AKYNZEO

Netupitant is an antiemitic drug approved by the FDA in October for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy.

Netupitant is a neurokinin 1 receptor antagonist.

The combination drug is marketed by Eisai Inc. and Helsinn Therapeutics (U.S). Inc. under the brand Akynzeo.

Netupitant is an antiemitic drug approved by the FDA in October for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy.

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. 12.2 Pharmacodynamics NK-1 Receptor Occupancy The receptor occupancy of netupitant was measured in a human Positron Emission Tomography (PET) study.

Netupitant was shown to cross the blood brain barrier with a NK-1 receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after oral administration of 300 mg netupitant.

AKYNZEO oral dose of 600 mg netupitant (2 times the recommended dose) and 1.5 mg palonosetron (3 times the recommended dose) did not prolong the QT interval to any clinically relevant extent.

The recommended dose of

AKYNZEO for injection (235 mg fosnetupitant and 0.25 mg palonosetron) did not prolong the QT interval to any clinically relevant extent. 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 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 to infinity; tmax: time to maximum concentration). Netupitant Palonosetron AUC inf (ng×h/mL) Healthy Subjects 14,402 56.7 Patients 17,365 58.3 C max (ng/mL) Healthy Subjects 434 1.53 Patients 496 0.95 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%.

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).

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).

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 to infinity; tmax: time to maximum concentration). Netupitant Palonosetron AUC 0-120 (ng×h/mL) Healthy Subjects 12,012 -

• Patients 8,922 28 C max (ng/mL) Healthy Subjects 841 -

• Patients 590 0.8 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 586 Patients 1982 663 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.

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.

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 to 32 hours for metabolites M1 and M3, respectively.

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.

• 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.

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.

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 to infinity ) C max (ng/mL) Healthy Subjects 6431 Patients 3478 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 Patients 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).

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.

Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma between 15 minutes and 3 hours after dosing.

Plasma concentrations reached

Cmax in approximately 5 hours.

There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg to 450 mg.

In cancer patients, Vz/F: 1982 ± 906 L (mean ± SD).

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.

M1, M2 and M3 were shown to bind to the substance P/neurokinin 1 (NK1) receptor.

Hover over products below to view reaction partners Netupitant Desmethyl Netupitant N-oxide Netupitant.

hours with CV% of 61.

Estimated systemic clearance of 20.3 ± 9.2 L/h (mean ± SD).

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Daily oral administration of netupitant in rats at doses up to 30 mg/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.

Recommended Dosage AKYNZEO capsules

The recommended dosage is one AKYNZEO capsule administered 1 hour prior to the start of chemotherapy, with or without food.

AKYNZEO injection is supplied either as a Ready-to-Use (with hanger) vial or a To-be-Diluted vial.

AKYNZEO for injection requires dilution prior to administration.

See full prescribing information for information on preparation, administration, and incompatibilities for each product. 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 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 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 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.

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.

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.

Use immediately once the stopper is punctured.

Injection (To-be-Diluted) See Table 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.

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.

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.

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 for preparation instructions of AKYZNEO for injection.

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 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.

AKYNZEO for injection contains no antimicrobial preservatives, is intended for single use only.

AKYNZEO for injection is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing AKYNZEO solution or infused simultaneously.

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 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.

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).

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) .

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).

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.

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.

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 and 1841 times the recommended oral dose in rats and rabbits, respectively.

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 to 4% and to 20%, respectively.

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 organogenesis through lactation produced no adverse effects in the offspring.

Daily intravenous administration of 39 mg/kg/day fosnetupitant in rats (3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis produced delayed ossification of pubis.

No effects on embryo-fetal development were observed with daily administration of up to 13 mg/kg fosnetupitant in rats (2 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy).

Due to the limited systemic exposure to fosnetupitant in pregnant rats, it is not possible to provide an AUC-based comparison of fosnetupitant exposure in rats and humans.

An increase in resorptions was observed with daily intravenous administration of fosnetupitant at 6 mg/kg/day and higher in rabbits (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) during the period of organogenesis.

No effects were observed in rabbits at 3 mg/kg/day (5.4 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 39 mg/kg fosnetupitant in rats (3 times the AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) during organogenesis through lactation produced lower bodyweight in offspring at birth through maturation, and delayed physical development (pinna detachment, eye opening, and preputial separation).

These effects were associated with maternal toxicity (reduced weight gain and food consumption).

No effects occurred in offspring or dams at 13 mg/kg/day (2 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy).

In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed in pregnant rats given oral doses up to 60 mg/kg/day (921 times the recommended oral dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (1841 times the recommended oral dose based on body surface area) during the period of organogenesis.

The safety and effectiveness of

AKYNZEO in patients below the age of 18 years have not been established.

Of the 1169 adult cancer patients treated with AKYNZEO capsules in clinical studies, 18% were aged 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 efficacy were performed in the two trials that compared AKYNZEO to palonosetron.

In Study in patients treated with cisplatin chemotherapy, among the patients less than age 65 years, 115 were treated with AKYNZEO and were treated with palonosetron alone.

Among the patients 65 years or older, 20 were treated with AKYNZEO and 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 in patients treated with anthracyclines plus cyclophosphamide chemotherapy, among the patients less than age 65 years, 608 were treated with AKYNZEO and were treated with palonosetron alone.

Among the patients 65 years or older, 116 were treated with AKYNZEO and were treated with palonosetron alone.

The difference in CR rates between

AKYNZEO and palonosetron alone (4% in <65 years and 2% in > 65 years) was similar between the two age groups in the acute phase.

In the delayed phase, the difference in CR rates between AKYNZEO and palonosetron alone (9% in <65 years and 1% in ≥ 65 years) was numerically higher in patients <65 years.

This difference between age groups in the delayed phase of Study 2 may be explained, in part, by higher CR in the delayed phase associated with palonosetron alone in the older (81%) relative to the younger patients treated with palonosetron alone (67%).

Of the 239 adult cancer patients treated with AKYNZEO for injection in clinical studies, 36% were aged and over, while 4% were aged 75 years and over.

In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.