AKYNZEO
®
(netupitant and palonosetron) capsules,for oral use
BRIEF SUMMARY OF PRESCRIBING INFORMATION
DOSAGE AND ADMINISTRATION
Highly Emetogenic Chemotherapy, including Cisplatin Based Chemotherapy
The recommended dosage in adults is one capsule ofAKYNZEO administered approximately 1 hour prior to the start of
chemotherapy with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 and 8 mg
orally once daily on days 2 to 4.
Anthracyclines and Cyclophosphamide Based Chemotherapy and Chemotherapy Not Considered Highly Emetogenic
The recommendeddosage inadults isonecapsuleofAKYNZEOapproximately1hourprior to thestartofchemotherapy
with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1. Administration of
dexamethasone on days 2 to 4 is not necessary.
AKYNZEO can be taken with or without food.
WARNINGS AND PRECAUTIONS
Hypersensitivity
: Hypersensitivity reactions, including anaphylaxis, have been reported with or without known
hypersensitivity to other 5-HT
3
receptor antagonists.
Serotonin Syndrome
:The development of serotonin syndrome has been reported with 5-HT
3
receptor antagonists.
Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake
inhibitors (SSRIs),serotoninandnorepinephrine reuptake inhibitors (SNRIs),monoamineoxidase inhibitors,mirtazapine,
fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin
syndrome occurring with overdose of another 5-HT
3
receptor antagonist alone has also been reported.The majority of
reports of serotonin syndrome related to 5-HT
3
receptor antagonist use occurred in a post-anesthesia care unit or an
infusion center.
Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental
status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Patientsshouldbemonitored for theemergenceofserotoninsyndrome,especiallywithconcomitantuseofAKYNZEOand
other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue AKYNZEO and initiate supportive
treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if AKYNZEO is used
concomitantly with other serotonergic drugs.
ADVERSE REACTIONS
Clinical Trials Experience
: Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The overall safety ofAKYNZEO was evaluated in 1538 cancer patients and healthy volunteers in clinical trials.The data
described below reflect exposure to AKYNZEO in 1169 cancer patients, receiving at least one cycle of cancer
chemotherapy in 3 active-controlled trials, including 782 exposed toAKYNZEO for at least 4 cycles and 321 exposed for
at least6cycles,up toamaximumof12cyclesofchemotherapy.Themedianagewas55,79%were female,83%were
White,13% wereAsian,and 4% were Hispanic.All patients received a single oral dose ofAKYNZEO 1 hour prior to the
start of each chemotherapy cycle. In all studies,dexamethasone was co-administered withAKYNZEO.
Cisplatin Based Highly Emetogenic Chemotherapy: In a single-cycle study of patients receiving cisplatin-based highly
emetogenic chemotherapy, 136 patients were treated with AKYNZEO. Table 1 shows adverse reactions defined as
adverse events reported at an incidence of at least 3% and for which theAKYNZEO rate exceeded palonosetron alone.
Table 1: Adverse Reactions Occurring in
≥
3% of Cancer Patients Receiving AKYNZEO and Cisplatin
Based Highly Emetogenic Chemotherapy (Cycle 1)
Adverse Reactions
AKYNZEO
netupitant 300 mg/ palonosetron 0.5 mg (N=136)
Palonosetron 0.5 mg
(N=136)
Dyspepsia
4%
2%
Fatigue
4%
2%
Constipation
3%
1%
Erythema
3%
2%
Anthracyclines and Cyclophosphamide Based Chemotherapy: In a study of patients receiving anthracycline and
cyclophosphamide based chemotherapy, 725 patients were treated with AKYNZEO during Cycle 1, and 635 of these
patients continued for up to 8 cycles in a multiple-cycle extension.Table 2 shows adverse reactions defined as adverse
events reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone during
Cycle 1.The adverse reaction profile in subsequent cycles was similar to that observed in Cycle 1.
Table 2: AdverseReactionsOccurringin
≥
3%ofCancerPatientsReceivingAKYNZEOandAnthracyclines
and Cyclophosphamide Based Chemotherapy (Cycle 1)
Adverse Reactions
AKYNZEO
netupitant 300 mg/ palonosetron 0.5 mg (N=725)
Palonosetron 0.5 mg
(N=725)
Headache
9%
7%
Asthenia
8%
7%
Fatigue
7%
5%
In addition to the adverse reactions shown above, there were reports of concomitant elevations of transaminases
> 3 x ULN and total bilirubin in both arms of the two trials that compared AKYNZEO to oral palonosetron, and the
frequency of these elevations was comparable between treatment groups.SeeTable 3.
Table 3: Liver Function Laboratory Abnormalities
Laboratory Changes
AKYNZEO
netupitant 300 mg/palonosetron 0.5 mg (N=861)
Palonosetron 0.5 mg
(N=861)
AST > 3 x ULN and/or
ALT > 3 x ULN with
Total Bilirubin > ULN
3 (0.3%)
5 (0.6%)
AST > 10 x ULN and/or
ALT > 10 x ULN with
Total Bilirubin > ULN
−
2 (0.2%)
AST > 3 x ULN and/or
ALT > 3 x ULN with
Total Bilirubin
≥
2 x ULN
1 (0.1%)
1 (0.1%)
In a multi-cycle safety study of 412 patients, the safety profile ofAKYNZEO (n = 308) was comparable to aprepitant and
palonosetron (n = 104) in patients undergoing initial and repeat cycles (median 5 cycles, range of 1-14 cycles) of
chemotherapy, including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens. There were no reports of
concomitant elevations of transaminases > 3 x ULN and total bilirubin in this study in either arm.
In a randomized, clinical non-inferiority study, that compared oral palonosetron 0.5 mg to intravenous palonosetron
0.25 mg in cancer patients scheduled to receive highly emetogenic cisplatin (
≥
70 mg/m
2
) based chemotherapy, there
were twopatients (0.5%;2/369) in the intravenouspalonosetronarmwhohadconcomitantelevationsof transaminases
and total bilirubin.Neither experienced transaminase elevations of > 10 x ULN.
DRUG INTERACTIONS
Effects of AKYNZEO on other drugs
Interaction with CYP3A4 substrates:
Netupitant,a component ofAKYNZEO is a moderate inhibitor of CYP3A4.
AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily metabolized
throughCYP3A4.TheplasmaconcentrationsofCYP3A4substratescan increasewhenco-administeredwithAKYNZEO.
The inhibitory effect on CYP3A4 can last for multiple days.
Dexamethasone:A two-fold increase in thesystemicexposureofdexamethasonewasobserved4daysaftersingledose
of netupitant.The duration of the effect was not studied beyond 4 days.Administer a reduced dose of dexamethasone
withAKYNZEO.
Midazolam: When administered with netupitant, the systemic exposure to midazolam was significantly increased.
Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized
via CYP3A4 (alprazolam, triazolam) when administering these drugs withAKYNZEO.
Interactionwithchemotherapeuticagents:ThesystemicexposureofchemotherapyagentsmetabolizedbyCYP3A4can
increasewhenadministeredwithAKYNZEO.Chemotherapyagents thatareknown tobemetabolizedbyCYP3A4 include
docetaxel, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, and
vincristine. Caution and monitoring for chemotherapeutic related adverse reactions are advised in patients receiving
chemotherapy agents metabolized primarily by CYP3A4.
Interaction with oral contraceptives: Clinically significant effect of AKYNZEO on the efficacy of the oral contraceptive
containing levonorgestrel and ethinyl estradiol is unlikely.
Effects of other drugs on AKYNZEO
Netupitant,a component ofAKYNZEO is mainly metabolized by CYP3A4.
In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in
the metabolism of palonosetron.
CYP3A4 Inducers:Avoid concomitant use of AKYNZEO in patients who are chronically using a strong CYP3A4 inducer
such as rifampin. A strong CYP3A inducer can decrease the efficacy of AKYNZEO by substantially reducing plasma
concentrations of the netupitant component.
CYP3A4 Inhibitors: Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor (e.g., ketoconazole) can significantly
increase thesystemicexposure to thenetupitantcomponentofAKYNZEO.However,nodosageadjustment isnecessary
for single dose administration ofAKYNZEO.
Serotonergic Drugs
:Serotonin syndrome (including altered mental status,autonomic instability,and neuromuscular
symptoms) has been described following the concomitant use of 5-HT
3
receptor antagonists and other serotonergic
drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake
inhibitors (SNRIs)
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Risk Summary:Adequate and well-controlled studies with AKYNZEO have not been conducted in pregnant women. In
animal reproduction studies, no effects on embryo-fetal development were observed following daily administration of
netupitant in pregnant rats during the period of organogenesis at doses up to 3.7 times the humanAUC (area under the
plasmaconcentration-timecurve)at therecommendedsinglehumandose tobegivenwitheachcycleofchemotherapy.
However, a dose-dependent increase in adverse effects on embryo-fetal development was observed following daily
administration of netupitant in pregnant rabbits during the period of organogenesis with doses at least 0.2 times the
humanAUC at the recommended single human dose to be given with each cycle of chemotherapy.Daily administration
of netupitant in rats up to 3.7 times the human AUC at the recommended human dose during organogenesis through
lactation produced no adverse effects in the offspring. In animal reproduction studies with palonosetron, no effects on
embryo-fetal development were observed following oral administration during the period of organogenesis at doses up
to 921 and 1841 times the recommended human oral dose in rats and rabbits, respectively.AKYNZEO should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data:Daily administration of up to 30 mg/kg netupitant in rats (3.7 times the humanAUC at the recommended
singlehumandose tobegivenwitheachcycleofchemotherapy)during theperiodoforganogenesisproducednoeffects
on embryo-fetal development. However, an increased incidence of external and skeletal abnormalities in rabbit fetuses
was observed following daily administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human
AUC at the recommended single human dose to be given with each cycle of chemotherapy) during the period of
organogenesis. These abnormalities included positional abnormalities in the limbs and paws, and fused sternebrae.
Reduction in fetal rabbit weight occurred at 30 mg/kg/day.Maternal toxicity in rabbits (i.e. loss of bodyweight during the
treatment period) was also observed at 30 mg/kg/day.Daily administration of up to 30 mg/kg netupitant (3.7 times the
human AUC at the recommended human dose) in rats during organogenesis through lactation produced no adverse
effects in the offspring.
In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed in pregnant
rats given oral doses up to 60 mg/kg/day (921 times the recommended human oral dose based on body surface area)
or pregnant rabbits given oral doses up to 60 mg/kg/day (1841 times the recommended human oral dose based on
body surface area) during the period of organogenesis.
Nursing Mothers
: It is not known whether AKYNZEO is present in human milk. Because many drugs are present in
human milk and because of the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.
Pediatric Use
:Safety and effectiveness in patients below the age of 18 years have not been established.
GeriatricUse
:Of the1169adultcancerpatients treatedwithAKYNZEO inclinicalstudies,18%wereaged65andover,
while 2% were aged 75 years and over. The nature and frequency of adverse reactions were similar in elderly and
younger patients.Exploratory analyses of the impact of age on efficacy were performed in the two trials that compared
AKYNZEO to palonosetron. In Study 1 in patients treated with cisplatin chemotherapy, among the patients less than
age 65 years, 115 were treated with AKYNZEO and 116 were treated with palonosetron alone. Among the patients
65 years or older, 20 were treated with AKYNZEO and 20 were treated with palonosetron alone. The difference in
Complete Response (CR) rates between AKYNZEO and palonosetron alone was similar between the two age groups
in both the acute and delayed phases. In Study 2 in patients treated with anthracyclines plus cyclophosphamide
chemotherapy, among the patients less than age 65 years, 608 were treated with AKYNZEO and 602 were treated
with palonosetron alone.Among the patients 65 years or older,116 were treated withAKYNZEO and 123 were treated
with palonosetron alone.The difference in CR rates between AKYNZEO and palonosetron alone (4% in <65 years and
2% in
≥
65 years) was similar between the two age groups in the acute phase. In the delayed phase, the difference in
CR rates betweenAKYNZEO and palonosetron alone (9% in <65 years and 1% in
≥
65 years) was numerically higher
in patients <65 years.This difference between age groups in the delayed phase of Study 2 may be explained, in part,by
higher CR in the delayed phase associated with palonosetron alone in the older age group (81%) relative to the younger
patients treated with palonosetron alone (67%).
In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or
cardiac function and concomitant disease or other drug therapy.
Hepatic Impairment
: No dosage adjustment for AKYNZEO is necessary for patients with mild to moderate hepatic
impairment (Child-Pugh score 5 to 8). Limited data are available with AKYNZEO in patients with severe hepatic
impairment (Child-Pugh score >9)/Avoid use ofAKYNZEO in patients with severe hepatic impairment.
Renal Impairment:
No dosage adjustment for AKYNZEO is necessary in patients with mild to moderate renal
impairment. The pharmacokinetics and safety of netupitant has not been studied in patients with severe renal
impairment, although severe renal impairment did not substantially affect pharmacokinetics of palonosetron. The
pharmacokinetics for netupitant and palonosetron was not studied in patients with end-stage renal disease
requiring hemodialysis.
OVERDOSAGE
: No specific information is available on the treatment of overdosage with AKYNZEO. In the event of
overdose, AKYNZEO should be discontinued and general supportive treatment and monitoring should be provided.
Becauseof theantiemeticactivityofAKYNZEO,drug-inducedemesismaynotbeeffective.Dialysisstudieshavenotbeen
performed;due to the largevolumeofdistribution,dialysis isunlikely tobeaneffective treatment forAKYNZEOoverdose.
A total of 33 adult cancer patients were administered oral palonosetron at a dose of 90 μg/kg (equivalent to 6 mg fixed
dose), as part of a dose ranging study. This is approximately 12 times the recommended oral dose of 0.5 mg
palonosetron.This dose group had a similar incidence of adverse events compared to the other dose groups and no
dose response effects were observed. The highest dose of netupitant administered to 1169 cancer patients was
300 mg. The highest dose of netupitant administered to 49 healthy subjects was 600 mg. A similar incidence of
adverse events was observed when compared to lower doses of netupitant in the respective populations of cancer
patients and healthy subjects.
JointlymanufacturedbyCatalentPharmaSolutions,Somerset,NJandHelsinnBirexPharmaceuticals,Dublin, Ireland for
Helsinn Healthcare SA,Switzerland
AKYNZEO
®
is a registered trademark of Helsinn Healthcare,SA,Lugano,Switzerland,used under license.
Distributed and marketed by Eisai Inc.,under license of Helsinn Healthcare SA,Switzerland.
© 2014All rights reserved.NEPA0004 10/14
