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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.. Slide 1 Risk Factors for Chemotherapy-Induced Nausea/Vomiting (CINV) Patient-Specific History of emesis Younger age Female gender Heightened anxiety Expectation of adverse effects Hospital roommate with nausea and vomiting Low motivation Low performance status Food intake Inadequate sleep Low alcohol intake Therapy-Specific Agents with increased emetogenic potential Combination regimens Higher-dose chemotherapy 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. Slide 2 Types of CINV Type Onset, Duration Acute emesis Within first 24 hours of chemotherapy Delayed emesis At least 24 hours after chemotherapy; can last up to seven days Anticipatory emesis Before 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. Slide 3 Need for Improved CINV Most Distressing Adverse Effects of Chemotherapy Before and During 5-HT3 Antagonist Era Rank 1983 (Pre–5-HT3 Antagonist Era) 1996 (During 5-HT3 Antagonist Era) 1 2 3 4 5 6 7 8 9 10 Being sick (vomiting) Feeling sick (nausea) Loss of hair Thought of coming for treatment Duration of treatment at the clinic Need to get a needle Shortness of breath Constantly tired Difficulty sleeping Affects family or partner Feeling sick (nausea) Loss of hair Being sick (vomiting) Constantly tired Need for an injection Constipation Thought of coming for treatment Affects family or partner Feeling low, miserable (depression) Feeling anxious or tense 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. Slide 4 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 Slide 5 CINV Compromises Quality of Daily Life Mean Changes in Functional-Domain Scores of Health-Related Quality of Life After 8 Days of Chemotherapy Group 1 (no nausea or vomiting) Group 2 (vomiting, no nausea) Group 3 (nausea, no vomiting) Group 4 (nausea and vomiting) Mean change in score 10 5.3 5.3 4.9 5 0.8 0 –5 –10 1.9b 0.6f –0.6–0.5 d –0.6–1.1c –1.1 –2.6 –3.8a Quality of Life Diminished –5.7 –8.7 –8.4 –8.8e –10 –7.4g –15 –20 Quality of Life Improved –14.2 Physical Emotional Cognitive Social Global Functional domain Group 1: n=166; Group 2: n=30; Group 3: n=157; Group 4: n=332 aGroup 1 vs. Group 4, p=0.007; bGroup 1 vs. Group 4, p=0.0001; cGroup 3 vs. Group 4, p=0.0002; dGroup 3 vs. Group 4, p=0.003; eGroup 1 vs. Group 4, p=0.0001; fGroup 2 vs. Group 4, p=0.0005; gGroup 3 vs. Group 4, p=0.002 Adapted from Osoba D et al Support Care Cancer 1997;5:307-313. Slide 6 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. Slide 7 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. Slide 8 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 (NK1) 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. Slide 9 Antiemetic Therapies • 5-HT3 antagonists (Zofran® [ondansetron hydrochloride], granisetron) • Dexamethasone • Antidopaminergics (prochlorperazine, fluphenazine) • Metoclopramide • NK1 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. Slide 10 EMEND® (aprepitant): The First NK1 Receptor Antagonist • Inhibits emesis by central action • Possesses selectivity 3000-fold greater for the NK1 receptor • • • • • versus other sites Crosses blood-brain barrier Occupies brain NK1 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 Slide 11 EMEND®: Pharmacokinetics* Absorption Tmax Cmax ~4 hr 1.5 µg/ml (day 1) AUC0-24h 19.65 µg•hr/ml (day 1) Distribution Vdss Crosses blood-brain barrier 66 L Yes Metabolism Pathway Largely by oxidation Elimination Route T½ Primarily by metabolism 9–13 hr *Following a 125 mg oral dose on day 1 and 80 mg once-daily oral doses on days 2 and 3 Tmax=time to maximum plasma concentration; Cmax=maximum plasma concentration; AUC0-24h= area under the time–concentration curve from time 0 (preadministration) through 24 hours afterward; Vdss=mean volume of distribution at steady state; T½ =terminal plasma half-life Slide 12 EMEND® Efficacy in Clinical Trials: Study Design Objective: Compare EMEND with control regimens vs. control regimens alone in two identically designed trials (N=1099) in the prevention of CINV Regimen EMEND with Control Regimen Control Regimen Day 1 EMEND 125 mg PO Zofran® a 32 mg IVb Dexamethasone 12 mg POc Zofran® 32 mg IV Dexamethasone 20 mg PO Days 2 and 3 Day 4 EMEND 80 mg PO Dexamethasone 8 mg PO once daily Dexamethasone 8 mg PO Dexamethasone 16 mgd PO Dexamethasone 16 mgd PO aZofran® (ondansetron hydrochloride) was administered at the maximum recommended dose of 32 mg IV on day 1 and was not followed by oral 5-HT3 therapy on days 2–5. bIV=intravenously; cPO=by mouth; d8 mg twice daily Slide 13 EMEND® Efficacy: Complete Response* in Acute Phase 100 13% improvement (p<0.001) % of patients 86 80 73 60 40 20 0 Acute (Day 1) Time after chemotherapy administration 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 *No emesis and no rescue medication Slide 14 EMEND® Efficacy: Complete Response* in Delayed Phase % of patients 100 21% improvement (p<0.001) 80 72 60 51 40 20 0 Delayed (Days 2–5) Time after chemotherapy administration 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 and no rescue medication Slide 15 EMEND® Efficacy: Complete Protection* in Acute Phase 100 12% improvement (p<0.001) % of patients 82 80 70 60 40 20 0 Acute (Day 1) Time after chemotherapy administration 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 *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) Slide 16 EMEND® Efficacy: Complete Protection* in Delayed Phase % of patients 100 16% improvement (p<0.001) 80 64 60 48 40 20 0 Delayed (Days 2–5) Time after chemotherapy administration 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) Slide 17 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 Slide 18 EMEND® Efficacy: Percentage of Patients with No Emesis* in Acute Phase 13% improvement (p<0.001) % of patients 100 80 87 74 60 40 20 0 Acute (Day 1) Time after chemotherapy administration 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 * No emetic episodes regardless of use of rescue medication Slide 19 EMEND® Efficacy: Percentage of Patients with No Emesis* in Delayed Phase % of patients 100 22% improvement (p<0.001) 76 80 60 54 40 20 0 Delayed (Days 2–5) Time after chemotherapy administration 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 emetic episodes regardless of use of rescue medication Slide 20 EMEND® Efficacy: Percentage of Patients Who Remained Free of Vomiting Over Time in Cycle 1 Day 1 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 1 100 % of patients 80 EMEND with control regimen (n=520) 60 40 P<0.001 Control regimen (n=523) Acute (0–24 hours) Delayed Days 2–4 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 20 0 Day 1 Dose 1 Day 2 Dose 2 Day 3 Day 4 Day 5 Dose 3 Days since initiation of cisplatin therapy Slide 21 EMEND® % of patients with favorable responses Efficacy in Clinical Trials: No Vomiting, No Significant Nauseaa in Cycles 1–6 EMEND with Control Regimens 100 90 Control Regimensb 80 c 70 c c c c c 4 5 6 60 50 40 30 20 1 2 3 Cycle d EMEND with Control Regimen n= 516 308 245 170 117 89 Control Regimen n= 522 281 203 142 95 78 a Nausea did not interfere with normal activities. 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. b Slide 22 EMEND®: Overall Adverse Experiences • 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%) *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 Slide 23 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. Slide 24 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. Slide 25 EMEND®: Dosage and Administration Regimen used in clinical studies EMEND* Dexamethasone** Zofran® (ondansetron hydrochloride) *** Day 1 Days 2 and 3 Day 4 125 mg 80 mg None 12 mg orally 8 mg orally 8 mg orally 32 mg IV None None * 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 Slide 26 Drug Interactions: Effect of EMEND® on the Pharmacokinetics of Other Agents Characteristic of Aprepitant Can increase plasma concentrations of coadministered agents that are metabolized through CYP3A4 Clinical Relevance Reduce oral corticosteroid doses by 50% when coadministered with EMEND and IV doses by 25% 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 Slide 27 Drug Interactions: Effect of EMEND® on the Pharmacokinetics of Other Agents (cont’d) Characteristic of Aprepitant Can decrease plasma concentrations of coadministered agents that are metabolized through CYP2C9 Clinical Relevance Closely monitor prothrombin time in patients receiving warfarin to establish and maintain dose after completion of 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 Slide 28 Drug Interactions: Effect of Other Agents on the Pharmacokinetics of EMEND® Characteristic of Other Agents Agents that strongly inhibit or induce CYP3A4 may increase or decrease plasma concentrations of aprepitant, respectively Source A (WPC), p. 5, ¶1, L1-3 Clinical Relevance Approach cautiously Coadministration of EMEND with strong inhibitors of CYP3A4 (e.g., ketoconazole) Coadministration of EMEND with strong inducers of CYP3A4 (e.g., rifampin) ¶2, L1-3 Slide 29 EMEND®: Overall Adverse Experiences • 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%) *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 Slide 30 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 NK1 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. Slide 31 Bibliography Please refer to notes page. Slide 32 Summary of Clinical Information: Role of EMEND® in Managing Chemotherapy-Induced Nausea and Vomiting 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 Slide 33