Palonosetron Hydrochloride, solution for injection vial, 250 micrograms in 5 mL, Onicit® - March 2010
Public Summary Document for Palonosetron Hydrochloride, solution for injection vial, 250 micrograms in 5 mL, Onicit® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: Palonosetron Hydrochloride, solution for
injection vial, 250 micrograms in 5 mL,
Onicit®
Sponsor: Specialised Therapeutics Australia Pty
Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application
The submission sought a Restricted benefit listing for the
management of nausea and vomiting associated with cytotoxic
chemotherapy being used to treat malignancy which occurs within 48
hours of chemotherapy administration.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Palonosetron was registered by the Therapeutic Goods Administration
(TGA) on 26 June 2006 for the prevention of nausea and vomiting
induced by cytotoxic chemotherapy.
4. Listing Requested and PBAC’s View
Restricted benefit
Management of nausea and vomiting associated with cytotoxic
chemotherapy being used to treat malignancy which occurs within 48
hours of chemotherapy administration.
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Nausea and vomiting can be a common side-effect of chemotherapy
treatment. The prevention of acute nausea and vomiting associated
with cytotoxic chemotherapy is currently managed with a combination
of the drugs aprepitant, dexamethasone and a 5 HT3
antagonist. Palonosetron would provide another 5-HT3
antagonist option.
6. Comparator
The submission nominated ondansetron as the main comparator. Data
was also provided for comparison with other 5-HT3
receptor antagonists. The PBAC agreed that the appropriate
comparator was ondansetron.
7. Clinical Trials
The submission presented seven randomised trials comparing
palonosetron (250 microgram IV and/or 750 microgram IV) with other
5-HT3 receptor antagonists, including ondansetron (32 mg
IV, 8 mg IV followed by 8 mg orally twice daily, or 8
mg/m2 IV every 8 hours while receiving chemotherapy
during hospitalisation), dolasetron (100 mg IV) and granisetron (3
mg IV or 40 microgram/kg IV), in patients receiving moderately or
highly emetogenic chemotherapy. The submission also presented one
abstract of a meta-analysis of four randomised trials comparing
palonosetron 250 microgram with other 5-HT3 receptor
antagonists (ondansetron, dolasetron and granisetron), and pooled
the results from the seven individual trials for palonosetron (all
doses) and other 5-HT3 receptor antagonists combined
(all doses). The dose regimens of the randomised therapies in the
trials were not all within those recommended in the relevant
product information documents or used in current clinical
practice.
In two studies, ondansetron was administered at 32 mg intravenously
(IV), which is a higher dose than that used in current clinical
practice. Both these trials used a single dose of
ondansetron.
The key trial in the submission was Bernardo et al. (2009), which
was the only study comparing palonosetron 250 micrograms and
ondansetron 8 mg IV followed by 8 mg orally twice daily for 3 days,
was only available as an abstract, and a 2008 poster which appeared
to be a subset of patients described in the 2009 abstract. This
study was classified by the submission as a randomised trial, but
the abstract made no mention of randomisation, referring only to
1:1 assignment to treatment groups.
The trials presented in the submission are shown below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct randomised trials | ||
| Palonosetron versus ondansetron | ||
| Palonosetron versus dolasetron | ||
| Palonosetron versus granisetron | ||
| Meta-analyses of direct randomised trials | ||
| Aapro et al. (2006) [Study PALO-99-05] | A phase III, double-blind, randomised trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. | Annals of Oncology 2006; 17: 1441–1449 |
| Palonosetron is effective in preventing acute and delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. | Support Care Cancer 11(6): 391, abstract A-17, 2003 MASCC (Poster) | |
| Palonosetron (PALO) is a safe and well-tolerated 5-HT3 receptor antagonist (RA): safety results of a phase III trial. | Proceedings of the American Society of Clinical Oncology 22: 753, abstract 3028, 2003 ASCO (Poster) | |
| Gralla et al. (2003) [Study PALO-99-03] | Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomised phase III trial comparing single doses of palonosetron with ondansetron. | Annals of Oncology 2003; 14: 1570–1577 |
| Single IV dose of palonosetron (PALO), a potent 5-HT3 receptor antagonist (RA), demonstrates sustained prevention of nausea and vomiting for 5 days following moderately emetogenic chemotherapy (MEC). | Proceedings of the American Society of Clinical Oncology 2003; 22: 760, abstract 3055, ASCO (Poster) | |
| Palonosetron (PALO) is more effective than ondansetron (OND) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC): results of a phase III trial. | Proceedings of the American Society of Clinical Oncology 2003; 22: 726, abstract 2918, ASCO (Abstract) | |
| Bernardo et al. (2009) (Abstract) |
Palonosetron compared to ondansetron in the prevention of chemotherapy-induced nausea and vomiting: Activity, safety, and cost-effectiveness evaluation. | J Clin Oncol 2009; 27 (15 Suppl): abstract e20573 |
| Improving patient care while considering cost effectiveness of new active prophylaxis for chemotherapy-induced nausea and vomiting (CINV): Results of a prospective phase II trial. | ESMO – Stockholm. 2008 (Poster) | |
| Sepúlveda-Vildósola (2008) | Palonosetron Hydrochloride Is an Effective and Safe Option to Prevent Chemotherapy-induced Nausea and Vomiting in Children. | Archives of Medical Research 2008; 39: 601-6 |
| Eisenberg et al. (2003) [Study PALO-99-04] | Improved Prevention of Moderately Emetogenic Chemotherapy-Induced Nausea and Vomiting with Palonosetron, a Pharmacologically Novel 5-HT3 Receptor Antagonist. Results of a Phase III, Single-Dose Trial Versus Dolasetron. | Cancer 2003; 98: 2473– 82 |
| Efficacy of palonosetron (RS-2529) compared with dolasetron in preventing acute and delayed moderately emetogenic chemotherapy-induced nausea and vomiting (CINV): results of a phase III randomized controlled trial. | Blood 2002; 100 (11 Suppl) (Part 2), 497b-498b, Abstract 5576 | |
| Palonosetron is active in preventing acute and delayed emesis following moderately emetogenic chemotherapy: results of a phase III trial. | Support Care Cancer 2002; 10(4), abstract P-113, MASCC (Abstract) | |
| Safety and efficacy of fixed-dose palonosetron in preventing acute and delayed emesis following moderately emetogenic chemotherapy: a phase III study. | International Pharmaceutical Abstracts 2002; 39, abstract P-643E, ASHP (Poster) | |
| Safety of palonosetron (RS-25259) compared with dolasetron in preventing acute and delayed moderately emetogenic chemotherapy-induced nausea and vomiting (CINV): results of a phase III, randomized, controlled trial. | Blood 2002; 100(Suppl.1): 499b, abstract 5582, ASH (Abstract) | |
| Saito et al. (2009) | Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial in the Japanese population. | Lancet Oncol 2009; 10: 115–24 |
| Yu et al. (2009) | The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicentre, randomised, double-blind, parallel, comparative clinical trial. | Support Care Cancer 2009; 17: 99– 102 |
| Clark et al. (2009) (Abstract) |
Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatments: Systematic review and meta-analysis. | Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No 15S (May 20 Supplement), 2009: e20620 |
8. Results of Trials
The proportions of patients achieving complete response during the
acute phase (0 to 24 hours) in the key study Bernardo et al. (2009)
are presented below. Results are presented by dose of palonosetron
and overall where available, and co-administration of dexamethasone
was noted. Complete response was defined as no emetic episode and
no rescue medication use.
| Trial ID | Palonosetron n/N (%) | Active comparator n/N (%) | Risk difference (95% CI) | Relative Risk (95% CI) |
|---|---|---|---|---|
| Bernardo et al (2009) (with dex) PALO 250 μg vs ONDA 8 mg IV then 8 mg orally twice daily for 3 days HEC AC MEC |
106/117 (90.6) NR (82) NR (93.4) NR (100) |
91/118 (68.6) NR (63.2) NR (80.6) NR (94.4) |
0.13 (0.04, 0.23) |
1.17 (1.05, 1.32) |
Abbreviations: CI= confidence interval, Dex= dexamethasone, HEC=
Highly emetogenic chemotherapy, IV= intravenously, MEC= moderately
emetogenic chemotherapy, AC = anthracycline-cyclophosphamide based
chemotherapy, ONDA= ondansetron, PALO= palonosetron, vs = versus,
μg= microgram, NR = not reported
Complete response rates were numerically higher for palonosetron
250 microgram than the active comparators in all trials in the
acute phase. Non-inferiority of palonosetron to the active
comparator in the acute phase was concluded for Aapro et al.
(2006), Gralla et al. (2003), Eisenberg et al. (2003), Saito et al.
(2009) and Yu et al. (2009). There was no evidence of dose-response
with palonosetron, as complete response rates were similar or
higher for the 250 microgram dose compared to the 750 microgram
dose.
The proportions of patients achieving complete response during the
delayed phase in the key study Bernardo et al. (2009) are presented
below. The delayed phase usually referred to the time period of 24
hours to 120 hours. Complete response rates were numerically higher
for palonosetron treated patients compared to comparator
5-HT3 receptor antagonists in all trials except for the
trial by Yu et al. (2009).
| Trial ID | Palonosetron n/N (%) | Active comparator n/N (%) | Risk difference (95% CI) | Relative Risk (95% CI) |
|---|---|---|---|---|
| Bernardo et al (2009) (with dex) PALO 250μg vs ONDA 8mg IV then 8mg orally twice daily for 3 days HEC AC MEC |
100/117 (85.5) NR (74.4) NR (90.2) NR (94) |
84/118 (71.2) NR (63.2) NR (71) NR (88.9) |
0.14 (0.04, 0.25) |
1.20 (1.05, 1.38) |
Abbreviations: CI = confidence interval, Dex = dexamethasone, HEC =
Highly emetogenic chemotherapy, IV = intravenously, MEC =
moderately emetogenic chemotherapy, AC =
anthracycline-cyclophosphamide based chemotherapy, ONDA=
ondansetron, PALO = palonosetron, vs = versus, μg = microgram,
NR = not reported
Non-inferiority of palonosetron 250 micrograms to the active
comparator in the delayed phase was concluded in Aapro et al.
(2006), Gralla et al. (2003) and Eisenberg et al. (2003). However,
it was difficult to interpret the clinical relevance of the
conclusion of non-inferiority in delayed chemotherapy induced
nausea and vomiting (CINV) due to the short half-life of the active
comparators, the potential administration of inadequate doses of
active comparator for delayed CINV, and the possibility that the
100 mg dose of dolasetron may have been suboptimal for some
patients. Gralla et al. (2003) and Eisenberg et al. (2003) also had
limited usage of concomitant corticosteroids (e.g. dexamethasone),
which is recommended by the guidelines for delayed CINV.
Saito et al. (2009) was the only trial which nominated complete
response rate in the delayed phase as one of the primary outcomes.
In this trial, the authors concluded that when administered with
dexamethasone, palonosetron 750 microgram was superior to
granisetron 40 microgram/kg in delayed phase CINV (Risk difference
12.2 % (95 % CI 6.4 %, 18.0 %)). However, the dosage of
palonosetron was higher than the TGA-approved dose and patients
were not taking aprepitant, which is recommended for the patient
population recruited.
Three trials reported the use of rescue anti-emetic medications in
the ‘delayed phase’ of CINV (Aapro et al. (2006),
Gralla et al. (2003), Bernardo et al. (2009)). Despite the
differences in data presented, fewer palonosetron treated patients
required rescue medications.
The submission pooled the results from the individual trials for
palonosetron (all doses) and other 5-HT3 receptor
antagonists combined (all doses). The results are tabulated
below:
| Pooled results | Palonosetron (all doses) n/N (%) | Other 5-HT 3 antagonists n/N (%) | Relative Risk (95% CI) | Odds Ratio (95% CI) | p-value |
|---|---|---|---|---|---|
| Acute phase | 1453/2028 (71.6) |
966/1428 (67.6) |
1.11 (1.05, 1.17) |
1.47 (1.17, 1.86) |
0.001 |
| Delayed Phase | 1182/2028 (58.3) |
668/1428 (46.8) |
1.26 (1.18, 1.34) |
1.68 (1.41, 2.00) |
<0.0001 |
| Overall phase | 1077/2028 (53.1) |
614/1428 (43.0) |
1.26 (1.17, 1.35) |
1.62 (1.39, 1.88) |
<0.0001 |
Abbreviation: 5-HT3 antagonist = selective serotonin
subtype 3 receptor antagonist, CI = confidence interval
The results of the meta-analysis suggested palonosetron is more
effective than other 5 HT3 receptor antagonists in the
acute, delayed and overall phases. The PBAC noted that these
analyses should be interpreted with caution. For PBAC’s
comments on these results, see Recommendation and
Reasons.
The safety of palonosetron was similar to the active comparators
(ondansetron and dolasetron). The Periodic Safety Update Reports
identified cardiac events, convulsions/seizure events, cases of
“lack of efficacy” and hypersensitivity reactions
including anaphylactic shock as areas for close monitoring and
re-evaluations.
9. Clinical Claim
The submission described palonosetron administered as a single IV
dose as therapeutically equivalent to other 5-HT3 receptor
antagonists administered as an IV bolus and oral doses for 2 to 3
subsequent days.
The key trial in the submission was Bernardo et al (2009), which
was the only study comparing palonosetron 250 micrograms and
ondansetron 8 mg IV followed by 8 mg orally twice daily for 3 days
and the PBAC considered this the most relevant to current use of
5-HT3 receptor antagonists in Australia. However, as this study was
only available in poster and abstract format, the PBAC agreed that
a sound, critical evaluation of the data could not be performed,
and as such uncertainty remains around the submission’s claim
of therapeutic equivalence of palonosetron 250 micrograms as a
single IV dose to other 5-HT3 receptor antagonists administered as
an IV bolus and oral doses for 2 to 3 subsequent days.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as palonosetron 250 microgram
as a single IV dose and ondansetron 8 mg IV followed by 8mg orally
twice daily for 3 days.
The table below summarises the cost-minimisation analysis of
palonosetron and ondansetron:
| Parameter | Palonosetron | Ondansetron | ||
|---|---|---|---|---|
| Dosage | Cost | Dosage | Cost | |
| Day 1 | 250μg IV | $121.95 | 8mg IV | $32.49* |
| Day 2 | NA | NA | 8mg orally twice daily | $28.45 |
| Day 3 | 8mg orally twice daily | $28.45 | ||
| Day 4 | 8mg orally twice daily | $28.45 | ||
| Total cost per cycle | $121.95
$117.84^ |
$117.84 | ||
Abbreviation: NA = not applicable; μg = microgram
* The dispensed price for maximum quantity of ondansetron 8 mg/4mL
injection was updated to reflect the price effective 1 December
2009
^ The proposed price for palonosetron was adjusted during the
evaluation to account for a price reduction for ondansetron,
effective 1 December 2009
The PBAC noted that the incremental cost of palonosetron compared
with other 5-HT3 receptor antagonists ranges from a cost saving of
$8.48 per cycle (when compared with granisetron), to an additional
cost of $12.47 per cycle (when compared with dolasetron or
tropisetron). This approach assumed the non-inferiority of
palonosetron with all other 5 HT3 receptor antagonists administered
as IV bolus plus an oral regimen for 3 days, however the clinical
data presented only provided information on comparators other than
ondansetron as a single IV dose.
11. Estimated PBS Usage and Financial Implications
During the evaluation a number of errors of methodology were
identified in the submission’s estimates of use and financial
implications, to the extent that the submission’s estimates
were not reliable to inform PBAC’s decision making. Therefore
a re-analysis was conducted during the evaluation. The number of
prescription from this re-analysis was in the range of 10,000
– 50,000 prescriptions in Year 5.
The financial cost/year to the PBS was estimated as a cost savings
of less than $15,000 in Year 5 from the re-analysis.
The PBAC noted that the estimated financial implications are highly
sensitive to the projected reduction in usage of oral 5-HT3
receptor antagonists should palonosetron be listed on the PBS. The
PBAC considered that this was unlikely to be realised and therefore
the submission may have substantially underestimated the costs to
the PBS.
12. Recommendation and Reasons
The PBAC recommended the listing of palonosetron on the PBS on a cost-minimisation
basis compared with intravenous ondansetron. The PBAC considered that the equi-effective
doses to be palonosetron 250 micrograms and intravenous ondansetron 12 mg.
The PBAC agreed that the appropriate comparator was ondansetron. The PBAC noted that
the submission presented seven randomised trials comparing palonosetron (250 microgram
IV and/or 750 microgram IV) with other 5-HT3 receptor antagonists, including ondansetron
(32 mg IV, 8 mg IV followed by 8 mg orally twice daily, or 8 mg/m2 IV every 8 hours while receiving chemotherapy during hospitalisation), dolasetron
(100 mg IV) and granisetron (3 mg IV or 40 microgram/kg IV), in patients receiving
moderately or highly emetogenic chemotherapy. The submission also presented one abstract
of a meta-analysis of four randomised trials comparing palonosetron 250 microgram
with other 5-HT3 receptor antagonists (ondansetron, dolasetron and granisetron), and
pooled the results from the seven individual trials for palonosetron (all doses) and
other 5-HT3 receptor antagonists combined (all doses). The PBAC noted that the dose
regimens of the randomised therapies in the trials were not all within those recommended
in the relevant product information documents or used in current clinical practice.
The key trial in the submission was Bernardo et al (2009), which was the only study
comparing palonosetron 250 micrograms and ondansetron 8 mg IV followed by 8 mg orally
twice daily for 3 days and the PBAC considered this the most relevant to current use
of 5-HT3 receptor antagonists in Australia. However, as this study was only available
in poster and abstract format, the PBAC agreed that a sound, critical evaluation of
the data could not be performed, and as such uncertainty remains around the submission’s
claim of therapeutic equivalence of palonosetron 250 micrograms as a single IV dose
to other 5-HT3 receptor antagonists administered as an IV bolus and oral doses for
2 to 3 subsequent days.
The PBAC agreed that based on the supporting data, palonosetron 250 microgram administered
as a single IV dose is at least non-inferior to other 5-HT3 receptor antagonists administered
as a single IV bolus in preventing CINV in the acute and delayed phases. However,
the PBAC considered that while allowing comparison of bolus IV doses, the supporting
studies did not inform the comparative efficacy of palonosetron single IV dose to
other 5-HT3 receptor antagonists administered as an IV bolus followed by oral administration
for 2-3 subsequent days. Further, it was noted that two of the supporting studies
used ondansetron at a dose of 32 mg IV, which the TGA considered as no more effective
than 8 mg except following cisplatin chemotherapy, and is not commonly used in Australia.
The PBAC did not consider that palonosetron 250 microgram IV and ondansetron 8 mg
IV followed by 8 mg orally twice daily for 3 days was equi-effective given the lack
of evidence to support this claim. The PBAC concluded that given the uncertainty around
the data presented to support the use of 5-HT3 antagonists for delayed nausea except
that which was presented in Bernardo et al 2009, in abstract form, that a pragmatic
approach was to allow cost-minimisation of palonosetron with ondansetron 12 mg intravenous
which would reflect current best clinical practice and was in accordance with the
National Comprehensive Cancer Network guidelines.
The submission proposed cost minimisation of palonosetron against any 5HT3 receptor
antagonist IV and 3 days oral therapy. The PBAC noted that the incremental cost of
palonosetron compared with other 5-HT3 receptor antagonists ranges from a cost saving
of $8.48 per cycle (when compared with granisetron), to an additional cost of $12.47
per cycle (when compared with dolasetron or tropisetron). This approach assumes the
non-inferiority of palonosetron with all other 5-HT3 receptor antagonists administered
as IV bolus plus an oral regimen for 3 days, however the clinical data presented only
provide information on comparators other than ondansetron as a single IV dose. The
PBAC also noted that the estimated financial implications are highly sensitive to
the projected reduction in usage of oral 5-HT3 receptor antagonists should palonosetron
be listed on the PBS. The PBAC considered that this was unlikely to be realised and
therefore the submission may have substantially underestimated the costs to the PBS.
Recommendation:
PALONOSETRON HYDROCHLORIDE, I.V injection, 250 microgram in 5 mL
Restriction: Restricted benefit
Management of nausea and vomiting associated with cytotoxic chemotherapy being used to treat malignancy which occurs within 48 hours of chemotherapy administration.
NOTE: No applications for increased maximum quantities will be authorised. Palonosetron is not PBS-subsidised for administration with oral 5-HT3 antagonists.
Maximum quantity: 1
Repeats: 0
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
Specialised Therapeutics Australia understands the analysis performed by the PBAC, and accepts the outcome. We welcome the opportunity to provide Palonosetron therapy to Australians.
