CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 2057180rig15000 LABELING HIGHLIGHTS OF PRESCRIBING INFORVIATION These highlights do not include all the information needed to use safely and effectively. See full prescribing information for AKYNZEOQ. (netnpitant and palonosetron) capsules, for oral use Initial U.S. Approval: 21314 AND AKYNZEO is a ?xed combination of netupitant. a substance Pe?neurolcinin receptor antagonist, and palonosetron, a serotonin?3 receptor antagonist 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. Oral 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. (I) DOSAGE AND One AKYNZEO capsule administered approximately 1 hour prior to the start of chemotherapy. (2) AKYNZEO can be taken with or Without food. (2) DOSAGE FORMS AND Capsule: 300 mg netupitantFU? palonosetron None WARNINGS AND I Hypersensitivity reactions, including anaphylaxis. have been reported in patients receiving palonosetron with or without known hypusensitivity to other 5-HT3 receptor antagonists I Serotonin has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs (5.2) REACTIONS Most common adverse reactions (incidence 23% and greater than palonosetron) are headache. asthenia, dyspepsia, fatigue. constipation and erythema (6.1) To report SUSPECTED ADVERSE REACTIONS, contact EISAI at 1-333-422?4743 or FDA at or I CYP3A4 Substrates: inlnbition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug that can last at least days and may last longer after single dosage administration of use with caution (I. 1] I CYP3A4 Inducers (cg. rifampin): decreased plasma concentrations of netupitant; avoid use (12) USE IN SPECIFIC I Hepatic Impainnent: Avoid use in patients with severe hepatic impairment (3.6) I Renal Impairment: Avoid use in patients with severe renal impairment or end-stage renal disease See 17 for PATIENT COUNSELING INFORMATION and approved patient labeling. Revised: 1022014 FULL PRESCRIBING INFORMATION: CONTENTS INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION DOSAGE PORN-IS AND CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity 5.2 Serotonin IE ADVERSE REACTIONS 6.1 Climcal Trials Experience DRUG INTERACTIONS i" .1 Effects of AKYNZEO on Other Drugs 7".2 Effects of Other Drugs on AKYNZEO i" .3 Serotonergic Drugs 3 USE IN SPECIFIC POPULATIONS 81 Pregnancy 8 .3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7" Renal Impairment Reference ID: 3642902 OVERDOSAGE 1] DESCRIPTION 12 CLINICAL PILARNIACOLOGY 12.1 Mechanism of Action 12.2 Pliarmacodynarnics 12.3 Pharmacoltinetics IS NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis. Mutagenesis, hnpainnent of Fertility 14 CLINICAL STUDIES IIS HOW SUPPLIEDISTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 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 ?xed combination of palorrosetr?on and netupitant: palorrosetron prevents nausea and vomiting during the acute phase and rretupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy. 2 DOSAGE AND ADMINISTRATION Highly Ernetogenic Chemotherapy, including Cisplatin Based The recommended dosage in adults is one capsule of AKENZEO administered approximately 1 hour prior to the start of chemotherapy with deaarnetlrasone 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 Smdies (I 4), Table Antln'acyclines 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 dexanrethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1. Administration of dexamethasone on days 2 to 4 is not necessary [see Clix-rice! Sordies Table AKYNZEO can be taken with or without food. 3 DOSAGE FORMS AND AKYNZEO (3 00 mg netupitantf?j mg palonosetron) capsules are hard gelatin capsules with white body and caramel cap with printed on the body. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Hypersensitivity reactions, including have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists. 5.2 Serotonin The development of serotonin has been reported with receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs selective serotonin reuptalce inhibitors (SSRIs), serotonin and nor?epineplnine reuptake inhibitors (SNRIs), Inonoarnine oxidase inhibitors, mirtazapine, ferrtanyl. lithium, trarnadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin related to receptor antagonist use occurred in a post-anesthesia care rmit or an infusion center. associated with serotonin may include the following combination of signs and mental status changes agitation, hallucinations, delirium, and coma), autonomic instability tachycardia, labile blood pressure, dizziness, diaphoresis, ?ushing, and hyperthermia), neuromuscular tremor. rigidity. myoclonus. hyperre?exia. and incoordination), seizures, with or without gastrointestinal nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin especially with concomitant use of AKYNZEO and other serotonergic drugs. If of serotonin occur, discontinue AKYNZEO and initiate supportive treatment- Patients should be informed of the increased risk of serotonin especially Reference ID: 3642902 if AKYNZEO is used concomitantly with other serotonergic drugs see Drug Interactions (TO, Patient Counseiiag Information (1 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted rmder widely varying conditions, adverse reaction rates observed in the clinical trials ot'a drug cannot be directly compared to rates in the clinical trials of another drug and may not re?ect 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 re?ect exposrue to AKYNZEO in 1169 cancer patients, receiving at least one cycle of cancer chemotherapy in 3 active-controlled trials [see Ciiaicai Studies including 782 exposed to AKYNZEO for at least 4 cycles and 321 exposed for at least 6 cycles, up to a 111aximlnn 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 1 hour prior to the start of each chemotherapy cycle. In all studies, dexamethasone was co-administered with AKYNZEO [see Ciinicai Sniciies Tobie 5 and Table ispiaiin Based 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 de?ned 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 23% of Cancer Patients Receiving AKYNZEO and Cisplatin Based Highly Enletogenic Chemotherapy (Cycle 1) AKYNZEO .. carcasses, ?Marga-5mg Dyspepsia 4% 2% Fatigue 4% 2% Constipation 3% 1% Erythema 3% 2% ariaF Cveiopiiasphamide Based Chemotherapy In a study of patients receiving anthracycline and cyclophosphaniide based chemotherapy, 7'25 patients were treated with AKYNZEO during Cycle 1, and 635 ofthese patients continued for up to 8 cycles in a multiple-cycle extension. Table 2 shows adverse reactions de?ned as adverse events repoited at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone dining Cycle 1. The adverse reaction profile in subsequent cycles was similar to that observed in Cycle 1. Table 2: Adverse Reactions Occurring in 33% of Cancer Patients Receiving AKYNZEO and Anthracyclines and Cyclophosphamide Based Chemotherapy (Cycle 1) AKYNZEO Adverse Reactions netupitant mgi palonusetrun 0.5 mg Palonosetron 0.5 mg fN=725) Headache 9 Asthenia 8% 7'91: Fatigue T93 5% Reference ID: 3642902 In addition to the adverse reactions shown above, there were reports of concomitant elevations of transaminases 3 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 AKYNZEO . netupitant 301] mg! Palonosetron 0.5 mg Labor ator} Changes palonosetron 0.5 mg AST 3? 3 ULN andtor ALT 3 with 3 Total Bilirubin 33* ULN AST 3? 10 ULN and-?or ALT 3? 10 ULN with 2 Total Bilirubin ULN AST 3* 3 ULN and-"or ALT 3 with Total Bilirubin 3 2 ULN In a multi-cycle safety study of 412 patients, the safety pro?le 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 2} 3 ULN and total bilirubin in [his 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 (370 mg/mi) based chemotherapy, there were two patients 2:369) in the intravenous palonosetron aim who had concomitant elevations of transaminases and total bilirnbin. Neither experienced transaminase elevations of 10 ULN. 7 DRUG INTERACTIONS 7.1 Effects of AKYNZEO on Other Drugs Interaction with CYP3A4 Substrates Netupitant, a component of AKYNZEO, is a moderate inhibitor of CYP3A4. AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when co- administered with AKYNZEO. The inhibitory effect on CYP3A4 can last for multiple days. Dexamethasone A two-fold increase in the systemic exposure of clexamethasone was observed 4 days after single close of netupitant. The duration of the effect was not studied beyond 4 days. Administer a reduced dose of dexamethasone with AKYNZEO [see Dosage and Administration (2), Clinical Pharmacology . Midazoi'am When administered with netupitant, the systemic exposure to midazolam was signi?cantly increased. Consider the potential effects of increased plasma concentrations of midaaolam or other benzodiazepines metabolized via CYP3 A4 {alprazolarrn triazolarn) when administering these drugs with AKYNZEO. Interaction with chemotherapeutic agents The systemic exposure of chemotherapy agents metabolized by CYP3A4 can increase when administered with AKYNZEO- Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, .4 Reference ID: 3642902 paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfarnide, imatinib, vinorelbine, vinblastine, and vincristine see Ciinienl Pharmacology (12. Caution and monitoring for chemotherapeutic related adverse reactions are advised in patients receiving chemotherapy agents metabolized primarily by CYP3A4. Interaction with omi cono?aceptives Clinically signi?cant effect of AKYNZEO on the ef?cacy of oral contraceptives containing levonorgestrel and ethinyl estradiol is milikely. 7.2 Effects of Other Drugs on AKYNZEO thupitant, a component of AKYNZEO, is mainly metabolized by CYP3A4 1' see Ciinicnl Pharmacology 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 CYPSA inducer can decrease the ef?cacy of AKYNZEO by substantially reducil'ig plasma concentratiol'is of the netupitant component {see Ciinicai Piiarnmcoiogv (l CYP3A4 Inhibitors Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor ketoconaaole} can signi?cantly increase the systemic exposure to the netupitant component of AKYNZEO. However, no dosage adjustment is necessary for single dose administration of AKYNZEO [see Clinical Pharmacology 7.3 Serotonergic Drugs Serotonin (including altered mental status, antonornic instability, and neuromnscular has been described following the concomitant use of receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (S SRls) and serotonin and noradrenaline reuptake inhibitors [see Warnings and Precautions (5. 8 USE IN SPECIFIC POPULATIONS 3.1 Pregnancy Pregnancy Category 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 human AUC (area under the plasma concentration-time curve) at the single human dose to be given with each cycle of chemotherapy. 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 human AUC at the single human dose to be given with each cycle of chemotherapy. Daily administration of netupitant in rats up to 3 .7 times the human AUG at the reconunended human dose during organogenesis through lactation produced no adverse effects in the 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 bene?t justi?es the potential risk to the fetus. Reference ID: 3642902 Animal Data Daily administration of up to 30 mg/kg netupitant in rats {3 .7 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy) during the period of orgauogenesis produced no effects 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 rug/kg/day and higher (0.2 times the human AUC at the recorrnnended single hmnan 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 occru?red at 30 Maternal toxicity in rabbits loss of bodyweight during the treatment period} was also observed at 30 mg/kg/day. Daily administration of 11p to 3D netupitant (3.7 times the human AUG at the recommended hmnan dose) in rats during organogenesis through lactation produced no adverse effects in the In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed in pregnant rats given oral doses up to 60 mg/kgtday (921 times the recommended human oral dose based on body surface area) or program rabbits given oral doses up to 60111g/kg/day{1841 times the recommended hrunan oral dose based on body surface area) during the period of organogenesis. 8.3 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 [see Toxicology 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. 8.4 Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. 8.5 Geriatric Use Of the 1169 adult cancer patients treated with AKYNZEO in clinical studies, 18% were aged 65 and over, 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 ef?cacy were performed in the two trials that compared AKYNZEO to palonosetron [see Clerical Studies 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 with AKYNZEO and 123 were treated with palonosetron alone. The difference in CR rates between AKYNZEO and palonosetron alone in <65 years and 2% in 365 years) was similar between the two age goups in the acute phase. In the delayed phase, the difference in CR rates between AKYNZEO and palonosetron alone in <65 years and 1% in 1: 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 goup relative to the yormger patients treated with palonosetron alone In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac fimction and concomitant disease or other drug therapy. 8.6 Hepatic Impairment No dosage adj ustrnent for AKWZEO 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 a9);f Avoid use of AKYNZEO in patients with severe hepatic impainnent. [see Overdosoge 0), Clinical Pharmacology (l Reference ID: 3642902 Renal Impairment No dosage adjustment for AKYNZEO is necessary in patients with mild to moderate renal impairment. The phatmacokinetics and safety of netupitant has not been studied in patients with severe renal impairment, although severe renal impairment did not substantially affect phannacokinetics of palonosetron. The phalrnacokinetics for netupitant and palonosen'on was not studied in patients with end- stage renal disease requiring hemodialysis. Avoid use of AKYNZEO in patients with severe renal impairment or end-stage renal disease [see Clinical Pharmacology 10 OWRDOSAGE No speci?c 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 rig/kg (equivalent to 6 mg ?xed dose), as part of a dose ranging study. This is approximately 12 times the oral dose of 0.5 trig 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. 1 1 DESCRIPTION AKYNZEO (3 00 mg netupitantf?j mg palonosetron) is art oral fixed combination product of netupitant, a substance Pinem?okinin (NKI) receptor antagonist, and palonosetron hydrochloride, a serotonin-3 (5- HT3) receptor antagonist. Both netupitant and palonosetron hydrochloride are anti-nausea and anti-emetic agents. Netupitant is chemically described: 2 propanamide. The empirical formula is 30H33135N40, with a molecular weight of 578.61. Netupitant exists as a single isomer and has the following structural formula: FF Palonosetron hydrochloride is chemically described: (3 [2.2.2joct-3-ylj- hydrochloride. The empirical formula is C19H34N20.HC1, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula: Reference ID: 3642902 in? -Ho Netupitant is white to off-white powder. It is freely soluble in toluene and acetone. soluble in isopropanol and ethanol, and very soluble in water. Palonosetron hydrochloride is a white to off-white powder. It is freely soluble in water. soluble in propylene glycol, and soluble in ethanol and 2-propano1. Each AKYNZEO (300 mg netupitantf?j mg palonosetron) capsule is composed of one white-caramel hard gelatin capsule which contains three tablets each containing 100 mg netupitant and one gelatin capsule containing 0.56 mg palonosetron hydrochloride {equivalent to 0.50 mg palonosetron). The inactive ingredients are cellulose, sucrose fatty acid esters, povidone 14-30, croscarmellose sodium. puri?ed water, silicon dioxide, sodium stearyl finnarate, magnesium stearate, mono- and di-glycerides of acid, glycerin, oleate, butylated hydroxyanisole (BHA), gelatin, sorbitol, titanium dioxide, yellow iron oxide, and red iron oxide. It may contain traces of medium-chain triglycerides. lecithin. and denatured ethanol. 12 CLINICAL 12.1 Mechanism of Action Netupitant is a selective antagonist of human substance anenrokinin 1 receptors. Palonosetron is a 5-HT3 receptor antagonist with a strong binding af?nity for this receptor and little or no af?nity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting. palticularly when certain agents. such as cisplatin. are used. 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 enterocln?omaffm cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting re?ex. The development of acute emesis is known to depend on serotonin and its 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 mediated responses. 12.2 Pharmacodynarnics Receptor Occupancy The receptor occupancy for the CINV dosing regimen of netupitant was measured in a hmnan 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 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 signi?cant effects on the interval. 12.3 Pharmacokinelics After single dose administration of AKYNZEO in healthy subjects, the peak plasma concentrations for netupitant and palonosetron were reached in about 5 hours. Reference ID: 3642902 Table 4: PK Parameters {mean and After Single Dose Administration of AKYNZEO in Healthy Subjects Netupitant Palonosetl'on cmax {ngt-?mn 434 (5a) 1.53 (25} rm1 5 {2-12) 5 {1-12) AUC (ng*himL) 14401 (51) 56.7 (33) 96 {61) 44 (34) 1 median (min-max} 1When 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 cyclophospharnide), the and AUC of netupitant and its metabolites were similar to those in healthy subjects. The mean Cum and AUC ofpalonosetron in cancer patients were similar to those in healthy subjects. No signi?cant changes in phannacokinetics 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 cum in approximately 5 hours. There was a. greater than dose-proportional increase in the systemic exposure with the dose increase from 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 (V1713: 1982 906 L) (mean :t Human plasma protein binding ofnetupitant is greater than 99.5% at drug concentrations ranging from 10-1300 ng/mL and protein binding of its major metabolites M2 and M3) is geater than 97% at drug concentrations ranging from 100 to 2000 ng/mL. Metaboiism Once absorbed, netupitant is extensively metabolized to form three major metabolites: desrnethyl derivative, Ml; N?oxide derivative, 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 Pineurokinm 1 receptor. Mean Cm 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 tmElx for metabolite M2 was 5 hours and was about 17-32 hours for metabolites M1 and M3. i iminott on Netupitant is eliminated from the body in a mold-exponential fashion, with an apparent elimination half- life in cancer patients of 80 :t 29 hours (mean i and with an estimated systemic clearance of 20.3 i 9.2 (mean 3: SD) after a. single oral dose of AKYNZEO. After a single oral administration of [HQ-netupitant, approximately half the administered radioactivity was recovered from urine and feces within 120 hours of dosing. The total of3.95% and 70.7% of the radioactive dose was recovered in the urine and feces collected over 336 hours. respectively. and the Reference ID: 3642902 mean fraction of an oral dose of netupitant excreted unchanged in urine is less than 1% suggesting renal clearance is not a signi?cant 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 92%. After single oral doses using buffered solution mean maximum palonosetron concentrations (Cum) and area under the concentration-time curve (AUCM) were dose proportional over the dose range of 3.0 to 80 rig/kg in healthy subjects. Distribution Palonosetron has a volume of distribution of approximately 8.3 i 2.5 Likg. Approximately 62% of palonosetron is bound to plasma proteins. Meioboiism 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% ofthe 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 signi?cantly different between poor and extensive metabolixers of CYP2D6 substrates. Eiimioatioo Following administration of a. single oral 0.75 mg dose of -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. W: was 48 i 19 hours. After a single-dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 i 35 rr1Lil1ikg{1nean i SD) and renal clearance was 66.5 i 18.2 rnLihi'kg. Speci?c Populations Gender In a pooled analysis, the Cm, 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 Cm, 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 "i 5 years old) did not in?uence the pharmacokinetics of netupitant or palonosetron. In healthy elderly subjects (>65 years old) the mean AUCW and 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 Inwoirmeni The effects of hepatic ilnpain'nent 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-P ugh score hepatic impairment- 10 Reference ID: 3642902 111 patients with mild or moderate hepatic impairment, the mean AUCOF of netupitant was 67% and 86% higher. respectively, than in healthy subjects and the mean Cmam for netupitant was about 40% and 41% higher, respectively, than in healthy subjects. In patients with mild or moderate hepatic i111pai1rne11t, the mean of palonosetron was 33% and 62% higher, respectively, than in healthy subjects and the mean Cm, for palonosetron was about 14% higher and unchanged, respectively, than in healthy subjects. The phannacokinetics 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. Rena! Impairment 111 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 phan'nacokinetic 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 phannacokinetics of either palonosetron or netupitant has not been studied in subjects with end-stage renal disease. Drug Interactions: In vr'tm studies have shown that netupitant and its metabolite M1 are inhibitors of CYP3A4. An in vivo study has that netupitant is a moderate inhibitor Based on the in vitae studies. netupitant and its metabolites? are unlikely to have in viva drug-drug interaction via inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 at the clinical dose of 300 mg. Netupitant and its metabolites, M1, M2 and M3, are not inducers of CYP1A2, CYP2C19 and CYP3A4. Their induction potential of CYP2B6 is unknown. Based on tn vitae 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 viva drug-drug interactions with human e?lux transporters BSEP, W2, and human uptake transporters OATPIB 1, OATS, and OCT2 at the clinical dose of300 mg. In vttro studies, palonosetron does not inhibit CYP1A2. CYP2A6, CYPZEI and or induce CYP1A2, or was not investigated. Dexametnnsone 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) signi?cantly increased exposure to dexamethasone. When netupitant was co-administered on Day 1, the mean AUC of dexarnethasone was increased by fold on Day 1 and up to 24-fold on Day 2 and Day 4. Chemotherapeutic Agents (docetoxef, etoposide, cyctophosphanrtde) Systemic exposure to intravenously administered chemotherapeutic agents that are metabolized by CYP3A4 was higher when AKYNZEO was co-adrninistered than when palonosetron alone was co- administered in cancer patients. With co-administration of AKYNZEO the mean Cmax and AUC of docetaxel were 49% and 35% higher, respectively, and mean Cm, and AUC of etoposide were increased by 10% and 28%, respectively, compared to when co-administered with palonosetron alone. 11 Reference ID: 3642902 Mean Gum and AUG for cyclophosphamide after co-administration with AKYNZEO was 27% and 20% higher compared to when co-administered with palonosetron alone. The mean AUG of palonosetron was about 65% higher when AKYNZEO was co-administered with docetaxel than with etoposide or cyclophosphamide, while the mean AUG of netupitant was similar among groups that received docetaxel, etoposide, or cyclophosphanride. Midozofom When co-administered with netupitant 300 mg the mean Gum and AUG of midazolam after single dose oral administration of 71.5 mg midaaolam was 36% and 126% higher, respectively. When 500 mg was co-administered with netupitant 300 mg, the systemic exposure of was highly variable and the mean Gum and AUG of were increased by 92% and 56%, respectively- Oral Contraceptives Single dose AKYNZEO, when given with a single oral dose of 60 pg ethinyl estradiol and 300 pg levonorgestrel, increased the AUG of levonorgestrel by 46%. AKYNZEO had no signi?cant effect on the AUC of ethinyl estradiol. Dtgoxin (To-administration of netupitant 450 mg did not signi?cantly affect the systemic exposure and urinary excretion of digoxin, a substrate of P-glycoprotein, at steady-state. Concurrent administration of AKWZEO with digoxin is not expected to affect the systemic exposure to digoxin. J?s??eets ofofher drugs? on AKWZEO Rtfampiein Single dose AKYNZEO was administered with rifarnpicin, a strong CYP3A4 inducer, following once daily administration of 600 111g rifampicin for 1? days. Pharmacokinetics of netupitant and palonosetron were compared to that alter administration of AKYNZEO alone. Go?administration of rifampicin decreased the mean Cmax and AUCUW of netupitant by 62% and 82%, respectively, compared to those after AKYNZEO alone. Go-adnlinistration of rifampicin decreased the mean Gm and AUG for palonosetron by 15% and 19%, respectively. Ketoeonozoie Single dose AKYNZEO was administered with ketoconazole, a strong CYP3 A4 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. Clo-administration with ketocona?eole increased mean Cmax and AUC of netupitant by 25% and 140%, respectively, compared to those after administration of AKYNZEO alone. The mean AUC and Gm of palonosetron were 10% and 15% higher, respectively, when co-administered with ketoconazole- 13 NONGLINIGAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Netwitont Long-term studies in animals to evaluate carcinogenic potential have not been performed with netupitant. Netupitant was not genotoxic in the Ames test, the mouse cell mutation test. or the in vivo rat micronucleus test- 12 Reference ID: 3642902 Daily oral administration of netupitant in rats at doses up to 30 rug/kg (1.9 times the human AUC in male rats and 3.7 times the human AUC in female rats at the recommended human dose) had no effects on fertility or reproductive performance. Palonosetron In a 104-week carcinogenicity study in CD-1 mice. animals were treated with oral doses ofpalonosetron at 10, 30, and 60 1'1'1gfkg1day. Treatment with palonosetron was not turnorigenic. The highest tested dose produced a systemic exposure to palonosetron (plasma AUC) of about 90 to 173 times the human exposure ng-hme) at the recommended oral dose of 0.5 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30, and 60 mga?lcgf day and 15. 45. and 90 mg/kg/day. respectively. The highest doses produced a systemic exposure to palonosetron (plasma AUC) of 82 and 185 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytorna. increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats. it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and co1r1bined adenoma and carcinoma. Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHOHIGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA (UDS) test, or the mouse micronucleus test- It was: however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal abelration test. Palonosetron at oral doses up to 60 {about 921 times the recommended human oral dose based on body surface area) was formd to have no effect on fertility and reproductive performance of male and female rats. 14 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 ef?cacy 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=?5 mgfmi}. 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 111g. Treatrrlerit regirrlens for the AKYNZEO and palonosetron arms are in Table 5. Table 5: Oral Autiemetir Treatment Regimen in the Highly Emetogenir Chemotherapy Study Treatment Di?, 1 Davs 2 to 4 Regimen - Ir AKYNZED AKYNZ-ED 300 mg neup1tant [3.5 mg palonosetron Dexamethasone 8 111g once a day Dexamethasone 12 mg Palonosetron [1.5 mg Dexarnethasone 20 mg Palonosetron Dexemethasone 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 of53 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 (3 ?uorouracil etoposide and doxorubicin 13 Reference ID: 3642902 The key ef?cacy endpoints were complete response (CR) (de?ned 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 of the key results ?om this study is shown in Table 6. Table 6: Proportion of Patients Responding by Treatment Group and Phase in Study 1 AKYNZEO mg netupitanhf Palonosetron 11.5 mg palonosetron 0.5 mg "Io p?value* COMPLETE RESPONSE Delayed Phaset 90.4 80.1 0.1332 Acute Phase: ass 89.? noon Overall Phase? 89.6 res noos p-t'alues for multiple comparisons using Cochran-Mantel-Haenszel test, strati?ed by gender. T'Delayed phase: 25 to 120 hours post-cisplatm treatment. iAente phase: 0 to 24 hours post-cisplatm treatment. ?0rerallz 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 {1.5 mg in cancer patients scheduled to receive the ?rst 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 in Table 7. Table 7: Oral Antiemetic Treatment Regimen in Study 2 Treatment Regimen Day 1 Days 2 to 3 AKWZEO 300 mg netnpitant.-" 0.5 mg palonosetron Dexamethasone 12 mg Palonosetron 0.5 mg Dexamethasone 20 mg AKYNZEG No antiemetic treatment Palonosetron 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-specifred 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=T25: palonosetron n=725) received study medication: of these, 1438 patients completed cycle 1 and 1286 patients 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 were women; 79% were White, 14% Asian, 6% Hispanic, and were Black or Other. Age ranged from 22 to 79 years, with a median age of 54 years. A total of 724 patients were treated with cyclophosplramide. All patients were additionally treated with either donorubicin or epimbicin Doing the ?rst cycle, 32% of the 725 patients treated with AKYNZEO received a concomitant chemotherapeutic agent in addition to protocol-Il'landated regimens, with the most chemotherapeutic being fluorouracil and docetaxel 14 Reference ID: 3642902 The primary ef?cacy endpoint was the CR rate in the delayed phase, 25-120 hours a?er the start of chemotherapy administration. Major secondary ef?cacy endpoints included CR for the acute and overall phases. A smmnary 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 Sill] mg netupitanta? Palonosetron mg palonosetmn [1.5 mg N=72s p?s?alne* PRIMARY ENDPOINT COMPLETE RESPONSE Delayed P112159 T63 69.5 0.001 MAJOR SECONDARY ENDPOINTS RESPONSE Acute Phasei ss.4 0.04? Overall Phasei are 66.6 .001 I?kp-yalue from Cochran-Mmttel-Haenszel test, strati?ed by age class and region. :Aeute phase: 0 to 24 hours after anthracycline and cyclophosphamide regimen. iDelayed phase: 25 to 120 hours after anthracycline and cyclophosphamide regimen. EOy'erall: to 1212) 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. 15 Reference ID: 3642902 Figure 1: Proportion of Patients with Complete Response in the Delayed Phase by Treatment Group and Cycle in Study 2 Complete Response .AKYHZEO Palnnosetron 100 Cycle 2 Cycle 3 Cycle :1 Cycle 5 Cycle ti AHMED 635 593 551 2?2 1'3?r Palonuulmn 551 505 560 249 191 12.9 10.? 8.2 5.6 [3.2115 [61:15.2] ol?erence between grmpa. [95% Con?dence Interval] Additional clinical trials (Study 3 and Study 4) were conducted to support the ef?cacy 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 AKWZEO: efficacy was maintained throughout all cycles. Study 4 In one multicenter. multinational, randomized, active-controlled. double-blind. double-dummy. parallel goup, clinical non-inferiority study, the ef?cacy 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 (370 lug/m2) based chemotherapy. The purpose of this study was to demonstrate that oral palonosetron 0.5 mg contributes to the ef?cacy of AKYNZEO during the acute phase (?rst 24 hours after cancer chemotherapy) in the setting of cisplatin based chemotherapy. A total of 739 patients (oral palonosetron 11:370; intravenous palonosetron n=3 69) received study medication. The primary ef?cacy endpoint was complete response (CR) (de?ned 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 of3 21% (99% CI: to 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 closer to zero) than the pre-de?ned non-inferiority margin set at. 16 HOW AND HANDLING it 62856-7'96-01, AKYNZEO (300 mg netupitanti?j mg palonosetron). AKYNZEO is supplied as hard gelatin capsules with white body and caramel cap with printed on the body, one capsule per blister. 16 Reference ID: 3642902 Storage Store excursions permitted from OF) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING Advise patients to read the FDA-approved patient labeling {Patient Information). Administration Advise patients to take AKYNZEO with or without food approximately 1 hour prior to the start of chemotherapy. Hypersensitivityr Reactions Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron. Advise patients to seek immediate medical attention if any signs or of a hypersensitivity reaction occur while taking AKYNZEO. Serotonin Advise patients of the possibility of serotonin especially with concomitant use of AKYNZEO and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek irrmrediatc medical attention iftlle following occur: changes in [mental status, autonomic instability, neuromuscular with or without gastrointestinal [see Wars-rings and Precautions Jointly manufactured by Catalent Phanna Solutions, Somerset, NJ and Helsinn Bir?ex 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 AKYNZEO is a registered trademark of Helsinn Healthcare, SA, Lugarro, Switzerland 2014 Eisai Inc, WoodcliffLake. NJ 07677 U.S.A. 201227 17 Reference ID: 3642902 Patient Information (a kin zee oh) (netupitant and palonosetron) capsules Read this Patient Information before you take AKYNZEO and each time you take AKYNZEO. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is AKYNZEO is a prescription medicine called an ?antiemetic.? AKYNZEO is used in people to help prevent the nausea and vomiting that happens right away or later with certain anti-cancer medicines (chemotherapy). It is not known if AKYNZEO is safe and effective in children under 18 years of age. What should I tell my doctor before taking Before taking AKYNZEO, tell your doctor about all of your medical conditions, including if you: have had an allergic reaction to palonosetron or another medicine for nausea or vomiting. have liver problems. are pregnant or plan to become pregnant. It is not known if AKYNZEO will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if AKYNZEO passes into your breast milk. You and your doctor should decide if you will take AKYNZEO or breastfeed. You should not do both. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I take 0 Take AKYNZEO exactly as your doctor tells you to take it. - Take 1 AKYNZEO capsule by mouth, about 1 hour before you get your anti-cancer medicine (chemotherapy). - Take AKYNZEO with or without food. . If you take too much AKYNZEO, call your doctor or go to the nearest emergency room right away. What are the possible side effects of AKYNZEO may cause serious side effects, including: Allergic reactions, such as anaphylaxis. Get emergency medical help right away if you get any of the following of a serious allergic reaction with AKYNZEO: hives, swollen face, trouble breathing, or chest pain. - Serotonin which can happen with AKYNZED particularly with certain other medicines such as anti-depressants and anti-migraine medicines and can lead to death. Go to the nearest hospital emergency room right away if you get any of the following agitation, hallucinations or other changes in mental status, dizziness, muscle twitching {overactive reflexes), or seizures. The most common side effects of AKYNZEO are headache, weakness, fatigue, upset stomach, constipation, and skin redness. These are not all the possible side effects of AKYNZEO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Store AKYNZEO at room temperature between 68 to (20 to 25 General information about the safe and effective use of AKYNZEO Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AKYNZEO for a condition for which it was not prescribed. Do not give AKYNZED to other people, even if they have the same you have. It may harm them. You can ask your doctor or pharmacist for information about AKYNZEO that is written for health professionals. What are the ingredients in Active ingredients: netupitant and palonosetron hydrochloride Inactive ingredients: cellulose, sucrose fatty acid esters, povidone K-30, croscarmellose sodium, purified water, silicon dioxide, sodium stearyl fumarate, magnesium stearate, mono- and di- glycerides of capryI/capric acid, glycerin, oleate, butylated hydroxyanisole (BHA), gelatin, sorbitol, titanium dioxide, yellow iron oxide, red iron oxide. AKYNZEO may contain small amounts of medium-chain triglycerides, lecithin, and denatured ethanol. Jointly manufactured by Catalent Pharma Solutions. Somerset, NJ and Helsinn Birex Pharmaceuticals, Dublin, Ireland Reference ID: 3642902 for Helsinn Healthcare SA, Switzerland Distributed and marketed by Eisal Inc. Lake, NJ under license of Healthcare SA, Switzerland AKYNZEO Is a registered trademark of Healtheare SA. Lugano, Switzerland 02:) 2?14 Elsal Inc.. Lake. NJ 137'67? USA. 213122? For more Information. go to This Patlent Information has been approved by the LLS. Food and Drug Instructions for opening the AKYNZEO pack: 1. Press buttons A and 3 together with one hand. I reunion: and palonosotrm] 41: a .9- mu- 2. Pull the tab card on the right hand side with other hand. 3. Release buttons A and while pulling the tab card. Immlumml. Who - 4. Keep pulling the tab card until the pack is Fully;r open. Reference ID: 3642902 Issued: October 2014 ?puqan ?uuqno ?pn S eaunaaewieqd anig uuislaH pue '13s13wos 'suogmos ewJelld meme) Aq pamuemuew aseq aai; 8w 090 o: Jualengnba apuo'uaonAu uonasouoled Sui 990 pure weudmau 8w oog sureluoo amsdea qaea ?samsdea (uonasouomd pue iueudmau) lo azuA) xu 10-961-99829 DON alnsde) 9/7 (4) ?samsdea (uonasouomd pue mendmau) 0 NBC 62856-796-01 nzeo (netupitant and palonosetron) capsules, 300mg/0.5mg Store at Excursions i permitted to See USP =3 Controlled Room Temperature. =0 See package insert for dosage and administration information. Ea =2 =3 Akynzeo? is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland, used under license. Distributed and marketed by Eisai Inc. Woodcliff Lake, NJ 07677 under license of Helsinn Healthcare SA, Switzerland. 202301 tant and palonosetron) capsules, 300mg/0.5mg Akynzeo~ i (netup ?l A a 6mm? 1d? 31636 MAM 1101 lNOlli N0 M01101 NidO 01 'puellamMS ?v5 uugspH go aiuajgi J?pun [[910 IN Aq pazmuum 1m: 'asuazgl Japun pasn ?pueuamms ?oue'?m aJejqzleaH uugsgaH )0 metuapm palalsl?zu es; gmummy mos'oazulqe-mw DJ 7 0? 1'1. g= 'uoumumwg unnensgugmpe pun a?esop nasug a?emd 935 ?$11 'aJmmadLual moon pauonuo; dS? 335 15.98%.65) 3505-3551 01' pamuu?ad (jazz?Mal 3.5: A 19-31019 bwgo/?wogg ?selnsdeo (uonasouoled pup, lueudmeu) Aluo xu EOBZUA), DUN liapsule NDC 62856-796-01 RX Only Akynzed eonose ron 2E 300m 0 5m i 3?39 438/9, Each capsule contains 300mg netupltantand a 3? 0.55 palonosetron hydrochloride equivalent to 050 mg palonosetron free base loinllv manufactured by Catalan: Pharma Solutions: Sumerget, NJ and Helsinn Blrex Pharmaceuticals lid! Dubl?n, Ireland. n?n-u-n-u-u?a-sn 77' 'x i-l_l_l_I-i-Ill? w/ :3 53363 33:0 l' $5 g?hy?EBE among; ?mwi?a? . ?j $22 ?gsa?mEZUw n. Eg?nus??fBE a gal? ?a 13ch ?82 VARNISH COATING 1 A PANEL Reference ID: 3638364 Reference ID: 3638364 INSIDE VARNISH COATING . . PANEL A Reference ID: 3638364 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JULIE G BEITZ 10/10/2014 Reference ID: 3638364