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  [ see Clinical Pharmacology (12.3)].

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Preparation of Fosaprepitant for Injection

Table 5

Preparation Instructions for Fosaprepitant for Injection (150 mg)

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)].

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 1600 adult 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 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.

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.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric 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 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 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.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric 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  show  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)].

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 11).  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 12 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 13) 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 13

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 14.

Table 14 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.