Aprepitant, pack containing 1 capsule 125 mg and 2 capsules 80 mg, Emend®, November 2009
Public Summary Document for Aprepitant, pack containing 1 capsule 125 mg and 2 capsules 80 mg, Emend®, November 2009
Page last updated: 19 March 2010
Public Summary Document
Product: Aprepitant, pack containing 1 capsule 125
mg and 2 capsules 80 mg, Emend®
Sponsor: Merck Sharp & Dohme (Australia) Pty
Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought to extend the current authority required
listing for aprepitant to include treatment of chemotherapy induced
nausea and vomiting (CINV) associated with moderately emetogenic
chemotherapy.
2. Background
At the November 2004 meeting, the PBAC recommended an authority
required listing for aprepitant capsule, pack of 1 x 125 mg and 2 x
80 mg, on the basis of acceptable cost-effectiveness when used with
certain emetogenic cytotoxic chemotherapy agents.
At the March 2006 meeting, the PBAC recommended extending the
authority required listing for aprepitant to include use in
patients undergoing treatment for breast cancer with
cyclophosphamide and an anthracycline on the basis of acceptable
cost-effectiveness as compared to placebo.
The PBAC expressed concern, that in time, other cytotoxic regimens
are likely to be identified as being highly emetogenic, and
foreshadowed the need to develop a mechanism to assess possible
future requests to expand PBS access. Variance in inter-patient
tolerability of different cytotoxic regimens was also noted to be a
potential factor necessitating expanding the clinical role of this
drug. The PBAC therefore requested that the sponsor be approached
to consider putting forward a future submission to expand PBS
access, in line with aprepitant’s evolving clinical place in
the treatment of nausea and vomiting associated with cancer
chemotherapy.
At the March 2007 meeting, the PBAC recommended a change to the
listing for aprepitant to allow repeats to be authorised to cover
all future cycles of chemotherapy on the basis of efficiency.
At the March 2008 meeting, the PBAC rejected a submission for
aprepitant to change the current restriction to expand PBS access
in line with evolving clinical practice as no data were provided to
demonstrate the cost-effectiveness of treatment in the expanded
population.
3. Registration Status
Aprepitant was TGA registered on 21 September 2005 for use in
combination with other antiemetic agents, for the prevention of
acute and delayed nausea and vomiting associated with initial and
repeat courses of moderately emetogenic cancer chemotherapy.
Aprepitant is also TGA registered for:
- use in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.
- the prevention of postoperative nausea and vomiting.
4. Listing Requested and PBAC’s View
(changes to the current restriction are in bold and strikethrough)
Authority Required
Management of nausea and vomiting associated with cytotoxic chemotherapy being used
to treat malignancy, in combination with a 5HT3 antagonist and dexamethasone, where any 1 of the following chemotherapy agents are
to be administered:
(a) altretamine;
(b) carmustine;
(c) cisplatin when a single dose constitutes a cycle of chemotherapy;
(d) intravenous cyclophosphamide at a dose of 1500 mg per square metre per day or greater
(e) dacarbazine;
(f) procarbazine when a single dose constitutes a cycle of chemotherapy;
(g) streptozocin;
(h) oxaliplatin;
(i) cytarabine at a dose of greater than 1 g per metre square;
(j) carboplatin;
(k) ifosfamide;
(l) doxorubicin;
(m) daunorubicin;
(n) epirubicin;
(o) idarubicin;
(p) irinotecan
No more than 1 pack containing 1 x 125 mg capsule and 2 x 80 mg capsules will be authorised
per cycle of cytotoxic chemotherapy.Management of nausea and vomiting associated with cytotoxic chemotherapy being used
to treat breast cancer, in combination with a 5HT3 antagonist and dexamethasone, where
cyclophosphamide and an anthracycline are to be co-administered.
No more than 1 pack containing 1 x 125 mg capsule and 2 x 80 mg capsules will be authorised
per cycle of cytotoxic chemotherapy.
NOTE: No applications for increased maximum quantities will be authorised. Prescribers
should advise Medicare Australia of the number of cycles planned when requesting approval
for repeats.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Chemotherapy induced nausea and vomiting (CINV) is the most common
side effect of cancer chemotherapy and can significantly affect a
patient’s quality of life.
Aprepitant would provide an additional option to current CINV
preventative treatment for patients treated with moderately
emetogenic chemotherapy.
For PBAC’s view, see Recommendation and
Reasons.
6. Comparator
The submission nominated standard antiemetic regimen including a
5HT3 antagonist (ondansetron) and a corticosteroid
(dexamethasone) as the comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented a comparison of the aprepitant CINV
regimen and the standard CINV regimen in patients treated with
moderately emetogenic intravenous chemotherapy based on one Cycle
of a head-to-head trial – Protocol 130. This was a
randomised, double-blind, controlled, parallel group, multicentre
study conducted under in-house blinding conditions that aimed to
determine the efficacy and tolerability of aprepitant for the
prevention of chemotherapy-induced nausea and vomiting associated
with moderately emetogenic chemotherapy. Protocol 130 assessed a
patient population that overlapped with the restriction requested
for widening access to aprepitant on the PBS. In the trial
population there is a large representation of women (76.9%), and of
tumour type, breast cancer makes up approximately 50% of both
arms.
Supplementary evidence provided in the submission included the
Cycle Two results from Protocol 130 and the per protocol data set
from Protocol 130. Details of associated reports presented in the
submission are in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Schmoll H et al | Aprepitant for the chemotherapy-induced nausea and vomiting associated with non-anthracycline/cyclophosphamide-based, moderately emetogenic chemotherapies: a randomised, double-blind study. | Poster, Multinational Association for Supportive Care in Cancer (MASCC) Symposium 2009 (accepted) |
| Rapoport B et al | PN130: Results of aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies (MEC) and tumour types. | MASCC 2009 (draft) |
| Schmoll H et al | Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumour types: a randomised, double-blind study. | Poster, American Society of Oncology (ASCO) 2009 (draft) |
| Boice J et al | Aprepitant in the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapies in patients with gastrointestinal cancer. | Poster, European Society for Medical Oncology World Congress on Gastrointestinal Cancer 2009 (draft) |
| Rapoport B et al | Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumour types: a randomised, double-blind study. | Support Care Cancer Journal 2009 (draft) |
The PBAC noted that the dose of dexamethasone in the CINV regimen +
aprepitant arm was lower than in the standard CINV arm (12mg vs.
20mg), and considered that this difference would tend to bias
against aprepitant.
Regimens compared in Study 130
| CINV + aprepitant | Standard CINV | |
| Day 1: | Aprepitant 125mg PO od | |
| Ondansetron 8mg PO bd | Ondansetron 8mg PO bd | |
| Dexamethasone 12mg PO od | Dexamethasone 20mg PO od | |
| Days 2&3 | Aprepitant 80mg PO od | Ondansetron 8mg PO bd |
PO = oral; od = once daily; bd = twice daily
8. Results of Trials
The primary and secondary health outcomes reported in Protocol 130
are presented in the table below. All results were from the Overall
Phase (Acute Phase and Delayed Phase) of Cycle One for the
population of patients fulfilling the requirements for the full
analysis set (FAS).
Primary and secondary outcomes from the FAS population of
the Overall Phase of Cycle One of Protocol 130
| Component | CINV regimen + aprepitant | Standard CINV regimen | Incremental outcome | P value |
| Primary outcome | ||||
| Health Outcome: No Vomiting | ||||
| Proportion of patients reaching No Vomiting | 76.2% | 62.1% | 14.1 | < 0.0001 |
| Secondary outcomes | ||||
| Health Outcome: Complete Response | ||||
| Proportion of patients reaching Complete Response | 68.7% | 56.3% | 12.4% | 0.0003 |
| Health Outcome: No Use of Rescue Medication | ||||
| Proportion of patients with No Use of Rescue Medication | 81.4% | 75.2% | 6.2% | NS |
| Health Outcome: No Impact of CINV on Daily Life | ||||
| Proportion of patients with No Impact of CINV on Daily Life | 73.4% | 66.3% | 7.1% | 0.035 |
CINV=Chemotherapy Induced Nausea and Vomiting; FAS=Full Analysis
Set
These outcomes formed the basis of the economic evaluation and
ranged from a significant difference in patients reaching the
‘No Vomiting’ and ‘Complete Response’
endpoints (in both acute and delayed phases) to no significant
difference in patients reaching the ‘No Use of Rescue
Medication’ endpoint between treatment groups.
The PBAC considered a key issue was that the interpretation of
these results in terms of the impact that aprepitant may be
expected to have on patient quality of life remains unclear. The
PBAC was advised it was reasonable to assume that no vomiting would
result in an improvement in quality of life. However, the size of
the effect was more difficult to assess. The submission did not
transform the results to QALYs.
The submission appropriately concluded that there appeared to be no
significant difference in comparative toxicity between CINV
regimens containing aprepitant and the standard CINV regimen from
the results of Protocol 130. The extended assessment of comparative
harms did not alter this conclusion.
9. Clinical Claim
The submission described the aprepitant regimen as superior in
terms of comparative effectiveness and equivalent in terms of
comparative safety over the standard regimen for treating
CINV.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a trial based cost-effectiveness analysis
using four health outcomes reported in Protocol 130 (No Vomiting,
Complete Response, No Use of Rescue Medication and No Impact of
CINV on Daily Life) as the basis of the analysis.
The base-case incremental cost-effectiveness ratio (ICER) per extra
patient reaching each of the four health outcomes was less than
$15,000.
Additional univariate sensitivity analyses based on estimates of
the Australian population (for age, gender, tumour type and
chemotherapy type) were also presented in the submission. In the
univariate sensitivity analyses each adjustment alone resulted in
an increased ICER, but remained below $15,000.
The PBAC noted that the presentation of a trial-based base case in
the submission was intended to allow the PBAC to compare the
cost-effectiveness of aprepitant with that of currently reimbursed
indications, and the claim that the additional sensitivity analyses
based on estimates of the Australian population demonstrated the
robustness of the results of the base-case economic
evaluation.
The sponsor’s Pre-PBAC response provided the results of a
univariate analysis for subgroups described by gender, age, tumour
type and chemotherapy type based on the trial population for the No
Vomiting endpoint and further adjusted to remove cost-offsets due
to differences in rescue medication and cumulative effect
calculated as a weighted average response. The ICER for the
weighted response was further increased but remained below
$15,000.
For PBAC’s view, 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 with an estimated financial cost per
year to the PBS of less than $10 million. The PBAC considered these
estimates to be uncertain.
12. Recommendation and Reasons
The PBAC accepted that the treatment algorithm presented in the
submission was consistent with evidence-based best practice, and
agreed that the comparator is appropriate, noting that aprepitant
is added to standard therapy on day one of treatment and
substitutes for 5HT3-antagonist and dexamethasone 8mg on
days 2-3. However, to ensure best practice if listed on the PBS, a
quality use of medicines program would be needed to ensure
appropriate use and adherence to the treatment algorithm so that
use of ondansetron and dexamethasone was restricted to day 1.
The PBAC accepted there was a clinical need for aprepitant for
patients receiving moderate emetogenic chemotherapy, however noted
that the current market, if listed for this indication, would
likely double. The PBAC considered that the clinical claim was
reasonable and, although not quantified, it was reasonable to
assume that there is some quality of life benefit associated with
the reduction in CINV.
The PBAC considered the main area of uncertainty in the submission
was issues with translation and that the outcomes presented in the
submission may not represent the true cost-effectiveness of the
CINV regimen that contains aprepitant for the following reasons:
- In particular, the extent of the cost offset per patient generated by aprepitant replacing 5HT3 antagonist use is unclear and not consistently supported by the relevant clinical CINV guidelines and may not be realised if ondansetron and dexamethasone are continued in clinical practice beyond day 1.
- The extent of the cost offset per patient generated by the assumption that patients receiving aprepitant require fewer days in hospital than those on the standard regimen is unclear and not supported by clinical evidence.
- It is unclear how the health outcomes assessed in the model relate to impact on patient quality of life.
- Uncertain magnitude of benefit in the requested PBS population as the trial outcome is driven by the breast cancer population in the trial (Protocol 130), and the majority of these patients already have access to aprepitant on the PBS.
The PBAC considered that the base case used in the economic
analysis was inappropriate, and should have included adjustments
for the key applicability issues of gender ratio, age distribution
and type of cancer most likely to be treated in the general
population. Any future submission should focus on the
non-doxorubicin/cyclophosphamide (AC) patients in the trial and
then further adjust for the Australian population.
The PBAC noted the sponsor’s Pre-PBAC Response provided the
results of a univariate analysis for subgroups described by gender,
age, tumour type and chemotherapy type based on the trial
population and further adjusted to remove cost-offsets due to
differences in rescue medication and cumulative effect calculated
as an a weighted average response. The ICER based on the Australian
population (weighted response) was increased from the base-case and
remained less than $15,000.
The PBAC noted that the weighted ICER was within the range of that
previously approved for highly emetogenic chemotherapy and AC for
breast cancer. However, the PBAC considered the health outcome
measure of no vomiting is more likely to be similar to that
achieved in the moderate emetogenic breast cancer population
receiving AC. Therefore, to achieve a similar ICER to the breast
cancer population a price decrease would be needed. Alternatively,
the sponsor may wish to consider seeking a secondary prophylaxis
listing for moderate emetogenic agents, so that aprepitant could be
used in combination with ondansetron and dexamethasone as
combination therapy similar to the current listing.
Therefore, the PBAC rejected the submission on the basis of high
and uncertain cost-effectiveness in the patient population
requested.
The PBAC noted that the submission meets the criteria for an
independent review.
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 is working with the PBAC to resolve the areas of
uncertainty.
