ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Infusion Site Reactions [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Infusion Site Reactions [see Warnings and Precautions (5.3)] Most common adverse reactions in adults (>=2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity. (6.1)Adverse reactions in pediatrics are similar to adults.To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions in adults (>=2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity. (6.1). Adverse reactions in pediatrics are similar to adults.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 EMEND 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 single dose of EMEND for injection in combination with ondansetron and dexamethasone (EMEND regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 6.Table Most Common Adverse Reactions in Patients Receiving MECReported in >=2% of patients treated with the EMEND regimen and at greater incidence than standard therapy. EMEND for injection, ondansetron, and dexamethasoneEMEND regimen (N=504)Ondansetron and dexamethasoneStandard therapy (N=497)fatigue15%13%diarrhea13%11%neutropenia8%7%asthenia4%3%anemia3%2%peripheral neuropathy3%2%leukopenia2%1%dyspepsia2%1%urinary tract infection2%1%pain in extremity2%1%Infusion-site reactions were reported in 2.2% of patients treated with the EMEND 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 EMEND 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 single dose of EMEND for injection compared to 1169 patients receiving the 3-day regimen of oral EMEND (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 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 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MEC Single-Dose EMEND for Injection RegimenThe safety of single dose of EMEND for injection in pediatric patients (6 months to 17 years) was evaluated in two active-controlled and 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 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 IV/Oral/Oral EMEND RegimenIn pediatric patients (12 to 17 years), the safety of the 3-day IV/oral/oral EMEND regimen was evaluated in single-arm clinical study including 12 patients who received regimen of either HEC or MEC. In pediatric patients months to 12 years of age, the safety of the 3-day IV/oral/oral EMEND regimen was not directly evaluated. The safety of single-dose of EMEND for injection (3 mg/kg) administered on day of the 3-day IV/oral/oral regimen was evaluated in one active-controlled and one single-arm study including 48 patients who received regimen of either HEC or MEC. Patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults and pediatric patients receiving single dose of EMEND for injection.Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for injection. See the full prescribing information for EMEND capsules for complete safety information regarding studies performed with oral aprepitant.. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of EMEND. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 EMEND and ifosfamide coadministration.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 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 to 1000 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 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced systemic exposure approximately 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.. MutagenesisAprepitant 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 FertilityFosaprepitant, 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 1000 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fosaprepitant is prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.Aprepitant is selective high-affinity antagonist of human substance P/neurokinin (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 ElectrophysiologyIn randomized, double-blind, positive-controlled, thorough QTc study, 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 AdministrationFollowing administration of single intravenous 150-mg dose of fosaprepitant, prodrug of aprepitant administered as 20-minute infusion to healthy subjects, the mean AUC0- of aprepitant was 37.4 (+- 14.8) mcghr/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.. DistributionAprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 in humans.Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1)].. Elimination. MetabolismFosaprepitant 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 single oral 300-mg dose of [14C]-aprepitant, indicating substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.. ExcretionFollowing administration of 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 to 13 hours.. Specific Populations. Age: Geriatric PopulationFollowing oral administration of single 125-mg dose of aprepitant on Day and 80 mg once daily on Days through 5, the AUC0-24hr of aprepitant was 21% higher on Day and 36% higher on Day in elderly (65 years and older) relative to younger adults. The Cmax was 10% higher on Day and 24% higher on Day 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 EMEND for Injection Regimen: Simulated systemic exposures of aprepitant in patients years to less than 12 years and observed systemic exposures in patients months to less than years and 12 to 17 years are shown in Table 9, including AUC0-24hr, peak plasma concentration (Cmax) on Day and concentrations at the end of Day (C24), Day (C48) and Day (C72).Table Systemic Exposures of Aprepitant for Single-Dose EMEND for Injection Regimen in Pediatric PatientsPopulationSingle-Dose of EMEND for Injection RegimenGeometric MeanAUC 0-24hr. (mcghr/mL)Cmax (mcg/mL)C24 (mcg/mL)C48 (mcg/mL)C72 (mcg/mL)12 Years to 17 Years150 mg29.43.40.7NDND Not Determined. Pharmacokinetic samples were not collected to support the parameter value of interest. ND Years to less than 12 Years4 mg/kg35.23.60.70.20.052 Years to less than Years28.23.10.40.10.026 Months to less than Years5 mg/kg32.73.30.4NENE Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. ND 3-Day IV/Oral/Oral EMEND Regimen: Simulated aprepitant systemic exposures in patients 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 and concentrations at the end of Day (C24), Day (C48) and Day (C72).Table 10 Systemic Exposures of Aprepitant for 3-Day IV/Oral/Oral Regimen in Pediatric PatientsPopulation3-Day Dose of EMEND (IV/Oral/OralIV on Day 1, Oral on Day 2, and Oral on Day 3)Geometric MeanAUC 0-24hr. (mcghr/mL)Cmax (mcg/mL)C24 (mcg/mL)C48 (mcg/mL)C72 (mcg/mL)12 Years to 17 Years115/80/80 mg18.03.00.40.2NENE Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. Years to less than 12 Years3/2/2 mg/kg25.72.70.50.30.32 Years to less than Years20.22.30.30.20.26 Months to less than Years16.61.90.20.10.1Plasma concentrations of fosaprepitant are negligible within 15 30 minutes after the completion of the infusion in pediatric patients.. SexFollowing oral administration of single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax 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 Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. 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.. Race/EthnicityFollowing oral administration of single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax between Caucasians and Blacks. These differences are not considered clinically meaningful. 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.. Renal ImpairmentA single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2 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 AUC0- of total aprepitant (unbound and protein bound) decreased by 21% and Cmax 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 AUC0- of total aprepitant decreased by 42% and Cmax 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 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.. Hepatic ImpairmentFosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant.Following administration of single 125-mg oral dose of aprepitant on Day and 80 mg once daily on Days and to patients with mild hepatic impairment (Child-Pugh score to 6), the AUC0-24hr 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 AUC0-24hr 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 AUC0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.6)].. Body Mass Index (BMI)For every kg/m2 increase in BMI, AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. This change is not considered clinically meaningful.. Drug Interactions StudiesFosaprepitant, given as single 150-mg dose, is weak inhibitor of CYP3A4, with no evidence of inhibition or induction of CYP3A4 observed on Day 4. The weak inhibition of CYP3A4 continues for days after single dose administration of fosaprepitant. Aprepitant is substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. 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 single intravenous dose on Day increased the AUC0- of midazolam by approximately 1.8-fold on Day and had no effect on Day when midazolam was coadministered as single oral dose of mg on Days and [see Drug Interactions (7.1)].. Corticosteroids:. Dexamethasone: Fosaprepitant administered as single 150 mg intravenous dose on Day increased the AUC0-24hr of dexamethasone, administered as single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days and [see Dosage and Administration (2.1), Drug Interactions (7.1)].. Methylprednisolone: When oral aprepitant as 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 [see Drug Interactions (7.1)].. Chemotherapeutic agents:. Docetaxel: In pharmacokinetic study, oral aprepitant administered as 3-day regimen (125-mg/80-mg/80-mg) did not influence the pharmacokinetics of docetaxel.. Vinorelbine: In pharmacokinetic study, oral aprepitant administered as 3-day regimen (125-mg/80-mg/80-mg) did not influence the pharmacokinetics of vinorelbine to clinically significant degree.. Oral contraceptives: When oral aprepitant was administered as 3-day regimen (125-mg/80-mg/80-mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for weeks post-treatment [see Drug Interactions (7.1)].. CYP2C9 substrates (Warfarin, Tolbutamide):. Warfarin: single 125-mg dose of oral aprepitant was administered on Day and 80 mg/day on Days and to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was 34% decrease in S(-) warfarin trough concentration accompanied by 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) days after completion of dosing with oral aprepitant [see Drug Interactions (7.1)].. Tolbutamide: Oral aprepitant, when given as 125 mg on Day and 80 mg/day on Days and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important.. Other Drugs. P-glycoprotein substrates: Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in clinical drug interaction study.. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).. Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant. Rifampin: When single 375-mg dose of oral aprepitant was administered on Day of 14-day regimen of 600 mg/day of rifampin, strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions (7.2)].. Ketoconazole: When single 125-mg dose of oral aprepitant was administered on Day of 10-day regimen of 400 mg/day of ketoconazole, strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions (7.2)].. Diltiazem: In study in 10 patients with mild to moderate hypertension, administration of 100 mg of fosaprepitant as an intravenous infusion with 120 mg of diltiazem, moderate CYP3A4 inhibitor administered three times daily, resulted in 1.5-fold increase in the aprepitant AUC and 1.4-fold increase in the diltiazem AUC.When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood pressure was significantly greater than that observed with diltiazem alone [24.3 +- 10.2 mm Hg with fosaprepitant versus 15.6 +- 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolic blood pressure was also greater after co-administration of diltiazem with fosaprepitant than administration of diltiazem alone [29.5 +- 7.9 mm Hg with fosaprepitant versus 23.8 +- 4.8 mm Hg without fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem alone [see Drug Interactions (7.2)].. Paroxetine: Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once daily, resulted in decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Prevention of Nausea and Vomiting Associated with HEC in Adults. In randomized, parallel, double-blind, active-controlled study, EMEND for injection 150 mg as single intravenous infusion (N=1147) was compared to 3-day oral EMEND regimen (N=1175) in patients receiving 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 mean age of 56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil (17%), gemcitabine (16%), paclitaxel (15%), and etoposide (12%).Table 11 Treatment Regimens in Adult HEC TrialEMEND for injection placebo, EMEND capsules placebo and dexamethasone placebo (in the evenings on Days and 4) were used to maintain blinding. Day 1Day 2Day 3Day 4EMEND Regimen EMEND for injection150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapynonenonenone Oral dexamethasoneDexamethasone was administered 30 minutes prior to chemotherapy treatment on Day and in the morning on Days through 4. Dexamethasone was also administered in the evenings on Days and 4. The 12 mg dose of dexamethasone on Day and the mg once daily dose on Day reflects dosage adjustment to account for drug interaction with the EMEND for injection regimen [see Clinical Pharmacology (12.3)]. 12 mg8 mg8 mg twice daily8 mg twice daily OndansetronOndansetronOndansetron 32 mg intravenous was used in the clinical trials of EMEND. 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. nonenonenoneOral EMEND Regimen EMEND capsules125 mg80 mg80 mgnone Oral dexamethasoneDexamethasone was administered 30 minutes prior to chemotherapy treatment on Day and in the morning on Days through 4. The 12 mg dose of dexamethasone on Day and the mg once daily dose on Days through reflects dosage adjustment to account for drug interaction with the oral EMEND regimen [see Clinical Pharmacology (12.3)]. 12 mg8 mg8 mg8 mg OndansetronOndansetron nonenonenoneThe efficacy of EMEND for injection was evaluated based on the primary and secondary endpoints 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%.Table 12 Percent of Adult Patients Receiving HEC Responding by Treatment Group and Phase -- Cycle 1ENDPOINTSEMEND for Injection Regimen(N 1106)N: Number of patients included in the primary analysis of complete response. %Oral EMEND Regimen(N 1134) %DifferenceDifference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for Gender. (95% CI)PRIMARY ENDPOINTComplete ResponseComplete Response no vomiting and no use of rescue therapy. OverallOverall 0 to 120 hours post-initiation of cisplatin chemotherapy. 71.972.3-0.4 (-4.1, 3.3)SECONDARY ENDPOINTSComplete Response Delayed phaseDelayed phase 25 to 120 hours post-initiation of cisplatin chemotherapy. 74.374.20.1 (-3.5, 3.7)No Vomiting Overall 72.974.6-1.7 (-5.3, 2.0). 14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults. In randomized, parallel, double-blind, active comparator-controlled study, EMEND for injection 150 mg as single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (EMEND regimen) was compared with ondansetron and dexamethasone alone (standard therapy) (N=498) (see Table 13) in patients receiving 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 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 TrialEMEND for injection placebo and dexamethasone placebo (on Day 1) were used to maintain blinding. Day 1Day 2Day 3EMEND Regimen EMEND for Injection150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapynonenone Oral DexamethasoneDexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose reflects dosage adjustment to account for drug interaction with the EMEND for injection regimen [see Clinical Pharmacology (12.3)]. 12 mgnonenone Oral OndansetronThe first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day and the second dose was administered hours after first ondansetron dose. mg for dosesnonenoneStandard Therapy Oral Dexamethasone20 mgnonenone Oral Ondansetron mg for doses8 mg twice daily8 mg twice dailyThe 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 GroupENDPOINTSEMEND for Injection Regimen(N 502)N: Number of patients included in the intention to treat population. %Standard Therapy Regimen(N 498) %P-ValueTreatment Difference(95% CI)PRIMARY ENDPOINTComplete ResponseComplete Response no vomiting and no use of rescue therapy. Delayed phaseDelayed phase 25 to 120 hours post-initiation of chemotherapy. 78.968.5<0.00110.4 (5.1, 15.9).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. EMEND 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 [see Warnings and Precautions (5.2), Adverse Reactions (6.2)].taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, known adverse reaction of pimozide [see Warnings and Precautions (5.1)]. who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported [see Warnings and Precautions (5.2), Adverse Reactions (6.2)].. taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, known adverse reaction of pimozide [see Warnings and Precautions (5.1)]. Known hypersensitivity to any component of this drug. (4, 5.2)Concurrent use with pimozide. (4). Known hypersensitivity to any component of this drug. (4, 5.2). Concurrent use with pimozide. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. EMEND (fosaprepitant) for injection is sterile, lyophilized formulation containing fosaprepitant dimeglumine, prodrug of aprepitant, substance P/neurokinin-1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt).Its empirical formula is C23H22F7N4O6P 2(C7H17NO5) and its structural formula is:Fosaprepitant dimeglumine is white to off-white amorphous powder with molecular weight of 1004.83. It is freely soluble in water.Each vial of EMEND for injection for administration as an intravenous infusion contains 150 mg of fosaprepitant (equivalent to 245.3 mg of fosaprepitant dimeglumine) and the following inactive ingredients: edetate disodium (5.4 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage (2.1, 2.2)Administer EMEND as an intravenous infusion; complete the infusion approximately 30 minutes prior to chemotherapy.Adults: 150 mg on Day 1.Pediatrics (6 months to 17 years): single-day of EMEND for injection on Day (for single dose chemotherapy regimens) or 3-day EMEND regimen of EMEND for injection on Day and EMEND capsules or oral suspension on Days and (for single or multi-day chemotherapy regimens).Administer EMEND for injection on Day as an intravenous infusion over 20 to 30 minutes (adults), 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years).In pediatrics, administer EMEND through central venous catheter.See Full Prescribing Information for dosages of concomitant antiemetic(s) and pediatric dosages of EMEND. (2.1, 2.2). Recommended Dosage (2.1, 2.2). Administer EMEND as an intravenous infusion; complete the infusion approximately 30 minutes prior to chemotherapy.. Adults: 150 mg on Day 1.. Pediatrics (6 months to 17 years): single-day of EMEND for injection on Day (for single dose chemotherapy regimens) or 3-day EMEND regimen of EMEND for injection on Day and EMEND capsules or oral suspension on Days and (for single or multi-day chemotherapy regimens).. Administer EMEND for injection on Day as an intravenous infusion over 20 to 30 minutes (adults), 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years).. In pediatrics, administer EMEND through central venous catheter.. See Full Prescribing Information for dosages of concomitant antiemetic(s) and pediatric dosages of EMEND. (2.1, 2.2). 2.1Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients. The recommended dosage of EMEND for injection, dexamethasone, and 5-HT3 antagonist for the prevention of nausea and vomiting associated with administration of HEC or MEC in adults is shown in Table or Table 2, respectively. Administer EMEND for injection as an intravenous infusion on Day over 20 to 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy.Table Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HECDay 1Day 2Day 3Day 4EMEND for injection150 mg intravenously over 20 to 30 minutesnonenonenoneDexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day and in the morning on Days through 4. Also administer dexamethasone in the evenings on Days and 4. 50% dosage reduction of dexamethasone on Days and is recommended to account for drug interaction with EMEND [see Clinical Pharmacology (12.3)]. 12 mg orally8 mg orally8 mg orally twice daily8 mg orally twice daily5-HT3 antagonistSee selected 5-HT3 antagonist prescribing information for the recommended dosagenonenonenoneTable Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MECDay 1EMEND for injection150 mg intravenously over 20 to 30 minutesDexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. 50% dosage reduction of dexamethasone is recommended to account for drug interaction with EMEND [see Clinical Pharmacology (12.3)]. 12 mg orally5-HT3 antagonistSee selected 5-HT3 antagonist prescribing information for the recommended dosage. 2.2Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients. The recommended pediatric dose regimens of EMEND, to be administered with 5-HT3 antagonist, with or without 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 single day only. Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is administered for or more days. EMEND Dosage Regimens for Use with Single-Day Chemotherapy RegimensFor pediatric patients weighing at least kg receiving single-day HEC or MEC, EMEND may be administered as: single dose regimen of EMEND for injection infused through central venous catheter on Day 1, as shown in Table 3; or as 3-day EMEND regimen consisting of EMEND for injection as an intravenous infusion through central venous catheter on Day and EMEND capsules or EMEND for oral suspension on Days and 3, as shown in Table 4. Administer EMEND for injection on Day 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 Single Dose Regimen of EMEND for injection for Pediatric Patients MonthsDosing in pediatric patients less than kg is not recommended to 17 Years for the Prevention of Nausea and Vomiting Associated with Single-Day Regimens of HEC or MECDrug AgeRegimenEMEND for injection 12 Years to 17 Years150 mgintravenously over 30 minutes2 Years to less than 12 Years4 mg/kg(maximum dose 150 mg)intravenously over 60 minutes6 Months to less than Years5 mg/kg(maximum dose 150 mg)intravenously over 60 minutesDexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 6 Months to 17 YearsIf corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days and 2.5-HT3 antagonist Months to 17 YearsSee selected 5-HT3 antagonist prescribing information for the recommended dosage. single dose regimen of EMEND for injection infused through central venous catheter on Day 1, as shown in Table 3; or as 3-day EMEND regimen consisting of EMEND for injection as an intravenous infusion through central venous catheter on Day and EMEND capsules or EMEND for oral suspension on Days and 3, as shown in Table 4. EMEND Dosage Regimen for Use with Multi-Day Chemotherapy RegimensFor pediatric patients weighing at least kg receiving multi-day regimens of HEC or MEC, administer EMEND on Days 1, 2, and 3. Administer EMEND for injection as an intravenous infusion through central venous catheter on Day and EMEND capsules or EMEND for oral suspension on Days and 3, as shown in Table 4. Administer EMEND for injection on Day 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 Pediatric Patients MonthsDosing in pediatric patients less than kg is not recommended to 17 Years Recommended 3-Day EMEND Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MECAge Group DrugDay 1Day 2Day 312 Years to 17 Years EMEND for injection115 mgintravenously over 30 minutes----EMEND capsulesFor patients 12 years to 17 years who cannot swallow oral capsules, EMEND for oral suspension can be used instead. --80 mg orally80 mg orally6 Months to Less than 12 Years EMEND for injection3 mg/kg(maximum dose 115 mg)intravenously over 60 minutes----EMEND for oral suspension--2 mg/kg orally(maximum 80 mg)2 mg/kg orally(maximum 80 mg)6 Months to 17 Years DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day If corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days through 46 Months to 17 Years 5-HT3 antagonistSee selected 5-HT3 antagonist prescribing information for the recommended dosage. 2.3Preparation of EMEND for injection. Table Preparation Instructions for EMEND for injection (150 mg)The recommended dose of EMEND for injection is based on the patients age and weight.Step Aseptically inject mL 0.9% Sodium Chloride Injection, USP into the vial. Assure that 0.9% Sodium Chloride Injection, USP is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting 0.9% Sodium Chloride Injection, USP into the vial.Step Aseptically prepare an infusion bag filled with 145 mL of 0.9% Sodium Chloride Injection, USP.Step Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 145 mL of 0.9% Sodium Chloride Injection, USP to yield total volume of 150 mL and final concentration of mg/mL. Step Gently invert the bag to times.Step Determine the volume to be administered from this prepared infusion bag, based on the recommended dose [see Dosage and Administration (2.1, 2.2)]. Adults The entire volume of the prepared infusion bag (150 mL) should be administered. Pediatrics In patients 12 years and older, the volume to be administered is calculated as follows:Volume to administer (mL) equals the recommended dose (mg)In patients months to less than 12 years, the volume to be administered is calculated as follows:Volume to administer (mL) recommended dose (mg/kg) weight (kg)Note: Do not exceed the maximum dose [see Dosage and Administration (2.2)] In pediatric patients, the entire volume in the infusion bag may not be required.Step If necessary, for volumes less than 150 mL, the calculated volume can be transferred to an appropriate size bag or syringe prior to administration by infusion.Step Before administration, inspect the bag for particulate matter and discoloration. Discard the bag if particulate and/or discoloration are observed.Caution: Do not mix or reconstitute EMEND for injection with solutions for which physical and chemical compatibility have not been established. EMEND for injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringers Solution and Hartmanns Solution.. Volume to administer (mL) equals the recommended dose (mg). Volume to administer (mL) recommended dose (mg/kg) weight (kg)Note: Do not exceed the maximum dose [see Dosage and Administration (2.2)] Note: Do not exceed the maximum dose [see Dosage and Administration (2.2)]. StorageThe reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25C (77F)]. Discard unused portion.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. EMEND for injection: 150 mg fosaprepitant, white to off-white lyophilized powder in single-dose glass vial for reconstitution. EMEND for injection: 150 mg fosaprepitant, lyophilized powder in single-dose vial for reconstitution. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. See Full Prescribing Information for list of clinically significant drug interactions. (4, 5.1, 5.4, 5.5, 7.1, 7.2). 7.1Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs. When administered intravenously, fosaprepitant, prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of EMEND for injection are likely to occur with drugs that interact with oral aprepitant.Fosaprepitant, given as single 150-mg dose, is weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is 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 EMEND [see Contraindications (4)]. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7.Table Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other DrugsCYP3A4 SubstratesPimozideClinical ImpactIncreased pimozide exposureInterventionEMEND is contraindicated [see Contraindications (4)]. BenzodiazepinesClinical ImpactIncreased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)]. InterventionMonitor for benzodiazepine-related adverse reactions.DexamethasoneClinical ImpactIncreased dexamethasone exposure [see Clinical Pharmacology (12.3)]. InterventionReduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1)]. MethylprednisoloneClinical ImpactIncreased methylprednisolone exposure [see Clinical Pharmacology (12.3)]. InterventionReduce the dose of oral methylprednisolone by approximately 50% on Days and for patients receiving HEC and on Day for patients receiving MEC.Reduce the dose of intravenous methylprednisolone by 25% on Days and for patients receiving HEC and on Day for patients receiving MEC.Chemotherapeutic agents that are metabolized by CYP3A4Clinical ImpactIncreased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)]. InterventionVinblastine, vincristine, or ifosfamide or other chemotherapeutic agentsMonitor for chemotherapeutic-related adverse reactions.Etoposide, vinorelbine, paclitaxel, and docetaxelNo dosage adjustment needed.Hormonal ContraceptivesClinical ImpactDecreased hormonal exposure during administration of and for 28 days after administration of the last dose of EMEND [see Warnings and Precautions (5.5), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)]. InterventionEffective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with EMEND and for month following administration of EMEND.Examplesbirth control pills, skin patches, implants, and certain IUDsCYP2C9 SubstratesWarfarinClinical ImpactDecreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)]. InterventionIn patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at to 10 days, following administration of EMEND with each chemotherapy cycle.Other5-HT3 AntagonistsClinical ImpactNo change in the exposure of the 5-HT3 antagonist [see Clinical Pharmacology (12.3)]. InterventionNo dosage adjustment neededExamplesondansetron, granisetron, dolasetron. Monitor for chemotherapeutic-related adverse reactions.. No dosage adjustment needed.. 7.2Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant. Aprepitant is CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Co-administration of EMEND 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.Table Effects of Other Drugs on Pharmacokinetics of Fosaprepitant/AprepitantModerate to Strong CYP3A4 InhibitorsClinical ImpactSignificantly increased exposure of aprepitant may increase the risk of adverse reactions associated with EMEND [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)]. InterventionAvoid concomitant use of EMENDExamplesModerate inhibitor:diltiazemStrong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavirStrong CYP3A4 InducersClinical ImpactSubstantially decreased exposure of aprepitant in patients chronically taking strong CYP3A4 inducer may decrease the efficacy of EMEND [see Clinical Pharmacology (12.3)]. InterventionAvoid concomitant use of EMENDExamplesrifampin, carbamazepine, phenytoin.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. ContraceptionUpon administration of EMEND, 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 EMEND and for month following the last dose [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 1649 adult cancer patients treated with intravenous EMEND in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with EMEND has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. No. 3061 -- Single-dose glass vial containing 150 mg of fosaprepitant as white to off-white lyophilized powder for reconstitution. Supplied as follows:NDC 0006-3061-001 vial per carton.. StorageEmend for injection vials must be refrigerated, store at 2C-8C (36F-46F).The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25C (77F)]. Discard unused portion.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. EMEND(R) for injection, in combination with other antiemetic agents, is indicated in adults and pediatric patients 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).. 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).. EMEND(R) for injection is substance P/neurokinin-1 (NK1) receptor antagonist, indicated in adults and pediatric patients months of age and older, in combination with other antiemetic agents, for the prevention of (1):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).Limitations of Use (1)EMEND has not been studied for treatment of established nausea and vomiting.. 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).. EMEND has not been studied for treatment of established nausea and vomiting.. Limitations of UseEMEND has not been studied for the treatment of established nausea and vomiting.. EMEND has not been studied for the treatment of established nausea and vomiting.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Hypersensitivity Advise patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients taking EMEND. Advise patients to seek immediate medical attention if they experience signs or symptoms of hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, or dizziness, rapid or weak heartbeat or feeling faint [see Warnings and Precautions (5.2)].. Infusion Site ReactionsAdvise patients to seek medical attention if they experience new or worsening signs or symptoms of an infusion site reaction, such as erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site [see Warnings and Precautions (5.3)].. Drug InteractionsAdvise patients to discuss all medications they are taking, including other prescription, non-prescription medication or herbal products [see Contraindications (4), Warnings and Precautions (5.1)]. Warfarin: Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at to 10 days, following initiation of EMEND with each chemotherapy cycle [see Warnings and Precautions (5.4)].. Hormonal Contraceptives: Advise patients that administration of EMEND may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of contraception (such as condoms and spermicides) during treatment with EMEND and for month following administration of EMEND [see Warnings and Precautions (5.5), Use in Specific Populations (8.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryLactation 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 mothers clinical need for EMEND and any potential adverse effects on the breastfed infant from EMEND or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fosaprepitant is prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.Aprepitant is selective high-affinity antagonist of human substance P/neurokinin (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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 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 to 1000 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 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced systemic exposure approximately 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.. MutagenesisAprepitant 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 FertilityFosaprepitant, 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 1000 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).

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of EMEND, drug-induced emesis may not be effective in cases of EMEND overdosage.Aprepitant is not removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 150 mg Vial Carton. NDC 0006-3061-00Emend(R) (fosaprepitant)for Injection150 mg per vialReconstitute with mL of 0.9% SodiumChloride for Injection.STERILE LYOPHILIZED POWDERFOR INTRAVENOUS USE ONLY AFTERRECONSTITUTION AND DILUTIONDO NOT USE WITH SOLUTIONSCONTAINING DIVALENT CATIONS(e.g., Ca2+, Mg2+) INCLUDINGLACTATED RINGERS SOLUTIONAND HARTMANNS SOLUTION.Rx onlySingle-Dose Vial -Discard Unused Portion. PRINCIPAL DISPLAY PANEL 150 mg Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of single dose regimen of EMEND for injection and 3-day IV/oral/oral EMEND regimen have been established in pediatric patients 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 EMEND in this age group is supported by evidence from adequate and well-controlled studies of EMEND for injection in adults, with additional safety, efficacy and pharmacokinetic data in pediatric patients months to 17 years. Efficacy was also supported by data from an adequate and well-controlled study of 3-day oral aprepitant regimen in pediatric patients months to 17 years. See the full prescribing information for EMEND 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 of EMEND for injection administered on consecutive days has not been established in pediatric patients months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC and MEC.The safety and effectiveness of EMEND for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than months of age.. Juvenile Animal Toxicity DataIn 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 toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 (equivalent to newborn human) to day 42 (approximately equivalent to 2 year old human), decreased testicular weight and Leydig cell size were seen in the males at mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues were seen in females from mg/kg/day. 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 newborn human) through Postnatal Day 58 (approximately equivalent to 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn randomized, double-blind, positive-controlled, thorough QTc study, single 200-mg dose of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc interval.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Aprepitant after Fosaprepitant AdministrationFollowing administration of single intravenous 150-mg dose of fosaprepitant, prodrug of aprepitant administered as 20-minute infusion to healthy subjects, the mean AUC0- of aprepitant was 37.4 (+- 14.8) mcghr/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.. DistributionAprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 in humans.Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1)].. Elimination. MetabolismFosaprepitant 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 single oral 300-mg dose of [14C]-aprepitant, indicating substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.. ExcretionFollowing administration of 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 to 13 hours.. Specific Populations. Age: Geriatric PopulationFollowing oral administration of single 125-mg dose of aprepitant on Day and 80 mg once daily on Days through 5, the AUC0-24hr of aprepitant was 21% higher on Day and 36% higher on Day in elderly (65 years and older) relative to younger adults. The Cmax was 10% higher on Day and 24% higher on Day 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 EMEND for Injection Regimen: Simulated systemic exposures of aprepitant in patients years to less than 12 years and observed systemic exposures in patients months to less than years and 12 to 17 years are shown in Table 9, including AUC0-24hr, peak plasma concentration (Cmax) on Day and concentrations at the end of Day (C24), Day (C48) and Day (C72).Table Systemic Exposures of Aprepitant for Single-Dose EMEND for Injection Regimen in Pediatric PatientsPopulationSingle-Dose of EMEND for Injection RegimenGeometric MeanAUC 0-24hr. (mcghr/mL)Cmax (mcg/mL)C24 (mcg/mL)C48 (mcg/mL)C72 (mcg/mL)12 Years to 17 Years150 mg29.43.40.7NDND Not Determined. Pharmacokinetic samples were not collected to support the parameter value of interest. ND Years to less than 12 Years4 mg/kg35.23.60.70.20.052 Years to less than Years28.23.10.40.10.026 Months to less than Years5 mg/kg32.73.30.4NENE Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. ND 3-Day IV/Oral/Oral EMEND Regimen: Simulated aprepitant systemic exposures in patients 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 and concentrations at the end of Day (C24), Day (C48) and Day (C72).Table 10 Systemic Exposures of Aprepitant for 3-Day IV/Oral/Oral Regimen in Pediatric PatientsPopulation3-Day Dose of EMEND (IV/Oral/OralIV on Day 1, Oral on Day 2, and Oral on Day 3)Geometric MeanAUC 0-24hr. (mcghr/mL)Cmax (mcg/mL)C24 (mcg/mL)C48 (mcg/mL)C72 (mcg/mL)12 Years to 17 Years115/80/80 mg18.03.00.40.2NENE Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. Years to less than 12 Years3/2/2 mg/kg25.72.70.50.30.32 Years to less than Years20.22.30.30.20.26 Months to less than Years16.61.90.20.10.1Plasma concentrations of fosaprepitant are negligible within 15 30 minutes after the completion of the infusion in pediatric patients.. SexFollowing oral administration of single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax 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 Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. 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.. Race/EthnicityFollowing oral administration of single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax between Caucasians and Blacks. These differences are not considered clinically meaningful. 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.. Renal ImpairmentA single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2 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 AUC0- of total aprepitant (unbound and protein bound) decreased by 21% and Cmax 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 AUC0- of total aprepitant decreased by 42% and Cmax 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 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.. Hepatic ImpairmentFosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant.Following administration of single 125-mg oral dose of aprepitant on Day and 80 mg once daily on Days and to patients with mild hepatic impairment (Child-Pugh score to 6), the AUC0-24hr 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 AUC0-24hr 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 AUC0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.6)].. Body Mass Index (BMI)For every kg/m2 increase in BMI, AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. This change is not considered clinically meaningful.. Drug Interactions StudiesFosaprepitant, given as single 150-mg dose, is weak inhibitor of CYP3A4, with no evidence of inhibition or induction of CYP3A4 observed on Day 4. The weak inhibition of CYP3A4 continues for days after single dose administration of fosaprepitant. Aprepitant is substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. 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 single intravenous dose on Day increased the AUC0- of midazolam by approximately 1.8-fold on Day and had no effect on Day when midazolam was coadministered as single oral dose of mg on Days and [see Drug Interactions (7.1)].. Corticosteroids:. Dexamethasone: Fosaprepitant administered as single 150 mg intravenous dose on Day increased the AUC0-24hr of dexamethasone, administered as single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days and [see Dosage and Administration (2.1), Drug Interactions (7.1)].. Methylprednisolone: When oral aprepitant as 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 [see Drug Interactions (7.1)].. Chemotherapeutic agents:. Docetaxel: In pharmacokinetic study, oral aprepitant administered as 3-day regimen (125-mg/80-mg/80-mg) did not influence the pharmacokinetics of docetaxel.. Vinorelbine: In pharmacokinetic study, oral aprepitant administered as 3-day regimen (125-mg/80-mg/80-mg) did not influence the pharmacokinetics of vinorelbine to clinically significant degree.. Oral contraceptives: When oral aprepitant was administered as 3-day regimen (125-mg/80-mg/80-mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for weeks post-treatment [see Drug Interactions (7.1)].. CYP2C9 substrates (Warfarin, Tolbutamide):. Warfarin: single 125-mg dose of oral aprepitant was administered on Day and 80 mg/day on Days and to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was 34% decrease in S(-) warfarin trough concentration accompanied by 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) days after completion of dosing with oral aprepitant [see Drug Interactions (7.1)].. Tolbutamide: Oral aprepitant, when given as 125 mg on Day and 80 mg/day on Days and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important.. Other Drugs. P-glycoprotein substrates: Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in clinical drug interaction study.. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).. Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant. Rifampin: When single 375-mg dose of oral aprepitant was administered on Day of 14-day regimen of 600 mg/day of rifampin, strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions (7.2)].. Ketoconazole: When single 125-mg dose of oral aprepitant was administered on Day of 10-day regimen of 400 mg/day of ketoconazole, strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions (7.2)].. Diltiazem: In study in 10 patients with mild to moderate hypertension, administration of 100 mg of fosaprepitant as an intravenous infusion with 120 mg of diltiazem, moderate CYP3A4 inhibitor administered three times daily, resulted in 1.5-fold increase in the aprepitant AUC and 1.4-fold increase in the diltiazem AUC.When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood pressure was significantly greater than that observed with diltiazem alone [24.3 +- 10.2 mm Hg with fosaprepitant versus 15.6 +- 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolic blood pressure was also greater after co-administration of diltiazem with fosaprepitant than administration of diltiazem alone [29.5 +- 7.9 mm Hg with fosaprepitant versus 23.8 +- 4.8 mm Hg without fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem alone [see Drug Interactions (7.2)].. Paroxetine: Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once daily, resulted in decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are insufficient data on use of EMEND in pregnant women to inform 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 to 4% and 15 to 20%, respectively.. Data. Animal DataIn 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: April 2018 Patient InformationEMEND(R) (EE mend)(fosaprepitant)for injectionRead this Patient Information before you start receiving EMEND for injection and each time you are scheduled to receive EMEND for injection. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.What is EMEND for injectionEMEND for injection is prescription medicine used with other medicines that treat nausea and vomiting in patients months of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines.EMEND for injection is not used to treat nausea and vomiting that you already have.It is not known if EMEND for injection is safe and effective in children less than months of age.Who should not receive EMEND for injectionDo not receive EMEND for injection if you:are allergic to fosaprepitant, aprepitant, or any of the ingredients in EMEND for injection. See the end of this leaflet for complete list of the ingredients in EMEND for injection.are taking pimozide (ORAP(R))What should tell my healthcare provider before receiving EMEND for injectionBefore receiving EMEND for injection, tell your healthcare provider if you:have liver problemsare pregnant or plan to become pregnant. It is not known if EMEND for injection can harm your unborn baby.Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use backup method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND for injection and for month after receiving EMEND for injection. are breastfeeding or plan to breastfeed. It is not known if EMEND for injection passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive EMEND for injection.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.EMEND for injection may affect the way other medicines work, and other medicines may affect the way EMEND for injection works, causing serious side effects.Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine.How will receive EMEND for injectionAdults 18 years of age and older:EMEND for injection will be given on Day of chemotherapy treatment. It will be given to you by intravenous (IV) infusion in your vein about 50 to 60 minutes before you start your chemotherapy treatment.Children months to 17 years of age:EMEND for injection will be given on Day of chemotherapy treatment. It will be given to your child by intravenous (IV) infusion into large vein through type of IV line called central venous catheter, about hour to 1/2 hours before the start of their chemotherapy treatment.Your child may also receive:capsules of EMEND or an oral suspension of EMEND on Days and 3. If your child will receive either of these, see the Patient Information for EMEND capsules or EMEND for oral suspension for further information. If you take the blood thinner medicine warfarin sodium (COUMADIN(R), JANTOVEN(R)), your healthcare provider may do blood tests after you receive EMEND for injection to check your blood clotting.What are the possible side effects of EMEND for injectionEMEND for injection may cause serious side effects, including:Serious allergic reactions. Allergic reactions can happen with EMEND for injection and may be serious. Tell your doctor or nurse right away if you have hives, rash, itching, flushing or redness of your face or skin, trouble breathing or swallowing, dizziness, rapid or weak heartbeat, or you feel faint during or soon after you receive EMEND for injection, as you may need emergency medical care.Severe skin reactions, which may include rash, skin peeling, or sores, may occur.Infusion site reactions (ISR) at or near the infusion site have happened with EMEND for Injection.Most severe ISR have happened with certain type of chemotherapy medicine that can burn or blister your skin (vesicant) with side effects, including pain, swelling and redness. Death of skin tissue (necrosis) has happened in some people getting this type of chemotherapy medicine. Most ISR can happen with the first, second, or third dose and some can last up to weeks or longer. Tell your healthcare provider right away if you get any infusion site side effects.In adults, the most common side effects of EMEND for injection include:tirednessdiarrhealow white blood cell and red blood cell countsweaknessfeeling weak or numb in your arms and legspainful, difficult, or changes in your digestion (dyspepsia)urinary tract infectionpain in your arms and legsIn children months to 17 years of age, the most common side effects of EMEND for injection include:low red blood cell countlow white blood cell countlow blood platelet countlow white blood cell count with feverTell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMEND for injection. For more information ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of EMEND for injection.If you would like more information about EMEND for injection, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about EMEND for injection that is written for health professionals. For more information about EMEND for injection call 1-800-622-4477 or go to www.emend.com.What are the ingredients in EMEND for injectionActive ingredient: fosaprepitantInactive ingredients: edetate disodium, polysorbate 80, lactose anhydrous, sodium hydroxide and/or hydrochloric acid (for pH adjustment)Manufactured for: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USAManufactured by: Patheon Manufacturing Services LLC, 5900 Martin Luther King Jr. Highway, Greenville, NC 27834, USAFor patent information: www.merck.com/product/patent/home.htmlThe brands listed in the above sections Who should not receive EMEND for injection and How will receive EMEND for injection are the registered trademarks of their respective owners and are not trademarks of Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc.Copyright (C) 2008-2018 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved.usppi-mk0517-iv-1804r014. EMEND for injection is not used to treat nausea and vomiting that you already have.. It is not known if EMEND for injection is safe and effective in children less than months of age.. are allergic to fosaprepitant, aprepitant, or any of the ingredients in EMEND for injection. See the end of this leaflet for complete list of the ingredients in EMEND for injection.. are taking pimozide (ORAP(R)). have liver problems. are pregnant or plan to become pregnant. It is not known if EMEND for injection can harm your unborn baby.Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use backup method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND for injection and for month after receiving EMEND for injection. Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use backup method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND for injection and for month after receiving EMEND for injection.. are breastfeeding or plan to breastfeed. It is not known if EMEND for injection passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive EMEND for injection.. Your child may also receive:capsules of EMEND or an oral suspension of EMEND on Days and 3. If your child will receive either of these, see the Patient Information for EMEND capsules or EMEND for oral suspension for further information. capsules of EMEND or an oral suspension of EMEND on Days and 3. If your child will receive either of these, see the Patient Information for EMEND capsules or EMEND for oral suspension for further information.. Serious allergic reactions. Allergic reactions can happen with EMEND for injection and may be serious. Tell your doctor or nurse right away if you have hives, rash, itching, flushing or redness of your face or skin, trouble breathing or swallowing, dizziness, rapid or weak heartbeat, or you feel faint during or soon after you receive EMEND for injection, as you may need emergency medical care.. Severe skin reactions, which may include rash, skin peeling, or sores, may occur.. Infusion site reactions (ISR) at or near the infusion site have happened with EMEND for Injection.Most severe ISR have happened with certain type of chemotherapy medicine that can burn or blister your skin (vesicant) with side effects, including pain, swelling and redness. Death of skin tissue (necrosis) has happened in some people getting this type of chemotherapy medicine. Most ISR can happen with the first, second, or third dose and some can last up to weeks or longer. Tell your healthcare provider right away if you get any infusion site side effects.. tiredness. diarrhea. low white blood cell and red blood cell counts. weakness. feeling weak or numb in your arms and legs. painful, difficult, or changes in your digestion (dyspepsia). urinary tract infection. pain in your arms and legs. low red blood cell count. low white blood cell count. low blood platelet count. low white blood cell count with fever.

SPL UNCLASSIFIED SECTION.

Limitations of UseEMEND has not been studied for the treatment of established nausea and vomiting.. EMEND has not been studied for the treatment of established nausea and vomiting.

STORAGE AND HANDLING SECTION.

StorageEmend for injection vials must be refrigerated, store at 2C-8C (36F-46F).The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25C (77F)]. Discard unused portion.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are insufficient data on use of EMEND in pregnant women to inform 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 to 4% and 15 to 20%, respectively.. Data. Animal DataIn 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 SummaryLactation 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 mothers clinical need for EMEND and any potential adverse effects on the breastfed infant from EMEND or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. ContraceptionUpon administration of EMEND, 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 EMEND and for month following the last dose [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 8.4 Pediatric Use. The safety and effectiveness of single dose regimen of EMEND for injection and 3-day IV/oral/oral EMEND regimen have been established in pediatric patients 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 EMEND in this age group is supported by evidence from adequate and well-controlled studies of EMEND for injection in adults, with additional safety, efficacy and pharmacokinetic data in pediatric patients months to 17 years. Efficacy was also supported by data from an adequate and well-controlled study of 3-day oral aprepitant regimen in pediatric patients months to 17 years. See the full prescribing information for EMEND 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 of EMEND for injection administered on consecutive days has not been established in pediatric patients months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC and MEC.The safety and effectiveness of EMEND for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than months of age.. Juvenile Animal Toxicity DataIn 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 toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 (equivalent to newborn human) to day 42 (approximately equivalent to 2 year old human), decreased testicular weight and Leydig cell size were seen in the males at mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues were seen in females from mg/kg/day. 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 newborn human) through Postnatal Day 58 (approximately equivalent to 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.. 8.5 Geriatric Use. Of the 1649 adult cancer patients treated with intravenous EMEND in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with EMEND has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].. 8.6Patients 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 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 EMEND is administered [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. CYP3A4 Interactions: Fosaprepitant is weak inhibitor of CYP3A4, and aprepitant, the active moiety, is substrate, inhibitor, and inducer of CYP3A4; see Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustment of EMEND and concomitant drugs. (4, 5.1, 7.1, 7.2)Hypersensitivity Reactions (including anaphylaxis and anaphylactic shock): May occur during or soon after infusion. If symptoms occur, discontinue the drug. Do not reinitiate EMEND if symptoms occur with previous use. (4, 5.2)Infusion Site Reactions (including thrombophlebitis, necrosis, and vasculitis): Majority of reactions reported in patients receiving vesicant chemotherapy. Avoid infusion into small veins. Discontinue infusion and administer treatment if severe reaction develops. (5.3)Warfarin (a CYP2C9 substrate): Risk of decreased INR of prothrombin time; monitor INR in 2-week period, particularly at to 10 days, following initiation of EMEND. (5.4, 7.1)Hormonal Contraceptives: Efficacy of contraceptives may be reduced during and for 28 days following administration of EMEND. Use effective alternative or back-up methods of contraception. (5.5, 7.1, 8.3). CYP3A4 Interactions: Fosaprepitant is weak inhibitor of CYP3A4, and aprepitant, the active moiety, is substrate, inhibitor, and inducer of CYP3A4; see Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustment of EMEND and concomitant drugs. (4, 5.1, 7.1, 7.2). Hypersensitivity Reactions (including anaphylaxis and anaphylactic shock): May occur during or soon after infusion. If symptoms occur, discontinue the drug. Do not reinitiate EMEND if symptoms occur with previous use. (4, 5.2). Infusion Site Reactions (including thrombophlebitis, necrosis, and vasculitis): Majority of reactions reported in patients receiving vesicant chemotherapy. Avoid infusion into small veins. Discontinue infusion and administer treatment if severe reaction develops. (5.3). Warfarin (a CYP2C9 substrate): Risk of decreased INR of prothrombin time; monitor INR in 2-week period, particularly at to 10 days, following initiation of EMEND. (5.4, 7.1). Hormonal Contraceptives: Efficacy of contraceptives may be reduced during and for 28 days following administration of EMEND. Use effective alternative or back-up methods of contraception. (5.5, 7.1, 8.3). 5.1Clinically Significant CYP3A4 Drug Interactions. Fosaprepitant, prodrug of aprepitant, is weak inhibitor of CYP3A4, and aprepitant is substrate, inhibitor, and inducer of CYP3A4.Use of EMEND with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.Use of pimozide with EMEND is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, known adverse reaction of pimozide [see Contraindications (4)]. Use of EMEND 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 EMEND.Use of EMEND with strong CYP3A4 inducers (e.g., rifampin) may result in reduction in aprepitant plasma concentrations and decreased efficacy of EMEND.See Table and Table for listing of potentially significant drug interactions [see Drug Interactions (7.1, 7.2)]. Use of EMEND with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.Use of pimozide with EMEND is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, known adverse reaction of pimozide [see Contraindications (4)]. Use of pimozide with EMEND is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, known adverse reaction of pimozide [see Contraindications (4)]. Use of EMEND 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 EMEND.. Use of EMEND with strong CYP3A4 inducers (e.g., rifampin) may result in reduction in aprepitant plasma concentrations and decreased efficacy of EMEND.. 5.2Hypersensitivity 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 EMEND in patients who experience these symptoms with previous use [see Contraindications (4)].. 5.3Infusion Site Reactions. Infusion site reactions (ISRs) have been reported with the use of EMEND 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 EMEND 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 EMEND for injection into small veins or through butterfly catheter. If severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment. 5.4Decrease in INR with Concomitant Warfarin. Coadministration of EMEND with warfarin, CYP2C9 substrate, may result in 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 to 10 days, following initiation of EMEND with each chemotherapy cycle [see Drug Interactions (7.1)].. 5.5Risk of Reduced Efficacy of Hormonal Contraceptives. Upon coadministration with EMEND, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of EMEND [see Clinical Pharmacology (12.3)]. Advise patients to use effective alternative or back-up methods of contraception during treatment with EMEND and for month following administration of EMEND [see Drug Interactions (7.1), Use in Specific Populations (8.3)].

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)5/2022.