Netupitant And Palonosetron

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 dissolution. Step 5 Before administration, inspect the final diluted solution for particulate matter and discoloration. Discard the vial or bag if particulates and/or discoloration are observed. Step 6 Administer over 30 minutes as an intravenous infusion. At the end of the infusion, flush the infusion line with the same carrier solution to ensure complete drug administration. AKYNZEO injection (To-be-Diluted) contains no antimicrobial preservatives and is intended for single use only. Compatibility AKYNZEO injection (To-be-Diluted) is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing AKYNZEO solution or infused simultaneously. Stability and Storage The total time from dilution to the start of the infusion, with or without intravenous dexamethasone sodium phosphate, should not exceed 24 hours. Store the final diluted solution at room temperature, 20ºC to 25ºC (68Fº to 77ºF). 2.3 Preparation and Administration of AKYNZEO for Injection See Table 4 for preparation instructions of AKYZNEO for injection. AKYNZEO for injection requires dilution prior to administration. Table 4: Preparation and Administration of AKYNZEO for Injection Step 1 Aseptically inject 20 mL 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP into the vial. Ensure the solvent is added to the vial along the vial wall and not jetted in order to prevent foaming. Swirl the vial gently. 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 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 dissolution. Step 5 Before administration, inspect the final diluted solution for particulate matter and discoloration. Discard the vial or bag if particulates and/or discoloration are observed. Step 6 Administer over 30 minutes as an intravenous infusion. At the end of the infusion, flush the infusion line with the same carrier solution to ensure complete drug administration. AKYNZEO for injection contains no antimicrobial preservatives, is intended for single use only. Compatibility AKYNZEO for injection is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing AKYNZEO solution or infused simultaneously. Stability and Storage The total time from reconstitution to the start of the infusion, with or without intravenous dexamethasone sodium phosphate, should not exceed 24 hours. Store the reconstituted solution and the final diluted solution at room temperature, 20ºC to 25ºC (68ºF to 77ºF). 2.4 Incompatibility of AKYNZEO for Injection and AKYZNEO Injection AKYNZEO for injection, AKYNZEO injection (Ready-to-Use) and AKYNZEO injection (To-be-Diluted) are incompatible with any solution containing divalent cations (e.g., calcium, magnesium), including Lactated Ringer’s injection and Hartmann's Solution. Limited data are available on the compatibility of AKYNZEO for injection, AKYNZEO injection (Ready-to-Use), and AKYNZEO injection (To-be-Diluted) with other intravenous substances, additives, or other medications with the exception of intravenous dexamethasone sodium phosphate [see Dosage and Administration ( 2.2 , 2.3 ) ] and they should not be added to the AKYNZEO solution or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, flush the line before and after infusion of AKYNZEO solution with 0.9% Sodium Chloride Injection, USP.

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 AKYNZEO capsules (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 greater than 3 times the upper limit of normal 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 (greater than or equal to 70 mg/m 2 ) 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 greater than 10 times the upper limit of normal. AKYNZEO for Injection The safety of AKYNZEO for injection was evaluated in 203 patients in an active-controlled multi-cycle (median 4 cycles, range of 1-4 cycles) safety clinical study in patients receiving HEC regimens, not including anthracycline plus cyclophosphamide, (e.g., cisplatin, cyclophosphamide, carmustine, dacarbazine and mechlorethamine) compared to 201 patients receiving AKYNZEO capsules ( NCT02517021 ). The median age was 60 years, 46% were female, 99.5 % were White, 0.3% were Asian, and 0.3% were Hispanic. All patients received a single dose of AKYNZEO for injection 30 minutes prior to the start of each chemotherapy cycle; dexamethasone was co-administered with AKYNZEO. The safety profile of AKYNZEO for injection was generally similar to that seen with AKYNZEO capsules.

12.3 Pharmacokinetics Netupitant and Palonosetron Absorption Upon single oral administration of AKYNZEO capsules to healthy subjects and patients, netupitant and palonosetron were measurable within 1 hour after administration and reached the maximum concentration (Cmax) in approximately 4 to 5 hours (Table 8). Table 8: Systemic Exposure (AUCinf and Cmax) of Netupitant and Palonosetron After a Single Oral Dose of AKYNZEO in Healthy Subjects and Cancer Patients Parameter Population Mean (CV% 2 1 median (min-max); 2 CV: coefficient of variation; AUC inf : area under the plasma concentration-time curve from time 0 to infinity; tmax: time to maximum concentration. ) Netupitant Palonosetron AUC inf (ng×h/mL) Healthy Subjects 14,402 (51) 56.7 (33) Patients 17,365 (39) 58.3 (50) C max (ng/mL) Healthy Subjects 434 (56) 1.53 (25) Patients 496 (49) 0.95 (35) t max (h) Healthy Subjects 5 (2 to 12) 5 (1 to 12) Patients 4 (2 to 8) 5 (1 to 12) Following oral administration, the absolute bioavailability of palonosetron was approximately 97%. When AKYNZEO capsules were administered under fed conditions, the systemic exposure to netupitant and palonosetron was similar to the exposure under fasting conditions. In cancer patients who received a single dose of AKYNZEO capsules 1 hour prior to chemotherapy (docetaxel, etoposide, or cyclophosphamide), the C max and the area under the concentration-time curve from time zero to infinity (AUC inf ) of netupitant and its metabolites were similar to those in healthy subjects. The mean C max and AUC inf of palonosetron in cancer patients were similar to those in healthy subjects. No changes in pharmacokinetics of netupitant and palonosetron were observed when 450 mg oral netupitant and 0.75 mg oral palonosetron were given alone or co-administered (1.5 times the recommended dose of AKYNZEO capsules). Dose Proportionality Netupitant There was a greater than dose-proportional increase in the systemic exposure (108-fold AUC inf increase for a 30-fold dose increase) when the oral netupitant dose was increased from 10 mg (approximately 3% the recommended dose in AKYNZEO capsules) to 300 mg of netupitant and a dose-proportional increase in the systemic exposure when the netupitant dose was increased from 300 mg to 450 mg of netupitant (1.5 times the recommended dose in AKYNZEO capsules). Palonosetron After single oral doses of palonosetron ranging from 0.25 to 6.8 mg (0.5 to 13.6 times the recommended dose in AKYNZEO capsules) using a buffered solution, the mean C max and AUC inf were dose proportional in healthy subjects. Following single intravenous doses of AKYNZEO for injection in patients or fosnetupitant in healthy subjects, C max of netupitant and palonosetron were achieved at the end of the 30-minute infusion (Table 9). Table 9: Systemic Exposure (AUC 0-120 and C max ) of Netupitant and Palonosetron After a Single Intravenous Dose of AKYNZEO for Injection in Cancer Patients or a Single Intravenous Dose of Fosnetupitant in Healthy Subjects Parameter Population Mean (CV% 2 1 median (min-max); 2 CV: coefficient of variation; AUC inf : area under the plasma concentration-time curve from time 0 to infinity; tmax: time to maximum concentration. ) Netupitant Palonosetron AUC 0-120 (ng×h/mL) Healthy Subjects 12,012 (19) -- Patients 8,922 (22) 28 (28) C max (ng/mL) Healthy Subjects 841 (21) -- Patients 590 (28) 0.8 (35) t max (h) Healthy Subjects 0.5 (0.5 to 0.4) -- Patients 0.6 (0.5 to 4) 0.6 (0.5 to 6) Distribution After single oral administration of AKYNZEO capsules, netupitant and palonosetron were widely distributed throughout the body (Table 10). Table 10: Volume of Distribution (Vz/F) in Healthy Subjects and Cancer Patients After a Single Oral Dose of AKYNZEO and In Vitro Protein Binding Parameter Population Mean (CV% c a Concentration range: 10 to 1300 ng/mL; b Concentration range: 100 to 200 ng/mL; c CV: coefficient of variation ) Netupitant Palonosetron Vz/F (L) Healthy Subjects 3314 (53) 586 (33) Patients 1982 (46) 663 (24) Plasma Protein Binding In vitro studies Netupitant: > 99.5% Major Metabolites: > 97% 62% After administration of single dose of AKYNZEO for injection in patients, the mean ± SD of volume of distribution (Vz) of netupitant and palonosetron were 2627 ± 990 L and 594 ± 239 L, respectively, consistent with previous estimates after single oral administration of AKYNZEO capsules in healthy subjects and cancer patients (Table 10). Elimination – Netupitant After a single dose of AKYNZEO capsules, netupitant is eliminated from the body in a multi-exponential fashion and the mean ± SD of apparent elimination half-life was of 96 ± 59 hours in healthy subjects and 80 ± 29 hours in cancer patients. The mean ± SD of estimated systemic clearance (CL/F) was 26.3 ± 12.5 L/h in healthy subjects and 20.3 ± 9.2 L/h in patients. In patients, following intravenous infusion of AKYNZEO for injection, the mean ± SD total body clearance (CL) and terminal half-life (t 1/2 ) of netupitant were 14.1 ± 5.3 L/h and 144 ± 73 hours, respectively. 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 (NK-1) receptor. The mean AUC inf for metabolites M1, M2 and M3 was 29%, 14% and 33% of netupitant, respectively. The median t max for metabolite M2 was 5 hours and was about 17 to 32 hours for metabolites M1 and M3, respectively. Excretion After a single oral administration of [ 14 C]­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 within 30 days post-dose. Elimination - Palonosetron Following oral administration of AKYNZEO capsules in healthy subjects and cancer patients, the mean ( ± SD) of half-life of palonosetron was 44 ± 15 hours and 50 ± 16 hours, respectively, whereas the mean ± SD of total body clearance (CL/F) was 9.6 ± 2.7 L/h and 10.0 ± 3.4 L/h, respectively. After a single intravenous palonosetron dose of 10 mcg/kg (approximately 3 times the recommended dose in AKYNZEO for injection), the mean ± SD of total body clearance (CL) of palonosetron in healthy subjects was 12.1 ± 3.7 L/h, and renal clearance (CL R ) was 5.1 ± 2.1 L/h. In patients, following intravenous infusion of AKYNZEO for injection, the mean ± SD total body clearance (CL) and terminal half-life (t 1/2 ) of palonosetron were 7.6 ± 2.6 L/h and 58 ± 27 h, respectively. Metabolism Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S­hydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT 3 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 such as C max , AUC inf , CL, CL R , V z and t 1/2 are not significantly different between poor and extensive metabolizers of CYP2D6 substrates. Excretion Following administration of a single oral 0.75 mg dose of [ 14 C]­palonosetron (1.5 times the recommended dose in AZKYNZEO capsules) 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. Fosnetupitant Absorption Following single intravenous doses of AKYNZEO for injection in patients (235 mg fosnetupitant and 0.25 mg palonosetron infused in 30 minutes) or fosnetupitant in healthy subjects (235 mg fosnetupitant infused in 30 minutes), maximum concentrations of fosnetupitant were achieved at the end of the 30-minute infusion (Table 11). Table 11: Systemic Exposure of Fosnetupitant After a Single Intravenous Dose of Fosnetupitant in Healthy Subjects or AKYNZEO for Injection in Cancer Patients Parameter Population Mean (CV% 2 1 median (min-max); 2 CV: coefficient of variation; AUC inf : AUC from time 0 to infinity ) C max (ng/mL) Healthy Subjects 6431 (14) Patients 3478 (45) t max (h) Healthy Subjects 0.5 (0.25 to 0.5) Patients 0.5 (0.5 to 0.6) AUC inf (ng×h/mL) Healthy Subjects 2938 (12) Patients 1401 (46) In cross-study comparisons, the mean C max and AUC inf of fosnetupitant were lower in patients than in healthy subjects. Similarly, AUC 0-120 and C max of netupitant in patients were 26% and 30% lower than in healthy subjects, respectively (Table 9). The differences in systemic exposures to netupitant are clinically insignificant. In healthy subjects, there was a dose-proportional increase in the systemic exposure when the dose of fosnetupitant was increased from 17.6 mg (7.5% of recommended dose in AKYNZEO for injection) to 353 mg (150% of recommended dose in AKYNZEO for injection). Distribution The mean ± SD volume of distribution (V z ) of fosnetupitant in healthy subjects and in patients was 124 ± 76 L and 296 ±535 L, respectively. The human plasma protein binding of fosnetupitant was 92% at 1 micromolar and 95% at 10 micromolar. Elimination After intravenous administration of AKYNZEO for injection, fosnetupitant plasma concentrations declined in a biexponential manner. Thirty minutes after the end of the infusion, the mean plasma concentration of fosnetupitant was less than 1% of C max . The mean ± SD of terminal elimination half-life and systemic plasma clearance (CL) of fosnetupitant were respectively 0.75 ± 0.40 hours and 249 ± 270 L/h in cancer patients after a single IV dose of AKYNZEO. They were 0.96 ± 0.55 hours (mean ± SD) and 90 ± 13 L/h in healthy subjects after a single intravenous dose of fosnetupitant. Metabolism Fosnetupitant is converted in vivo to netupitant by metabolic hydrolysis. In patients receiving AKYNZEO intravenously, netupitant exposure was 17-fold fosnetupitant exposure, as determined by their AUC inf ratio. Netupitant metabolites M1, M2 and M3 were generated from the released netupitant. In patients, metabolite M1, M2 and M3 exposures were 32%, 21% and 28% of netupitant exposure. The median t max for M1, M2, and M3 were 12, 2 and 12 hours, respectively. Specific Populations Geriatric Patients In cancer patients receiving AKYNZEO capsules, population pharmacokinetic analysis indicated that age (within the range of 29 to 75 years) did not influence the pharmacokinetics of netupitant or palonosetron. In healthy elderly subjects (greater than 65 years of age) the mean AUC inf and C max was 25% and 36% higher, respectively, for netupitant, and 37% and 10% higher, respectively, for palonosetron compared to those in healthy younger adults (22 to 45 years of age). The increase in the systemic exposure to netupitant in the elderly subjects is not considered to be clinically significant. Male and Female Patients In a pooled analysis of data following AKYNZEO capsules, the C max for netupitant was 35% higher in females than in males while the AUC inf was similar between males and females. In female subjects, the mean AUC inf for palonosetron was 35% higher and the mean C max was 26% higher than in male subjects. Sex did not affect the pharmacokinetics of fosnetupitant, netupitant, netupitant metabolites and palonosetron after a single intravenous dose of AKYNZEO in patients. In healthy subjects, no effect of sex was observed on the pharmacokinetics of fosnetupitant, netupitant and its metabolites after a single intravenous dose of fosnetupitant alone. The mean ± SD of netupitant AUC inf and C max in patients were 15672 ± 5496 ng×h/mL and 567 ± 174 ng/mL, respectively in males and 15518 ± 4814 ng×h/mL and 609 ± 161 ng/mL, respectively in females. Patients with Renal Impairment Population pharmacokinetic analysis showed that mild and moderate renal impairment (creatinine clearance 30 to 60 mL/min) did not significantly affect the pharmacokinetics of netupitant in cancer patients. Netupitant has not been studied in patients with severe renal impairment (creatinine clearance less than 30 mL/min). 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 palonosetron and netupitant have not been studied in subjects with end-stage renal disease (creatinine clearance < 15 mL/min not on dialysis) [see Use in Specific Populations ( 8.7 )] . Patients with Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics 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 AUC inf of netupitant was 67% and 86% higher, respectively, than in healthy subjects and the mean C max for netupitant was about 40% and 41% higher, respectively, than in healthy subjects. In patients with mild or moderate hepatic impairment, the mean AUC inf of palonosetron was 33% and 62% higher, respectively, than in healthy subjects and the mean C max for palonosetron was about 14% higher and unchanged, respectively, than in healthy subjects. The pharmacokinetics of netupitant and palonosetron were available from only two patients with severe hepatic impairment. As such the data are too limited to draw a conclusion [see Use in Specific Populations ( 8.6 )]. Drug Interaction Studies Effect of Netupitant/Fosnetupitant and/or Palonosetron on Other Drugs CYP3A4 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. Dexamethasone In healthy subjects, the oral administration of a single AKYNZEO capsule with the CYP3A4 substrate dexamethasone (12 mg on day 1 followed by once-a-day administrations of 8 mg on days 2, 3, 4, 6, 8 and 10), increased the plasma concentrations of dexamethasone for 6 days (Table 12). Table 12: Effect of a Single Dose of Oral AKYNZEO (Day 1) on the Systemic Exposure of a Co-administered CYP3A4 Substrate (Dexamethasone) in Healthy Subjects *the interacting drug (dexamethasone 12 mg) was administered on day 1 with AKYNZEO and alone (8 mg) on days 2, 3, 4, 6, 8 and 10; AUC 0-t : AUC from time zero to time t of last measurable concentration after dexamethasone administration on Days 1, 4, 6 and 8 ↑ = Increased; ↓ = Decreased % Change for Dexamethasone Day 1 Day 4 Day 6 Day 8 C max AUC 0-t C max AUC 0-t C max AUC 0-t C max AUC 0-t 2%↓ 58%↑ 54%↑ 139%↑ 29%↑ 49%↑ 7%↑ 20%↑ In healthy subjects, co-administration of a single intravenous fosnetupitant dose (235 mg) with a 20 mg oral dexamethasone on day 1 followed by twice-a-day administrations of 8 mg dexamethasone on days 2, 3, and 4, increased dexamethasone exposure 2.4-fold on day 4 (Table 13). Table 13: Effect of a Single 235 mg Dose of Intravenous Fosnetupitant (Day 1) on the Systemic Exposure of a Co-administered CYP3A4 Substrate (Dexamethasone) in Healthy Subjects *the interacting drug (dexamethasone 20 mg) was administered on day 1 with AKYNZEO and alone (8 mg bid) on Days 2, 3, 4; AUC 0-24 : AUC from time 0 to 24h after dexamethasone administration on Day 1; AUC 84-108 : AUC from time 84h to 108h after dexamethasone administration on Day 4 ↑ = Increased; ↓ = Decreased % Change for Dexamethasone Day 1 Day 4 C max AUC 0-24 C max AUC 84-108 3%↓ 50%↑ 70%↑ 142%↑ Considering the limited fosnetupitant exposure in human plasma and its conversion to netupitant within 30 minutes after completion of infusion, the effects are ascribed to netupitant [see Drug Interactions ( 7.1 )] . Midazolam When co-administered with netupitant 300 mg the mean C max and AUC inf of midazolam after single dose oral administration of 7.5 mg midazolam was 36% and 126% higher, respectively [see Drug Interactions ( 7.1 )] . Chemotherapeutic Agents (docetaxel, etoposide, cyclophosphamide) Systemic exposure to intravenously administered chemotherapeutic agents that are metabolized by CYP3A4 was higher when AKYNZEO capsules was co-administered in cancer patients than when palonosetron alone was co-administered (see Table 14). Table 14: Effect of a Single Dose of Oral AKYNZEO on the Systemic Exposure of Co-administered Chemotherapy Agents Metabolized by CYP3A4 in Patients with Cancer Co-administered Chemotherapeutic Agent a a Following a single oral dose of AKYNZEO compared to co-administered with palonosetron alone b AUC 0-t : AUC from time zero to time t of last measurable concentration ↑ = Increased; ↓ = Decreased Change in Systemic Exposures of Chemotherapeutic Agents when Co-administered with AKYNZEO Capsules Compared to Co-administration with Palonosetron AUC 0-t b C max Docetaxel 75 to 100 mg/m 2 35%↑ 49%↑ Etoposide 35 to 100 mg/m 2 28%↑ 10%↑ Cyclophosphamide 500 to 1000 mg/m 2 20%↑ 27%↑ The mean AUC inf of palonosetron was about 65% higher when AKYNZEO capsules was co-administered with docetaxel than with etoposide or cyclophosphamide, while the mean AUC inf of netupitant was similar among groups that received docetaxel, etoposide, or cyclophosphamide [see Drug Interactions ( 7.1 )]. 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 AUCinf of erythromycin were increased by 92% and 56%, respectively. The change in exposure is not clinically significant. Oral Contraceptives A single dose of AKYNZEO capsules, when given with a single oral dose of 60 mcg ethinyl estradiol and 300 mcg levonorgestrel, showed no effect on C max and increased the AUC 0-t of levonorgestrel by 46%. The C max and AUC 0-t of ethinyl estradiol increased by 5% and 16% respectively. The change in exposure is not clinically significant [see Drug Interactions ( 7.1 )]. Other CYP P450 enzymes 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 oral AKYNZEO. Netupitant and its metabolites, M1, M2 and M3, are not inducers of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4. In in vitro studies, palonosetron did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 or induce CYP1A2, CYP2D6 or CYP3A4/5. CYP2C19 was not investigated. Transporters P-gp and BCRP Based on in vitro studies, netupitant is an inhibitor of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporters. In vitro studies indicated that fosnetupitant is an inhibitor of P-gp. However, an in vivo interaction between AKYNZEO for injection and P-gp substrates is considered unlikely. In vitro , palonosetron was an inhibitor of MATE1, MATE2-K, OCT1, OCT2 and OAT3 transporters. An in vivo interaction between AKYNZEO capsules or injection and transporter substrates is considered unlikely. Digoxin P-gp Substrate Co-administration of oral netupitant 450 mg (1.5 times the recommended dose in AKYNZEO capsules) did not significantly affect the systemic exposure (4% increase of AUC 0-24 at steady state) and urinary excretion (2% increase) of oral digoxin, a substrate of P-gp, at steady-state. Concurrent administration of AKYNZEO capsules or AKYNZEO for injection with digoxin is not expected to affect the systemic exposure to digoxin. Other Transporters 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 indicated that fosnetupitant is an inhibitor of OATP1B1 and OATP1B3 transporters. However, an in vivo interaction between AKYNZEO for injection and OATP1B1, OATP1B3, and P-gp substrates is considered unlikely. In vitro studies indicated that fosnetupitant is not an inhibitor of MATE2-K transporter. Effects of Other Drugs on Netupitant/Fosnetupitant and/or Palonosetron Based on in vitro studies, fosnetupitant is not a substrate of BCRP, BSEP, MDR1 and MATE1, MATE2-K, OAT1, OAT3, OATP2B1, OCT1 and OCT2. Netupitant is not a substrate for P-gp. However, metabolite M2 is a substrate for P-gp. Netupitant and palonosetron are CYP3A4 substrates. Co-administration of strong CYP3A4 inhibitors, such as ketoconazole, or strong CYP3A4 inducers, such as rifampin, with a single oral administration of AKYNZEO capsules affects with clinical significance the exposure to netupitant but not to palonosetron (Table 15). Table 15: Change in Systemic Exposure to Netupitant and Palonosetrona When a Single Dose of AKYNZEO is Co‑Administered with Either a CYP3A4 Inhibitor or a CYP3A4 Inducer in Healthy Subjects Co-administered Drug Netupitant b a Following a single oral dose of AKYNZEO; b Geometric Mean AUC inf and C max ; ↑ = Increased; ↓ = Decreased Palonosetron b AUC inf C max AUC inf C max Strong CYP3A4 Inhibitor Ketoconazole 400 mg once daily for 12 days 140%↑ 25%↑ 10%↑ 15%↑ Strong CYP3A4 Inducer Rifampin 600 mg once daily for 17 days 62%↓ 82%↓ 19%↓ 15%↓