Asenapine, sublingual wafer, 5 mg and 10 mg (as maleate), Saphris® - July 2011
Page last updated: 28 October 2011
Public Summary Document
Product: Asenapine, sublingual wafer, 5 mg and 10
mg (as maleate), Saphris®
Sponsor: Lundbeck Australia Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required (STREAMLINED) listing
for treatment, for up to 6 months, of an episode of acute mania or
mixed episodes associated with bipolar I disorder, and maintenance
treatment, as monotherapy, of bipolar I disorder. The submission
also proposed the alternative listing of “treatment of
bipolar I disorder”.
2. Background
This drug had not been previously considered by the PBAC.
In a separate submission to the July 2011 meeting, the sponsor
requested an Authority required (STREAMLINED) listing for asenapine
for the treatment of schizophrenia.
3. Registration Status
Asenapine was TGA registered on 11 March 2011 for the following indications:
- Treatment of schizophrenia in adults;
- Treatment of acute manic or mixed episodes associated with bipolar I disorder in adults as monotherapy or in combination with lithium or sodium valproate;
- Prevention of relapse of manic or mixed episodes in bipolar I disorder in adults as monotherapy or in combination with lithium or sodium valproate.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Treatment, for up to 6 months, of an episode of acute mania or
mixed episodes associated with bipolar I disorder.
Maintenance treatment, as monotherapy, of bipolar I disorder.
Alternatively, the submission states that “as
monotherapy” could be removed from the restriction for
maintenance treatment, depending on the decision of the TGA
delegate, and the restriction be simplified to:
Authority required (STREAMLINED)
Bipolar I disorder.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Bipolar disorder occurs in at least 1% to 2% of the population.
Characterised by distinct episodes of mania and depression, the
impact of the illness is severe, impinging on relationships,
career, self-esteem and longevity. Some episodes manifest with both
manic and depressed symptoms—these 'mixed episodes' are
usually a variant of mania. Most patients with bipolar disorder
also experience periods of low-grade depression between the major
mood episodes. Where symptoms are less severe and of shorter
duration, the term hypomania is used. If patients have had at least
one manic episode at any stage of their life, the condition is
termed bipolar I disorder. If there have been only hypomanic and
depressed episodes, this is called bipolar II disorder.
The submission proposed that the place in therapy of asenapine is
as an alternative treatment option to those agents currently listed
on the PBS for the treatment of bipolar I disorder.
6. Comparator
The submission nominated olanzapine as the main comparator. The
submission also presented a secondary comparison with
quetiapine.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The basis of the submission is described below:
Monotherapy direct comparison:
two direct randomised comparative trials (A7501004 and A7501005)
and two associated continuation trials (A7501006 and A7501007)
comparing asenapine with olanzapine. The comparisons between the
asenapine and olanzapine were not an a priori objective in Trials
A7501004 and A7501005, and were conducted post hoc.
Monotherapy (indirect comparison, placebo as common comparator):
trials A7501004 and A7501005 comparing asenapine with placebo as
well as four direct randomised comparative trials (Bowden 2005,
McIntyre 2005, Vieta 2010 and D144CC00004) comparing quetiapine
with placebo.
The submission did not present separate data for acute versus
maintenance therapy. Analyses of the longer term efficacy of
asenapine compared to olanzapine and quetiapine (monotherapy) are
derived from the continuation trials (A7501006 and A7501007).
Adjunctive therapy to mood stabilisers (indirect comparison, placebo as common comparator):
one direct randomised comparative trial (A7501008) and associated
continuation trial (A7501009) comparing asenapine + mood stabiliser
with placebo + mood stabiliser and two randomised trials (Sachs
2004 and Yatham 2007) comparing quetiapine with placebo, and two
randomised comparative trials (Houston 2009 and Tohen 2002)
comparing olanzapine with placebo as adjunctive therapy to a mood
stabiliser. No longer term comparative analyses (beyond 6 weeks) of
asenapine versus olanzapine and quetiapine were presented.
Studies Suppes 2009, Vieta 2008, D1447C00144 and Tohen 2004 were
relapse prevention trials and were included only in the assessment
of comparative safety.
Details of the trials published at the time of the submission are in the table below.
| Outcome | Time point | Asenapine vs olanzapine Direct analysis (95% CI) | Asenapine vs quetiapine Indirect analysis (95% CI) |
| Monotherapy | |||
| LSM Difference in change from baseline YMRS | 3 weeks | 2.43 (0.92, 3.93) | 0.51 (-3.02, 2.01) |
| 12 weeks | -2.80 (-4.55, -1.05)* 1.2 ( -0.55, 2.95)** | ||
| 52 weeks | 0.4 ( -2.45, 3.25) | ||
| Responders (≥ 50% reduction in YMRS) | 3 weeks | RR 0.81 ( 0.70, 0.94) | RR 0.93 (0.67, 1.31) |
| 12 weeks | RR 0.93 ( 0.84, 1.03) | ||
| 52 weeks | RR 0.97 ( 0.89, 1.05) | ||
| Remitters (YMRS total score ≤12) | 3 weeks | RR 0.88 ( 0.67, 1.17) | RR 0.90 (0.56, 1.47) |
| 12 weeks | RR 0.94 ( 0.85, 1.05) | ||
| 52 weeks | RR 0.97 ( 0.89, 1.05) | ||
| Difference in change from baseline in CGI-BP severity overall illness | 3 weeks | 0.30 ( 0.12, 0.48) | 0.04 (-0.33, 0.41) |
| 12 weeks | 0.10 ( -0.16, 0.36) | ||
| 52 weeks | -0.20 ( -0.61, 0.21) | ||
| Difference in change from baseline in CGI-BP severity of mania | 3 weeks | 0.25 ( 0.06, 0.44) | |
| 12 weeks | 0.10 (-0.14, 0.34) | ||
| 52 weeks | -0.10 (-0.46, 0.26) | ||
| Difference in change from baseline in CGI-BP severity of depression | 3 weeks | 0.04 (-0.08, 0.17) | |
| 12 weeks | 0.00 (-0.24, 0.24) | ||
| 52 weeks | -0.20 (-0.53, 0.12) | ||
*Based on adjusted analysis used in error in the submission.
** A corrected analysis conducted during the evaluation.
Asenapine vs. olanzapine (monotherapy)
For monotherapy, at 3 weeks, olanzapine was associated with larger
changes from baseline in YMRS total scores than asenapine (the
difference was statistically significant but not clinically
important, applying a MCID of 3-5 points). Olanzapine was
associated with statistically significantly more responders, more
remitters (although the difference was not statistically
significant), and statistically significantly larger CGI-BP
severity of illness and severity of mania score reductions than
asenapine treated patients.
The results for the corrected analysis at 12 weeks were consistent
with asenapine being non-inferior to olanzapine; there were no
statistically significant differences between olanzapine and
asenapine at 52 weeks. The analyses at 12 weeks and 52 weeks were
based on extension phases of Trials A7501004 and A7501005; the
successively smaller proportions of patients entering the
continuation trials may suggest some selection biases. Kaplan Meier
curves of the time to failure of response in continuation trial
A7501007 showed a statistically significantly longer time to
failure of response in patients treated with olanzapine compared to
those treated with asenapine (p = 0.0127) at 52 weeks.
Asenapine vs. quetiapine (monotherapy)
While the results numerically favoured quetiapine, there were no
statistically significant differences between asenapine and
quetiapine at 3 weeks in change from baseline YMRS scores or the
secondary outcomes (responders, remitters, changes in CGI-BP
scores). However, the indirect comparison of differences in the
change from baseline in YMRS total score excluded two quetiapine
trials (Bowden 2005, McIntyre 2005) with apparently larger
reductions in YMRS. There were no statistically significant
differences in change in CGI-BP severity of illness scores between
quetiapine and asenapine at 3 weeks. There were no analyses of
quetiapine versus asenapine treatment beyond 3 weeks presented in
the submission.
Asenapine vs. olanzapine and quetiapine (adjunctive therapy to mood stabilisers)
The results of the indirect comparison of asenapine versus
olanzapine and quetiapine in the adjunctive treatment setting are
shown in the table below.
Summary of comparisons, asenapine vs olanzapine or quetiapine as adjunctive therapy to mood stabilisers
| Outcome | Time point | Asenapine vs olanzapine Indirect analysis (95% CI) | Asenapine vs quetiapine Indirect analysis (95% CI) |
| Adjunctive therapy to mood stabilisers | |||
| LSM Difference in change from baseline YMRS | 6 weeks | 0.64 (-2.13, 3.41) | |
| Responders (≥ 50% reduction in YMRS) | 3 weeks | RR 0.94 (0.57, 1.56) | |
| 6 weeks | RR 0.81 (0.53, 1.24) | RR 1.08 (0.75, 1.54) | |
| Remitters (YMRS total score ≤12) | 3 weeks | RR 1.08 (0.69, 1.69) | |
| 6 weeks | RR 1.22 (0.87, 1.72) | RR 1.23 (0.84, 1.79) | |
| Difference in change from baseline in CGI-BP improvement | 3 weeks | RR 1.08 (0.70, 1.68) | |
| 6 weeks | RR 1.10 (0.75, 1.62) | ||
Overall, outcomes generally numerically favoured olanzapine and
quetiapine over asenapine.
For PBAC’s comments on these results, see Recommendation
and Reasons.
The PBAC noted that overall, asenapine treated patients appeared to
experience more treatment emergent adverse events and serious
adverse events compared to olanzapine and quetiapine; particularly
headache, dizziness, mania, depression, insomnia, sedation,
arthralgia, pain in extremities, nausea, vomiting, anorexia, weight
loss and diarrhoea. There was a higher proportion of asenapine
treated patients reporting agitation related adverse events and
depressive symptoms compared to olanzapine or quetiapine but no
analyses of these differences were presented. Asenapine treated
patients generally reported less sedation and less weight gain
compared to olanzapine treated patients in longer term therapy. The
PBAC considered that asenapine is difficult to tolerate in the
short-term, highlighted by the range of adverse events experienced
in the trials. However, the PBAC noted that asenapine is associated
with less weight gain and a better metabolic profile in the longer
term compared to olanzapine, which the PBAC considered may
represent a potential clinical benefit.
There were statistically significantly more asenapine treated
patients withdrawing due to adverse events compared to olanzapine
at 3 weeks, but the differences were not statistically significant
at 12 and 52 weeks. The extended assessment of comparative harms of
asenapine was consistent with the safety profile observed in the
randomised trials, and other antipsychotic agents of this
class.
The PBAC was concerned that a serious quality use of medicines
(QUM) issue exists with regard to the bioavailability of asenapine.
The PBAC noted that the bioavailability of the sublingual wafer is
35% when administered sublingually, but drops to less than 2% if it
is ingested, and that the intake of water several (2 or 5 minutes)
after asenapine administration reduces the bioavailability (to 19 %
and 10 % respectively). The PBAC noted the sponsor’s advice
that both the Product Information and Consumer Medicines
Information provide instructions on the correct use of the
sublingual formulation. Notwithstanding, the PBAC requested the
National Prescribing Service provide comprehensive information for
health professionals in view of the serious QUM issues due to the
markedly reduced bioavailability of asenapine if it is not
administered correctly.
9. Clinical Claim
The submission described asenapine monotherapy as non-inferior in
terms of comparative effectiveness over olanzapine monotherapy.
This was not accepted by the PBAC.
The submission described asenapine monotherapy as non-inferior in
terms of comparative effectiveness over quetiapine monotherapy. The
PBAC considered that the results of the indirect comparison of
asenapine versus quetiapine supported this claim.
The submission described asenapine as adjunctive therapy to mood
stabilisers as non-inferior in terms of comparative effectiveness
over olanzapine adjunctive therapy, and non-inferior in terms of
comparative effectiveness over quetiapine adjunctive therapy.
The submission described asenapine as non-inferior in terms of
comparative safety over olanzapine and quetiapine.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as weighted means of the
equi-effective doses derived from the clinical trials in
monotherapy and adjunctive therapy to mood stabilisers. They are:
asenapine 13.7mg daily and olanzapine 12.9mg mean daily dose,
assuming a split of usage between indications of 10% as monotherapy
and 90% as adjunctive therapy to mood stabilisers.
The equi-effective doses for the secondary comparator quetiapine
were asenapine 16.3 mg and quetiapine 556.9 mg in the monotherapy
setting and asenapine 13.4 mg and quetiapine 506.7 mg in the
adjunctive setting.
11. Estimated PBS Usage and Financial Implications
The likely number of packs dispensed per year (5 mg and 10 mg
combined) was estimated in the submission to be between 10,000 and
50,000 in Year 5, with estimated net savings to the PBS of less
than $10 million in Year 5. The financial implications are to be
further verified.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC recommended the listing of asenapine sublingual wafers as
an Authority Required (STREAMLINED) listing for treatment, for up
to 6 months, of an episode of acute mania or mixed episodes
associated with bipolar I disorder (as monotherapy or in
combination with lithium or sodium valproate) and as monotherapy
for maintenance treatment of bipolar I disorder on a
cost-minimisation basis with quetiapine. The equi-effective doses
are asenapine 16.3 mg and quetiapine 556.9 mg in the monotherapy
setting and asenapine 13.4 mg and quetiapine 506.7 mg in the
adjunctive setting.
The PBAC agreed that the requested listing for “treatment of
bipolar I disorder” was not appropriate, as no data to
support use of asenapine in bipolar depression were presented. In
addition, the PBAC noted that no comparative analyses beyond 6
weeks were presented for use of asenapine in the adjunctive
treatment setting and therefore recommended the restriction should
limit use of asenapine to monotherapy only for maintenance
treatment.
The PBAC considered that while olanzapine may be an appropriate
comparator in clinical practice, it does not have PBS listing for
use in the acute treatment setting. Furthermore, the comparison
with quetiapine was considered informative as the Committee did not
have confidence in the non-inferiority of asenapine and olanzapine,
based on the clinical data presented in the submission.
From the pooled results of the direct comparison of asenapine and
olanzapine as monotherapy, the PBAC noted that at 3 weeks,
olanzapine was associated with a statistically significantly larger
change from baseline in Young Mania Rating Scale (YMRS) scores than
asenapine (2.43 [95% CI: 0.92, 3.93]), although this was less than
the Minimum Clinically Important Difference (MCID) of 4-6 points on
YMRS total score previously accepted by the PBAC. Olanzapine was
also associated with statistically significantly more responders,
remitters (although the difference was not statistically
significant), and statistically significantly larger
Clinician’s Global Impression scale for use in bipolar
illness (CGI-BP) severity of illness and severity of mania score
reductions than asenapine. At 12 and 52 weeks, there were no
statistically significant differences between olanzapine and
asenapine.
The PBAC noted that in acute mania, the early phase of treatment is
critical. The PBAC considered that the 3-week results of the direct
comparison were of most interest and that it could not be concluded
from these results that asenapine is non-inferior to
olanzapine.
From the results of the indirect comparison of asenapine versus
quetiapine as monotherapy using placebo as the common comparator,
the PBAC noted there were no statistically significant differences
at 3 weeks in change from baseline YMRS scores, responders,
remitters or changes in CGI-PB scores, supporting a conclusion that
asenapine is most likely to be non-inferior to quetiapine.
In the adjunctive treatment setting, the PBAC noted the results of
the indirect comparison of asenapine versus olanzapine and
quetiapine showed no statistically significant differences in
change from baseline YMRS, or the secondary endpoints. The PBAC
noted that no analyses beyond 6 weeks were presented to support the
use of asenapine as adjunctive treatment to lithium and sodium
valproate in the maintenance treatment of bipolar I disorder.
The PBAC noted that overall, asenapine was associated with more
treatment emergent adverse events and serious adverse events
compared to olanzapine or quetiapine. However, it was noted that
asenapine is associated with less weight gain and a better
metabolic profile in the longer term than olanzapine, which the
PBAC considered may represent a potential clinical benefit.
The PBAC was concerned that a serious quality use of medicines
(QUM) issue exists with regard to the bioavailability of asenapine.
The PBAC noted that the bioavailability of the sublingual wafer is
35% when administered sublingually, but drops to less than 2% if it
is ingested, and that the intake of water several (2 or 5 minutes)
after asenapine administration reduces the bioavailability (to 19 %
and 10 % respectively). The PBAC noted the sponsor’s advice
that both the Product Information and Consumer Medicines
Information provide instructions on the correct use of the
sublingual formulation. Notwithstanding, the PBAC requested the
National Prescribing Service provide comprehensive information for
health professionals in view of the serious QUM issues due to the
markedly reduced bioavailability of asenapine if it is not
administered correctly.
The PBAC considered that the listing of asenapine would provide an
additional treatment choice in a stable market and would be
unlikely to increase the cost of treating bipolar disease. Listing
on a cost-minimisation basis with quetiapine may provide cost
savings to the PBS if patients were to switch to asenapine from
olanzapine. However, savings would not be realised if patients were
to switch from less costly PBS listed drugs.
The PBAC noted the consumer comments received in its consideration
of asenapine.
The PBAC recommended that asenapine be included in the PBS
medicines for prescribing by nurse practitioners within
collaborative arrangements as a shared care model.
Recommendation:
ASENAPINE, sublingual wafer, 5 mg, 10 mg (as maleate)
Restriction:
Authority required (STREAMLINED)
Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder.
Maintenance treatment, as monotherapy, of bipolar I disorder.
Note:
Shared Care Model:
For prescribing by nurse practitioners where care of a patient is shared between a nurse practitioner and medical practitioner in a formalised arrangement with an agreed management plan. Further information can be found in the Explanatory Notes for Nurse Practitioners.
Maximum quantity: 60
Repeats: 5
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 has no comment.
