2.1 Prevention of Nausea and Vomiting Associated with HEC  and MEC in Adult Patients

 The recommended dosage of fosaprepitant for injection, dexamethasone, and a 5-HT3 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 fosaprepitant for injection as an intravenous infusion on Day 1 over 20 to 30 minutes completing the infusion approximately 30 minutes, prior to chemotherapy.
 Table 1Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HEC

*Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)].

Table 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MEC

*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 fosaprepitant for injection [ see Clinical Pharmacology (12.3)].

2.2 Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients

The recommended pediatric dosage regimens of fosaprepitant   for injection, to be administered with a 5-HT3 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 3 and 4. Single-day chemotherapy regimens include 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.
Fosaprepitant for injection Dosage Regimens for Use with Single-Day Chemotherapy Regimens
For pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, fosaprepitant for injection may be administered as:

• a single dose regimen of fosaprepitant for injection infused through a central venous catheter on Day 1, as shown in Table 3; or

• as a 3-day fosaprepitant for injection regimen consisting of fosaprepitant for injection as an intravenous infusion through a central venous catheter on Day 1 and aprepitant capsules or fosaprepitant for oral suspension on Days 2 and 3, as shown in Table 4.

Administer fosaprepitant for injection 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     Fosaprepitant for Injection Single Dose Regimen for the Prevention of Nausea and Vomiting Associated with Single- Day Regimens of HEC or MEC in Pediatric Patients 6 Months* to 17 Years 
                              

 * Dosing in pediatric patients less than 6 kg is not recommended
† Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1
Fosaprepitant for injection 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 fosaprepitant   for injection on Days 1, 2, and 3. Administer fosaprepitant for injection as an intravenous infusion through a central venous catheter on Day 1 and aprepitant capsules or fosaprepitant for oral suspension on Days 2 and 3, as shown in Table 4.
Administer fosaprepitant for injection 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 for Injection Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MEC in Pediatric Patients 6 Months* to 17 Years

* Dosing in pediatric patients less than 6 kg is not recommended.
† For patients 12 years to 17 years unable to swallow oral capsules, fosaprepitant for oral suspension can be used instead on Days 2 and 3
‡ 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 instead on Days 2 and 3
§ Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1.

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.

2.3 Preparation of Fosaprepitant for Injection

Table 5     Preparation Instructions for fosaprepitant for injection (150 mg)

The recommended dose of fosaprepitant for injection is based on the patient’s age and weight.
Caution: Do not mix or reconstitute fosaprepitant for injection with solutions for which physical and chemical compatibility have not been established. Fosaprepitant for injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer’s Solution and Hartmann's Solution.
Storage
The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25°C (77°F)]. Discard unused portion.

5.1 Clinically Significant CYP3A4 Drug Interactions

 Fosaprepitant, a  prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of  CYP3A4.

•  Use of fosaprepitant with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.
  • Use of pimozide with fosaprepitant is contraindicated due to the risk of significantly increased plasma  concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide [see Contraindications (4) ].
•  Use of fosaprepitant with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to fosaprepitant.
• Use of fosaprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of fosaprepitant.

      See Table 7 and  Table 8 for a listing of potentially significant drug interactions [see Drug Interactions (7.1,7.2) ].

5.2 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon after infusion of fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea, hypotension and syncope have been reported [see Adverse Reactions (6.2)].
Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate fosaprepitant in patients who experience these symptoms with previous use [see Contraindications (4)].

5.3 Infusion Site Reactions

Infusion site reactions (ISRs) have been reported with the use of fosaprepitant for injection [see Adverse Reactions (6.1)]. The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Most ISRs occurred with the first, second or third exposure to single doses of fosaprepitant for injection and in some cases, reactions persisted for two weeks or longer. Treatment of severe ISRs consisted of medical, and in some cases surgical, intervention.
Avoid infusion of fosaprepitant for injection into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment.

5.4 Decrease in INR with Concomitant Warfarin

Coadministration of  fosaprepitant with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time [see Clinical Pharmacology (12.3)].  Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions (7.1)].

5.5 Risk of Reduced Efficacy of Hormonal Contraceptives

Upon  coadministration with fosaprepitant, the efficacy of hormonal contraceptives   may be reduced during administration of and for 28 days following the last dose of fosaprepitant [see Clinical Pharmacology (12.3)]. Advise patients to use effective alternative or back-up methods of   contraception during  treatment  with  fosaprepitant  and  for  1  month  following  administration  of  fosaprepitant [see Drug Interactions (7.1),

Use  in Specific Populations (8.3)].

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 overall safety of fosaprepitant for injection 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 fosaprepitant for injection in combination with ondansetron and dexamethasone (fosaprepitant dimeglumine 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*

*Reported in ≥2% of patients treated with the fosaprepitant dimeglumine regimen and at a greater incidence than standard therapy.
† Fosaprepitant dimeglumine regimen
‡Standard therapy
Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant dimeglumine 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 fosaprepitant dimeglumine 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 fosaprepitant for injection compared to 1169 patients receiving the 3-day regimen of oral aprepitant [ see Clinical Studies (14.1)]. 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.
Adverse Reactions in Pediatric Patients 6 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MEC
Single Dose fosaprepitant  for Injection Regimen
The safety of a single dose of fosaprepitant for injection 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 fosaprepitant dimeglumine Regimen
In pediatric patients 12 to 17 years, the safety of the 3-day IV/oral/oral fosaprepitant dimeglumine 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 IV/oral/oral fosaprepitant dimeglumine regimen was not directly evaluated. The safety of a single dose of fosaprepitant for injection (3 mg/kg) administered on day 1 of the 3-day IV/oral/oral regimen was evaluated in one active-controlled and one single-arm study including 48 pediatric patients 6 months to 12 years of age 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 in pediatric patients was similar to the profile in adult patients receiving a single dose of fosaprepitant for injection.
Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with fosaprepitant for injection. 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 [ see Warnings and Precautions (5.2)].
Immune system disorders: hypersensitivity reactions including anaphylaxis and anaphylactic shock [ see Contraindications (4),Warnings and Precautions (5.2)].
Nervous system disorders: ifosfamide-induced neurotoxicity reported after fosaprepitant and ifosfamide coadministration.

7.1 Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

When administered intravenously, fosaprepitant, a prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of fosaprepitant for injection are likely to occur with drugs that interact with oral aprepitant.
Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [ see Clinical Pharmacology (12.3)].
Some substrates of CYP3A4 are contraindicated with fosaprepitant [ see Contraindications (4)].Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7.

Table 7     Effects of fosaprepitant/aprepitant on the Pharmacokinetics of Other Drugs

7.2 Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant

Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Co-administration of  fosaprepitant with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 8.

8.1 Pregnancy

Risk Summary
There are insufficient data on use of fosaprepitant in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental   effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 25 mg/kg/day were   approximately equivalent to the exposure at the RHD of 150 mg. Aprepitant crosses the placenta in rats and rabbits. 

8.2 Lactation

 Risk Summary

Lactation  studies have not been conducted to assess the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental  and health benefits of breastfeeding should be considered along with the mother’s clinical need for fosaprepitant and any potential adverse effects on the breastfed infant from fosaprepitant or from the underlying maternal condition. 

8.3 Females and Males of Reproductive Potential

Contraception

Upon administration of  fosaprepitant, the efficacy of hormonal contraceptives may be reduced. Advise  females of  reproductive potential using  hormonal contraceptives to use  an effective alternative or back-up non-hormonal contraceptive (such as condoms  and  spermicides) during treatment with fosaprepitant and for 1  month following the last dose [see Drug Interactions (7.1), Clinical Pharmacology (12.3) ].

8.4 Pediatric Use

The safety and effectiveness of a single dose and a 3-day regimen of fosaprepitant 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 fosaprepitant in this age group is supported by evidence from adequate and well-controlled studies of fosaprepitant for injection 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 [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
The safety and effectiveness of fosaprepitant dimeglumine for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months of age.
Juvenile Animal Toxicity Data
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.

8.5 Geriatric Use

Of the 1649 adult cancer patients treated with intravenous fosaprepitant in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with fosaprepitant has not identified differences in responses between elderly and younger patients. 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 [ see Clinical Pharmacology (12.3)].

8.6 Patients with Hepatic Impairment

The   pharmacokinetics of aprepitant in patients with mild and moderate hepatic   impairment were  similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse  reactions in these patients may be warranted when fosaprepitant is administered [see Clinical Pharmacology (12.3) ].

12.1 Mechanism of Action

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(NK1)  receptors. Aprepitant has little or no affinity for serotonin (5-HT3),   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  NK1  receptors.  Animal  and  human  studies have  shown  that  aprepitant  augments   the  antiemetic  activity of  the  5-HT3 -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 AUC0-∞ of aprepitant was 37.4 (±14.8) mcg•hr/mL and the mean maximal aprepitant concentration (Cmax ) 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.
Distribution
Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans.
Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1)].
Elimination
Metabolism
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 [14C]-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.
Excretion
Following administration of a single intravenous 100-mg dose of [14C]-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 9 to 13 hours.
Specific Populations
Age: Geriatric Population
Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations (8.5)].

Age: Pediatric Population
Single Dose Fosaprepitant for Injection 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 12 to 17 years are shown in Table 9, including AUC0-24hr, peak plasma concentration (Cmax) on Day 1 and concentrations at the end of Day 1 (C24), Day 2 (C48) and Day 3 (C72).

Table 9     Systemic Exposures of Aprepitant for Single Dose Fosaprepitant for Injection Regimen in Pediatric Patients

*ND = Not Determined. Pharmacokinetic samples were not collected to support the parameter value of interest.
†NE = Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification.
3-Day IV/Oral/Oral Fosaprepitant Regimen: Simulated aprepitant systemic exposures in patients 6 months to less than 12 years and observed systemic exposures in patients 12 to 17 years are shown in Table 10, including AUC0-24hr, peak plasma concentration (Cmax) on Day 1 and concentrations at the end of Day 1 (C24), Day 2 (C48) and Day 3 (C72).
Table 10     Systemic Exposures of Aprepitant for 3-Day IV/Oral/Oral Regimen in Pediatric Patients
                                                

*IV on Day 1, Oral on Day 2, and Oral on Day 3 
†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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1,000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant approximately equivalent to (female rats) or less than (male rats) the adult human exposure at the RHD of 150 mg. Treatment with aprepitant at doses of 5 to 1,000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1,000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2,000 mg/kg/day. The highest dose produced a systemic exposure approximately 2 times the adult human exposure at the RHD of 150 mg. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.
Mutagenesis
Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test.
Impairment of Fertility
 Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility   studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were   obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose  of 1,000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended adult human dose of 150 mg and exposure in female rats approximately equivalent to the adult human exposure).

14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults

In a randomized, parallel, double-blind, active-controlled study, fosaprepitant for injection 150 mg as a single intravenous infusion (N=1147) was compared to a 3-day oral aprepitant regimen (N=1175) in patients receiving a HEC regimen that included cisplatin (≥70 mg/m2). All patients in both groups  received dexamethasone and ondansetron (see Table 12). Patient demographics were similar between the two treatment groups. Of the total 2322 patients, 63% were men, 56% White, 26% Asian, 3% American Indian/Alaska Native, 2% Black, 13% Multi-Racial, and 33% Hispanic/Latino ethnicity. Patient ages ranged from 19 to 86 years of age, with a mean age of 56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil (17%), gemcitabine (16%), paclitaxel (15%), and etoposide (12%).                                                          

* Fosaprepitant for injection placebo, aprepitant capsules placebo and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding.
†Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Dexamethasone was also administered in the evenings on Days 3 and 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Day 2 reflects a dosage adjustment to account for a drug interaction with the fosaprepitant for injection regimen [see Clinical Pharmacology (12.3)].
‡Ondansetron 32 mg intravenous was used in the clinical trials of fosaprepitant. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
§Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Days 2 through 4 reflects a dosage adjustment to account for a drug interaction with the oral aprepitant regimen [see Clinical Pharmacology (12.3)].
The efficacy of fosaprepitant for injection was evaluated based on the primary and secondary  end points  listed  in  Table 13 and was shown to be non-inferior to that of the 3-day oral  aprepitant regimen with  regard  to  complete response in each of the evaluated   phases.The pre-specified non-inferiority margin  for  complete  response  in the overall phase was 7%.The pre-specified non-inferiority  margin   for   complete response in  the  delayed  phase  was  7.3%. The pre -specified non - inferiority margin for no vomiting in the overall phase was  8.2%.

*N: Number of patients included in the primary analysis of complete response.
†Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for Gender.
‡Complete Response = no vomiting and no use of rescue therapy.
§Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy.
¶Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.

14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults

In a randomized, parallel, double-blind, active comparator-controlled study, fosaprepitant for injection 150 mg as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (fosaprepitant dimeglumine regimen) was compared with ondansetron and dexamethasone alone (standard therapy) (N=498) (see Table 14) in patients receiving a MEC regimen. Patient demographics were similar between the two treatment groups. Of the total 1,000 patients included in the efficacy analysis, 41% were men, 84% White, 4% Asian, 1% American Indian/Alaska Native, 2% Black, 10% Multi-Racial, and 19% Hispanic/Latino ethnicity. Patient ages ranged from 23 to 88 years of age, with a mean age of 60 years. The most commonly administered MEC chemotherapeutic agents were carboplatin (51%), oxaliplatin (24%), and cyclophosphamide (12%).
Table 14     Treatment Regimens in Adult MEC Trial*

* Fosaprepitant for injection placebo and dexamethasone placebo (on Day 1) were used to maintain blinding.
†Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose reflects a dosage adjustment to account for a drug interaction with the Fosaprepitant  for injection regimen [ see Clinical Pharmacology (12.3)].
‡The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose.

The primary endpoint was complete response (defined as no vomiting and no rescue therapy) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting. The results by treatment group are shown in Table 15.

Table 15 Percent of Adult Patients Receiving MEC Responding by Treatment Group

*N: Number of patients included in the intention to treat population.
†Complete Response = no vomiting and no use of rescue therapy.
‡Delayed phase = 25 to 120 hours post-initiation of chemotherapy.