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FDA Approves EMEND(R) (Aprepitant), in Combination With Other Antiemetics, for the Prevention of Nausea and Vomiting in Cancer Patients Undergoing Moderately Emetogenic Chemotherapy

Posted on: Wednesday, 11 January 2006, 09:00 CST

Merck & Co., Inc. announced today that the Food and Drug Administration (FDA) has approved EMEND(R) (aprepitant) for use with other antiemetic medicines for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, which are likely to cause nausea and vomiting. EMEND, in combination with other antiemetics, is also approved for the prevention of nausea and vomiting caused by initial and repeat courses of highly emetogenic chemotherapy treatments, which are highly likely to cause nausea and vomiting, including high dose cisplatin.

The FDA approval for EMEND is based on the findings of a study published in April 2005 in the Journal of Clinical Oncology (JCO) that enrolled 866 breast cancer patients, of whom 99.5 percent were women. The study compared a regimen including EMEND (EMEND in combination with ondansetron, a 5-HT3 receptor antagonist, and dexamethasone, a corticosteroid, on day 1 followed by EMEND on day 2 and 3) and a standard regimen (ondansetron and dexamethasone on day 1 followed by ondansetron on day 2 and 3).

Results from this study of breast cancer patients who received moderately emetogenic chemotherapy treatments, which are likely to cause nausea and vomiting, showed that a significantly higher proportion of patients treated with the regimen including EMEND in Cycle 1 reported a complete response (defined as no vomiting and no use of other therapies for nausea or vomiting) in the five days after initiation of chemotherapy compared to a standard regimen (51% vs. 42% , p=0.015). 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 regimen including EMEND in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving the standard regimen; however, the treatment group differences failed to reach statistical significance after multiplicity adjustments.

"Patients with cancer are not only facing a serious illness, they also face the possibility of distressing side effects such as nausea and vomiting from their chemotherapy, and breast cancer patients are particularly susceptible to these side effects," said Kelly Pendergrass, M.D., clinical investigator and medical oncologist at the Kansas City Cancer Center. "The good news is that, with this expanded indication, EMEND can now be used with other antiemetics in the wider population of patients receiving moderately emetogenic chemotherapy to help prevent these worrisome and challenging side effects before they occur."

The study also showed that more patients receiving EMEND reported minimal or no impact of nausea and vomiting on their daily life (64% vs. 56%). This difference between treatment groups was primarily driven by the "No Vomiting Domain" of this composite endpoint. Patients were permitted to continue into a multiple-cycle extension of the study for up to three additional cycles of chemotherapy. Results showed that antiemetic effectiveness for the patients receiving the regimen including EMEND was maintained during all cycles.

In Cycle 1, clinical adverse experiences were reported in approximately 73 percent of patients treated with the regimen including EMEND compared with approximately 75 percent of patients treated with the standard regimen. Adverse events reported at an equal to or higher incidence in Cycle 1 with the regimen including EMEND vs. standard regimen, respectively, were hair loss (24% vs. 22.2%), fatigue (21.9% vs. 21.5%), headache (16.4% vs. 16.4%), neutropenia (8.9% vs. 8.4%), dyspepsia (8.4% vs. 4.9%), stomatitis (5.3% vs. 4.4%), pharyngolaryngeal pain (3% vs. 2.3%), and hot flush (3% vs. 1.4%). The adverse experience profile was generally comparable to the highly emetogenic chemotherapy studies.

In the highly emetogenic studies, the most common side effects reported in Cycle 1 with the regimen including EMEND vs. standard regimen, respectively, were tiredness (17.8% vs. 11.8%), nausea (12.7% vs. 11.8%), hiccups (10.8% vs. 5.6%), constipation (10.3% vs. 12.2%), diarrhea (10.3% vs. 7.5%), and loss of appetite (10.1% vs. 9.5%).

About the study

This multicenter, randomized, double-blind, parallel-group study enrolled 866 breast cancer patients (99.5 percent women) who had never before undergone emetogenic chemotherapy. Patients were randomized to receive either the regimen including EMEND (N=438) or a standard regimen (N=428). Patients in the group who received the regimen including EMEND ranged from 25-78 years of age with a mean age of 53. Approximately 80 percent of the patients were White, eight percent Black, eight percent Asian, four percent Hispanic and less than one percent were other. Patients in the study received chemotherapy regimens that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin ((less than or equal to 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). In this study, the most common combinations were cyclophosphamide plus doxorubicin (60.6%); and cyclophosphamide plus epirubicin plus fluorouracil (21.6%).

Dosing for the regimen including EMEND was EMEND 125 mg orally one hour before chemotherapy, ondansetron 8 mg orally 30-60 minutes before chemotherapy followed by ondansetron 8 mg orally eight hours after the first ondansetron dose, and dexamethasone 12 mg orally 30 minutes before chemotherapy (dose chosen to account for drug interactions) on day 1 and EMEND 80 mg once daily in the morning on days 2-3. Dosing for the standard regimen was ondansetron 8 mg 30-60 minutes before chemotherapy, dexamethasone 20 mg 30 minutes before chemotherapy and ondansetron 8 mg eight hours after the first ondansetron dose on day 1 and ondansetron 8 mg every 12 hours on days 2-3. Patients reported incidences of nausea, vomiting and use of other medications for nausea or vomiting in a diary for five days.

Important information about EMEND

EMEND is only used to help prevent nausea and vomiting caused by chemotherapy. It is not used to get rid of nausea and vomiting after they start.

Patients should tell their doctor about all other medicines they are taking, if they are pregnant or plan to become pregnant, or if they have liver problems. Patients should not take EMEND with ORAP(R) (pimozide), SELDANE(R) (terfenadine), HISMANAL(R) (astemizole) or PROPULSID(R) (cisapride) as EMEND may cause serious or life-threatening problems if taken with these medicines. EMEND may also affect some medicines, including chemotherapy, causing them to work differently in the body. Women who use birth control medicines during treatment with EMEND and for up to one month after using EMEND should also use a backup method of contraception to avoid pregnancy.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2004, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

EMEND(R) is a registered trademark of Merck & Co., Inc. The brands listed are the registered trademarks of their respective owners and are not trademarks of Merck & Co., Inc.

Prescribing information and patient product information for EMEND(R) are attached.

9565004

EMEND(R)

(aprepitant)

CAPSULES

DESCRIPTION

EMEND* (aprepitant) is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 5-(((2R,3S)-2-((1R)-1-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-morpholinyl) methyl)-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its empirical formula is C23H21F7N4O3, and its structural formula is:

(GRAPHIC OMITTED)

Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.

Each capsule of EMEND for oral administration contains either 80 mg or 125 mg of aprepitant and the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 125-mg capsule also contains red ferric oxide and yellow ferric oxide.

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).

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.

Pharmacokinetics

Absorption

The mean absolute oral bioavailability of aprepitant is approximately 60 to 65% and the mean peak plasma concentration (Cmax) of aprepitant occurred at approximately 4 hours (Tmax). Oral administration of the capsule with a standard 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-(Infinity) was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.

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.

* Registered trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey, 08889 USA

COPYRIGHT (C) 2003,2005 MERCK & CO., Inc.

All rights reserved

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 (see CLINICAL PHARMACOLOGY, Mechanism of Action).

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 half-life 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 ((greater than or equal to)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

The pharmacokinetics of EMEND have 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

EMEND was well tolerated in patients with mild to moderate 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 insufficiency (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 insufficiency (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 insufficiency.

There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9) (see PRECAUTIONS).

Renal Insufficiency

A single 240-mg dose of EMEND was administered to patients with severe renal insufficiency (CrCl<30 mL/min) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal insufficiency, the AUC0-(Infinity) 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-(Infinity) 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 insufficiency 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 insufficiency or for patients with ESRD undergoing hemodialysis.

Clinical Studies

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

In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see table below) 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 the table below. Treatment Regimens Highly Emetogenic Chemotherapy Trials ---------------------------------------------------------------------- Treatment Regimen Day 1 Days 2 to 4 ---------------------------------------------------------------------- Aprepitant Aprepitant 125 mg PO Aprepitant 80 mg PO Dexamethasone 12 mg PO Daily (Days 2 and 3 Ondansetron 32 mg IV only) Dexamethasone 8 mg PO Daily (morning) ---------------------------------------------------------------------- Standard Therapy Dexamethasone 20 mg PO Dexamethasone 8 mg PO Ondansetron 32 mg IV 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 post-cisplatin 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 1 and in Table 2. Table 1 Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 1 -- Cycle 1 ---------------------------------------------------------------------- ENDPOINTS Aprepitant Standard p-Value Regimen Therapy (N = 260)+ (N = 261) + % % ---------------------------------------------------------------------- PRIMARY ENDPOINT ---------------------------------------------------------------------- Complete Response ---------------------------------------------------------------------- less Overall++ 73 52 than 0.001 ---------------------------------------------------------------------- OTHER PRESPECIFIED ENDPOINTS ---------------------------------------------------------------------- Complete Response ---------------------------------------------------------------------- less Acute phase ss. 89 78 than 0.001 less Delayed phase|| 75 56 than 0.001 ---------------------------------------------------------------------- Complete Protection ---------------------------------------------------------------------- Overall 63 49 0.001 Acute phase 85 75 NS* less Delayed phase 66 52 than 0.001 ---------------------------------------------------------------------- No Emesis ---------------------------------------------------------------------- less Overall 78 55 than 0.001 Acute phase 90 79 0.001 less Delayed phase 81 59 than 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. ss. 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 2 Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 2 -- Cycle 1 ---------------------------------------------------------------------- ENDPOINTS Aprepitant Standard p-Value Regimen Therapy (N = 261)+ (N = 263)+ % % PRIMARY ENDPOINT ---------------------------------------------------------------------- Complete Response ---------------------------------------------------------------------- less Overall++ 63 43 than 0.001 ---------------------------------------------------------------------- OTHER PRESPECIFIED ENDPOINTS ---------------------------------------------------------------------- Complete Response ---------------------------------------------------------------------- less Acute phase ss. 83 68 than 0.001 less Delayed phase|| 68 47 than 0.001 ---------------------------------------------------------------------- Complete Protection ---------------------------------------------------------------------- less Overall 56 41 than 0.001 less Acute phase 80 65 than 0.001 less Delayed phase 61 44 than 0.001 ---------------------------------------------------------------------- No Emesis ---------------------------------------------------------------------- less Overall 66 44 than 0.001 less Acute phase 84 69 than 0.001 less Delayed phase 72 48 than 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. ss. 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 (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 (GRAPHIC OMITTED) p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.

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 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 >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 (GRAPHIC OMITTED)

Moderately Emetogenic Chemotherapy

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see table that follows) 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 the table that follows. Treatment Regimens Moderately Emetogenic Chemotherapy Trial ---------------------------------------------------------------------- Treatment Regimen Day 1 Days 2 to 3 ---------------------------------------------------------------------- Aprepitant Aprepitant 125 mg PO+ Aprepitant 80 mg Dexamethasone 12 mg PO++ PO Daily Ondansetron 8 mg PO x 2 dosesss. ---------------------------------------------------------------------- Standard Therapy Dexamethasone 20 mg PO Ondansetron 8 mg Ondansetron 8 mg PO x 2 doses 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. ss. 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 3.

Table 3 Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group and Phase -- Cycle 1 ---------------------------------------------------------------------- ENDPOINTS Aprepitant Standard Therapy p-Value Regimen (N = 424)+ (N = 433)+ % % ---------------------------------------------------------------------- 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.

INDICATIONS AND USAGE

EMEND, in combination with other antiemetic agents, is indicated for the:

-- prevention of acute and delayed nausea and vomiting associated

with initial and repeat courses of highly emetogenic cancer

chemotherapy including high-dose cisplatin

-- prevention of nausea and vomiting associated with initial and

repeat courses of moderately emetogenic cancer chemotherapy

(see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

EMEND is a moderate CYP3A4 inhibitor. EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see PRECAUTIONS, Drug Interactions).

EMEND is contraindicated in patients who are hypersensitive to any component of the product.

PRECAUTIONS

General

EMEND should be used with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these concomitant medicinal products. The effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is expected to be greater than the effect of EMEND on the pharmacokinetics of intravenously administered CYP3A4 substrates (see PRECAUTIONS, Drug Interactions).

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, EMEND was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In a separate pharmacokinetic study in patients receiving docetaxel, which is also metabolized by CYP3A4, EMEND did not influence the pharmacokinetics of docetaxel.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied (see PRECAUTIONS, Drug Interactions).

Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.

Coadministration of EMEND with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle (see PRECAUTIONS, Drug Interactions).

Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND (see PRECAUTIONS, Drug Interactions).

There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION).

Information for Patients

Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.

Patients should be instructed to take EMEND only as prescribed. Patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment.

EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle.

Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.

Drug Interactions

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Effect of aprepitant on the pharmacokinetics of other agents

As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4 (see CONTRAINDICATIONS).

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in 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).

Corticosteroids:

Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND, to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone (see DOSAGE AND ADMINISTRATION).

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, a CYP3A4 substrate, 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. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND.

Chemotherapeutic agents: See PRECAUTIONS, General.

Docetaxel: In a pharmacokinetic study, EMEND did not influence the pharmacokinetics of docetaxel.

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 (a CYP2C9 substrate) 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. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. The coadministration of EMEND may reduce the efficacy of hormonal contraceptives during and for 28 days after administration of the last dose of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND.

Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND.

In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

Effect of other agents on the pharmacokinetics of aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND.

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. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of EMEND 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.

Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND.

Additional 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, 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.

Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Three 2-year carcinogenicity studies of aprepitant (two in Sprague-Dawley rats and one in CD-1 mice) were conducted with aprepitant. Dose selection for the studies was based on saturation of absorption in both species. In the rat carcinogenicity studies, animals were treated with oral doses of 0.05, 0.25, 1, 5, 25, 125 mg/kg twice daily. The highest dose tested produced a systemic exposure to aprepitant (plasma AUC0-24hr) of 0.4 to 1.4 times the human exposure (AUC0-24hr = 19.6 mcg--hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 125 mg/kg twice per day produced thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced increased incidences of hepatocellular adenoma at 25 and 125 mg/kg twice daily, and thyroid follicular adenoma at the 125 mg/kg twice daily dose. In the mouse carcinogenicity study, animals were treated with oral doses of 2.5, 25, 125, and 500 mg/kg/day. The highest tested dose produced a systemic exposure of about 2.2 to 2.7 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas in male mice of 125 and 500 mg/kg/day groups.

Aprepitant 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.

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

Pregnancy. Teratogenic Effects: Category B. Teratology studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0-24hr of 31.3 mcg--hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg--hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of EMEND in pediatric patients have not been established.

Geriatric Use

In 2 well-controlled clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

ADVERSE REACTIONS

The overall safety of aprepitant was evaluated in approximately 3800 individuals.

Highly Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone and was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity.

In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence (>=)3%. Table 4 Percent of Patients Receiving Highly Emetogenic Chemotherapy With Clinical Adverse Experiences (Incidence (greater than=)3%) - Cycle 1 Aprepitant Standard Regimen Therapy (N = 544) (N = 550) ---------------------------------------------------------------------- Body as a Whole/ Site Unspecified Abdominal Pain 4.6 3.3 Asthenia/Fatigue 17.8 11.8 Dehydration 5.9 5.1 Dizziness 6.6 4.4 Fever 2.9 3.5 Mucous Membrane Disorder 2.6 3.1 ---------------------------------------------------------------------- Digestive System Constipation 10.3 12.2 Diarrhea 10.3 7.5 Epigastric Discomfort 4.0 3.1 Gastritis 4.2 3.1 Heartburn 5.3 4.9 Nausea 12.7 11.8 Vomiting 7.5 7.6 ---------------------------------------------------------------------- Eyes, Ears, Nose, and Throat Tinnitus 3.7 3.8 ---------------------------------------------------------------------- Hemic and Lymphatic System Neutropenia 3.1 2.9 ---------------------------------------------------------------------- Metabolism and Nutrition Anorexia 10.1 9.5 ---------------------------------------------------------------------- Nervous System Headache 8.5 8.7 Insomnia 2.9 3.1 ---------------------------------------------------------------------- Respiratory System Hiccups 10.8 5.6 ----------------------------------------------------------------------

In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy

During Cycle 1 of a moderately emetogenic chemotherapy study, 438 patients were treated with the aprepitant regimen and 385 of these patients continued into the Multiple-Cycle extension for up to 4 cycles of chemotherapy. In Cycle 1, clinical adverse experiences were reported in approximately 73% of patients treated with the aprepitant regimen compared with approximately 75% of patients treated with standard therapy.

The adverse experience profile in the moderately emetogenic chemotherapy study was generally comparable to the highly emetogenic chemotherapy studies. Table 5 shows the percent of patients with clinical adverse experiences reported at an incidence (>=)3%. Table 5 Percent of Patients Receiving Moderately Emetogenic Chemotherapy With Clinical Adverse Experiences (Incidence (greater than=)3%) -- Cycle 1 ---------------------------------------------------------------------- Aprepitant Standard Regimen Therapy (N = 438) (N = 428) ---------------------------------------------------------------------- Blood and Lymphatic System Disorders Neutropenia 8.9 8.4 ---------------------------------------------------------------------- Metabolism and Nutrition Disorders Anorexia 4.3 5.8 ---------------------------------------------------------------------- Psychiatric Disorders Insomnia 4.1 5.6 ---------------------------------------------------------------------- Nervous System Disorders Dizziness 3.4 4.2 Headache 16.4 16.4 ---------------------------------------------------------------------- Vascular Disorders Hot Flush 3.0 1.4 ---------------------------------------------------------------------- Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 3.0 2.3 ---------------------------------------------------------------------- Gastrointestinal Disorders Constipation 12.3 18.0 Diarrhea 5.5 6.3 Dyspepsia 8.4 4.9 Nausea 7.1 7.5 Stomatitis 5.3 4.4 ---------------------------------------------------------------------- Skin and Subcutaneous Tissue Disorders Alopecia 24.0 22.2 ---------------------------------------------------------------------- General Disorders and General Administration Site Conditions Asthenia 3.4 3.7 Fatigue 21.9 21.5 Mucosal inflammation 2.5 3.5 ----------------------------------------------------------------------

Isolated cases of serious adverse experiences, regardless of causality, of dehydration, enterocolitis, febrile neutropenia, hypertension, hypoaesthesia, neutropenic sepsis, pneumonia, and sinus tachycardia were reported in the moderately emetogenic CINV clinical study.

Highly and Moderately Emetogenic Chemotherapy

The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, pharyngitis, septic shock, upper respiratory infection, urinary tract infection.

Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non-small cell lung carcinoma.

Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia.

Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia.

Psychiatric disorders: anxiety disorder, confusion, depression.

Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor.

Eye disorders: conjunctivitis.

Cardiac disorders: myocardial infarction, palpitations, tachycardia.

Vascular disorders: deep venous thrombosis, flushing, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance.

Gastrointestinal disorders: acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased.

Skin and subcutaneous tissue disorders: acne, diaphoresis, rash.

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia.

Renal and urinary disorders: dysuria, renal insufficiency.

Reproductive system and breast disorders: pelvic pain.

General disorders and administrative site conditions: edema, malaise, rigors.

Investigations: weight loss.

Laboratory Adverse Experiences

Table 6 shows the percent of patients with laboratory adverse experiences reported at an incidence (>=)3% in patients receiving highly emetogenic chemotherapy. Table 6 Percent of Patients Receiving Highly Emetogenic Chemotherapy With Laboratory Adverse Experiences (Incidence (greater than=)3%) - Cycle 1 --------------------------------------------------------------------- Aprepitant Standard Regimen Therapy (N = 544) (N = 550) --------------------------------------------------------------------- ALT Increased 6.0 4.3 AST Increased 3.0 1.3 Blood Urea Nitrogen Increased 4.7 3.5 Serum Creatinine Increased 3.7 4.3 Proteinuria 6.8 5.3 ---------------------------------------------------------------------

The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.

The adverse experiences of increased AST and ALT were generally mild and transient.

The following laboratory adverse experiences were reported at an incidence (>=)3% during Cycle 1 of the moderately emetogenic chemotherapy study in patients treated with the aprepitant regimen or standard therapy, respectively: decreased hemoglobin (2.3%, 4.7%) and decreased white blood cell count (9.3%, 9.0%).

The adverse experience profiles in the Multiple-Cycle extensions for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Steven

Source: Business Wire

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