www.aloxi.net
www.helsinn.com
EMETOGENICITY OF
CHEMOTHERAPY REGIMENS
A Pocket Guide To
STARTS STRONG
LASTS LONG
Version 2012
Information included herein is based on data from
the latest ASCO, ESMO, MASCC, NCCN, and
NCI guidelines, and it has been integrated with
relevant evidences from the international scientific
literature.
While it offers information on CT regimens’
schedules and emetogenicities, this guide is not a
tool for CT choice.
Please, consult guidelines and package inserts for
exact dosages, notes and warnings on CT agents and
combinations.
This pocket guide is designed as a practical tool
for the Oncologists, aimed at facilitating the
decision making on the antiemetic therapy to be
administered to patients undergoing a specific CT
regimen.
Before using this book
ASCO and MASCC-ESMO guidelines recommends
palonosetron as the 5-HT3 receptor antagonist to be
used in pure MEC.2-5 Based on the MASCC-ESMO
guidelines, palonosetron should be preferred in AC
chemotherapy if a NK1 RA is not available.2,4
The latest release of NCCN antiemetic guidelines
(Version 1.2012) indicates palonosetron as the
preferred agent in both highly and moderately
emetogenic chemotherapy (HEC and MEC) settings.1
In the tables included in this guide the stamps identify
emetogenicities in which treatment with palonosetron
is indicated, according to the international guidelines.
Preferred choice in international guidelines
Palonosetron
ii
when a NK1 RA is not available
ASCO
NCCN
1.NCCN Antiemetic Guidelines v. 1.2012: www.nccn.org
2.MASCC/ESMO Antiemetic Guidelines 2011: www.mascc.org
3.ASCO 2011 Antiemetics Guideline: www.asco.org
4.Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21 [suppl 5]:v232-v243.
5.Basch E, et al, Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update, J Clin Oncol Nov 1, 2011:398-401.
References
Palonosetron is recommended as one of the possible choices of 5-HT3 RAs
Palonosetron is recommended as the preferred agent among 5-HT3 RAs
*AC/EC based regimens are considered as HEC by ASCO and NCCN, as MEC by MASCC/ESMO
Moderately Emetogenic
Chemotherapy (MEC)
AC/EC*
Highly Emetogenic
Chemotherapy (HEC)
MASCC/ESMO
Palonosetron recommendation
iii
Area Under the Curve
twice daily
continuous infusion
AUC
bid
CI
European Society for Medical Oncology
kgkilograms
IVintravenous
ITintrathecal
ggrams
ESMO
CTchemotherapy
MASCC
American Society of Clinical Oncology
ASCO
Multinational Association for
Supportive Care in Cancer
square meter
National Comprehensive Cancer Network
National Cancer Institute
NCCN
NCI
wksweeks
SCSubcutaneous
POoral
million units
MIU mgmilligrams
m2 5-HT35-Hydroxytryptamine3
Abbreviations
iv
Several international organizations have developed
evidence-based antiemetic guidelines. MASCC
(Multinational Association for Supportive Care in
Cancer) organization and ESMO (European Society
for Medical Oncology) have developed a rating
system for anticancer agents based on intrinsic
emetogenicity (risk of acute [within the first 24 hours
after chemotherapy administration] emesis without
concomitant antiemetic treatment) of the individual
agents I. Several organizations, such as ASCO (American
Society of Clinical Oncology), and NCCN (National
Comprehensive Cancer Network), have also adopted
this classification system for developing guidelines for
antiemetics in oncology II-III. Intravenous agents have
been classified across four broad emetic risk categories:
high, moderate, low, and minimal. Since oral agents are
more commonly dispensed on multiple-day schedules,
careful observation of overall emetogenicity without a
distinction between acute and delayed (more than 24
hours after chemotherapy administration) emesis may
represent the only valid method of risk assessment
for such agents. Therefore, the MASCC consensus
conference has proposed a separate listing of oral
agents I. It also should be noted that considerable
uncertainty prevails for the emetogenic risk of oral
agents. In general, emetogenicity of oral agents has
been classified based on that of a full course of therapy
as clinically employed IV.
The intrinsic emetogenicity of a given anticancer agent
should serve as the primary consideration in guiding
decision about antiemetic prophylaxis. However, the
classification system based on this characteristic retains
some limitations. The classification of chemotherapeutic
agents is based on the risk of acute emesis and,
therefore, it may underestimate the potential of
delayed emesis resulting from certain agents. In
addition to emetogenicity, the dose and schedule
used are also very important factors. For example, an
agent with a low emetic risk given in high doses may
cause a dramatic increase in the potential to induce
emesis. Further important factors to consider are the
use of combination chemotherapy regimens (see also
emetogenicity of combination chemotherapy regimens
in this tool), and specific patient characteristics.
Emetogenicity of anticancer agents:
background
v
The NCCN guidelines also include newer agents
that have been listed in Tables 1 and 2. Of note,
Table 2 endeavors to reconcile the latest version of
classification schemes for oral agents devised from
both MASCC/ESMO and NCCN.
Combination chemotherapy regimens used in the
treatment of most non-hematologic malignancies
are most frequently administered intravenously
over the course of a single day. Often, the most
emetic agents are given only on day 1.
The decision about the optimal prophylaxis should
be guided by two considerations: the emetic risk of
the regimen and whether there is a substantial risk
of delayed nausea and vomiting. It is also important
to consider that, in patients receiving single-day
chemotherapy, combination regimens may achieve
a higher emetic risk than that of any single included
agent. The combination of an anthracycline and
cyclophosphamide (AC) is frequently used to treat
a large group of cancer patients, most typically
women with breast cancer. Women receiving the
AC chemotherapy represent a situation with a
particularly high emetic potential II-IV.
Patient-related factors, such as female gender
(increased risk), age younger than 50 years
(increased risk), and history of no significant
ethanol consumption (increased risk) should be
also taken into account in assessing emetic risk of
a given regimen. This approach may allow tailoring
the appropriate anti-emetic regimen to individual
patients who could benefit from extended or brief
anti-emetic coverage.
Emetogenicity of combination chemotherapy
regimens: key issues
In the present tool, the emetogenicity of the individual
intravenous and oral agents listed, respectively, in
Table 1 and 2 has been classified according to the
latest version of the MASCC/ESMO, ASCO and NCCN
guidelines I-IV.
vi
Female gender
Exposure to previous chemotherapy lines
Uncontrolled/poorly controlled CINV in prior
chemotherapy lines
Poor control of acute CINV in current chemotherapy
cycle
History of nausea in pregnancy
Administration of other emetic drugs [*] concurrently
with cancer chemotherapy
Younger age [<50 years]
Female gender
Exposure to previous chemotherapy lines
Uncontrolled/poorly controlled CINV during previous
chemotherapy lines
Poorly controlled CINV symptoms in prior cycles of
the current chemotherapy line
History of motion sickness
Logistics: inpatients vs outpatients
Treatment with multiple-day chemotherapy regimens
Hystory of low or no alcohol assumption
Anxiety
[*] Intravenous antibiotics and/or anti-fungals, opioids/opioids patch, anti-depressants, ergot alkaloids, amifostine, bisphosphonates,
non-steroidal anti-inflammatory drugs
Patient perspective: expectation of CINV
Depression
Anxiety
History of nausea in pregnancy
Administration of other emetic drugs [*] concurrently Patient perspective: expectation of CINV
with cancer chemotherapy
Delayed CINV
Acute CINV
Patient-related Risk Factors for chemotherapy induced nausea and vomiting (CINV)V
vii
The NCCN guidelines recommend palonosetron
as the preferred 5-HT3 receptor antagonist in the
setting of both HEC and MECIV. The recently updated
MASCC/ESMO and ASCO guidelines recommend
anti-emetic prophylaxis consisting of palonosetron
plus dexamethasone before MECII,IV. In particular,
the MASCC/ESMO guidelines also recommend that
women undergoing AC-containing chemotherapy
should receive palonosetron when a NK1 receptor
antagonist is not availableIV.
Some chemotherapy regimens are administered on
multiple, consecutive days. There has been limited
progress in the prophylaxis of nausea and emesis in
patients receiving multiple-day chemotherapy, such as
consecutive-day administration of cisplatin. Current
MASCC/ESMO guidelines recommend that patients
receiving multiple-day cisplatin should receive a
5-HT3 receptor antagonist plus dexamethasone for
acute nausea and vomiting and dexamethasone for
delayed symptomsIV. The latest version of the NCCN
guidelines suggests that palonosetron may be used
prior to the start of a 3-day chemotherapy regimen,
instead of multiple daily doses of older 5-HT3 receptor
antagonistsIII.
The emetic risk of combination chemotherapy
regimens commonly used in the treatment of nonhematologic and hematologic malignancies has been
shown in Tables 3 and 4-5, respectively. It is important
to note that the tables do not intend to be an
exhaustive compendium of chemotherapy regimens
used in the treatment of cancer patients. Only
regimens considered to induce a substantial (high to
moderate) risk of emesis have been reported in the
two tables. Please, consult international treatment
guidelines by tumor type for any unreported regimen,
as well as the reference section for dosing schedules
of the individual regimens listed in Tables 3, 4 and 5.
It is important to remember that the present
tool should be only used to guide decisions
about antiemetic prophylaxis, and not as a
decision tool for the selection of anticancer
therapy.
viii
I. Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity –
state of the art. Supp Care Cancer 2011; 19(suppl 1):S43-S47 available at: www.mascc.org
II.Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin
Oncol 2011; 29:4189-4198.
III.NCCN Guidelines for Supportive Care: Antiemesis v.1.2012 at www.nccn.org Accessed on November 4, 2011.
IV.Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21(suppl 5):v232-v243 available at:
www.mascc.org
V.Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J 2008;14:85-93.
REFERENCES
ix
Single anticancer agents
Single anticancer agents
Emetogenicity of
Agent
- Carmustine
- Cisplatin
- Cyclophosphamide ≥1,500 mg/m2
- Dacarbazine
- Dactinomycin
- Mechlorethamine
- Streptozotocin
- Aldesleukin >12-15 MIU/m2
- Alemtuzumab
- Amifostine >300 mg/m2
- Arsenic trioxide
- Azacitidine
- Bendamustine
- Busulfan
- Carboplatin
- Clofarabine
- Cyclophosphamide <1,500 mg/m2
- Cytarabine >1,000 mg/m2
- Daunorubicin
- Doxorubicin
- Epirubicin
Emetic risk category
High
(>90% of patients experiencing emesis in the
absence of antiemetic prophylaxis)
Moderate
(30-90% of patients experiencing emesis in
the absence of antiemetic prophylaxis)
- Idarubicin
- Ifosfamide
- Interferon alpha ≥10 MIU/m2
- Irinotecan
- Melphalan
- Oxaliplatin
- Temozolomide
Table 1. Emetogenicity of single intravenous anticancer agents
Palonosetron
recommendation (*)
- Asparaginase
- Bevacizumab
- Bleomycin
- Busulfan
- Cladribine (2-chlorodeoxyadenosine)
- Cytarabine <100 mg/m2
- Decitabine
- Denileukin diftitox
- Dexrazoxane
- Fludarabine
- Interferon alpha ≤5 MIU/m2
Minimal
(<10% of patients experiencing emesis in the
absence of antiemetic prophylaxis)
Single anticancer agents
(*) Refer to page ii
- Amifostine ≤300 mg/m2
- Aldesleukin ≤12 MIU/m2
- Bortezomib
- Cabazitaxel
- Catumaxumab
- Cetuximab
- Cytarabine ≤ 1,000 mg/m2
- Docetaxel
- Doxorubicin (liposomal)
-Eribulin
- Etoposide
- Fluorouracil
- Floxuridine
- Gemcitabine
- Interferon alpha >5 to <10 MIU/m2
- Ixabepilone
Low
(10-30% of patients experiencing emesis in
the absence of antiemetic prophylaxis)
- Ipilimumab
- Nelarabine
- Pegaspargase
- Peginterferon
- Pralatrexate
- Rituximab
- Valrubicin
- Vinblastine
- Vincristine
- Vinorelbine
- Methotrexate
- Mitomycin
- Mitoxantrone
- Paclitaxel
- Paclitaxel-albumin
- Panitumumab
- Pemetrexed
- Pentostatin
- Romidepsin
- Temsirolimus
- Thiotepa
- Topotecan
- Trastuzumab
- Altretamine
- Busulfan ≥4 mg/day
- Cyclophosphamide ≥100 mg/m2/day
- Estramustine
- Imatinib
- Lomustine (single day)
- Procarbazine
- Temozolomide >75 mg/m2/day
- Vinorelbine
- Bexarotene
- Busulfan <4 mg/day
- Capecitabine
- Chlorambucil
- Cyclophosphamide <100 mg/m2/day
- Dasatinib
- Erlotinib
- Etoposide
- Everolimus
- Fludarabine
- Gefitinib
- Hydroxyurea
- Lapatinib
- Lenalidomide
- Melphalan
High to Moderate
(>90% to 30% of patients experiencing
emesis in the absence of antiemetic
prophylaxis)
Low to Minimal
(30% to <10% of patients experiencing
emesis in the absence of antiemetic
prophylaxis)
(*) Refer to page ii
Prophylaxis when necessary
Prophylaxis recommended
Agent
Emetic risk category
- Mercaptopurine
- Methotrexate
- Nilotinib
- Pazopanib
- Sorafenib
- Sunitinib
- Tegafur uracil
- Temozolomide ≤75 mg/m2/day
- Thalidomide
- Thioguanine
- Topotecan
- Tretinoin
- Vandetanib
- Vorinostat
Table 2. Emetogenicity of single oral anticancer agents
Palonosetron
recommendation (*)
Solid tumors
used in the treatment of
solid tumors
Combination CT regimens
Emetogenicity of
Agent/dose (mg/m2)/route
Doxorubicin/75/IV
Cyclophosphamide/600/IV
Methotrexate/40/IV
Fluorouracil/600/IV
Doxorubicin/60/IV
Cyclophosphamide/600/IV
Doxorubicin/60/IV
Cyclophosphamide/600/IV
Docetaxel/100/IV
Doxorubicin/60/IV
Cyclophosphamide/600/IV
Paclitaxel/80/IV
Doxorubicin/60/IV
Cyclophosphamide/600/IV
Paclitaxel/175/IV
Doxorubicin/50/IV
Docetaxel/75/IV
Doxorubicin/50/IV
Paclitaxel/125-220/IV
Bleomycin/30 Units/IV
Etoposide/100 day/IV
Cisplatin/20 day/IV
Regimen (reference)
A followed by CMF
[1]
AC
[2]
AC followed by D
[3]
AC followed by T
[3]
Dose-dense AC followed by T
[4]
AD
[5]
AT
[6]
BEP
[7]
3 (days 1,8,15)
5 (days 1-5)
5 (days 1-5)
1
1
1
1
1
1
1
1
1
(weekly for 12 wks)
1
1
1
1
1
1
1
1
1
Days of administration
in a single cycle
Cisplatin
Doxorubicin
Doxorubicin
Cyclophosphamide
Doxorubicin
Cyclophosphamide
Doxorubicin
Cyclophosphamide
Doxorubicin
Cyclophosphamide
Doxorubicin
Cyclophosphamide
Doxorubicin
Most emetogenic
agent
Moderate
Moderate
Moderate
High for AC
Low for T
High for AC
Low for T
High for AC
Low for D
High
Moderate for A
Moderate for CMF
Emetic risk
of the regimen (*)
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
Palonosetron
recommendation (**)
Table 3. Emetic risk of combination CT regimens used in the treatment of
solid tumors (regimens listed in alphabetical order)
1
1
1
1
Cyclophosphamide/1000/IV
Doxorubicin/45/IV
Vincristine/1.4/IV
Carboplatin/AUC5-6/IV
Docetaxel/60-75/IV
Carboplatin/AUC5-6/IV
Etoposide/100 day/IV
Carboplatin/AUC5/IV
Irinotecan/50/IV
Paclitaxel/200/IV
Carboplatin/AUC6/IV
Paclitaxel/175/IV
Carboplatin/AUC6/IV
Cyclophosphamide/75 day/PO
Epirubicin/60/IV
Fluorouracil/500/IV
Cisplatin/80/IV
Capecitabine/2000 day/PO
CAV
[10]
Carbo+Docetaxel
[11]
Carbo+Etoposide
[12]
Carbo+Irinotecan
[13]
Carbo+Paclitaxel±
Bevacizumab
[14]
Carbo+Paclitaxel+
Trastuzumab
[15]
CEF
[16]
Cis+Capecitabine
[17]
Cisplatin
Cyclophosphamide
Epirubicin
Carboplatin
Carboplatin
Carboplatin
Irinotecan
Carboplatin
Carboplatin
Cyclophosphamide
Doxorubicin
Oxaliplatin
Cyclophosphamide
Doxorubicin
High
High
Moderate
Moderate
Moderate
Moderate
Moderate
High
Moderate
High
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
Solid tumors
(*) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence
(**) Refer to page ii
1
14 (days 1-14)
14 (days 1-14)
2 (days 1,8)
2 (days 1,8)
1
3 (days 1,8,15)
1
3 (days 1-3)
1
1
1
1
1
14 (days 1-14)
1
Capecitabine/2000 day/PO
Oxaliplatin/130/IV
CapOx±Bevacizumab
[9]
14 (days 1-14)
2 (days 1,8)
2 (days 1,8)
Cyclophosphamide/100 day/PO
Doxorubicin/30/IV
Fluorouracil/500/IV
CAF
[8]
Agent/dose (mg/m2)/route
Cisplatin/100/IV
Cisplatin/75/IV
Docetaxel/75/IV
Cisplatin/50/IV
Doxorubicin/60/IV
Cisplatin/80/IV
Etoposide/100 day/IV
Cisplatin/25 day/IV
Etoposide/100 day/IV
Cisplatin/100/IV
Fluorouracil/1000 day/CI
Cisplatin/75/IV
Gemcitabine/1250/IV
Cisplatin/25/IV
Gemcitabine/1000/IV
Cisplatin/60/IV
Irinotecan/60/IV
Cisplatin/75/IV
Paclitaxel/175/IV
Cisplatin/75/IV
Pemetrexed/500/IV
Cisplatin/80/IV
Vinorelbine/25/IV
Regimen (reference)
Cis+Cetuximab
[18]
Cis+Docetaxel
[19]
Cis+Doxorubicin
[20]
Cis+Etoposide
[21]
Cis+Etoposide
[22]
Cis+Fluorouracil
[23]
Cis+Gemcitabine
[24]
Cis+Gemcitabine
[25]
Cis+Irinotecan
[26]
Cis+Paclitaxel
[27]
Cis+Pemetrexed
[24]
Cis+Vinorelbine
[28]
1
2 (days 1,8)
1
1
1
1
1
3 (days 1,8,15)
1
2 (days 1,8)
1
2 (days 1,8)
1
5 (days 1-5)
3 (days 1-3)
3 (days 1-3)
1
3 (days 1-3)
1
1
1
1
1
Days of administration
in a single cycle
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Cisplatin
Most emetogenic
agent
High
High
High
High
Moderate
High
High
Moderate
High
High
High
High
Emetic risk
of the regimen (*)
Palonosetron
recommendation (**)
Cyclophosphamide/100 day/PO
Methotrexate/40/IV
Fluorouracil/600/IV
Docetaxel/75/IV
Cyclophosphamide/600/IV
Docetaxel/75/IV
Carboplatin/AUC6/IV
Docetaxel/75/IV
Cisplatin/75/IV
Fluorouracil/750 day/CI
Epirubicin/75/IV
Cyclophosphamide/600/IV
Epirubicin/50/IV
Cisplatin/60/IV
Fluorouracil/200 day/CI
Epirubicin/50/IV
Cisplatin/60/IV
Capecitabine/1250 day/PO
Epirubicin/50/IV
Oxaliplatin/130/IV
Capecitabine/1250 day/PO
CMF
[30]
DC
[31]
DC+Trastuzumab
[32]
DCF
[23]
EC
[33]
ECF
[34]
ECX
[34]
EOX
[34]
1
1
21 (days 1-21)
1
1
21 (days 1-21)
1
1
21 (days 1-21)
High
Moderate
Epirubicin
Oxaliplatin
High
High
High
Moderate
Moderate
Moderate
Moderate
Cisplatin
Cisplatin
Cyclophosphamide
Epirubicin
Cisplatin
1
1
5 (days 1-5)
1
1
Carboplatin
Cyclophosphamide
Cyclophosphamide
Cisplatin
Ifosfamide
1
1
1
1
14 (days 1-14)
2 (days 1,8)
2 (days 1,8)
4 (days 1-4)
4 (days 1-4)
MASCC’s recommendation
when a NK1 is not available
Solid tumors
(*) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence
(**) Refer to page ii
Cisplatin/20 day/IV
Ifosfamide/1500 day/IV
(Mesna/IV)
CIM
[29]
Agent/dose (mg/m2)/route
Epirubicin/75/IV
Paclitaxel/200/IV
Fluorouracil/500/IV
Doxorubicin/50/IV
Cyclophosphamide/500/IV
Fluorouracil/500/IV
Epirubicin/100/IV
Cyclophosphamide 500/IV
Fluorouracil/500/IV
Epirubicin/100/IV
Cyclophosphamide/500/IV
Docetaxel/100/IV
Fluorouracil/400/IV
Leucovorin/400/IV
Fluorouracil/1200 day/CI
Irinotecan/180/IV
Fluorouracil/400 day/IV
Leucovorin/200 day/IV
Fluorouracil/600 day/CI
Oxaliplatin/85/IV
Irinotecan/165/IV
Oxaliplatin/85/IV
Fluorouracil/400 day/IV
Leucovorin/200/IV
Fluorouracil/1600 day/CI
Gemcitabine/1000/IV
Oxaliplatin/130/IV
Regimen (reference)
ET
[33]
FAC
[35]
FEC
[36]
FEC followed by D
[36]
FOLFIRI±
a] Bevacizumab
b] Cetuximab
[37]
FOLFOX-4±
a] Bevacizumab
b] Cetuximab
[38]
FOLFOXIRI
[39]
GEMOX
[40]
Oxaliplatin
Moderate
Moderate
Irinotecan
Oxaliplatin
1
1
1
1
2 (days 1,2)
2 (days 1,8)
1
Moderate
Moderate
High for FEC
Low for D
High
High
Moderate
Emetic risk
of the regimen (*)
Oxaliplatin
Irinotecan
Cyclophosphamide
Epirubicin
Cyclophosphamide
Epirubicin
Cyclophosphamide
Doxorubicin
Epirubicin
Most emetogenic
agent
2 (days 1,2)
2 (days 1,2)
2 (days 1,2)
1
1
1
2 (days 1,2)
1
1
1
1
1
1
1
1
2 (days 1,8)
1
1
1
1
Days of administration
in a single cycle
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
MASCC’s recommendation
when a NK1 is not available
Palonosetron
recommendation (**)
Cyclophosphamide
Doxorubicin
1
1
1
Docetaxel/75/IV
Doxorubicin/50/IV
Cyclophosphamide/500/IV
Paclitaxel/160/IV
Doxorubicin/45/IV
Cisplatin/50/IV
Paclitaxel/250/IV
(Mesna/IV)
Ifosfamide/1500 day/IV
Cisplatin/25 day/IV
Vinblastine/0.11mg/kg day/IV
(Mesna/IV)
Ifosfamide/1200 day/IV
Cisplatin/20 day/IV
Etoposide/75 day/IV
(Mesna/IV)
Ifosfamide/1200 day/IV
Cisplatin/20 day/IV
TAC
[44]
TAP
[20]
TIP
[45]
VeIP
[46]
VIP
[47]
Cisplatin
Ifosfamide
Cisplatin
Ifosfamide
Cisplatin
Ifosfamide
Moderate
Moderate
Moderate
High
High
Moderate
Moderate
Moderate
MASCC’s recommendation
when a NK1 is not available
Solid tumors
(*) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence
(**) Refer to page ii
5 (days 1-5)
5 (days 1-5)
5 (days 1-5)
5 (days 1-5)
5 (days 1-5)
2 (days 1,2)
4 (days 2-5)
4 (days 2-5)
1
Cisplatin
Oxaliplatin
1
1
2 (days 1,2)
1
Fluorouracil/400/IV
Leucovorin/400/IV
Fluorouracil/1200 day/CI
Oxaliplatin/85/IV
mFOLFOX-6
[43]
1
1
1
Irinotecan
1
Irinotecan/350/IV
Ifosfamide
Irinotecan+Cetuximab
[42]
3 (days 1-3)
1
Ifosfamide/1600 day/IV
Paclitaxel/135/IV
(Mesna/IV)
Ifosfamide+
Paclitaxel
[41]
used in the treatment of
hematological malignancies
Hematological malignancies
Combination CT regimens
Emetogenicity of
High
High
Moderate
Moderate
High
Dacarbazine
Procarbazine
Bendamustine
Cyclophosphamide
Procarbazine
2 (days 1,15)
2 (days 1,15)
2 (days 1,15)
2 (days 1,15)
1
3 (days 1-3)
1
1
1
7 (days 1-7)
14 (days 1-14)
2 (days 1-2)
2 (days 2-3)
1
1
1
5 (days 1-5)
2 (days 1,8)
3 (days 1-3)
10 (days 1-10)
10 (days 1-10)
Doxorubicin/25/IV
Bleomycin/10 Units/IV
Vinblastine/6/IV
Dacarbazine/375/IV
Bleomycin/10 Units/IV
Etoposide/200 day/IV
Doxorubicin/35/IV
Cyclophosphamide/1250/IV
Vincristine/1.4/IV
Procarbazine/100 day/PO
Prednisone/40/IV
Bendamustine alone/100/IV
Bendamustine(+Rituximab)/90/IV
Cyclophosphamide/750/IV
Liposomal Doxorubicin/30/IV
Vincristine/1.4/IV
Prednisone/40 day/PO
Cyclophosphamide/600 day/IV
Etoposide/70 day/IV
Procarbazine/60 day/PO
Prednisone/60 day/PO
BEACOPP
(escalated-dose)
[52]
Bendamustine
±Rituximab
[53,54,55,56]
CDOP+Rituximab
[57]
CEPP
±Rituximab
[58]
ABVD
[51]
Emetic risk
of the regimen (*)
Moderate
Most emetogenic
agent
5-Azacitidine
5-Azacitidine/75/SC
Azacitidine
[48, 49, 50]
Days of administration
in a single cycle
7 (days 1-7)
Agent/dose (mg/m2)/route
Regimen (reference)
Palonosetron
recommendation(**)
Table 4. Emetic risk of combination CT regimens used in the treatment of
hematological malignancies (regimens listed in alphabetical order)
Cyclophosphamide/750/IV
Doxorubicin/50/IV
Vincristine/1.4/IV
Prednisone/40 day/PO
Cyclophosphamide/600/IV
Mitoxantrone/10/IV
Vincristine/1/IV
Prednisolone/40mg day/PO
Cyclophosphamide/800/IV
Vincristine/1.5/IV
Doxorubicin/40/IV
Cytarabine/70mg/IT
Cyclophosphamide/200 day/IV
Methotrexate/100-300/IV
Methotrexate/900-2700/IV
Leucovorin/15/IV
Methotrexate/12mg/IT
Leucovorin/15mg/PO
(alternating with IVAC, see below)
Cyclophosphamide/750 day/IV
Liposomal doxorubicin/50/IV
Vincristine/1.4/IV
Prednisone/40 day/PO
Cyclophosphamide/750 day/IV
Vincristine/1.4/IV
Prednisone/40 day/PO
CHOP
±Rituximab
[60]
CNOP
[61]
CODOX-M
(dose-modified)
[62]
COMP+Rituximab
[63,64]
CVP
±Rituximab
[65]
1
1
5 (days 1-5)
1
1
1
5 (days 1-5)
Cyclophosphamide
Cyclophosphamide
Liposomal
Doxorubicin
Cyclophosphamide
Doxorubicin
Methotrexate
Cyclophosphamide
1
1
1
5 (days 1-5)
1 (day 1)
2 (days 1,8)
1 (day 1)
2 (days 1,3)
4 (days 2-5)
1 (day 10)
1 (day 10)
(see reference)
1 (day 15)
1 (day 16)
Cyclophosphamide
Doxorubicin
Cyclophosphamide
1
1
1
5 (days 1-5)
3 (days 3-5)
3 (days 3-5)
3 (days 1,3,5)
Moderate
Moderate
High
Moderate
Moderate
Moderate
Hematological malignancies
(*) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence
(**) Refer to page ii
Cyclophosphamide/200 day/IV
Fludarabine/20 day/IV
Alemtuzumab/30/IV
CFA+Rituximab
[59]
Moderate
High
Cyclophosphamide
Doxorubicin
Cisplatin
Cytarabine
4 (days 1-4)
(daily)
4 (days 1-4)
4 (days 1-4)
4 (days 1-4)
4 (days 1-4)
3 (days 2-4)
14 (days 1-14)
3 (days 2-4)
1
3 (days 2-4)
4 (days 1-4)
4 (days 1-4)
1
4 (days 1-4)
Dexamethasone/40mg day/PO
Thalidomide/400mg day/PO
Cisplatin/10 day/CI
Doxorubicin/10 day/CI
Cyclophosphamide/400 day/CI
Etoposide/40 day/CI
Etoposide/65 day/CI
Prednisone/60 day/PO
Vincristine/0.5 day/CI
Cyclophosphamide/750/IV
Doxorubicin/15 day/CI
Etoposide/60 day/IV
Prednisolone/250-500mg day/IV
Cytarabine/2000/IV
Cisplatin/25 day/CI
Fludarabine/25 day/IV
Cyclophosphamide/250 day/IV
DT-PACE
[71]
EPOCH
±Rituximab
[72]
ESHAP
±Rituximab
[73]
FC +Rituximab
[74]
3 (days 1-3)
3 (days 1-3)
High
Cisplatin
Cyclophosphamide
Doxorubicin
4 (days 3-6)
1
1
Dexamethasone/40mg day/PO or IV
Cisplatin/100/CI
Cytarabine/2000 bid/IV
DHAP
±Rituximab
[70]
Cyclophosphamide
Cisplatin
3 (days 1-3)
Moderate
High
High
Decitabine
5 (days 1-5)
Decitabine/20/IV
or
Decitabine/15 thrice daily/IV
Decitabine
[67,68,69]
Moderate
Cisplatin
Cyclophosphamide
4 (days 1-4)
4 (days 1-4)
4 (days 1-4)
4 (days 1-4)
Dexamethasone/40mg day/IV
Cyclophosphamide/400 day/CI
Etoposide/40 day/CI
Cisplatin/10 day/CI
DCEP
[66]
Emetic risk
of the regimen (*)
Most emetogenic
agent
Days of administration
in a single cycle
Agent/dose (mg/m2)/route
Regimen (reference)
Palonosetron
Recommendation(**)
Fotemustine/120/IV
Gemcitabine/1000/IV
Oxaliplatin/100/IV
Gemcitabine/1200/IV
Oxaliplatin/120/IV
Gemcitabine/100/IV
Ifosfamide/5000/CI
Oxaliplatin/130/IV
Gemcitabine/1000/IV
Dexamethasone/40mg day/PO
Cisplatin/75/IV
Cycles 1, 3, 5, and 7:
Cyclophosphamide/300 bid/IV
(Mesna/IV)
Vincristine/2mg/IV
Doxorubicin/50/CI
Dexamethasone/40mg day/PO or IV
(alternating with high-dose
methotrexate and cytarabine)
Ifosfamide/5000/IV
(Mesna/IV)
Carboplatin/AUC5/IV
Etoposide/100 day/IV
Fotemustine
[76]
GEMOX +Rituximab
[77]
GEMOX +Rituximab
[78]
GIFOX +Rituximab
[79]
GDP
±Rituximab
[80]
HyperCVAD
±Rituximab
[81]
ICE
±Rituximab
[82]
1
1
1
3 (days 3-5)
2 (days 4,11)
1
8 (days 1-4, and 11-14)
3 (days 1-3)
2 (days 1,8)
4 (days 1-4)
1
1 (day 2)
1 (day 3)
1 (day 3)
2 (days 1,8)
1 (day 2)
1
1
1
3 (days 1-3)
3 (days 1-3)
1
Carboplatin
Ifosfamide
Cyclophosphamide
Doxorubicin
Cisplatin
Ifosfamide
Oxaliplatin
Oxaliplatin
Oxaliplatin
Fotemustine
Cyclophosphamide
Moderate
Moderate
High
Moderate
Moderate
Moderate
Moderate
Moderate
Hematological malignancies
(*) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence
(**) Refer to page ii
Fludarabine/25 day/IV
Cyclophosphamide/200 day/IV
Mitoxantrone/6/IV
FCM +Rituximab
[75]
4 (days 1-4)
2 (days 1,4)
1
4 (days 1-4)
Ifosfamide/2000 day/IV
Gemcitabine/800 day/IV
Vinorelbine/20/IV
Prednisolone/100mg day/PO or IV
Ifosfamide/1500 day/IV
Methotrexate/30/IV
Etoposide/100 day/IV
Prednisolone/120mg day/PO
Etoposide/60 day/IV
Ifosfamide/1000-1500 day/IV
(Mesna/IV)
Cytarabine/1000-2000 day/IV
Methotrexate/12mg/IT
Leucovorin/15mg/PO
(alternating with CODOX-M, see above)
Ifosfamide/3000 day/CIV 24 hrs
Epirubicin/50/IV
Etoposide/200/IV
(Mesna/IV)
Ifosfamide/1330 day/IV
Mitoxantrone/8/IV
Etoposide/65 day/IV
Carmustine/60/IV
Cytarabine/100 bid/IV
Etoposide/75 day/IV
Melphalan/30/IV
Pentostatin/4/IV
Cyclophosphamide/600/IV
IGEV
[84]
IMEP
[85]
IVAC
[62]
IVE
[86]
MINE
±Rituximab
[87]
Mini-BEAM
[88]
PC+Rituximab
[89]
1
1
1
4 (days 2-5)
4 (days 2-5)
1
3 (days 1-3)
1
3 (days 1-3)
3 (days 1-3)
1
3 (days 1-3)
2 (days 1-2)
1 (day 5)
1 (day 6)
5 (days 1-5)
5 (days 1-5)
3 (days 1-3)
2 (days 3,10)
3 (days 1-3)
5 (days 1-5)
3 (days 1-3)
1
3 (days 1-3)
Ifosfamide/2500 day/IV
Epirubicin/100/IV
Etoposite/150/IV
IEV
[83]
Days of administration
in a single cycle
Agent/dose (mg/m2)/route
Regimen (reference)
Cyclophosphamide
Carmustine
Melphalan
Ifosfamide
Ifosfamide
Epirubicin
Cytarabine
Ifosfamide
Ifosfamide
Ifosfamide
Ifosfamide
Epirubicin
Most emetogenic
agent
Moderate
High
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Emetic risk
of the regimen (*)
Palonosetron
Recommendation(**)
Clofarabine/40 or 30/IV
Clofarabine/40/IV
Cytarabine/1000/2-hour IV
Clofarabine
[95]
Clofarabine + Cytarabine
[96]
Clofarabine
Cytarabine
Clofarabine
Moderate
Moderate
Hematological malignancies
(*) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence
(**) Refer to page ii
5 (days 2-6)
5 (days 1-5)
5 (days 1-5)
Moderate
Cytarabine
Fludarabine/30/IV
Cytarabine/2000/4-hour IV
G-CSF 5 μg/kg body weight SC
FLAG
[94]
Moderate
5 (days 1-5)
5 (days 1-5)
6 (-1-5)
Cytarabine/1000-3000/ IV/q 12 hours
High dose Cytarabine
[92,93]
Idarubicin
Moderate
High
3 (days 1-3)
7 (days 1-7)
Idarubicin/12/IV
Cytarabine /100 day/CI
Idarubicin +
Cytarabine
[92]
Daunorubicin
Cytarabine (200)
Moderate
Bendamustine
Cytarabine
3 (days 1-3)
7 (days 1-7)
Daunorubicin/45-50 to 90/IV
Cytarabine /100 or 200 day/CI
Daunorubicin +
Cytarabine
[92]
High
Mechloretamine
3 to 6 (days 1-3 or 1-6)
1, 8, 15, 22
1, 2
(see referece)
Bortezomib/1.6/IV
Bendamustine/90/IV
VB+Rituximab
[91]
1 (on wks 1,3,5,7,9,11)
1 (on wks 1,3,5,7,9,11)
1 (on wks 2,4,6,8,10,12)
1 (on wks 2,4,6,8,10,12)
1 (on wks 1,5,9)
1 (on wks 3,7,11)
(see reference)
Chemo given weekly for 12 wks:
Vinblastine/6/IV
Doxorubicin/25/IV
Vincristine/1.4/IV
Bleomycin/5 Units/IV
Mechloretamine/6/IV
Etoposide/60 bid/IV
Prednisone/40/PO
Stanford V
[90]
Autologous and allogeneic stem cell transplantation
are increasingly been adopted in the management of
several hematopoietic malignancies, severe genetic
disorders and selected solid tumors. Unfortunately, only
a slight minority of patients, about 20%, is completely
protected from nausea and vomiting associated to pretransplant conditioning chemotherapy .
There are multiple factors leading to such
unfavorable picture that are related to both the
design of conditioning regimens and the peculiar
clinical profile of patients undergoing stem cell
transplantation. Conditioning regimens typically
consist of single, but more frequently, multiple agents
given at very high doses over a multi-day schedule
of 2 to 7 days. All drugs are highly emetogenic as
single agents at the employed doses and their use
in combination over several days manifolds the
emetic risk of such regimens, with a special regard
to delayed emesis. Highly emetogenic total body
irradiation is sometimes utilized. The disruption of
gastrointestinal mucosa, a later event associated to
high dose conditioning, further enhances substance
P-related mechanisms of delayed nausea and
vomiting.
Patients undergoing conditioning had usually been
treated with at least two previous lines of highly and/
or moderately emetic chemotherapy, often through
a multi-day schedule, and are concomitantly been
given other emetogenic agents including multiple
intravenous antimicrobial therapy and opioids. Such
patients also suffer from several psychological and
logistic conditions (anxiety, depression, isolation,
dietary restrictions, and sleep disturbances) further
promoting and sustaining severe emesis.
Given the unsatisfactory results of current antiemetic
prophylaxis, prevention of nausea and vomiting in
these patients represents a typical unmet medical
need. In this setting the major international guidelines
(such as: MASCC, ESMO, ASCO) committees were
still unable to release any formal recommendation.
High dose conditioning regimens for
hematopoietic stem cell transplantation
Hematological malignancies
• López-Jiménez J, Martín-Ballesteros E, Sureda A, et al. Chemotherapy-induced nausea and in acute leukemia and stem cell transplant
patients: results of a multicenter, observational study. Haematologica 2006; 91:84-91.
• Einhorn LH, Grunberg SM, Rapoport B, et al. Antiemetic therapy for multiple-day chemotherapy and additional topics consisting of
rescue antiemetics and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support Care Cancer
2011 Mar; 19 Suppl 1:S1-4.
REFERENCES
Bendamustine/200/IV
Etoposide/200/IV
Cytarabine/400/IV
Melphalan/140/IV
Busulphan/(4 mg/kg)/PO
Cyclophosphamide/(60 mg/kg)/IV
Busulphan/(3.2 mg/kg; q 6 hrs)/IV
Cyclophosphamide/(120 mg/kg)/IV
Busulphan/(0.8 mg/kg; q 6 hrs)/IV
Cyclophosphamide/(50 mg/kg)/IV
Etoposide/400/IV
BuCy
[101, 102, 103]
BuCy
[104]
BuCyE
[105]
High
High
Busulphan*
Cyclophosphamide*
Etoposide**
-7 to -5
-3 and -2
-5 and -4
High
High
Busulphan*
Cyclophosphamide*
Busulphan*
Cyclophosphamide*
Bendamustine*
Etoposide**
Cytarabine**
Melphalan**
-7 to -4
-3 and -2
-6 to -4
-2 to -1
-7 and -6
-5 to -2
-5 to -2
-1
-5 to -2
-5 to -2
-1
Etoposide/200/IV
Cytarabine/400/IV
Melphalan/140/IV
BeEAM
[100]
-6
High
Carmustine*
Melphalan**
Cytarabine**
Etoposide**
-7 and -6
Carmustine/150/IV
or
Carmustine/300/IV
BEAM
[97, 98, 99]
High
Carmustine*
Cyclophosphamide*
Cytarabine**
Etoposide**
-7
-6 to -3
-6 to -3
-6 to -3
Carmustine/300/IV
Etoposide/800/IV
Cytarabine/800/IV
Cyclophosphamide/(35 mg/kg)/IV
BEAC
[97, 98]
Emetic risk
of the regimen ( §)
Emetogenic potential
of single agents
(descending order)
Agent/dose (mg/m2)/route
Regimen (reference)
Days of administration
(day 0: stem cells
infusion)
Palonosetron
recommendation (†)
Table 5 Emetic risk of high-dose chemotherapy programs most widely used as
conditioning regimens for autologous stem cell transplantation (regimens listed
in alphabetical order)
Mitoxantrone/60/IV
Melphalan/180/IV
Thiotepa/300/IV
Busulphan/(9.6 mg/kg)/IV
Cyclophosphamide/2000/IV
Thiotepa/250/IV
Busulphan/(8 mg/kg)/IV
Cyclophosphamide/(60 mg/kg)/IV
Thiotepa/166/IV
Etoposide/250/IV
Carboplatin/266/IV
Mito-MEL
[110]
TBC
[111]
TBC
[112, 113]
TEC
[114]
High
High
High
High
Thiotepa*
Busulphan*
Cyclophosphamide**
Thiotepa*
Busulphan*
Cyclophosphamide**
Thiotepa*
Etoposide**
Carboplatin**
-8 and -7
-6 to -4
-3 to -2
-9 to -7
-6 to -4
-3 and -2
-6 to -4
-7 to -4
-6 to -4
High
Mitoxantrone*
Melphalan**
High-dose melphalan
-5
-2
-1 and -2
Hematological malignancies
(*) High emetic risk as a single agent at the indicated dose level
(**) Moderate emetic risk as a single agent at the indicated dose level
(§) Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic
potential of the individual agents and their sequence.
(†) Refer to page ii
Melphalan/100/IV
-5 to -2
-5 to -2
-1
Etoposide/200/IV
Cytarabine/400/IV
Melphalan/140/IV
Hi-MEL
[108, 109]
-6
High
Fotemustine*
Melphalan**
Cytarabine**
Etoposide**
-7 and -6
Fotemustine/150/IV
or
Fotemustine/300/IV
FEAM
[107]
High
Busulphan*
Cyclophosphamide*
Etoposide**
-7 to -5
-3 to -2
-3 to -2
Busulphan/(0.8 mg/kg; q 6 hrs)/IV
Cyclophosphamide/(60mg/kg)/civ
Etoposide/60mg/kg)/civ
BuCyVP
[106]
15.
14.
13.
12.
11.
10.
9.
8.
7.
6.
5.
3.
4.
2.
1.
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setron (as hydrochloride). Each vial of 5 ml of solution contains 250 micrograms palonosetron (as
hydrochloride). For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for
injection. Clear, colourless solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aloxi is indicated for • the prevention of acute nausea and vomiting associated with highly emetogenic
cancer chemotherapy in adults, • the prevention of nausea and vomiting associated with moderately
emetogenic cancer chemotherapy in adults. 4.2 Posology and method of administration Aloxi
should be used only before chemotherapy administration. This medicinal product should be administered by a healthcare professional under appropriate medical supervision. Posology Adults 250
micrograms palonosetron administered as a single intravenous bolus approximately 30 minutes before the start of chemotherapy. Aloxi should be injected over 30 seconds. The efficacy of Aloxi in the
prevention of nausea and vomiting induced by highly emetogenic chemotherapy may be enhanced
by the addition of a corticosteroid administered prior to chemotherapy. Elderly population No dose
adjustment is necessary for the elderly. Paediatric population The safety and efficacy in children have
not been established. Currently available data are described in section 5.1 and section 5.2, but no
recommendation on posology can be made. Hepatic impairment No dose adjustment is necessary
for patients with impaired hepatic function. Renal impairment No dose adjustment is necessary
for patients with impaired renal function. No data are available for patients with end stage renal
disease undergoing haemodialysis. Method of administration For intravenous use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings
and precautions for use As palonosetron may increase large bowel transit time, patients with a
history of constipation or signs of subacute intestinal obstruction should be monitored following
administration. Two cases of constipation with faecal impaction requiring hospitalisation have been
reported in association with palonosetron 750 micrograms. At all dose levels tested, palonosetron
did not induce clinically relevant prolongation of the QTc interval. A specific thorough QT/QTc study
was conducted in healthy volunteers for definitive data demonstrating the effect of palonosetron on
QT/QTc (see section 5.1). However, as for other 5-HT3 antagonists, caution should be exercised in the
concomitant use of palonosetron with medicinal products that increase the QT interval or in patients
STARTS
STRONG
1. NAME OF THE MEDICINAL PRODUCT Aloxi 250 micrograms solution for injection. 2. QUALILASTS
LONGEach ml of solution contains 50 micrograms palonoTATIVE AND
QUANTITATIVE COMPOSITION
SUMMARY OF PRODUCT
CHARACTERISTICS
who have or are likely to develop prolongation of the QT interval. Aloxi should not be used to prevent
or treat nausea and vomiting in the days following chemotherapy if not associated with another
chemotherapy administration. This medicinal product contains less than 1 mmol sodium (23 mg)
per vial, i.e. essentially ‘sodiumfree’. 4.5 Interaction with other medicinal products and other
forms of interaction Palonosetron is mainly metabolised by CYP2D6, with minor contribution by
CYP3A4 and CYP1A2 isoenzymes. Based on in vitro studies, palonosetron does not inhibit or induce
cytochrome P450 isoenzyme at clinically relevant concentrations. Chemotherapeutic agents In preclinical studies, palonosetron did not inhibit the antitumour activity of the five chemotherapeutic
agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C). Metoclopramide In a clinical study, no significant pharmacokinetic interaction was shown between a single
intravenous dose of palonosetron and steady state concentration of oral metoclopramide, which is
a CYP2D6 inhibitor. CYP2D6 inducers and inhibitors In a population pharmacokinetic analysis, it has
been shown that there was no significant effect on palonosetron clearance when co-administered
with CYP2D6 inducers (dexamethasone and rifampicin) and inhibitors (including amiodarone,
celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine,haloperidol, paroxetine, quinidine,
ranitidine, ritonavir, sertraline or terbinafine). Corticosteroids Palonosetron has been administered
safely with corticosteroids. Other medicinal products Palonosetron has been administered safely
with analgesics, antiemetic/antinauseants, antispasmodics and anticholinergic medicinal products.
4.6 Fertility, pregnancy and lactation For Palonosetron no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to
pregnancy, embryonal/foetal development, parturition or postnatal development. Only limited
data from animal studies are available regarding the placental transfer (see section 5.3). There is
no experience of palonosetron in human pregnancy. Therefore, palonosetron should not be used in
pregnant women unless it is considered essential by the physician. As there are no data concerning
palonosetron excretion in breast milk, breast-feeding should be discontinued during therapy. There
are no data concerning the effect of palonosetron on fertility. 4.7 Effects on ability to drive and
use machines No studies on the effects on the ability to drive and use machines have been performed. Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned
when driving or operating machines. 4.8 Undesirable effects In clinical studies at a dose of 250
micrograms (total 633 patients) the most frequently observed adverse reactions, at least possibly
related to Aloxi, were headache (9 %) and constipation (5 %). In the clinical studies the following
adverse reactions (ARs) were observed as possibly or probably related to Aloxi. These were classified
as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to <1/100). Very rare (<1/10,000) adverse reactions were reported post-marketing. Within each frequency grouping, adverse reactions are
presented below in order of decreasing seriousness.
Hypersensitivity
Immune system
disorders
Motion sickness, tinnitus
Tachycardia, bradycardia,
extrasystoles, myocardial
ischaemia, sinus tachycardia,
sinus arrhythmia,
supraventricular extrasystoles
Hypotension, hypertension,
vein discolouration, vein
distended
Hiccups
Dyspepsia, abdominal pain,
abdominal pain upper, dry
mouth, flatulence
Cardiac disorders
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Constipation
Diarrhoea
Eye irritation, amblyopia
Somnolence, insomnia,
paraesthesia, hypersomnia,
peripheral sensory
neuropathy
Nervous system
disorders
Ear and labyrinth
disorders
Anxiety, euphoric mood
Psychiatric disorders
Eye disorders
Hyperkalaemia, metabolic
disorders, hypocalcaemia,
hypokalaemia, anorexia,
hyperglycaemia, appetite
decreased
Metabolism and
nutrition disorders
Headache
Dizziness
Very rare ARs°
(<1/10,000)
System organ class Common ARs
Uncommon ARs
(≥1/100 to<1/10) (≥1/1,000 to <1/100)
Dermatitis allergic, pruritic rash
Arthralgia
Urinary retention, glycosuria
Asthenia, pyrexia, fatigue,
feeling hot, influenza like
illness
Elevated transaminases-,
electrocardiogram QT
prolonged
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Renal and urinary
disorders
General disorders
and administration
site conditions
Investigations
Injection site
reaction*
4.9 Overdose No case of overdose has been reported. Doses of up to 6 mg have been used in clinical
studies. The highest dose group showed a similar incidence of adverse reactions compared to the
other dose groups and no dose response effects were observed. In the unlikely event of overdose
with Aloxi, this should be managed with supportive care. Dialysis studies have not been performed,
however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment
for Aloxi overdose. 5.PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT3) antagonists. ATC
code: A04AA05 Palonosetron is a selective high-affinity receptor antagonist of the 5HT3 receptor.
In two randomised, double-blind studies with a total of 1,132 patients receiving moderately
emetogenic chemotherapy that included cisplatin ≤50 mg/m2, carboplatin, cyclophosphamide
≤1,500 mg/m2 and doxorubicin >25 mg/m2, palonosetron 250 micrograms and 750 micrograms
were compared with ondansetron 32 mg (half-life 4 hours) or dolasetron 100 mg (half-life 7.3
hours) administered intravenously on Day 1, without dexamethasone. In a randomised, doubleblind study with a total of 667 patients receiving highly emetogenic chemotherapy that included
cisplatin ≥ 60 mg/m2, cyclophosphamide > 1,500 mg/m2 and dacarbazine, palonosetron
250 micrograms and 750 micrograms were compared with ondansetron 32 mg administered
° From post-marketing experience
* Includes the following: burning, induration, discomfort and pain
Hyperbilirubinaemia
Hepatobiliary
disorders
97.5 % CI b
[1.8%, 22.8%]
[7.5%, 30.3%]
[7.4%, 30.7%]
p-value c
NS
0.001
0.001
p-value c
NS
NS
NS
b
a
Intent-to-treat cohort.
The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates
non-inferiority between Aloxi and comparator.
c
Chi-square test. Significance level at α=0.05.
Aloxi
Ondansetron
250 micrograms
32 milligrams
(n= 189)
(n= 185)
Delta
%
%
%
Complete Response (No Emesis and No Rescue Medication)
0 – 24 hours
81.0
68.6
12.4
24 – 120 hours
74.1
55.1
19.0
0 – 120 hours
69.3
50.3
19.0
Complete Control (Complete Response and No More Than Mild Nausea)
0 – 24 hours
76.2
65.4
10.8
24 – 120 hours
66.7
50.3
16.4
0 – 120 hours
63.0
44.9
18.1
No Nausea (Likert Scale)
0 – 24 hours
60.3
56.8
3.5
24 – 120 hours
51.9
39.5
12.4
0 – 120 hours
45.0
36.2
8.8
intravenously on Day 1. Dexamethasone was administered prophylactically before chemotherapy in
67 % of patients. The pivotal studies were not designed to assess efficacy of palonosetron in delayed
onset nausea and vomiting. The antiemetic activity was observed during 0-24 hours, 24-120 hours
and 0-120 hours. Results for the studies on moderately emetogenic chemotherapy and for the study
on highly emetogenic chemotherapy are summarised in the following tables. Palonosetron was
non-inferior versus the comparators in the acute phase of emesis both in moderately and highly
emetogenic setting. Although comparative efficacy of palonosetron in multiple cycles has not
been demonstrated in controlled clinical studies, 875 patients enrolled in the three phase 3 trials
continued in an open label safety study and were treated with palonosetron 750 micrograms for up
to 9 additional cycles of chemotherapy. The overall safety was maintained during all cycles.
Table 1: Percentage of patientsa responding by treatment group and phase in the
Moderately Emetogenic Chemotherapy study versus ondansetron
97.5 % CI b
[-1.7%, 21.9%]
[3.4 %, 27.1 %]
[0.3 %, 23.7 %]
p-value c
NS
0.018
0.027
p-value c
NS
0.001
0.014
b
Intent-to-treat cohort.
The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates
non-inferiority between Aloxi and comparator.
c
Chi-square test. Significance level at α=0.05.
a
Aloxi 250
Dolasetron 100
micrograms
milligrams (n=
(n= 185)
191)
Delta
%
%
%
Complete Response (No Emesis and No Rescue Medication)
0 – 24 hours
63.0
52.9
10.1
24 – 120 hours
54.0
38.7
15.3
0 – 120 hours
46.0
34.0
12.0
Complete Control (Complete Response and No More Than Mild Nausea)
0 – 24 hours
57.1
47.6
9.5
24 – 120 hours
48.1
36.1
12.0
0 – 120 hours
41.8
30.9
10.9
No Nausea (Likert Scale)
0 – 24 hours
48.7
41.4
7.3
24 – 120 hours
41.8
26.2
15.6
0 – 120 hours
33.9
22.5
11.4
Table 2: Percentage of patientsa responding by treatment group and phase in the
Moderately Emetogenic Chemotherapy study versus dolasetron
NS
NS
NS
p-value c
NS
NS
NS
97.5 % CI b
[-8.8%, 13.1%]
[-4.6%, 17.3%]
[-2.9%, 18.5%]
p-value c
The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were
comparable to ondansetron and dolasetron in CINV clinical studies. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarisation and
to prolong action potential duration. The effect of palonosetron on QTc interval was evaluated in a
double blind, randomised, parallel, placebo and positive (moxifloxacin) controlled trial in adult men
and women. The objective was to evaluate the ECG effects of IV administered palonosetron at single
doses of 0.25, 0.75 or 2.25 mg in 221 healthy subjects. The study demonstrated no effect on QT/QTc
interval duration as well as any other ECG interval at doses up to 2.25 mg. No clinically significant
b
a
Intent-to-treat cohort.
The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates
non-inferiority between Aloxi and comparator.
c
Chi-square test. Significance level at α=0.05.
Aloxi
Ondansetron
250 micrograms 32 milligrams
(n= 223)
(n= 221)
Delta
%
%
%
Complete Response (No Emesis and No Rescue Medication)
0 – 24 hours
59.2
57.0
2.2
24 – 120 hours
45.3
38.9
6.4
0 – 120 hours
40.8
33.0
7.8
Complete Control (Complete Response and No More Than Mild
Nausea)
0 – 24 hours
56.5
51.6
4.9
24 – 120 hours
40.8
35.3
5.5
0 – 120 hours
37.7
29.0
8.7
No Nausea (Likert Scale)
0 – 24 hours
53.8
49.3
4.5
24 – 120 hours
35.4
32.1
3.3
0 – 120 hours
33.6
32.1
1.5
Table 3: Percentage of patientsa responding by treatment group and phase in the Highly
Emetogenic Chemotherapy study versus ondansetron
changes were shown on heart rate, atrioventricular (AV) conduction and cardiac repolarisation. Paediatric population Prevention of Chemotherapy Induced Nausea and Vomiting (CINV): The safety and
efficacy of Palonosetron i.v at single doses of 3μg/kg and 10μg/kg was investigated in a clinical study
in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11 years (31
patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was the
proportion of patients with a complete response (CR, defined as no emetic episode and no rescue
medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after palonosetron 10 μg/kg compared to palonosetron 3μg/kg was 54.1% and 37.1% respectively.
Pharmacokinetic information is provided in section 5.2. Prevention of Post Operative Nausea and
Vomiting (PONV): The safety and efficacy of Palonosetron i.v at single doses of 1μg/kg and 3μg/kg
was compared in a clinical study in 150 patients in the following age groups, >28 days to 23 months
(7 patients), 2 to 11 years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective
surgery. No safety concerns were raised in either treatment group. The proportion of patients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 μg/kg or 3 μg/
kg (88% vs 84%). Please see section 4.2 for information on paediatric use. 5.2 Pharmacokinetic
properties Absorption Following intravenous administration, an initial decline in plasma concentrations is followed by slow elimination from the body with a mean terminal elimination half-life of
approximately 40 hours. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generally dose-proportional over the dose range of 0.3–90 μg/kg
in healthy subjects and in cancer patients. Following intravenous administration of palonosetron
0.25 mg once every other day for 3 doses in 11 testicular cancer patients, the mean (± SD) increase
in plasma concentration from Day 1 to Day 5 was 42 ± 34 %. After intravenous administration of palonosetron 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (± SD) increase in plasma
palonosetron concentration from Day 1 to Day 3 was 110 ± 45 %. Pharmacokinetic simulations indicate that the overall exposure (AUC0-∞) of 0.25 mg intravenous palonosetron administered once
daily for 3 consecutive days was similar to a single intravenous dose of 0.75 mg, although Cmax of
the 0.75 mg single dose was higher. Distribution Palonosetron at the recommended dose is widely
distributed in the body with a volume of distribution of approximately 6.9 to 7.9 l/kg. Approximately
62 % of palonosetron is bound to plasma proteins. Biotransformation Palonosetron is eliminated by
dual route, about 40 % eliminated through the kidney and with approximately 50 % metabolised
to form two primary metabolites, which have less than 1 % of the 5HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have shown thatCYP2D6 and to a lesser extent,
CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of palonosetron. However, clinical
pharmacokinetic parameters are not significantly different between poor and extensive metaboli-
sers of CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at
clinically relevant concentrations. Elimination After a single intravenous dose of 10 micrograms/kg
[14C]-palonosetron, approximately 80 % of the dose was recovered within 144 hours in the urine
with palonosetron representing approximately 40 % of the administered dose, as unchanged active substance. After a single intravenous bolus administration in healthy subjects the total body
clearance of palonosetron was 173 ± 73 ml/min and renal clearance was 53 ± 29 ml/min. The low
total body clearance and large volume of distribution resulted in a terminal elimination half-life in
plasma of approximately 40 hours. Ten percent of patients have a mean terminal elimination halflife greater than 100 hours. Pharmacokinetics in special populations Elderly Age does not affect the
pharmacokinetics of palonosetron. No dosage adjustment is necessary in elderly patients. Gender
Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary
based on gender. Paediatric population Across all age groups, (>28 days to 23 months (11 patients),
2 to 11 years (30 patients), and 12 to 17 years of age (29 patients)) of CINV paediatric patients, exposure to palonosetron was generally dose proportional for the 3μg/kg and 10μg/kg dose levels.
Both clearance and volume of distribution appear to increase with increasing age largely due to the
expected increase in body weight among the age groups. Mean terminal elimination half-life values
ranged from 21-37 hours and did not change with dose or age. There was no effect of gender on
clearance, volume of distribution or half-life. Please see section 4.2 for information on paediatric
use. Renal impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Severe renal impairment reduces renal clearance, however total
body clearance in these patients is similar to healthy subjects. No dosage adjustment is necessary
in patients with renal insufficiency. No pharmacokinetic data in haemodialysis patients are available. Hepatic impairment Hepatic impairment does not significantly affect total body clearance of
palonosetron compared to the healthy subjects. While the terminal elimination half-life and mean
systemic exposure of palonosetron is increased in the subjects with severe hepatic impairment, this
does not warrant dose reduction. 5.3 Preclinical safety data Effects in non-clinical studies were
observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Non-clinical studies indicate that palonosetron, only at very
high concentrations, may block ion channels involved in ventricular de- and re-polarisation and
prolong action potential duration. Animal studies do not indicate direct or indirect harmful effects
with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Only limited data from animal studies are available regarding the placental transfer (see section 4.6).
Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 30 times the
human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours,
endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but
not in mice. The underlying mechanisms are not fully understood, but because of the high doses employed and since Aloxi is intended for single application in humans, these findings are not considered
relevant for clinical use. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol,
Disodium edentate, Sodium citrate, Citric acid monohydrate, Sodium hydroxide (for pH adjustment),
Hydrochloric acid (for pH adjustment), Water for injections. 6.2 Incompatibilities This medicinal
product must not be mixed with other medicinal products. 6.3 Shelf life 5 years. Upon opening of
the vial, use immediately and discard any unused solution. 6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. 6.5 Nature and contents
of container Type I glass vial with chlorobutyl siliconised rubber stopper and aluminium cap. Available in packs of 1 vial containing 5 ml of solution. 6.6 Special precautions for disposal Single
use only, any unused solution should be discarded. Any unused product or waste material should be
disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Helsinn Birex Pharmaceuticals Ltd., Damastown, Mulhuddart - Dublin 15 – Ireland
8. MARKETING AUTHORISATION NUMBER
EU/1/04/306/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22 March 2005/23 March 2010
10. DATE OF REVISION OF THE TEXT
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.ema.europa.eu
All rights reserved. No part of this publication may be translated into other language, reproduced, stored in a retrieval system, or transmitted in any form or by any means - that is electronic,
mechanical, photocopying, recording or any other - without the prior permission in writing of Helsinn Healthcare SA and Sintesi InfoMedica.
May 2012
Published by Sintesi InfoMedica S.r.l.
via Ripamonti 89 – 20141 Milano (Italy)
Copyright © 2012 Helsinn Healthcare SA
via Pian Scairolo 9 – 6912 Pazzallo
PO BOX 357 – 6915 Pambio Noranco – Switzerland
This pocket guide is a summary of cancer therapeutic agents and regimens and of their emetogenicity according to the available evidences and guidelines. Although detailed, this pocket guide
is not intended or designed as an exhaustive review. No liability will be assumed by Helsinn Healthcare SA for the use of this pocket guide and the absence of errors, omissions, or inaccuracies
is not guaranteed. For detailed information on single agents, regimens, dosages, and indications, the reader is invited to consult drugs’ prescribing information as well as international literature
and guidelines.
We greatly acknowledge the work and contribution of Dr. Luigi Celio and Dr. Antonio Pinto.