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

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

The FDA approval for EMEND is based on the findings of a studypublished in April 2005 in the Journal of Clinical Oncology (JCO) thatenrolled 866 breast cancer patients, of whom 99.5 percent were women.The study compared a regimen including EMEND (EMEND in combinationwith ondansetron, a 5-HT3 receptor antagonist, and dexamethasone, acorticosteroid, on day 1 followed by EMEND on day 2 and 3) and astandard regimen (ondansetron and dexamethasone on day 1 followed byondansetron on day 2 and 3).

Results from this study of breast cancer patients who receivedmoderately emetogenic chemotherapy treatments, which are likely tocause nausea and vomiting, showed that a significantly higherproportion of patients treated with the regimen including EMEND inCycle 1 reported a complete response (defined as no vomiting and nouse of other therapies for nausea or vomiting) in the five days afterinitiation of chemotherapy compared to a standard regimen (51% vs. 42%, p=0.015). The difference between treatment groups was primarilydriven by the "No Emesis Endpoint", a principal component of thiscomposite primary endpoint. In addition, a higher proportion ofpatients receiving the regimen including EMEND in Cycle 1 had acomplete response during the acute (0-24 hours) and delayed (25-120hours) phases compared with patients receiving the standard regimen;however, the treatment group differences failed to reach statisticalsignificance after multiplicity adjustments.

"Patients with cancer are not only facing a serious illness, theyalso face the possibility of distressing side effects such as nauseaand vomiting from their chemotherapy, and breast cancer patients areparticularly susceptible to these side effects," said KellyPendergrass, M.D., clinical investigator and medical oncologist at theKansas City Cancer Center. "The good news is that, with this expandedindication, EMEND can now be used with other antiemetics in the widerpopulation of patients receiving moderately emetogenic chemotherapy tohelp prevent these worrisome and challenging side effects before theyoccur."

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

In Cycle 1, clinical adverse experiences were reported inapproximately 73 percent of patients treated with the regimenincluding EMEND compared with approximately 75 percent of patientstreated with the standard regimen. Adverse events reported at an equalto 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 thehighly emetogenic chemotherapy studies.

In the highly emetogenic studies, the most common side effectsreported in Cycle 1 with the regimen including EMEND vs. standardregimen, 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 studyenrolled 866 breast cancer patients (99.5 percent women) who had neverbefore undergone emetogenic chemotherapy. Patients were randomized toreceive either the regimen including EMEND (N=438) or a standardregimen (N=428). Patients in the group who received the regimenincluding EMEND ranged from 25-78 years of age with a mean age of 53.Approximately 80 percent of the patients were White, eight percentBlack, eight percent Asian, four percent Hispanic and less than onepercent were other. Patients in the study received chemotherapyregimens that included cyclophosphamide 750-1500 mg/m2; orcyclophosphamide 500-1500 mg/m2 and doxorubicin ((less than or equalto 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). In thisstudy, the most common combinations were cyclophosphamide plusdoxorubicin (60.6%); and cyclophosphamide plus epirubicin plusfluorouracil (21.6%).

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

Important information about EMEND

EMEND is only used to help prevent nausea and vomiting caused bychemotherapy. It is not used to get rid of nausea and vomiting afterthey start.

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

About Merck

Merck & Co., Inc. is a global research-driven pharmaceuticalcompany dedicated to putting patients first. Established in 1891,Merck currently discovers, develops, manufactures and markets vaccinesand medicines to address unmet medical needs. The company devotesextensive efforts to increase access to medicines through far-reachingprograms that not only donate Merck medicines but help deliver them tothe people who need them. Merck also publishes unbiased healthinformation as a not-for-profit service. For more information, visitwww.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as thatterm is defined in the Private Securities Litigation Reform Act of1995. These statements are based on management's current expectationsand involve risks and uncertainties, which may cause results to differmaterially from those set forth in the statements. The forward-lookingstatements may include statements regarding product development,product potential or financial performance. No forward-lookingstatement can be guaranteed, and actual results may differ materiallyfrom those projected. Merck undertakes no obligation to publiclyupdate any forward-looking statement, whether as a result of newinformation, future events, or otherwise. Forward-looking statementsin this press release should be evaluated together with the manyuncertainties that affect Merck's business, particularly thosementioned in the cautionary statements in Item 1 of Merck's Form 10-Kfor the year ended Dec. 31, 2004, and in its periodic reports on Form10-Q and Form 8-K, which the company incorporates by reference.

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

Prescribing information and patient product information forEMEND(R) are attached.

9565004

EMEND(R)

(aprepitant)

CAPSULES

DESCRIPTION

EMEND* (aprepitant) is a substance P/neurokinin 1 (NK1) receptorantagonist, 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 formulais: (GRAPHIC OMITTED)

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

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

CLINICAL PHARMACOLOGY

Mechanism of Action

Aprepitant is a selective high-affinity antagonist of humansubstance P/neurokinin 1 (NK1) receptors. Aprepitant has little or noaffinity for serotonin (5-HT3), dopamine, and corticosteroidreceptors, the targets of existing therapies for chemotherapy-inducednausea and vomiting (CINV).

Aprepitant has been shown in animal models to inhibit emesisinduced by cytotoxic chemotherapeutic agents, such as cisplatin, viacentral actions. Animal and human Positron Emission Tomography (PET)studies with aprepitant have shown that it crosses the blood brainbarrier and occupies brain NK1 receptors. Animal and human studiesshow that aprepitant augments the antiemetic activity of the5-HT3-receptor antagonist ondansetron and the corticosteroiddexamethasone and inhibits both the acute and delayed phases ofcisplatin-induced emesis.

Pharmacokinetics

Absorption

The mean absolute oral bioavailability of aprepitant isapproximately 60 to 65% and the mean peak plasma concentration (Cmax)of aprepitant occurred at approximately 4 hours (Tmax). Oraladministration of the capsule with a standard breakfast had noclinically meaningful effect on the bioavailability of aprepitant.

The pharmacokinetics of aprepitant are non-linear across theclinical dose range. In healthy young adults, the increase inAUC0-(Infinity) was 26% greater than dose proportional between 80-mgand 125-mg single doses administered in the fed state.

Following oral administration of a single 125-mg dose of EMEND onDay 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr wasapproximately 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 inapproximately 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 meanapparent volume of distribution at steady state (Vdss) isapproximately 70 L in humans.

Aprepitant crosses the placenta in rats and rabbits and crossesthe blood brain barrier in humans (see CLINICAL PHARMACOLOGY,Mechanism of Action).

Metabolism

Aprepitant undergoes extensive metabolism. In vitro studies usinghuman liver microsomes indicate that aprepitant is metabolizedprimarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19.Metabolism is largely via oxidation at the morpholine ring and itsside chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected.In healthy young adults, aprepitant accounts for approximately 24% ofthe radioactivity in plasma over 72 hours following a single oral300-mg dose of (14C)-aprepitant, indicating a substantial presence ofmetabolites in the plasma. Seven metabolites of aprepitant, which areonly 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 radioactivitywas recovered in urine and 45% in feces. A study was not conductedwith radiolabeled capsule formulation. The results after oraladministration may differ.

Aprepitant is eliminated primarily by metabolism; aprepitant isnot renally excreted. The apparent plasma clearance of aprepitantranged from approximately 62 to 90 mL/min. The apparent terminalhalf-life ranged from approximately 9 to 13 hours.

Special Populations

Gender

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

Geriatric

Following oral administration of a single 125-mg dose of EMEND onDay 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr ofaprepitant 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. TheCmax was 10% higher on Day 1 and 24% higher on Day 5 in elderlyrelative to younger adults. These differences are not consideredclinically meaningful. No dosage adjustment for EMEND is necessary inelderly patients.

Pediatric

The pharmacokinetics of EMEND have not been evaluated in patientsbelow 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 ascompared 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 wasno difference in AUC0-24hr or Cmax between Whites and Blacks. Nodosage adjustment for EMEND is necessary based on race.

Hepatic Insufficiency

EMEND was well tolerated in patients with mild to moderate hepaticinsufficiency. Following administration of a single 125-mg dose ofEMEND on Day 1 and 80 mg once daily on Days 2 and 3 to patients withmild hepatic insufficiency (Child-Pugh score 5 to 6), the AUC0-24hr ofaprepitant was 11% lower on Day 1 and 36% lower on Day 3, as comparedwith healthy subjects given the same regimen. In patients withmoderate hepatic insufficiency (Child-Pugh score 7 to 9), theAUC0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day3, as compared with healthy subjects given the same regimen. Thesedifferences in AUC0-24hr are not considered clinically meaningful;therefore, no dosage adjustment for EMEND is necessary in patientswith mild to moderate hepatic insufficiency.

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

Renal Insufficiency

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

In patients with severe renal insufficiency, the AUC0-(Infinity)of total aprepitant (unbound and protein bound) decreased by 21% andCmax decreased by 32%, relative to healthy subjects. In patients withESRD undergoing hemodialysis, the AUC0-(Infinity) of total aprepitantdecreased by 42% and Cmax decreased by 32%. Due to modest decreases inprotein binding of aprepitant in patients with renal disease, the AUCof pharmacologically active unbound drug was not significantlyaffected in patients with renal insufficiency compared with healthysubjects. Hemodialysis conducted 4 or 48 hours after dosing had nosignificant effect on the pharmacokinetics of aprepitant; less than0.2% of the dose was recovered in the dialysate.

No dosage adjustment for EMEND is necessary for patients withrenal insufficiency or for patients with ESRD undergoing hemodialysis.

Clinical Studies

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

Highly Emetogenic Chemotherapy

In 2 multicenter, randomized, parallel, double-blind, controlledclinical studies, the aprepitant regimen (see table below) wascompared with standard therapy in patients receiving a chemotherapyregimen that included cisplatin >50 mg/m2 (mean cisplatin dose = 80.2mg/m2). Of the 550 patients who were randomized to receive theaprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5%Black, 12% Hispanic American, and 21% Multi-Racial. Theaprepitant-treated patients in these clinical studies ranged from 14to 84 years of age, with a mean age of 56 years. 170 patients were 65years or older, with 29 patients being 75 years or older.

Patients (N = 1105) were randomized to either the aprepitantregimen (N = 550) or standard therapy (N = 555). The treatmentregimens 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 groupreceived a concomitant chemotherapeutic agent in addition toprotocol-mandated cisplatin. The most common chemotherapeutic agentsand 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 acutephase (0 to 24 hours post-cisplatin treatment), the delayed phase (25to 120 hours post-cisplatin treatment) and overall (0 to 120 hourspost-cisplatin treatment) in Cycle 1. Efficacy was based on evaluationof 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 studyanalysis 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 proportionof patients receiving the aprepitant regimen in Cycle 1 had a completeresponse (primary endpoint), compared with patients receiving standardtherapy. A statistically significant difference in complete responsein favor of the aprepitant regimen was also observed when the acutephase and the delayed phase were analyzed separately.

In both studies, the estimated time to first emesis afterinitiation of cisplatin treatment was longer with the aprepitantregimen, and the incidence of first emesis was reduced in theaprepitant regimen group compared with standard therapy group asdepicted 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 onpatients' daily lives was assessed in Cycle 1 of both Phase IIIstudies using the Functional Living Index-Emesis (FLIE), a validatednausea- and vomiting-specific patient-reported outcome measure.Minimal or no impact of nausea and vomiting on patients' daily livesis defined as a FLIE total score >108. In each of the 2 studies, ahigher proportion of patients receiving the aprepitant regimenreported 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, patientscontinued into the Multiple-Cycle extension for up to 5 additionalcycles of chemotherapy. The proportion of patients with no emesis andno significant nausea by treatment group at each cycle is depicted inFigure 2. Antiemetic effectiveness for the patients receiving theaprepitant regimen is maintained throughout repeat cycles for thosepatients 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 (seetable that follows) was compared with a standard of care therapy inpatients receiving a moderately emetogenic chemotherapy regimen thatincluded cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500mg/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 aprepitantregimen, 99.5% were women. Of these, approximately 80% were White, 8%Black, 8% Asian, 4% Hispanic, and <1% Other. The aprepitant-treatedpatients 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, with12 patients being over 74 years.

Patients (N = 866) were randomized to either the aprepitantregimen (N = 438) or standard therapy (N = 428). The treatmentregimens 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 thefollowing endpoints:

Primary endpoint:

Complete response (defined as no emetic episodes and no use ofrescue therapy) in the overall phase (0 to 120 hourspost-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) higherproportion of patients receiving the aprepitant regimen (51%) in Cycle1 had a complete response (primary endpoint) during the overall phasecompared with patients receiving standard therapy (42%). Thedifference between treatment groups was primarily driven by the "NoEmesis Endpoint", a principal component of this composite primaryendpoint. In addition, a higher proportion of patients receiving theaprepitant regimen in Cycle 1 had a complete response during the acute(0-24 hours) and delayed (25-120 hours) phases compared with patientsreceiving standard therapy; however, the treatment group differencesfailed to reach statistical significance, after multiplicityadjustments.

Patient-Reported Outcomes: In a phase III study in patientsreceiving moderately emetogenic chemotherapy, the impact of nausea andvomiting on patients' daily lives was assessed in Cycle 1 using theFLIE. A higher proportion of patients receiving the aprepitant regimenreported minimal or no impact on daily life (64% versus 56%). Thisdifference between treatment groups was primarily driven by the "NoVomiting Domain" of this composite endpoint.

Multiple-Cycle Extension: Patients receiving moderately emetogenicchemotherapy were permitted to continue into the Multiple-Cycleextension of the study for up to 3 additional cycles of chemotherapy.Antiemetic effect for patients receiving the aprepitant regimen ismaintained during all cycles.

INDICATIONS AND USAGE

EMEND, in combination with other antiemetic agents, is indicatedfor 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 usedconcurrently with pimozide, terfenadine, astemizole, or cisapride.Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitantcould result in elevated plasma concentrations of these drugs,potentially causing serious or life-threatening reactions (seePRECAUTIONS, Drug Interactions).

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

PRECAUTIONS

General

EMEND should be used with caution in patients receivingconcomitant medicinal products, including chemotherapy agents that areprimarily metabolized through CYP3A4. Inhibition of CYP3A4 byaprepitant could result in elevated plasma concentrations of theseconcomitant medicinal products. The effect of EMEND on thepharmacokinetics of orally administered CYP3A4 substrates is expectedto be greater than the effect of EMEND on the pharmacokinetics ofintravenously administered CYP3A4 substrates (see PRECAUTIONS, DrugInteractions).

Chemotherapy agents that are known to be metabolized by CYP3A4include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide,imatinib, vinorelbine, vinblastine and vincristine. In clinicalstudies, EMEND was administered commonly with etoposide, vinorelbine,or paclitaxel. The doses of these agents were not adjusted to accountfor potential drug interactions.

In a separate pharmacokinetic study in patients receivingdocetaxel, which is also metabolized by CYP3A4, EMEND did notinfluence the pharmacokinetics of docetaxel.

Due to the small number of patients in clinical studies whoreceived the CYP3A4 substrates vinblastine, vincristine, orifosfamide, particular caution and careful monitoring are advised inpatients receiving these agents or other chemotherapy agentsmetabolized primarily by CYP3A4 that were not studied (seePRECAUTIONS, Drug Interactions).

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

Coadministration of EMEND with warfarin may result in a clinicallysignificant decrease in International Normalized Ratio (INR) ofprothrombin time. In patients on chronic warfarin therapy, the INRshould be closely monitored in the 2-week period, particularly at 7 to10 days, following initiation of the 3-day regimen of EMEND with eachchemotherapy cycle (see PRECAUTIONS, Drug Interactions).

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

There are no clinical or pharmacokinetic data in patients withsevere hepatic insufficiency (Child-Pugh score >9). Therefore, cautionshould be exercised when EMEND is administered in these patients (seeCLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency andDOSAGE AND ADMINISTRATION).

Information for Patients

Physicians should instruct their patients to read the patientpackage insert before starting therapy with EMEND and to reread iteach 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 EMEND1 hour prior to chemotherapy treatment.

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

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

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

Drug Interactions

Aprepitant is a substrate, a moderate inhibitor, and an inducer ofCYP3A4. 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 plasmaconcentrations of coadministered medicinal products that aremetabolized 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 areknown to be metabolized by CYP2C9, such as phenytoin, may result inlower plasma concentrations of these drugs.

EMEND is unlikely to interact with drugs that are substrates forthe P-glycoprotein transporter, as demonstrated by the lack ofinteraction of EMEND with digoxin in a clinical drug interactionstudy.

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

Corticosteroids:

Dexamethasone: EMEND, when given as a regimen of 125 mg withdexamethasone coadministered orally as 20 mg on Day 1, and EMEND whengiven as 80 mg/day with dexamethasone coadministered orally as 8 mg onDays 2 through 5, increased the AUC of dexamethasone, a CYP3A4substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone dosesshould be reduced by approximately 50% when coadministered with EMEND,to achieve exposures of dexamethasone similar to those obtained whenit is given without EMEND. The daily dose of dexamethasoneadministered in clinical studies with EMEND reflects an approximate50% reduction of the dose of dexamethasone (see DOSAGE ANDADMINISTRATION).

Methylprednisolone: EMEND, when given as a regimen of 125 mg onDay 1 and 80 mg/day on Days 2 and 3, increased the AUC ofmethylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by2.5-fold on Day 3, when methylprednisolone was coadministeredintravenously 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 byapproximately 50% when coadministered with EMEND to achieve exposuresof methylprednisolone similar to those obtained when it is givenwithout EMEND.

Chemotherapeutic agents: See PRECAUTIONS, General.

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

Warfarin: A single 125-mg dose of EMEND was administered on Day 1and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilizedon chronic warfarin therapy. Although there was no effect of EMEND onthe plasma AUC of R(+) or S(-) warfarin determined on Day 3, there wasa 34% decrease in S(-) warfarin (a CYP2C9 substrate) troughconcentration accompanied by a 14% decrease in the prothrombin time(reported as International Normalized Ratio or INR) 5 days aftercompletion of dosing with EMEND. In patients on chronic warfarintherapy, the prothrombin time (INR) should be closely monitored in the2-week period, particularly at 7 to 10 days, following initiation ofthe 3-day regimen of EMEND with each chemotherapy cycle.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day onDays 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose oftolbutamide 500 mg was administered orally prior to the administrationof the 3-day regimen of EMEND and on Days 4, 8, and 15.

Oral contraceptives: Aprepitant, when given once daily for 14 daysas a 100-mg capsule with an oral contraceptive containing 35 mcg ofethinyl estradiol and 1 mg of norethindrone, decreased the AUC ofethinyl estradiol by 43%, and decreased the AUC of norethindrone by8%.

In another study, a daily dose of an oral contraceptive containingethinyl estradiol and norethindrone was administered on Days 1 through21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oraldexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day10 and there was as much as a 64% decrease in ethinyl estradiol troughconcentrations during Days 9 through 21. While there was no effect ofEMEND on the AUC of norethindrone on Day 10, there was as much as a60% decrease in norethindrone trough concentrations during Days 9through 21. The coadministration of EMEND may reduce the efficacy ofhormonal contraceptives during and for 28 days after administration ofthe last dose of EMEND. Alternative or back-up methods ofcontraception should be used during treatment with EMEND and for 1month following the last dose of EMEND.

Midazolam: EMEND increased the AUC of midazolam, a sensitiveCYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when asingle oral dose of midazolam 2 mg was coadministered on Day 1 and Day5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2through 5. The potential effects of increased plasma concentrations ofmidazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam,triazolam) should be considered when coadministering these agents withEMEND.

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, andmidazolam 2 mg IV was given prior to the administration of the 3-dayregimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC ofmidazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% onDay 8 relative to the dosing of EMEND on Days 1 through 3. Theseeffects were not considered clinically important. The AUC of midazolamon 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, coadministrationof EMEND with drugs that inhibit CYP3A4 activity may result inincreased 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 withcaution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) resultin a 2-fold increase in plasma concentrations of aprepitant,concomitant administration should also be approached with caution.

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

Ketoconazole: When a single 125-mg dose of EMEND was administeredon Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strongCYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-foldand the mean terminal half-life of aprepitant increased approximately3-fold. Concomitant administration of EMEND with strong CYP3A4inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of EMEND was administered onDay 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4inducer, the AUC of aprepitant decreased approximately 11-fold and themean terminal half-life decreased approximately 3-fold.

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

Additional interactions

Diltiazem: In patients with mild to moderate hypertension,administration of aprepitant once daily, as a tablet formulationcomparable to 230 mg of the capsule formulation, with diltiazem 120 mg3 times daily for 5 days, resulted in a 2-fold increase of aprepitantAUC and a simultaneous 1.7-fold increase of diltiazem AUC. Thesepharmacokinetic effects did not result in clinically meaningfulchanges in ECG, heart rate or blood pressure beyond those changesinduced by diltiazem alone.

Paroxetine: Coadministration of once daily doses of aprepitant, asa tablet formulation comparable to 85 mg or 170 mg of the capsuleformulation, with paroxetine 20 mg once daily, resulted in a decreasein AUC by approximately 25% and Cmax by approximately 20% of bothaprepitant and paroxetine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Aprepitant was not genotoxic in the Ames test, the humanlymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNAstrand break test, the Chinese hamster ovary (CHO) cell chromosomeaberration test and the mouse micronucleus test.

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

Pregnancy. Teratogenic Effects: Category B. Teratology studieshave 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 humanexposure at the recommended dose) and in rabbits at oral doses up to25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg--hr/mL, about 1.4 times thehuman exposure at the recommended dose) and have revealed no evidenceof impaired fertility or harm to the fetus due to aprepitant. Thereare, however, no adequate and well-controlled studies in pregnantwomen. Because animal reproduction studies are not always predictiveof human response, this drug should be used during pregnancy only ifclearly needed.

Nursing Mothers

Aprepitant is excreted in the milk of rats. It is not knownwhether this drug is excreted in human milk. Because many drugs areexcreted in human milk and because of the potential for possibleserious adverse reactions in nursing infants from aprepitant andbecause of the potential for tumorigenicity shown for aprepitant inrodent carcinogenicity studies, a decision should be made whether todiscontinue nursing or to discontinue the drug, taking into accountthe importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of EMEND in pediatric patients have notbeen established.

Geriatric Use

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

ADVERSE REACTIONS

The overall safety of aprepitant was evaluated in approximately3800 individuals.

Highly Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving highlyemetogenic cancer chemotherapy, 544 patients were treated withaprepitant during Cycle 1 of chemotherapy and 413 of these patientscontinued into the Multiple-Cycle extension for up to 6 cycles ofchemotherapy. EMEND was given in combination with ondansetron anddexamethasone and was generally well tolerated. Most adverseexperiences reported in these clinical studies were described as mildto moderate in intensity.

In Cycle 1, clinical adverse experiences were reported inapproximately 69% of patients treated with the aprepitant regimencompared with approximately 68% of patients treated with standardtherapy. Table 4 shows the percent of patients with clinical adverseexperiences 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, andperforating duodenal ulcer were reported in highly emetogenic CINVclinical studies.

Moderately Emetogenic Chemotherapy

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

The adverse experience profile in the moderately emetogenicchemotherapy study was generally comparable to the highly emetogenicchemotherapy studies. Table 5 shows the percent of patients withclinical 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 ofcausality, of dehydration, enterocolitis, febrile neutropenia,hypertension, hypoaesthesia, neutropenic sepsis, pneumonia, and sinustachycardia were reported in the moderately emetogenic CINV clinicalstudy.

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, lowerrespiratory infection, pharyngitis, septic shock, upper respiratoryinfection, urinary tract infection.

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

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

Metabolism and nutrition disorders: appetite decreased, diabetesmellitus, hypokalemia.

Psychiatric disorders: anxiety disorder, confusion, depression.

Nervous system: peripheral neuropathy, sensory neuropathy, tastedisturbance, 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, respiratoryinsufficiency, vocal disturbance.

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

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

Musculoskeletal and connective tissue disorders: arthralgia, backpain, 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 adverseexperiences reported at an incidence (>=)3% in patients receivinghighly 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: alkalinephosphatase increased, hyperglycemia, hyponatremia, leukocytesincreased, erythrocyturia, leukocyturia.

The adverse experiences of increased AST and ALT were generallymild and transient.

The following laboratory adverse experiences were reported at anincidence (>=)3% during Cycle 1 of the moderately emetogenicchemotherapy study in patients treated with the aprepitant regimen orstandard therapy, respectively: decreased hemoglobin (2.3%, 4.7%) anddecreased white blood cell count (9.3%, 9.0%).

The adverse experience profiles in the Multiple-Cycle extensionsfor up to 6 cycles of chemotherapy were generally similar to thatobserved in Cycle 1.

Stevens-Johnson syndrome was reported in a patient receivingaprepitant with cancer chemotherapy in another CINV study. Angioedemaand urticaria were reported in a patient receiving aprepitant in anon-CINV study.

OVERDOSAGE

No specific information is available on the treatment ofoverdosage with EMEND. Single doses up to 600 mg of aprepitant weregenerally well tolerated in healthy subjects. Aprepitant was generallywell tolerated when administered as 375 mg once daily for up to 42days to patients in non-CINV studies. In 33 cancer patients,administration of a single 375-mg dose of aprepitant on Day 1 and 250mg once daily on Days 2 to 5 was generally well tolerated.

Drowsiness and headache were reported in one patient who ingested1440 mg of aprepitant.

In the event of overdose, EMEND should be discontinued and generalsupportive treatment and monitoring should be provided. Because of theantiemetic activity of aprepitant, drug-induced emesis may not beeffective.

Aprepitant cannot be removed by hemodialysis.

DOSAGE AND ADMINISTRATION

EMEND is given for 3 days as part of a regimen that includes acorticosteroid and a 5-HT3 antagonist. The recommended dose of EMENDis 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80mg once daily in the morning on Days 2 and 3.

In clinical studies, the following regimen was used for theprevention of nausea and vomiting associated with highly emetogeniccancer chemotherapy:
Day 1 Day 2 Day 3 Day 4
----------------------------------------------------------------------
EMEND* 125 mg 80 mg 80 mg none
----------------------------------------------------------------------
Dexamethasone** 12 mg 8 mg 8 mg 8 mg
orally orally orally orally
----------------------------------------------------------------------
Ondansetron+ 32 mg none none none
IV
----------------------------------------------------------------------

* EMEND was administered orally 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 dose of
dexamethasone was chosen to account for drug interactions.

+ Ondansetron was administered 30 minutes prior to chemotherapy
treatment on Day 1.

In a clinical study, the following regimen was used for theprevention of nausea and vomiting associated with moderatelyemetogenic cancer chemotherapy:

Day 1 Day 2 Day 3
----------------------------------------------------------------------
EMEND* 125 mg 80 mg 80 mg
----------------------------------------------------------------------
Dexamethasone** 12 mg orally none none
----------------------------------------------------------------------
Ondansetron+ 2 x 8 mg orally none none
----------------------------------------------------------------------

* EMEND was administered orally 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. The dose of dexamethasone was chosen to account
for drug interactions.

+ Ondansetron 8-mg capsule was administered 30 to 60 minutes prior
to chemotherapy treatment and one 8-mg capsule was administered 8
hours after the first dose on Day 1.

EMEND has not been studied for the treatment of established nauseaand vomiting.

Chronic continuous administration is not recommended (seePRECAUTIONS).

See PRECAUTIONS, Drug Interactions for additional information ondose adjustment for corticosteroids when coadministered with EMEND.

Refer to the full prescribing information for coadministeredantiemetic agents.

EMEND may be taken with or without food.

No dosage adjustment is necessary for the elderly.

No dosage adjustment is necessary for patients with renalinsufficiency or for patients with end stage renal disease undergoinghemodialysis.

No dosage adjustment is necessary for patients with mild tomoderate hepatic insufficiency (Child-Pugh score 5 to 9). There are noclinical data in patients with severe hepatic insufficiency(Child-Pugh score >9).

HOW SUPPLIED

No. 3854 -- 80 mg capsules: White, opaque, hard gelatin capsulewith "461" and "80 mg" printed radially in black ink on the body. Theyare supplied as follows:

NDC 0006-0461-30 bottles of 30 (with desiccant)

NDC 0006-0461-05 unit-dose packages of 5.

No. 3855 -- 125 mg capsules: Opaque, hard gelatin capsule withwhite body and pink cap with "462" and "125 mg" printed radially inblack ink on the body. They are supplied as follows:

NDC 0006-0462-30 bottles of 30 (with desiccant)

NDC 0006-0462-05 unit-dose packages of 5.

No. 3862 -- Unit-of-use tri-fold pack containing one 125 mgcapsule and two 80 mg capsules.

NDC 0006-3862-03.

Storage

Bottles: Store at 20-25(degree)C (68-77(degree)F) (see USPControlled Room Temperature). The desiccant should remain in theoriginal bottle.

Blisters: Store at 20-25(degree)C (68-77(degree)F) (see USPControlled Room Temperature).

Rx only

Merck & Co., Inc., Whitehouse Station, NJ 08889, USA

Issued October 2005

Printed in USA

9565103

Patient Information EMEND(R) (EE mend) (aprepitant) Capsules

You should read this information before you start taking EMEND*.Also, read the leaflet each time you refill your prescription, in caseany information has changed. This leaflet provides only a summary ofcertain information about EMEND. Your doctor or pharmacist can giveyou an additional leaflet that is written for health professionalsthat contains more complete information. This leaflet does not takethe place of careful discussions with your doctor. You and your doctorshould discuss EMEND when you start taking your medicine.

What is EMEND?

EMEND is an antiemetic medicine for use in adult patients. Anantiemetic is a medicine used to prevent and control nausea andvomiting. EMEND is always used WITH OTHER MEDICINES to prevent andcontrol nausea and vomiting caused by your chemotherapy treatment.EMEND is not used to treat nausea and vomiting that you already have.

Who should not take EMEND**?

Do not take EMEND if you:

-- are taking any of the following medicines:

-- ORAP(R) (pimozide)

-- SELDANE(R) (terfenadine)

-- HISMANAL(R) (astemizole)

-- PROPULSID(R) (cisapride)

Taking EMEND with these medicines could cause serious orlife-threatening problems.

-- are allergic to any of the ingredients in EMEND. The active ingredient is aprepitant. See the end of this leaflet for a list of all the ingredients in EMEND.

What should I tell my doctor before and during treatment withEMEND?

Tell your doctor:

-- if you are pregnant or plan to become pregnant. It is not known if EMEND can harm your unborn baby.

-- if you are breast-feeding. It is not known if EMEND passes into your milk and if it can harm your baby.

-- if you have liver problems.

-- about all your medical problems.

-- about all the medicines that you are taking or plan to take, prescription and nonprescription medicines, vitamins, and herbal supplements. EMEND may cause serious life-threatening reactions if used with certain medicines (see the section Who should not take EMEND?). Some medicines can affect EMEND. EMEND may also affect some medicines, including chemotherapy, causing them to work differently in your body.

Your doctor may check to make sure your other medicines areworking, while you are taking EMEND. Patients who take COUMADIN(R)(warfarin) may need to have blood tests after each 3-day treatmentwith EMEND to check their blood clotting.

Women who use birth control medicines during treatment with EMENDand for up to 1 month after using EMEND should also use a back-upmethod of contraception to avoid pregnancy.

* Registered trademark of MERCK & CO., Inc.

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

All rights reserved.

** The brands listed are the registered trademarks of theirrespective owners and are not trademarks of Merck & Co., Inc.

How should I take EMEND?

-- Take EMEND exactly as prescribed.

-- EMEND is a capsule that you swallow with a drink.

The recommended dose of EMEND is:

-- Take one 125-mg capsule (white/pink) by mouth 1 hour before you start your chemotherapy treatment;

AND

-- Take one 80-mg capsule (white) each morning for the 2 days following your chemotherapy treatment.

-- EMEND may be taken with or without food.

-- Do not start taking EMEND if you already have nausea and vomiting. Ask your doctor what to do.

-- If you take too much EMEND, call your doctor, local emergency room or poison control center right away.

What are the possible side effects of EMEND?

The most common side effects with EMEND are:

-- tiredness

-- nausea

-- hiccups

-- constipation

-- diarrhea

-- loss of appetite

-- headache

-- hair loss

These are not all of the possible side effects of EMEND. Forfurther information ask your doctor or pharmacist. Talk to your doctorabout any side effect that bothers you.

General information about the use of EMEND

Medicines are sometimes prescribed for conditions that are notmentioned in patient information leaflets. Do not use EMEND for acondition for which it was not prescribed. Do not give EMEND to otherpeople, even if they have the same symptoms you have. It may harmthem. Keep EMEND and all medicines out of the reach of children.

This leaflet summarizes the most important information aboutEMEND. If you would like to know more information, talk with yourdoctor. You can ask your doctor or pharmacist for information aboutEMEND that is written for health professionals.

What are the ingredients in EMEND?

Active ingredient: aprepitant

Inactive ingredients: sucrose, microcrystalline cellulose,hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shellexcipients are gelatin, titanium dioxide, and may contain sodiumlauryl sulfate and silicon dioxide. The 125-mg capsule shell alsocontains red ferric oxide and yellow ferric oxide.

Issued October 2005

MERCK & CO., Inc.

Whitehouse Station, NJ 08889, USA