, 100 mg, 150
mg, 200 mg and 250 mg (as hydrochloride) (sustained release),
Palexia SR®
Sponsor: CSL Biotherapies
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought a Restricted Benefit listing for the
treatment of chronic severe disabling pain not responding to
non-narcotic analgesics.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Tapentadol SR tablets were TGA registered on 19 January 2011 for
the management of moderate to severe chronic pain un-responsive to
non-narcotic analgesia. There is currently no clinical trial data
available regarding the safety and efficacy of tapentadol SR in
patients with pain due to malignancy.
4. Listing Requested and PBAC’s View
CAUTION:
The risk of drug dependence is high.
Restricted Benefit
Chronic severe disabling pain not responding to non-narcotic
analgesics.
NOTE:
Authorities for increased maximum quantities and/or repeats will be
granted only for:
(i) chronic severe disabling pain associated with proven malignant
neoplasia; or
(ii) chronic severe disabling pain not responding to non-narcotic
analgesics where the total duration of narcotic analgesic treatment
is less than 12 months; or
(iii) first application for treatment beyond 12 months of chronic
severe disabling pain not responding to non-narcotic analgesics
where the patient's pain management has been reviewed through
consultation by the patient with another medical practitioner, and
the clinical need for continuing narcotic analgesic treatment has
been confirmed. The date of the consultation must be no more than 3
months prior to the application for a PBS authority. The full name
of the medical practitioner consulted and the date of consultation
are to be provided at the time of application; or
(iv) subsequent application for treatment of chronic severe
disabling pain not responding to non-narcotic analgesics where a
PBS authority prescription for treatment beyond 12 months has
previously been issued for this patient.
For PBAC’s view, see Recommendation and
Reasons
5. Clinical Place for the Proposed Therapy
Chronic pain has a prevalence of approximately 1 in 5 Australians,
of which over 75% is due to osteoarthritis or back pain. Opioid
analgesics such as oxycodone and morphine have demonstrated
efficacy in the management of moderate to severe pain. However,
adverse effects of these drugs include gastrointestinal symptoms,
central nervous system symptoms and pruritis, all of which may
impact on compliance to the treatment.
The submission proposed that tapentadol would be an alternative to
other PBS-listed opioids.
6. Comparator
The submission nominated oxycodone hydrochloride controlled release
as the main comparator.
For PBAC’s view, see Recommendation and
Reasons
7. Clinical Trials
The submission presented three pivotal randomised trials comparing
tapentadol SR, oxycodone CR and placebo (Trials KF11, KF12, KF23)
in patients with moderate to severe pain who were dissatisfied with
their current analgesia.
The key efficacy data were derived from a pre-specified pooled
analysis of these three trials (Pooled Analysis and Active
Comparator Analysis).
There were three supplementary trials – KF24 a one year
safety study; KF19 a short-term Phase 2 dosing study; and KF41 with
2 week tapentadol immediate release phase followed by 4 week
tapentadol SR phase to assess analgesic efficacy and GI
tolerability.
Trials recruited subjects with osteoarthritis of the knee and hip
or low back pain. None of the trials were conducted in patients
with cancer-related pain.
The key trials published at the time of submission are shown in the
table below:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| Direct randomised trials | ||
| Pivotal trials | ||
| KF11 | A Randomized Double-Blind, Placebo- and Active-Control, Parallel-Arm, Phase 3 Study With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee | Clinical Study Report |
| Afilalo M et al 2010 | Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: A randomized, double-blind, placebo-and active-controlled phase III study. | Clinical Drug Investigation 2010; 30 (8):489-505 |
| KF12 | A Randomized Double-Blind, Placebo- and Active-Control, Parallel-Arm, Phase 3 Study With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee. | Clinical Study Report |
| KF23 | A Randomized Double-Blind, Placebo- and Active-Control, Parallel-Arm, Phase 3 Study With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Low Back Pain. | Clinical Study Report |
| Buynak R et al 2010 | Efficacy and safety of tapentadol extended release for the management of chronic low back pain: Results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. | Expert Opinion on Pharmacotherapy 2010; 11(11):1787-1804. |
| Supplementary trials | ||
| KF24 | A One-Year, Randomized, Open-Label, Parallel-Arm, Phase 3 Long-Term Safety Study, With Controlled Adjustment of Dose, of Multiple Doses of Tapentadol Extended-Release (ER) and Oxycodone Controlled-Release (CR) in Subjects With Chronic Pain. | Clinical Study Report |
| Wild et al 2010 | Long-term Safety and Tolerability of Tapentadol Extended Release for the Management of Chronic Low Back Pain or Osteoarthritis Pain | Pain Practice 2010; 10:416-427 |
| KF19 | A 4-Week Randomized, Multicenter, Double-Blind, Placebo- and Active-Controlled, Parallel-Group, Forced-Titration Phase 2b Study Comparing Efficacy and Safety of Ascending Doses of CG5503 Prolonged Release (PR) Up to 233 mg b.i.d. and Oxycodone CR 20mg Prolonged Release Up to 20mg b.i.d. to Placebo in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee. | Clinical Study Report |
| KF41 | A Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Arm, Multicenter Study in Subjects With End-Stage Joint Disease to Compare the Frequency of Constipation Symptoms in Subjects Treated With Tapentadol IR and Oxycodone IR Using a Bowel Function Patient Diary Protocol; Phase 3b. | Clinical Study Report |
| Meta-analyses of direct randomised trials | ||
| KF5503/PR-IS-01 Lange B et al 2010 | Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. | Advances in Therapy 2010;27(6):381-99. |
CR: controlled release; ER: extended release; IR: immediate
release
8. Results of Trials
Pooled analysis
The primary efficacy outcome for the pooled efficacy analyses for
the pivotal trials KF11, KF12 and KF23, was pain intensity,
measured using an 11-point numerical rating scale (NRS) with a
higher score representing greater pain intensity. Two primary
efficacy endpoints were defined. For the US regulatory authority,
the primary efficacy outcome was defined as the change from
baseline to the last week of the maintenance period (Week 12) in
pain intensity, referred to as ‘Change from baseline to week
12’. For the non-US regulatory authorities, the primary
efficacy endpoint was change from baseline to the average pain
intensity over the 12-week maintenance period, referred to as
‘Change from baseline to overall maintenance’.
Tapentadol SR versus placebo:
The results of the pooled analyses showed statistically significant
superiority of tapentadol SR over placebo in change from baseline
in average pain intensity at Week 12 of the maintenance period (US
regulatory outcome) and 12 week maintenance period (non-US
regulatory outcome) using last observation carried forward (LOCF)
imputation and the various alternative imputation methods. There
were statistically significantly larger proportions of patients
with 30% and 50% reductions in pain intensity scores for tapentadol
SR versus placebo. More tapentadol SR than placebo treated patients
reported pain ‘very much improved’ or ‘much
improved’ at endpoint (56.7% vs 37.5%). The placebo responses
for all three pain measures were substantial. There was no
statistically significant difference between tapentadol and placebo
in time to treatment discontinuation (median: 118.0 days for
tapentadol versus 124.0 days for placebo; p=0.223).
Oxycodone CR versus placebo:
The results of the pooled analyses showed statistically significant
superiority of oxycodone CR over placebo in change from baseline in
average pain intensity over the 12 week maintenance period (non-US
regulatory outcome) using LOCF imputation, and at Week 12 of the
maintenance period (US regulatory outcome). The results were not
consistent across all imputation methods, with non-significant
results for imputation using the Modified Baseline Observation
Carried Forward (ModBOCF). More placebo than oxycodone CR treated
patients had ≥30% and ≥50% improvements in pain intensity
score, this difference was statistically significant for the
≥30% response. However, more oxycodone CR than placebo treated
patients reported pain ‘very much improved’ or
‘much improved’ at endpoint (49.3% vs 37.5%). There was
a statistically significant difference between oxycodone and
placebo in time to treatment discontinuation (median: 39.0 days for
oxycodone versus 124 days for placebo; p<0.001).
Tapentadol SR versus oxycodone CR:
The pooled results of the trials suggest that tapentadol SR is
statistically significantly superior to oxycodone CR (LS mean
difference for both change from baseline to week 12 and overall
maintenance, responder rates). However, the differences between
tapentadol SR and oxycodone CR in reduction in pain scores are
small. The PBAC did not consider this improvement over oxycodone
(0.3 units on the 11-point numerical scale rating (NRS)) to be
clinically meaningful.
Treatment discontinuations
Fewer oxycodone CR treated patients completed 15 weeks treatment
(38.3%) compared to placebo (59.4%) and tapentadol SR (56.5%), with
discontinuations more common in the titration phase. The time to
discontinuation was consistently shorter in oxycodone CR treated
patients. There was a statistically significant difference between
tapentadol and oxycodone in time to treatment discontinuation
(median: 118.0 days for tapentadol versus 39.0 days for oxycodone;
p<0.001).
Discontinuation rates for tapentadol SR and placebo were very
similar (43.5% compared with 40.6%). There were a higher proportion
of patients that discontinued oxycodone due to adverse effects
(39.4% compared with 18.3%). A category called ‘Subject
Choice’ was also listed as a reason for discontinuation of
therapy, however, there was no information provided as to the
reasons behind the patients’ choice resulting in
discontinuation.
Quality of life data
EQ-5D and SF-36:
Results of the assessments of quality of life (SF-36, EQ-5D)
suggest some differences between tapentadol SR and oxycodone CR,
however there was no consistent pattern of better quality of life
outcomes with tapentadol SR. Differences in subscales and summary
scores on the SF-36 and EQ-5D were small and it is unclear these
represent clinically important differences. On the other hand, the
PBAC considered that the results support both statistical and
clinical non-inferiority of tapentadol SR vs oxycodone in relation
to pain efficacy, using LOCF to account for missing data.
Active comparator analysis
The active comparator analysis was conducted to establish the
superior gastrointestinal tolerability profile of tapentadol SR
over oxycodone CR and the non-inferiority of tapentadol SR and
oxycodone CR for efficacy.
Superiority of tapentadol SR versus oxycodone CR was demonstrated
in terms of gastrointestinal tolerability. Non-inferiority of
tapentadol SR versus oxycodone CR was demonstrated for efficacy for
both overall maintenance and at week 12.
The results of the pooled analysis for gastrointestinal
tolerability are presented in following table:
Gastrointestinal tolerability – Pooled Analysis (%
patients)
| Tapentadol SR (N=981) | Oxycodone CR (N=1001) | |
| Subjects with GI adverse events | 42.8% | 65.6% |
| - vomiting or nausea | 23.3% | 42.7% |
| - nausea | 20.7% | 36.2% |
| - constipation | 16.9% | 33.0% |
PAC-SYM (Patient Assessment of Constipation Symptom scale)
The PBAC noted there were few statistically significant differences
between tapentadol SR and oxycodone CR in patients without
constipation at endpoint. The only statistically significant
differences were in Trial KF12 where oxycodone CR was statistically
significantly worse than placebo in reduction in pain scores.
For PBAC’s comments on these trials, see Recommendation
and Reasons.
The PBAC noted the most frequently reported adverse events (AEs)
were gastrointestinal events (nausea, vomiting, constipation),
nervous system AEs (dizziness, headache somnolence), and skin
disorders (hyperhidrosis and pruritis).
9. Clinical Claim
The submission described tapentadol SR as superior in terms of
comparative effectiveness and superior in terms of comparative
safety to oxycodone CR. The submission claimed that tapentadol SR
shows greater efficacy in pain reduction compared to oxycodone CR,
lower discontinuation rates, greater improvements in quality of
life, and improved safety with lower rates of GI adverse
events.
Based on the supporting data the PBAC considered the efficacy claim
was not reasonable.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The model was a Markov
model, comparing patients with severe pain initiating treatment
with either tapentadol SR or oxycodone CR. Patients could continue
treatment, discontinue treatment, or switch to another sustained
release opioid. The model duration was one year, with 52 weekly
cycles. The costs included in the model were drug costs only, based
on mean daily doses from the key trials.
The submission estimated the incremental cost per QALY gained to be
less than $15,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost/year to the PBS was estimated by the
submission to be in the range of $10 - $30 million in Year 5.
12. Recommendation and Reasons
The PBAC noted the requested restriction would allow use in cancer
pain, when no evidence had been presented to support such
use.
The PBAC noted that tapentadol would likely substitute for less
expensive therapies as well as oxycodone SR, eg long-acting oral
morphine, as well as for tramadol SR. Although tapentadol has a
different proposed PBS restriction, TGA indication and different
poison scheduling from tramadol, clinicians would likely consider
tapentadol as an alternative to tramadol, given that they are
chemically similar and have the same mode of action. Although the
issue of whether prophylactic laxatives should have been included
in the comparison was raised in the Commentary, the PBAC
acknowledged that the pivotal clinical trials neither excluded nor
mandated their use and that use across the arms of the trial is
unknown. The PBAC also noted that many patients purchase laxatives
over the counter.
The pooled results of the trials suggest that tapentadol SR is
statistically significantly superior to oxycodone CR (least squares
mean difference for both change from baseline to week 12 and
overall maintenance, responder rates). However, the differences
between tapentadol SR and oxycodone CR in reduction in pain scores
are small, the 95% confidence limits are well within the ±2
points (on the 11-point numerical rating scale) suggested to
demonstrate equivalent analgesic efficacy between IR and SR
formulations in Trial KF39. The differences are unlikely to
represent a clinically important difference between tapentadol SR
and oxycodone CR.
The PBAC noted that tapentadol causes less constipation and nausea
than oxycodone. Adverse events were more frequent in the titration
phase than in the maintenance phase of the trials.
Fewer oxycodone CR treated patients completed 15 weeks treatment
(38.3%) compared to placebo (59.4%) and tapentadol SR (56.5%), with
discontinuations more common in the titration phase. The time to
discontinuation was consistently shorter in oxycodone CR treated
patients. There was a statistically significant difference between
tapentadol and oxycodone in time to treatment discontinuation
(median: 118.0 days for tapentadol versus 39.0 days for oxycodone;
p<0.001).
Discontinuation rates for tapentadol SR and placebo were very
similar (43.5% compared with 40.6%). There were a higher proportion
of patients that discontinued oxycodone due to adverse effects
(39.4% compared with 18.3% for tapentadol). A category called
subject choice was also listed as a reason for discontinuation of
therapy. However, there was no information provided as to the
reasons behind the patients’ choice resulting in
discontinuation. Overall, the discontinuation rates were considered
to be high considering the short duration of the trials (15 weeks).
Also, the PBAC considered that the discontinuation rates are
difficult to interpret because they are a composite endpoint that
includes discontinuations due to toxicity, lack of pain relief, and
other unspecified patient factors. Further, the lowest
discontinuation rates were for placebo.
The PBAC noted that the model structure is based on differences in
continuation rates between the treatment arms from the pooled
trials, which is uncertain and may be overestimated in the
extrapolation out to 52 weeks. Extrapolating discontinuations to
health outcomes is problematic as differences in continuation rates
do not necessarily translate into differences in clinical outcomes.
The pre-PBAC comment argued that that discontinuation rates were
not the primary outcome in either the trials or the model and that
the PBAC should instead focus on the EQ-5D results collected in the
trials. The PBAC noted that the model is structured to apply
differences in utilities for patients who continue treatment and
patients who discontinue treatment. This post-hoc analysis of EQ-5D
results may not be reliable. The results of the EQ-5D premodelling
study show no difference between tapentadol SR and oxycodone CR for
both continuing patients and for discontinuing patients. However,
differences between treatment arms are modelled for continuing and
discontinuing patients. As noted above, differences in the EQ-5D
were small and it is unclear these represent clinically important
differences. Further, it is not reasonable to assume that 95% of
patients discontinuing therapy would not switch to an alternative
drug and remain at the utility of a discontinuing patient from the
trial period over the duration of the model. The PBAC thus agreed
that the utility gain exhibited by tapentadol SR in the model is
likely to be higher than would be seen in practice. The model does
not provide a robust analysis to inform PBAC of what is a
reasonable price to pay for reduced AEs, including constipation.
The PBAC therefore considered that the incremental cost
effectiveness ratios in the submission were highly uncertain.
The PBAC rejected the submission because of uncertain clinical
benefit 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 working with the PBAC to ensure that this medication is available for patients with chronic severe disabling pain not responding to non-narcotic analgesics.
