Emend Capsules

Mechanism Of Action

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) 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 NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Pharmacodynamics

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral EMEND doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK1 receptor occupancies were ~50% and ~90%, respectively. The oral EMEND regimen for CINV produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of EMEND has not been established.

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. Maximum aprepitant concentrations after a single 200-mg dose of fosaprepitant were 4-and 9-fold higher than that achieved with oral EMEND 125 mg and 40 mg, respectively. QT prolongation with the oral EMEND dosing regimens for CINV and PONV is not expected.

Pharmacokinetics

Absorption

Following oral administration of a single 40-mg dose of EMEND in the fasted state, mean area under the plasma concentration-time curve (AUC0-∞) was 7.8 mcg.hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (Tmax). The absolute bioavailability at the 40-mg dose has not been determined.

Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.6 mcg•hr/mL and 21.2 mcg•hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80 to 125 mg, the mean absolute oral bioavailability of EMEND is approximately 60 to 65%. Oral administration of the capsule with a standard high-fat breakfast had no clinically meaningful effect on the bioavailability of aprepitant.

The pharmacokinetics of aprepitant were non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.

Distribution

Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans.

Aprepitant crosses the blood brain barrier in humans [see Mechanism Of Action].

Elimination

Metabolism

Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant (2.4 times the maximum recommended dose), indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

Excretion

Following administration of a single intravenous 100-mg dose of [14C]-aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. A 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 9 to 13 hours.

Specific Populations

Age

Geriatric Population

Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 through 5 (2 additional days of dosing compared to the recommended duration), the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use In Specific Populations].

Age

Pediatric Population

As part of a 3-day regimen, dosing of aprepitant capsules (125-mg/80-mg/80-mg) in 18 pediatric patients (aged 12 through 17 years) achieved a mean AUC0-24hr of 17 mcg•hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.3 mcg/mL occurring at approximately 4 hours. The mean concentrations at the end of Day 2 (N=8) and Day 3 (N=16) were both at 0.6 mcg/mL

As part of a 3-day regimen, weight-based dosing of aprepitant powder for oral suspension (3mg/kg;2-mg/kg;2-mg/kg) in 18 pediatric patients aged 6 months to less than 12 years achieved a mean AUC0-24hr of 20.9 mcg•hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.8 mcg/mL (N=19), occurring at approximately 6 hours. The mean concentrations at the end of Day 2 (N=18) and Day 3 (N=19) were 0.4 mcg/mL and 0.5 mcg/mL, respectively [see DOSAGE AND ADMINISTRATION].

A population pharmacokinetic analysis of aprepitant in pediatric patients (aged 6 months through 17 years) suggests that sex and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.

Sex

Following oral administration of a single dose of EMEND ranging from 40 mg to 375 mg (3 times the maximum recommended dose), the AUC0-24hr and Cmax are 9% and 17% higher in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful.

Race/Ethnicity

Following oral administration of a single dose of EMEND ranging from 40 mg to 375 mg (3 times the maximum recommended dose), the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax between Caucasians and Blacks. These differences are not considered clinically meaningful.

Renal Impairment

A single 240-mg dose of EMEND (approximately 1.9 times the maximum recommended dose) was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2 as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 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].

Hepatic Impairment

Following administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use In Specific Populations].

Body Mass Index (BMI)

For every 5 kg/m2 increase in BMI, AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. This change is not considered clinically meaningful.

Drug Interactions Studies

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

Effects Of Aprepitant On The Pharmacokinetics Of Other Drugs

CYP3A4 substrates (i.e., midazolam): Interactions between EMEND and coadministered midazolam are listed in Table 12 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”).

Table 12: Pharmacokinetic Interaction Data for EMEND and Coadministered Midazolam

Dosage of EMEND	Dosage of Midazolam	Observed Drug Interactions
EMEND 125 mg on Day 1 and 80 mg on Days 2 to 5	oral 2 mg single dose on Days 1 and 5	midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 [see DRUG INTERACTIONS]
EMEND 125 mg on Day 1 and 80 mg on Days 2 and 3	intravenous 2 mg prior to 3-day regimen of EMEND and on Days 4, 8 and 15	midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8 and AUC ↓ 4% on Day 15
EMEND 125 mg	intravenous 2 mg given 1 hour after EMEND	midazolam AUC↑ 1.5-fold
EMEND 40 mg	oral 2 mg	midazolam AUC↑1.2-fold on Day 1

A difference of less than 2-fold increase of midazolam AUC is not considered clinically important.

Corticosteroids:

Dexamethasone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg dexamethasone on Day 1 and 8-mg dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5 [see DOSAGE AND ADMINISTRATION]. A single dose of EMEND (40 mg) when coadministered with a single dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold, which is not considered clinically significant.

Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. Although the concomitant administration of methylprednisolone with the single 40-mg dose of EMEND has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree.

Chemotherapeutic Agents

Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

Oral contraceptives: When EMEND was administered as a 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 3 weeks post-treatment.

When a daily dosage of an oral contraceptive containing ethinyl estradiol and norgestimate was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8, the AUC of ethinyl estradiol decreased by 4% and by 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone [see DRUG INTERACTIONS].

CYP2C9 substrates (e.g., warfarin): A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with EMEND [see DRUG INTERACTIONS].

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. This effect was not considered clinically important.

EMEND, when given as a 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 a single dose of tolbutamide 500 mg was administered prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered significant.

P-glycoprotein substrates: EMEND is unlikely to interact with drugs that are substrates for the Pglycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect Of Other Drugs On The Pharmacokinetics Of Aprepitant

Ketoconazole

When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a 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].

Rifampin

When a single 375-mg dose of EMEND (3 times the maximum recommended dose) was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see DRUG INTERACTIONS].

Diltiazem

In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation (approximately 1.8 times the recommended dose), with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a 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].

Paroxetine

Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation (approximately 0.7 and 1.4 times the maximum recommended dose), with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

Clinical Studies

Prevention Of Nausea And Vomiting Associated With HEC In Adults

Oral administration of EMEND in combination with ondansetron and dexamethasone (EMEND regimen) has been shown to prevent acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin, and nausea and vomiting associated with MEC.

In Studies 1 and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving a chemotherapy regimen that included cisplatin greater than 50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). See Table 13.

In these studies, 95% of the patients in the EMEND group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of EMEND patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).

Of the 550 patients who were randomized to receive the EMEND regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The EMEND-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. A total of 170 patients were 65 years or older, with 29 patients being 75 years or older.

Table 13: HEC Treatment Regimens – Studies 1 and 2*

	Day 1	Day 2	Day 3	Day 4
CINV EMEND Regimen
Oral EMEND†	125 mg	80 mg	80 mg	none
Oral Dexamethasone‡	12 mg	8 mg	8 mg	8 mg
Ondansetron	5-HT3 antagonist§	none	none	none
CINV Standard Therapy
Oral Dexamethasone	20 mg	8 mg twice daily	8 mg twice daily	8 mg twice daily
Ondansetron	5-HT3 antagonist§	none	none	none
*EMEND placebo and dexamethasone placebo were used to maintain blinding. †EMEND was administered 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3. ‡Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen [see CLINICAL PHARMACOLOGY]. §Ondansetron 32 mg intravenous was used in the clinical trials of EMEND. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.

The antiemetic activity of EMEND was evaluated during the acute phase (0 to 24 hours postcisplatin 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 a maximum nausea visual analogue scale [VAS] score less than 25 mm on a 0 to 100 mm scale)
• no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS less than 25 mm on a 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, a statistically significantly higher proportion of patients receiving the EMEND regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the EMEND regimen was also observed when the acute phase and the delayed phase were analyzed separately.

Table 14: Percent of Patients Receiving HEC Responding by Treatment Group and Phase – Cycle 1

	Study 1			Study 2
ENDPOINTS	EMEND Regimen (N=260)* %	Standard Therapy (N=261)* %	p-Value	EMEND Regimen (N=261)* %	Standard Therapy (N=263)* %	p-Value
PRIMARY ENDPOINT
Complete Response
Overall†	73	52	<0.001	63	43	<0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phase‡	89	78	<0.001	83	68	<0.001
Delayed phase§	75	56	<0.001	68	47	<0.001
Complete Protection
Overall	63	49	0.001	56	41	<0.001
Acute phase	85	75	NS¶	80	65	<0.001
Delayed phase	66	52	<0.001	61	44	<0.001
No Emesis
Overall	78	55	<0.001	66	44	<0.001
Acute phase	90	79	0.001	84	69	<0.001
Delayed phase	81	59	<0.001	72	48	<0.001
No Nausea
Overall	48	44	NS#	49	39	NS¶
Delayed phase	51	48	NS#	53	40	NS¶
No Significant Nausea
Overall	73	66	NS#	71	64	NS#
Delayed phase	75	69	NS#	73	65	NS#
Visual analogue scale (VAS) score range: 0 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: 0 to 120 hours post-cisplatin treatment. ‡Acute phase: 0 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 EMEND regimen, and the incidence of first emesis was reduced in the EMEND regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.

Figure 1: Percent of Patients Receiving HEC Who Remain Emesis Free Over Time – Cycle 1

Additional Patient-Reported Outcomes

The impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 of both studies using the Functional Living Index.Emesis (FLIE), a validated nausea-and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients’ daily lives is defined as a FLIE total score greater than 108. In each of the 2 studies, a higher proportion of patients receiving the EMEND regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%).

Multiple-Cycle Extension

In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the EMEND regimen was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Figure 2: Proportion of Patients Receiving HEC with No Emesis and No Significant Nausea by Treatment Group and Cycle

Prevention Of Nausea And Vomiting Associated With MEC In Adults

EMEND was studied in two randomized, double-blind, parallel-group studies (Studies 3 and 4) in adult patients receiving MEC.

In Study 3, in breast cancer patients, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 50024 1500 mg/m2 and doxorubicin (less than or equal to 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). See Table 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 EMEND regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The EMEND-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.

Table 15: MEC Treatment Regimens – Studies 3 and 4*

	Day 1	Day 2	Day 3
CINV EMEND Regimen
Oral EMEND†	125 mg	80 mg	80 mg
Oral Dexamethasone	12 mg‡	none	none
Oral Ondansetron	8 mg x 2 doses§	none	none
CINV Standard Therapy
Oral Dexamethasone	20 mg‡	none	none
Oral Ondansetron	8 mg x 2 doses§	8 mg twice daily	8 mg twice daily
*EMEND placebo and dexamethasone placebo were used to maintain blinding. †EMEND was administered 1 hour prior to chemotherapy treatment on Day 1 and in the mornings on Days 2 and 3. ‡Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen [see CLINICAL PHARMACOLOGY]. §The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose.

The antiemetic activity of EMEND was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:

• Complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) in the overall phase (0 to 120 hours post-chemotherapy) Other prespecified endpoints:
• no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS less than 25 mm on a 0 to 100 mm scale)
• complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score less than 25 mm on a 0 to 100 mm scale)
• complete response during the acute and delayed phases.

A summary of the key results from Study 3 is shown in Table 16. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the EMEND regimen (51%) in Cycle 1 had a 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”, a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the EMEND regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

Table 16: Percent of Patients Receiving MEC Responding by Treatment Group and Phase – Cycle 1 of Study 3

ENDPOINTS	EMEND Regimen (N=433)* %	Standard Therapy (N=424)* %	p-Value
PRIMARY ENDPOINT†
Complete Response	51	42	0.015
OTHER PRESPECIFIED ENDPOINTS†
No Emesis	76	59	NS‡
No Nausea	33	33	NS
No Significant Nausea	61	56	NS
No Rescue Therapy	59	56	NS
Complete Protection	43	37	NS
*N: Number of patients included in the primary analysis of complete response. †Overall: 0 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 1 using the FLIE. A higher proportion of patients receiving the EMEND regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the “No Vomiting Domain” of this composite endpoint.

Multiple-Cycle Extension

In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. The antiemetic effect for patients receiving the EMEND regimen was maintained during all cycles.

In Study 4, EMEND in combination with ondansetron and dexamethasone was compared with a standard therapy (ondansetron and dexamethasone alone) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m2); or cytarabine intravenous (greater than 1 g/m2). See Table 15. Patients receiving the EMEND regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers.

Of the 430 patients who were randomized to receive the EMEND regimen, 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The EMEND-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years.

The antiemetic activity of EMEND was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period.

A summary of the key results from Study 4 is shown in Table 17. In Study 4, a statistically significantly higher proportion of patients receiving the EMEND regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the EMEND regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively).

In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving EMEND were observed to have no vomiting and complete response compared to patients receiving standard therapy. For sex, the difference in complete response rates between the EMEND and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for sex was observed for the no vomiting endpoint.

Table 17: Percent of Patients Receiving MEC Responding by Treatment Group – Cycle 1 of Study 4

ENDPOINTS	EMEND Regimen (N=433)* %	Standard Therapy (N=424)* %	p-Value
No Vomiting Overall	76	62	<0.0001
Complete Response Overall	69	56	0.0003
*N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation.

Prevention Of Nausea And Vomiting Associated With HEC Or MEC In Pediatric Patients

In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, EMEND in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting a dosage adjustment to account for a drug interaction [see CLINICAL PHARMACOLOGY]. 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 a chemotherapy regimen not previously tolerated due to vomiting along with ondansetron as part of their antiemetic regimen.

Of the 152 pediatric patients randomized to receive the EMEND regimen, 55% were male, 45% female, 78% White, 7% Asian, 0% Black, 24% Hispanic, and 13% Multi-Racial. The most common primary malignancies in subjects receiving the EMEND regimen were osteosarcoma (11%), Ewing’s sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). Other concomitant chemotherapy agents commonly administered and the number of EMEND patients exposed were: vincristine sulfate (65), etoposide (59), doxorubicin (48), ifosfamide (45), carboplatin (39), and cisplatin (35).

The treatment regimens in Study 5 for pediatric patients are defined in Table 18. Of the pediatric patients, 29% in the EMEND regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.

Table 18: HEC and MEC Treatment Regimens* for Pediatric Patients 6 Months to 17 Years of Age – Study 5

	Day 1	Day 2	Day 3
CINV EMEND Regimen
Pediatric Patients 6 Months to less than 12 Years of Age†	3 mg/kg body weight oral suspension	2 mg/kg body weight oral suspension	2 mg/kg body weight oral suspension
Pediatric Patients 12 to 17 Years of Age†	125 mg capsule	80 mg capsule	80 mg capsule
Ondansetron	Per standard of care‡	none	none
CINV Control Regimen§
Ondansetron	Per standard of care‡	none	none
*Intravenous dexamethasone was permitted at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting a dosage adjustment to account for a drug interaction [see CLINICAL PHARMACOLOGY]. No dexamethasone dose reduction was required for patients in the control regimen. †EMEND was administered 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days 2 and 3, EMEND was administered in the morning. ‡Ondansetron was administered 30 minutes prior to chemotherapy on Day 1 §EMEND placebo was used to maintain blinding.

The antiemetic activity of EMEND was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint in Study 5 was complete response in the delayed phase (25 to 120 hours following chemotherapy) in Cycle 1. Patients had the opportunity to receive open-label EMEND in subsequent cycles (Optional Cycles 2-6); however efficacy was not assessed in these optional cycles. Overall efficacy was based on the evaluation of the following endpoints:

Primary endpoint:

• complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy) Other prespecified endpoints:
• complete response in the acute phase (0 to 24 hours following initiation of chemotherapy)
• complete response in the overall phase (up to 120 hours following initiation of chemotherapy)
• no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phase
• safety and tolerability

A 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 1 of Study 5

	EMEND Regimen n/m (%)	Control Regimen n/m (%)
PRIMARY ENDPOINT
Complete Response* -Delayed phase	77/152 (50.7)†	39/150 (26.0)
OTHER PRESPECIFIED ENDPOINTS
Complete 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: 0 to 24 hours following initiation of chemotherapy. Delayed Phase: 25 to 120 hours following initiation of chemotherapy. Overall Phase: 0 to 120 hours following initiation of chemotherapy.

Prevention Of PONV In Adults

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (Studies 7 and 8), EMEND 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 7 was a multinational study including the U.S., whereas, Study 8 was conducted entirely in the U.S.

In the two studies, patients were randomized to receive 40-mg EMEND, 125-mg EMEND, or 4-mg ondansetron as a single dose. EMEND was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the EMEND 125-mg dose did not demonstrate any additional clinical benefit over the 40-mg dose and is not a recommended dosage regimen [see DOSAGE AND ADMINISTRATION].

Of the 564 patients who received 40-mg EMEND, 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 EMEND ranged from 19 to 84 years, with a 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 EMEND was evaluated during the 0 to 48 hour period following the end of surgery.

Efficacy measures in Study 7 included:

• no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
• complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
• no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary)
• time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory)
• time to first emesis in the 0 to 48 hours following the end of surgery (exploratory).

A closed testing procedure was applied to control the type I error for the primary endpoints.

The results of the primary and secondary endpoints for 40-mg EMEND and 4-mg ondansetron are described in Table 20:

Table 20: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population) – Study 7

Treatment	n/m (%)	EMEND vs. Ondansetron
		Δ	Odds ratio*	Analysis
PRIMARY ENDPOINTS
No Vomiting 0 to 24 hours (Superiority) (no emetic episodes)
EMEND 40 mg	246/293 (84.0)	12.6%	2.1	P<0.001†
Ondansetron	200/280 (71.4)
Complete Response (Non-inferiority: If LB‡ >0.65) (no emesis and no rescue therapy, 0 to 24 hours)
EMEND 40 mg	187/293 (63.8)	8.8%	1.4	LB=1.02
Ondansetron	154/280 (55.0)
Complete Response (Superiority: If LB >1.0) (no emesis and no rescue therapy, 0 to 24 hours)
EMEND 40 mg	187/293 (63.8)	8.8%	1.4	LB=1.02‡
Ondansetron	154/280 (55.0)
SECONDARY ENDPOINT
No Vomiting 0 to 48 hours (Superiority) (no emetic episodes)
EMEND 40 mg	238/292 (81.5)	15.2%	2.3	P<0.001§
Ondansetron	185/279 (66.3)
n/m = Number of responders/number of patients in analysis. Δ Difference (%):EMEND 40 mg minus Ondansetron. *Estimated odds ratio for EMEND versus Ondansetron. A value of >1 favors EMEND 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, EMEND 40 mg was not superior to Ondansetron.

In Study 7, the use of EMEND did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of EMEND 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 7

Efficacy measures in Study 8 included:

• complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
• no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary)
• no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary)
• no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary).

Study 8 failed to satisfy its primary hypothesis that EMEND 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 EMEND had a clinically meaningful effect with respect to the secondary endpoint “no vomiting” during the first 24 hours after surgery and was associated with a 16% improvement over ondansetron for the no vomiting endpoint.

Table 21: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population) – Study 8

Treatment	n/m (%)	EMEND vs. Ondansetron
		Δ	Odds ratio*	Analysis
PRIMARY ENDPOINTS
Complete Response (no emesis and no rescue therapy, 0 to 24 hours)
EMEND 40 mg	111/248 (44.8)	2.5%	1.1	0.61
Ondansetron	104/246 (42.3)
SECONDARY ENDPOINTS
No Vomiting (no emetic episodes, 0 to 24 hours)
EMEND 40 mg	223/248 (89.9)	16.3%	3.2	<0.001†
Ondansetron	181/246 (73.6)
No Use of Rescue Medication (for established emesis or nausea, 0 to 24 hours)
EMEND 40 mg	112/248 (45.2)	-0.7%	1.0	0.83
Ondansetron	113/246 (45.9)
No Vomiting 0 to 48 hours (Superiority) (no emetic episodes, 0 to 48 hours)
EMEND 40 mg	209/247 (84.6)	17.7%	2.7	<0.001*
Ondansetron	164/245 (66.9)
n/m = Number of responders/number of patients in analysis. Δ Difference (%):EMEND 40 mg minus Ondansetron. *Estimated odds ratio for EMEND versus Ondansetron. A value of >1 favors EMEND 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, EMEND 40 mg was not superior to Ondansetron.

Do not take aprepitant if you are taking any of the following drugs: cisapride (Propulsid) or pimozide (Orap). These drugs may cause life-threatening interactions when taken together with aprepitant.

If you have liver disease, you may need an aprepitant dose adjustment or special tests.

Aprepitant can make birth control pills less effective, resulting in pregnancy. This effect can last for up to 28 days after your last dose of this medication. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking aprepitant and for at least 1 month after your treatment ends.

There are many other drugs that can interact with aprepitant. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

You should not use aprepitant if you are allergic to it.

These other drugs can cause serious or life-threatening medical problems if you take them together with aprepitant:

• cisapride (Propulsid); or
• pimozide (Orap).

If you have liver disease, you may need an aprepitant dose adjustment or special tests.

FDA pregnancy category B. Aprepitant is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether aprepitant passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety of EMEND was evaluated in approximately 6800 individuals.

Adverse Reactions In Adults In The Prevention Of Nausea And Vomiting Associated With HEC And MEC

In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies].

In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies]. The most common adverse reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%).

Across these 4 studies there were 1412 patients treated with the EMEND regimen during Cycle 1 of chemotherapy and 1099 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, 3 and 4 are listed in Table 5.

Table 5: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies*

	EMEND, ondansetron, and dexamethasone† (N=1412)	Ondansetron and dexamethasone‡ (N=1396)
fatigue	13%	12%
diarrhea	9%	8%
asthenia	7%	6%
dyspepsia	7%	5%
abdominal pain	6%	5%
hiccups	5%	3%
white blood cell count decreased	4%	3%
dehydration	3%	2%
alanine aminotransferase increased	3%	2%
*Reported in ≥ 3% of patients treated with the EMEND regimen and at a greater incidence than standard therapy. †EMEND regimen ‡Standard therapy

In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the EMEND regimen are listed in Table 6.

Table 6: Less Common Adverse Reactions in EMEND-Treated Patients from a Pooled Analysis of HEC and MEC Studies*

Infection and Infestations	oral candidiasis, pharyngitis
Blood and the Lymphatic System Disorders	anemia, febrile neutropenia, neutropenia, thrombocytopenia
Metabolism and Nutrition Disorders	decreased appetite, hypokalemia
Psychiatric Disorders	anxiety
Nervous System Disorders	dizziness, dysgeusia, peripheral neuropathy
Cardiac Disorders	palpitations
Vascular Disorders	flushing, hot flush
Respiratory, Thoracic and Mediastinal Disorders	cough, dyspnea, oropharyngeal pain
Gastrointestinal Disorders	dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting
Skin and Subcutaneous Tissue Disorders	alopecia, hyperhidrosis, rash
Musculoskeletal and Connective Tissue Disorders	musculoskeletal pain
General Disorders and Administration Site Condition	edema peripheral, malaise
Investigations	aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased
*Reported in > 0.5% of patients treated with the EMEND regimen, at a greater incidence than standard therapy and not previously described in Table 5.

In an additional active-controlled clinical study in 1169 patients receiving EMEND and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with EMEND.

In another CINV study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving the EMEND regimen with cancer chemotherapy.

Adverse reactions in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Adverse Reactions In Pediatric Patients 6 Months To 17 Years Of Age In The Prevention Of Nausea And Vomiting Associated With HEC Or MEC

In a pooled analysis of 2 active-controlled clinical trials in pediatric patients aged 6 months to 17 years who received highly or moderately emetogenic cancer chemotherapy (Study 5 and a safety study, Study 6), EMEND in combination with ondansetron with or without dexamethasone (EMEND regimen) was compared to ondansetron with or without dexamethasone (control regimen).

There were 184 patients treated with the EMEND regimen during Cycle 1 and 215 patients received open-label EMEND for up to 9 additional cycles of chemotherapy.

In Cycle 1, the most common adverse reactions reported in pediatric patients treated with the EMEND regimen in pooled Studies 5 and 6 are listed in Table 7.

Table 7: Most Common Adverse Reactions in EMEND-Treated Pediatric Patients in HEC and MEC Pooled Studies 5 and 6*

	EMEND and ondansetron† (N=184)	Ondansetron‡ (N=168)
neutropenia	13%	11%
headache	9%	5%
diarrhea	6%	5%
decreased appetite	5%	4%
cough	5%	3%
fatigue	5%	2%
hemoglobin decreased	5%	4%
dizziness	5%	1%
hiccups	4%	1%
*Reported in ≥3% of patients treated with the EMEND regimen and at a greater incidence than control regimen. †EMEND 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 and CLINICAL PHARMACOLOGY].

Adverse Reactions In Adult Patients In The Prevention Of PONV

In 2 active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies 7 and 8), 40-mg oral EMEND was compared to 4-mg intravenous ondansetron [see Clinical Studies].

There were 564 patients treated with EMEND and 538 patients treated with ondansetron.

The most common adverse reactions reported in patients treated with EMEND for PONV in pooled Studies 7 and 8 are listed in Table 8.

Table 8: Most Common Adverse Reactions in EMEND-Treated Patients in a Pooled Analysis of PONV Studies*

	EMEND 40 mg (N = 564)	Ondansetron (N = 538)
constipation	9%	8%
hypotension	6%	5%
*Reported in ≥ 3% of patients treated with the EMEND 40 mg and at a greater incidence than ondansetron.

In a pooled analysis of PONV studies, less common adverse reactions reported in patients treated with EMEND are listed in Table 9.

Table 9: Less Common Adverse Reactions in EMEND-Treated Patients in a Pooled Analysis of PONV Studies*

Infection and Infestations	postoperative infection
Metabolism and Nutrition Disorders	hypokalemia, hypovolemia
Nervous System Disorders	dizziness, hypoesthesia, syncope
Cardiac Disorders	bradycardia
Vascular Disorders	hematoma
Respiratory, Thoracic and Mediastinal Disorders	dyspnea, hypoxia, respiratory depression
Gastrointestinal Disorders	abdominal pain, dry mouth, dyspepsia
Skin and Subcutaneous Tissue Disorders	urticaria
General Disorders and Administration Site Conditions	hypothermia
Investigations	blood albumin decreased, bilirubin increased, blood glucose increased, blood potassium decreased
Injury, Poisoning and Procedural Complications	operative hemorrhage, wound dehiscence
*Reported in > 0.5% of patients treated with EMEND and at a greater incidence than ondansetron

In addition, two serious adverse reactions were reported in PONV clinical studies in patients taking a higher than recommended dose of EMEND: one case of constipation, and one case of sub-ileus.

Other Studies

Angioedema and urticaria were reported as serious adverse reactions in a patient receiving EMEND in a non-CINV/non-PONV study (EMEND is only approved in the CINV and PONV populations).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of EMEND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions [see CONTRAINDICATIONS].

Nervous system disorders: ifosfamide-induced neurotoxicity reported after EMEND and ifosfamide coadministration.

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