QUETIAPINE, tablets, 25 mg, 100 mg, 200 mg and 300 mg (as fumarate), Seroquel®, and tablets (modified release), 50 mg, 200 mg, 300 mg and 400 mg (as fumarate), Seroquel XR®
Page last updated: 21 October 2010
Public Summary Document
Product: QUETIAPINE, tablets, 25 mg, 100 mg, 200
mg and 300 mg (as fumarate), Seroquel®, and tablets
(modified release), 50 mg, 200 mg, 300 mg and 400 mg (as fumarate),
Seroquel XR®
Sponsor: AstraZeneca Australia Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission requested the current Authority Required
(Streamlined) listing for quetiapine immediate release and modified
release tablets be simplified to “treatment of bipolar
disorder”. The submission also proposed an alternative
listing for maintenance therapy as follows: “the monotherapy
treatment of bipolar disorder with the addition of a mood
stabiliser (lithium or sodium valproate) as clinically
appropriate.”
2. Background
Quetiapine (immediate release)
At the June 2000 meeting, the PBAC recommended an authority
required listing for immediate release quetiapine for the treatment
of schizophrenia on a cost-minimisation basis compared with
risperidone. Listing was effective from 1 November 2000.
At the July 2007 meeting, the PBAC recommended extending the
authority required PBS listing for quetiapine immediate release to
include the treatment, as monotherapy, for up to 6 months, of an
episode of acute mania associated with bipolar I disorder. Listing
for this indication was effective from 1 December 2007.
At the March 2009 meeting, the PBAC recommended extending the
listing for quetiapine immediate release to include maintenance
treatment of bipolar I disorder, in combination with lithium or
sodium valproate. Listing was effective from 1 August 2009. At the
same meeting, the PBAC rejected an application to extend the
listing to include treatment of a patient with depressive episodes
associated with bipolar disorder.
At the November 2009 meeting, the PBAC rejected submissions to (a)
extend the listing for quetiapine immediate release to include
treatment, for up to 6 months, of an episode of acute mania
associated with bipolar I disorder, in combination with lithium or
sodium valproate; and (b) extend the listing for quetiapine
immediate release to include maintenance treatment of bipolar I
disorder, as monotherapy.
Quetiapine (modified release)
At the July 2008 meeting, the PBAC recommended an authority
required (Streamlined) listing for quetiapine modified release for
the treatment of schizophrenia on a cost-minimisation basis against
immediate release quetiapine on mg per mg basis.
At the November 2009 meeting, the PBAC recommended that quetiapine
modified release tablets be listed with the same restrictions as
the immediate release preparations for the treatment of bipolar I
disorder on the basis of demonstrated efficacy in the treatment of
acute mania and bipolar depression. Listing was effective from 1
April 2010.
3. Registration Status
Quetiapine fumarate immediate release and modified release tablets are TGA approved for use in bipolar disorder as:
- Maintenance treatment of bipolar I disorder, as monotherapy or in combination with lithium or sodium valproate, for the prevention of relapse/recurrence of manic, depressive or mixed episodes.
- Treatment of depressive episodes associated with bipolar disorder.
- Treatment of acute mania associated with bipolar I disorder as monotherapy or in combination with lithium or sodium valproate
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Treatment of bipolar disorder
or
The monotherapy treatment of bipolar disorder with the addition of
a mood stabiliser (lithium or sodium valproate) as clinically
appropriate.
For PBAC’s view, see Recommendations and
Reasons.
5. Clinical Place for the Proposed Therapy
Bipolar I disorder is a psychiatric illness that is characterised
by one or more manic, depressed or mixed episodes. The listing
requested would allow treatment with quetiapine as monotherapy for
the maintenance indication as well as combination therapy with
lithium and sodium valproate.
6. Comparator
The submission nominated olanzapine as the main comparator.
For PBAC’s view, see Recommendations and
Reasons.
7. Clinical Trials
The submission presented as key evidence two randomised trials of
treatments in patients with bipolar I disorder to form an indirect
comparison of quetiapine and olanzapine with placebo as the common
reference. Study 144 compares quetiapine at a maintenance dose of
between 300 and 800mg/day compared with a placebo and lithium arm.
Tohen 2006 compares olanzapine at a dose of between 5 and 20 mg/day
with placebo. The key outcomes assessed in both trials were time to
recurrence of a mood event of any type
(manic/mixed/depressed).
Tohen 2005, was presented as supportive evidence. It assessed
maintenance treatment of bipolar I disorder with olanzapine (dosed
between 5 and 20 mg/day) as compared with lithium. The outcome of
recurrence is numeric without a focus on the length of delay.
Details of the studies published at the time of submission are in
the table below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Tohen 2006 | Randomised, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. | Am J Psychiatry 2006; 163: 247-256 |
| Tohen 2005 | Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomised, double-blind, controlled clinical trial. | Am J Psychiatry 2005; 162: 1281-1290 |
8. Results of Trials
Comparative effectiveness
The key results of the two trials (Study 144 and Tohen 2006) incorporated in the submission’s
indirect comparison of quetiapine and olanzapine in time to recurrence of a mood event
using interim intention to treat (ITT) population (patients for whom data was collected
up to the interim stop date) and intention to treat (ITT) population (all randomised
patients who received treatment) were as follows: Study 144 reported a significant
advantage in time to recurrence of any type of event for quetiapine over placebo and
likewise the Tohen 2006 trial of olanzapine reported a significant benefit for olanzapine
over placebo in time to recurrence of any type of event.
The PBAC noted that there were three issues which reduced the comparability of the
two trials used in the indirect comparison:
1. Structure of the trial. Both trials incorporated an open-label treatment stabilisation phase before the
patients were randomised for the double-blind monotherapy maintenance treatment. Both
trials saw a substantial number of withdrawals between enrolment and randomisation.
This structure artificially selects a trial population that tolerates and responds
to active treatment. The requested listing did not require patients to have been treated
with quetiapine during its acute phase. The patient population who would get access
to quetiapine under the proposed new PBS criteria may be more like the enrolment population
of Study 144 and less like the randomised population. The inclusion criteria for Study
144 required that patients have had a past mood event within 26 weeks and have been
treated with quetiapine continuously since. This criterion is applied pre-enrolment
and there was still a large proportion of patients who did not make it to randomisation
indicating that the quetiapine results may be overstated. A similar issue applies
to the olanzapine trial.
2. Baseline demographics. The Tohen 2006 trial had a higher proportion of patients relative to Study 144 enrolled
with rapid cycling bipolar I disorder (44.1-52.9% vs. 11.6-15.1%, respectively). These
patients are recognised as more difficult to treat than patients without rapid cycling
and as such this may have biased the results of an indirect comparison in favour of
quetiapine. The submission addressed this by highlighting that, in Study 144, quetiapine
had a significant effect over placebo for time to recurrence of any mood event regardless
of rapid cycler status.
3. Differences in defining an acute manic and depression mood event. Both Study 144 and Tohen 2006 categorised a manic mood event using the Young Mania
Rating Scale (YMRS) although Study 144 required two consecutive scores of ≥20 when
Tohen 2006 required just one of ≥15. For categorising a depressed event Study 144
used the Montgomery-Asberg Depression Rating Scale (MADRS) requiring two consecutive
scores of ≥20 while Tohen 2006 used the Hamilton Rating Scale for Depression (HAM-D)
requiring one score of ≥15. The Tohen 2006 trial may have had a lower threshold for
classifying an event and, therefore, the indirect comparison could be biased against
olanzapine.
Comparative toxicity
The PBAC noted that an indirect comparison between quetiapine and olanzapine using
placebo as common reference in specific adverse events was not performed in the submission
due to a lack of reported data in Tohen 2006 but considered the treatments similar
in their adverse event profile. In terms of weight gain, both trials reported the
percentage of patients who gained ≥7% of their body weight and, from an indirect comparison
performed during evaluation, quetiapine was not found to be significantly different
from olanzapine.
9. Clinical Claim
The submission claimed that quetiapine, based on the clinical
evidence is non-inferior to, and non-interchangeable with,
olanzapine in terms of efficacy and safety.
For PBAC’s view, see Recommendations and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as 546mg/day of quetiapine
ongoing as maintenance therapy and 12.5mg/day of olanzapine ongoing
as maintenance therapy.
Using the current prices for the equi-effective doses of quetiapine
and olanzapine, the submission estimated the difference in annual
cost between quetiapine treatment and olanzapine treatment was less
than $100 per patient per year. The submission used the difference
between the estimated annual cost of quetiapine treatment and
olanzapine as justification for a price increase.
For PBAC’s view, see Recommendations and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission assumed that quetiapine usage will likely be
unaffected by any additional bipolar listing, with the exception of
bipolar depression (which would be an additional population
eligible under the broader PBS listing requested of
“treatment of bipolar disorder” of less than 10,000
patients in Year 1 of listing).
The submission estimated the likely number of prescriptions
dispensed per year to be between 10,000 and 50,000 in Year 4 of
listing, for both bipolar I and II depression. Values for Year 5
were calculated during the evaluation, using the same methodology
used in the submission to give a higher estimated number of
prescriptions dispensed, while remaining in the range of 10,000
– 50,000 per year.
The submission estimated a net cost to the PBS of less than $10
million per year in Year 5. The submission’s estimates were
for the use in bipolar I and II depression. The submission assumed
no financial impact for the proposed quetiapine listing for
monotherapy maintenance treatment. No cost offsets for reduced
treatments with olanzapine or mood stabilisers were considered in
the submission.
For PBAC’s view, see Recommendations and
Reasons.
12. Recommendation and Reasons
The PBAC recommended extending the Authority Required (Streamlined)
listing of quetiapine (as fumarate) 25 mg, 100 mg, 200 mg and 300
mg tablets and quetiapine (as fumarate) 50 mg, 200 mg, 300 mg and
400 mg tablets (modified release) on the PBS to include the
maintenance treatment of bipolar I disorder as monotherapy on a
cost minimisation basis with olanzapine tablets. The equi-effective
doses are 546 mg of quetiapine (as fumarate) and 12.5 mg of
olanzapine.
The PBAC considered olanzapine was an appropriate comparator, as it
is the only atypical antipsychotic currently listed on the PBS for
the maintenance treatment of bipolar 1 disorder as
monotherapy.
The PBAC considered there was uncertainty in the claim of clinical
non-inferiority based on the indirect comparison presented of study
144 and Tohen 2006, due to differences between the trials,
including the different baseline populations and differences in the
design of the trials. However the PBAC considered, on the basis of
the evidence presented overall, that quetiapine is of non-inferior
efficacy and safety to olanzapine for the maintenance treatment of
bipolar I disorder, as monotherapy. The PBAC noted that no evidence
was presented to support the broader listing requested of treatment
of bipolar disorder and hence that the listing should be restricted
to maintenance treatment of bipolar I disorder.
The PBAC considered that the utilisation estimates in the
submission were uncertain, and the assumption in the submission
that patients are already being treated with quetiapine for the
maintenance of bipolar I disorder as monotherapy under the PBS
outside the current restriction inappropriate. The PBAC hence did
not accept that the listing of quetiapine for the maintenance
treatment of bipolar I disorder as monotherapy would result in nil
costs to the PBS. The PBAC also considered the submission’s
estimate of the number of prescriptions per year uncertain, as it
was likely that the number for the higher strength of quetiapine
were underestimated.
Recommendation:
QUETIAPINE, tablets, 25 mg, 100 mg, 200 mg and 300 mg (as
fumarate), and tablets (modified release), 50 mg, 200 mg, 300 mg
and 400 mg (as fumarate)
Amend the current restriction for use in bipolar I disorder as
follows:
Restriction:
Authority Required (STREAMLINED)
Schizophrenia;Monotherapy, for up to 6 months, of an episode of acute mania associated with bipolar I disorder;
Maintenance treatment of bipolar I disorder.
Maximum quantity: 60 (25 mg, 50 mg, 200 mg, 300 mg and 400
mg)
90 (100 mg)
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
AstraZeneca is pleased with this recommendation and acknowledges that this is an important step toward securing ideal access to quetiapine for Australians with bipolar disorder.
