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) and postoperative nausea and vomiting (PONV). 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 EMEND® (aprepitant) 9985512 receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis. See package insert for complete information.

EMEND® is a substance P/neurokinin 1 (NK1) receptor antagonist, indicated: • in combination with other antiemetic agents for the: • prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) ncluding high-dose cisplatin. •prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). • for the prevention of postoperative nausea and vomiting (PONV) Limitations of Use. • Not studied for the treatment of established nausea and vomiting. • Chronic continuous administration is not recommended.

Prevention of Chemotherapy Induced Nausea and Vomiting. • EMEND is given for 3 days as part of the chemotherapy-induced nausea and vomiting (CINV) 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 orally once daily in the morning on Days 2 and 3. • EMEND (fosaprepitant dimeglumine) for Injection may be substituted for oral EMEND (125 mg) on Day 1 only as part of the CINV regimen. Prevention of Postoperative Nausea and Vomiting • The recommended oral dosage of EMEND for the postoperative nausea and vomiting (PONV) indication is 40 mg within 3 hours prior to induction of nesthesia.

• Clinical adverse experiences for the CINV regimen in conjunction with highly and moderately emetogenic chemotherapy (incidence >10% are alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, and nausea. • Clinical adverse experiences for the PONV regimen (incidence >5%) are constipation, hypotension, nausea, pruritus, and pyrexia.

• Hypersensitivity to any component of this medication. • EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride, since inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs,potentially causing serious or life-threatening reactions.

• Coadministration of aprepitant with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. • The efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used. • EMEND is a dose-dependent inhibitor of CYP3A4, and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. • Caution should be exercised when administered in patients with severe hepatic impairment.