ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions are 6.1): Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)Adults (>=3%): fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased.Pediatrics (>=3%): neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups.PONVAdults (>=3%): constipation and hypotension.To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adults (>=3%): fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased.. Pediatrics (>=3%): neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups.. Adults (>=3%): constipation and hypotension.. 6.1 Clinical 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 aprepitant was evaluated in approximately 6800 individuals.Adverse Reactions in Adults in the Prevention of Nausea and Vomiting Associated with HEC and MECIn active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies and 2), aprepitant in combination with ondansetron and dexamethasone (aprepitant 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), aprepitant in combination with ondansetron and dexamethasone (aprepitant 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 aprepitant 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 3: Most Common Adverse Reactions in Patients Receiving HEC and MEC from Pooled Analysis of HEC and MEC Studies Aprepitant, ondansetron, and dexamethasone (N=1412)Ondansetron and dexamethasone (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%Reported in >= 3% of patients treated with the aprepitant regimen and at greater incidence than standard therapy. +Aprepitant regimen Standard therapy In pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the aprepitant regimen are listed in Table 6.Table 4: Less Common Adverse Reactions in Aprepitant-Treated Patients from Pooled Analysis of HEC and MEC Studies 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 decreasedReported in 0.5% of patients treated with the aprepitant regimen, at greater incidence than standard therapy and not previously described in Table 5. In an additional active-controlled clinical study in 1169 patients receiving aprepitant and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with aprepitant.In another CINV study, Stevens-Johnson syndrome was reported as serious adverse reaction in patient receiving the aprepitant 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.Adverse Reactions in Pediatric Patients Months to 17 Years of Age in the Prevention of Nausea and Vomiting Associated with HEC or MECIn 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), aprepitant in combination with ondansetron with or without dexamethasone (aprepitant regimen) was compared to ondansetron with or without dexamethasone (control regimen).There were 184 patients treated with the aprepitant regimen during Cycle and 215 patients received open-label aprepitant for up to additional cycles of chemotherapy.In Cycle 1, the most common adverse reactions reported in pediatric patients treated with the aprepitant regimen in pooled Studies and are listed in Table 7.Table 7: Most Common Adverse Reactions in Aprepitant -Treated Pediatric Patients in HEC and MEC Pooled Studies and 6Aprepitant and ondansetron+(N=184)Ondansetron(N=168)neutropenia13%11%headache9%5%diarrhea6%5%decreased appetite5%4%cough5%3%fatigue5%2%hemoglobin decreased5%4%dizziness5%1%hiccups4%1%Reported in >=3% of patients treated with the aprepitant regimen and at greater incidence than control regimen. +Aprepitant regimen Control regimen 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)]. Adverse Reactions in Adult Patients in the Prevention of PONVIn active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies and 8), 40 mg oral aprepitant was compared to mg intravenous ondansetron [see Clinical Studies 14.4)]. There were 564 patients treated with aprepitant and 538 patients treated with ondansetron.The most common adverse reactions reported in patients treated with aprepitant for PONV in pooled Studies and are listed in Table 8.Table 5: Most Common Adverse Reactions in Aprepitant-Treated Patients in Pooled Analysis of PONV Studies Aprepitant 40 mg(N 564)Ondansetron(N 538)constipation9%8%hypotension6%5%Reported in >= 3% of patients treated with the aprepitant 40 mg and at greater incidence than ondansetron. In pooled analysis of PONV studies, less common adverse reactions reported in patients treated with aprepitant are listed in Table 9.Table 6: Less Common Adverse Reactions in Aprepitant-Treated Patients in Pooled Analysis of PONV Studies Infections and Infestationspostoperative infectionMetabolism and Nutrition Disordershypokalemia, hypovolemiaNervous System Disordersdizziness, hypoesthesia, syncopeCardiac DisordersbradycardiaVascular DisordershematomaRespiratory, Thoracic and Mediastinal Disordersdyspnea, hypoxia, respiratory depressionGastrointestinal Disordersabdominal pain, dry mouth, dyspepsiaSkin and Subcutaneous Tissue DisordersurticariaGeneral Disorders and Administration Site ConditionshypothermiaInvestigationsblood albumin decreased, bilirubin increased, blood glucose increased, blood potassium decreasedInjury, Poisoning and Procedural Complicationsoperative hemorrhage, wound dehiscenceReported in 0.5% of patients treated with aprepitant and at greater incidence than ondansetron In addition, two serious adverse reactions were reported in PONV clinical studies in patients taking higher than recommended dose of aprepitant: one case of constipation, and one case of sub-ileus.Other StudiesAngioedema and urticaria were reported as serious adverse reactions in patient receiving aprepitant in non-CINV/non-PONV study (aprepitant is only approved in the CINV and PONV populations).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of aprepitant. 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 aprepitant and ifosfamide coadministration.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced systemic exposure to aprepitant (AUC) of 0.7 to 1.6 times the adult human exposure at the 125 mg/80 mg/80 mg aprepitant 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 aprepitant 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 aprepitant regimen).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Aprepitant is selective high-affinity antagonist of human substance P/neurokinin (NK 1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK 1receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT 3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis. 12.2 Pharmacodynamics. NK 1Receptor Occupancy In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral aprepitant 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 NK 1receptor 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 NK 1receptor occupancies were approximately 50% and 90%, respectively. The oral aprepitant 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 NK 1receptor occupancy. However, the receptor occupancy has not been determined. In addition, the relationship between NK 1receptor occupancy and the clinical efficacy of aprepitant 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- and 9-fold higher than that achieved with oral aprepitant 125 mg and 40 mg, respectively. QT prolongation with the oral aprepitant dosing regimens is not expected.. 12.3 Pharmacokinetics. AbsorptionFollowing oral administration of single 40 mg dose of aprepitant in the fasted state, mean area under the plasma concentration-time curve (AUC 0-) was 7.8 mcgohr/mL and mean peak plasma concentration (C max) was 0.7 mcg/mL, occurring at approximately hours postdose (T max). The absolute bioavailability at the 40 mg dose has not been determined. Following oral administration of single 125 mg dose of aprepitant on Day and 80 mg once daily on Days and 3, the AUC 0-24hrwas approximately 19.6 mcgohr/mL and 21.2 mcgohr/mL on Day and Day 3, respectively. The maxof 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately hours (T max) on Day and Day 3, respectively. At the dose range of 80 to 125 mg, the mean absolute oral bioavailability of aprepitant 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 AUC 0-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 (Vd ss) was approximately 70 in humans. Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology 12.1)] EliminationMetabolismAprepitant undergoes extensive metabolism. In vitrostudies 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 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 PopulationsGeriatric PatientsFollowing oral administration of single 125 mg dose of aprepitant on Day and 80 mg once daily on Days through (2 additional days of dosing compared to the recommended duration), the AUC 0-24hrof aprepitant was 21% higher on Day and 36% higher on Day in elderly (65 years and older) relative to younger adults. The maxwas 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 AUC 0-24hrof 17 mcgohr/mL on Day with mean peak plasma concentration (C max) 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/mL. 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 aprepitant recommended dose), the AUC 0-24hrand maxare 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 maxoccurs 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 aprepitant recommended dose), the AUC 0-24hrand maxare approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC 0-24hrand maxwere 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hror maxbetween 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 aprepitant recommended dose) was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 2as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis. In patients with severe renal impairment, the AUC 0-of total aprepitant (unbound and protein bound) decreased by 21% and maxdecreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC 0-of total aprepitant decreased by 42% and maxdecreased 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 aprepitant on Day and 80 mg once daily on Days and to patients with mild hepatic impairment (Child-Pugh score to 6), the AUC 0-24hrof aprepitant was 11% lower on Day and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score to 9), the AUC 0-24hrof aprepitant was 10% higher on Day and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC 0-24hrare 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/m 2increase in BMI, AUC 0-24hrand maxof aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m 2to 36 kg/m 2. 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 DrugsCYP3A4 substrates (i.e., midazolam):Interactions between aprepitant and coadministered midazolam are listed in Table 12 (increase is indicated as , decrease as , no change as <->). Table 9: Pharmacokinetic Interaction Data for Aprepitant and Coadministered MidazolamDosage of AprepitantDosage of MidazolamObserved Drug InteractionsAprepitant 125 mg on Day and 80 mg on Days to 5oral mg single dose on Days and midazolam AUC 2.3-fold on Day and 3.3-fold on Day [see Drug Interactions 7.1)] Aprepitant 125 mg on Day and 80 mg on Days and intravenous mg prior to 3-day regimen of aprepitant and on Days 4, and 15 midazolam AUC 25% on Day 4, AUC 19% on Day and AUC 4% on Day 15 Aprepitant 125 mg intravenous mg given hour after aprepitant midazolam AUC 1.5-fold Aprepitant 40 mgoral mgmidazolam AUC 1.2-fold on Day 1A difference of less than 2-fold increase of midazolam AUC is not considered clinically important.Corticosteroids:Dexamethasone:Aprepitant, 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 mg dexamethasone on Days through 5, increased the AUC of dexamethasone by 2.2-fold on Days and [see Dosage and Administration 2.1)] A single dose of aprepitant (40 mg) when coadministered with single dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold, which is not considered clinically significant. Methylprednisolone:Aprepitant, 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, aprepitant (125 mg/80 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In pharmacokinetic study, aprepitant (125 mg/80 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine to clinically significant degree. CYP2C9 substrates (Warfarin, Tolbutamide):Warfarin:A single 125 mg dose of aprepitant 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 aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was 34% decrease in S(-) warfarin trough concentration accompanied by 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) days after completion of dosing with aprepitant [see Drug Interactions 7.1)] Tolbutamide:Aprepitant, when given as 125 mg on Day and 80 mg/day on Days and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important. Aprepitant, when given as 40 mg single dose on Day 1, decreased the AUC of tolbutamide by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when single dose of tolbutamide 500 mg was administered prior to the administration of aprepitant 40 mg and on Days 2, 4, 8, and 15. This effect was not considered significant.Other DrugsOral contraceptives:When aprepitant was administered as 3-day regimen (125 mg/80 mg/80 mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for weeks post-treatment. P-glycoprotein substrates:Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoproteintransporter, as demonstrated by the lack of interaction of aprepitant with digoxin in clinical drug interaction study. 5-HT 3antagonists: 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 AprepitantKetoconazole:When single 125 mg dose of aprepitant was administered on Day of 10-day regimen of 400 mg/day of ketoconazole, strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions 7.2)] Rifampin:When single 375 mg dose of aprepitant (3 times the maximum aprepitant 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 aprepitant 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 aprepitant maximum recommended dose), with paroxetine 20 mg once daily, resulted in decrease in AUC by approximately 25% and maxby approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults. Oral administration of aprepitant in combination with ondansetron and dexamethasone (aprepitant 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, aprepitant 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/m 2(mean cisplatin dose 80.2 mg/m 2). See Table 13. In these studies, 95% of the patients in the aprepitant group received concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant 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 aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-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 10: HEC Treatment Regimens Studies and 2Day 1Day 2Day 3Day 4CINV Aprepitant Regimen Oral Aprepitant 125 mg80 mg80 mgnone Oral Dexamethasone 12 mg8 mg8 mg8 mg Ondansetron5-HT 3antagonist nonenonenoneCINV Standard Therapy Oral Dexamethasone20 mg8 mg twice daily8 mg twice daily8 mg twice daily Ondansetron5-HT 3antagonist nonenonenoneAprepitant placebo and dexamethasone placebo were used to maintain blinding. +Aprepitant was administered hour prior to chemotherapy treatment on Day and in the morning on Days and 3. Dexamethasone 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 aprepitant regimen [see Clinical Pharmacology 12.3)] Ondansetron 32 mg intravenous was used in the clinical trials of aprepitant. 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. The antiemetic activity of aprepitant 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 14. In both studies, statistically significantly higher proportion of patients receiving the aprepitant 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 aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.Table 11: Percent of Patients Receiving HEC Responding by Treatment Group and Phase -- Cycle 1Study 1Study 2ENDPOINTSAprepitant Regimen (N=260) %Standard Therapy(N=261) %p-ValueAprepitant Regimen (N=261) %Standard Therapy(N=263) %p-ValuePRIMARY ENDPOINTComplete ResponseOverall 7352<0.0016343<0.001OTHER PRESPECIFIED ENDPOINTSComplete ResponseAcute phase Delayed phase 89 75 78 56 <0.001 <0.001 83 68 68 47 <0.001 <0.001 Complete ProtectionOverall Acute phase Delayed phase 63 85 66 49 75 52 0.001 NS <0.001 56 80 61 41 65 44 <0.001 <0.001 <0.001 No EmesisOverall Acute phase Delayed phase 78 90 81 55 79 59 <0.001 0.001 <0.001 66 84 72 44 69 48 <0.001 <0.001 <0.001 No NauseaOverall Delayed phase 48 51 44 48 NS NS 49 53 39 40 NS NS No Significant NauseaOverall Delayed phase 73 75 66 69 NS NS 71 73 64 65 NS NS Visual analogue scale (VAS) score range: mm=no nausea; 100 mm=nausea as bad as it could be.N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation. +Overall: to 120 hours post-cisplatin treatment. Acute phase: to 24 hours post-cisplatin treatment. Delayed phase: 25 to 120 hours post-cisplatin treatment. Not statistically significant when adjusted for multiple comparisons. Not statistically significant. In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant 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.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 aprepitant 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 aprepitant 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. 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). figure1. figure2. 14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults. Aprepitant 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, aprepitant in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving MEC regimen that included cyclophosphamide 750 to 1500 mg/m 2; or cyclophosphamide 500 to 1500 mg/m 2and doxorubicin (less than or equal to 60 mg/m 2) or epirubicin (less than or equal to 100 mg/m 2). See Table 15. 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 aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The aprepitant-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 12: MEC Treatment Regimens Studies and Day 1Day 2Day 3CINV Aprepitant Regimen Oral Aprepitant 125 mg80 mg80 mg Oral Dexamethasone12 mg nonenone Oral Ondansetron8 mg 2 doses nonenoneCINV Standard Therapy Oral Dexamethasone20 mg nonenone Oral Ondansetron8 mg 2 doses mg twice daily8 mg twice dailyAprepitant placebo and dexamethasone placebo were used to maintain blinding. +Aprepitant was administered hour prior to chemotherapy treatment on Day and in the mornings on Days and 3. Dexamethasone 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 aprepitant regimen [see Clinical Pharmacology 12.3)] The 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. The antiemetic activity of aprepitant 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 16. In Study 3, statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant 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 aprepitant regimen in Cycle had complete response during the acute (0 to 24 hours) and delayed (25 to 120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.Table 13: Percent of Patients Receiving MEC Responding by Treatment Group and Phase -- Cycle of Study 3ENDPOINTSAprepitantRegimen(N=433) %Standard Therapy(N=424) %p-ValuePRIMARY ENDPOINT Complete Response51420.015OTHER PRESPECIFIED ENDPOINTS No Emesis7659NS No Nausea3333NS No Significant Nausea6156NS No Rescue Therapy5956NS Complete Protection4337NSN: Number of patients included in the primary analysis of complete response. +Overall: to 120 hours post-chemotherapy treatment. NS when adjusted for prespecified multiple comparisons rule; unadjusted p-value <0.001. 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 aprepitant 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 aprepitant regimen was maintained during all cycles. In Study 4, aprepitant 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/m 2); or cytarabine intravenous (greater than g/m 2). See Table 15. Patients receiving the aprepitant 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 aprepitant 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 aprepitant-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 aprepitant 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 17. In Study 4, statistically significantly higher proportion of patients receiving the aprepitant 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 aprepitant regimen (69%) in Cycle had complete response in the overall phase (0 to 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 aprepitant 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 aprepitant 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 aprepitant 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 aprepitant 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 14: Percent of Patients Receiving MEC Responding by Treatment Group -- Cycle of Study 4ENDPOINTSAprepitant Regimen(N=430)%Standard Therapy(N=418)%p-ValueNo Vomiting Overall7662<0.0001Complete Response Overall69560.0003N Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation. 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.. 14.3 Prevention 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, aprepitant 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 aprepitant 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 aprepitant 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 aprepitant regimen were osteosarcoma (11%), Ewings sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). Other concomitant chemotherapy agents commonly administered and the number of aprepitant 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 18. Of the pediatric patients, 29% in the aprepitant regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.Table 18: HEC and MEC Treatment Regimens for Pediatric Patients Months to 17 Years of Age-- Study 5Day 1Day 2Day 3CINV aprepitant RegimenPediatric Patients Months to less than12 Years of Age+3 mg/kg body weight oral suspension2 mg/kg body weight oral suspension2 mg/kg body weight oral suspensionPediatric Patients 12 to 17 Years of Age+125 mg capsule80 mg capsule80 mg capsuleOndansetronPer standard of carenonenoneCINV Control RegimenOndansetronPer standard of carenonenoneIntravenous dexamethasone was permitted at the discretion of the physician. 50% dose reduction of dexamethasone was required for patients in the aprepitant 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. +Aprepitant was administered hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days and 3, aprepitant was administered in the morning.Ondansetron was administered 30 minutes prior to chemotherapy on Day aprepitant placebo was used to maintain blinding. The antiemetic activity of aprepitant 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 aprepitant 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 are shown in Table 19.Table 19: Percent of Patients Who Responded to Treatment by Treatment Group and Phase Cycle of Study 5AprepitantRegimenn/m (%)ControlRegimenn/m (%)PRIMARY ENDPOINTComplete Response Delayed phase77/152 (50.7)39/150 (26.0)OTHER PRESPECIFIED ENDPOINTSComplete Response Acute phase 101/152 (66.4)78/150 (52.0)Complete Response Overall phase 61/152 (40.1) 30/150 (20.0)Complete Response No vomiting or retching and no use of rescue medication.+p<0.01 when compared to Control Regimen p<0.05 when compared to Control Regimen 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.. Intravenous dexamethasone was permitted at the discretion of the physician. 50% dose reduction of dexamethasone was required for patients in the aprepitant 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. +Aprepitant was administered hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days and 3, aprepitant was administered in the morning.. 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 phase. safety and tolerability. 14.4 Prevention of PONV in Adults. In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (Studies and 8), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. These two studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. Study was multinational study including the U.S., whereas, Study was conducted entirely in the U.S.In the two studies, patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or mg ondansetron as single dose. Aprepitant was given orally with 50 mL of water to hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. comparison between the aprepitant 125 mg dose did not demonstrate any additional clinical benefit over the 40 mg dose and is not recommended dosage regimen [see Dosage and Administration 2.2)] Of the 564 patients who received 40 mg aprepitant, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40 mg aprepitant ranged from 19 to 84 years, with mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older.The antiemetic activity of aprepitant was evaluated during the to 48 hour period following the end of surgery.Efficacy measures in Study included:no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 24 hours following the end of surgery (primary)complete response (defined as no emetic episodes and no use of rescue therapy) in the to 24 hours following the end of surgery (primary)no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 48 hours following the end of surgery (secondary)time to first use of rescue medication in the to 24 hours following the end of surgery (exploratory)time to first emesis in the to 48 hours following the end of surgery (exploratory).A closed testing procedure was applied to control the type error for the primary endpoints.The results of the primary and secondary endpoints for 40 mg aprepitant and mg ondansetron are described in Table 20:Table 20: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population) Study 7n/m Number of responders/number of patients in analysis. Difference (%): Aprepitant 40 mg minus Ondansetron.Treatmentn/m (%)Aprepitantvs.OndansetronOdds ratio AnalysisPRIMARY ENDPOINTSNo Vomiting0 to 24 hours (Superiority) (no emetic episodes) Aprepitant 40 mg246/293 (84.0)12.6%2.1P<0.001 Ondansetron200/280 (71.4)Complete Response(Non-inferiority: If LB >0.65) (no emesis and no rescue therapy, to 24 hours) Aprepitant 40 mg187/293 (63.8)8.8%1.4LB=1.02Ondansetron154/280 (55.0)Complete Response(Superiority: If LB >1.0) (no emesis and no rescue therapy, to 24 hours) Aprepitant 40 mg187/293 (63.8)8.8%1.4LB=1.02 Ondansetron154/280 (55.0)SECONDARY ENDPOINTNo Vomiting0 to 48 hours (Superiority) (no emetic episodes) Aprepitant 40 mg238/292 (81.5)15.2%2.3P<0.001 Ondansetron185/279 (66.3)Estimated odds ratio for aprepitant versus Ondansetron. value of >1 favors aprepitant over Ondansetron. +P-value of two-sided test <0.05. LB lower bound of 1-sided 97.5% confidence interval for the odds ratio. Based on the prespecified fixed sequence multiplicity strategy, aprepitant 40 mg was not superior to Ondansetron. In Study 7, the use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant delayed the time to first vomiting, as depicted in Figure 3.Figure 3: Percent of Patients Who Remain Emesis Free During the 48 Hours Following End of Surgery Study 7Efficacy measures in Study included:complete response (defined as no emetic episodes and no use of rescue therapy) in the to 24 hours following the end of surgery (primary)no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 24 hours following the end of surgery (secondary)no use of rescue therapy in the to 24 hours following the end of surgery (secondary)no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 48 hours following the end of surgery (secondary).Study failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery.The study demonstrated that 40 mg aprepitant had clinically meaningful effect with respect to the secondary endpoint no vomiting during the first 24 hours after surgery and was associated with 16% improvement over ondansetron for the no vomiting endpoint.Table 21: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-TreatPopulation) Study 8Treatmentn/m (%)Aprepitantvs.OndansetronOdds ratio AnalysisPRIMARY ENDPOINTComplete Response (no emesis and no rescue therapy, to 24 hours) Aprepitant 40 mg111/248 (44.8)2.5%1.10.61Ondansetron104/246 (42.3)SECONDARY ENDPOINTSNo Vomiting (no emetic episodes, to 24 hours) Aprepitant 40 mg223/248 (89.9)16.3%3.2<0.001 Ondansetron 181/246 (73.6) No Use of Rescue Medication (for established emesis or nausea, to 24 hours) Aprepitant 40 mg112/248 (45.2)-0.7%1.00.83Ondansetron113/246 (45.9)No Vomiting0 to 48 hours (Superiority) (no emetic episodes, to 48 hours) Aprepitant 40 mg209/247 (84.6)17.7%2.7<0.001 Ondansetron164/245 (66.9)n/m Number of responders/number of patients in analysis. Difference (%): Aprepitant 40 mg minus Ondansetron.Estimated odds ratio: Aprepitant 40 mg versus Ondansetron. +Not statistically significant after pre-specified multiplicity adjustment. Efficacy measures in Study included:. no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 24 hours following the end of surgery (primary). complete response (defined as no emetic episodes and no use of rescue therapy) in the to 24 hours following the end of surgery (primary). no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 48 hours following the end of surgery (secondary). time to first use of rescue medication in the to 24 hours following the end of surgery (exploratory). time to first emesis in the to 48 hours following the end of surgery (exploratory).. Efficacy measures in Study included:. complete response (defined as no emetic episodes and no use of rescue therapy) in the to 24 hours following the end of surgery (primary). no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 24 hours following the end of surgery (secondary). no use of rescue therapy in the to 24 hours following the end of surgery (secondary). no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the to 48 hours following the end of surgery (secondary).. figure3.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Aprepitant 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).

DESCRIPTION SECTION.

11 DESCRIPTION. Aprepitant Capsules USP contain the active ingredient aprepitant, USP. Aprepitant, USP is substance P/neurokinin (NK 1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2 R,3 S)-2-[(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3 H-1,2,4-triazol-3-one. Its empirical formula is 23H 21F 7N 4O 3, and its structural formula is: Aprepitant, USP is white to off-white powder, with molecular weight of 534.43 g/mol. It is soluble in methanol and in acetone, sparingly soluble in ethanol, and practically insoluble in water.Each capsule for oral administration contains either 40 mg, 80 mg, or 125 mg of aprepitant, USP and the following inactive ingredients: colloidal silicon dioxide, hydroxyethyl cellulose, microcrystalline cellulose, mannitol, poloxamer, povidone, sodium stearyl fumarate, vitamin polyethylene glycol succinate, and purified water. The capsule shell excipients are gelatin, sodium lauryl sulphate and titanium dioxide. The 40 mg capsule shell also contains iron oxide yellow, and the 125 mg capsule also contains FD&C Red 3. Non-volatile solvents in the imprinting ink are shellac, iron oxide black and potassium hydroxide.USP dissolution test pending.. Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage for Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)( 2.1) Aprepitant capsules in adults and pediatric patients 12 years of age and older: is 125 mg on Day and 80 mg on Days and 3.Administer aprepitant hour prior to chemotherapy on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer aprepitant in morning.See Full Prescribing Information for recommended dosages of concomitant dexamethasone and 5-HT 3antagonist for HEC and MEC. Recommended Dosage for PONV( 2.2) Adults: 40 mg aprepitant capsules within hours prior to induction of anesthesia.Administration( 2.4) Aprepitant capsules can be administered with or without food.Swallow aprepitant capsules whole.. Aprepitant capsules in adults and pediatric patients 12 years of age and older: is 125 mg on Day and 80 mg on Days and 3.. Administer aprepitant hour prior to chemotherapy on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer aprepitant in morning.. See Full Prescribing Information for recommended dosages of concomitant dexamethasone and 5-HT 3antagonist for HEC and MEC. Adults: 40 mg aprepitant capsules within hours prior to induction of anesthesia.. Aprepitant capsules can be administered with or without food.. Swallow aprepitant capsules whole.. 2.1 Recommended Dosage For Chemotherapy Induced Nausea and Vomiting (CINV). Adults and Pediatric Patients 12 Years of Age and OlderThe recommended oral dosage of aprepitant capsules, dexamethasone, and 5-HT 3antagonist 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. Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HECPopulationDay 1Day 2Day 3Day 4Aprepitant capsules 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)] 5-HT 3antagonist Adults and Pediatric Patients 12 Years and OlderSee selected 5-HT 3antagonist prescribing information for the recommended dosage nonenonenoneAdminister aprepitant capsules hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer aprepitant capsules in the morning. +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 aprepitant [see Clinical Pharmacology 12.3)] Table 2: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MECPopulationDay 1Day 2Day 3Aprepitant capsules 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)].+ 5-HT 3antagonist Adults and Pediatric Patients 12 Years and OlderSee the selected 5-HT 3antagonist prescribing information for recommended dosage nonenoneAdminister aprepitant capsules hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days and 3, administer aprepitant capsules in the morning. +Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. 50% dosage reduction of dexamethasone is recommended to account for drug interaction with aprepitant [see Clinical Pharmacology 12.3)]. 2.2 Recommended Dosage For Postoperative Nausea and Vomiting (PONV). The recommended oral dosage of aprepitant capsules in adults is 40 mg within hours prior to induction of anesthesia.. 2.4 Administration Instructions. Aprepitant capsules can be administered with or without food.Aprepitant capsulesSwallow capsules whole.. Swallow capsules whole.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Aprepitant Capsules, USP:40 mg: hard gelatin capsules with mustard yellow colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 583 in black ink.80 mg: hard gelatin capsules with white opaque colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 584 in black ink.125 mg: hard gelatin capsules with pink opaque colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 585 in black ink.. 40 mg: hard gelatin capsules with mustard yellow colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 583 in black ink.. 80 mg: hard gelatin capsules with white opaque colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 584 in black ink.. 125 mg: hard gelatin capsules with pink opaque colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 585 in black ink.. Aprepitant Capsules, USP: 40 mg; 80 mg; 125 mg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. See Full Prescribing Information for list of clinically significant drug interactions. 4, 5.1, 5.2, 5.3, 7.1, 7.2) 7.1 Effect 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. Aprepitant acts as weak inhibitor when administered as single 40 mg dose and has not been shown to alter the plasma concentrations of concomitant drugs that are primarily metabolized through CYP3A4. Some substrates of CYP3A4 are contraindicated with aprepitant [see Contraindications 4)] Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 10. Table 7: Effects of Aprepitant on the Pharmacokinetics of Other DrugsCYP3A4 SubstratesPimozideClinical ImpactIncreased pimozide exposure.InterventionAprepitant 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)]. Intervention3-day aprepitant regimenMonitor for benzodiazepine-related adverse reactions.Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolamSingle 40 mg dose of aprepitantNo dosage adjustment of the benzodiazepine neededDexamethasoneClinical ImpactIncreased dexamethasone exposure [see Clinical Pharmacology 12.3)]. Intervention3-day aprepitant regimenReduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration 2.1)]. Single 40 mg dose of aprepitantNo dosage adjustment of oral dexamethasone neededMethylprednisoloneClinical ImpactIncreased methylprednisolone exposure [see Clinical Pharmacology 12.3)]. Intervention3-day aprepitant regimenReduce the dose of intravenous methylprednisolone by approximately 25%Reduce the dose of oral methylprednisolone by approximately 50%Single 40 mg dose of aprepitantNo dosage adjustment of methylprednisolone neededChemotherapeutic 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 aprepitant [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 aprepitant and for month following the last dose of aprepitant.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 aprepitant regimen with each chemotherapy cycle, or following administration of single 40 mg dose of aprepitant.Other5-HT 3Antagonists Clinical ImpactNo change in the exposure of the 5-HT 3antagonist [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. No dosage adjustment of the benzodiazepine needed. Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration 2.1)]. No dosage adjustment of oral dexamethasone needed. Reduce the dose of intravenous methylprednisolone by approximately 25%. Reduce the dose of oral methylprednisolone by approximately 50%. No dosage adjustment of methylprednisolone needed. Monitor for chemotherapeutic-related adverse reactions.. No dosage adjustment needed.. 7.2 Effect of Other Drugs on the Pharmacokinetics of Aprepitant. Aprepitant is CYP3A4 substrate [see Clinical Pharmacology 12.3)] Co-administration of aprepitant with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 11. Table 8: 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 aprepitant [see Adverse Reactions 6.1) and Clinical Pharmacology 12.3)] InterventionAvoid concomitant use of aprepitantExamplesModerate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 InducersClinical ImpactSubstantially decreased exposure of aprepitant in patients chronically taking strong CYP3A4 inducer may decrease the efficacy of aprepitant [see Clinical Pharmacology 12.3)] InterventionAvoid concomitant use of aprepitantExamplesrifampin, carbamazepine, phenytoin. Moderate inhibitor: diltiazem.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 544 adult cancer patients treated with aprepitant in CINV clinical studies, 31% were aged 65 and over, while 5% were aged 75 and over. Of the 1120 adult cancer patients treated with aprepitant in PONV clinical studies, 7% were aged 65 and over, while 2% were aged 75 and over. Other reported clinical experience with aprepitant has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology 12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Aprepitant Capsules USP, 40 mg:hard gelatin capsules with mustard yellow colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 583 in black ink. They are supplied as follows: NDC 68001-666-17 Carton of capsules (containing x unit-dose blisters) NDC 68001-666-01 Carton of capsule (containing unit-dose blister) Aprepitant Capsules USP, 80 mg:hard gelatin capsules with white opaque colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 584 in black ink. They are supplied as follows: NDC 68001-667-19 Carton of capsules (containing x unit-dose blisters) NDC 68001-667-44 Unit-dose blister pack NDC 68001-667-01 Blister card of capsules (2-day pack containing two 80 mg capsules) Aprepitant Capsules USP, 125 mg:hard gelatin capsules with pink opaque colored cap imprinted with Glenmark logo in black ink and white opaque colored body imprinted with 585 in black ink. They are supplied as follows: NDC 68001-668-19 Carton of capsules (containing x unit-dose blisters) NDC 68001-668-44 Unit-dose blister pack Aprepitant Capsules USP, 3-day pack (125 mg/80 mg/80 mg):NDC 68001-669-15 Blister card of capsules (3-day pack containing one 125 mg capsule and two 80 mg capsules)Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].. capsules).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Aprepitant is substance P/neurokinin (NK 1) receptor antagonist. Aprepitant capsules are 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 1.1) nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) 1.1) for prevention of postoperative nausea and vomiting (PONV) in adults 1.2) Limitations of Use: 1.3) Aprepitant has not been studied for treatment of established nausea and vomiting.Chronic continuous administration of aprepitant is not recommended.. 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 1.1) nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) 1.1) acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin 1.1) nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) 1.1) for prevention of postoperative nausea and vomiting (PONV) in adults 1.2) Aprepitant has not been studied for treatment of established nausea and vomiting.. Chronic continuous administration of aprepitant is not recommended.. 1.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV). Aprepitant capsules, in combination with other antiemetic agents, are 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).. 1.2 Prevention of Postoperative Nausea and Vomiting (PONV). Aprepitant capsules are indicated in adults for the prevention of postoperative nausea and vomiting.. 1.3 Limitations of Use. Aprepitant has not been studied for the treatment of established nausea and vomiting.Chronic continuous administration of aprepitant is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.. Aprepitant has not been studied for the treatment of established nausea and vomiting.. Chronic continuous administration of aprepitant 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.

17 PATIENT 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 aprepitant. Advise patients to stop taking aprepitant 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 aprepitant with each chemotherapy cycle, or following administration of single 40-mg dose of aprepitant for the prevention of postoperative nausea and vomiting [see Warnings and Precautions 5.2)] Hormonal Contraceptives:Advise patients that administration of aprepitant 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 aprepitant and for month following the last dose of aprepitant [see Warnings and Precautions 5.3), Use in Specific Populations 8.3)] Manufactured by:Glenmark Pharmaceuticals LimitedPlot No. 2, Phase-2, Pharma Zone SEZPithampur, Dist.-DharMadhya Pradesh 454 775, IndiaQuestions (888) 721-7115For BluePoint LaboratoriesAmerican Health Packagingis registered trademark ofAMERISOURCEBERGENSERVICES CORPORATION1 West First AvenueConshohocken, PA, USA, 19428Revised: May 2020.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Aprepitant is selective high-affinity antagonist of human substance P/neurokinin (NK 1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK 1receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT 3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced systemic exposure to aprepitant (AUC) of 0.7 to 1.6 times the adult human exposure at the 125 mg/80 mg/80 mg aprepitant 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 aprepitant 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 aprepitant regimen).

OVERDOSAGE SECTION.

10 OVERDOSAGE. No specific information is available on the treatment of overdosage.Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant (approximately 11 times the maximum recommended single dose).In the event of overdose, aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective in cases of aprepitant overdosage.Aprepitant is not removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. Caron Aprepitant capsules USP 40mg 1s pack. Blister foil Aprepitant Capsules USP 40mg 1s pack.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Prevention of Nausea and Vomiting Associated with HEC or MECThe safety and effectiveness of aprepitant 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 aprepitant in these age groups is supported by evidence from 95 pediatric patients in randomized, double-blind, active comparator controlled clinical study (n 95 patients aged 12 through 17 years). Aprepitant 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 aprepitant for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than months.Prevention of Postoperative Nausea and Vomiting (PONV)The safety and effectiveness of aprepitant have not been established for the prevention of postoperative nausea and vomiting in pediatric patients.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.

12.2 Pharmacodynamics. NK 1Receptor Occupancy In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral aprepitant 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 NK 1receptor 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 NK 1receptor occupancies were approximately 50% and 90%, respectively. The oral aprepitant 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 NK 1receptor occupancy. However, the receptor occupancy has not been determined. In addition, the relationship between NK 1receptor occupancy and the clinical efficacy of aprepitant 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- and 9-fold higher than that achieved with oral aprepitant 125 mg and 40 mg, respectively. QT prolongation with the oral aprepitant dosing regimens is not expected.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration of single 40 mg dose of aprepitant in the fasted state, mean area under the plasma concentration-time curve (AUC 0-) was 7.8 mcgohr/mL and mean peak plasma concentration (C max) was 0.7 mcg/mL, occurring at approximately hours postdose (T max). The absolute bioavailability at the 40 mg dose has not been determined. Following oral administration of single 125 mg dose of aprepitant on Day and 80 mg once daily on Days and 3, the AUC 0-24hrwas approximately 19.6 mcgohr/mL and 21.2 mcgohr/mL on Day and Day 3, respectively. The maxof 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately hours (T max) on Day and Day 3, respectively. At the dose range of 80 to 125 mg, the mean absolute oral bioavailability of aprepitant 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 AUC 0-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 (Vd ss) was approximately 70 in humans. Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology 12.1)] EliminationMetabolismAprepitant undergoes extensive metabolism. In vitrostudies 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 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 PopulationsGeriatric PatientsFollowing oral administration of single 125 mg dose of aprepitant on Day and 80 mg once daily on Days through (2 additional days of dosing compared to the recommended duration), the AUC 0-24hrof aprepitant was 21% higher on Day and 36% higher on Day in elderly (65 years and older) relative to younger adults. The maxwas 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 AUC 0-24hrof 17 mcgohr/mL on Day with mean peak plasma concentration (C max) 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/mL. 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 aprepitant recommended dose), the AUC 0-24hrand maxare 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 maxoccurs 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 aprepitant recommended dose), the AUC 0-24hrand maxare approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC 0-24hrand maxwere 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hror maxbetween 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 aprepitant recommended dose) was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 2as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis. In patients with severe renal impairment, the AUC 0-of total aprepitant (unbound and protein bound) decreased by 21% and maxdecreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC 0-of total aprepitant decreased by 42% and maxdecreased 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 aprepitant on Day and 80 mg once daily on Days and to patients with mild hepatic impairment (Child-Pugh score to 6), the AUC 0-24hrof aprepitant was 11% lower on Day and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score to 9), the AUC 0-24hrof aprepitant was 10% higher on Day and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC 0-24hrare 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/m 2increase in BMI, AUC 0-24hrand maxof aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m 2to 36 kg/m 2. 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 DrugsCYP3A4 substrates (i.e., midazolam):Interactions between aprepitant and coadministered midazolam are listed in Table 12 (increase is indicated as , decrease as , no change as <->). Table 9: Pharmacokinetic Interaction Data for Aprepitant and Coadministered MidazolamDosage of AprepitantDosage of MidazolamObserved Drug InteractionsAprepitant 125 mg on Day and 80 mg on Days to 5oral mg single dose on Days and midazolam AUC 2.3-fold on Day and 3.3-fold on Day [see Drug Interactions 7.1)] Aprepitant 125 mg on Day and 80 mg on Days and intravenous mg prior to 3-day regimen of aprepitant and on Days 4, and 15 midazolam AUC 25% on Day 4, AUC 19% on Day and AUC 4% on Day 15 Aprepitant 125 mg intravenous mg given hour after aprepitant midazolam AUC 1.5-fold Aprepitant 40 mgoral mgmidazolam AUC 1.2-fold on Day 1A difference of less than 2-fold increase of midazolam AUC is not considered clinically important.Corticosteroids:Dexamethasone:Aprepitant, 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 mg dexamethasone on Days through 5, increased the AUC of dexamethasone by 2.2-fold on Days and [see Dosage and Administration 2.1)] A single dose of aprepitant (40 mg) when coadministered with single dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold, which is not considered clinically significant. Methylprednisolone:Aprepitant, 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, aprepitant (125 mg/80 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In pharmacokinetic study, aprepitant (125 mg/80 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine to clinically significant degree. CYP2C9 substrates (Warfarin, Tolbutamide):Warfarin:A single 125 mg dose of aprepitant 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 aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was 34% decrease in S(-) warfarin trough concentration accompanied by 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) days after completion of dosing with aprepitant [see Drug Interactions 7.1)] Tolbutamide:Aprepitant, when given as 125 mg on Day and 80 mg/day on Days and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important. Aprepitant, when given as 40 mg single dose on Day 1, decreased the AUC of tolbutamide by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when single dose of tolbutamide 500 mg was administered prior to the administration of aprepitant 40 mg and on Days 2, 4, 8, and 15. This effect was not considered significant.Other DrugsOral contraceptives:When aprepitant was administered as 3-day regimen (125 mg/80 mg/80 mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for weeks post-treatment. P-glycoprotein substrates:Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoproteintransporter, as demonstrated by the lack of interaction of aprepitant with digoxin in clinical drug interaction study. 5-HT 3antagonists: 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 AprepitantKetoconazole:When single 125 mg dose of aprepitant was administered on Day of 10-day regimen of 400 mg/day of ketoconazole, strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions 7.2)] Rifampin:When single 375 mg dose of aprepitant (3 times the maximum aprepitant 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 aprepitant 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 aprepitant maximum recommended dose), with paroxetine 20 mg once daily, resulted in decrease in AUC by approximately 25% and maxby approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are insufficient data on use of aprepitant 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 aprepitant 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.DataAnimal 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 aprepitant regimen. Aprepitant crosses the placenta in rats and rabbits.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationAprepitant (a-PRE-pi-tant)CapsulesRead this Patient Information before you start taking aprepitant capsules 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 are aprepitant capsulesAprepitant capsulesare 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) medicinesIn adults to prevent nausea and vomiting after surgeryAprepitant capsules are not used to treat nausea and vomiting that you already have.Aprepitant capsules should not be used continuously for long time (chronic use).Who should not take aprepitant capsulesDo not take aprepitant capsules if you:are allergic to aprepitant or any of the ingredients in aprepitant capsules. See the end of this leaflet for complete list of ingredients in aprepitant capsules.are taking pimozide (ORAP (R)) What should tell my healthcare provider before taking aprepitant capsulesBefore you take aprepitant capsules, tell your healthcare provider if you:have liver problemsare pregnant or plan to become pregnant. It is not known if aprepitant capsules 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 aprepitant capsules and for month after your last dose of aprepitant capsules. are breastfeeding or plan to breastfeed. It is not known if aprepitant passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take aprepitant capsules.Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. Aprepitant capsules may affect the way other medicines work, and other medicines may affect how aprepitant capsules work 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 aprepitant capsulesTake aprepitant capsules exactly as prescribed.Swallow aprepitant capsules whole.Aprepitant capsules may be taken with or without food.If you take too much aprepitant, call your healthcare provider, or go to the nearest hospital emergency room.Aprepitant capsules are taken as doses over days starting on the day you have chemotherapy, and for the following days.In adults, your healthcare provider may prescribe aprepitant capsules for you:Capsules of aprepitant by mouth for all doses:You should get package that has capsules of aprepitant.Day (Day of chemotherapy):Take one 125 mg capsule of aprepitant (white and pink) by mouth hour before you start your chemotherapy treatment. Day and Day 3:Take one 80 mg capsule of aprepitant (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, aprepitant capsules should be taken in the morning. In children 12 years of age and older who can swallow capsules by mouth, aprepitant is prescribed as capsules of aprepitant by mouth for all doses:You should get package that has capsules of aprepitant capsules.Day (Day of chemotherapy): Take one 125 mg capsule of aprepitant capsules (white and pink) by mouth hour before you start your chemotherapy treatment. Day and Day 3:Take one 80 mg capsule of aprepitant (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, aprepitant should be taken in the morning. If you are an adult and are having surgery:Your doctor will prescribe 40 mg capsule of aprepitant for you before surgery. Take aprepitant within hours before surgery.Follow your healthcare providers instructions about restrictions on eating and drinking before surgery.If you take the blood thinner medicine warfarin sodium (COUMADIN (R), JANTOVEN (R)), your healthcare provider may do blood tests after you take aprepitant capsules to check your blood clotting. What are the possible side effects of aprepitant capsulesIn adults taking aprepitant capsules to prevent nausea and vomiting caused by chemotherapy, 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 adults taking aprepitant capsules to prevent nausea and vomiting after surgery, the most common side effects include constipation and low blood pressure (hypotension).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 aprepitant capsules. 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 aprepitant capsulesStore at room temperature, between 68F to 77F (20C to 25C).Keep aprepitant capsules and all medicines out of the reach of children.General information about the safe and effective use of aprepitant capsulesMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use aprepitant capsules for condition for which they were not prescribed. Do not give aprepitant capsules to other people, even if they have the same symptoms you have. They may harm them. You can ask your healthcare provider or pharmacist for information about aprepitant capsules that is written for health professionals. For more information about aprepitant capsules call (888) 721-7115.What are the ingredients in aprepitant capsulesActive ingredient:aprepitant Inactive ingredients:colloidal silicon dioxide, hydroxyethyl cellulose, microcrystalline cellulose, mannitol, poloxamer, povidone, sodium stearyl fumarate, vitamin polyethylene glycol succinate, and purified water. The capsule shell excipients are gelatin, sodium lauryl sulphate and titanium dioxide. The 40-mg capsule shell also contains iron oxide yellow, and the 125-mg capsule also contains FD&C Red 3. Non-volatile solvents in the imprinting ink are shellac, iron oxide black and potassium hydroxide. All trademarks are the property of their respective owners.Manufactured by:Glenmark Pharmaceuticals LimitedPlot No. 2, Phase-2, Pharma Zone SEZPithampur, Dist.-DharMadhya Pradesh 454 775, IndiaQuestions (888) 721-7115For BluePoint LaboratoriesAmerican Health Packagingis registered trademark ofAMERISOURCEBERGENSERVICES CORPORATION1 West First AvenueConshohocken, PA, USA, 19428Revised: May 2020This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: May 2020. 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. In adults to prevent nausea and vomiting after surgery. are allergic to aprepitant or any of the ingredients in aprepitant capsules. See the end of this leaflet for complete list of ingredients in aprepitant capsules.. are taking pimozide (ORAP (R)) have liver problems. are pregnant or plan to become pregnant. It is not known if aprepitant capsules 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 aprepitant capsules and for month after your last dose of aprepitant capsules. 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 aprepitant capsules and for month after your last dose of aprepitant capsules.. are breastfeeding or plan to breastfeed. It is not known if aprepitant passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take aprepitant capsules.. Take aprepitant capsules exactly as prescribed.. Swallow aprepitant capsules whole.. Aprepitant capsules may be taken with or without food.. If you take too much aprepitant, call your healthcare provider, or go to the nearest hospital emergency room.. Aprepitant capsules are taken as doses over days starting on the day you have chemotherapy, and for the following days.. In adults, your healthcare provider may prescribe aprepitant capsules for you:. Capsules of aprepitant by mouth for all doses:. You should get package that has capsules of aprepitant.. Day (Day of chemotherapy):Take one 125 mg capsule of aprepitant (white and pink) by mouth hour before you start your chemotherapy treatment. Day and Day 3:Take one 80 mg capsule of aprepitant (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, aprepitant capsules should be taken in the morning. In children 12 years of age and older who can swallow capsules by mouth, aprepitant is prescribed as capsules of aprepitant by mouth for all doses:. You should get package that has capsules of aprepitant capsules.. Day (Day of chemotherapy): Take one 125 mg capsule of aprepitant capsules (white and pink) by mouth hour before you start your chemotherapy treatment. Day and Day 3:Take one 80 mg capsule of aprepitant (white) by mouth hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days and 3, aprepitant should be taken in the morning. If you are an adult and are having surgery:. Your doctor will prescribe 40 mg capsule of aprepitant for you before surgery. Take aprepitant within hours before surgery.. Follow your healthcare providers instructions about restrictions on eating and drinking before surgery.. If you take the blood thinner medicine warfarin sodium (COUMADIN (R), JANTOVEN (R)), your healthcare provider may do blood tests after you take aprepitant capsules to check your blood clotting. In adults taking aprepitant capsules to prevent nausea and vomiting caused by chemotherapy, 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 adults taking aprepitant capsules to prevent nausea and vomiting after surgery, the most common side effects include constipation and low blood pressure (hypotension).. 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 at room temperature, between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

1.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV). Aprepitant capsules, in combination with other antiemetic agents, are 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).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are insufficient data on use of aprepitant 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 aprepitant 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.DataAnimal 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 aprepitant regimen. Aprepitant crosses the placenta in rats and rabbits.. 8.2 Lactation. Risk SummaryLactation studies have not been conducted to assess the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for aprepitant and any potential adverse effects on the breastfed infant from aprepitant or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. ContraceptionUpon administration of aprepitant, 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 aprepitant and for month following the last dose [see Drug Interactions 7.1), Clinical Pharmacology 12.3)] . 8.4 Pediatric Use. Prevention of Nausea and Vomiting Associated with HEC or MECThe safety and effectiveness of aprepitant 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 aprepitant in these age groups is supported by evidence from 95 pediatric patients in randomized, double-blind, active comparator controlled clinical study (n 95 patients aged 12 through 17 years). Aprepitant 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 aprepitant for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than months.Prevention of Postoperative Nausea and Vomiting (PONV)The safety and effectiveness of aprepitant have not been established for the prevention of postoperative nausea and vomiting in pediatric patients.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.. 8.5 Geriatric Use. Of the 544 adult cancer patients treated with aprepitant in CINV clinical studies, 31% were aged 65 and over, while 5% were aged 75 and over. Of the 1120 adult cancer patients treated with aprepitant in PONV clinical studies, 7% were aged 65 and over, while 2% were aged 75 and over. Other reported clinical experience with aprepitant 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)] . 8.6 Patients 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.. 8.7 Patients with Hepatic Impairment. The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 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 aprepitant is administered [see Clinical Pharmacology 12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS 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 aprepitant 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 aprepitant. 5.2, 7.1) Hormonal Contraceptives: Efficacy of contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant. 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 aprepitant 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 aprepitant. 5.2, 7.1) Hormonal Contraceptives: Efficacy of contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant. Use effective alternative or back-up methods of contraception. 5.3, 7.1, 8.3) 5.1 Clinically Significant CYP3A4 Drug Interactions. Aprepitant is substrate, weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4.Use of aprepitant with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. Use of pimozide with aprepitant 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 aprepitant 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 aprepitant.Use of aprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in reduction in aprepitant plasma concentrations and decreased efficacy of aprepitant.See Table 10 and Table 11 for listing of potentially significant drug interactions [see Drug Interactions 7.1, 7.2)]. Use of aprepitant with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. Use of pimozide with aprepitant 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 aprepitant 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 aprepitant 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 aprepitant.. Use of aprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in reduction in aprepitant plasma concentrations and decreased efficacy of aprepitant.. 5.2 Decrease in INR with Concomitant Warfarin. Coadministration of aprepitant 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 aprepitant with each chemotherapy cycle, or following administration of single 40 mg dose of aprepitant for the prevention of postoperative nausea and vomiting [see Drug Interactions 7.1)] . 5.3 Risk of Reduced Efficacy of Hormonal Contraceptives. Upon coadministration with aprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant [see Clinical Pharmacology 12.3)] Advise patients to use effective alternative or back-up methods of contraception during treatment with aprepitant and for month following the last dose of aprepitant [see Drug Interactions 7.1), Use in Specific Populations 8.3)].