Aprepitant (Emend®)
[Developed, December 2003; Revised, January 2006; February 2006; October 2009]
MEDICAID DRUG USE REVIEW CRITERIA FOR OUTPATIENT USE
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied
retrospectively; prospective application is indicated with [*].
1. * Dosage
Adults
Current therapies for chemotherapy induced nausea/vomiting (CINV) and post-operative nausea and
vomiting (PONV) target corticosteroid, dopamine, and serotonin (5-HT3) receptors. In the central
nervous system, tachykinins and neurokinins play a role in some autonomic reflexes and behaviors.
Aprepitant is a selective human substance P/neurokinin 1 (NK1) antagonist with a high affinity for
NK1 receptors and little, if any, attraction for corticosteroid, dopamine, or 5-HT3 receptors.
Aprepitant is FDA-approved for prophylaxis of CINV due to high and moderate emetogenic agents
including high dose cisplatin, as well as prophylaxis for PONV. For CINV with highly emetogenic
agents, the recommended aprepitant dose is 125mg 1 hour prior to chemotherapy on day 1 and 80 mg
daily on days 2 and 3. Aprepitant is generally prescribed in combination with a 5-HT3 receptor
antagonist and corticosteroids based on data from available published anti-emetic guidelines. Maximum
recommended doses for aprepitant are summarized in Table 1. Dosages exceeding those listed in
Table 1 will be reviewed.
Table 1
Maximum Recommended Oral Aprepitant Dosages in Adults
INDICATION
MAXIMUM RECOMMENDED DOSE
CINV:
aprepitant (Emend®)
day 1
days 2 and 3
PONV:
aprepitant
within 3 hours of anesthesia induction
125 mg/day
80 mg/day
40 mg as a single dose
Pediatrics
Aprepitant is not recommended for use in pediatric patients because safety and efficacy have not been
established in children.
2. Duration of Therapy
The maximum treatment duration for aprepitant is three days per chemotherapy cycle for moderately or
highly emetogenic chemotherapy regimens. Chemotherapy regimens are administered for one to several
days within a 30-day time period and repeated in cycles. The number of cycles varies based on the type of
cancer being treated. Unless otherwise specified, aprepitant treatment regimens continuing for greater than
three days per chemotherapy cycle will be reviewed for appropriateness of use.
3. * Duplicative Therapy
Aprepitant is the first medication in the class of selective human substance P/NK1 antagonists.
Fosaprepitant, the injectable formulation of aprepitant, is only indicated for use on day 1 of the
chemotherapy cycle with oral aprepitant administered on days 2 and 3. Dosage regimens
incorporating more than one day of fosprepitant therapy in conjunction with two days of oral
aprepitant will be reviewed.
4. * Drug-Drug Interactions
Patient profiles will be monitored to identify regimens that may have clinically significant drug-drug
interactions.
The following drug-drug interactions are considered clinically relevant for aprepitant. Only interactions
classified as clinical significance level 1, contraindicated, or life threatening which have not been classified
will be reviewed:
a. CYP3A4 substrates (e.g., diltiazem, docetaxel, paclitaxel, etoposide, imatinib, ifosfamide, irinotecan,
vinorelbine, vinblastine, vincristine) [clinical significance level – major (DrugReax); 4 (DIF)]
Concurrent administration of aprepitant with agents metabolized by CYP3A4 may result in elevated
substrate plasma levels and the potential for toxicity. Aprepitant is a known inhibitor of CYP3A4 and
may interfere with metabolism of medications metabolized by CYP3A4. Aprepitant should be used
cautiously with compounds metabolized by CYP3A4 and patients should be carefully monitored
for signs and symptoms of substrate toxicity.
b. CYP3A4 inhibitors (e.g., itraconazole, nefazodone, clarithromycin, ritonavir) [clinical significance
level – major (DrugReax); 4 (DIF)]
Combined administration of aprepitant and known CYP3A4 inhibitors may result in reduced aprepitant
metabolism, increased serum aprepitant concentrations, and the potential for adverse effects.
Practitioners prescribing aprepitant and a CYP3A4 inhibitor concurrently should monitor patients for
aprepitant toxicity, and, if necessary, modify the aprepitant dose or choose an alternative anti-emetic
agent that does not interact with CYP3A4 inhibitors.
c. CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) [clinical significance level – moderate
(DrugReax); rifampin - 2 (DIF)]
Drugs that are known to strongly induce CYP3A4 enzyme activity such as rifampin, carbamazepine, and
phenytoin may induce aprepitant metabolism, which may result in reduced aprepitant serum levels and
decreased aprepitant efficacy. Practitioners prescribing aprepitant and a CYP3A4 inducer concurrently
should monitor patients for aprepitant efficacy, and, if necessary, modify the aprepitant dose or choose
an alternative anti-emetic agent that does not interact with CYP3A4 inducers.
d. Warfarin [clinical significance level – major (DrugReax); 4 (DIF)]
Coadministration of aprepitant with warfarin may result in significant decreases in the INR and the
potential for decreased warfarin efficacy. Aprepitant induces CYP2C9, the enzyme responsible for
warfarin metabolism. Patients prescribed aprepitant while receiving warfarin therapy should have
clotting status closely monitored 7 to 10 days after each chemotherapy regimen or following single dose
therapy for postoperative nausea and vomiting.
e. Oral Contraceptives [clinical significance level - moderate (DrugReax); 1 (DIF)]
Concurrent administration of aprepitant with oral contraceptives may result in reduced efficacy as the
AUC for both the estrogen and progestin component of combination oral contraceptives may be
reduced. Patients may desire to use alternative or back-up methods of contraception during the time that
aprepitant is prescribed.
f. Pimozide [clinical significance level - contraindicated (DrugReax); 1 (DIF)]
Aprepitant administered concurrently with pimozide may result in elevated plasma pimozide
concentrations and an increased risk for QT interval prolongation and cardiac arrhythmias. Aprepitant
inhibits CYP3A4, the enzyme responsible for pimozide metabolism. Combined use of aprepitant and
pimozide is not recommended and will be reviewed.
REFERENCES
1. Aprepitant (Emend) for prevention of nausea and vomiting due to cancer chemotherapy. Med Lett Drugs
Ther. 2003;45:62-3.
2. Aprepitant capsules (Emend®) Package Insert. Merck & Co., Inc., July 2009.
3. Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, et al. Establishing the dose of
the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting.
Cancer. 2003;97:2290-300.
4. Gralla RJ, deWit R, Herrstedt J, et al. Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a
5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition
to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials. Cancer.
2005;104:864-8.
5. Massaro AM, Lenz KL. Aprepitant: a novel antiemetic for chemotherapy-induced nausea and vomiting.
Ann Pharmacother. 2005;39:77-85.
6. Dando TM, Perry CM. Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea
and vomiting. Drugs. 2004;64:777-94.
7. 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;21:4112-9.
8. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2009. Available at:
http://www.clinicalpharmacology.com. Accessed October 6th, 2009.
9. Facts and Comparisons 4.0 [database online]. St. Louis, MO: Wolters Kluwer Health Inc.; 2009.
Available at: http://online.factsandcomparisons.com. Accessed October 6th, 2009.
10. Patacchini R, Maggi CA. Tachykinin receptors and receptor subtypes. Arch Int Pharmacodyn Ther.
1995; 329(1):161-84.
11. Klasko RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood
Village, CO, USA. Available at: http://www.thomsonhc.com. Accessed October 6th, 2009.
12. Hansten PD, Horn JR, eds. Hansten and Horn’s drug interactions analysis and management. St.
Louis, MO: Wolters Kluwer Health Inc.; 2009.
13. Klasko RK (Ed): DRUG-REAX® System (electronic version). Thomson Micromedex, Greenwood
Village, CO, USA. Available at: http://www.thomsonhc.com. Accessed October 6th, 2009.
14. Herrstedt J, Muss HB, Warr DG, et al. Efficacy and tolerability of aprepitant for the prevention of
chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic
chemotherapy. Cancer. 2005; 104(7):1548-55.
15. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regimen with a multipleday ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin
treatment. Ann Oncol. 2006;17(6):1000-6.
16. Herrington JD, Jaskiewicz AD, Song J. Randomized, placebo controlled, pilot study evaluating
aprepitant single dose plus palonsetron and dexamethasone for the prevention of acute and delayed
chemotherapy-induced nausea and vomiting. Cancer. 2008;112(9):2080-7.
17. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for
antiemetics in oncology: update 2006. J Clin Oncol. 2006; 24:2932-2947.
Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and
the College of Pharmacy, The University of Texas at Austin.