INDICATIONS
AKYNZEO IS INDICATED FOR THE PREVENTION OF ACUTE AND DELAYED NAUSEA AND VOMITING ASSOCIATED WITH INITIAL AND REPEAT COURSES OF CANCER CHEMOTHERAPY, INCLUDING, BUT NOT LIMITED TO, HIGHLY EMETOGENIC CHEMOTHERAPY. AKYNZEO IS AN ORAL FIXED COMBINATION OF PALONOSETRON AND NETUPITANT: PALONOSETRON PREVENTS NAUSEA AND VOMITING DURING THE ACUTE PHASE AND NETUPITANT PREVENTS NAUSEA AND VOMITING DURING BOTH THE ACUTE AND DELAYED PHASE AFTER CANCER CHEMOTHERAPY.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
AKYNZEO (300 MG NETUPITANT/0.5 MG PALONOSETRON) CAPSULES ARE HARD GELATIN CAPSULES WITH WHITE BODY AND CARAMEL CAP WITH "HE1" PRINTED ON THE BODY.
STORAGE AND HANDLING
NDC # 62856-796-01, AKYNZEO (300 MG NETUPITANT/0.5 MG PALONOSETRON). AKYNZEO IS SUPPLIED AS HARD GELATIN CAPSULES WITH WHITE BODY AND CARAMEL CAP WITH "HE1" PRINTED ON THE BODY, ONE CAPSULE PER BLISTER.
STORAGE
STORE AT 20 °C TO 25 °C (68 °F TO 77 °F); EXCURSIONS PERMITTED FROM 15 °C TO 30 °C (59 °F TO 86 °F) [SEE USP CONTROLLED ROOM TEMPERATURE].
JOINTLY MANUFACTURED BY CATALENT PHARMA SOLUTIONS, SOMERSET, NJ AND HELSINN BIREX PHARMACEUTICALS, DUBLIN, IRELAND FOR HELSINN HEALTHCARE SA, SWITZERLAND DISTRIBUTED AND MARKETED BY EISAI INC. WOODCLIFF LAKE, NJ 07677 UNDER LICENSE OF HELSINN HEALTHCARE SA, SWITZERLAND. FOR MORE INFORMATION, GO TO WWW.AKYNZEO.COM. ISSUED: OCTOBER 2014
DOSAGE AND ADMINISTRATION
HIGHLY EMETOGENIC CHEMOTHERAPY, INCLUDING CISPLATIN BASED CHEMOTHERAPY
THE RECOMMENDED DOSAGE IN ADULTS IS ONE CAPSULE OF AKYNZEO 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 [SEE CLINICAL STUDIES,TABLE 5].
ANTHRACYCLINES AND CYCLOPHOSPHAMIDE BASED CHEMOTHERAPY AND CHEMOTHERAPY NOT CONSIDERED HIGHLY EMETOGENIC
THE RECOMMENDED DOSAGE IN ADULTS IS ONE CAPSULE OF AKYNZEO APPROXIMATELY 1 HOUR PRIOR TO THE START OF CHEMOTHERAPY 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 [SEE CLINICAL STUDIES, TABLE 7].
AKYNZEO CAN BE TAKEN WITH OR WITHOUT FOOD.
SIDE EFFECTS
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 OF AKYNZEO 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 [SEE CLINICAL STUDIES], INCLUDING 782 EXPOSED TO AKYNZEO FOR AT LEAST 4 CYCLES AND 321 EXPOSED FOR AT LEAST 6 CYCLES, UP TO A MAXIMUM OF 12 CYCLES OF CHEMOTHERAPY. THE MEDIAN AGE WAS 55, 79% WERE FEMALE, 83% WERE WHITE, 13% WERE ASIAN, AND 4% WERE HISPANIC. ALL PATIENTS RECEIVED A SINGLE ORAL DOSE OF AKYNZEO 1 HOUR PRIOR TO THE START OF EACH CHEMOTHERAPY CYCLE. IN ALL STUDIES, DEXAMETHASONE WAS CO-ADMINISTERED WITH AKYNZEO [SEE CLINICAL STUDIES, TABLE 5 AND TABLE 7].
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 THE AKYNZEO 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: ADVERSE REACTIONS OCCURRING IN ? 3% OF CANCER PATIENTS RECEIVING AKYNZEO AND ANTHRACYCLINES 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. SEE TABLE 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 OF AKYNZEO (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/M²) BASED CHEMOTHERAPY, THERE WERE TWO PATIENTS (0.5%; 2/369) IN THE INTRAVENOUS PALONOSETRON ARM WHO HAD CONCOMITANT ELEVATIONS OF TRANSAMINASES AND TOTAL BILIRUBIN. NEITHER EXPERIENCED TRANSAMINASE ELEVATIONS OF > 10 X ULN.
READ THE AKYNZEO (NETUPITANT AND PALONOSETRON CAPSULES) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
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. BECAUSE OF THE ANTIEMETIC ACTIVITY OF AKYNZEO, DRUG-INDUCED EMESIS MAY NOT BE EFFECTIVE. DIALYSIS STUDIES HAVE NOT BEEN PERFORMED; DUE TO THE LARGE VOLUME OF DISTRIBUTION, DIALYSIS IS UNLIKELY TO BE AN EFFECTIVE TREATMENT FOR AKYNZEO OVERDOSE.
A TOTAL OF 33 ADULT CANCER PATIENTS WERE ADMINISTERED ORAL PALONOSETRON AT A DOSE OF 90 ?G/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.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
NETUPITANT IS A SELECTIVE ANTAGONIST OF HUMAN SUBSTANCE P/NEUROKININ 1 (NK1) RECEPTORS.
PALONOSETRON IS A 5-HT3 RECEPTOR ANTAGONIST WITH A STRONG BINDING AFFINITY FOR THIS RECEPTOR AND LITTLE OR NO AFFINITY FOR OTHER RECEPTORS. CANCER CHEMOTHERAPY MAY BE ASSOCIATED WITH A HIGH INCIDENCE OF NAUSEA AND VOMITING, PARTICULARLY WHEN CERTAIN AGENTS, SUCH AS CISPLATIN, ARE USED. 5-HT3 RECEPTORS ARE LOCATED ON THE NERVE TERMINALS OF THE VAGUS IN THE PERIPHERY AND CENTRALLY IN THE CHEMORECEPTOR TRIGGER ZONE OF THE AREA POSTREMA. CHEMOTHERAPEUTIC AGENTS PRODUCE NAUSEA AND VOMITING BY STIMULATING THE RELEASE OF SEROTONIN FROM THE ENTEROCHROMAFFIN CELLS OF THE SMALL INTESTINE. SEROTONIN THEN ACTIVATES 5-HT3 RECEPTORS LOCATED ON VAGAL AFFERENTS TO INITIATE THE VOMITING REFLEX. THE DEVELOPMENT OF ACUTE EMESIS IS KNOWN TO DEPEND ON SEROTONIN AND ITS 5-HT3 RECEPTORS HAVE BEEN DEMONSTRATED TO SELECTIVELY STIMULATE THE EMETIC RESPONSE.
DELAYED EMESIS HAS BEEN LARGELY ASSOCIATED WITH THE ACTIVATION OF TACHYKININ FAMILY NEUROKININ 1 (NK1) RECEPTORS (BROADLY DISTRIBUTED IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS) BY SUBSTANCE P. AS SHOWN IN IN VITRO AND IN VIVO STUDIES, NETUPITANT INHIBITS SUBSTANCE P MEDIATED RESPONSES.
PHARMACODYNAMICS
NK1 RECEPTOR OCCUPANCY
THE RECEPTOR OCCUPANCY FOR THE CINV DOSING REGIMEN OF NETUPITANT WAS MEASURED IN A HUMAN POSITRON EMISSION TOMOGRAPHY (PET) STUDY. NETUPITANT WAS SHOWN TO CROSS THE BLOOD BRAIN BARRIER WITH A NK1 RECEPTOR OCCUPANCY OF 92.5%, 86.5%, 85.0%, 78.0%, AND 76.0% IN STRIATUM AT 6, 24, 48, 72, AND 96 HOURS, RESPECTIVELY, AFTER ADMINISTRATION OF 300 MG NETUPITANT.
CARDIAC ELECTROPHYSIOLOGY
CO-ADMINISTRATION OF SINGLE DOSE NETUPITANT 600 MG AND PALONOSETRON 1.5 MG HAD NO SIGNIFICANT EFFECTS ON THE QTC INTERVAL.
PHARMACOKINETICS
AFTER SINGLE DOSE ADMINISTRATION OF AKYNZEO IN HEALTHY SUBJECTS, THE PEAK PLASMA CONCENTRATIONS FOR NETUPITANT AND PALONOSETRON WERE REACHED IN ABOUT 5 HOURS.
TABLE 4: PK PARAMETERS (MEAN AND CV%) AFTER SINGLE DOSE ADMINISTRATION OF AKYNZEO IN HEALTHY SUBJECTS
NETUPITANT PALONOSETRON
CMAX (NG/ML) 434 (56) 1.53 (25)
TMAX1 (H) 5(2-12) 5(1-12)
AUC (NG*H/ML) 14401 (51) 56.7 (33)
T½ (H) 96 (61) 44 (34)
1MEDIAN (MIN-MAX)
WHEN ADMINISTERED UNDER FED CONDITION, THE SYSTEMIC EXPOSURE TO NETUPITANT AND PALONOSETRON WAS SIMILAR TO THOSE OBTAINED UNDER FASTING CONDITION.
IN CANCER PATIENTS WHO RECEIVED A SINGLE DOSE OF AKYNZEO 1 HOUR PRIOR TO CHEMOTHERAPY (DOCETAXEL, ETOPOSIDE, OR CYCLOPHOSPHAMIDE), THE CMAX AND AUC OF NETUPITANT AND ITS METABOLITES WERE SIMILAR TO THOSE IN HEALTHY SUBJECTS. THE MEAN CMAX AND AUC OF PALONOSETRON IN CANCER PATIENTS WERE SIMILAR TO THOSE IN HEALTHY SUBJECTS.
NO SIGNIFICANT CHANGES IN PHARMACOKINETICS OF NETUPITANT AND PALONOSETRON WERE OBSERVED WHEN 450 MG ORAL NETUPITANT AND 0.75 MG ORAL PALONOSETRON WERE CO-ADMINISTERED.
NETUPITANT
ABSORPTION
UPON ORAL ADMINISTRATION OF A SINGLE DOSE OF NETUPITANT, NETUPITANT STARTED TO BE MEASURABLE IN PLASMA BETWEEN 15 MINUTES AND 3 HOURS AFTER DOSING. PLASMA CONCENTRATIONS REACHED CMAX IN APPROXIMATELY 5 HOURS. THERE WAS A GREATER THAN DOSE-PROPORTIONAL INCREASE IN THE SYSTEMIC EXPOSURE WITH THE DOSE INCREASE FROM 10 MG TO 300 MG AND A DOSE-PROPORTIONAL INCREASE IN SYSTEMIC EXPOSURE WITH A DOSE INCREASE FROM 300 MG TO 450 MG.
DISTRIBUTION
IN CANCER PATIENTS NETUPITANT DISPOSITION WAS CHARACTERIZED BY A LARGE APPARENT VOLUME OF DISTRIBUTION (VZ/F: 1982 ± 906 L) (MEAN ± SD). HUMAN PLASMA PROTEIN BINDING OF NETUPITANT IS GREATER THAN 99.5% AT DRUG CONCENTRATIONS RANGING FROM 10-1300 NG/ML AND PROTEIN BINDING OF ITS MAJOR METABOLITES (M1, M2 AND M3) IS GREATER THAN 97% AT DRUG CONCENTRATIONS RANGING FROM 100 TO 2000 NG/ML.
METABOLISM
ONCE ABSORBED, NETUPITANT IS EXTENSIVELY METABOLIZED TO FORM THREE MAJOR METABOLITES: DESMETHYL DERIVATIVE, M1; N-OXIDE DERIVATIVE, M2; AND OH-METHYL DERIVATIVE, M3. METABOLISM IS MEDIATED PRIMARILY BY CYP3A4 AND TO A LESSER EXTENT BY CYP2C9 AND CYP2D6. METABOLITES M1, M2 AND M3 WERE SHOWN TO BIND TO THE SUBSTANCE P/NEUROKININ 1 (NK1) RECEPTOR.
MEAN CMAX WAS APPROXIMATELY 11%, 47% AND 16% OF NETUPITANT FOR METABOLITES M1, M2 AND M3, RESPECTIVELY. MEAN AUC FOR METABOLITES M1, M2 AND M3 WAS 29%, 14% AND 33% OF NETUPITANT, RESPECTIVELY. THE MEDIAN TMAX FOR METABOLITE M2 WAS 5 HOURS AND WAS ABOUT 17-32 HOURS FOR METABOLITES M1 AND M3.
ELIMINATION
NETUPITANT IS ELIMINATED FROM THE BODY IN A MULTI-EXPONENTIAL FASHION, WITH AN APPARENT ELIMINATION HALF-LIFE IN CANCER PATIENTS OF 80 ± 29 HOURS (MEAN ± SD) AND WITH AN ESTIMATED SYSTEMIC CLEARANCE OF 20.3 ± 9.2 L/H (MEAN ± SD) AFTER A SINGLE ORAL DOSE OF AKYNZEO.
AFTER A SINGLE ORAL ADMINISTRATION OF [14C]-NETUPITANT, APPROXIMATELY HALF THE ADMINISTERED RADIOACTIVITY WAS RECOVERED FROM URINE AND FECES WITHIN 120 HOURS OF DOSING. THE TOTAL OF 3.95% AND 70.7% OF THE RADIOACTIVE DOSE WAS RECOVERED IN THE URINE AND FECES COLLECTED OVER 336 HOURS, RESPECTIVELY, AND THE MEAN FRACTION OF AN ORAL DOSE OF NETUPITANT EXCRETED UNCHANGED IN URINE IS LESS THAN 1% SUGGESTING RENAL CLEARANCE IS NOT A SIGNIFICANT ELIMINATION ROUTE FOR THE NETUPITANT-RELATED ENTITIES. ABOUT 86.5% AND 4.7% OF ADMINISTERED RADIOACTIVITY WAS ESTIMATED TO BE EXCRETED VIA THE FECES AND URINE IN 30 DAYS POST-DOSE
PALONOSETRON
ABSORPTION
FOLLOWING ORAL ADMINISTRATION, PALONOSETRON IS WELL ABSORBED WITH ITS ABSOLUTE BIOAVAILABILITY REACHING 97%. AFTER SINGLE ORAL DOSES USING BUFFERED SOLUTION MEAN MAXIMUM PALONOSETRON CONCENTRATIONS (CMAX) AND AREA UNDER THE CONCENTRATION-TIME CURVE (AUC0-?) WERE DOSE PROPORTIONAL OVER THE DOSE RANGE OF 3.0 TO 80 ?G/KG IN HEALTHY SUBJECTS.
DISTRIBUTION
PALONOSETRON HAS A VOLUME OF DISTRIBUTION OF APPROXIMATELY 8.3 ± 2.5 L/KG. APPROXIMATELY 62% OF PALONOSETRON IS BOUND TO PLASMA PROTEINS.
METABOLISM
PALONOSETRON IS ELIMINATED BY MULTIPLE ROUTES WITH APPROXIMATELY 50% METABOLIZED TO FORM TWO PRIMARY METABOLITES: N-OXIDE-PALONOSETRON AND 6-S-HYDROXY-PALONOSETRON. THESE METABOLITES EACH HAVE LESS THAN 1% OF THE 5-HT3 RECEPTOR ANTAGONIST ACTIVITY OF PALONOSETRON. IN VITRO METABOLISM STUDIES HAVE SUGGESTED THAT CYP2D6 AND TO A LESSER EXTENT CYP3A4 AND CYP1A2 ARE INVOLVED IN THE METABOLISM OF PALONOSETRON. HOWEVER, CLINICAL PHARMACOKINETIC PARAMETERS ARE NOT SIGNIFICANTLY DIFFERENT BETWEEN POOR AND EXTENSIVE METABOLIZERS OF CYP2D6 SUBSTRATES.
ELIMINATION
FOLLOWING ADMINISTRATION OF A SINGLE ORAL 0.75 MG DOSE OF [14C]-PALONOSETRON TO SIX HEALTHY SUBJECTS, 85% TO 93% OF THE TOTAL RADIOACTIVITY WAS EXCRETED IN URINE, AND 5% TO 8% WAS ELIMINATED IN FECES. THE AMOUNT OF UNCHANGED PALONOSETRON EXCRETED IN THE URINE REPRESENTED APPROXIMATELY 40% OF THE ADMINISTERED DOSE. IN CANCER PATIENTS, T½ WAS 48 ± 19 HOURS. AFTER A SINGLE-DOSE OF APPROXIMATELY 0.75 MG INTRAVENOUS PALONOSETRON, THE TOTAL BODY CLEARANCE OF PALONOSETRON IN HEALTHY SUBJECTS WAS 160 ± 35 ML/H/KG (MEAN ± SD) AND RENAL CLEARANCE WAS 66.5 ± 18.2 ML/H/KG.
SPECIFIC POPULATIONS
GENDER
IN A POOLED ANALYSIS, THE CMAX FOR NETUPITANT WAS 35% HIGHER IN FEMALES THAN IN MALES WHILE THE AUC WAS SIMILAR BETWEEN MALES AND FEMALES. IN FEMALE SUBJECTS, THE MEAN AUC FOR PALONOSETRON WAS 35% HIGHER AND THE MEAN CMAX WAS 26% HIGHER THAN IN MALE SUBJECTS.
GERIATRICS
IN CANCER PATIENTS RECEIVING AKYNZEO, POPULATION PK ANALYSIS INDICATED THAT AGE (WITHIN THE RANGE OF 29 TO 75 YEARS OLD) DID NOT INFLUENCE THE PHARMACOKINETICS OF NETUPITANT OR PALONOSETRON. IN HEALTHY ELDERLY SUBJECTS ( > 65 YEARS OLD) THE MEAN AUC0-? AND CMAX WAS 25% AND 36% HIGHER, RESPECTIVELY, FOR NETUPITANT, AND 37% AND 10% HIGHER, RESPECTIVELY, FOR PALONOSETRON COMPARED TO THOSE IN HEALTHY YOUNGER ADULTS (22-45 YEARS OLD).
HEPATIC IMPAIRMENT
THE EFFECTS OF HEPATIC IMPAIRMENT ON THE PK OF NETUPITANT AND PALONOSETRON WERE STUDIED FOLLOWING ADMINISTRATION OF A SINGLE ORAL DOSE OF AKYNZEO TO PATIENTS WITH MILD (CHILD-PUGH SCORE 5 TO 6), MODERATE (CHILD-PUGH SCORE 7 TO 9), OR SEVERE (CHILD-PUGH SCORE > 9) HEPATIC IMPAIRMENT.
IN PATIENTS WITH MILD OR MODERATE HEPATIC IMPAIRMENT, THE MEAN AUC0-? OF NETUPITANT WAS 67% AND 86% HIGHER, RESPECTIVELY, THAN IN HEALTHY SUBJECTS AND THE MEAN CMAX FOR NETUPITANT WAS ABOUT 40% AND 41% HIGHER, RESPECTIVELY, THAN IN HEALTHY SUBJECTS.
IN PATIENTS WITH MILD OR MODERATE HEPATIC IMPAIRMENT, THE MEAN AUC0-? OF PALONOSETRON WAS 33% AND 62% HIGHER, RESPECTIVELY, THAN IN HEALTHY SUBJECTS AND THE MEAN CMAX FOR PALONOSETRON WAS ABOUT 14% HIGHER AND UNCHANGED, RESPECTIVELY, THAN IN HEALTHY SUBJECTS.
THE PHARMACOKINETICS OF NETUPITANT AND PALONOSETRON WAS AVAILABLE FROM ONLY TWO PATIENTS WITH SEVERE HEPATIC IMPAIRMENT. AS SUCH THE DATA ARE TOO LIMITED TO DRAW A CONCLUSION.
RENAL IMPAIRMENT
IN A POPULATION PK ANALYSIS, MILD AND MODERATE RENAL IMPAIRMENT DID NOT SIGNIFICANTLY AFFECT THE PHARMACOKINETICS OF NETUPITANT IN CANCER PATIENTS. NETUPITANT HAS NOT BEEN STUDIED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT.
MILD TO MODERATE RENAL IMPAIRMENT DOES NOT SIGNIFICANTLY AFFECT PALONOSETRON PHARMACOKINETIC PARAMETERS. IN A STUDY WITH INTRAVENOUS PALONOSETRON, TOTAL SYSTEMIC EXPOSURE TO PALONOSETRON INCREASED BY APPROXIMATELY 28% IN PATIENTS WITH SEVERE RENAL IMPAIRMENT RELATIVE TO HEALTHY SUBJECTS.
THE PHARMACOKINETICS OF EITHER PALONOSETRON OR NETUPITANT HAS NOT BEEN STUDIED IN SUBJECTS WITH END-STAGE RENAL DISEASE.
DRUG INTERACTIONS
IN VITRO STUDIES HAVE SHOWN THAT NETUPITANT AND ITS METABOLITE M1 ARE INHIBITORS OF CYP3A4. AN IN VIVO STUDY HAS CONFIRMED THAT NETUPITANT IS A MODERATE INHIBITOR OF CYP3A4.
BASED ON THE IN VITRO STUDIES, NETUPITANT AND ITS METABOLITES' ARE UNLIKELY TO HAVE IN VIVO DRUG-DRUG INTERACTION VIA INHIBITION OF CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, AND CYP2D6 AT THE CLINICAL DOSE OF 300 MG.
NETUPITANT AND ITS METABOLITES, M1, M2 AND M3, ARE NOT INDUCERS OF CYP1A2, CYP2C9, CYP2C19 AND CYP3A4. THEIR INDUCTION POTENTIAL OF CYP2B6 IS UNKNOWN.
BASED ON IN VITRO STUDIES, NETUPITANT IS AN INHIBITOR OF P-GP AND BCRP TRANSPORTERS. IN ADDITION, METABOLITE M2 IS A SUBSTRATE FOR P-GP. NETUPITANT'S POTENTIAL FOR BEING A SUBSTRATE FOR P-GP IS UNKNOWN. IN VITRO STUDIES INDICATE THAT NETUPITANT AND ITS THREE MAJOR METABOLITES ARE UNLIKELY TO HAVE IN VIVO DRUG-DRUG INTERACTIONS WITH HUMAN EFFLUX TRANSPORTERS BSEP, MRP2, AND HUMAN UPTAKE TRANSPORTERS OATP1B1, OATP1B3, OAT1, OAT3, OCT1, AND OCT2 AT THE CLINICAL DOSE OF 300 MG.
IN VITRO STUDIES, PALONOSETRON DOES NOT INHIBIT CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 AND CYP3A4/5 OR INDUCE CYP1A2, CYP2D6 OR CYP3A4/5. CYP2C19 WAS NOT INVESTIGATED.
DEXAMETHASONE
CO-ADMINISTRATION OF A SINGLE DOSE OF NETUPITANT (300 MG) WITH A DEXAMETHASONE REGIMEN (20 MG ON DAY 1, FOLLOWED BY 8 MG B.I.D. FROM DAY 2 TO DAY 4) SIGNIFICANTLY INCREASED EXPOSURE TO DEXAMETHASONE. WHEN NETUPITANT WAS CO-ADMINISTERED ON DAY 1, THE MEAN AUC OF DEXAMETHASONE WAS INCREASED BY 1.7FOLD ON DAY 1 AND UP TO 2.4-FOLD ON DAY 2 AND DAY 4.
CHEMOTHERAPEUTIC AGENTS (DOCETAXEL, ETOPOSIDE, CYCLOPHOSPHAMIDE)
SYSTEMIC EXPOSURE TO INTRAVENOUSLY ADMINISTERED CHEMOTHERAPEUTIC AGENTS THAT ARE METABOLIZED BY CYP3A4 WAS HIGHER WHEN AKYNZEO WAS CO-ADMINISTERED THAN WHEN PALONOSETRON ALONE WAS COADMINISTERED IN CANCER PATIENTS.
WITH CO-ADMINISTRATION OF AKYNZEO THE MEAN CMAX AND AUC OF DOCETAXEL WERE 49% AND 35% HIGHER, RESPECTIVELY, AND MEAN CMAX AND AUC OF ETOPOSIDE WERE INCREASED BY 10% AND 28%, RESPECTIVELY, COMPARED TO WHEN CO-ADMINISTERED WITH PALONOSETRON ALONE.
MEAN CMAX AND AUC FOR CYCLOPHOSPHAMIDE AFTER CO-ADMINISTRATION WITH AKYNZEO WAS 27% AND 20% HIGHER COMPARED TO WHEN CO-ADMINISTERED WITH PALONOSETRON ALONE.
THE MEAN AUC OF PALONOSETRON WAS ABOUT 65% HIGHER WHEN AKYNZEO WAS CO-ADMINISTERED WITH DOCETAXEL THAN WITH ETOPOSIDE OR CYCLOPHOSPHAMIDE, WHILE THE MEAN AUC OF NETUPITANT WAS SIMILAR AMONG GROUPS THAT RECEIVED DOCETAXEL, ETOPOSIDE, OR CYCLOPHOSPHAMIDE.
MIDAZOLAM
WHEN CO-ADMINISTERED WITH NETUPITANT 300 MG THE MEAN CMAX AND AUC OF MIDAZOLAM AFTER SINGLE DOSE ORAL ADMINISTRATION OF 7.5 MG MIDAZOLAM WAS 36% AND 126% HIGHER, RESPECTIVELY.
ERYTHROMYCIN
WHEN 500 MG ERYTHROMYCIN WAS CO-ADMINISTERED WITH NETUPITANT 300 MG, THE SYSTEMIC EXPOSURE OF ERYTHROMYCIN WAS HIGHLY VARIABLE AND THE MEAN CMAX AND AUC OF ERYTHROMYCIN WERE INCREASED BY 92% AND 56%, RESPECTIVELY.
ORAL CONTRACEPTIVES
SINGLE DOSE AKYNZEO, WHEN GIVEN WITH A SINGLE ORAL DOSE OF 60 ?G ETHINYL ESTRADIOL AND 300 ?G LEVONORGESTREL, INCREASED THE AUC OF LEVONORGESTREL BY 46%. AKYNZEO HAD NO SIGNIFICANT EFFECT ON THE AUC OF ETHINYL ESTRADIOL.
DIGOXIN
CO-ADMINISTRATION OF NETUPITANT 450 MG DID NOT SIGNIFICANTLY AFFECT THE SYSTEMIC EXPOSURE AND URINARY EXCRETION OF DIGOXIN, A SUBSTRATE OF P-GLYCOPROTEIN, AT STEADY-STATE. CONCURRENT ADMINISTRATION OF AKYNZEO WITH DIGOXIN IS NOT EXPECTED TO AFFECT THE SYSTEMIC EXPOSURE TO DIGOXIN.
EFFECTS OF OTHER DRUGS ON AKYNZEO
RIFAMPICIN
SINGLE DOSE AKYNZEO WAS ADMINISTERED WITH RIFAMPICIN, A STRONG CYP3A4 INDUCER, FOLLOWING ONCE DAILY ADMINISTRATION OF 600 MG RIFAMPICIN FOR 17 DAYS. PHARMACOKINETICS OF NETUPITANT AND PALONOSETRON WERE COMPARED TO THAT AFTER ADMINISTRATION OF AKYNZEO ALONE. CO-ADMINISTRATION OF RIFAMPICIN DECREASED THE MEAN CMAX AND AUC0-? OF NETUPITANT BY 62% AND 82%, RESPECTIVELY, COMPARED TO THOSE AFTER AKYNZEO ALONE. CO-ADMINISTRATION OF RIFAMPICIN DECREASED THE MEAN CMAX AND AUC FOR PALONOSETRON BY 15% AND 19%, RESPECTIVELY.
KETOCONAZOLE
SINGLE DOSE AKYNZEO WAS ADMINISTERED WITH KETOCONAZOLE, A STRONG CYP3A4 INHIBITOR, FOLLOWING ONCE DAILY ADMINISTRATION OF 400 MG KETOCONAZOLE FOR 12 DAYS. PHARMACOKINETICS OF NETUPITANT AND PALONOSETRON WERE COMPARED TO THAT AFTER ADMINISTRATION OF AKYNZEO ALONE. CO-ADMINISTRATION WITH KETOCONAZOLE INCREASED MEAN CMAX AND AUC OF NETUPITANT BY 25% AND 140%, RESPECTIVELY, COMPARED TO THOSE AFTER ADMINISTRATION OF AKYNZEO ALONE. THE MEAN AUC AND CMAX OF PALONOSETRON WERE 10% AND 15% HIGHER, RESPECTIVELY, WHEN CO-ADMINISTERED WITH KETOCONAZOLE.
CLINICAL STUDIES
ORAL ADMINISTRATION OF AKYNZEO IN COMBINATION WITH DEXAMETHASONE HAS BEEN SHOWN TO PREVENT ACUTE AND DELAYED NAUSEA AND VOMITING ASSOCIATED WITH INITIAL AND REPEAT COURSES OF CHEMOTHERAPY IN TWO TRIALS.
STUDY 1
IN A MULTICENTER, RANDOMIZED, PARALLEL, DOUBLE-BLIND, CONTROLLED CLINICAL TRIAL OF 694 PATIENTS, THE EFFICACY AND SAFETY OF A SINGLE DOSE OF ORAL NETUPITANT IN COMBINATION WITH ORAL PALONOSETRON WAS COMPARED WITH A SINGLE ORAL DOSE OF PALONOSETRON IN CANCER PATIENTS RECEIVING A CHEMOTHERAPY REGIMEN THAT INCLUDED CISPLATIN (MEDIAN DOSE=75 MG/M²). THE EFFICACY OF AKYNZEO WAS ASSESSED IN 135 PATIENTS WHO RECEIVED AKYNZEO (NETUPITANT 300 MG AND PALONOSETRON 0.5 MG) AND 136 PATIENTS WHO RECEIVED ORAL PALONOSETRON 0.5 MG.
TREATMENT REGIMENS FOR THE AKYNZEO AND PALONOSETRON ARMS ARE SUMMARIZED IN TABLE 5.
TABLE 5: ORAL ANTIEMETIC TREATMENT REGIMEN IN THE HIGHLY EMETOGENIC CHEMOTHERAPY STUDY
TREATMENT REGIMEN DAY 1 DAYS 2 TO 4
AKYNZEO AKYNZEO 300 MG NEUPITANT/0.5 MG PALONOSETRON DEXAMETHASONE 12 MG DEXAMETHASONE 8 MG ONCE A DAY
PALONOSETRON PALONOSETRON 0.5 MG DEXAMETHASONE 20 MG DEXAMETHASONE 8 MG TWICE A DAY
OF THE 135 PATIENTS WHO RECEIVED AKYNZEO, 43% WERE WOMEN, AND ALL PATIENTS WERE WHITE. THE AGE RANGED FROM 19 TO 77 YEARS, WITH A MEDIAN AGE OF 53 YEARS.
DURING THE STUDY, 86% OF THE 135 TREATED PATIENTS IN THE AKYNZEO ARM RECEIVED A CONCOMITANT CHEMOTHERAPEUTIC AGENT IN ADDITION TO PROTOCOL-MANDATED CISPLATIN. THE MOST COMMON CHEMOTHERAPEUTIC AGENTS AND THE PROPORTION OF PATIENTS EXPOSED WERE CYCLOPHOSPHAMIDE (34%), FLUOROURACIL (24%), ETOPOSIDE (21%), AND DOXORUBICIN (16%).
THE KEY EFFICACY ENDPOINTS WERE COMPLETE RESPONSE (CR) (DEFINED AS NO EMETIC EPISODE AND NO USE OF RESCUE MEDICATION) FOR THE 25-120 HOUR INTERVAL (DELAYED PHASE), CR FOR THE 0-24 HOUR INTERVAL (ACUTE PHASE), AND CR WITHIN 120 HOURS (OVERALL PHASE) AFTER THE START OF THE CHEMOTHERAPY ADMINISTRATION.
A SUMMARY OF THE KEY RESULTS FROM THIS STUDY IS SHOWN IN TABLE 6.
TABLE 6: PROPORTION OF PATIENTS RESPONDING BY TREATMENT GROUP AND PHASE IN STUDY 1
AKYNZEO 300 MG NETUPITANT/ 0.5 MG PALONOSETRON
N=135 % PALONOSETRON 0.5 MG
N=136 % P-VALUE*
COMPLETE RESPONSE
DELAYED PHASE† 90.4 80.1 0.032
ACUTE PHASE‡ 98.5 89.7 0.002
OVERALL PHASE§ 89.6 76.5 0.003
*ADJUSTED P-VALUES FOR MULTIPLE COMPARISONS USING COCHRAN-MANTEL-HAENSZEL TEST, STRATIFIED BY GENDER.
†DELAYED PHASE: 25 TO 120 HOURS POST-CISPLATIN TREATMENT.
‡ACUTE PHASE: 0 TO 24 HOURS POST-CISPLATIN TREATMENT.
§OVERALL: 0 TO 120 HOURS POST-CISPLATIN TREATMENT.
STUDY 2
IN A MULTICENTER, RANDOMIZED, PARALLEL, DOUBLE-BLIND, ACTIVE CONTROLLED, SUPERIORITY TRIAL, THE EFFICACY AND SAFETY OF A SINGLE ORAL DOSE OF AKYNZEO WAS COMPARED WITH A SINGLE ORAL DOSE OF PALONOSETRON 0.5 MG IN CANCER PATIENTS SCHEDULED TO RECEIVE THE FIRST CYCLE OF AN ANTHRACYCLINE AND CYCLOPHOSPHAMIDE (AC) REGIMEN FOR THE TREATMENT OF A SOLID MALIGNANT TUMOR (STUDY 2). ALL PATIENTS RECEIVED A SINGLE ORAL DOSE OF DEXAMETHASONE.
TREATMENT REGIMENS FOR THE AKYNZEO AND PALONOSETRON ARMS ARE SUMMARIZED IN TABLE 7.
TABLE 7: ORAL ANTIEMETIC TREATMENT REGIMEN IN STUDY 2
TREATMENT REGIMEN DAY 1 DAYS 2 TO 3
AKYNZEO AKYNZEO 300 MG NETUPITANT/ 0.5 MG PALONOSETRON DEXAMETHASONE 12 MG NO ANTIEMETIC TREATMENT
PALONOSETRON PALONOSETRON 0.5 MG DEXAMETHASONE 20 MG NO ANTIEMETIC TREATMENT
AFTER COMPLETION OF CYCLE 1, PATIENTS HAD THE OPTION TO PARTICIPATE IN A MULTIPLE-CYCLE EXTENSION, RECEIVING THE SAME TREATMENT AS ASSIGNED IN CYCLE 1. THERE WAS NO PRE-SPECIFIED LIMIT OF THE NUMBER OF REPEAT CONSECUTIVE CYCLES FOR ANY PATIENT.
A TOTAL OF 1455 PATIENTS WERE RANDOMIZED TO THE AKYNZEO ARM OR PALONOSETRON ARM. A TOTAL OF 1450 PATIENTS (AKYNZEO N=725; PALONOSETRON N=725) RECEIVED STUDY MEDICATION: OF THESE, 1438 PATIENTS (98.8%) COMPLETED CYCLE 1 AND 1286 PATIENTS (88.4%) CONTINUED TREATMENT IN THE MULTIPLE-CYCLE EXTENSION. A TOTAL OF 907 PATIENTS (62.3%) COMPLETED THE MULTIPLE-CYCLE EXTENSION UP TO A MAXIMUM OF EIGHT TREATMENT CYCLES.
OF THE 725 PATIENTS WHO RECEIVED AKYNZEO, 711 (98%) WERE WOMEN; 79% WERE WHITE, 14% ASIAN, 6% HISPANIC, AND < 1% WERE BLACK OR OTHER. AGE RANGED FROM 22 TO 79 YEARS, WITH A MEDIAN AGE OF 54 YEARS. A TOTAL OF 724 PATIENTS (99.9%) WERE TREATED WITH CYCLOPHOSPHAMIDE. ALL PATIENTS WERE ADDITIONALLY TREATED WITH EITHER DOXORUBICIN (68.0%) OR EPIRUBICIN (32.0%).
DURING THE FIRST CYCLE, 32% OF THE 725 PATIENTS TREATED WITH AKYNZEO RECEIVED A CONCOMITANT CHEMOTHERAPEUTIC AGENT IN ADDITION TO PROTOCOL-MANDATED REGIMENS, WITH THE MOST COMMON CHEMOTHERAPEUTIC BEING FLUOROURACIL (28.3%) AND DOCETAXEL (2.6%).
THE PRIMARY EFFICACY ENDPOINT WAS THE CR RATE IN THE DELAYED PHASE, 25-120 HOURS AFTER THE START OF CHEMOTHERAPY ADMINISTRATION.
MAJOR SECONDARY EFFICACY ENDPOINTS INCLUDED CR FOR THE ACUTE AND OVERALL PHASES.
A SUMMARY OF KEY RESULTS FROM STUDY 2 IS SHOWN IN TABLE 8.
TABLE 8 : PROPORTION OF PATIENTS RESPONDING BY TREATMENT GROUP AND PHASE - CYCLE 1 IN STUDY 2
AKYNZEO 300 MG NETUPITANT/ 0.5 MG PALONOSETRON
N=724 % PALONOSETRON 0.5 MG
N=725 % P-VALUE*
PRIMARY ENDPOINT
COMPLETE RESPONSE
DELAYED PHASE† 76.9 69.5 0.001
MAJOR SECONDARY ENDPOINTS
COMPLETE RESPONSE
ACUTE PHASE‡ 88.4 85.0 0.047
OVERALL PHASE§ 74.3 66.6 0.001
*P-VALUE FROM COCHRAN-MANTEL-HAENSZEL TEST, STRATIFIED BY AGE CLASS AND REGION.
‡ACUTE PHASE: 0 TO 24 HOURS AFTER ANTHRACYCLINE AND CYCLOPHOSPHAMIDE REGIMEN.
†DELAYED PHASE: 25 TO 120 HOURS AFTER ANTHRACYCLINE AND CYCLOPHOSPHAMIDE REGIMEN.
§OVERALL: 0 TO 120 HOURS AFTER ANTHRACYCLINE AND CYCLOPHOSPHAMIDE REGIMEN.
MULTIPLE CYCLES
PATIENTS CONTINUED INTO THE MULTIPLE-CYCLE EXTENSION FOR UP TO 7 ADDITIONAL CYCLES OF CHEMOTHERAPY. THE PROPORTION OF PATIENTS WITH COMPLETE RESPONSE IN THE DELAYED PHASE BY TREATMENT GROUP AT EACH CYCLE (CYCLES 2 TO 6) IS DISPLAYED IN FIGURE 1. A LIMITED NUMBER OF PATIENTS RECEIVED TREATMENT BEYOND CYCLE 6. DURING ALL CYCLES THE CR RATE IN THE DELAYED PHASE WAS HIGHER FOR AKYNZEO THAN FOR PALONOSETRON. ANTIEMETIC ACTIVITY OF AKYNZEO WAS MAINTAINED THROUGHOUT REPEAT CYCLES FOR THOSE PATIENTS CONTINUING IN EACH OF THE MULTIPLE CYCLES.
FIGURE 1: PROPORTION OF PATIENTS WITH COMPLETE RESPONSE IN THE DELAYED PHASE BY TREATMENT GROUP AND CYCLE IN STUDY 2
ADDITIONAL CLINICAL TRIALS (STUDY 3 AND STUDY 4) WERE CONDUCTED TO SUPPORT THE EFFICACY OF AKYNZEO.
STUDY 3
IN A SEPARATE STUDY, 309 PATIENTS UNDERGOING INITIAL AND REPEAT CYCLES OF CHEMOTHERAPY (INCLUDING CARBOPLATIN, CISPLATIN, OXALIPLATIN, AND DOXORUBICIN REGIMENS) RECEIVED AKYNZEO; EFFICACY WAS MAINTAINED THROUGHOUT ALL CYCLES.
STUDY 4
IN ONE MULTICENTER, MULTINATIONAL, RANDOMIZED, ACTIVE-CONTROLLED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL GROUP, CLINICAL NON-INFERIORITY STUDY, THE EFFICACY AND SAFETY OF A SINGLE DOSE OF ORAL PALONOSETRON 0.50 MG WAS COMPARED TO INTRAVENOUS PALONOSETRON 0.25 MG IN CANCER PATIENTS SCHEDULED TO RECEIVE HIGHLY EMETOGENIC CISPLATIN ( > 70 MG/M²) BASED CHEMOTHERAPY. THE PURPOSE OF THIS STUDY WAS TO DEMONSTRATE THAT ORAL PALONOSETRON 0.5 MG CONTRIBUTES TO THE EFFICACY OF AKYNZEO DURING THE ACUTE PHASE (FIRST 24 HOURS AFTER CANCER CHEMOTHERAPY) IN THE SETTING OF CISPLATIN BASED CHEMOTHERAPY. A TOTAL OF 739 PATIENTS (ORAL PALONOSETRON N=370; INTRAVENOUS PALONOSETRON N=369) RECEIVED STUDY MEDICATION.
THE PRIMARY EFFICACY ENDPOINT WAS COMPLETE RESPONSE (CR) (DEFINED AS NO EMETIC EPISODE AND NO USE OF RESCUE MEDICATION) WITHIN 24 HOURS (ACUTE PHASE) AFTER THE START OF CISPLATIN-BASED CHEMOTHERAPY ADMINISTRATION. IN THE ORAL PALONOSETRON ARM, 89.4% OF PATIENTS ACHIEVED A CR IN THE ACUTE PHASE COMPARED TO 86.2% OF PATIENTS IN THE INTRAVENOUS PALONOSETRON ARM, WITH A DIFFERENCE OF 3.21% (99% CI: -2.74% TO 9.17%). NON-INFERIORITY OF ORAL PALONOSETRON VERSUS INTRAVENOUS PALONOSETRON WAS DEMONSTRATED SINCE THE LOWER LIMIT OF THE TWO-SIDED 99% CI FOR THE DIFFERENCE IN PROPORTIONS OF PATIENTS WITH CR WAS GREATER (I.E., CLOSER TO ZERO) THAN THE PRE-DEFINED NON-INFERIORITY MARGIN SET AT -15%.