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Emend

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Emend Capsules

CLINICAL PHARMACOLOGY

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 control 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 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 aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations > 500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in > 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 aprepitant 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. QT prolongation with the oral dosing regimens for CINV and PONV are 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 80-125 mg, the mean absolute oral bioavailability of aprepitant 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 are 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) is approximately 70 L in humans.

Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans.

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, 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 IV 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 halflife ranged from approximately 9 to 13 hours.

Special Populations

Gender

Following oral administration of a single 125-mg dose of EMEND, no difference in AUC0-24hr was observed between males and females. The Cmax for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary based on gender.

Geriatric

Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly ( ≥ 65 years) 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. No dosage adjustment for EMEND is necessary in elderly patients.

Pediatric

EMEND has not been evaluated in patients below 18 years of age.

Race

Following oral administration of a single 125-mg dose of EMEND, the AUC0-24hr is approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, respectively. The Cmax is 22% and 31% higher in Hispanics as compared with Whites and Blacks, respectively. These differences are not considered clinically meaningful. There was no difference in AUC0-24hr or Cmax between Whites and Blacks. No dosage adjustment for EMEND is necessary based on race.

Hepatic Insufficiency

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; therefore, no dosage adjustment for EMEND is necessary in patients with mild to moderate hepatic impairment.

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score > 9) [see WARNINGS AND PRECAUTIONS].

Renal Insufficiency

A single 240-mg dose of EMEND was administered to patients with severe renal impairment (CrCl < 30 mL/min) 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. 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.

No dosage adjustment for EMEND is necessary for patients with renal impairment or for patients with ESRD undergoing hemodialysis.

Clinical Studies

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

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

Highly Emetogenic Chemotherapy (HEC)

In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see Table 6) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin > 50 mg/m² (mean cisplatin dose = 80.2 mg/m²). 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 a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older.

Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in Table 5.

Table 5: Treatment Regimens in Highly Emetogenic Chemotherapy Trials

Treatment Regimen Day 1 Days 2 to 4
Aprepitant Aprepitant 125 mg PO Dexamethasone 12 mg PO Ondansetron 32 mg I.V. Aprepitant 80 mg PO Daily (Days 2 and 3 only) Dexamethasone 8 mg PO Daily (morning)
Standard Therapy Dexamethasone 20 mg PO Ondansetron 32 mg I.V. Dexamethasone 8 mg PO Daily (morning) Dexamethasone 8 mg PO Daily (evening)
Aprepitant placebo and dexamethasone placebo were used to maintain blinding.

During these studies 95% of the patients in the aprepitant group received a 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).

The antiemetic activity of EMEND was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours postcisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints:

Primary endpoint:

  • complete response (defined as no emetic episodes and no use of rescue therapy)

Other prespecified endpoints:

  • complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score < 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 < 5 mm on a 0 to 100 mm scale)
  • no significant nausea (maximum VAS < 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 6 and in Table 7.

Table 6 : Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 1 — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 260)† %
Standard Therapy
(N = 261)† + %
p-Value
PRIMARY ENDPOINT
Complete Response
Overall‡ 73 52 < 0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phase§ 89 78 < 0.001
Delayed phase|| 75 56 < 0.001
Complete Protection
Overall 63 49 0.001
Acute phase 85 75 NS*
Delayed phase 66 52 < 0.001
No Emesis
Overall 78 55 < 0.001
Acute phase 90 79 0.001
Delayed phase 81 59 < 0.001
No Nausea
Overall 48 44 NS**
Delayed phase 51 48 NS**
No Significant Nausea
Overall 73 66 NS**
Delayed phase 75 69 NS**
†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.
Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be.

Table 7: Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 2 — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 261)† %
Standard Therapy
(N = 263)† %
p-Value
PRIMARY ENDPOINT
Complete Response
Overall* 63 43 < 0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phase§ 83 68 < 0.001
Delayed phase|| 68 47 < 0.001
Complete Protection
Overall 56 41 < 0.001
Acute phase 80 65 < 0.001
Delayed phase 61 44 < 0.001
No Emesis
Overall 66 44 < 0.001
Acute phase 84 69 < 0.001
Delayed phase 72 48 < 0.001
No Nausea
Overall 49 39 NS*
Delayed phase 53 40 NS*
No Significant Nausea
Overall 71 64 NS**
Delayed phase 73 65 NS**
†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.
Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be.

In both studies, a statistically significantly higher proportion of patients receiving the aprepitant 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 aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.

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 Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time — Cycle 1

Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time - Illustration

Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both Phase III studies using the Functional Living Index–Emesis (FLIE), a validated nauseaand 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 > 108. In each of the 2 studies, a 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 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 aprepitant regimen is maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

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

Proportion of Patients Receiving Highly Emetogenic Chemotherapy with No Emesis and No Significant Nausea - Illustration

Moderately Emetogenic Chemotherapy (MEC)

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see Table 9) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m²; or cyclophosphamide 500-1500 mg/m² and doxorubicin ( ≤ 60 mg/m²) or epirubicin ( ≤ 100 mg/m²).

In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%).

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 < 1% Other. The aprepitant-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.

Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 8.

Table 8: Treatment Regimens in Moderately Emetogenic Chemotherapy Trials

Treatment Regimen Day 1 Days 2 to 3
Aprepitant Aprepitant 125 mg PO† Dexamethasone 12 mg PO‡ Ondansetron 8 mg PO x 2 doses§ Aprepitant 80 mg PO Daily
Standard Therapy Dexamethasone 20 mg PO Ondansetron 8 mg PO x 2 doses Ondansetron 8 mg PO Daily (every 12 hours)
Aprepitant placebo and dexamethasone placebo were used to maintain blinding.
†1 hour prior to chemotherapy.
‡30 minutes prior to chemotherapy.
§30 to 60 minutes prior to chemotherapy and 8 hours after first ondansetron dose.

The antiemetic activity of EMEND was evaluated based on the following endpoints:

Primary endpoint

  • Complete response (defined as no emetic episodes and no use of rescue therapy) 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 < 5 mm on a 0 to 100 mm scale)
  • no significant nausea (maximum VAS < 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 < 25 mm on a 0 to 100 mm scale)
  • complete response during the acute and delayed phases.

A summary of the key results from this study is shown in Table 9.

Table 9: Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group and Phase — Cycle 1

ENDPOINTS Aprepitant 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.

In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant 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 aprepitant 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.

Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, 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 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: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles.

Postmarketing Trial: In a postmarketing, multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the aprepitant regimen (N=430) was compared with a standard of care therapy (N=418) in patients receiving a moderately emetogenic chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV ( < 1500 mg/m²); or cytarabine IV ( > 1 g/m²).

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 aprepitanttreated 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. Patients receiving the aprepitant 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.

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 this study is shown in Table 10.

Table 10 :Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group for Study 2 — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 430)† %
Standard Therapy
(N = 418)†%
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.

In this study, a statistically significantly higher proportion of patients receiving the aprepitant 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 aprepitant 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 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), a 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 a subgroup analysis by tumor type, a numerically higher proportion of patients receiving aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For gender, 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. A similar difference for gender was observed for the no vomiting endpoint.

Prevention of Postoperative Nausea and Vomiting (PONV)

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (PONV Studies 1 and 2), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. Patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron. Aprepitant 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 125 mg dose and the 40 mg dose did not demonstrate any additional clinical benefit. The remainder of this section will focus on the results in the 40 mg aprepitant dose recommended for PONV.

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 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. The two pivotal studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. PONV Study 1 was a multinational study including the U.S., whereas, PONV Study 2 was conducted entirely in the U.S.

Efficacy measures in PONV Study 1 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 aprepitant and 4 mg ondansetron are described in Table 11:

Table 11: PONV Study 1 Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population)

Treatment n/m (%) Aprepitant vs Ondansetron
Δ Odds ratio† Analysis
Primary Endpoints
No Vomiting 0 to 24 hours (Superiority) (no emetic episodes)
Aprepitant 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)
Aprepitant 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)
Aprepitant 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 (Superiority) (no emetic episodes)
Aprepitant 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 (%): Aprepitant 40 mg minus Ondansetron.
‡ LB= lower bound of 1-sided 97.5% confidence interval for the odds ratio.
* P-value of two-sided test < 0.05.
+ Based on the prespecified fixed sequence multiplicity strategy, Aprepitant 40 mg was not superior to Ondansetron.
† Estimated odds ratio for Aprepitant versus Ondansetron. A value of > 1 favors Aprepitant over Ondansetron.

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

Percent of Patients Who Remain Emesis Free During the 48 Hours Following End of Surgery - Illustration

Efficacy measures in PONV Study 2 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).

PONV Study 2 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 both dose levels of aprepitant had a clinically meaningful effect with respect to the secondary endpoint “no vomiting” during the first 24 hours after surgery and showed that the use of 40 mg aprepitant was associated with a 16% improvement over ondansetron for the no vomiting endpoint.

Table 12 : PONV Study 2 (Modified-Intention-to-Treat Population)

Treatment n/m (%) Aprepitant vs Ondansetron n
Δ Odds ratio† p-Value
Primary Endpoint
Complete Response (no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 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)
Aprepitant 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)
Aprepitant 40 mg 112/248 (45.2) -0.7% 1.0 0.83
Ondansetron 113/246 (45.9)      
No Vomiting 0 to 48 (Superiority) (no emetic episodes, 0 to 48 hours)
Aprepitant 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 (%): Aprepitant 40 mg minus Ondansetron.
† Estimated odds ratio: Aprepitant 40 mg versus Ondansetron.
* Not statistically significant after pre-specified multiplicity adjustment.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

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