Paliperidone palmitate, aqueous suspension for injection, 25 mg, 50 mg, 75 mg, 100 mg and 150 mg, pre-filled syringe, Invega® Sustenna™
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25 mg, 50 mg, 75 mg, 100 mg and 150 mg, pre-filled syringe, Invega ® Sustenna™ (PDF
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Product: Paliperidone palmitate, aqueous
suspension for injection, 25 mg, 50 mg, 75 mg, 100 mg and 150 mg,
pre-filled syringe, Invega® Sustenna™
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought an Authority Required (Streamlined) listing
for the treatment of schizophrenia.
2. Background
This injectable preparation of paliperidone had not previously been
considered by the PBAC.
At its November 2007 meeting, the PBAC recommended the listing of
paliperidone tablets on the PBS for schizophrenia on a
cost-minimisation basis compared with olanzapine. The
equi-effective doses were paliperidone 9.83 mg per day and
olanzapine 12.91 mg per day. Paliperidone 3, 6 and 9 mg tablets
were listed on 1 April 2008. The 12 mg tablet was listed on 1
October 2008 and deleted from the PBS on 1 December 2009.
3. Registration Status
Paliperidone palmitate aqueous suspension for injection, 25 mg, 50
mg, 75 mg, 100 mg and 150 mg were TGA registered on 28 July 2010
for the acute and maintenance treatment of schizophrenia in
adults.
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Schizophrenia
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Schizophrenia is a chronic and severe psychiatric illness
characterised by disturbances in speech, perception, cognition,
volition and emotion.
The submission claimed that paliperidone injection would provide an
alternative atypical antipsychotic depot injection to risperidone
and olanzapine for the treatment of schizophrenia.
6. Comparator
The submission nominated risperidone modified release injection as
the main comparator, on the basis that it is the most commonly
prescribed long acting atypical antipsychotic injection on the
PBS.
The PBAC agreed that this was the appropriate comparator as it is
the product most likely to be replaced in clinical practice if the
decision to use a depot formulation is made
.
7. Clinical Trials
The submission presented two direct randomised trials comparing
paliperidone long acting injection (LAI) with risperidone LAI
treatment in patients aged ≥18 years, with schizophrenia for
≥1 year and a total Positive and Negative Syndrome Scale (PANSS)
score of 60−120 at baseline. Trial PSY-3006 (double-blind,
double-dummy, 78% European, 22% US) was used as primary evidence
and Trial PSY-3008 (open-label, 100% Chinese) was used as
supportive evidence. The studies were not yet published at the time
of the submission.
8. Results of Trials
The primary outcome of the trials was change in PANSS total scores
from baseline to endpoint. The non-inferiority margin was defined
as −5 points in Trial PSY-3006 and −5.5 points in Trial
PSY-3008.
There were no statistically significant differences between
paliperidone LAI and risperidone LAI in change in PANSS total score
from baseline in either trial except for the intention-to-treat
(ITT) analysis in Trial PSY-3008 where the results of the ITT
analysis favoured risperidone LAI.
For Trial PSY-3006, paliperidone LAI was non-inferior to
risperidone LAI as the lower bound of the 95% CI for the difference
in mean change in PANSS total scores was greater than −5
points.
For Trial PSY-3008, paliperidone LAI was non-inferior to
risperidone LAI as the lower bound of the 95% CI for the difference
in mean change in PANSS total scores was greater than −5.5
points. The submission argued that the lower bound of the 95% CI in
the ITT analysis was bordering the 7-point difference previously
accepted by the PBAC as a clinically unimportant difference.
In Trial PSY-3006, the most common Treatment Emergent Adverse
Events (TEAE) were insomnia, headache, somnolence and injection
site pain in the paliperidone LAI group and insomnia and headache
in the risperidone LAI group. In Trial PSY-3008, akathisia and
tremor were also common.
There was a significantly increased risk of possibly drug-related
adverse events, ‘psychiatric disorders’ including
anxiety, and ‘general disorders and administration site
conditions’ including injection site pain with paliperidone
LAI treatment in Trial PSY-3006. In Trial PSY-3008 there were more
nervous system disorders reported for risperidone LAI compared with
paliperidone palmitate LAI primarily due to a significantly greater
incidence of tremor reported in the risperidone group.
In the direct clinical trials, injection site pain was reported in
a small proportion of patients.
The submission reported that no additional safety issues were
identified in the first Periodic Safety Update Report (PSUR) for
paliperidone LAI or in the most recent PSUR for oral
paliperidone.
No data on the effects of long-term exposure to paliperidone
palmitate were presented in the submission.
9. Clinical Claim
The submission claimed that paliperidone LAI is superior in terms
of overall effectiveness (non-inferior in clinical trial end-points
but superior in actual clinical practice) and similar in terms of
safety over risperidone LAI.
The PBAC considered that based on the evidence presented, the claim
of superiority in clinical practice was not justified.
For PBAC’s view, see Recommendation and Reasons.
10. Economic Analysis
The submission’s approach to calculating dose relativity is summarised below
| Issue | Results |
|
Dose relativity in actual clinical practice The weighted final doses in Trial PSY-3006 represent mean doses for ‘non-steady state’ patients; dose relativity using weighted dose at study endpoint: 1 mg risperidone LAI: 1.76 mg paliperidone LAI |
Weighted average dose of paliperidone LAI based on post-launch US sales data in April 2010 was used as proxy for weighted average dose of paliperidone LAI in actual clinical practice in Australia Weighted average dose of risperidone LAI was based on scripts processed through Medicare Australia in April 2010 The dose relativity in actual clinical practice in Australia was proposed as 1 mg risperidone LAI: 1.32 mg paliperidone LAI |
The submission stated that in the clinical trials patients commenced treatment in
a non-steady state due to the wash out period and thus patients only achieved an on-treatment
steady state with paliperidone LAI at Day 8 because they had received the loading
dose of 150 mg and 100 mg on Day 1 and Day 8, respectively. The clinical trials thus
do not capture patients who switch therapies in the steady state condition and hence
commence at a dose based on a 1:1 ratio. Therefore, the submission concluded that
an overall average dose (and dose-relativity) for paliperidone palmitate LAI and risperidone
LAI that reflects both the non-steady-state and steady state patients is required.
The submission also calculated cost-offsets associated with the decreased frequency
of injection.
Consistent with a claim of superiority, the submission originally presented a stepped
economic evaluation versus risperidone LAI as the primary analysis and a cost comparison
versus olanzapine LAI as a secondary analysis. The type of economic evaluation presented
was a cost-utility analysis.
However, following advice from the PBAC’s Economics Sub-Committee (ESC), the sponsor
presented a cost-minimisation analysis which accounted for differences in administration
costs and oral antipsychotic supplementation requirements. The PBAC agreed that this
was more appropriate than the cost-utility analysis originally presented in the submission.
See Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to
be less than 10,000 in year 5. This was considered a likely
underestimate.
Based on the original cost-effectiveness approach, the submission
estimated the net cost per year to the PBS to be less than $10
million in year 5. Revised estimated net costs based on the
cost-minimisation approach were not provided.
12. Recommendation and Reasons
The PBAC recommended the listing of paliperidone palmitate LAI on
the PBS as an Authority Required (Streamlined) listing for the
treatment of schizophrenia on a cost-minimisation basis compared
with risperidone modified release injection. The pragmatic dose
relativity accepted by the PBAC for pricing purposes was 1:1.32 for
injected risperidone and injected paliperidone, respectively, based
on USA sales and Medicare data. In view of the uncertainty
regarding the dose relativity, the PBAC considered that this dose
relativity should be reviewed in 12 months time based on PBS data.
For pricing purposes, the PBAC agreed that there could also be an
offset for the use of oral risperidone during titration of injected
risperidone due to its 3-week lag of onset of effect, as well as
for the administration of an extra dose of injected risperidone
every four weeks, given it is administered fortnightly whereas
paliperidone is administered once every four weeks.
The PBAC agreed that risperidone modified release injection was the
appropriate comparator as it is the product most likely to be
replaced in clinical practice if the decision to use a depot
formulation is made.
The PBAC considered that the results of trials PSY-3006 and
PSY-3008 suggest no statistically significant differences between
paliperidone LAI and risperidone modified release injection in the
primary outcome of change in PANSS total score from baseline, and
in the secondary outcomes assessed. The PBAC noted that there were
differences in dosing frequencies between paliperidone and
risperidone in the trials (4-weekly versus 2-weekly).
The PBAC noted the sponsor’s proposal in its pre-PBAC
response to present a cost-minimisation analysis following the
advice of the ESC, including accounting for differences in
administration costs and oral antipsychotic supplementation
requirements. The PBAC agreed that this was more appropriate than
the cost-utility analysis presented in the submission.
The PBAC considered the main issues relating to the
cost-minimisation approach to be the determination of dose
relativity and cost-offsets due to reduced administration costs
with less frequent dose administration, and there being no
requirement for oral supplementation with paliperidone compared
with risperidone during the initiation phase (as noted in the
clinical trials presented).
The PBAC noted that determining the equi-effective doses based on
the doses being used at the end of clinical trial data for the
population of patients switching from oral antipsychotics would not
include the impact of the need for a loading dose. The washout
period may also not have been adequate for patients who were
already on long acting injections. The PBAC agreed that the trial
data were not at steady state and were immature. Therefore, the
dose relativity of 1:1.76 for injected risperidone to injected
paliperidone at study endpoint may not be informative of the
equi-effective doses in this instance.
The PBAC also accepted the submission’s argument that, based
on the paliperidone product information, the population of patients
switching from injected risperidone to injected paliperidone would
do so on a 1:1 dose relativity basis. The PBAC noted that the
submission provided no basis to weight the different dose
relativities across the two populations determined by what product
patients were receiving before starting injected
paliperidone.
The PBAC further noted the paliperidone dose from USA sales data
was similar to that at the end of the trial. The average dose of
risperidone at the end of the trial was less than both the USA
sales data and the Australian Medicare data. The PBAC considered
that the difference in dose relativities provided in the submission
appeared to be driven by the injected risperidone dose in the trial
compared with those obtained from the utilisation data.
Overall, the PBAC agreed that, in this instance, the proposed dose
relativity of 1:1.32 based on USA sales and Australian Medicare
data may be a more pragmatic basis for determining a dose
relativity for pricing purposes, noting that it lies between the
two estimates for the two populations and because it also
represents an approximation of the steady state dose. This
pragmatic approach was agreed due to the inadequacies of the
usually preferred trial basis for determining equi-effective doses
for patients switching from oral antipsychotics, and the inability
to estimate the relative proportions of the two populations to
determine a weighting for an evidence-based estimation of
equi-effective doses.
Regarding the cost-offsets, the submission calculated a cost-offset
per risperidone modified release injection avoided, using a sponsor
commissioned survey which took into account labour costs and travel
time. The PBAC considered the usual method of determining
cost-offsets to account for administration costs is to use a
Medicare schedule fee for the extra consultation every four weeks,
and in this case a Level B consultation fee was deemed
appropriate.
The PBAC noted the consumer comments received for this item.
Recommendation:
PALIPERIDONE PALMITATE, aqueous suspension for injection, 25 mg, 50
mg, 75 mg, 100 mg and 150 mg, pre-filled syringe
Restriction: Authority Required (STREAMLINED)
Schizophrenia
Maximum quantity: 1
Repeats: 5
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.
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
Janssen-Cilag welcomes this recommendation by the PBAC to provide
access to a new long-acting injectable treatment option for
Australian schizophrenia patients.
