Olanzapine pamoate monohydrate, powder for injection with diluent vial, 210 mg, 300 mg and 405 mg, Zyprexa Relprevv®
Public summary document for Olanzapine pamoate monohydrate, powder for injection with diluent vial, 210 mg, 300 mg and 405 mg, Zyprexa Relprevv®
Page last updated: 30 October 2009
Public Summary Document
Product: Olanzapine pamoate monohydrate, powder
for injection with diluent vial, 210 mg, 300 mg and 405 mg, Zyprexa
Relprevv®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request an Authority required listing for maintenance treatment
of schizophrenia in adults stabilised during acute treatment with
oral olanzapine.
2. Background
This formulation of olanzapine had not previously been considered
by the PBAC.
At the March 1997 PBAC meeting, the PBAC recommended the listing of
oral olanzapine as an Authority required PBS benefit for
schizophrenia and related psychoses where other antipsychotic
therapy has failed or is inappropriate.
At the July 2004 meeting the PBAC recommended an extension to the
Authority required listing of olanzapine to include the maintenance
treatment of bipolar 1 disorder based on acceptable
cost-effectiveness compared with lithium.
3. Registration status
Olanzapine (as pamoate monohydrate) powder for injection vial with
diluent vial was TGA registered on 3 March 2009 for the maintenance
treatment of schizophrenia in adult patients sufficiently
stabilised during acute treatment with oral olanzapine.
4. Listing Requested and PBAC’s View
Authority Required:
For maintenance treatment of schizophrenia in adult patients
sufficiently stabilised during acute treatment with oral
olanzapine.
For PBAC’s views see Recommendation and
Reasons.
5. Clinical place for the proposed therapy
Olanzapine modified release injection would provide an alternative
atypical antipsychotic depot injection option to risperidone for
the treatment of schizophrenia.
6. Comparator
The submission nominated oral olanzapine as the clinical
comparator. For pricing purposes the submission nominated
risperidone modified release injection.
7. Clinical trials
The submission presented an indirect comparison of olanzapine long
acting injection (OLAI) and risperidone long-acting injection
(RLAI) with placebo as a common comparator, based on one trial of
OLAI vs placebo (HGJZ) and one trial of RLAI vs placebo (Kane
2003).
Publication details of the trials are presented in the following
table:
| Trial ID | Protocol / Publication title | Date/citation |
| OLAI vs placebo | ||
| HGJZ | Lauriello et al (2008) An 8-week, double-blind, randomised, placebo-controlled study of olanzapine long-acting injection in acutely ill patients with schizophrenia. | J Clin Psychiatry 2008; 69: 790-799. |
| RLAI vs placebo | ||
| Kane 2003 | Long-Acting Injectable Risperidone: Efficacy and Safety of the First Long-Acting Atypical Antipsychotic. | Am J Psychiatry 2003; 160: 1125-1132. |
| Lauriello et al 2005. Long-acting risperidone vs. placebo in the treatment of hospital inpatients with schizophrenia. | Schizophrenia Research 2005;72(2-3):249-58. | |
The submission presented one direct randomised comparative trial of
OLAI vs oral olanzapine (Trial HGKA) in patients with schizophrenia
previously stabilised on oral olanzapine as the pivotal evidence.
The submission also presented one supportive trial of three doses
of OLAI vs placebo (Trial HGJZ), and one supportive single arm,
long term study of safety and efficacy (Study HGKB).
8. Results of Trials
OLAI vs RLAI
Both trial HGJZ and Kane 2003 investigated mean change from
baseline to endpoint in Positive and Negative Symptom Score (PANSS)
total score as a primary outcome. The results for each trial are
presented in the table below.
Mean change from baseline of PANSS Total scores
| Trial HGJZ | N | Baseline: mean (SE) | Change: mean (SE) | p value vs placebo: adjusted* |
| OLAI 210 mg /2 wks | 106 | 99.6 (1.5) | -22.5 (2.1) | <0.001 |
| OLAI 405 mg /4 wks | 100 | 101.3 (1.4) | -22.6 (2.2) | <0.001 |
| OLAI 300 mg /2 wks | 98 | 102.6 (1.6) | -26.3 (2.5) | <0.001 |
| Placebo | 98 | 100.6 (1.7) | -8.5 (2.3) | - |
| Kane 2003 | N | Baseline: mean (SD) | Change: mean (SD) | p value vs placebo: adjusted † |
| RLAI 25 mg/ 2 wks | 93 | 81.7 (12.5) | -6.2 16.9 | 0.002 |
| RLAI 50 mg /2 wks | 98 | 82.3 (13.9) | -8.5 16.9 | <0.001 |
| RLAI 75 mg/ 2 wks | 87 | 80.1 (14.0) | -7.4 16.9 | <0.001 |
| Placebo | 92 | 82.0 (14.4) | 2.6 16.9 | - |
PANSS = Positive and
Negative Symptom Score; OLAI = olanzapine long acting
injection;
RLAI = risperidone long acting injection; SE = standard error; SD =
standard deviation; wks = weeks
* adjusted for base PANSS score
† adjusted using Dunnett’s multiple
comparisons method in Kane 2003
The submission did not provide an explanation of how the results of
the differences in baseline to endpoint changes in PANSS Total
scores for each group in either trial were combined for comparison
with indirect analysis. It appeared that in each trial the three
active treatment arms were pooled to give a weighted mean. The
results of the indirect comparison are presented below.
Summary of results of indirect comparison of OLAI with RLAI via placebo
| Outcome | Risk estimate (95% CI) | p value | |
| PANSS total score | weighted mean difference | -5.1 (-11.8, 1.7) | 0.14 |
| Response 20%* | Odds ratio | 0.8 (0.4, 1.7) | 0.55 |
| Anticholinergic use | Odds ratio | 0.9 (0.3, 2.5) | 0.78 |
PANSS = Positive and Negative Symptom Scale.
* number of patients having a response of at least 20% improvement
in PANSS Total score.
The indirect analysis of OLAI and RLAI showed no statistically
significant differences in PANSS Total score, the number of
patients with at least a 20% improvement in PANSS Total score, or
use of anticholinergics (used as a proxy of extrapyramidal adverse
events). However, the different durations of the trials and
difference in severity of patients in each trial made these results
difficult to interpret.
OLAI vs ORAL OLANZAPINE
The primary outcome was the difference in exacerbation rates of
schizophrenia between the pooled 150 mg/2 weeks and 300 mg/2 weeks
doses compared with oral olanzapine (10 mg, 15 mg or 20 mg/day
pooled) in Trial HGKA. The specified non-inferiority rate was a
delta of 0.20.
The differences in exacerbation-free rates (for schizophrenia) were
within the specified noninferiority margin for the primary analysis
and the post-hoc subgroup analysis. However, there was a
statistically significant difference between the 150 mg/2 weeks
dose compared with oral olanzapine in discontinuations due to
relapse and risk of exacerbation of schizophrenia. The submission
stated that the dose of 150 mg/2 weeks will not be marketed in
Australia, but the 300 mg dose given every 4 weeks was equivalent.
No clinical data were provided for a dose of 300 mg/4 weeks.
With respect to adverse events, OLAI appeared to have a similar
adverse events profile as oral olanzapine with the exception of
post injection syndrome (inadvertent intravascular injection) which
resulted in a clinical picture of olanzapine overdose. There was a
statistically significantly higher number of treatment emergent and
serious adverse events reported for the 150 mg/2 week dose group
compared with oral olanzapine in Trial HGKA. However, as these
events included “schizophrenia” and other symptoms and
signs related to psychosis (e.g. delusions, paranoia), these appear
to be related to the efficacy in this group on the underlying
condition, rather than drug related adverse events.
A risk management plan was provided for adverse events associated
with the administration of OLAI, including postmarketing
surveillance and an observational study of post-injection syndrome,
provision of appropriate labelling with descriptions of the
clinical manifestations, the type and duration of observations to
monitor patients for post-injection syndrome, management if post
injection syndrome should occur, and provision of appropriate
training for health professionals who administer OLAI.
9. Clinical Claim
The submission claimed that olanzapine long acting injection was no
worse than risperidone long acting injection in terms of efficacy.
The submission did not make a formal claim with respect to the
comparative safety of OLAI and RLAI.
For PBAC’s views see Recommendation and
Reasons.
10. Economic Analysis
In summary, the submission requested a higher price for OLAI in
comparison with oral olanzapine by using RLAI as the main
comparator, which had previously been accepted by the PBAC as being
superior to oral risperidone.
Cost-minimisation against RLAI with the stated objective of pricing
OLAI “such that the relative price of OLAI to oral olanzapine
is no greater than the relative price of RLAI to oral risperidone
in absolute terms.”
Based on equating oral risperidone 4 mg/day with oral olanzapine 15
mg/day, the submission calculated the equi-effective doses for RLAI
and OLAI as presented in the table below:
Equi-effective doses for RLAI and OLAI as presented in the submission
| RLAI | Oral risperidone | Oral olanzapine | OLAI |
| 25 mg / 2 weeks | NS | NS | No equivalent |
| 37.5 mg / 2 weeks | NS | 10 mg / day | 300 mg / 4 weeks |
| 50 mg / 2 weeks | 4 mg / day | 15 mg / day | 210 mg / 2 weeks, 405 mg / 4 weeks. |
| No equivalent | NS | 20 mg / day | 300 mg / 2 wks |
NS = not stated
During the evaluation it was noted that the Davis and Chen (2004)
study reported that the near-maximal effective dose
(ED95) of risperidone was 4 mg per day, and the
ED95 of olanzapine was greater than 16 mg per day, and
may in fact be as high as 20 mg per day or more. They also found
that the median effective dose (ED50) of risperidone was
2mg per day, and of olanzapine was 9 mg per day. Thus, the PBAC was
advised it may be more accurate to equate the 4 mg dose of
risperidone to the 20 mg dose of olanzapine. Based on equating oral
risperidone 4 mg/day with oral olanzapine 20 mg/day, the
equi-effective doses for RLAI and OLAI were re-calculated during
the evaluation as presented in the table below:
Recalculated equi-effective doses for RLAI and OLAI
| RLAI | Oral risperidone | Oral olanzapine | OLAI |
| 25mg / 2 weeks | < 2 mg / day | 10 mg / day | 300 mg / 4 weeks |
| 25 to 37.5 mg / 2 weeks | 2 to 4 mg / day | 15 mg / day | 210 mg / 2 weeks or 405 mg / 4 weeks |
| 37.5 to 50 mg / 2 weeks | 4 mg / day | 20 mg / day | 300 mg / 2 wks |
Source: Antipsychotic Drug Guidelines 2006, Western Australian
Psychotropic Drugs Committee, Davis and Chen 2004, Citrome and
Volavka 2002
The cost-minimisation analysis presented in the submission was
based on the expected daily treatment cost associated with OLAI and
RLAI.
The submission derived a saving per patient per year for OLAI
treatment compared with RLAI. Using the alternative dose
equivalence derived during the evaluation, treatment with OLAI
resulted in an additional cost of approximately per patient per
year compared with RLAI. Both of these costs were calculated
without including any costs of administration of OLAI, including
monitoring patients for 3 hours in case of the occurrence of post
injection syndrome. The cost-minimisation analysis was sensitive to
the assumed equi-effective doses and the proportions of different
doses of OLAI and RLAI used in the population.
11. Estimated PBS usage and Financial Implications
The likely number of patients per year was less than 10,000
patients per year The financial cost per year to the PBS was less
than $10 million per year.
12. Recommendation and Reasons
The PBAC recommended the listing of olanzapine pamoate monohydrate
modified release (MR) injection as an Authority required
(Streamlined) benefit for the treatment of schizophrenia. The PBAC
recommended that, consistent with its recommendation for modified
release risperidone injection, the relative price advantage for
olanzapine pamoate monohydrate modified release injection over the
monthly treatment cost of oral olanzapine should be the same as
haloperidol decanoate intramuscular injection had over oral
haloperidol (1:1.79), with a reduction to off-set the cost of
monitoring olanzapine for post injection syndrome. The
equi-effective doses are 10 mg daily oral olanzapine to 300 mg
every four weeks olanzapine MR injection, 15 mg daily oral
olanzapine to 210 mg every two weeks or 405 mg every four weeks
olanzapine MR injection and 20 mg daily oral olanzapine to 300 mg
every two weeks olanzapine MR injection.
The PBAC considered the method used in the submission to calculate
equi-effective doses against modified release risperidone injection
was complex and highly uncertain and hence did not accept the
pricing proposed in the submission based on these calculations or
that proposed during evaluation.
The PBAC considered the evidence presented (trial HGKA) supports
the non-inferiority of olanzapine MR injection to oral olanzapine.
The indirect comparison of trial HGJZ and Kane 2003 also suggests
non-inferiority of olanzapine MR injection to risperidone MR
injection, however this conclusion is somewhat uncertain due to the
indirect nature of the analysis and differences in the duration of
the trials and the severity of the trial patients. The PBAC
considered the evidence presented indicates that olanzapine MR
injection has a similar side effect profile to oral olanzapine with
the exception of post injection syndrome. The PBAC was concerned
about the potential for post injection syndrome to occur and hence
recommended adding a CAUTION to the restriction highlighting the
Product Information recommendation to monitor the patient for the
signs and symptoms of post injection syndrome for at least three
hours after administration.
The PBAC considered the listing will provide prescribers with an
additional long acting atypical antipsychotic treatment option for
schizophrenia. The PBAC requested that the National Prescribing
Service consider providing education on the use of olanzapine
modified release injection in the treatment of schizophrenia and
the importance of monitoring for the signs and symptoms of post
injection syndrome for at least three hours after administration of
each injection.
Recommendation
OLANZAPINE PAMOATE MONOHYDRATE, powder for injection with diluent
vial, 210 mg, 300 mg and 405 mg
Restriction:
CAUTION:
Monitor for post-injection syndrome for at least three hours after
each injection.
Authority Required (STREAMLINED)
Schizophrenia in a patient who can be stabilised with oral olanzapine.
NOTE:
No applications for increased maximum quantities and/or repeats will be authorised.
Max qty: 2 (210 mg and 300 mg), 1 (405 mg)
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
The sponsor welcomes the decision by the PBAC to provide an alternative long acting depot formulation for the treatment of schizophrenia
.
