1. Slide 1 Summary of Clinical Information: Role of EMEND ® in Managing Chemotherapy-Induced Nausea and Vomiting Summary of Clinical Information: Role of EMEND ® in Managing Chemotherapy-Induced Nausea and Vomiting A Slide/Lecture Presentation Reg. No.'s: 80 mg - A38/5.7.2/0626; 125 mg - A38/5.7.2/0627; Combi Pack - A38/5.7.2/0625, EMEND S4 Each capsule contains 80 mg or 125 mg Aprepitant150 ® Registered Trademark of MERCK & CO., INC., Whitehouse Station, N.J., U.S.A..

2. Slide 2 Risk Factors for Chemotherapy-Induced Nausea/Vomiting (CINV) Patient-Specific History of emesisYounger ageFemale gender Heightened anxietyExpectation of Hospital roommate with adverse effects nausea and vomiting Low motivationLow performance statusFood intake Inadequate sleepLow alcohol intake Therapy-Specific Agents with increasedCombination regimensHigher-dose chemotherapy emetogenic potential Faster infusion rates Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880; Antiemetic Subcommittee Ann Oncol 1998;9:811-819.

3. Slide 3 Types of CINV TypeOnset, Duration Acute emesisWithin first 24 hours of chemotherapy Delayed emesisAt least 24 hours after chemotherapy; can last up to seven days Anticipatory emesisBefore second or subsequent courses of chemotherapy but may begin during or after chemotherapy in any treatment cycle Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880; Antiemetic Subcommittee Ann Oncol 1998;9:811-819.

4. Slide 4 Need for Improved CINV 19831996 Rank(Pre–5-HT 3 Antagonist Era)(During 5-HT 3 Antagonist Era) 1Being sick (vomiting)Feeling sick (nausea) 2Feeling sick (nausea)Loss of hair 3Loss of hairBeing sick (vomiting) 4Thought of coming for treatmentConstantly tired 5Duration of treatment at the clinicNeed for an injection 6Need to get a needleConstipation 7Shortness of breathThought of coming for treatment 8Constantly tiredAffects family or partner 9Difficulty sleepingFeeling low, miserable (depression) 10Affects family or partnerFeeling anxious or tense Most Distressing Adverse Effects of Chemotherapy Before and During 5-HT 3 Antagonist Era Adapted from de Boer-Dennert M et al Br J Cancer 1997;76(8):1055-1061; Coates A et al Eur J Cancer Clin Oncol 1983;19:203-208.

5. Slide 5 Unmet Need ANCHOR Study –298 cancer patients and 24 oncology practitioners –Demonstrated an unmet need for better control of both acute and delayed vomiting –Reports of acute experiences were generally accurate –Many more patients reported delayed nausea and vomiting than was predicted EONS Study –248 cancer patients –13% of patients had acute emesis –Up to 38% had delayed emesis ANCHOR=Anti-Nausea CHemOtherapy Registry; EONS=European Oncology Nursing Society Adapted from Grunberg SM et al Cancer 2004;100:2261-2268; Glaus A et al Support Care Cancer 2004;12:708-715

6. Slide 6 CINV Compromises Quality of Daily Life Group 1: n=166; Group 2: n=30; Group 3: n=157; Group 4: n=332 a Group 1 vs. Group 4, p=0.007; b Group 1 vs. Group 4, p=0.0001; c Group 3 vs. Group 4, p=0.0002; d Group 3 vs. Group 4, p=0.003; e Group 1 vs. Group 4, p=0.0001; f Group 2 vs. Group 4, p=0.0005; g Group 3 vs. Group 4, p=0.002 Adapted from Osoba D et al Support Care Cancer 1997;5:307-313. Mean Changes in Functional-Domain Scores of Health-Related Quality of Life After 8 Days of Chemotherapy Mean change in score Quality of Life Diminished Quality of Life Improved Group 1 (no nausea or vomiting) Group 2 (vomiting, no nausea) Group 3 (nausea, no vomiting) Group 4 (nausea and vomiting) –20 –15 –10 –5 0 5 10 1.9 b –0.6 –1.1 c –8.4 –2.6 –0.6 –0.5 d –8.8 e 0.6 f –1.1 –7.4 g –14.2 –3.8 a –5.7 –8.7 –10 5.3 4.9 0.8 PhysicalEmotionalCognitiveSocialGlobal Functional domain

7. Slide 7 Goals of Antiemetic Therapy Primary –Prevent CINV as completely as possible Related –Minimize impact of CINV on health-related quality of life –Provide therapy that is maximally convenient for patients and health care personnel –Reduce hospitalization, overall use of health care resources, and associated costs –Eliminate potential adverse effects of therapy Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880; Gralla RJ et al J Clin Oncol 1999;17(9):2971-2994.

8. Slide 8 Mechanisms of CINV Stimulation of chemoreceptor trigger zone (CTZ) Peripheral mechanisms Damage of gastrointestinal mucosa Stimulation of gastrointestinal neurotransmitter receptors Cortical mechanisms Direct cerebral activation Indirect (psychogenic) mechanisms Vestibular mechanisms Alterations of taste Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880.

9. Slide 9 Role of Substance P and Other Neurotransmitters in CINV Neurotransmitters involved in emesis –Dopamine –Serotonin –Histamine –Norepinephrine –Substance P Substance P exerts an emetic effect by binding to neurokinin-1 (NK 1 ) receptors in the CTZ Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880.

10. Slide 10 Antiemetic Therapies 5-HT 3 antagonists (Zofran ® [ondansetron hydrochloride], granisetron) Dexamethasone Antidopaminergics (prochlorperazine, fluphenazine) Metoclopramide NK 1 receptor antagonist—EMEND ® (aprepitant) Zofran (ondansetron hydrochloride) is a registered trademark of GlaxoSmithKline Group of Companies. Adapted from Beers MH, Berkow R, eds. The Merck Manual. 19th ed. Rahway, NJ: Merck Research Laboratories, 1999; Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880. ® Registered Trademark of MERCK & CO., INC., Whitehouse Station, N.J., U.S.A.

11. Slide 11 EMEND ® (aprepitant): The First NK 1 Receptor Antagonist Inhibits emesis by central action Possesses selectivity 3000-fold greater for the NK 1 receptor versus other sites Crosses blood-brain barrier Occupies brain NK 1 receptors Maintains long duration of central activity Inhibits acute and delayed emesis associated with highly emetogenic chemotherapy as part of a regimen Augments activity of existing antiemetic therapy against cisplatin-induced emesis

12. Slide 12 EMEND ® : Pharmacokinetics* Absorption T max ~4 hr C max 1.5 µg/ml (day 1) AUC 0-24h 19.65 µghr/ml (day 1) DistributionVd ss 66 L Crosses blood-brain barrierYes MetabolismPathwayLargely by oxidation EliminationRoutePrimarily by metabolism T ½ 9–13 hr *Following a 125 mg oral dose on day 1 and 80 mg once-daily oral doses on days 2 and 3 T max =time to maximum plasma concentration; C max =maximum plasma concentration; AUC 0-24h = area under the time–concentration curve from time 0 (preadministration) through 24 hours afterward; Vd ss =mean volume of distribution at steady state; T ½ =terminal plasma half-life

13. Slide 13 EMEND ® Efficacy in Clinical Trials: Study Design RegimenDay 1Days 2 and 3Day 4 EMEND with EMEND 125 mg POEMEND 80 mg PO Control RegimenZofran ® a 32 mg IV b Dexamethasone 12 mg PO c Dexamethasone 8 mg Dexamethasone 8 mg PO once dailyPO Control RegimenZofran ® 32 mg IV Dexamethasone 20 mg PODexamethasone 16 mg d Dexamethasone 16 mg d PO a Zofran ® (ondansetron hydrochloride) was administered at the maximum recommended dose of 32 mg IV on day 1 and was not followed by oral 5-HT 3 therapy on days 2–5. b IV=intravenously; c PO=by mouth; d 8 mg twice daily Objective:Compare EMEND with control regimens vs. control regimens alone in two identically designed trials (N=1099) in the prevention of CINV

14. Slide 14 *No emesis and no rescue medication EMEND ® Efficacy: Complete Response* in Acute Phase Time after chemotherapy administration 86 73 Acute (Day 1) 0 20 40 60 80 100 % of patients Control Regimen (n=523) Zofran ® 32 mg IV, dexamethasone 20 mg PO, and placebo EMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran ® 32 mg IV, and dexamethasone 12 mg PO 13% improvement (p<0.001)

15. Slide 15 EMEND ® Efficacy: Complete Response* in Delayed Phase Time after chemotherapy administration 72 51 Delayed (Days 2–5) 0 20 40 60 80 100 % of patients 21% improvement (p<0.001) *No emesis and no rescue medication Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4 EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3, and dexamethasone 8 mg PO Days 2–4

16. Slide 16 EMEND ® Efficacy: Complete Protection* in Acute Phase Time after chemotherapy administration 82 70 Acute (Day 1) 0 20 40 60 80 100 % of patients 12% improvement (p<0.001) *No emesis, no rescue medication, and no significant nausea (VAS <25 mm when 0=no nausea and 100 mm=nausea as bad as it could be) Control Regimen (n=523) Zofran ® 32 mg IV, dexamethasone 20 mg PO, and placebo EMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran ® 32 mg IV, and dexamethasone 12 mg PO

17. Slide 17 EMEND ® Efficacy: Complete Protection* in Delayed Phase Time after chemotherapy administration 64 48 Delayed (Days 2–5) 0 20 40 60 80 100 % of patients 16% improvement (p<0.001) Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4 EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3, and dexamethasone 8 mg PO Days 2–4 *No emesis, no rescue medication, and no significant nausea (VAS <25 mm when 0=no nausea and 100 mm=nausea as bad as it could be)

18. Slide 18 EMEND® Efficacy: Impact of CINV on Daily Life in Cycle 1 Functional Living Index–Emesis (FLIE) measured the impact of chemotherapy-induced nausea and vomiting on daily life activities Substantially fewer patients reported that nausea and vomiting interfered with daily living when EMEND was added to control regimens* vs. control regimens** alone (p<0.001) *EMEND with — Day 1: EMEND 125 mg PO, Zofran ® 32 mg IV, and dexamethasone 12 mg PO Control Regimen Day 2: EMEND 80 mg PO Days 2 and 3, and dexamethasone 8 mg PO Days 2–4 **Control Regimen — Day 1: Zofran ® 32 mg IV, dexamethasone 20 mg PO, and placebo; Day 2: Dexamethasone 16 mg PO and placebo Days 2–4

19. Slide 19 EMEND ® Efficacy: Percentage of Patients with No Emesis* in Acute Phase *No emetic episodes regardless of use of rescue medication Time after chemotherapy administration 87 74 Acute (Day 1) 0 20 40 60 80 100 % of patients 13% improvement (p<0.001) Control Regimen (n=523) Zofran ® 32 mg IV, dexamethasone 20 mg PO, and placebo EMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran ® 32 mg IV, and dexamethasone 12 mg PO

20. Slide 20 EMEND ® Efficacy: Percentage of Patients with No Emesis* in Delayed Phase *No emetic episodes regardless of use of rescue medication Time after chemotherapy administration 76 54 Delayed (Days 2–5) 0 20 40 60 80 100 % of patients 22% improvement (p<0.001) Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4 EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3, and dexamethasone 8 mg PO Days 2–4

21. Slide 21 EMEND ® Efficacy: Percentage of Patients Who Remained Free of Vomiting Over Time in Cycle 1 Days since initiation of cisplatin therapy Day 1 0 20 40 60 80 100 EMEND with control regimen (n=520) % of patients Control regimen (n=523) Day 2Day 3 Day 5 Dose 1Dose 2 Dose 3 Acute (0–24 hours) Delayed P<0.001 Day 4 Control Regimen Zofran ® (32 mg IV), dexamethasone 20 mg PO, and placebo Day 1 EMEND with Control Regimen EMEND 125 mg PO, Zofran ® 32 mg IV, and dexamethasone 12 mg PO Day 1 Day 1 Control Regimen Dexamethasone 16 mg PO and placebo Days 2–4 EMEND with Control Regimen EMEND 80 mg PO Days 2 and 3; dexamethasone 8 mg PO Days 2–4 Days 2–4

22. Slide 22 EMEND ® Efficacy in Clinical Trials: No Vomiting, No Significant Nausea a in Cycles 1–6 a Nausea did not interfere with normal activities. b Control regimens consisted of Zofran ® (ondansetron hydrochloride) plus dexamethasone on day 1; and dexamethasone alone on days 2-4. c p<0.001 d After cycle 1 data were analyzed, some patients continued their treatment regimen for up to 6 cycles of chemotherapy. Adapted from deWit R et al Eur J Cancer 2004;40:403–410. 40 50 60 70 80 90 100 % of patients with favorable responses 1 Cycle d 30 20 62345 EMEND with Control Regimens b Control Regimens b EMEND with Control Regimen n=51630824517011789 Control Regimen n=5222812031429578 c c c c c c

23. Slide 23 EMEND ® : Overall Adverse Experiences *EMEND 125 mg orally on day 1 plus Zofran ® (ondansetron hydrochloride) 32 mg IV and dexamethasone 12 mg orally; EMEND 80 mg orally once daily on days 2 and 3 plus dexamethasone 8 mg orally; dexamethasone 8 mg orally once daily on day 4 **Placebo plus Zofran ® (ondansetron hydrochloride) 32 mg IV and dexamethasone 20 mg orally on day 1; dexamethasone 8 mg orally twice daily on days 2 to 4 ALT=alanine aminotransferase Most adverse experiences were mild to moderate in intensity Drug-related adverse experiences: Cycle 1 –Approximately 17% of patients treated with EMEND with control regimens* reported clinical adverse experiences compared with approximately 13% of patients treated with control regimens** alone –Drug-related clinical adverse experiences led to discontinuation in 0.6% of patients treated with EMEND with control regimens compared with 0.4% of patients treated with control regimens alone –The most common drug-related adverse experiences reported in patients treated with EMEND with control regimens were hiccups (4.6%), asthenia/fatigue (2.9%), constipation (2.2%), headache (2.2%), anorexia (2.0%), and increased ALT (2.8%)

24. Slide 24 EMEND ® : Indications 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.

25. Slide 25 EMEND ® : Contraindications EMEND is contraindicated in patients who are hypersensitive to any component of the product. EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride.

26. Slide 26 EMEND ® : Dosage and Administration Day 1Days 2 and 3Day 4 EMEND*125 mg80 mgNone Dexamethasone**12 mg orally8 mg orally8 mg orally Zofran ® (ondansetron hydrochloride) ***32 mg IVNoneNone *Administered orally one hour prior to chemotherapy on day 1 and in the morning on days 2 and 3 **Administered 30 minutes prior to chemotherapy on day 1 and in the morning on days 2 through 4 (dose chosen to account for drug interactions) ***Administered 30 minutes prior to chemotherapy on day 1 Regimen used in clinical studies

27. Slide 27 Drug Interactions: Effect of EMEND ® on the Pharmacokinetics of Other Agents Characteristic of AprepitantClinical Relevance Can increase plasma concentrations Reduce oral corticosteroid doses by 50% when of coadministered agents that arecoadministered with EMEND and IV doses by 25% metabolized through CYP3A4 Consider potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (e.g., alprazolam, triazolam) when coadministered with EMEND Do not use EMEND concurrently with pimozide, terfenadine, astemizole, cisapride Caution is advised when EMEND is administered with the following chemotherapeutic agents: etoposide, vinorelbine, docetaxel, and paclitaxel Continued

28. Slide 28 Drug Interactions: Effect of EMEND ® on the Pharmacokinetics of Other Agents (cont’d) Characteristic of AprepitantClinical Relevance Can decrease plasma concentrations Closely monitor prothrombin time in patients receiving of coadministered agents that are warfarin to establish and maintain dose after completion of metabolized through CYP2C9 3-day regimen of EMEND with each chemotherapy course Consider potential effects of decreased plasma concentrations of tolbutamide Efficacy of oral contraceptives may be reduced during administration of EMEND; therefore, alternative or backup methods of contraception should be used

29. Slide 29 Characteristic of Other AgentsClinical Relevance Agents that strongly inhibit orApproach cautiously induce CYP3A4 may increase or decrease plasma concentrations of Coadministration of EMEND with strong inhibitors aprepitant, respectivelyof CYP3A4 (e.g., ketoconazole) Coadministration of EMEND with strong inducers of CYP3A4 (e.g., rifampin) Drug Interactions: Effect of Other Agents on the Pharmacokinetics of EMEND ® Source A (WPC), p. 5, ¶1, L1-3 ¶2, L1-3

30. Slide 30 EMEND ® : Overall Adverse Experiences *EMEND 125 mg orally on day 1 plus Zofran ® (ondansetron hydrochloride) 32 mg IV on day 1 and dexamethasone 12 mg orally; EMEND 80 mg orally once daily on days 2 and 3 plus dexamethasone 8 mg orally; dexamethasone 8 mg orally once daily on day 4 **Placebo plus Zofran ® (ondansetron hydrochloride) 32 mg IV on day 1 and dexamethasone 20 mg orally on day 1; dexamethasone 8 mg orally twice daily on days 2 to 4 ALT=alanine aminotransferase Most adverse experiences were mild to moderate in intensity Drug-related adverse experiences: Cycle 1 –Approximately 17% of patients treated with EMEND* with control regimens reported clinical adverse experiences compared with approximately 13% of patients treated with control regimens** alone –Drug-related clinical adverse experiences led to discontinuation in 0.6% of patients treated with EMEND with control regimens compared with 0.4% of patients treated with control regimens alone –The most common drug-related adverse experiences reported in patients treated with EMEND with control regimens were hiccups (4.6%), asthenia/fatigue (2.9%), constipation (2.2%), headache (2.2%), anorexia (2.0%), and increased ALT (2.8%)

31. Slide 31 Summary CINV: common and highly distressing Treatment goals: complete prevention of CINV and reduction of its impact on patients’ health-related daily life activities EMEND ® (aprepitant) –Unique, highly effective NK 1 receptor antagonist –Improved response to antiemetic therapy and protection from CINV –Generally well tolerated Adapted from Gralla RJ et al J Clin Oncol 1997;17(9):2971-2994; de Boer-Dennert M et al Br J Cancer 1997;76(8):1055-1061; Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880.

32. Slide 32 Bibliography Please refer to notes page.

33. Slide 33 Before prescribing any of the products mentioned in this slide presentation, please consult the full package insert. MSD (Pty) Ltd (Reg. No. 1996/003791/07), Private Bag 3, Halfway House 1685 Copyright © 2003–2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 4-05 EMD 2004-W-6141-EM 12-2006-EMD-05-ZA-40-SS Summary of Clinical Information: Role of EMEND ® in Managing Chemotherapy-Induced Nausea and Vomiting