Approved January 25, 2008

FOSAPREPITANT DIMEGLUMINE
(FDA Category 2S)

EMEND (Merck): Fosaprepitant dimeglumine is a prodrug of aprepitant, which is a selective, highaffinity antagonist of human substance P/neurokinin 1 (NK-1) 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). In animal studies, aprepitant acts centrally at the brain NK-1 receptors to inhibit emesis induced by cytotoxic chemotherapeutic agents.

DOSING INFORMATION: The recommended dose is fosaprepitant 115 mg IV 30 minutes prior to chemotherapy on day 1 only. Thereafter, oral doses of aprepitant (80 mg once daily in the morning on day 2 and 3) should be administered. Dexamethasone and ondansetron should be administered as adjunctive agents.

PHARMACOKINETICS: Fosaprepitant is rapidly converted to aprepitant in the liver and multiple extrahepatic tissues, including kidney, lung and ileum. Aprepitant is greater than 95% bound to plasma protein. Aprepitant is extensively metabolized, primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19 in the liver. Metabolism is largely via oxidation at the morpholine ring and its side chains. Metabolism by CYP2D6, CYP2C9, and CYP2E1 has not been detected. The terminal half-life of aprepitant ranged between approximately 9 and 13 hours

CAUTIONS: Concurrent use of pimozide, terfenadine, astemizole, or cisapride is contraindicated. Chronic continuous use for nausea and vomiting prevention is not recommended. Concomitant use with warfarin may significantly decrease INR. Common adverse effects are injection site pain, diarrhea, asthenia, hiccoughs, and fatigue. Stevens-Johnson syndrome has been reported.

FDA APPROVED INDICATIONS: Fosaprepitant is indicated, in combination with other antiemetics, for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy and for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy, including high-dose cisplatin. Fosaprepitant has not been evaluated for the treatment of established nausea and vomiting. Chronic continuous administration is not recommended.