FOSEMRED

(fosaprepitant injection) is a sterile, ready-to-use, clear and colorless solution formulation containing fosaprepitant dimeglumine, a prodrug of aprepitant, a substance P/neurokinin-1 (NK 1 ) receptor antagonist, an antiemetic agent, chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2 R,3S)-2-[(1 R )-1-[3,5bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1 H -1,2,4triazol-1-yl]phosphonate (2:1) (salt).

Its empirical formula is

C 23 H 22 F 7 N 4 O 6 P ⋅ 2(C 7 H 17 NO 5 ) and its structural formula is: Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83.

It is freely soluble in water.

Each 50 mL vial of FOCINVEZ for administration as an intravenous infusion contains 150 mg of fosaprepitant (equivalent to 245.3 mg of fosaprepitant dimeglumine) and the following inactive ingredients: Betadex sulfobutyl ether sodium (8 g), edetate disodium (5.4 mg), sodium hydroxide (for pH adjustment) in water for injection. structure.

in combination with other antiemetic agents, is indicated in adults and pediatric patients 6 months of age and older for the prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

FOCINVEZ has not been studied for the treatment of established nausea and vomiting.

FOCINVEZ is a substance

P/neurokinin-1 (NK 1 ) receptor antagonist, indicated in adults and pediatric patients 6 months of age and older, in combination with other antiemetic agents, for the prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

FOCINVEZ has not been studied for treatment of established nausea and vomiting.

Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK 1 ) receptors.

Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV).

Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions.

Animal and human Positron Emission

Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK 1 receptors.

Animal and human studies have shown that aprepitant augments the antiemetic activity of the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis. 12.2 Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc interval. 12.3 Pharmacokinetics Aprepitant after Fosaprepitant Administration Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant administered as a 20-minute infusion to healthy subjects, the mean AUC 0-∞ of aprepitant was 37.4 (± 14.8) mcg•hr/mL and the mean maximal aprepitant concentration (C max ) was 4.2 (± 1.2) mcg/mL.

Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion.

Aprepitant is greater than 95% bound to plasma proteins.

The mean apparent volume of distribution at steady state (Vd ss ) was approximately 70 L in humans.

Aprepitant crosses the blood brain barrier in humans.

Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and in S9 preparations from multiple other human tissues including kidney, lung and ileum.

Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver.

Aprepitant undergoes extensive metabolism.

In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19.

Metabolism is largely via oxidation at the morpholine ring and its side chains.

No metabolism by

CYP2D6, CYP2C9, or CYP2E1 was detected.

In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [ 14 C]-aprepitant, indicating a substantial presence of metabolites in the plasma.

Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

Following administration of a single intravenous 100-mg dose of [ 14 C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces.

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted.

The apparent terminal half-life ranged from approximately to 13 hours.

Following oral administration of a single 125-mg dose of aprepitant on Day and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21% higher on Day and 36% higher on Day in healthy elderly subjects (65 years and older) relative to younger adult subjects.

C max was 10% higher on Day and 24% higher on Day in healthy elderly subjects relative to younger adult subjects.

These differences are not considered clinically meaningful.

Pediatric Patients Single-Dose Intravenous Fosaprepitant Regimen

Simulated systemic exposures of aprepitant in patients 2 years to less than 12 years and observed systemic exposures in patients 6 months to less than 2 years and to 17 years are shown in Table 9, including AUC 0-24hr, peak plasma concentration (C max ) on Day and concentrations at the end of Day 1 (C 24 ), Day 2 (C 48 ) and Day 3 (C 72 ).

Table 9 Systemic Exposures of Aprepitant for Single-Dose Intravenous Fosaprepitant Regimen in Pediatric Patients Population Single-Dose of Intravenous Fosaprepitant Regimen Geometric Mean AUC 0-24hr. (mcg*hr/mL) C max (mcg/mL) C 24 (mcg/mL) C 48 (mcg/mL) C 72 (mcg/mL) 12 Years to 17 Years 150 mg 29.4 3.4 0.7 ND a ND a 6 Years to less than 12 Years 4 mg/kg 35.2 3.6 0.7 0.2 0.05 2 Years to less than 6 Years 28.2 3.1 0.4 0.1 0.02 6 Months to less than 2 Years 5 mg/kg 32.7 3.3 0.4 NE b ND a a ND = Not Determined.

Pharmacokinetic samples were not collected to support the parameter value of interest. b NE = Not Estimated.

The geometric mean could not be estimated due to values being below the limitation of quantification. 3-Day Intravenous fosaprepitant/Oral aprepitant/Oral aprepitant Regimen: Simulated aprepitant systemic exposures in patients 6 months to less than 12 years and observed systemic exposures in patients to 17 years are shown in Table 10, including AUC 0-24hr, peak plasma concentration (C max ) on Day and concentrations at the end of Day 1 (C 24 ), Day 2 (C 48 ) and Day 3 (C 72 ).

Table 10 Systemic Exposures of Aprepitant for 3-Day Intravenous/Oral/Oral Regimen in Pediatric Patients Population 3-Day Dose of fosaprepitant/ aprepitant (IV/Oral/Oral a ) Geometric Mean AUC 0-24hr. (mcg*hr/mL) C max (mcg/mL) C 24 (mcg/mL) C 48 (mcg/mL) C 72 (mcg/mL) 12 Years to 17 Years 115/80/80 mg 18.0 3.0 0.4 0.2 NE b 6 Years to less than 12 Years 3/2/2 mg/kg 25.7 2.7 0.5 0.3 0.3 2 Years to less than 6 Years 20.2 2.3 0.3 0.2 0.2 6 Months to less than 2 Years 16.6 1.9 0.2 0.1 0.1 a Intravenous fosaprepitant on Day 1, oral aprepitant on Day 2, and oral aprepitant on Day 3 b NE = Not Estimated.

The geometric mean could not be estimated due to values being below the limitation of quantification.

Plasma concentrations of fosaprepitant are negligible within 15-30 minutes after the completion of the infusion in pediatric patients.

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are 9% and 17% higher in females as compared with males.

The half-life of aprepitant is approximately 25% lower in females as compared with males and T max occurs at approximately the same time.

A population pharmacokinetic analysis of aprepitant in pediatric patients (6 months to 17 years) suggests that sex has no clinically meaningful effect on the pharmacokinetics of aprepitant.

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are approximately 27% and 19% higher in Hispanics as compared with Caucasians.

AUC 0-24hr and C max were 74% and 47% higher in Asians as compared to Caucasians.

There was no difference in

AUC 0-24hr or C max between Caucasians and Blacks.

A population pharmacokinetic analysis of aprepitant in pediatric patients (6 months to 17 years) suggests that race has no clinically meaningful effect on the pharmacokinetics of aprepitant.

A single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC 0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C max decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method).

In patients with

ESRD undergoing hemodialysis, the AUC 0-∞ of total aprepitant decreased by 42% and C max decreased by 32%.

Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects.

Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

Fosaprepitant is metabolized in various extrahepatic tissues; therefore, hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant.

Following administration of a single 125-mg oral dose of aprepitant on Day and 80 mg once daily on Days and 3 to patients with mild hepatic impairment (Child-Pugh score to 6), the AUC 0-24hr of aprepitant was 11% lower on Day and 36% lower on Day 3, as compared with healthy subjects given the same regimen.

In patients with moderate hepatic impairment (Child-Pugh score to 9), the AUC 0-24hr of aprepitant was 10% higher on Day and 18% higher on Day 3, as compared with healthy subjects given the same regimen.

These differences in

AUC 0-24hr are not considered clinically meaningful.

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) .

Index (BMI) For every 5 kg/m 2 increase in BMI, AUC 0-24hr and C max of aprepitant decrease by 9% and 10%.

BMI of subjects in the analysis ranged from 18 kg/m to 36 kg/m 2.

This change is not considered clinically meaningful.

Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, with no evidence of inhibition or induction of CYP3A4 observed on Day 4.

The weak inhibition of

CYP3A4 continues for 2 days after single dose administration of fosaprepitant.

Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4.

Aprepitant is also an inducer of

Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

Effects of

Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs CYP3A4 Substrates Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC 0-∞ of midazolam by approximately 1.8-fold on Day and had no effect on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days and 4.

Dexamethasone: Fosaprepitant administered as a single 150 mg intravenous dose on Day 1 increased the AUC 0-24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days and 2.

When oral aprepitant as a 3-day regimen (125-mg/80-mg/80-mg) was administered with intravenous methylprednisolone 125 mg on Day and oral methylprednisolone 40 mg on Days and 3, the AUC of methylprednisolone was increased by 1.34-fold on Day and by 2.5-fold on Day 3.

Chemotherapeutic agents

Docetaxel: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125mg/80-mg/80-mg) did not influence the pharmacokinetics of docetaxel.

In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125mg/80-mg/80-mg) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

Oral contraceptives

When oral aprepitant was administered as a 3-day regimen (125-mg/80mg/80-mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl es.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Infusion Site Reactions Most common adverse reactions in adults (≥2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity.

Adverse reactions in pediatric patients are similar to adults.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 clinical practice.

The safety of

FOCINVEZ has been established from adequate and well-controlled studies of another intravenous formulation of fosaprepitant.

Below is a display of the adverse reactions of fosaprepitant in these studies.

The overall safety of intravenous fosaprepitant was evaluated in approximately 1800 adult and pediatric patients.

Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with MEC In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of intravenous fosaprepitant in combination with ondansetron and dexamethasone (intravenous fosaprepitant regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy).

The most common adverse reactions are listed in Table 6.

Table 6 Most Common Adverse Reactions in Patients Receiving MEC a Intravenous fosaprepitant, ondansetron, and dexamethasone b (N=504) Ondansetron and dexamethasone c (N=497) fatigue 15% 13% diarrhea 13% 11% neutropenia 8% 7% asthenia 4% 3% anemia 3% 2% peripheral neuropathy 3% 2% leukopenia 2% 1% dyspepsia 2% 1% urinary tract infection 2% 1% pain in extremity 2% 1% a Reported in ≥2% of patients treated with the intravenous fosaprepitant regimen and at a greater incidence than standard therapy (ondansetron and dexamethasone alone). b Intravenous fosaprepitant regimen c Standard therapy Infusion-site reactions were reported in 2.2% of patients treated with the intravenous fosaprepitant regimen compared to 0.6% of patients treated with standard therapy.

The infusion-site reactions included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and infusion-site thrombophlebitis (0.6%, 0.0%), reported in the intravenous fosaprepitant regimen compared to standard therapy, respectively.

Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with HEC In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients receiving a single dose of intravenous fosaprepitant compared to 1169 patients receiving the 3-day regimen of oral aprepitant.

The safety profile was generally similar to that seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant.

However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%).

The following additional infusion-site reactions occurred in the HEC study and were not reported in the MEC study described above: infusion-site erythema (0.5%, 0.1%), infusion-site pruritus (0.3%, 0.0%), and infusion-site induration (0.2%, 0.1%), reported in the fosaprepitant group compared to the aprepitant group, respectively.

Patients 6 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MEC Single-Dose Intravenous Fosaprepitant Regimen The safety of a single dose of intravenous fosaprepitant in pediatric patients (6 months to 17 years) was evaluated in two active-controlled and a single-arm clinical study in patients who received either HEC or MEC.

Patients also received ondansetron with or without dexamethasone.

The adverse reaction profile was similar to adults.

The safety analysis included 69 pediatric patients who received the recommended dose.

An additional 70 patients received a single, higher-than-recommended dose.

The most common adverse reactions that occurred in >15% of patients who received the recommended dose were anemia, neutropenia, thrombocytopenia, and febrile neutropenia. 3-Day Intravenous Fosaprepitant/Oral Aprepitant/Oral Aprepitant Regimen In pediatric patients (12 to 17 years), the safety of the 3-day intravenous fosaprepitant/oral aprepitant/oral aprepitant regimen was evaluated in a single-arm clinical study including 12 patients who received a regimen of either HEC or MEC.

In pediatric patients 6 months to 12 years of age, the safety of the 3-day regimen was not directly evaluated.

The safety of a single-dose of intravenous fosaprepitant (3 mg/kg) administered on day of the 3-day regimen was evaluated in one active-controlled and one single-arm study including 48 patients who received a regimen of either HEC or MEC.

In these clinical studies, pediatric patients also received ondansetron with or without dexamethasone.

The adverse reaction profile was similar to adults and pediatric patients receiving a single dose of intravenous fosaprepitant.

Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with intravenous fosaprepitant.

See the full prescribing information for aprepitant capsules for complete safety information regarding studies performed with oral aprepitant.

Additional pediatric use information is approved for Merck Sharp & Dohme LLC’s EMEND (fosaprepitant) for injection.

However, due to Merck Sharp & Dohme LLC’s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of fosaprepitant.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylaxis and anaphylactic shock.

Nervous system disorders: ifosfamide-induced neurotoxicity reported after fosaprepitant and ifosfamide coadministration.

There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.

In the event of overdose, FOCINVEZ should be discontinued and general supportive treatment and monitoring should be provided.

Aprepitant is not removed by hemodialysis.

is contraindicated in patients: who are hypersensitive to any component of the product.

Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported. taking pimozide.

Inhibition of

CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide.

Known hypersensitivity to any component of this drug.

Concurrent use with pimozide.

FOCINVEZ 150 mg on Day as an intravenous infusion over to 30 minutes; Complete the infusion approximately 30 minutes prior to chemotherapy.

Patients (6 months to 17 years) Weighing at Least 6 kg See Full Prescribing Information for pediatric dosage regimens by age. single dose chemotherapy regimens: single dose of FOCINVEZ on Day 1. single or multi-day chemotherapy regimens: 3-day regimen of FOCINVEZ on Day and aprepitant capsules or aprepitant for oral suspension on Days and 3.

Administer FOCINVEZ through a central venous catheter on Day as an intravenous infusion over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years).

Complete the infusion approximately 30 minutes prior to chemotherapy.

Information for additional information. 2.1 Recommended Dosage for the Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients The recommended dosage of FOCINVEZ, dexamethasone, and a 5-HT 3 antagonist for the prevention of nausea and vomiting associated with administration of HEC or MEC in adults is shown in Table 1 or Table 2, respectively.

Administer FOCINVEZ as an intravenous infusion on Day 1 over to 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy.

Table 1 Recommended Adult Dosage for the Prevention of Nausea and Vomiting Associated with HEC Day 1 Day 2 Day 3 Day 4 FOCINVEZ a 150 mg intravenously over to 30 minutes none none none Dexamethasone b 12 mg orally 8 mg orally 8 mg orally twice daily 8 mg orally twice daily 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage none none none a The concentration of FOCINVEZ is 3 mg/mL b Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day and in the morning on Days 2 through 4.

Also administer dexamethasone in the evenings on Days and 4.

A 50% dosage reduction of dexamethasone on Days and 2 is recommended to account for a drug interaction with FOCINVEZ.

Table 2 Recommended Adult Dosage for the Prevention of Nausea and Vomiting Associated with MEC Day 1 FOCINVEZ a 150 mg intravenously over to 30 minutes Dexamethasone b 12 mg orally 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage a The concentration of FOCINVEZ is 3 mg/mL. b Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1.

A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with FOCINVEZ. 2.2 Recommended Dosage for the Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients The recommended pediatric dosage regimens of FOCINVEZ, to be administered with a 5-HT 3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of single or multi-day chemotherapy regimens of HEC or MEC, are shown in Tables and 4.

Single-day chemotherapy regimens include those regimens in which HEC or MEC is administered for a single day only.

Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is administered for 2 or more days.

FOCINVEZ Dosage Regimens for Use with Single-Day Chemotherapy Regimens For pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, FOCINVEZ may be administered as: a single dose regimen of FOCINVEZ infused through a central venous catheter on Day 1, as shown in Table 3; or as a 3-day fosaprepitant/aprepitant regimen consisting of FOCINVEZ as an intravenous infusion through a central venous catheter on Day and aprepitant capsules or aprepitant for oral suspension on Days and 3, as shown in Table 4.

Administer FOCINVEZ on

Day 1 over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy.

Table 3 FOCINVEZ Single Dose Regimen for the Prevention of Nausea and Vomiting Associated with Single-Day Regimens of HEC or MEC in Pediatric Patients 6 Months a to 17 Years Drug Age Regimen FOCINVEZ b 12 Years to 17 Years 150 mg intravenously over 30 minutes 2 Years to less than 12 Years 4 mg/kg (maximum dose 150 mg) intravenously over 60 minutes 6 Months to less than 2 Years 5 mg/kg (maximum dose 150 mg) intravenously over 60 minutes Dexamethasone c 6 Months to 17 Years If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days and 2. 5-HT 3 antagonist 6 Months to 17 Years See selected 5-HT 3 antagonist prescribing information for the recommended dosage a Dosing in pediatric patients less than 6 kg is not recommended b The concentration of FOCINVEZ is 3mg/mL. c Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 FOCINVEZ Dosage Regimen for Use with Multi-Day Chemotherapy Regimens For pediatric patients weighing at least 6 kg receiving multi-day regimens of HEC or MEC, administer FOCINVEZ as an intravenous infusion through a central venous catheter on Day and aprepitant capsules or aprepitant for oral suspension on Days and 3, as shown in Table 4.

FOCINVEZ over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy.

Table 4. 3-Day Fosaprepitant/Aprepitant Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MEC in Pediatric Patients 6 Months a to 17 Years Drug Day 1 Day 2 Day 3 12 Years to 17 Years FOCINVEZ b 115 mg intravenously over 30 minutes.

• Aprepitant capsules c.

• 80 mg orally 80 mg orally 6 Months to Less than 12 Years FOCINVEZ 3 mg/kg (maximum dose 115 mg) intravenously over 60 minutes.

• Aprepitant for oral suspension d.

• 2 mg/kg orally (maximum 80 mg) 2 mg/kg orally (maximum 80 mg) 6 Months to 17 Years Dexamethasone e If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 6 Months to 17 Years 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage a Dosing in pediatric patients less than 6 kg is not recommended b The concentration of FOCINVEZ is 3 mg/mL. c For patients 12 years to 17 years who cannot swallow oral capsules, aprepitant for oral suspension can be used instead. d For patients less than 12 years of age who weigh at least 40 kg and who are able to swallow oral capsules, aprepitant capsules can be used on Days and 3. e Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1.

Additional pediatric use information is approved for Merck Sharp & Dohme LLCs EMEND (fosaprepitant) for injection.

However, due to Merck Sharp & Dohme LLCs marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Preparation and Administration of FOCINVEZ FOCINVEZ is ready-to-use for intravenous infusion.

The concentration of

FOCINVEZ is 3 mg/mL.

Determine the volume to be administered from the injection vial directly based on the recommended dose.

The entire volume of the vial (50 mL) should be administered.

In patients 12 years and older, the volume to be administered is calculated as follows: Volume to administer (mL) = the recommended dose (mg) / 3 (mg/mL) In patients 6 months to less than 12 years, the volume to be administered is calculated as follows: Volume to administer (mL) = the recommended dose (mg/kg) x weight (kg) / 3 (mg/mL) Note: Do not exceed the maximum dose In pediatric patients, the entire volume in vial may NOT be required.

Discard the unused portion. * The recommended dose of FOCINVEZ is based on the patient’s age and weight.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not use if solution is cloudy, contains precipitates, or if the red flip top cap is not intact.

FOCINVEZ to come to room temperature before use if the injection is NOT stored at room temperature.

Use a vented infusion set when

FOCINVEZ is infused from the bottle.

The vial hanger can be separated from the vial label.

Gently invert the bottle and hang the bottle using the attached hanger and start infusion.

FOCINVEZ is compatible with 0.9% Sodium Chloride Injection.

Do not mix FOCINVEZ with solutions for which physical and chemical compatibility have not been established.

FOCINVEZ is incompatible with any solutions containing divalent cations (e.g., Ca 2+ , Mg 2+ ), including Lactated Ringer’s Solution and Hartmann's Solution.

Following administration of

FOCINVEZ, flush the IV set with a sufficient volume of 0.9% Sodium Chloride Injection to ensure the full length of the tubing and catheter lumen is completely cleared of residual medication to prevent precipitation.

Proceed with the administration of other medications through the same line only after the line has been completely flushed.

(fosaprepitant injection) contains 150 mg/50 mL of fosaprepitant as a clear and colorless ready-to-use injection solution in a single-dose vial.

Supplied as follows

NDC 82449-231-01 1 vial per carton.

FOCINVEZ at 2°C to 8°C (36°F to 46°F).

FOCINVEZ vials, when kept in original carton, can remain at room temperature 20°C to 25°C (68°F to 77°F) for up to 90 days.

The safety and effectiveness of a single dose regimen of FOCINVEZ and a 3-day intravenous fosaprepitant/oral aprepitant/oral aprepitant regimen have been established in pediatric patients 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC and MEC.

Use of

FOCINVEZ in this is supported by evidence from adequate and well-controlled studies of intravenous fosaprepitant in adults, with additional safety, efficacy and pharmacokinetic data in pediatric patients 6 months to 17 years.

Efficacy and safety were also supported by data from an adequate and well controlled study of a 3-day oral aprepitant regimen in pediatric patients 6 months to 17 years.

See the full prescribing information for aprepitant capsules for complete clinical information regarding studies performed with oral aprepitant.

Adverse reactions were similar to those reported in adult patients. .

The safety and effectiveness of

FOCINVEZ for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months of age.

In juvenile dogs treated with fosaprepitant, changes in reproductive organs were observed.

In juvenile rats treated with aprepitant, slight changes in sexual maturation were observed without an effect on reproduction.

No effects on neurobehavior, sensory and motor function, or learning and memory were observed in rats.

In a toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 (equivalent to a newborn human) to day 42 (approximately equivalent to a 2 year old human), decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues were seen in females from 4 mg/kg/day. A study was also conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and sexual development.

Rats were treated at oral doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male and female rats lower than the exposure at the recommended pediatric human dose) from the early postnatal period (Postnatal Day 10 (equivalent to a newborn human) through Postnatal Day 58 (approximately equivalent to a 15 year old human)).

Slight changes in the onset of sexual maturation were observed in female and male rats; however, there were no effects on mating, fertility, embryonic-fetal survival, or histomorphology of the reproductive organs.

There were no effects in neurobehavioral tests of sensory function, motor function, and learning and memory.

Additional pediatric use information is approved for Merck Sharp & Dohme LLC’s EMEND (fosaprepitant) for injection.

However, due to Merck Sharp & Dohme LLC’s marketing exclusivity rights, this drug product is not labeled with that information.

Of the 1649 adult cancer patients treated with intravenous fosaprepitant in HEC and MEC clinical studies, 27% were aged and over, while 5% were aged and over.

Other reported clinical experience with fosaprepitant has not identified differences in responses between elderly and younger adult patients.

No clinically meaningful differences in the pharmacokinetics of oral aprepitant were observed in healthy subjects 65 years of age and over compared to younger adult subjects.