CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. EMEND is contraindicated in patients:who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported [see Adverse Reactions (6.2)].taking pimozide. Inhibition of CYP3A4 by aprepitant 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 have been reported [see Adverse Reactions (6.2)].. taking pimozide. Inhibition of CYP3A4 by aprepitant 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)Concurrent use with pimozide. (4). Known hypersensitivity to any component of this drug. (4). Concurrent use with pimozide. (4).

ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. Most common adverse reactions (>=3%) are (6.1):Adults: fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased.Pediatrics: neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups.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.. Adults: fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased.. Pediatrics: neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups.. 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 was evaluated in approximately 6800 individuals.. AdultsIn active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies and 2), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies (14.1)].In active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies and 4), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies (14.2)]. The most common adverse reaction reported in patients who received MEC in pooled Studies and was dyspepsia (6% versus 4%).Across these studies there were 1412 patients treated with the EMEND regimen during Cycle of chemotherapy and 1099 of these patients continued into the Multiple-Cycle extension for up to cycles of chemotherapy. The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, and are listed in Table 5.Table 5: Most Common Adverse Reactions in Patients Receiving HEC and MEC from Pooled Analysis of HEC and MEC StudiesReported in >= 3% of patients treated with the EMEND regimen and at greater incidence than standard therapy. EMEND, ondansetron, and dexamethasoneEMEND regimen (N=1412)Ondansetron and dexamethasoneStandard therapy (N=1396)fatigue13%12%diarrhea9%8%asthenia7%6%dyspepsia7%5%abdominal pain6%5%hiccups5%3%white blood cell count decreased4%3%dehydration3%2%alanine aminotransferase increased3%2%In pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the EMEND regimen are listed in Table 6.Table 6: Less Common Adverse Reactions in EMEND-Treated Patients from Pooled Analysis of HEC and MEC StudiesReported in 0.5% of patients treated with the EMEND regimen, at greater incidence than standard therapy and not previously described in Table 5. Infection and Infestationsoral candidiasis, pharyngitisBlood and the Lymphatic System Disordersanemia, febrile neutropenia, neutropenia, thrombocytopeniaMetabolism and Nutrition Disordersdecreased appetite, hypokalemiaPsychiatric DisordersanxietyNervous System Disordersdizziness, dysgeusia, peripheral neuropathyCardiac DisorderspalpitationsVascular Disordersflushing, hot flushRespiratory, Thoracic and Mediastinal Disorderscough, dyspnea, oropharyngeal painGastrointestinal Disordersdry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomitingSkin and Subcutaneous Tissue Disordersalopecia, hyperhidrosis, rashMusculoskeletal and Connective Tissue Disordersmusculoskeletal painGeneral Disorders and Administration Site Conditionedema peripheral, malaiseInvestigationsaspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreasedIn an additional active-controlled clinical study in 1169 patients receiving EMEND and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with EMEND.In another CINV study, Stevens-Johnson syndrome was reported as serious adverse reaction in patient receiving the EMEND regimen with cancer chemotherapy.Adverse reactions in the Multiple-Cycle extensions of HEC and MEC studies for up to cycles of chemotherapy were generally similar to that observed in Cycle 1.. Pediatric Patients Months to 17 Years of AgeIn pooled analysis of active-controlled clinical trials in pediatric patients aged months to 17 years who received highly or moderately emetogenic cancer chemotherapy (Study and safety study, Study 6), EMEND in combination with ondansetron with or without dexamethasone (EMEND regimen) was compared to ondansetron with or without dexamethasone (control regimen).There were 184 patients treated with the EMEND regimen during Cycle and 215 patients received open-label EMEND for up to additional cycles of chemotherapy.In Cycle 1, the most common adverse reactions reported in pediatric patients treated with the EMEND regimen in pooled Studies and are listed in Table 7.Table 7: Most Common Adverse Reactions in EMEND-Treated Pediatric Patients in HEC and MEC Pooled Studies and 6Reported in >=3% of patients treated with the EMEND regimen and at greater incidence than control regimen. EMEND and ondansetronEMEND regimen (N=184)OndansetronControl regimen (N=168)neutropenia13%11%headache9%5%diarrhea6%5%decreased appetite5%4%cough5%3%fatigue5%2%hemoglobin decreased5%4%dizziness5%1%hiccups4%1%Forty-nine patients were treated with ifosfamide chemotherapy in each arm. Two of the patients treated with ifosfamide in the aprepitant arm developed behavioral changes (agitation 1; abnormal behavior 1), whereas no patient treated with ifosfamide in the control arm developed behavioral changes. Aprepitant has the potential for increasing ifosfamide-mediated neurotoxicity through induction of CYP3A4 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].. Non-CINV StudiesSerious adverse reactions reported in adult patients receiving non-recommended dosage of EMEND in non-CINV studies include single cases of each of the following: angioedema and urticaria, constipation, and sub-ileus. EMEND is only approved in the CINV population.. 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.Immune system disorders: hypersensitivity reactions including anaphylactic reactions [see Contraindications (4)].Nervous system disorders: ifosfamide-induced neurotoxicity reported after EMEND and ifosfamide coadministration.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, 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 exposure to aprepitant (AUC) of 0.7 to 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen. 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 of about 2.8 to 3.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.. MutagenesisAprepitant was 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 FertilityAprepitant 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 and exposure in female rats at about 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen).

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. 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 show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.. 12.2Pharmacodynamics. NK1 Receptor OccupancyIn two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral EMEND doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with or subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of approximately 10 ng/mL and 100 ng/mL, the NK1 receptor occupancies were approximately 50% and 90%, respectively. The oral EMEND regimen produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK1 receptor occupancy. However, the receptor occupancy has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of EMEND has not been established.. Cardiac ElectrophysiologyIn randomized, double-blind, positive-controlled, thorough QTc study, single 200-mg dose of fosaprepitant had no effect on the QTc interval. Maximum aprepitant concentrations after single 200-mg dose of fosaprepitant were 4-fold higher than that achieved with oral EMEND 125 mg. QT prolongation with the recommended oral EMEND dosing regimens is not expected.. 12.3Pharmacokinetics. AbsorptionFollowing oral administration of single 125-mg dose of EMEND on Day and 80 mg once daily on Days and 3, the AUC0-24hr was approximately 19.6 mcghr/mL and 21.2 mcghr/mL on Day and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately hours (Tmax) on Day and Day 3, respectively. At the dose range of 80 to 125 mg, the mean absolute oral bioavailability of EMEND is approximately 60 to 65%. Oral administration of the capsule with standard high-fat breakfast had no clinically meaningful effect on the bioavailability of aprepitant.The pharmacokinetics of aprepitant were non-linear across the clinical dose range. In healthy young adults, the increase in AUC0- was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.. 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. MetabolismAprepitant 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 (2.4 times the maximum EMEND recommended dose), 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]-aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. study was not conducted with radiolabeled capsule formulation. The results after oral administration may differ.Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma clearance of aprepitant ranged from approximately 62 to 90 mL/min. The apparent terminal half-life ranged from approximately to 13 hours.. Specific Populations. Geriatric PatientsFollowing oral administration of single 125-mg dose of EMEND on Day and 80 mg once daily on Days through (2 additional days of dosing compared to the recommended duration), 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)]. Pediatric PatientsAs part of 3-day regimen, dosing of aprepitant capsules (125-mg/80-mg/80-mg) in 18 pediatric patients (aged 12 through 17 years) achieved mean AUC0-24hr of 17 mcghr/mL on Day with mean peak plasma concentration (Cmax) at 1.3 mcg/mL occurring at approximately hours. The mean concentrations at the end of Day (N=8) and Day (N=16) were both at 0.6 mcg/mLAs part of 3-day regimen, weight-based dosing of aprepitant powder for oral suspension (3-mg/kg;2-mg/kg;2-mg/kg) in 18 pediatric patients aged months to less than 12 years achieved mean AUC0-24hr of 20.9 mcghr/mL on Day with mean peak plasma concentration (Cmax) at 1.8 mcg/mL (N=19), occurring at approximately hours. The mean concentrations at the end of Day (N=18) and Day (N=19) were 0.4 mcg/mL and 0.5 mcg/mL, respectively [see Dosage and Administration (2.1)].A population pharmacokinetic analysis of aprepitant in pediatric patients (aged months through 17 years) suggests that sex and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.. Male and Female PatientsFollowing oral administration of single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum EMEND recommended dose), 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.. Racial or Ethnic GroupsFollowing oral administration of single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum EMEND recommended dose), 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.. Patients with Renal ImpairmentA single 240-mg dose of aprepitant (approximately 1.9 times the maximum EMEND recommended dose) 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 [see Use in Specific Populations (8.6)].. Patients with Hepatic ImpairmentFollowing administration of single 125-mg dose of EMEND 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 (8.7)].. 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 StudiesAprepitant is substrate, moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.. Effects of Aprepitant on the Pharmacokinetics of Other Drugs. CYP3A4 substrates (i.e., midazolam): Interactions between EMEND and coadministered midazolam are listed in Table 10 (increase is indicated as , decrease as , no change as <->).Table 10: Pharmacokinetic Interaction Data for EMEND and Coadministered MidazolamDosage of EMENDDosage of MidazolamObserved Drug InteractionsEMEND 125 mg on Day and 80 mg on Days to 5oral mg single dose on Days and 5midazolam AUC 2.3-fold on Day and 3.3-fold on Day [see Drug Interactions (7.1)] EMEND 125 mg on Day and 80 mg on Days and 3intravenous mg prior to 3-day regimen of EMEND and on Days 4, and 15midazolam AUC 25% on Day 4, AUC 19% on Day and AUC 4% on Day 15EMEND 125 mg on Day 1intravenous mg given hour after EMENDmidazolam AUC 1.5-foldA difference of less than 2-fold increase of midazolam AUC is not considered clinically important.. Corticosteroids:. Dexamethasone: EMEND, when given as regimen of 125 mg on Day and 80 mg/day on Days through 5, coadministered with 20-mg dexamethasone on Day and 8-mg dexamethasone on Days through 5, increased the AUC of dexamethasone by 2.2-fold on Days and [see Dosage and Administration (2.1)].. Methylprednisolone: EMEND, when given as regimen of 125 mg on Day and 80 mg/day on Days and 3, coadministered with 125 mg methylprednisolone IV on Day and 40 mg methylprednisolone orally on Days and 3, increased the AUC of methylprednisolone by 1.34-fold on Day and by 2.5-fold on Day 3.. Chemotherapeutic agents:. Docetaxel: In pharmacokinetic study, EMEND (125-mg/80-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel.. Vinorelbine: In pharmacokinetic study, EMEND (125-mg/80-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to clinically significant degree.. CYP2C9 substrates (Warfarin, Tolbutamide):. Warfarin: single 125-mg dose of EMEND was administered on Day and 80 mg/day on Days and to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND 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 EMEND [see Drug Interactions (7.1)].. Tolbutamide: EMEND, 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 EMEND and on Days 4, 8, and 15. This effect was not considered clinically important.. Other Drugs. Oral contraceptives: When EMEND 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.. P-glycoprotein substrates: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND 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 Aprepitant. Ketoconazole: When single 125-mg dose of EMEND 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)].. Rifampin: When single 375-mg dose of aprepitant (3 times the maximum EMEND recommended dose) 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)].. Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as tablet formulation comparable to 230 mg of the capsule formulation (approximately 1.8 times the EMEND recommended dose), with diltiazem 120 mg times daily for days, resulted in 2-fold increase of aprepitant AUC and simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone [see Drug Interactions (7.2)].. Paroxetine: Coadministration of once daily doses of aprepitant, as tablet formulation comparable to 85 mg or 170 mg of the capsule formulation (approximately 0.7 and 1.4 times the maximum EMEND recommended dose), 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.


14CLINICAL STUDIES. 14.1Prevention of Nausea and Vomiting Associated with HEC in Adults. Oral administration of EMEND in combination with ondansetron and dexamethasone (EMEND regimen) has been shown to prevent acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin, and nausea and vomiting associated with MEC.In Studies and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving chemotherapy regimen that included cisplatin greater than 50 mg/m2 (mean cisplatin dose 80.2 mg/m2). See Table 11.In these studies, 95% of the patients in the EMEND group received concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of EMEND patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).Of the 550 patients who were randomized to receive the EMEND regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The EMEND-treated patients in these clinical studies ranged from 14 to 84 years of age, with mean age of 56 years. total of 170 patients were 65 years or older, with 29 patients being 75 years or older.Table 11: HEC Treatment Regimens Studies and 2EMEND placebo and dexamethasone placebo were used to maintain blinding. Day 1Day 2Day 3Day 4CINV EMEND Regimen Oral EMENDEMEND was administered hour prior to chemotherapy treatment on Day and in the morning on Days and 3. 125 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 reflects dosage adjustment to account for drug interaction with the EMEND regimen [see Clinical Pharmacology (12.3)]. 12 mg8 mg8 mg8 mg Ondansetron5-HT3 antagonistOndansetron 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. nonenonenoneCINV Standard Therapy Oral Dexamethasone20 mg8 mg twice daily8 mg twice daily8 mg twice daily Ondansetron5-HT3 antagonist nonenonenoneThe antiemetic activity of EMEND was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:Primary endpoint:complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries)Other prespecified endpoints:complete protection (defined as no emetic episodes, no use of rescue therapy, and maximum nausea visual analogue scale [VAS] score less than 25 mm on 0 to 100 mm scale)no emesis (defined as no emetic episodes regardless of use of rescue therapy)no nausea (maximum VAS less than mm on 0 to 100 mm scale)no significant nausea (maximum VAS less than 25 mm on 0 to 100 mm scale)A summary of the key study results from each individual study analysis is shown in Table 12. In both studies, statistically significantly higher proportion of patients receiving the EMEND regimen in Cycle had complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. statistically significant difference in complete response in favor of the EMEND regimen was also observed when the acute phase and the delayed phase were analyzed separately.Table 12: Percent of Patients Receiving HEC Responding by Treatment Group and Phase -- Cycle 1Study 1Study 2ENDPOINTSEMEND Regimen (N=260)N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation. %Standard Therapy(N=261) %p-ValueEMEND Regimen (N=261) %Standard Therapy (N=263) %p-ValueVisual analogue scale (VAS) score range: mm=no nausea; 100 mm=nausea as bad as it could be.PRIMARY ENDPOINTComplete Response OverallOverall: to 120 hours post-cisplatin treatment. 7352<0.0016343<0.001OTHER PRESPECIFIED ENDPOINTSComplete Response Acute phaseAcute phase: to 24 hours post-cisplatin treatment. 8978<0.0018368<0.001 Delayed phaseDelayed phase: 25 to 120 hours post-cisplatin treatment. 7556<0.0016847<0.001Complete Protection Overall63490.0015641<0.001 Acute phase8575NSNot statistically significant when adjusted for multiple comparisons. 8065<0.001 Delayed phase6652<0.0016144<0.001No Emesis Overall7855<0.0016644<0.001 Acute phase90790.0018469<0.001 Delayed phase8159<0.0017248<0.001No Nausea Overall4844NSNot statistically significant. 4939NS Delayed phase5148NS 5340NS No Significant Nausea Overall7366NS 7164NS Delayed phase7569NS 7365NS In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the EMEND regimen, and the incidence of first emesis was reduced in the EMEND regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.Figure 1: Percent of Patients Receiving HEC Who Remain Emesis Free Over Time -- Cycle 1p-Value <0.001 based on log rank test for Study and Study 2; nominal p-values not adjusted for multiplicity.. complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries). complete protection (defined as no emetic episodes, no use of rescue therapy, and maximum nausea visual analogue scale [VAS] score less than 25 mm on 0 to 100 mm scale). no emesis (defined as no emetic episodes regardless of use of rescue therapy). no nausea (maximum VAS less than mm on 0 to 100 mm scale). no significant nausea (maximum VAS less than 25 mm on 0 to 100 mm scale). Figure 1. Additional Patient-Reported Outcomes: The impact of nausea and vomiting on patients daily lives was assessed in Cycle of both studies using the Functional Living Index-Emesis (FLIE), validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients daily lives is defined as FLIE total score greater than 108. In each of the studies, higher proportion of patients receiving the EMEND regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%).. Multiple-Cycle Extension: In the same clinical studies, patients continued into the Multiple-Cycle extension for up to additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the EMEND regimen was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.Figure 2: Proportion of Patients Receiving HEC with No Emesis and No Significant Nausea by Treatment Group and Cycle. Figure 2. 14.2Prevention of Nausea and Vomiting Associated with MEC in Adults. EMEND was studied in two randomized, double-blind, parallel-group studies (Studies and 4) in adult patients receiving MEC.In Study 3, in breast cancer patients, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving MEC regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (less than or equal to 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). See Table 13.In this study, the most common combinations were cyclophosphamide doxorubicin (61%); and cyclophosphamide epirubicin fluorouracil (22%).Of the 438 patients who were randomized to receive the EMEND regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The EMEND-treated patients in this clinical study ranged from 25 to 78 years of age, with mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.Table 13: MEC Treatment Regimens Studies and 4EMEND placebo and dexamethasone placebo were used to maintain blinding. Day 1Day 2Day 3CINV EMEND Regimen Oral EMENDEMEND was administered hour prior to chemotherapy treatment on Day and in the mornings on Days and 3. 125 mg80 mg80 mg Oral Dexamethasone12 mgDexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose of dexamethasone on Day reflects dosage adjustment to account for drug interaction with the EMEND regimen [see Clinical Pharmacology (12.3)]. nonenone Oral Ondansetron8 mg 2 dosesThe 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. nonenoneCINV Standard Therapy Oral Dexamethasone20 mg nonenone Oral Ondansetron8 mg 2 doses mg twice daily8 mg twice dailyThe antiemetic activity of EMEND was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:Primary endpoint:complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) in the overall phase (0 to 120 hours post-chemotherapy)Other prespecified endpoints:no emesis (defined as no emetic episodes regardless of use of rescue therapy)no nausea (maximum VAS less than mm on 0 to 100 mm scale)no significant nausea (maximum VAS less than 25 mm on 0 to 100 mm scale)complete protection (defined as no emetic episodes, no use of rescue therapy, and maximum nausea visual analogue scale [VAS] score less than 25 mm on 0 to 100 mm scale)complete response during the acute and delayed phases.A summary of the key results from Study is shown in Table 14. In Study 3, statistically significantly (p=0.015) higher proportion of patients receiving the EMEND regimen (51%) in Cycle had complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the No Emesis Endpoint, principal component of this composite primary endpoint. In addition, higher proportion of patients receiving the EMEND regimen in Cycle had complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.Table 14: Percent of Patients Receiving MEC Responding by Treatment Group and Phase -- Cycle of Study 3ENDPOINTSEMEND Regimen(N=433)N: Number of patients included in the primary analysis of complete response. %Standard Therapy(N=424) %p-ValuePRIMARY ENDPOINTOverall: to 120 hours post-chemotherapy treatment. Complete Response51420.015OTHER PRESPECIFIED ENDPOINTS No Emesis7659NSNS when adjusted for prespecified multiple comparisons rule; unadjusted p-value <0.001. No Nausea3333NS No Significant Nausea6156NS No Rescue Therapy5956NS Complete Protection4337NS. complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) in the overall phase (0 to 120 hours post-chemotherapy). no emesis (defined as no emetic episodes regardless of use of rescue therapy). no nausea (maximum VAS less than mm on 0 to 100 mm scale). no significant nausea (maximum VAS less than 25 mm on 0 to 100 mm scale). complete protection (defined as no emetic episodes, no use of rescue therapy, and maximum nausea visual analogue scale [VAS] score less than 25 mm on 0 to 100 mm scale). complete response during the acute and delayed phases.. Additional Patient-Reported Outcomes: In Study 3, in patients receiving MEC, the impact of nausea and vomiting on patients daily lives was assessed in Cycle using the FLIE. higher proportion of patients receiving the EMEND regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the No Vomiting Domain of this composite endpoint.. Multiple-Cycle Extension: In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to additional cycles of chemotherapy. The antiemetic effect for patients receiving the EMEND regimen was maintained during all cycles.In Study 4, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m2); or cytarabine intravenous (greater than g/m2). See Table 13. Patients receiving the EMEND regimen were receiving chemotherapy for variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers.Of the 430 patients who were randomized to receive the EMEND regimen, 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The EMEND-treated patients in this clinical study ranged from 22 to 85 years of age, with mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years.The antiemetic activity of EMEND was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period.A summary of the key results from Study is shown in Table 15. In Study 4, statistically significantly higher proportion of patients receiving the EMEND regimen (76%) in Cycle had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, higher proportion of patients receiving the EMEND regimen (69%) in Cycle had complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively).In subgroup analysis by tumor type, numerically higher proportion of patients receiving EMEND were observed to have no vomiting and complete response compared to patients receiving standard therapy. For sex, the difference in complete response rates between the EMEND and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. similar difference for sex was observed for the no vomiting endpoint.Table 15: Percent of Patients Receiving MEC Responding by Treatment Group -- Cycle of Study 4ENDPOINTSEMEND Regimen(N=430)N Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation. %Standard Therapy(N=418) %p-ValueNo Vomiting Overall7662<0.0001Complete Response Overall69560.0003. 14.3Prevention of Nausea and Vomiting Associated with HEC or MEC in Pediatric Patients. In randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged months to 17 years receiving HEC or MEC, EMEND in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting dosage adjustment to account for drug interaction [see Clinical Pharmacology (12.3)]. No dexamethasone dose reduction was required for patients who received the control regimen.Eligible patients had documented malignancy at either an original diagnosis or relapse and were scheduled to receive emetogenic chemotherapy or chemotherapy regimen not previously tolerated due to vomiting along with ondansetron as part of their antiemetic regimen.Of the 152 pediatric patients randomized to receive the EMEND regimen, 55% were male, 45% female, 78% White, 7% Asian, 0% Black, 24% Hispanic, and 13% Multi-Racial. The most common primary malignancies in subjects receiving the EMEND regimen were osteosarcoma (11%), Ewings sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). Other concomitant chemotherapy agents commonly administered and the number of EMEND patients exposed were: vincristine sulfate (65), etoposide (59), doxorubicin (48), ifosfamide (45), carboplatin (39), and cisplatin (35).The treatment regimens in Study for pediatric patients are defined in Table 16. Of the pediatric patients, 29% in the EMEND regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.Table 16: HEC and MEC Treatment RegimensIntravenous dexamethasone was permitted at the discretion of the physician. 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting dosage adjustment to account for drug interaction [see Clinical Pharmacology (12.3)]. No dexamethasone dose reduction was required for patients in the control regimen. for Pediatric Patients Months to 17 Years of Age-- Study 5Day 1Day 2Day 3CINV EMEND Regimen Pediatric Patients Months to less than 12 Years of AgeEMEND was administered hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days and 3, EMEND was administered in the morning. mg/kg body weight oral suspension2 mg/kg body weight oral suspension2 mg/kg body weight oral suspension Pediatric Patients 12 to 17 Years of Age 125 mg capsule80 mg capsule80 mg capsule OndansetronPer standard of careOndansetron was administered 30 minutes prior to chemotherapy on Day nonenoneCINV Control RegimenEMEND placebo was used to maintain blinding. OndansetronPer standard of care nonenoneThe antiemetic activity of EMEND was evaluated over 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint in Study was complete response in the delayed phase (25 to 120 hours following chemotherapy) in Cycle 1. Patients had the opportunity to receive open-label EMEND in subsequent cycles (Optional Cycles 2-6); however, efficacy was not assessed in these optional cycles. Overall efficacy was based on the evaluation of the following endpoints:Primary endpoint:complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy)Other prespecified endpoints:complete response in the acute phase (0 to 24 hours following initiation of chemotherapy)complete response in the overall phase (up to 120 hours following initiation of chemotherapy)no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phasesafety and tolerabilityA summary of the key study results is shown in Table 17.Table 17: Percent of Patients Who Responded to Treatment by Treatment Group and Phase Cycle of Study 5EMEND Regimenn/m (%)Control Regimenn/m (%)n/m Number of patients with desired response/number of patients included in time point.Acute Phase: to 24 hours following initiation of chemotherapy.Delayed Phase: 25 to 120 hours following initiation of chemotherapy.Overall Phase: to 120 hours following initiation of chemotherapy.PRIMARY ENDPOINTComplete ResponseComplete Response No vomiting or retching and no use of rescue medication. Delayed phase77/152 (50.7)p<0.01 when compared to Control Regimen 39/150 (26.0)OTHER PRESPECIFIED ENDPOINTSComplete Response Acute phase101/152 (66.4)p<0.05 when compared to Control Regimen 78/150 (52.0)Complete Response Overall phase61/152 (40.1) 30/150 (20.0). complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy). complete response in the acute phase (0 to 24 hours following initiation of chemotherapy). complete response in the overall phase (up to 120 hours following initiation of chemotherapy). no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phase. safety and tolerability.

DESCRIPTION SECTION.


11DESCRIPTION. EMEND capsules contain the active ingredient, aprepitant. Aprepitant is substance P/neurokinin (NK1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.Its empirical formula is C23H21F7N4O3, and its structural formula is:Aprepitant is white to off-white crystalline solid, with molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.Each capsule of EMEND for oral administration contains either 80 mg or 125 mg of aprepitant and the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 125-mg capsule also contains red ferric oxide and yellow ferric oxide.Each pouch of EMEND for oral suspension 125 mg contains 125 mg of aprepitant and the following inactive ingredients: sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. Recommended Dosage (2.1)EMEND capsules in adults and pediatric patients 12 years of age and older: is 125 mg on Day and 80 mg on Days and 3.EMEND for oral suspension in pediatric patients months to less than 12 years of age or pediatric and adult patients unable to swallow capsules: see dosing recommendations in Table in the Full Prescribing Information.Administer EMEND hour prior to chemotherapy on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer EMEND in morning.See Full Prescribing Information for recommended dosages of concomitant dexamethasone and 5-HT3 antagonist for HEC and MEC.Preparation and Administration (2.2, 2.3)EMEND capsules and EMEND for oral suspension can be administered with or without food.Swallow EMEND capsules whole.EMEND for oral suspension should be prepared by healthcare provider. Once prepared, it may be administered either by healthcare provider, patient, or caregiver.For details on preparation see Full Prescribing Information.. EMEND capsules in adults and pediatric patients 12 years of age and older: is 125 mg on Day and 80 mg on Days and 3.. EMEND for oral suspension in pediatric patients months to less than 12 years of age or pediatric and adult patients unable to swallow capsules: see dosing recommendations in Table in the Full Prescribing Information.. Administer EMEND hour prior to chemotherapy on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer EMEND in morning.. See Full Prescribing Information for recommended dosages of concomitant dexamethasone and 5-HT3 antagonist for HEC and MEC.. EMEND capsules and EMEND for oral suspension can be administered with or without food.. Swallow EMEND capsules whole.. EMEND for oral suspension should be prepared by healthcare provider. Once prepared, it may be administered either by healthcare provider, patient, or caregiver.. For details on preparation see Full Prescribing Information.. 2.1Recommended Dosage. Adults and Pediatric Patients 12 Years of Age and OlderThe recommended oral dosage of EMEND capsules, dexamethasone, and 5-HT3 antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table or Table 2, respectively. For patients who cannot swallow oral capsules, EMEND for oral suspension can be used instead of EMEND capsules as shown in Table 3.Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HECPopulationDay 1Day 2Day 3Day 4EMEND capsulesAdminister EMEND capsules hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer EMEND capsules in the morning. Adults and Pediatric Patients 12 Years and Older125 mg orally80 mg orally80 mg orallynoneDexamethasoneAdults12 mg orally8 mg orally8 mg orally8 mg orallyPediatric Patients 12 Years and OlderIf corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days through [see Clinical Studies (14.3)].Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day and in the morning on Days through 4. 50% dosage reduction of dexamethasone is recommended to account for drug interaction with EMEND [see Clinical Pharmacology (12.3)]. 5-HT3 antagonistAdults and Pediatric Patients 12 Years and OlderSee selected 5-HT3 antagonist prescribing information for the recommended dosagenonenonenoneTable 2: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MECPopulationDay 1Day 2Day 3EMEND capsulesAdminister EMEND capsules hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer EMEND capsules in the morning. Adults and Pediatric Patients 12 Years and Older125 mg orally80 mg orally80 mg orallyDexamethasoneAdults12 mg orallynonenonePediatric Patients 12 Years and OlderIf corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days through [see Clinical Studies (14.3)].Administer 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)]. 5-HT3 antagonistAdults and Pediatric Patients 12 Years and OlderSee the selected 5-HT3 antagonist prescribing information for recommended dosagenonenone. Pediatric Patients Months to less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow CapsulesThe recommended dose of EMEND for oral suspension to be administered with 5-HT3 antagonist, with or without corticosteroid, for the prevention of nausea and vomiting associated with administration of HEC or MEC is specified in Table 3. Dosing of EMEND for oral suspension is based on weight, to maximum of 125 mg on Day and 80 mg on Days and 3. Dosing in pediatric patients less than kg is not recommended.Table 3: Recommended Dosing in Pediatric Patients Months to Less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow CapsulesPopulationDay 1Day 2Day 3Day 4EMEND for oral suspensionAfter preparation, the final concentration of EMEND for oral suspension is 25 mg/mL [see Dosage and Administration (2.3)]. Administer EMEND for oral suspension hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer EMEND for oral suspension in the morning. Pediatric Patients Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules3 mg/kg orally Maximum dose 125 mg2 mg/kg orally Maximum dose 80 mg2 mg/kg orally Maximum dose 80 mgnoneDexamethasoneAdults Unable to Swallow CapsulesSee Table or See Table or See Table or See Table or Pediatric Patients Months to Less than12 Years or Pediatric Patients Unable to Swallow CapsulesIf corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days through [see Clinical Studies (14.3)].Administer 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)]. 5-HT3 antagonistPediatric Patients Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow CapsulesSee selected 5-HT3 antagonist prescribing information for the recommended dosagenonenonenone. 2.2Preparation Instructions for EMEND for Oral Suspension -- for Healthcare Providers. EMEND for oral suspension should be prepared by healthcare provider. Once prepared, it may be administered either by healthcare provider, patient, or caregiver. Before preparing EMEND:Do not open the pouch of EMEND until ready to prepare the medicine.Store the pouch at room temperature [between 68F-77F (20C-25C)].Table 4: Instructions for Healthcare Providers on How to Prepare EMEND for Oral SuspensionEMEND for oral suspension is packaged as kit with one mL oral dosing dispenser, one mL oral dosing dispenser, one cap and one mixing cup.1.Fill the mixing cup with room temperature drinking water.2.Fill the mL oral dosing dispenser with 4.6 mL of water from the mixing cup. Make sure no air is in the dispenser if air is present, remove. 3.Discard all the unused water remaining in the mixing cup.4.Add the 4.6 mL of water from the dispenser back into the mixing cup.5.Each pouch of EMEND for oral suspension contains 125 mg of aprepitant which is to be suspended in 4.6 mL of water giving final concentration of 25 mg/mL. Hold the EMEND for oral suspension pouch upright and shake the contents to the bottom before opening the pouch.6.Pour the entire contents of the pouch into the 4.6 mL of water in the mixing cup and snap the lid shut.7.Mix the EMEND suspension gently by swirling 20 times; then gently invert the mixing cup times. To prevent foaming, do not shake the mixing cup. The mixture will be cloudy pink to light pink.8.Check the EMEND mixture for any clumps or foaming:If any clumps are present, repeat Step until there are no clumps.If there is any foam, wait for the foam to disappear before going on to Step 9. 9.Fill the dispenser with the prescribed dose shown above in Table 3.Choose the dispenser based on dose:Use mL dispenser if dose is mL or less.Use mL dispenser if dose is more than mL. Fill the dispenser with the prescribed dose from the cup.If the dose is less than mL round to the nearest 0.1 mL.If the dose is more than mL round to the nearest 0.2 mL. It is common to have medicine leftover in the cup. Make sure no air is in the dispenser if air is present, remove. Make sure the dispenser contains the prescribed dose.10. Place the cap on the dispenser until it clicks.11.If the dose is not administered immediately after measuring, store filled oral dosing dispenser(s) in the refrigerator [between 36F-46F (2C-8C)] for up to 72 hours prior to use. When dispensing dose(s) to the patient or caregiver, instruct them to refrigerate the oral dosing dispenser(s) until they are ready to administer the dose.12. When ready to use, the mixture can be kept at room temperature [between 68F-77F (20C-25C)] for up to hours.13. Discard the mixing cup along with any remaining suspension.. Do not open the pouch of EMEND until ready to prepare the medicine.. Store the pouch at room temperature [between 68F-77F (20C-25C)].. 1.Fill the mixing cup with room temperature drinking water.. 2.Fill the mL oral dosing dispenser with 4.6 mL of water from the mixing cup. Make sure no air is in the dispenser if air is present, remove. 3.Discard all the unused water remaining in the mixing cup.. 4.Add the 4.6 mL of water from the dispenser back into the mixing cup.. 5.Each pouch of EMEND for oral suspension contains 125 mg of aprepitant which is to be suspended in 4.6 mL of water giving final concentration of 25 mg/mL. Hold the EMEND for oral suspension pouch upright and shake the contents to the bottom before opening the pouch.. 6.Pour the entire contents of the pouch into the 4.6 mL of water in the mixing cup and snap the lid shut.. 7.Mix the EMEND suspension gently by swirling 20 times; then gently invert the mixing cup times. To prevent foaming, do not shake the mixing cup. The mixture will be cloudy pink to light pink.. 8.Check the EMEND mixture for any clumps or foaming:If any clumps are present, repeat Step until there are no clumps.If there is any foam, wait for the foam to disappear before going on to Step 9. If any clumps are present, repeat Step until there are no clumps.. If there is any foam, wait for the foam to disappear before going on to Step 9.. 9.Fill the dispenser with the prescribed dose shown above in Table 3.Choose the dispenser based on dose:Use mL dispenser if dose is mL or less.Use mL dispenser if dose is more than mL. Fill the dispenser with the prescribed dose from the cup.If the dose is less than mL round to the nearest 0.1 mL.If the dose is more than mL round to the nearest 0.2 mL. It is common to have medicine leftover in the cup. Choose the dispenser based on dose:Use mL dispenser if dose is mL or less.Use mL dispenser if dose is more than mL. Use mL dispenser if dose is mL or less.. Use mL dispenser if dose is more than mL.. Fill the dispenser with the prescribed dose from the cup.If the dose is less than mL round to the nearest 0.1 mL.If the dose is more than mL round to the nearest 0.2 mL. If the dose is less than mL round to the nearest 0.1 mL.. If the dose is more than mL round to the nearest 0.2 mL.. It is common to have medicine leftover in the cup.. 10. Place the cap on the dispenser until it clicks.. 11.If the dose is not administered immediately after measuring, store filled oral dosing dispenser(s) in the refrigerator [between 36F-46F (2C-8C)] for up to 72 hours prior to use. When dispensing dose(s) to the patient or caregiver, instruct them to refrigerate the oral dosing dispenser(s) until they are ready to administer the dose.. 12. When ready to use, the mixture can be kept at room temperature [between 68F-77F (20C-25C)] for up to hours.. 13. Discard the mixing cup along with any remaining suspension.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. 2.3Administration Instructions. EMEND capsules and EMEND for oral suspension can be administered with or without food.. EMEND capsulesSwallow capsules whole.. Swallow capsules whole.. EMEND for oral suspensionThe dose will be prepared by the healthcare provider and dispensed to the patient or caregiver in an oral dispenser.Keep the dispenser in the refrigerator until administered to the patient. The dose can be stored at room temperature for up to hours before use.When ready to use, take the cap off the dispenser, place the dispenser in the patients mouth along the inner cheek on either the right or left side. Slowly dispense the medicine.The dose must be used within 72 hours of preparation.Discard any doses remaining after 72 hours.. The dose will be prepared by the healthcare provider and dispensed to the patient or caregiver in an oral dispenser.. Keep the dispenser in the refrigerator until administered to the patient. The dose can be stored at room temperature for up to hours before use.. When ready to use, take the cap off the dispenser, place the dispenser in the patients mouth along the inner cheek on either the right or left side. Slowly dispense the medicine.. The dose must be used within 72 hours of preparation.. Discard any doses remaining after 72 hours.

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. EMEND capsules: 80 mg and 125 mg (3)EMEND for oral suspension: 125 mg (3). EMEND capsules:80 mg: white body and cap with 461 and 80 mg printed radially in black ink on the body.125 mg: white body and pink cap with 462 and 125 mg printed radially in black ink on the body.. 80 mg: white body and cap with 461 and 80 mg printed radially in black ink on the body.. 125 mg: white body and pink cap with 462 and 125 mg printed radially in black ink on the body.. EMEND for oral suspension:125 mg as pink to light pink powder in single-use pouch with one mL oral dosing dispenser, one mL oral dosing dispenser, one cap and mixing cup.. 125 mg as pink to light pink powder in single-use pouch with one mL oral dosing dispenser, one mL oral dosing dispenser, one cap and mixing cup.

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. See Full Prescribing Information for list of clinically significant drug interactions. (4, 5.1, 5.2, 5.3, 7.1, 7.2). 7.1Effect of Aprepitant on the Pharmacokinetics of Other Drugs. Aprepitant is substrate, weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology (12.3)].Aprepitant acts as moderate inhibitor of CYP3A4 when administered as 3-day regimen (125-mg/80-mg/80-mg) and can increase plasma concentrations of concomitant drugs that are substrates for CYP3A4. 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 8.Table 8: Effects of Aprepitant on the Pharmacokinetics of Other DrugsCYP3A4 SubstratesPimozideClinical ImpactIncreased pimozide exposure.InterventionEMEND 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.Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolamDexamethasoneClinical 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 intravenous methylprednisolone by approximately 25%Reduce the dose of oral methylprednisolone by approximately 50%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 (5.3), Use in Specific Populations (8.3), 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 the last dose of EMEND.Examplesbirth control pills, skin patches, implants, and certain IUDsCYP2C9 SubstratesWarfarinClinical ImpactDecreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.2), 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 initiation of the 3-day EMEND regimen 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 benzodiazepine-related adverse reactions.. Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam. Reduce the dose of intravenous methylprednisolone by approximately 25%. Reduce the dose of oral methylprednisolone by approximately 50%. Monitor for chemotherapeutic-related adverse reactions.. No dosage adjustment needed.. 7.2Effect of Other Drugs on the Pharmacokinetics of 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 9.Table 9: Effects of Other Drugs on Pharmacokinetics of 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) and Clinical Pharmacology (12.3)].InterventionAvoid concomitant use of EMEND.ExamplesModerate inhibitor: diltiazem Strong 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 EMEND.Examplesrifampin, carbamazepine, phenytoin.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3Females 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.


8.5Geriatric Use. Of the 544 adult cancer patients treated with EMEND in CINV clinical studies, 31% 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)].

HEPATIC IMPAIRMENT SUBSECTION.


8.7Patients 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)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. No. 3854 -- 80-mg capsules: White, opaque, hard gelatin capsule with 461 and 80 mg printed radially in black ink on the body. They are supplied as follows:NDC 0006-0461-02 unit-of-use BiPack of 2No. 3862 -- Unit-of-use TriPack containing one 125-mg capsule and two 80-mg capsules. 125 mg-capsules: Opaque, hard gelatin capsule with white body and pink cap with 462 and 125 mg printed radially in black ink on the body. 80-mg capsules: White, opaque, hard gelatin capsule with 461 and 80 mg printed radially in black ink on the body.NDC 0006-3862-03.No. 3066 -- 125 mg for oral suspension: Pink to light pink powder, in single-use pouch, packaged as kit with one mL oral dosing dispenser, one mL oral dosing dispenser, one cap and one mixing cup. It is supplied as follows:NDC 0006-3066-03 unit of use carton.. Storage and Handling. CapsulesStore at 20-25C (68-77F) [see USP Controlled Room Temperature].. For Oral SuspensionStore unopened pouch at 20-25C (68-77F); excursions permitted between 15-30C (between 59-86F). Store in the original container. Do not open pouch until ready for use.Once prepared, if suspension is not used immediately, store refrigerated [between 36F-46F (2C-8C)] for up to 72 hours prior to use. When ready to use, the mixture can be kept at room temperature [between 68F-77F (20C-25C)] for up to hours.

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. EMEND(R) for oral suspension, in combination with other antiemetic agents, is indicated in 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.nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).EMEND(R) capsules, in combination with other antiemetic agents, is indicated in patients 12 years 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.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.. 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.. nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).. EMEND(R) is substance P/neurokinin (NK1) receptor antagonist.EMEND for oral suspension is indicatedin combination with other antiemetic agents, in patients months of age and older for prevention of:acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin (1)nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1) EMEND capsules is indicatedin combination with other antiemetic agents, in patients 12 years of age and older for prevention of:acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin (1)nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1) Limitations of Use (1)EMEND has not been studied for treatment of established nausea and vomiting.Chronic continuous administration of EMEND is not recommended.. in combination with other antiemetic agents, in patients months of age and older for prevention of:acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin (1)nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1) acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin (1). nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1). in combination with other antiemetic agents, in patients 12 years of age and older for prevention of:acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin (1)nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1) acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin (1). nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1). EMEND has not been studied for treatment of established nausea and vomiting.. Chronic continuous administration of EMEND is not recommended.. Limitations of UseEMEND has not been studied for the treatment of established nausea and vomiting.Chronic continuous administration of EMEND is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.. EMEND has not been studied for the treatment of established nausea and vomiting.. Chronic continuous administration of EMEND is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients taking EMEND. Advise patients to stop taking EMEND and seek immediate medical attention if they experience signs or symptoms of hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, or difficulty in breathing or swallowing.. 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 the 3-day regimen of EMEND with each chemotherapy cycle [see Warnings and Precautions (5.2)].. 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 the last dose of EMEND [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)].

INSTRUCTIONS FOR USE SECTION.


Instructions for UseEMEND(R) (EE-mend) (aprepitant) for oral suspension Read the Patient Information and Instructions forUse for EMEND for oral suspension before you take or before you give dose to your childTake by mouth onlyHow to give dose of EMEND for oral suspensionThe healthcare provider has prepared the dose of EMEND for you or your child.1.You will get EMEND in an oral dosing dispenser2.Keep the oral dosing dispenser in the refrigerator until you give EMEND to yourself or your childStore EMEND in the refrigerator between 36F to 46F (2C to 8C). Use EMEND within days of getting the medicine from the healthcare provider.When ready to use, EMEND can be kept at room temperature, between 68F to 77F (20C to 25C) for up to hours.Keep EMEND and all medicines out of the reach of children. 3.Give EMEND4.Throw away the oral dosing dispenser and capThe color of the medicine in the oral dosing dispenser may be different shades of pink (light pink to dark pink). This is normal and the medicine is okay to use.Take the cap off the oral dosing dispenser.Place the tip of the oral dosing dispenser in your mouth or in your childs mouth along the inner cheek on either the right or left side.Slowly push the plunger all the way down to give all of the medicine in the oral dosing dispenser. Call the healthcare provider if you or your child is not able to take the prescribed dose. For more information go to www.emend.com or call 1-800-622-4477. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USA For patent information: www.merck.com/product/patent/home.html Copyright (C) 2015 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved. Issued: 12/2015 usifu-mk0869-mf-1512r000. 1.You will get EMEND in an oral dosing dispenser. 2.Keep the oral dosing dispenser in the refrigerator until you give EMEND to yourself or your child. Store EMEND in the refrigerator between 36F to 46F (2C to 8C). Use EMEND within days of getting the medicine from the healthcare provider.. When ready to use, EMEND can be kept at room temperature, between 68F to 77F (20C to 25C) for up to hours.. Keep EMEND and all medicines out of the reach of children.. 3.Give EMEND. 4.Throw away the oral dosing dispenser and cap. Take the cap off the oral dosing dispenser.. Place the tip of the oral dosing dispenser in your mouth or in your childs mouth along the inner cheek on either the right or left side.. Slowly push the plunger all the way down to give all of the medicine in the oral dosing dispenser.. Warning. Figure. Figure. Figure. Figure.

LACTATION SECTION.


8.2Lactation. 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.


12.1Mechanism of Action. 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 show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, 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 exposure to aprepitant (AUC) of 0.7 to 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen. 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 of about 2.8 to 3.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.. MutagenesisAprepitant was 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 FertilityAprepitant 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 and exposure in female rats at about 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen).

OVERDOSAGE SECTION.


10OVERDOSAGE. No specific information is available on the treatment of overdosage.Drowsiness and headache were reported in one patient who ingested 1440 mg of EMEND (approximately 11 times the maximum recommended single dose).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 80 mg Capsule Dose Pack. NDC 0006-0461-02BiPack2 capsulesEMEND(R)(aprepitant) capsules80mgFor Adults andPediatric Patients12 years of Age and OlderYou have already been givena capsule of EMEND (aprepitant) toprevent nausea and vomiting beforeyour chemotherapy on Day 1.The two capsules in this packageare to be taken on Days and 3.Each capsule contains 80 mgof aprepitant.USUAL DOSAGE:See accompanying circular.Rx onlyKeep this and all drugs out ofthe reach of children.Dist. by: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC.,Whitehouse Station, NJ 08889, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandAprepitant (active ingred.) Made in Switzerland.Formulated in Ireland.. PRINCIPAL DISPLAY PANEL 80 mg Capsule Dose Pack.

PEDIATRIC USE SECTION.


8.4Pediatric Use. The safety and effectiveness of EMEND for oral suspension have been established in pediatric patients months of age and older and EMEND capsules in pediatric patients 12 years of age and older for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC, including high-dose cisplatin, and MEC. Use of EMEND in these age groups is supported by evidence from 302 pediatric patients in randomized, double-blind, active comparator controlled clinical study (n 207 patients aged months to less than 12 years, = 95 patients aged 12 through 17 years). EMEND was studied in combination with ondansetron with or without dexamethasone (at the discretion of the physician) [see Clinical Studies (14.3)]. Adverse reactions were similar to those reported in adult patients [see Adverse Reactions (6.1)].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.. Juvenile Animal StudyA study was 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 rats lower than the exposure at the recommended pediatric human dose and exposure in female rats equivalent to the pediatric human exposure) from the early postnatal period (Postnatal Day 10) through Postnatal Day 58. 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.


12.2Pharmacodynamics. NK1 Receptor OccupancyIn two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral EMEND doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with or subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of approximately 10 ng/mL and 100 ng/mL, the NK1 receptor occupancies were approximately 50% and 90%, respectively. The oral EMEND regimen produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK1 receptor occupancy. However, the receptor occupancy has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of EMEND has not been established.. Cardiac ElectrophysiologyIn randomized, double-blind, positive-controlled, thorough QTc study, single 200-mg dose of fosaprepitant had no effect on the QTc interval. Maximum aprepitant concentrations after single 200-mg dose of fosaprepitant were 4-fold higher than that achieved with oral EMEND 125 mg. QT prolongation with the recommended oral EMEND dosing regimens is not expected.

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics. AbsorptionFollowing oral administration of single 125-mg dose of EMEND on Day and 80 mg once daily on Days and 3, the AUC0-24hr was approximately 19.6 mcghr/mL and 21.2 mcghr/mL on Day and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately hours (Tmax) on Day and Day 3, respectively. At the dose range of 80 to 125 mg, the mean absolute oral bioavailability of EMEND is approximately 60 to 65%. Oral administration of the capsule with standard high-fat breakfast had no clinically meaningful effect on the bioavailability of aprepitant.The pharmacokinetics of aprepitant were non-linear across the clinical dose range. In healthy young adults, the increase in AUC0- was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.. 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. MetabolismAprepitant 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 (2.4 times the maximum EMEND recommended dose), 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]-aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. study was not conducted with radiolabeled capsule formulation. The results after oral administration may differ.Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma clearance of aprepitant ranged from approximately 62 to 90 mL/min. The apparent terminal half-life ranged from approximately to 13 hours.. Specific Populations. Geriatric PatientsFollowing oral administration of single 125-mg dose of EMEND on Day and 80 mg once daily on Days through (2 additional days of dosing compared to the recommended duration), 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)]. Pediatric PatientsAs part of 3-day regimen, dosing of aprepitant capsules (125-mg/80-mg/80-mg) in 18 pediatric patients (aged 12 through 17 years) achieved mean AUC0-24hr of 17 mcghr/mL on Day with mean peak plasma concentration (Cmax) at 1.3 mcg/mL occurring at approximately hours. The mean concentrations at the end of Day (N=8) and Day (N=16) were both at 0.6 mcg/mLAs part of 3-day regimen, weight-based dosing of aprepitant powder for oral suspension (3-mg/kg;2-mg/kg;2-mg/kg) in 18 pediatric patients aged months to less than 12 years achieved mean AUC0-24hr of 20.9 mcghr/mL on Day with mean peak plasma concentration (Cmax) at 1.8 mcg/mL (N=19), occurring at approximately hours. The mean concentrations at the end of Day (N=18) and Day (N=19) were 0.4 mcg/mL and 0.5 mcg/mL, respectively [see Dosage and Administration (2.1)].A population pharmacokinetic analysis of aprepitant in pediatric patients (aged months through 17 years) suggests that sex and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.. Male and Female PatientsFollowing oral administration of single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum EMEND recommended dose), 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.. Racial or Ethnic GroupsFollowing oral administration of single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum EMEND recommended dose), 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.. Patients with Renal ImpairmentA single 240-mg dose of aprepitant (approximately 1.9 times the maximum EMEND recommended dose) 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 [see Use in Specific Populations (8.6)].. Patients with Hepatic ImpairmentFollowing administration of single 125-mg dose of EMEND 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 (8.7)].. 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 StudiesAprepitant is substrate, moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.. Effects of Aprepitant on the Pharmacokinetics of Other Drugs. CYP3A4 substrates (i.e., midazolam): Interactions between EMEND and coadministered midazolam are listed in Table 10 (increase is indicated as , decrease as , no change as <->).Table 10: Pharmacokinetic Interaction Data for EMEND and Coadministered MidazolamDosage of EMENDDosage of MidazolamObserved Drug InteractionsEMEND 125 mg on Day and 80 mg on Days to 5oral mg single dose on Days and 5midazolam AUC 2.3-fold on Day and 3.3-fold on Day [see Drug Interactions (7.1)] EMEND 125 mg on Day and 80 mg on Days and 3intravenous mg prior to 3-day regimen of EMEND and on Days 4, and 15midazolam AUC 25% on Day 4, AUC 19% on Day and AUC 4% on Day 15EMEND 125 mg on Day 1intravenous mg given hour after EMENDmidazolam AUC 1.5-foldA difference of less than 2-fold increase of midazolam AUC is not considered clinically important.. Corticosteroids:. Dexamethasone: EMEND, when given as regimen of 125 mg on Day and 80 mg/day on Days through 5, coadministered with 20-mg dexamethasone on Day and 8-mg dexamethasone on Days through 5, increased the AUC of dexamethasone by 2.2-fold on Days and [see Dosage and Administration (2.1)].. Methylprednisolone: EMEND, when given as regimen of 125 mg on Day and 80 mg/day on Days and 3, coadministered with 125 mg methylprednisolone IV on Day and 40 mg methylprednisolone orally on Days and 3, increased the AUC of methylprednisolone by 1.34-fold on Day and by 2.5-fold on Day 3.. Chemotherapeutic agents:. Docetaxel: In pharmacokinetic study, EMEND (125-mg/80-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel.. Vinorelbine: In pharmacokinetic study, EMEND (125-mg/80-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to clinically significant degree.. CYP2C9 substrates (Warfarin, Tolbutamide):. Warfarin: single 125-mg dose of EMEND was administered on Day and 80 mg/day on Days and to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND 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 EMEND [see Drug Interactions (7.1)].. Tolbutamide: EMEND, 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 EMEND and on Days 4, 8, and 15. This effect was not considered clinically important.. Other Drugs. Oral contraceptives: When EMEND 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.. P-glycoprotein substrates: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND 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 Aprepitant. Ketoconazole: When single 125-mg dose of EMEND 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)].. Rifampin: When single 375-mg dose of aprepitant (3 times the maximum EMEND recommended dose) 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)].. Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as tablet formulation comparable to 230 mg of the capsule formulation (approximately 1.8 times the EMEND recommended dose), with diltiazem 120 mg times daily for days, resulted in 2-fold increase of aprepitant AUC and simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone [see Drug Interactions (7.2)].. Paroxetine: Coadministration of once daily doses of aprepitant, as tablet formulation comparable to 85 mg or 170 mg of the capsule formulation (approximately 0.7 and 1.4 times the maximum EMEND recommended dose), 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.


8.1Pregnancy. 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 1.5 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen [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 in rats and up to the maximum tolerated dose of 25 mg/kg/day in 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 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125-mg/80-mg/80-mg EMEND regimen. Aprepitant crosses the placenta in rats and rabbits.

RENAL IMPAIRMENT SUBSECTION.


8.6Patients with Renal Impairment. The pharmacokinetics of aprepitant in patients with severe renal impairment and those with end stage renal disease (ESRD) requiring hemodialysis were similar to those of healthy subjects with normal renal function. No dosage adjustment is necessary for patients with any degree of renal impairment or for patients with ESRD undergoing hemodialysis.

SPL PATIENT PACKAGE INSERT SECTION.


Patient InformationEMEND(R) (EE mend)(aprepitant)capsulesEMEND(R) (EE mend)(aprepitant)for oral suspensionThis Patient Information has been approved by the U.S. Food and Drug Administration.Revised: September 2019 Read this Patient Information before you start taking EMEND and each time you get refill. 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 EMENDEMEND for oral suspension 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) medicinesEMEND capsules is prescription medicine used:with other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicinesEMEND is not used to treat nausea and vomiting that you already have.EMEND should not be used continuously for long time (chronic use).Who should not take EMENDDo not take EMEND if you:are allergic to aprepitant or any of the ingredients in EMEND. See the end of this leaflet for complete list of ingredients in EMEND.are taking pimozide (ORAP(R))What should tell my healthcare provider before taking EMENDBefore you take EMEND, tell your healthcare provider if you:have liver problemsare pregnant or plan to become pregnant. It is not known if EMEND 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 back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND and for month after your last dose of EMEND. are breastfeeding or plan to breastfeed. It is not known if EMEND passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take EMEND.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.EMEND may affect the way other medicines work, and other medicines may affect how EMEND 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 should take EMENDTake EMEND exactly as prescribed.Swallow EMEND capsules whole.EMEND may be taken with or without food.If you take too much EMEND, call your healthcare provider, or go to the nearest hospital emergency room.EMEND is taken as doses over days starting on the day you have chemotherapy, and for the following days.In adults, there are ways your healthcare provider may prescribe EMEND for you:1.Capsules of EMEND by mouth for all doses:You should get package that has capsules of EMEND.Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.2.Oral suspension of EMEND by mouth for all doses, for adults who are not able to swallow capsules:For each dose of EMEND for oral suspension, you will get pre-filled oral dosing dispenser that contains your prescribed dose.See the detailed Instructions for Use that comes with EMEND for oral suspension for information about the correct way to take dose of EMEND for oral suspension. If you have questions about how to take EMEND for oral suspension, talk to your healthcare provider.Day (Day of chemotherapy): Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND for oral suspension should be taken in the morning.In children 12 years of age and older who can swallow capsules by mouth, EMEND is prescribed as capsules of EMEND by mouth for all doses:You should get package that has capsules of EMEND.Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.In children months to less than 12 years of age or in children 12 years of age and older who are not able to swallow capsules, EMEND is prescribed as oral suspension of EMEND by mouth for all doses:For each dose of EMEND, you will get pre-filled oral dosing dispenser that contains your childs prescribed dose.See the detailed Instructions for Use that comes with EMEND for oral suspension, for information about the correct way to give dose of EMEND for oral suspension. If you have questions about how to give EMEND for oral suspension, talk to your childs healthcare provider.Day (Day of chemotherapy): Give dose of EMEND for oral suspension to your child by mouth hour before they start their chemotherapy treatment.Day and Day 3: Give dose of EMEND for oral suspension to your child by mouth hour before they start their chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be given in the morning.If you take the blood thinner medicine warfarin sodium (COUMADIN(R), JANTOVEN(R)), your healthcare provider may do blood tests after you take EMEND to check your blood clotting.What are the possible side effects of EMENDIn adults taking EMEND, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests.In children months to 17 years of age, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups.Tell 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 more information ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store EMENDEMEND capsulesStore EMEND capsules at room temperature, between 68F to 77F (20C to 25C).EMEND for oral suspensionStore EMEND for oral suspension in the refrigerator, between 36F to 46F (2C to 8C).Use EMEND for oral suspension within days of getting the medicine from your healthcare provider.When ready to use, EMEND for oral suspension can be kept at room temperature, between 68F to 77F (20C to 25C) for up to hours.Keep EMEND and all medicines out of the reach of children.General information about the safe and effective use of EMENDMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use EMEND for condition for which it was not prescribed. Do not give EMEND to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about EMEND that is written for health professionals. For more information about EMEND call 1-800-622-4477 or go to www.emend.com.What are the ingredients in EMENDEMEND capsules:Active ingredient: aprepitantInactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 125 mg capsule shell also contains red ferric oxide and yellow ferric oxide.EMEND for oral suspension:Active ingredient: aprepitantInactive ingredients: sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.Distributed by: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USA For patent information: www.merck.com/product/patent/home.html The brands listed in the above sections Who should not take EMEND and How should take EMEND are the registered trademarks of their respective owners and are not trademarks of Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. Copyright (C) 2003-2019 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved. usppi-mk0869-mf-1909r007. 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. with other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines. are allergic to aprepitant or any of the ingredients in EMEND. See the end of this leaflet for complete list of ingredients in EMEND.. are taking pimozide (ORAP(R)). have liver problems. are pregnant or plan to become pregnant. It is not known if EMEND 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 back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND and for month after your last dose of EMEND. Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND and for month after your last dose of EMEND.. are breastfeeding or plan to breastfeed. It is not known if EMEND passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take EMEND.. Take EMEND exactly as prescribed.. Swallow EMEND capsules whole.. EMEND may be taken with or without food.. If you take too much EMEND, call your healthcare provider, or go to the nearest hospital emergency room.. EMEND is taken as doses over days starting on the day you have chemotherapy, and for the following days.. In adults, there are ways your healthcare provider may prescribe EMEND for you:1.Capsules of EMEND by mouth for all doses:You should get package that has capsules of EMEND.Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.2.Oral suspension of EMEND by mouth for all doses, for adults who are not able to swallow capsules:For each dose of EMEND for oral suspension, you will get pre-filled oral dosing dispenser that contains your prescribed dose.See the detailed Instructions for Use that comes with EMEND for oral suspension for information about the correct way to take dose of EMEND for oral suspension. If you have questions about how to take EMEND for oral suspension, talk to your healthcare provider.Day (Day of chemotherapy): Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND for oral suspension should be taken in the morning.. 1.Capsules of EMEND by mouth for all doses:You should get package that has capsules of EMEND.Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.. You should get package that has capsules of EMEND.. Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.. Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.. 2.Oral suspension of EMEND by mouth for all doses, for adults who are not able to swallow capsules:For each dose of EMEND for oral suspension, you will get pre-filled oral dosing dispenser that contains your prescribed dose.See the detailed Instructions for Use that comes with EMEND for oral suspension for information about the correct way to take dose of EMEND for oral suspension. If you have questions about how to take EMEND for oral suspension, talk to your healthcare provider.Day (Day of chemotherapy): Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND for oral suspension should be taken in the morning.. For each dose of EMEND for oral suspension, you will get pre-filled oral dosing dispenser that contains your prescribed dose.. See the detailed Instructions for Use that comes with EMEND for oral suspension for information about the correct way to take dose of EMEND for oral suspension. If you have questions about how to take EMEND for oral suspension, talk to your healthcare provider.. Day (Day of chemotherapy): Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment.. Day and Day 3: Take dose of EMEND for oral suspension by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND for oral suspension should be taken in the morning.. In children 12 years of age and older who can swallow capsules by mouth, EMEND is prescribed as capsules of EMEND by mouth for all doses:You should get package that has capsules of EMEND.Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.. You should get package that has capsules of EMEND.. Day (Day of chemotherapy): Take one 125 mg capsule of EMEND (white and pink) by mouth hour before you start your chemotherapy treatment.. Day and Day 3: Take one 80 mg capsule of EMEND (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be taken in the morning.. In children months to less than 12 years of age or in children 12 years of age and older who are not able to swallow capsules, EMEND is prescribed as oral suspension of EMEND by mouth for all doses:For each dose of EMEND, you will get pre-filled oral dosing dispenser that contains your childs prescribed dose.See the detailed Instructions for Use that comes with EMEND for oral suspension, for information about the correct way to give dose of EMEND for oral suspension. If you have questions about how to give EMEND for oral suspension, talk to your childs healthcare provider.Day (Day of chemotherapy): Give dose of EMEND for oral suspension to your child by mouth hour before they start their chemotherapy treatment.Day and Day 3: Give dose of EMEND for oral suspension to your child by mouth hour before they start their chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be given in the morning.. For each dose of EMEND, you will get pre-filled oral dosing dispenser that contains your childs prescribed dose.. See the detailed Instructions for Use that comes with EMEND for oral suspension, for information about the correct way to give dose of EMEND for oral suspension. If you have questions about how to give EMEND for oral suspension, talk to your childs healthcare provider.. Day (Day of chemotherapy): Give dose of EMEND for oral suspension to your child by mouth hour before they start their chemotherapy treatment.. Day and Day 3: Give dose of EMEND for oral suspension to your child by mouth hour before they start their chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, EMEND should be given in the morning.. If you take the blood thinner medicine warfarin sodium (COUMADIN(R), JANTOVEN(R)), your healthcare provider may do blood tests after you take EMEND to check your blood clotting.. In adults taking EMEND, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests.. In children months to 17 years of age, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups.. Store EMEND capsules at room temperature, between 68F to 77F (20C to 25C).. Store EMEND for oral suspension in the refrigerator, between 36F to 46F (2C to 8C).. Use EMEND for oral suspension within days of getting the medicine from your healthcare provider.. When ready to use, EMEND for oral suspension can be kept at room temperature, between 68F to 77F (20C to 25C) for up to hours.

SPL UNCLASSIFIED SECTION.


Limitations of UseEMEND has not been studied for the treatment of established nausea and vomiting.Chronic continuous administration of EMEND is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.. EMEND has not been studied for the treatment of established nausea and vomiting.. Chronic continuous administration of EMEND is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.

STORAGE AND HANDLING SECTION.


Storage and Handling. CapsulesStore at 20-25C (68-77F) [see USP Controlled Room Temperature].. For Oral SuspensionStore unopened pouch at 20-25C (68-77F); excursions permitted between 15-30C (between 59-86F). Store in the original container. Do not open pouch until ready for use.Once prepared, if suspension is not used immediately, store refrigerated [between 36F-46F (2C-8C)] for up to 72 hours prior to use. When ready to use, the mixture can be kept at room temperature [between 68F-77F (20C-25C)] for up to hours.

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. 8.1Pregnancy. 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 1.5 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen [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 in rats and up to the maximum tolerated dose of 25 mg/kg/day in 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 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125-mg/80-mg/80-mg EMEND regimen. Aprepitant crosses the placenta in rats and rabbits.. 8.2Lactation. 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.. 8.3Females 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)].. 8.4Pediatric Use. The safety and effectiveness of EMEND for oral suspension have been established in pediatric patients months of age and older and EMEND capsules in pediatric patients 12 years of age and older for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC, including high-dose cisplatin, and MEC. Use of EMEND in these age groups is supported by evidence from 302 pediatric patients in randomized, double-blind, active comparator controlled clinical study (n 207 patients aged months to less than 12 years, = 95 patients aged 12 through 17 years). EMEND was studied in combination with ondansetron with or without dexamethasone (at the discretion of the physician) [see Clinical Studies (14.3)]. Adverse reactions were similar to those reported in adult patients [see Adverse Reactions (6.1)].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.. Juvenile Animal StudyA study was 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 rats lower than the exposure at the recommended pediatric human dose and exposure in female rats equivalent to the pediatric human exposure) from the early postnatal period (Postnatal Day 10) through Postnatal Day 58. 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.. 8.5Geriatric Use. Of the 544 adult cancer patients treated with EMEND in CINV clinical studies, 31% 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 Renal Impairment. The pharmacokinetics of aprepitant in patients with severe renal impairment and those with end stage renal disease (ESRD) requiring hemodialysis were similar to those of healthy subjects with normal renal function. No dosage adjustment is necessary for patients with any degree of renal impairment or for patients with ESRD undergoing hemodialysis.. 8.7Patients 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.


5WARNINGS AND PRECAUTIONS. CYP3A4 Interactions: Aprepitant is substrate, weak-to-moderate inhibitor and inducer of CYP3A4; See Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustments of EMEND and concomitant drugs. (4, 5.1, 7.1, 7.2)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. (5.2, 7.1)Hormonal Contraceptives: Efficacy of contraceptives may be reduced during administration of and for 28 days following the last dose of EMEND. Use effective alternative or back-up methods of contraception. (5.3, 7.1, 8.3). CYP3A4 Interactions: Aprepitant is substrate, weak-to-moderate inhibitor and inducer of CYP3A4; See Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustments of EMEND and concomitant drugs. (4, 5.1, 7.1, 7.2). 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. (5.2, 7.1). Hormonal Contraceptives: Efficacy of contraceptives may be reduced during administration of and for 28 days following the last dose of EMEND. Use effective alternative or back-up methods of contraception. (5.3, 7.1, 8.3). 5.1Clinically Significant CYP3A4 Drug Interactions. Aprepitant is substrate, weak-to-moderate (dose-dependent) inhibitor, and an 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.. 5.2Decrease in INR with Concomitant Warfarin. Coadministration of EMEND with warfarin, CYP2C9 substrate, may result in clinically significant decrease in 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 the 3-day regimen of EMEND with each chemotherapy cycle [see Drug Interactions (7.1)].. 5.3Risk 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 the last dose of EMEND [see Drug Interactions (7.1), Use in Specific Populations (8.3)].