Sertindole, tablet, 4 mg, 12 mg, 16 mg, 20 mg, Serdolect® - March 2011
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Public Summary Document
Product: Sertindole, tablet, 4 mg, 12 mg, 16 mg,
20 mg, Serdolect®
Sponsor: Lundbeck Australia Pty Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an Authority required (STREAMLINED) listing
for the treatment of schizophrenia in patients who have had prior
treatment with at least one other antipsychotic.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Sertindole was TGA registered on 6 July 2010 for the treatment of
schizophrenia. Due to cardiovascular safety concerns, sertindole
should be used only for people who are not responsive to, or
intolerant of at least one other antipsychotic medicine. Due to its
slow onset of action, sertindole should not be used in emergency
situations for urgent relief of symptoms in acutely disturbed
patients.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
For treatment of schizophrenia in people who have had prior
treatment with at least one other anti-psychotic.
Not be used in emergency situations for urgent relief of symptoms
in acutely disturbed people.
For PBAC’s view, see Recommendation and
Reasons.
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 such as
risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole
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 submission proposed that the place of sertindole is as an
alternative second line treatment of schizophrenia.
6. Comparator
The submission nominated risperidone as the main comparator, with
olanzapine as a secondary comparator.
The PBAC considered that olanzapine was a more appropriate choice
of main comparator than risperidone.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented two head-to-head randomised trials
(M95-372, 97203) comparing sertindole with risperidone using
post-hoc analyses (re-definition of ITT populations), one
head-to-head randomised comparative trial comparing sertindole with
olanzapine (11286) and one randomised, open label, long term trial
comparing the safety of sertindole with risperidone (99824).
Supportive analyses were provided in an indirect meta-analysis of 4
trials comparing sertindole with haloperidol and 8 trials comparing
olanzapine with haloperidol, using haloperidol as common
comparator. Four Cochrane reviews are also presented as supporting
evidence.
The table below details the published trials presented in the
submission:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| Sertindole vs Risperidone (Direct randomised trials) | ||
| Azorin JM et al 2006 | A double-blind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia. | International Clinical Psychopharmacology. 2006, 21(1):49-56. |
| Supplementary randomised trials | ||
| Thomas S et al 2010 | Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP). | Acta Psychiatr Scand 2010:1-11. |
| Sertindole vs Haloperidol | ||
| Indirect randomised trials | ||
| Zimbroff DL et al 1997 | Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. | The American Journal of Psychiatry. 1997, 154(6):782-91. |
| Hale AS et al 2000 | Sertindole improves both the positive and negative symptoms of schizophrenia: results of a phase III trial. | Int J Psych Clin Pract. 2000a, 4:55-62. |
| Hale AS et al 2000 | Sertindole is associated with a low level of extrapyramidal symptoms in schizophrenic patients: results of a phase III trial. | Int J Psych Clin Pract. 2000b, 4:47-54. |
| Olanzapine vs Haloperidol | ||
| Indirect randomised trials | ||
| Beasley et al 1996 | Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial. | Neuropsychopharmacology1996,14: 111-123. |
| Beasley et al 1997 | Olanzapine versus haloperidol: Acute phase results of the international double-blind olanzapine trial. | European Neuro-psychopharmacology. 1997, 7:125-137. |
| Bernardo et al 2001 | Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: A baseline-endpoint IBZM SPECT study, | Psychiatry Research Neuroimaging. 2001, 107: 87-97. |
| Ishigooka et al 2001 | Olanzapine versus haloperidol in the treatment of patients with chronic schizophrenia: Results of the Japan multicenter, double-blind olanzapine trial. | Psychiatry and Clinical Neurosciences. 2001, 55: 403-414. |
| Kongsakon et al 2006 | Asian outpatients with schizophrenia: A double-blind randomized comparison of quality of life and clinical outcomes for patients treated with olanzapine or haloperidol, | Journal of the Medical Association of Thailand. 2006, 89: 1157-1170. |
| Lindenmayer et al 2007 | A randomized controlled trial of olanzapine versus haloperidol in the treatment of primary negative symptoms and neurocognitive deficits in schizophrenia. | Journal of Clinical Psychiatry. 2007, 68(3):368-79. |
| Tollefson et al 1997 | Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. | The American Journal of Psychiatry. 1997, 154:457-465. |
| Volavka et al 2002 | Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. | American Journal of Psychiatry. 2002, 159:255-262. |
| Meta-analyses of randomised trials | ||
| Lewis R et al 2005 | Sertindole for schizophrenia. | Cochrane Database of Systematic Reviews. 2005, Issue 3. |
| Komossa K et al 2009 | Sertindole versus other atypical antipsychotics for schizophrenia. | Cochrane Database of Systematic Reviews. 2009, issue 1. |
| Duggan L et al 2005 | Olanzapine for schizophrenia. | Cochrane Database of Systematic Reviews. 2005, Issue 2. |
| Komossa K et al 2010 | Olanzapine versus other atypical antipsychotics for schizophrenia. | Cochrane Database of Systematic Reviews. 2010, Issue 6. |
8. Results of Trials
Sertindole vs risperidone
The submission presented results for the primary outcome in trials
M95-372 and 97203, mean difference (sertindole – risperidone)
in change from baseline in Positive And Negative Syndrome Scale
(PANSS) total score at 12 weeks.
There was no statistically significant difference in the primary
outcome of mean difference in change from baseline Positive and
Negative Syndrome Scale (PANSS) total score at 12 weeks in the
pooled results of trials M95-372 and 97203 for the post hoc
analysis using last observation carried forward (LOCF). However,
the post hoc analysis using LOCF did not meet the non-inferiority
margin of a 7 point difference in PANSS total score, as previously
accepted by the PBAC.
The submission also presented the mean difference (sertindole
– risperidone) in change from baseline in PANSS and CGI-S
scores at 12 weeks - post hoc analyses (LOCF) of trials
M95-372 and 97203.
Statistically significant differences were not observed for the
secondary outcomes of change from baseline PANSS subscale scores
and Clinical Global Impression Severity (CGI-S) scale scores.
There were no statistically significant differences in proportions
of responders (≥ 40% improvement in PANSS Total score) for
trials M95-372 and 97203 between sertindole and risperidone in
either trial, although there were numerically more responders in
the risperidone treated arms.
For PBAC’s comments on these results, see Recommendation
and Reasons.
Sertindole vs olanzapine (direct comparison)
A non-inferiority criterion of an upper confidence interval for
treatment difference of ≤ 7.0 (PANSS total score) was
pre-specified.
The submission presented the primary & secondary outcomes in
Trial 11286, mean difference (sertindole – olanzapine) in
change from baseline in PANSS and CGI-S scores at 12 weeks
(LOCF).
Olanzapine treated patients showed numerically larger reductions in
PANSS total score and the upper confidence interval for the mean
difference in change from baseline PANSS total score did not meet
the trial’s pre-specified non-inferiority criterion.
There were statistically significantly more responders (by
improvement in PANSS Total score; olanzapine/sertindole in the Full
Analysis Set (FAS) population) in olanzapine treated patients than
sertindole treated patients using both the LOCF and the observed
cases (OC) approach to missing data, at both ≥ 25% and ≥ 35%
decreases in PANSS Total scores and at all time points.
For PBAC’s comments on these results, see Recommendation
and Reasons.
Sertindole vs olanzapine (indirect comparisons)
The results for the indirect comparison (pooled olanzapine –
pooled sertindole) with haloperidol as common comparator of mean
difference in change from baseline in PANSS, Brief Psychiatric
rating Scale (BPRS) and CGI-S indicated that there are
statistically significant differences favouring olanzapine compared
to sertindole in mean change from baseline PANSS (including Total
score and all sub scales excluding Negative score) and BPRS scores
at 12 weeks.
The submission compared the safety of sertindole with risperidone
in the long term, open label post-marketing safety trial 99824
(designed to investigate whether treatment with sertindole
increased all cause mortality, cardiac mortality and cardiac
related hospitalisations compared to treatment with risperidone,
requested as a condition of resumption of registration by the EMEA)
and the direct randomised controlled trials M95-372 and 97203, and
with olanzapine in the direct randomised controlled trial
11286.
The PBAC noted the results of the safety study 99824 showed
statistically significantly higher rates of cardiac deaths
(Independent Safety Committee (ISC)), and a higher rate of
discontinuation of treatment in patients treated with sertindole
compared to risperidone. There was no statistically significantly
difference in cardiac events (including arrhythmias, requiring
hospitalisation), fatal and non-fatal suicide attempts (ISC) and
all cause mortality. All cause mortality was low in both
cohorts.
The PBAC noted that there was a lower rate of suicides in
sertindole treated patients compared to risperidone treated
patients, however the difference was not statistically
significant.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission described sertindole as non-inferior in terms of
comparative effectiveness and equivalent in terms of comparative
safety compared to risperidone or olanzapine, which the PBAC did
not accept.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis versus
risperidone. The equi-effective doses are estimated as sertindole
19 mg daily and risperidone 8 mg daily. For the alternative
comparator the equi-effective doses are estimated as sertindole 16
mg daily and olanzapine 10 mg daily.
11. Estimated PBS Usage and Financial Implications
The financial savings/year to the PBS were
estimated by the submission to be less than $500,000 in Year
5.
12. Recommendation and Reasons
The PBAC noted that the requested restriction for use in patients
who have had prior treatment with at least one other anti-psychotic
would allow use in a broader patient population than that specified
the TGA approved indication, which limits use to patients who are
not responsive to, or intolerant of at least one other
anti-psychotic medicine.
The PBAC considered that olanzapine was a more appropriate choice
of main comparator than risperidone, noting evidence from the
survey of clinicians presented in the submission and supportive
Medicare Australia data, which indicated that olanzapine was likely
to be the most frequently prescribed atypical anti-psychotic in the
second-line setting.
For the comparison of sertindole versus risperidone, the PBAC noted
that there was no statistically significant difference in the
primary outcome of mean difference in change from baseline Positive
and Negative Syndrome Scale (PANSS) total score at 12 weeks in the
pooled results of trials M95-372 and 97203 for the post hoc
analysis using LOCF, however the post hoc analysis using LOCF did
not meet the non-inferiority margin of a 7 point difference in
PANSS total score, as previously accepted by the PBAC.
Statistically significant differences were not observed for the
secondary outcomes of change from baseline PANSS subscale scores
and Clinical Global Impression Severity (CGI-S) scale scores.
For the comparison of sertindole versus olanzapine, the PBAC noted
the results for the primary outcome of trial 11268 did not support
the claim that sertindole is non-inferior to olanzapine. Olanzapine
treated patients showed numerically larger reductions in PANSS
total score and the upper confidence interval for the mean
difference in change from baseline PANSS total score did not meet
the trial’s pre-specified non-inferiority criterion.
The PBAC noted the results of the safety study 99824 showed
statistically significantly higher rates of cardiac deaths
(Independent Safety Committee (ISC)), and a higher rate of
discontinuation of treatment in patients treated with sertindole
compared to risperidone. There was no statistically significantly
difference in cardiac events (including arrhythmias, requiring
hospitalisation), fatal and non-fatal suicide attempts (ISC) and
all cause mortality. All cause mortality was low in both
cohorts.
The PBAC noted that QT interval prolongation, in particular QTc
(heart rate corrected QT) was reported more frequently in
sertindole treated patients than risperidone treated patients in
the direct randomised trials and appeared to be dose related. The
PBAC noted that there is an association between prolonged QTc and
the potentially fatal ventricular tachyarrthymia, Torsades de
Pointes.
The PBAC accepted that treatment with sertindole was associated
with a lower rate of extrapyramidal side effects than
risperidone
.
The PBAC was concerned that potentially serious drug interactions
with sertindole were not addressed in the submission. The PBAC
noted that sertindole is a substrate for the cytochrome P450 CYP2D6
and CYP3A isozymes, which can be inhibited by a number of commonly
prescribed drugs including fluoxetine and paroxetine, however,
SSRIs may be given concurrently for co-morbid depression and
obsessive-compulsive disorder in this patient population. The PBAC
was also concerned that the question of cross-tapering with other
anti-psychotic agents was not addressed in the submission,
particularly given the slow onset of action of sertindole
.
Overall, the PBAC did not accept the submission’s claim that
sertindole is non-inferior in terms of comparative efficacy and
equivalent in terms of comparative safety compared to risperidone
or olanzapine.
The PBAC noted the sponsor’s Pre-PBAC Response and the
clinician’s opinion at the hearing, that there is a high
clinical need for additional anti-psychotic treatment options in a
few patients who derive no benefit from existing treatments, and
those who are only partially responsive. However, the PBAC
considered that the current average market share of sertindole in
European markets did not support the existence of a high clinical
need. The PBAC noted that no evidence of the efficacy of sertindole
in treatment resistant patients had been presented in the
submission, and that there are a number of PBS-subsidised treatment
options currently available for this patient population. There are
also options, other than olanzapine, for patients with metabolic
syndrome or diabetes risks. Thus, the clinical need was not clearly
established and did not justify the PBS listing of sertindole
treatment given the safety risks
.
The PBAC therefore rejected the submission, on the basis of
uncertain clinical need, and concerns regarding relative efficacy,
cardiovascular adverse effects and potential drug
interactions.
The PBAC acknowledged and noted the consumer comments on this
item.
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
The sponsor disagrees with the PBAC’s comments on the
comparator, and continues to believe that there is a high clinical
need for Serdolect in a subpopulation of Australian schizophrenia
patients. The sponsor would also like to point out that there is a
risk management plan in place to minimise potential cardiac risk
associated with Serdolect.
