AKYNZEO

1 INDICATIONS AND USAGE AKYNZEO capsules is indicated in combination with dexamethasone in adults 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 capsules is a 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. AKYNZEO for injection and AKYNZEO injection are indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. AKYNZEO for injection is a combination of palonosetron and fosnetupitant, a prodrug of netupitant: palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy. Limitations of Use AKYNZEO for injection and AKYNZEO injection have not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy. AKYNZEO capsules is indicated in combination with dexamethasone in adults 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 for injection and AKYNZEO injection are indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Limitations of Use AKYNZEO for injection and AKYNZEO injection have not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy. AKYNZEO is a combination of palonosetron, a serotonin-3 (5-HT3) receptor antagonist, and netupitant or fosnetupitant, substance P/neurokinin-1 (NK-1) receptor antagonists: palonosetron prevents nausea and vomiting during the acute phase and netupitant/fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage AKYNZEO capsules: The recommended dosage is one AKYNZEO capsule administered 1 hour prior to the start of chemotherapy, with or without food. ( 2.1 ) Preparation and Administration AKYNZEO injection is supplied either as a Ready-to-Use (with hanger) vial or a To-be-Diluted vial. (2.2) AKYNZEO for injection requires dilution prior to administration. ( 2.3 ) See full prescribing information for information on preparation, administration, and incompatibilities for each product. (2.2, 2.3, 2.4 ) 2.1 Recommended Dosage The recommended dosages of AKYNZEO and dexamethasone in adults for the prevention of nausea and vomiting associated with administration of emetogenic chemotherapy are shown in Table 1. AKYNZEO capsules can be taken with or without food. Table 1: Antiemetic Treatment Regimen Treatment Regimen Day 1 Days 2 to 4 Highly Emetogenic Chemotherapy, including Cisplatin-Based Chemotherapy AKYNZEO capsules 1 capsule of AKYNZEO 1 hour before chemotherapy Dexamethasone 8 mg once a day Dexamethasone 12 mg 30 minutes before chemotherapy AKYNZEO for injection and AKYNZEO injection 1 vial of AKYNZEO Infuse over 30 minutes starting 30 minutes before chemotherapy [see Dosage and Administration (2.2)] Dexamethasone 8 mg once a day Dexamethasone 12 mg 30 minutes before chemotherapy Anthracyclines and Cyclophosphamide-Based Chemotherapy and Chemotherapy Not Considered Highly Emetogenic AKYNZEO capsules 1 capsule of AKYNZEO 1 hour before chemotherapy None Dexamethasone 12 mg 30 minutes before chemotherapy 2.2 Preparation and Administration of AKYNZEO Injection (Ready-to-Use and To-be-Diluted) AKYNZEO injection is supplied as either a Ready-to-Use (with hanger) vial or a To-be-Diluted vial. AKYNZEO injection (Ready-to-Use; with hanger) See Table 2 for preparation instructions of AKYNZEO injection (Ready-to-Use) for intravenous infusion. AKYNZEO injection (Ready-to-Use) does not require dilution prior to administration. Table 2: Preparation and Administration of AKYNZEO Injection (Ready-to-Use) for Intravenous Infusion Step 1 Before administration, inspect the solution for particulate matter and discoloration. Discard the vial if particulates and/or discoloration are observed. Step 2 Using aseptic technique, insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately. Step 3 To administer, invert and hang the vial utilizing the strap affixed to the bottom of the vial. Step 4 Administer over 30 minutes as an intravenous infusion. At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection, USP or with 5% Dextrose injection, USP to ensure complete drug administration. AKYNZEO injection (Ready-to-Use) contains no antimicrobial preservatives and is intended for single use only. Compatibility AKYNZEO injection (Ready-to-Use) is compatible with intravenous dexamethasone sodium phosphate which can be infused simultaneously. Do not add dexamethasone sodium phosphate to the AKYNZEO injection (Ready-to-Use) vial. Stability and Storage Use immediately once the stopper is punctured. AKYNZEO Injection (To-be-Diluted) See Table 3 for preparation instructions of AKYNZEO injection (To-be-Diluted) for intravenous infusion with dilution. Table 3: Preparation and Administration of AKYNZEO Injection (To-be-Diluted) for Intravenous Infusion Step 1 Before administration, inspect the solution for particulate matter and discoloration. Discard the vial if particulates and/or discoloration are observed. Step 2 Aseptically prepare an infusion vial or bag filled with 30 mL of 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP. Step 3 Aseptically withdraw the entire volume of solution from the AKYNZEO vial (20 mL) and transfer it into the infusion vial or bag containing 30 mL of 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP to yield a total volume of 50 mL. Step 4 Gently invert the vial or bag until complete dis …

3 DOSAGE FORMS AND STRENGTHS Capsules: 300 mg netupitant/0.5 mg palonosetron in a hard gelatin capsule with white body and caramel cap with “HE1” printed on the body. For Injection: 235 mg fosnetupitant/0.25 mg palonosetron white to off-white lyophilized powder in single-dose vial for reconstitution. Injection: 235 mg fosnetupitant/0.25 mg palonosetron per 20 mL (11.75 mg/0.0125 mg per mL) as a clear solution in single-dose vial. Ready-to-Use (with hanger) To-be-Diluted Capsules : 300 mg netupitant/0.5 mg palonosetron. (3) For Injection : 235 mg fosnetupitant/0.25 mg palonosetron as a lyophilized powder in single-dose vial for reconstitution. (3) Injection : 235 mg fosnetupitant/0.25 mg palonosetron (235 mg/0.25 mg per 20 mL (11.75 mg/0.0125 mg per mL) solution in single-dose vial. (3) Ready-to-Use (with hanger) To-be-Diluted

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are found elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Most common adverse reactions (≥3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema ( 6.1 ) The safety profile of AKYNZEO for injection was generally similar to that seen with AKYNZEO capsules. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact HELSINN at 1-844-357-4668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. AKYNZEO Capsules The overall safety of AKYNZEO capsules was evaluated in 1538 cancer patients and healthy subjects 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 ( 14 .1 )] , 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 ( 14.1 ), Table 16 and Table 18 ]. 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 5 shows adverse reactions reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone. Table 5: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO capsules 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 capsules during Cycle 1, and 635 of these patients continued for up to 8 cycles in a multiple-cycle extension. Table 6 shows adverse reactions reported at an incidence of at least 3% and for which the AKYNZEO capsules rate exceeded palonosetron alone during Cycle 1. The adverse reaction profile in subsequent cycles was similar to that observed in Cycle 1. Table 6: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO capsules 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 greater than 3 times the upper limit of normal and total bilirubin in both arms of the two trials that compared AKYNZEO capsules to oral palonosetron, and the frequency of these elevations was comparable between treatment groups. See Table 7. Table 7: Liver Function Laboratory Abnormalities ULN = upper limit of normal 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 …

7 DRUG INTERACTIONS CYP3A4 Substrates: inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug for 6 days after single dosage administration of AKYNZEO; avoid concomitant CYP3A4 substrates for one week, if feasible. If not avoidable, consider dose reduction of the CYP3A4 substrate ( 7.1 ) CYP3A4 Inducers (e.g., rifampin): decreased plasma concentrations of netupitant; avoid use ( 7.2 ) 7.1 Effects of AKYNZEO on Other Drugs Interaction with CYP3A4 Substrates Netupitant is a moderate inhibitor of CYP3A4. AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. A single oral dose of netupitant 300 mg significantly inhibits CYP3A4 for 6 days. Avoid concomitant use of drugs that are CYP3A4 substrates for one week, if feasible. If not avoidable, consider dose reduction of CYP3A4 substrates. Dexamethasone A single oral dose of netupitant 300 mg or a single fosnetupitant infusion of 235 mg increased the systemic exposure of concomitant dexamethasone more than 2-fold on Days 2 and 4. Administer a reduced dose of dexamethasone with AKYNZEO [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 )] . 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 with AKYNZEO [see Clinical Pharmacology ( 12.3 )] . 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, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine [see Clinical Pharmacology ( 12.3 )] . Caution and monitoring for chemotherapeutic related adverse reactions are advised in patients receiving chemotherapy agents metabolized primarily by CYP3A4. Oral Contraceptives There is no clinically significant effect of AKYNZEO on the efficacy of oral contraceptives containing levonorgestrel and ethinyl estradiol [see Clinical Pharmacology ( 12.3 )] . Warfarin Although it was predicted that co-administration of intravenous AKYNZEO with warfarin would not substantially increase the systemic exposure to S-warfarin (CYP2C9 substrate), the active enantiomer, the effects of AKYNZEO for injection and AKYNZEO capsules on INR and prothrombin time have not been studied. Monitor INR and adjust the dosage of warfarin, as needed with concomitant use of AKYNZEO, to maintain the target INR range. 7.2 Effects of Other Drugs on AKYNZEO Netupitant is mainly metabolized by CYP3A4. Palonosetron is mainly metabolized by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. 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 [see Clinical Pharmacology ( 12.3 )] . CYP3A4 Inhibitors Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor (e.g., ketoconazole) can 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 ( 12.3 )] . 7.3 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). If symptoms occur, discontinue AKYNZEO and initiate supportive treatment [see Warnings and Precautions ( 5.2 )].

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm ( 8.1 ). Hepatic Impairment: Avoid use in patients with severe hepatic impairment ( 8.6 ) Renal Impairment: Avoid use in patients with severe renal impairment or end-stage renal disease ( 8.7 ) 8.1 Pregnancy Risk Summary Limited available data with AKYNZEO use in pregnant women are insufficient to inform a drug- associated risk of adverse developmental outcomes. In animal reproduction studies with netupitant, no effects on embryo-fetal development were observed following daily oral administration 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 recommended single 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 oral administration of netupitant in pregnant rabbits during the period of organogenesis with doses at least 0.2 times the human AUC at the recommended single dose to be given with each cycle of chemotherapy. Daily oral administration of netupitant in rats up to 3.7 times the human AUC at the recommended dose during organogenesis through lactation produced no adverse effects in the offspring (see Data). In animal reproduction studies with fosnetupitant, delayed ossification of pubis occurred after intravenous administration in rats during the period of organogenesis at a dose 3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy. In pregnant rabbits, an increase in resorptions was observed with daily intravenous administration of fosnetupitant during the period of organogenesis at doses up to 9 times the human AUC for fosnetupitant and 0.4 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy. Daily intravenous administration of fosnetupitant (3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) in rats during organogenesis through lactation produced lower bodyweight in offspring at birth through maturation, and delayed physical development (see Data). 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 oral dose in rats and rabbits, respectively (see Data). Based on animal data from netupitant studies, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Netupitant Daily oral administration of up to 30 mg/kg netupitant in rats (3.7 times the human AUC at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis produced no effects on embryo-fetal development. However, an increased incidence of external and skeletal abnormalities in rabbit fetuses was observed following daily oral administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human AUC at the recommended single 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 oral administration of up to 30 mg/kg netupitant (3.7 times the human AUC at the recommended dose) in rats during organogen …

12.1 Mechanism of Action Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK-1) receptors. Palonosetron is a 5-HT 3 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-HT 3 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-HT 3 receptors located on vagal afferents to initiate the vomiting reflex. The development of acute emesis is known to depend on serotonin and its 5-HT 3 receptors have been demonstrated to selectively stimulate the emetic response. Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 (NK-1) 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.

11 DESCRIPTION AKYNZEO (300 mg netupitant/0.5 mg palonosetron) capsules are an oral combination product of netupitant, a substance P/neurokinin 1 (NK-1) receptor antagonist, and palonosetron hydrochloride, a serotonin-3 (5-HT 3 ) receptor antagonist. Both netupitant and palonosetron hydrochloride are anti-nausea and anti-emetic agents. Netupitant is chemically described: 2-[3,5-bis(trifluoromethyl)phenyl]-N, 2 dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl] propanamide. The empirical formula is C 30 H 32 F 6 N 4 O, with a molecular weight of 578.61. Netupitant exists as a single isomer and has the following structural formula: Palonosetron hydrochloride is chemically described: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline hydrochloride. The empirical formula is C 19 H 24 N 2 O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula: Netupitant is white to off-white crystalline powder. It is freely soluble in toluene and acetone, soluble in isopropanol and ethanol, and very slightly soluble in water. Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol. Each AKYNZEO capsule is composed of one white-caramel hard gelatin capsule which contains three tablets each containing 100 mg netupitant and one gelatin capsule containing 0.5 mg palonosetron (equivalent to 0.56 mg palonosetron hydrochloride). The inactive ingredients are butylated hydroxyanisole (BHA), croscarmellose sodium, gelatin, glycerin, magnesium stearate, microcrystalline cellulose, mono- and di-glycerides of capryl/capric acid, polyglyceryl dioleate, povidone K-30, purified water, red iron oxide, silicon dioxide, sodium stearyl fumarate, sorbitol, sucrose fatty acid esters, titanium dioxide and yellow iron oxide. It may contain traces of medium-chain triglycerides, lecithin, and denatured ethanol. AKYNZEO (235 mg fosnetupitant/0.25 mg palonosetron) for injection is a combination product of fosnetupitant, a prodrug of netupitant, which is a substance P/neurokinin 1 (NK-1) receptor antagonist, and palonosetron hydrochloride, a serotonin-3 (5-HT 3 ) receptor antagonist. Fosnetupitant chloride hydrochloride is chemically described as 2-(3,5-bis-trifluoromethylphenyl)-N-methyl-N-[6-(4-methyl-4-O-methylene-phosphatepiperazinium-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide chloride hydrochloride. The empirical formula is C 31 H 36 F 6 N 4 O 5 P•Cl•HCl, with a molecular weight of 761.53. Fosnetupitant chloride hydrochloride exists as a single isomer and has the following structural formula: Fosnetupitant chloride hydrochloride is white to off-white to yellowish solid or powder. Its solubility is pH dependent: at acidic pH (pH 2), its solubility is 1.4 mg/mL; at basic pH (pH 10), its solubility is 11.5 mg/mL. Palonosetron hydrochloride is described above in this section. AKYNZEO for injection is available for intravenous infusion supplied as a sterile lyophilized powder. Each vial of AKYNZEO for injection contains 235 mg of fosnetupitant (equivalent to 260 mg fosnetupitant chloride hydrochloride) and 0.25 mg of palonosetron (equivalent to 0.28 mg of palonosetron hydrochloride). The inactive ingredients are edetate disodium (6.4 mg), mannitol (760 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment). AKYNZEO injection is available for intravenous infusion supplied as a sterile solution in a single-dose vial. Each vial of AKYNZEO injection contains 235 mg of fosnetupitant (equivalent to 260 mg fosnetupitant chloride hydrochloride) and 0.25 mg of palonosetron (equivalent to 0.28 mg of palonosetron hydrochloride). The inactive ingredients are edetate disodium (3.2 mg), mannitol (760 mg), water for injection, sodium hydroxide and/or hydrochloric acid (for pH adjustment). Netupitant chemical struct …

10 OVERDOSAGE 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 mcg/kg (approximately 12 times the recommended dose in AKYNZEO capsules), as part of a dose ranging study and had a similar incidence of adverse reactions compared to lower doses. A single dose of 600 mg (2 times the recommended dose in AKYNZEO capsules) of oral netupitant was administered to 49 healthy subjects and a similar incidence of adverse reactions was observed when compared to lower doses of netupitant in cancer patients and healthy subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING Capsules AKYNZEO (300 mg netupitant/0.5 mg palonosetron) capsules: hard gelatin capsules with white body and caramel cap with “HE1” printed on the body. They are supplied as follows: NDC # 69639-101-01: pack of one capsule in one blister NDC # 69639-101-04: pack of four capsules (two capsules per blister strip). Storage AKYNZEO capsules should be stored 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]. For Injection AKYNZEO (235 mg fosnetupitant/0.25 mg palonosetron) for injection: sterile, white to off-white lyophilized powder in single-dose vial for reconstitution. NDC # 69639-102-01: pack of one vial of lyophilized powder Storage Store AKYNZEO for injection in carton, protected from light at 2° to 8°C (35.6 F to 46.4°F). Injection (Ready-to-Use and To-be-Diluted) AKYNZEO 235 mg fosnetupitant/0.25 mg palonosetron per 20 mL (11.75 mg/0.0125 mg per mL) injection: sterile, clear solution in a single-dose vial. NDC # 69639-106-01: pack of one vial of solution with hanger (Ready-to-Use) NDC # 69639-105-01: pack of one vial of solution (To-be-Diluted) Storage Store AKYNZEO injection in carton, protected from light at 20°C to 25°C (68°F to 77°F).