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 of schizophrenia.
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, for up to 6 months, of an episode of acute mania
or mixed episodes associated with bipolar I disorder, and
maintenance treatment, as monotherapy (or monotherapy and
combination therapy) of bipolar I disorder. The submission proposed
an alternative listing of “treatment of bipolar I
disorder”.
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)
Schizophrenia
The PBAC had no objection to the requested wording of the
restriction.
5. Clinical Place for the Proposed Therapy
Schizophrenia is a severe psychiatric illness, which is likely to
affect seven in every thousand Australians during their lifetime.
It is characterised by disturbances in speech, perception,
cognition, volition and emotion. Males are more commonly and more
severely affected than females. Peak age of onset is in the late
teens and early twenties. Atypical antipsychotics are usually used
as first-line treatment as they are associated with fewer side
effects, although multiple switches between drugs may be required.
Clozapine and typical antipsychotics are generally trialled if
treatment with several atypical antipsychotics has failed.
The likely place in therapy of asenapine is an alternate treatment
option to those agents currently listed on the PBS for treatment of
schizophrenia – olanzapine, quetiapine, risperidone,
amisulpride, aripiprazole, ziprasidone and paliperidone.
6. Comparator
The submission nominated olanzapine as the main comparator. A
secondary comparison with risperidone was also provided. This was
accepted by the PBAC.
7. Clinical Trials
The basis of the submission was four randomised head-to-head trials
comparing asenapine and olanzapine (Trials 41021, 41022, 25517 and
25543) with three associated unblinded extension studies (Trials
41512, 25520 and 25544) and one direct randomised trial comparing
asenapine and risperidone (Trial 41004) with one associated
unblinded extension study (Trial 41500).
Only Trial 41004 was published at the time of the submission.
Trials and associated reports presented in the submission
| Trial ID | Protocol title/ Publication title | Publication citation |
| Trials of asenapine versus risperidone (secondary comparator) | ||
| 41004 Potkin et al. (2007) | Efficacy and tolerability of asenapine in acute schizophrenia: A placebo- and risperidone-controlled trial. | Journal of Clinical Psychiatry, 68 (10), 1492-1500. |
8. Results of Trials
Comparative effectiveness
Asenapine versus olanzapine:
The results of the head-to-head trials of asenapine and olanzapine showed no statistically
significant differences in reductions in Positive and Negative Syndrome Scale (PANSS)
total scores at 6 weeks, Negative Symptoms Assessment (NSA) total scores at 6 and
26 weeks, PANSS positive scores at 6 weeks, PANSS negative scores at 6 and 26 weeks,
Calgary Depression Scale for Schizophrenia (CDSS) scores at 6 weeks and Clinical Global
Impression – Severity of Illness (CGI-S) scores at 26 weeks. There were statistically
significant differences favouring olanzapine at 26 weeks in PANSS total score, PANSS
positive scores, CDSS scores and CGI-S scores, and in PANSS total score at 52 weeks.
The PBAC noted that the differences in PANSS total score were small and did not meet
the minimum clinically important difference (MCID) of 7 points, previously accepted
by the PBAC. The differences in reductions in CDSS and CGI-S scores were small and
unlikely to be clinically important.
There were no statistically significant differences in the proportion of treatment
responders (defined as achieving a 30% or greater reduction from baseline in PANSS
total score) at 6 weeks between asenapine and olanzapine treated patients. However,
there were statistically significantly more treatment responders to olanzapine at
26 and 52 weeks. The response at 6 weeks is patient relevant, particularly for patients
with negative symptoms.
The PBAC noted that the rate of discontinuation in the trials was generally higher
for patients treated with asenapine than for those treated with olanzapine.
Asenapine versus risperidone
The short-term results of the direct comparison of asenapine and risperidone (Trial
41004) are shown in the table below.
Summary of comparisons of asenapine vs. risperidone for schizophrenia
| Outcome | Time point | Asenapine vs risperidone Direct analysis (95% CI) ; p value | |
| Baseline-to-endpoint change in PANSS total score | 6 weeks | -4.93 (12.27, 2.41); | p = 0.19 |
| Baseline-to-endpoint change in PANSS positive score | 6 weeks | -0.35 (-2.83, 2.13); | p = 0.78 |
| Baseline-to-endpoint change in PANSS negative score | 6 weeks | -2.16 (-4.18, -0.14); | p = 0.04 |
| Baseline-to-endpoint change in CGI-S score | 6 weeks | 0.01 (-0.33, 0.35); | p = 0.95 |
Abbreviations: WMD = weighted mean difference; SD = standard deviation; SE = standard
error;
asen = asenapine; risp = risperidone; PANSS = Positive and Negative Syndrome Scale;
CGI-S = Clinical Global Impression - severity of illness.
There were no statistically significant differences between asenapine and risperidone
treated patients in changes from baseline in PANSS total score, PANSS positive score
and CGI-S score at week 6. There was a statistically significant difference in PANSS
negative score favouring asenapine at week 6. However, the difference was small and
unlikely to be clinically important.
The proportion of treatment responders (≥ 30% reduction from baseline in PANSS total
score) are shown in the table below.
Proportions of treatment responders at 6 weeks (≥ 30% reduction from baseline PANSS total score; ITT, LOCF)
| Trial ID | Asenapine | Risperidone | RR (95% CI) | ||
| N | n with events (%) | N | n with events (%) | ||
| 41004 a | 58 | 22 (37.9%) | 56 | 22 (39.3%) | 0.97 (0.61, 1.53) |
Abbreviations: RR = relative risk; PANSS = Positive and Negative Syndrome Scale.
a Recalculated during the evaluation.
There was no statistically significant difference in the proportion of responders
in asenapine treated patients compared to risperidone treated patients at week 6.
The consistency of results across changes in PANSS total scores and subscales and
responder rates, suggested that asenapine may be considered non-inferior to risperidone.
However, Trial 41004 was a small, fixed dose, three arm trial designed to compare
asenapine and placebo with risperidone as an active control arm (doses were asenapine
5mg twice daily, risperidone 3mg twice daily). Drop out rates in this small trial
were also high.
For PBAC’s comments on these results, see Recommendation and Reasons.
For the comparison of asenapine versus olanzapine, the adverse events most frequently
reported by asenapine treated patients were headache, nausea, insomnia, agitation,
dyspepsia and sedation. More asenapine treated patients reported symptoms of schizophrenia,
anxiety, agitation, depression and akathisia compared to olanzapine treated patients.
Patients treated with asenapine also reported statistically significantly less weight
gain than patients treated with olanzapine.
Changes from baseline total cholesterol, fasting triglycerides and fasting BSL were
more favourable in asenapine treated patients compared to olanzapine treated patients.
It is uncertain if the small differences reported are clinically important. There
were no significant differences in change from baseline serum low density lipids,
HbA1c and prolactin.
For the comparison of asenapine versus risperidone, in Trial 41502 more asenapine
treated patients reported symptoms of schizophrenia, and fewer reported weight gain
compared to patients treated with risperidone. However, treatment arms were very small.
Overall, the extended assessment of comparative harms of asenapine was consistent
with the safety profile observed in the clinical trials, and other antipsychotic agents
of this class.
For PBAC’s view, see Recommendation and Reasons.
9. Clinical Claim
The submission described asenapine monotherapy as non-inferior in terms of comparative
effectiveness over olanzapine. Overall, the PBAC was not satisfied that the results
of the direct comparison adequately supported this claim.
The submission described asenapine as non-inferior in terms of comparative safety
over olanzapine. Asenapine was associated with more anxiety, agitation, depression
and akathisia compared to olanzapine, but less weight gain. The PBAC agreed that asenapine
is difficult to tolerate in the short-term, highlighted by the range of adverse events
experienced in the trials. However, it was noted that asenapine is associated with
less weight gain and a better metabolic profile compared to olanzapine.
The submission described asenapine as non-inferior in terms of comparative effectiveness
and non-inferior in terms of comparative safety over risperidone in the treatment
of schizophrenia.
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 extension
studies related to the clinical trials. They are: asenapine 14.7 mg daily and olanzapine
13.6 mg mean daily dose (dose relativity 1.08:1).
For the comparison with risperidone, the equi-effective doses derived from the fixed
dose short term Trial 41004 were estimated as asenapine 8.3mg and risperidone 5.3mg
(dose relativity 1.57:1. The PBAC noted that this comparison with risperidone would
represent a lower price compared with the price proposed in the submission versus
olanzapine.
11. Estimated PBS Usage and Financial Implications
The number of packs dispensed per year (5 mg and 10 mg combined) was estimated in
the submission to be more than 200,000 in Year 5, with estimated net savings per year
to the PBS of less than $10 million in Year 5.
The PBAC did not accept the submission’s estimated cost savings to the PBS and noted
the sponsor’s acknowledgement that these savings may not be realised.
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 of
schizophrenia on a cost-minimisation basis with risperidone. The
equi-effective doses are asenapine 8.3 mg daily and risperidone 5.3
mg daily.
The PBAC accepted that olanzapine was the appropriate comparator
based on likely market share, and that risperidone was an
appropriate secondary comparator.
From the pooled results of the comparison of asenapine versus
olanzapine, the PBAC noted there were no statistically significant
differences in the primary efficacy endpoint of change from
baseline in Positive and Negative Syndrome Scale (PANSS) total
score at 6 weeks, nor were there statistically significant
differences in the secondary outcomes of Negative Symptoms
Assessment (NSA) total scores at weeks 6 and 26, PANSS positive
scores at 6 weeks, PANSS negative scores at 6 and 26 weeks, Calgary
Depression Scale Score for Schizophrenia (CDSS) scores at 6 weeks
and Clinician Global Impression of Severity (CGI-S) scores at 6
weeks. There were statistically significant differences favouring
olanzapine at 26 weeks in PANSS total score, PANSS positive scores,
CDSS scores and CGI-S scores, and in PANSS total score at 52
weeks.
The PBAC noted that the differences in PANSS total score were small
and did not meet the minimum clinically important difference (MCID)
of 7 points, previously accepted by the PBAC.
The PBAC noted that for the proportion of treatment responders
(defined as achieving a 30% or greater reduction from baseline in
PANSS total score), there were no statistically significant
differences between asenapine and olanzapine at 6 weeks. However
there were statistically significantly more treatment responders to
olanzapine at 26 and 52 weeks.
Overall, the PBAC was not satisfied that the results of the direct
comparison adequately supported the claim of non-inferiority of
asenapine compared to olanzapine.
From the results of the direct comparison of asenapine versus
risperidone from the 6-week Trial 41004, the PBAC noted that there
were no statistically significant differences between asenapine and
risperidone treated patients in changes from baseline in PANSS
total score, PANSS positive score and CGI-S score at week 6. There
was a statistically significant difference in PANSS negative score
favouring asenapine at week 6. However, the difference was small
and unlikely to be clinically important. There were no
statistically significant differences in the proportion of
responders in asenapine treated patients compared to risperidone
treated patients at week 6.
The PBAC acknowledged that there are limited data on which to make
a clinical claim against risperidone. However, the PBAC agreed with
the ESC that the consistency of results across PANSS total scores
and subscales and responder rates from Trial 41004 suggests that
asenapine may be considered non-inferior to risperidone, at least
in the short-term. Overall, although there are no longer term data
to make a comparison of asenapine with risperidone, the PBAC was
more confident about accepting non-inferiority with risperidone
because of its lower price
In terms of comparative safety, the PBAC agreed with the ESC that
asenapine appears to be difficult to tolerate in the short term.
However, it is associated with less weight gain at 6 and 26 weeks
and is associated with a better metabolic profile compared to
olanzapine, which the PBAC considered may represent a potential
clinical benefit.
The PBAC noted that the United States FDA has included asenapine on
its list of drugs to monitor due to reports of hypersensitivity
reactions, and that this may be consistent with the small number of
patients in the clinical trials reporting oropharyngeal swelling
and oral hypoaesthesia when taking sublingual asenapine.
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 in
its pre-PBAC response 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 did not accept the submission’s estimated cost
savings to the PBS and noted the sponsor’s acknowledgement in
its pre-PBAC response that these savings may not be realised. The
PBAC further noted that the submission’s calculation of the
financial implications to the PBS was based on the therapeutic
relativity of asenapine to olanzapine of 1.08:1 and that revised
estimates of costs will be required based on the therapeutic
relativity of asenapine to risperidone of 1.57:1.
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)
Schizophrenia
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.
