Ziprasidone hydrochloride, capsules 20 mg, 40 mg, 60 mg and 80 mg, Zeldox®, November 2008
Public summary document for Ziprasidone Hydrochloride, capsules, 20 mg, 40 mg, 60 mg, 80 mg, Zeldox®
Page last updated: 24 March 2009
Public Summary Document
Product: Ziprasidone hydrochloride, capsules 20
mg, 40 mg, 60 mg and 80 mg, Zeldox®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission sought an extension of the current Authority
Required (STREAMLINED) listing for ziprasidone to include
monotherapy, for up to six months, of an episode of acute mania or
mixed episodes associated with bipolar I disorder.
2. Background
This drug had not previously been considered by the PBAC for the
treatment of bipolar I disorder.
At the November 2006 meeting, the PBAC recommended listing of
ziprasidone for the treatment of schizophrenia on a
cost-minimisation basis with olanzapine.
3. Registration Status
Ziprasidone hydrochloride was first registered by the TGA on 24
October 2001 for the treatment of schizophrenia and related
psychoses, prevention of relapse and for maintenance of clinical
improvement during continuation therapy. On 21 September 2006, the
approved indications were extended to include monotherapy, for the
short-term treatment of acute manic or mixed episodes associated
with bipolar I disorder.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Monotherapy, for up to 6 months, of an episode of acute mania or
mixed episodes associated with bipolar I disorder.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Bipolar disorder (BPD, manic-depressive illness) is characterised
by distinct episodes of mania and depression, with full
inter-episode symptomatic recovery for most individuals. The
clinical features of mania are elevated, expansive or irritable
mood, accelerated speech, racing thoughts, increased activity and
reduced sleep. Patients may develop grandiose ideas, act recklessly
and show increased sexual drive and activity. When symptoms are
less severe and of shorter duration, the term hypomania is used.
Peak onset of illness is usually in early adult life and there is a
strong genetic basis.
There are two types of BPD, type I defined as having at least one
manic episode, with or without depressive episodes, and type II
defined as hypomania and depression.
Ziprasidone is an atypical antipsychotic that will provide an
alternative (when used as monotherapy) to currently available drugs
to treat bipolar I disorder.
6. Comparator
The submission nominated olanzapine as the main comparator. The
PBAC considered this appropriate.
7. Clinical Trials
The submission presented a meta-analysis of six randomised trials
comparing ziprasidone with olanzapine (placebo and haloperidol as
common comparators) in patients with BPD.
The trials and associated reports presented in the submission are
presented in the table below.
| Trial ID | Protocol title | Publication citation |
| Ziprasidone | ||
| 128-601 | Ziprasidone in the treatment of acute bipolar mania: a 3 week, placebo controlled, double blind randomized trial. A phase III, randomized, placebo controlled study evaluating the safety and outcome of treatment with oral ziprasidone in subjects with mania. | Keck PE, Versiani M, Potkin S, et al Am J Psych, 2003; 160:741 8. |
| A1281083 | Ziprasidone in acute bipolar mania: a 21 day randomised double blind, placebo controlled replication trial. A phase III, randomised, placebo controlled study evaluating the safety and outcome of treatment with oral ziprasidone in subjects with mania. | Potkin SG, Keck PE, Segal S, et al J Clin Psychopharmacol 2005; 25:301 10. |
| A1281052 | Ziprasidone efficacy and safety in acute bipolar mania: 12 week study. | Ramey TS, Giller EL, Riesenberg R, et al Bipolar Disord 2005a; 7 (Suppl. 2): 89 (Abstract P193) |
| Olanzapine | ||
| Tohen et al (1999) | Olanzapine versus placebo in the treatment of acute mania. | Tohen M, Sanger TM, McElroy SL, et al.Am J Psychiatry 1999; 156:702 9. |
| Tohen et al (2000) | Efficacy of olanzapine in acute bipolar mania. | Tohen M, Jacobs TG, Grundy SL, et al. Arch Gen Psychiatry 2000; 57:841 9. |
| Tohen et al (2003) | A 12 week, double blind comparison of olanzapine vs haloperidol in the treatment of acute mania. | Tohen M, Goldberg JF, Gonzalez Pinto AM, et al. Arch Gen Psychiatry 2003; 60:1218 26. |
8. Results of Trials
The results for the primary outcome, change from baseline in
(Young) Mania Rating Scale (Y/MRS), are presented below.
Mean change in Y/MRS from baseline of the indirect
comparison – placebo and haloperidol as common
comparator
| Ziprasidone | Olanzapine | |||||
| PLACEBO COMMON COMPARATOR | ||||||
| Trial ID | Diff (95% CI) | ZIP Mean change (SD) | PBO Mean change (SD) | OLZ Mean change (SD) | Diff (95% CI) | Indirect Diff (95% CI) |
| 128-601 | -4.6 (-8.4, -0.9) | -12.4 (12.0) | -7.8 (12.9) | |||
| A1281083 | -5.5 (-8.5, -2.5) | -11.1 (11.5) | -5.6 (9.6) | |||
| A1281052 | -4.3 (-7.0, -1.7) | -10.4 (11.1) | -6.1 (9.9) | |||
| Tohen 1999 | -4.9 (11.6) | -10.3 (13.4) | -5.4 (-9.6, -1.2) | |||
| Tohen 2000 | -8.1 (12.7) | -14.8 (12.5) | -6.7 (-11.4, -1.9) | |||
| Pooled REM | -4.8 (-6.5, -3.0) | -5.9 (-9.1, -2.8) | 1.2 (-2.4, 4.8) | |||
| Network meta-analysis | 2.5 (-0.3, 5.3) | |||||
| HALOPERIDOL COMMON COMPARATOR | ||||||
| Trial ID | Diff (95% CI) | ZIP Mean change (SD) | HAL Mean change (SD) | OLZ Mean change (SD) | Diff (95% CI) | Indirect Diff (95% CI) |
| A1281052 | 5.5 (3.2, 7.8) | -10.4 (11.1) | -15.9 (10.6) | |||
| Tohen 2003 | -23.5 (10.8) | -21.3 (11.0) | 2.2 (0.2, 4.2) | 3.3 (0.3, 6.4) | ||
Abbreviations: ZIP ziprasidone, HAL haloperidol, OLZ olanzapine,
PBO placebo; REM random effects method; CI confidence interval;
Y/MRS Young/ Mania Rating Scale
The changes from baseline in Y/MRS scores for placebo were similar
(5-8 points) across the ziprasidone versus placebo and the
olanzapine versus placebo trials. Both ziprasidone and olanzapine
resulted in a statistically significant difference in change from
baseline in Y/MRS scores compared to placebo. The indirect
comparison of ziprasidone and olanzapine showed no significant
difference in change from baseline in Y/MRS 1.2 (95% CI: -2.4,
4.8). The minimum clinically important difference for the Y/MRS
rating scale is of the order of 3-5 points.
The changes from baseline Y/MRS scores for haloperidol were not
similar (16, 24 points) across the ziprasidone versus haloperidol
and the olanzapine versus haloperidol trials. Both ziprasidone and
olanzapine resulted in a statistically significant difference in
change from baseline in Y/MRS scores compared to haloperidol. The
indirect comparison of ziprasidone and olanzapine showed a
significant difference in favour of olanzapine 3.3 (95% CI: 0.3,
6.4) but this is not likely to be clinically important. The
PBAC noted that haloperidol was superior to both ziprasidone and
olanzapine for change from baseline in Y/MRS scores.
A network meta-analysis (which combines the data from the placebo
and haloperidol controlled trials for the primary outcome) showed
no statistically significant difference between olanzapine and
ziprasidone in change from baseline in Y/MRS scores (2.5 [95% CI:
-0.3, 5.3).
The most common adverse events with ziprasidone (occurring more
frequently than with placebo) were somnolence, dizziness,
hypertonia, akathisia, extrapyramidal syndrome (EPS), and dystonia.
The most common adverse events with olanzapine (that were more
frequent than with placebo) were somnolence, dry mouth, dizziness,
and asthenia. Ziprasidone was associated with more EPS, whereas
olanzapine was associated with more weight gain and somnolence. The
submission noted that, overall, the AE burden was considered to be
of a similar magnitude with both agents.
9. Clinical Claim
The submission described ziprasidone as equivalent in terms of
comparative effectiveness and similar in terms of comparative
safety over olanzapine.
10. Economic Analysis
The submission presented a cost minimisation analysis. The PBAC
accepted the equi-effective doses of ziprasidone 119.85 mg daily
and olanzapine 15.19 mg daily (risperidone 5.4 mg
daily).
11.Estimated PBS Usage and Financial Implications
The submission estimates that the requested listing will not
increase the current market as it assumes that ziprasidone will
substitute for other agents. The likely number of prescriptions
dispensed per year in year 5 was estimated in the submission to be
between 10,000 and 50,000. The total cost of ziprasidone was
estimated at less than $10 million in year 5.
12. Recommendation and Reasons
The PBAC recommended an extension to the listing for ziprasidone to
include the treatment of acute mania or mixed episodes associated
with bipolar disorder I on a cost-minimisation basis with
olanzapine and recommended that the equi-effective doses are
ziprasidone 119.85 mg and olanzapine 15.19 mg daily (risperidone
5.4 mg daily).
The PBAC noted that the submission proposed a weighting to the
indications bipolar I to schizophrenia and that the Pharmaceutical
Benefits Pricing Authority (PBPA) would need to determine the
appropriate weighting between the two indications.
The PBAC agreed that the indirect comparison between olanzapine and
ziprasidone using placebo as a common comparator was acceptable.
The PBAC noted that the changes from baseline in Young/ Mania
Rating Scores (Y/ MRS) for placebo were similar (5-8 points) across
the ziprasidone versus placebo and the olanzapine versus placebo
trials. Both ziprasidone and olanzapine resulted in a statistically
significant difference in change from baseline in Y/ MRS scores
compared to placebo. The indirect comparison of ziprasidone and
olanzapine showed no significant difference in change from baseline
in Y/MRS 1.2 (95% CI: -2.4, 4.8). The minimum clinically important
difference for the Y/MRS rating scale is of the order of 3-5
points.
The PBAC noted that it would be difficult to restrict the use of
ziprasidone to 6 months and that there was also potential for use
outside the listing criteria due to the Streamlined Authority
listing.
The PBAC noted that there was inconsistency in the wording of the
restrictions for quetiapine, olanzapine and ziprasidone and that
although the restriction wording specified use as monotherapy for
ziprasidone and quetiapine, lithium was recommended for use in
conjunction with the atypicals. The PBAC agreed to review the
restriction wording at a future date.
Recommendation
ZIPRASIDONE, capsule, 20 mg, 40 mg, 60 mg and 80 mg
Restriction: Authority Required (STREAMLINED)
Monotherapy, for up to 6 months, of an episode of acute mania or
mixed episodes associated with bipolar I disorderMaximum quantity:
60 (all strengths)
Number of repeats: 5 (all strengths)
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
Pfizer Australia welcomes the PBAC recommendation for ziprasidone
(Zeldox®) to be listed on the PBS. The Sponsor
believes the availability of Zeldox® will provide an
important additional management option for individuals with acute
mania and mixed episodes associated with bipolar I disorder. As
part of Pfizer Australia’s ongoing commitment to the
appropriate use of our medicines we look forward to the continued
implementation of the Quality Use of Medicine programme for
Zeldox®, the details of which were provided in this
application to the PBAC.
