Combined Analysis Showed an Antiemetic Regimen Including EMEND Significantly Improved Control of Chemotherapy-Induced Nausea and Vomiting in Both Women and Men, Compared to Control Regimen.

Business Editors/Pharmaceutical Writers

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Dec. 8, 2003

First Study to Show Equal Efficacy in Both Women and Men

A post-hoc analysis of two Phase III trials for EMEND(R) (aprepitant) presented Saturday at the 26th Annual San Antonio Breast Cancer Symposium showed that treatment with EMEND in combination with a 5-HT3 receptor antagonist and a corticosteroid ("regimen with EMEND") significantly improved emetic control in both genders and was generally well tolerated compared to a 5-HT3 receptor antagonist and a corticosteroid alone ("control regimen"). Although women generally experience more nausea and vomiting after undergoing chemotherapy, women have not responded as well as men have to antiemetic therapies in large, randomized studies using highly emetogenic chemotherapy (chemotherapy that causes most patients to vomit if they do not receive anti-vomiting medicines prior to treatment).

In addition, the analysis showed that EMEND in combination with standard antiemetics provided similar efficacy for both women and men, in both the acute (day one) and delayed (days two through five) phases of nausea and vomiting.

"In this analysis, with the addition of EMEND, we saw equal protection from nausea and vomiting in both women and men," said Richard J. Gralla, M.D., President, Multinational Association of Supportive Care in Cancer (MASCC). "This is the first study to demonstrate equal protection from nausea and vomiting in both genders."

The multi-center, randomized, double-blind, placebo-controlled clinical trials evaluated 1,043 patients (435 female; 608 male) who were randomly assigned to one of two treatment groups: a control regimen or a regimen with EMEND. Patients were asked to record episodes of nausea and vomiting in a diary, and the primary endpoint was complete response (no emesis and no rescue therapy for nausea or vomiting). In an analysis of the combined study data for each gender, the percentage of patients with overall complete response (days 1-5) was significantly higher in the group receiving the regimen including EMEND than in the control regimen group (66 percent versus 41 percent for women and 69 percent versus 53 percent for men). The rates of control in this analysis of complete response were nearly identical for men and women receiving the regimen with EMEND.

In separate comparisons for complete response on day 1 (acute emesis) and during days 2-5 (delayed emesis), similar superiority was observed with the regimen including EMEND in both genders (acute phase: 86 percent versus 66 percent for women and 87 percent versus 80 percent for men; delayed phase: 76 percent versus 47 percent for women and 77 percent versus 58 percent for men). In an analysis of each study separately, the trend of the treatment effect is the same in both Phase III studies.

The regimen with EMEND was generally well tolerated, with a side effect profile similar to the control group.

About EMEND

EMEND is approved in the United States for use in combination with other anti-vomiting medicines 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. EMEND is an oral capsule that is taken once daily for three days. The recommended dosing regimen is EMEND 125mg orally one hour prior to chemotherapy treatment (Day 1) and 80mg once daily in the morning on Days 2 and 3. EMEND may be taken with or without food. 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.

Important information about EMEND

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

Patients should tell their doctor about all their medical problems, and about all the medicines they 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. Some medicines can affect EMEND. EMEND may also affect some medicines, including chemotherapy, causing them to work differently in your body. Women who use birth control pills while taking EMEND should also use a backup method of contraception to avoid pregnancy.

Patients should tell their doctor if they are pregnant or plan to become pregnant, if they are breast-feeding, or if they have liver problems. It is not known if EMEND passes into breast milk and if it can harm the baby.

Patients should not take EMEND if they are taking any of the following medicines: ORAP(R) (pimozide), SELDANE(R) (terfenadine), HISMANAL(R) (astemizole) or PROPULSID(R) (cisapride). Taking EMEND with these medicines could cause serious or life-threatening problems.

Patients should not take EMEND if they are allergic to any of the ingredients in EMEND. The active ingredient is aprepitant.

A patient's doctor may check to make sure their other medicines are working while they are taking EMEND. Patients who take COUMADIN(R) (warfarin) may need to have blood tests after each 3-day treatment with EMEND to check their blood clotting.

The overall safety of EMEND was evaluated in approximately 3,300 individuals. In two well-controlled clinical studies in patients receiving highly emetogenic chemotherapy, 544 patients were treated with EMEND during the first cycle of chemotherapy and 413 of those patients continued into the multiple cycle extension for up to six cycles of chemotherapy. The most common side effects with EMEND are tiredness, nausea, hiccups, constipation, diarrhea, and loss of appetite. These are not all of the possible side effects of EMEND. For further information patients should speak with their doctor or pharmacist. Patients should read the patient information before starting therapy with EMEND and reread it each time the prescription is renewed in case any information has changed. EMEND is not used to treat nausea and vomiting that patients already have. For more information on EMEND visit www.emend.com.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical products company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly and through its joint ventures.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements include statements regarding product development. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. We undertake 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 our businesses, particularly those mentioned in the cautionary statements in Item 1 of our Form 10-K for the year ended Dec. 31, 2002, and in our periodic reports on Form 10-Q and Form 8-K (if any) which we incorporate by reference.

Note to Editors: EMEND(R) is a registered trademark of Merck & Co., Inc.

                                                          9565001
    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:

    (OBJECT 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 and
titanium 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.

    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 = 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 greater than 9) (see
PRECAUTIONS).

    Renal Insufficiency

    A single 240-mg dose of EMEND was administered to patients with
severe renal insufficiency (CrCl less than 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.
    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 greater than 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

Treatment Regimen             Day 1                 Days 2 to 4
-------------------------------------------- -------------------------
Aprepitant           Aprepitant 125 mg PO    Aprepitant 80 mg PO Daily
                                             (Days 2 and 3 only)

                     Dexamethasone 12 mg PO  Dexamethasone 8 mg PO
                                              Daily (morning)

                     Ondansetron   32 mg IV

-------------------------------------------- -------------------------
Standard Therapy     Dexamethasone 20 mg PO  Dexamethasone 8 mg PO
                                              Daily (morning)

                     Ondansetron 32 mg IV    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 (secondary and exploratory) endpoints:

    --  complete protection (defined as no emetic episodes, no use of
        rescue therapy, and a maximum nausea visual analogue scale
        (VAS) score less than 25 mm on a 0 to 100 mm scale)

    --  no emesis (defined as no emetic episodes regardless of use of
        rescue therapy)

    --  no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale)

    --  no significant nausea (maximum VAS less than 25 mm on a 0 to
        100 mm scale)

    A summary of the key study results from each individual study
analysis is shown in Table 1 and in Table 2.


                                Table 1

Percent of Patients 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
----------------------------------------------------------------------
      Overall++                 73           52        less than 0.001
----------------------------------------------------------------------


OTHER PRESPECIFIED (SECONDARY AND EXPLORATORY) ENDPOINTS
----------------------------------------------------------------------
 Complete Response
----------------------------------------------------------------------
     Acute phase(a)             89           78        less than 0.001
     Delayed phase(b)           75           56        less than 0.001
----------------------------------------------------------------------
 Complete Protection
----------------------------------------------------------------------
      Overall                   63           49                  0.001
Acute phase                     85           75                  0.005
Delayed phase                   66           52        less than 0.001
----------------------------------------------------------------------
 No Emesis
----------------------------------------------------------------------
      Overall                   78           55        less than 0.001
Acute phase                     90           79                  0.001
Delayed phase                   81           59        less than 0.001
----------------------------------------------------------------------
 No Nausea
----------------------------------------------------------------------
      Overall                   48           44     greater than 0.050
Delayed phase                   51           48     greater than 0.050
----------------------------------------------------------------------
 No Significant Nausea
----------------------------------------------------------------------
      Overall                   73           66     greater than 0.050
Delayed phase                   75           69     greater than 0.050
----------------------------------------------------------------------

    +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.

    (a)Acute phase: 0 to 24 hours post-cisplatin treatment.

    (b)Delayed phase: 25 to 120 hours post-cisplatin treatment.

    Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm
= nausea as bad as it could be.

    Table 1 includes nominal p-values not adjusted for multiplicity.



                                Table 2

    Percent of Patients 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
----------------------------------------------------------------------
      Overall++                 63           43        less than 0.001
----------------------------------------------------------------------

OTHER PRESPECIFIED (SECONDARY AND EXPLORATORY) ENDPOINTS
----------------------------------------------------------------------
 Complete Response
----------------------------------------------------------------------
      Acute phase(a)            83           68        less than 0.001
Delayed phase(b)                68           47        less than 0.001
----------------------------------------------------------------------
 Complete Protection
----------------------------------------------------------------------
      Overall                   56           41        less than 0.001
Acute phase                     80           65        less than 0.001
Delayed phase                   61           44        less than 0.001
----------------------------------------------------------------------
 No Emesis
----------------------------------------------------------------------
      Overall                   66           44        less than 0.001
Acute phase                     84           69        less than 0.001
Delayed phase                   72           48        less than 0.001
----------------------------------------------------------------------
 No Nausea
----------------------------------------------------------------------
      Overall                   49           39                  0.021
Delayed phase                   53           40                  0.004
----------------------------------------------------------------------
 No Significant Nausea
----------------------------------------------------------------------
      Overall                   71           64     greater than 0.050
Delayed phase                   73           65     greater than 0.050
----------------------------------------------------------------------

    +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.

    (a)Acute phase: 0 to 24 hours post-cisplatin treatment.

    (b)Delayed phase: 25 to 120 hours post-cisplatin treatment.

    Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm
= nausea as bad as it could be.

    Table 2 includes nominal p-values not adjusted for multiplicity.

    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 Who Remain Emesis Free Over Time -
Cycle 1

    (OBJECT OMITTED)

    p-Value less than 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 greater than 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 With No Emesis and No Significant
Nausea by Treatment Group and Cycle

    (OBJECT OMITTED)


    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 (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.
    Due to the small number of patients in clinical studies who
received the CYP3A4 substrates docetaxel, 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).
    The efficacy of oral contraceptives during administration of EMEND
may be reduced. Although effects on contraception with a 3-day regimen
of EMEND given concomitantly with oral contraceptives has not been
studied, alternative or back-up methods of contraception should be
used (see PRECAUTIONS, Drug Interactions).
    There are no clinical or pharmacokinetic data in patients with
severe hepatic insufficiency (Child-Pugh score greater than 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 oral
contraceptives. Patients should be advised to use alternative or
back-up methods of contraception.

    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 or granisetron. No clinical or drug
interaction study was conducted with 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.

    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%; therefore, the efficacy of oral contraceptives during
administration of EMEND may be reduced. Although a 3-day regimen of
EMEND given concomitantly with oral contraceptives has not been
studied, alternative or back-up methods of contraception should be
used.
    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 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
3300 individuals.
    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 3 shows the percent of patients with clinical adverse
experiences reported at an incidence greater than or equal to 3%
during Cycle 1 of the 2 combined Phase III studies.

    (OBJECT OMITTED)

    The following additional clinical adverse experiences (incidence
greater than 0.5% and greater than standard therapy), regardless of
causality, were reported in patients treated with aprepitant regimen:
    Body as a whole: diaphoresis, edema, flushing, malaise, malignant
neoplasm, pelvic pain, septic shock, upper respiratory infection.
    Cardiovascular system: deep venous thrombosis, hypertension,
hypotension, myocardial infarction, pulmonary embolism, tachycardia.
    Digestive system: acid reflux, deglutition disorder, dysgeusia,
dyspepsia, dysphagia, flatulence, obstipation, salivation increased,
taste disturbance.
    Endocrine system: diabetes mellitus.
    Eyes, ears, nose, and throat: nasal secretion, pharyngitis, vocal
disturbance.
    Hemic and lymphatic system: anemia, febrile neutropenia,
thrombocytopenia.
    Metabolism and nutrition: appetite decreased, hypokalemia, weight
lo(a)
    Musculoskeletal system: muscular weakness, musculoskeletal pain,
myalgia.
    Nervous system: peripheral neuropathy, sensory neuropathy.
    Psychiatric disorder: anxiety disorder, confusion, depression.
    Respiratory system: cough, dyspnea, lower respiratory infection,
non-small cell lung carcinoma, pneumonitis, respiratory insufficiency.
    Skin and skin appendages: alopecia, rash.
    Urogenital system: dysuria, renal insufficiency.

    Laboratory Adverse Experiences

    Table 4 shows the percent of patients with laboratory adverse
experiences reported at an incidence greater than or equal to 3%
during Cycle 1 of the 2 combined Phase III studies.

    (OBJECT OMITTED)

    The following additional laboratory adverse experiences (incidence
greater than 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 adverse experience profile in the Multiple-Cycle extension for
up to 6 cycles of chemotherapy was generally similar to that observed
in Cycle 1.
    In addition, isolated cases of serious adverse experiences,
regardless of causality, of bradycardia, disorientation, and
perforating duodenal ulcer were reported in CINV clinical studies.
    Stevens-Johnson syndrome was reported in a patient receiving
aprepitant with cancer chemotherapy in another CINV study. Angioedema
and urticaria were reported in a patient receiving aprepitant in a
non-CINV study.

    OVERDOSAGE

    No specific information is available on the treatment of
overdosage with EMEND. Single doses up to 600 mg of aprepitant were
generally well tolerated in healthy subjects. Aprepitant was generally
well tolerated when administered as 375 mg once daily for up to 42
days to patients in non-CINV studies. In 33 cancer patients,
administration of a single 375-mg dose of aprepitant on Day 1 and 250
mg once daily on Days 2 to 5 was generally well tolerated.
    Drowsiness and headache were reported in one patient who ingested
1440 mg of aprepitant.
    In the event of overdose, EMEND should be discontinued and general
supportive treatment and monitoring should be provided. Because of the
antiemetic activity of aprepitant, drug-induced emesis may not be
effective.
    Aprepitant cannot be removed by hemodialysis.

    DOSAGE AND ADMINISTRATION

    EMEND is given for 3 days as part of a regimen that includes a
corticosteroid and a 5-HT3 antagonist. The recommended dose of EMEND
is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80
mg once daily in the morning on Days 2 and 3. EMEND has not been
studied for the treatment of established nausea and vomiting.

    In clinical studies, the following regimen was used:


                    Day 1           Day 2       Day 3          Day 4
--------------- -------------  ------------  ------------- -----------
EMEND*             125 mg          80 mg        80 mg          none
--------------- -------------  ------------  ------------  -----------
Dexamethasone**  12 mg orally   8 mg orally   8 mg orally  8 mg orally
--------------- -------------  ------------  ------------  -----------
Ondansetron+      32 mg IV         none           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 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.

    Chronic continuous administration is not recommended (see
PRECAUTIONS).
    See PRECAUTIONS, Drug Interactions for additional information on
dose adjustment for corticosteroids when coadministered with EMEND.
    Refer to the full prescribing information for coadministered
antiemetic 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 renal
insufficiency or for patients with end stage renal disease undergoing
hemodialysis.
    No dosage adjustment is necessary for patients with mild to
moderate hepatic insufficiency (Child-Pugh score 5 to 9). There are no
clinical data in patients with severe hepatic insufficiency
(Child-Pugh score greater than 9).

    HOW SUPPLIED

    No. 3854 -- 80 mg capsules: White, opaque, hard gelatin capsule
with "461" and "80 mg" printed radially in black ink on the body. They
are 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 with
white body and pink cap with "462" and "125 mg" printed radially in
black 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 mg
capsule and two 80 mg capsules.

    NDC 0006-3862-03.

    Storage

    Bottles: Store at 20-25(degree)C (68-77(degree)F) (see USP
Controlled Room Temperature). The desiccant should remain in the
original bottle.
    Blisters: Store at 20-25(degree)C (68-77(degree)F) (see USP
Controlled Room Temperature).

    Rx only

    Issued May 2003

    Printed in USA

                                                          9565100

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

    You should read this information before you start taking EMEND(a).
Also, read the leaflet each time you refill your prescription, in case
any information has changed. This leaflet provides only a summary of
certain information about EMEND. Your doctor or pharmacist can give
you an additional leaflet that is written for health professionals
that contains more complete information. This leaflet does not take
the place of careful discussions with your doctor. You and your doctor
should discuss EMEND when you start taking your medicine.

    What is EMEND?

    EMEND is an antiemetic medicine for use in adult patients. An
antiemetic is a medicine used to prevent and control nausea and
vomiting. EMEND is always used WITH OTHER MEDICINES to prevent and
control 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(b)?

    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 or
    life-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 with
EMEND?

    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 are
working, while you are taking EMEND. Patients who take COUMADIN(R)
(warfarin) may need to have blood tests after each 3-day treatment
with EMEND to check their blood clotting.

    Women who use birth control pills while taking EMEND should also
use a back-up method of contraception to avoid pregnancy.

    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

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

    General information about the use of EMEND

    Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use EMEND for a
condition for which it was not prescribed. Do not give EMEND to other
people, even if they have the same symptoms you have. It may harm
them. Keep EMEND and all medicines out of the reach of children.
    This leaflet summarizes the most important information about
EMEND. If you would like to know more information, talk with your
doctor. You can ask your doctor or pharmacist for information about
EMEND 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 shell
excipients are gelatin and titanium dioxide. The 125-mg capsule shell
also contains red ferric oxide and yellow ferric oxide.

Issued March 2003

MERCK & CO., Inc.
Whitehouse Station, NJ 08889, USA

(a) Registered trademark of MERCK & CO., Inc. COPYRIGHT (C) MERCK &
    CO., Inc., 2003 All rights reserved.

(b) The brands listed are the registered trademarks of their
    respective owners and are not trademarks of Merck & Co., Inc.