From the Start.Combination therapy with EMEND™

helps prevent CINV—from Cycle 1, Day 1.

Introducing EMEND™ (aprepitant)The First Neurokinin-1 (NK1) Receptor Antagonist

For patients receiving highly emetogenic chemotherapy and women receiving anthracycline and cyclophosphamide-based chemotherapy

INDIcATIoNSEMEND™ (aprepitant), in combination with a 5-HT3 antagonist class of antiemetics and dexamethasone, is indicated for the:

1. prevention of acute and delayed nausea and vomiting due to highly emetogenic cancer chemotherapy

2. prevention of nausea and vomiting in women due to treatment with moderately emetogenic cancer chemotherapy consisting of cyclophosphamide and anthracycline

coNTRAINDIcATIoNSEMEND™ is contraindicated in patients who are hypersensitive to any component of the formulation. 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.

DRug INTERAcTIoNSSerious Drug Interactions• EMEND™ should be used with caution in patients receiving

concomitant medicinal products that are primarily metabolized through CYP3A4 and CYP2C9, including chemotherapy agents. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these concomitant medicinal products. Induction of CYP2C9 by aprepitant could result in decreased plasma concentrations of these concomitant medicinal products.

• The effect of EMEND™ on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of EMEND™ on the pharmacokinetics of intravenously administered CYP3A4 substrates.

• The efficacy of hormonal contraceptives during and for 28 days after administration of EMEND™ may be reduced. Alternative

or back-up methods of contraception should be used during treatment with EMEND™ and for 1 month following the last dose of EMEND™.

ADVERSE REAcTIoNSClinical Trial Adverse ExperiencesThe most common adverse experiences, regardless of causality, occurring in patients receiving highly emetogenic chemotherapy who were treated with aprepitant in clinical studies (cycle 1) were: asthenia/ fatigue (17.8%), nausea (12.7%), hiccups (10.8%), diarrhea (10.3%), constipation (10.3%), anorexia (10.1%). The most common adverse experiences, regardless of causality, occurring in patients receiving moderately emetogenic chemotherapy who were treated with aprepitant in clinical studies (cycle 1) were: alopecia (24.0%), fatigue (21.9%), headache (16.4%), constipation (12.3%), neutropenia (8.9%).

Reference:1. Data on file, Merck Frosst Canada Ltd.: EMEND™ — Product Monograph, 2007.

CINV = chemotherapy-induced nausea and vomiting EMEND™ is a Trademark of Merck & Co., Inc. Used under license.

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Reference:Grunberg SM, Deuson RR, Mavros P et al. Incidence of chemotherapy-induced nausea and vomiting

after modern antiemetics. Cancer 2004;100:2261–2268.

CINV = chemotherapy-induced nausea and vomiting EMEND™ is a Trademark of Merck & Co., Inc. Used under license.

33%

50%0 10 20 30 40 50 60 70

AcuteDay 1

DelayedDay 2–5

Nausea

Vomiting

0 10 20 30 40 50 60 70

12%

60%

37%

13%

52%

28%

Nausea

% of patients with nausea or vomiting (N=67)

% of patients with nausea or vomiting (N=231)

Vomiting

AcuteDay 1

DelayedDay 2–5

Nausea

Vomiting

Nausea

Vomiting

Observed Incidence of Nausea and Vomiting in PatientsReceiving Highly Emetogenic Chemotherapy (Cycle 1)

CINV Remains a Critical Problem

Observed Incidence of Nausea and Vomiting in PatientsReceiving Moderately Emetogenic Chemotherapy (Cycle 1)

• Up to 60% of patients treated with antiemetics continued to experience nausea and vomiting

• Up to 52% of patients treated with antiemetics continued to experience nausea and vomiting

5-HT3 receptor antagonists may not be enough

How Many of Your Patients Treated With a 5-HT3 Receptor Antagonist Still Experience chemotherapy-induced Nausea and Vomiting?

Study Design and ResultsIn this multinational, prospective, observational study, physicians/nurses (N=13/11) estimated the frequency of acute (Day 1) and delayed (Days 2-5) nausea and vomiting after first administration of highly or moderately emetogenic chemotherapy and antiemetic treatment. Chemotherapy-naive patients older than 18 years (N=298) received either single-agent or combination therapy: highly emetogenic chemotherapy, such as cisplatin >50 mg/m2 or cyclophosphamide >1500 mg/m2, or moderately emetogenic chemotherapy, such as doxorubicin >20 mg/m2 or cyclophosphamide <1500 mg/m2. Patients recorded emetic episodes, nausea assessments, and antiemetic medications taken daily in a 6-day diary, which was then evaluated and matched against the medical predictions. Most patients (97%) received 5-HT3 antagonist; 78% also received a corticosteroid (mean 2.3 antiemetic agents per patient). The most common duration of 5-HT3 antagonist and corticosteroid therapy was 3 days.

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Reference: 1. Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time

course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39:1074–1080.

2. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med. 1993;329:1790–1796.

EMEND™ is a Trademark of Merck & Co., Inc. Used under license.

EMEND™ + 5-HT3 Receptor Antagonist Target Both Pathways

Adapted from Grunberg et al2 and Hesketh et al.1

central Pathway

Activated by substance P

Mediated by NK1 receptors in the emetic center of the brain

Blocked by NK1 receptor antagonist

— EMEND™

Peripheral Pathway

Activated by serotonin

Mediated by 5-HT3 receptors in the gut

Blocked by 5-HT3 receptor antagonists

— Zofran® (ondansetron)— Kytril® (granisetron)— Anzemet® (dolasetron)

Chemotherapy-induced nausea and vomiting

2 Key Pathways can Trigger Emetic Response1

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Reference: Hesketh PJ, Grunberg SM, Gralla RJ, et al; the Aprepitant Protocol 052 Study Group.

The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin-

the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-9.

EMEND™ is a Trademark of Merck & Co., Inc. Used under license.

In many patients receiving cisplatin-based chemotherapy,

EMEND™ From the Start Helped Significantly More Patients to Remain Free of Vomiting over 5 Days

Day 1 Day 2 Day 3 Day 4 Day 5

EMENDTM regimen (n=260)

Control regimen (n=260)

Acute0–24 hours

Delayed

p<0.001

100

90

80

70

60

50

40

Days Since Initiation of Chemotherapy

Perc

enta

ge

of P

atie

nts

With

No

Vom

iting

Time to First Emesis

Days 2–4Control regimen Dexamethasone 16 mg PO and placebo Days 2–4

EMENDTM regimen EMENDTM 80 mg PO Days 2 and 3; dexamethasone 8 mg PO Days 2–4

Day 1Control regimen Zofran® (32 mg IV), dexamethasone 20 mg PO, and placebo Day 1

EMENDTM regimen EMENDTM 125 mg PO, Zofran® 32 mg IV, and dexamethasone 12 mg PO Day 1

Dose 1 Dose 2 Dose 3

Study Design and ResultsIn a multicenter, randomized, double-blind, placebo-controlled clinical study, combination therapy with EMENDTM was compared with a 5-HT3 receptor antagonist regimen in 530 cisplatin-naive patients receiving a chemotherapy regimen that included cisplatin ≥70 mg/m2. Some patients also received additional chemotherapeutic agents. The primary clinical end point was “complete response” (overall, Days 1–5), defined as no vomiting and no rescue medication for nausea or vomiting. The percentage of patients achieving a complete response over 5 days were significantly improved with the EMEND™ regimen than the control regimen, respectively: overall phase 72.7% vs 52.3%; acute phase 89.2% vs 78.1%; delayed phase 75.4% vs 55.8%, p<0.001). The most common drug-related adverse experiences reported in patients treated with the aprepitant regimen and greater than control therapy were: hiccups, asthenia/fatigue and nausea occuring after day 5.

Therapy Regimen* Combination therapy with EMENDTM=3 days EMENDTM (125 mg PO on Day 1 and 80 mg PO once daily on Days 2 and 3); plus 1 day ZOFRAN® (ondansetron) (32 mg IV on Day 1); plus 4 days dexamethasone (12 mg PO on Day 1 and 8 mg PO once daily on Days 2–4).

* * Control regimen=ZOFRAN® was administered at maximum dose of 32 mg IV on Day 1 and not followed by oral 5-HT3 therapy on Days 2-5.

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