VA Class:GA605

ATC Class:A04AD12

AHFS Class:

• Neurokinin-1 Receptor Antagonists 56:22.32

Generic Name(s):

• Aprepitant

• Fosaprepitant Dimeglumine

Chemical Name:

• 5-[[(2R,3S)-2-[(1R)-1-[3,5,bis (trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2,-dihydro-3H-1,2,4,-triazol-3-one

• [3-[[(2 R ,3 S )-2-[(1 R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1 H -1,2,4-triazol-1-yl]phosphonate-1-deoxy-1-(methylamino)-d-glucitol

Molecular Formula:

• C₂₃H₂₁F₇N₄O₃

• C₂₃H₂₂F₇N₄O₆P•2C₇H₁₇NO₅

Fosaprepitant dimeglumine, a prodrug of aprepitant, and aprepitant, a selective, high-affinity antagonist at substance P/neurokinin-1 (NK₁) receptors, are antiemetics.1,2,3,4,7,8,9,11,12,16

Cancer Chemotherapy-induced Nausea and Vomiting

Aprepitant and fosaprepitant dimeglumine are used in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately to highly emetogenic cancer chemotherapy, including high-dose cisplatin therapy in adults.1,4,7,8,9,11,12,16

To prevent chemotherapy-induced nausea and vomiting associated with highly emetogenic chemotherapy regimens (including an anthracycline plus cyclophosphamide), the American Society of Clinical Oncology (ASCO) currently recommends a 3-drug antiemetic regimen consisting of a neurokinin-1 (NK₁) receptor antagonist (e.g., either oral aprepitant or IV fosaprepitant dimeglumine), a type 3 serotonin (5-HT₃) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, ramosetron [not commercially available in the US], tropisetron [not commercially available in the US]), and dexamethasone.19,20 ASCO states that the oral, fixed-combination of netupitant and palonosetron plus dexamethasone is an additional antiemetic treatment option in this setting.20

For patients receiving moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone.19,20 If palonosetron is not available, a first-generation 5-HT₃ receptor antagonist (preferably granisetron or ondansetron) may be substituted.19 Limited evidence suggests that aprepitant may be added to this regimen; in such cases, ASCO states that any of the 5-HT₃ receptor antagonists is appropriate.19

For patients receiving chemotherapy regimens with a low emetogenic risk , ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.19

In patients receiving chemotherapy regimens with a minimal emetogenic risk , antiemetics should not be routinely administered prior to or following chemotherapy.19

Safety and efficacy of aprepitant for chronic use or for treatment of established nausea and vomiting have not been established.1

Clinical Experience

Pivotal clinical efficacy studies for the prevention of acute and delayed nausea and vomiting associated with chemotherapy were conducted with oral aprepitant.12 Efficacy of aprepitant in patients receiving highly emetogenic chemotherapy was established in 2 controlled clinical studies comparing a regimen containing aprepitant in combination with a 5-HT₃ receptor antagonist (ondansetron) and a corticosteroid (dexamethasone) with a standard regimen containing ondansetron and dexamethasone alone.1,8,9 In these studies, 63-73% of those receiving the regimen with oral aprepitant or 43-52% of those receiving the standard regimen experienced a complete response (i.e., no emetic episodes and no use of rescue therapy) from 0-120 hours after treatment with cisplatin.1,8,9 In the acute phase (0-24 hours) after cisplatin treatment, 83-89% of patients receiving the aprepitant regimen or 68-78% of those receiving the standard regimen experienced a complete response.1,8,9 In the delayed phase (25-120 hours) after cisplatin treatment, 68-75% of patients receiving the aprepitant regimen or 47-56% of those receiving the standard regimen experienced complete response.1,8,9 In addition, antiemetic efficacy of the regimen containing aprepitant was maintained through up to 5 additional chemotherapy cycles in patients who continued into a multiple-cycle extension phase of these 2 studies.1

Efficacy of aprepitant in patients receiving moderately emetogenic chemotherapy was established in a double-blind clinical study comparing a regimen containing aprepitant in combination with a 5-HT₃ receptor antagonist (ondansetron) and a corticosteroid (dexamethasone) with a standard regimen containing ondansetron and dexamethasone alone.1,11 In this study, a significantly higher proportion of patients with breast cancer receiving the aprepitant regimen (51%) had a complete response (i.e., no emetic episodes and no use of rescue therapy) compared with those receiving the standard regimen (42%) from 0-120 hours after treatment with cyclophosphamide and doxorubicin or epirubicin.1,11 In addition, more patients in the aprepitant group than in the standard regimen group reported minimal or no impact of chemotherapy-induced nausea and vomiting on daily living overall (64 versus 56%, respectively).1,11 Antiemetic efficacy of the regimen containing aprepitant was maintained through up to 3 additional chemotherapy cycles in patients who continued into a multiple-cycle extension phase of this study.1

Postoperative Nausea and Vomiting

Aprepitant is used for the prevention of postoperative nausea and vomiting in adults.1,2,6,14,15 Efficacy of aprepitant was established in 2 randomized, double-blind, active-comparator (ondansetron) clinical studies of similar design in 1658 patients.1,6,14,15 Patients were randomized to receive an oral aprepitant dose of 40 or 125 mg given 1-3 hours prior to anesthesia, or an IV ondansetron dose of 4 mg immediately before anesthesia induction.1,6,14,15 Aprepitant doses of 125 mg did not appear to provide additional benefit compared with 40-mg aprepitant doses.1,6 In the first study, significantly more patients receiving aprepitant 40-mg doses experienced no emesis (i.e., no emetic episodes regardless of use of rescue therapy) compared with patients receiving IV ondansetron (84 versus 71%, respectively) in the initial 24-hour period following surgery.1,6,14 Complete response (i.e., no emetic episodes and no use of rescue therapy) was reported in about 64 or 55% of those receiving aprepitant or ondansetron, respectively.1,6,14 Similar results were observed for up to 48 hours following surgery;1,6 no emesis was reported in about 82 or 66% of patients receiving aprepitant or ondansetron, respectively.1,6,14 Although aprepitant delayed the time to first emetic episode, it did not affect time to first use of rescue therapy compared with ondansetron.1,6,14

The second study failed to support the primary hypothesis that a 40-mg oral aprepitant dose is superior to a 4-mg IV ondansetron dose in the prevention of postoperative nausea and vomiting as measured by the proportion of patients with complete response in the 24 hours following end of surgery.1,6 A similar percentage of patients who received 40 mg of aprepitant orally or 4 mg of IV ondansetron (45 versus 42%, respectively) achieved a complete response, and did not require rescue therapy for established emesis or nausea in the initial 24-hour period following surgery.1,6,15 A higher proportion of patients receiving aprepitant had a clinically meaningful effect compared with those receiving IV ondansetron (about 90 versus 74%, respectively) in the initial 24-hour period following surgery.1,6

A combined analysis of the 2 pivotal studies showed that both aprepitant doses (40 and 125 mg) improved protection against nausea and vomiting and reduced the need for rescue therapy, compared with ondansetron.6 The 40-mg aprepitant dose also was found to be superior to ondansetron on the 3 measures of efficacy (accounting for any nausea, any vomiting, and any use of rescue therapy in the same patient).6

Aprepitant capsules and fosaprepitant dimeglumine for injection have not been studied for chronic use or treatment of established nausea and vomiting.1,2

Administration

Dispensing and Administration Precautions

Because of similarities in spelling and/or pronunciation between Emend^® (the trade name for aprepitant) and Amen^® (a former trade name for medroxyprogesterone acetate; no longer commercially available under this trade name in the US) or Vfend^® (the trade name for voriconazole), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.5 (See Dispensing and Administration Precautions under Warnings/Precautions: General Precautions, in Cautions.)

Oral Administration

Aprepitant is administered orally without regard to meals.1,2,4

IV Administration

Fosaprepitant dimeglumine is administered by IV infusion over a period of 15 minutes.12 Fosaprepitant should not be mixed or reconstituted with solutions containing divalent cations (e.g., lactated Ringer's injection, Hartmann's solution).12

For the prevention of cancer chemotherapy-induced nausea and vomiting, fosaprepitant dimeglumine injection should be reconstituted with 5 mL of 0.9% sodium chloride injection.12 The solution should be gently swirled; shaking and jetting saline into the vial should be avoided.12 The entire volume from the vial should be withdrawn aseptically and transferred into an infusion bag containing 110 mL of 0.9% sodium chloride injection, yielding a total volume of 115 mL and a final concentration of 1 mg/mL.12 The solution should be mixed by gentle inversion of the bag 2-3 times.12

Dosage

Dosage of fosaprepitant dimeglumine is expressed in terms of fosaprepitant.12

Cancer Chemotherapy-induced Nausea and Vomiting

Aprepitant is administered orally for 3 days as part of a regimen that includes a 5-HT₃ receptor antagonist and a corticosteroid.1,2,4,16

The recommended oral adult dosage of aprepitant for moderately to highly emetogenic cancer chemotherapy is 125 mg administered 1 hour before chemotherapy on day 1, followed by 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.1,2,4,7,8,9,11

Alternatively, a 115-mg dose of fosaprepitant, infused over 15 minutes and administered 30 minutes prior to chemotherapy, may be substituted for aprepitant 125 mg on day 1 only of the 3-day regimen.1,12

In clinical studies, the aprepitant regimen included 1 or 4 days of ondansetron and dexamethasone for moderately or highly emetogenic chemotherapy, respectively.1,8,9,11 For moderately emetogenic chemotherapy, ondansetron 8 mg was administered orally 30-60 minutes before chemotherapy and repeated 8 hours later on day 1 and dexamethasone 12 mg was administered orally 30 minutes prior to chemotherapy on day 1.1,11 For highly emetogenic chemotherapy, 1,4,8,9 ondansetron 32 mg was administered IV 30 minutes before chemotherapy on day 1.1,4,8,9 Dexamethasone was given orally as 12 mg administered 30 minutes before chemotherapy on day 1, followed by 8 mg once daily in the morning on days 2-4.1,8,9 These are reduced dexamethasone dosages relative to the dosages often used to prevent cancer chemotherapy-induced nausea and vomiting to account for decreased dexamethasone metabolism when aprepitant is used concomitantly.1,4

Postoperative Nausea and Vomiting

The recommended oral adult dosage of aprepitant for the prevention of postoperative nausea and vomiting is 40 mg administered once within 3 hours before anesthesia induction.1,6

Special Populations

No special population dosage recommendations at this time.1,4

Contraindications

Concomitant use of aprepitant or fosaprepitant dimeglumine with astemizole (no longer commercially available in the US), cisapride (currently commercially available in the US only under a limited-access protocol), pimozide, or terfenadine (no longer commercially available in the US).1,2,4,12 (See Drug Interactions: Drugs Metabolized by Hepatic Microsomal Enzymes.)

Known hypersensitivity to aprepitant, fosaprepitant dimeglumine, polysorbate 80, or any ingredient in the formulations.1,2,4,12

Warnings/Precautions

Sensitivity Reactions

Stevens-Johnson syndrome has been reported in one patient receiving aprepitant with antineoplastic agents.1,4 Hypersensitivity reactions, including anaphylaxis, hives, rash, itching, and urticaria, which may be serious and can cause difficulty in breathing or swallowing, have been reported in patients receiving aprepitant or fosaprepitant.1,2,12,17 Angioedema was reported in one patient receiving aprepitant.1,4

General Precautions

Dispensing and Administration Precautions

A potential dispensing error exists because of the similarity in spelling and/or pronunciation of Emend^® (the trade name for aprepitant and fosaprepitant dimeglumine) and Amen^® (a former trade name for medroxyprogesterone acetate; no longer commercially available under this trade name in the US) or Vfend^® (the trade name for voriconazole).5 The manufacturer advises precautionary measures, including removal of Amen^® from the drug database, alerting pharmacy personnel about the potential for error, verifying verbal or telephone orders by spelling the drug name to the prescriber, and confirmation of the patient's understanding of the prescribed drug's purpose and use during patient counseling.5

Specific Populations

Pregnancy

Category B.1,2,4,12 (See Users Guide.)

Lactation

Aprepitant is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.1,2,12 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,12

Gender

In women, peak plasma concentrations of oral aprepitant are 16% higher, and plasma half-life is decreased compared with those reported in men.1 Not considered to be clinically important, and no dosage adjustment is necessary.1

Pediatric Use

Safety and efficacy of fosaprepitant dimeglumine and aprepitant not established in children younger than 18 years of age.1,4,6,12

Geriatric Use

No substantial differences in safety, efficacy, or pharmacokinetics of oral aprepitant relative to younger adults; no dosage adjustment necessary.1,4,12

Hepatic Impairment

Oral aprepitant has not been adequately studied in patients with severe hepatic impairment (Child-Pugh score exceeding 9).1,4,12 No specific dosage adjustment is recommended by the manufacturer, but caution is advised in such patients.1,12 Area under the plasma concentration-time curve (AUC) decreased in patients with mild hepatic impairment, but increased in those with moderate hepatic impairment.1,12 However, these changes were not considered clinically important, and no dosage adjustment is necessary.1,4,12

Fosaprepitant is metabolized by extrahepatic tissue; therefore hepatic insufficiency not expected to alter conversion of fosaprepitant to aprepitant.12

Renal Impairment

Total (protein bound and unbound) aprepitant AUCs and peak plasma concentrations are decreased in patients with severe renal impairment or end-stage renal disease requiring hemodialysis, but AUC of active unbound drug is unaffected.1 No dosage adjustment necessary in such patients.1,4 Hemodialysis had no substantial effect on pharmacokinetics of aprepitant.1,4

Common Adverse Effects

Adverse effects occurring in 3% or more of patients receiving oral aprepitant capsules and more frequently than in those receiving standard therapy include asthenia and/or fatigue, dizziness, hypoesthesia, disorientation, nausea, anorexia, constipation, diarrhea, dyspepsia, heartburn, abdominal pain, epigastric discomfort, stomatitis, gastritis, hiccups, perforating duodenal ulcer, enterocolitis, neutropenia, alopecia, bradycardia, hypotension, hypertension, sinus tachycardia, hot flush, pharyngolaryngeal pain, neutropenic sepsis, pneumonia, pruritus, and dehydration.1,2

Since fosaprepitant dimeglumine for injection is converted into aprepitant, adverse effects associated with aprepitant also may be expected to occur with the injection.12 Adverse effects occurring with IV fosaprepitant dimeglumine include infusion site reactions (e.g., pain, induration) and headache.12,13,16

Because fosaprepitant is rapidly metabolized to aprepitant in vivo, interactions reported with aprepitant are expected to occur with fosaprepitant.12

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of cytochrome P-450 (CYP) 3A4 (CYP3A4) isoenzyme: Potential pharmacokinetic interaction (altered metabolism of CYP3A4 substrates).1,4 Aprepitant is an inhibitor and inducer of CYP3A4 and an inducer of CYP2C9.1,4,12,16 There is evidence that aprepitant-induced CYP3A4 inhibition is dose dependent.1,6 A single 40-mg dose of aprepitant is a weak inhibitor of CYP3A4 and is not expected to have a clinically important effect on plasma concentrations of concomitantly administered drugs that are primarily metabolized by this enzyme. However, when given at higher dosages (i.e., in a regimen consisting of 125 mg on day 1 followed by 80 mg on days 2 and 3) or in repeated doses at any dose level, aprepitant is a moderate inhibitor of CYP3A4, and concomitant administration with drugs metabolized primarily by this enzyme may result in a clinically important effect.1,6,16 Aprepitant (at a dosage level of 125 mg on day 1 followed by 80 mg on days 2 and 3) may increase plasma concentrations of a CYP3A4 substrate to a lesser extent when the substrate is given IV rather than orally.1,6,18 Use with caution; dosage adjustment of concomitantly administered drugs (e.g., dexamethasone) may be necessary.1,4,12 (See Dosage and Administration: Cancer Chemotherapy-induced Nausea and Vomiting and see Drug Interactions: Corticosteroids.) Serious or life-threatening reactions may occur if aprepitant is used concomitantly with astemizole (no longer commercially available in the US), cisapride (currently commercially available in the US only under a limited-access protocol), pimozide, or terfenadine (no longer commercially available in the US).1,2,4

Substrates of CYP2C9: Potential pharmacokinetic interaction (increased metabolism of CYP2C9 substrates [e.g., phenytoin, tolbutamide, S -warfarin] resulting in decreased plasma concentrations).1,4,6,12

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 (e.g., clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin): Potential pharmacokinetic interaction (decreased aprepitant metabolism, resulting in increased plasma aprepitant concentrations).1,4,12 Use with caution.1,4,12,16

Inducers of CYP3A4 (e.g., carbamazepine, phenytoin, rifampin): Potential pharmacokinetic interaction (increased aprepitant metabolism).1,4 Decreased efficacy possible with strong CYP3A4 inducers (e.g., rifampin).1,4,12

Antineoplastic Agents

Potential pharmacokinetic interaction (increased plasma antineoplastic concentrations) with antineoplastic agents that are metabolized by CYP3A4.1,4 Use with caution and careful monitoring.1,4

5-HT3 Receptor Antagonists

Pharmacokinetic interaction unlikely.1,4,12,16

Corticosteroids

Potential pharmacokinetic interaction (increased plasma corticosteroid concentrations) with corticosteroids that are metabolized by CYP3A4 (e.g., dexamethasone, methylprednisolone), particularly when given concomitantly with the 3-day aprepitant regimen (consisting of 125 mg on day 1 followed by 80 mg on days 2 and 3) or with fosaprepitant followed by aprepitant.1,4,12 Decreased dosage of oral and IV corticosteroids may be necessary.1,4,12 The manufacturer of fosaprepitant dimeglumine and aprepitant recommends that dosages of oral dexamethasone and methylprednisolone be reduced by 50% and IV dosage of methylprednisolone be reduced by 25% when these drugs are used concomitantly with fosaprepitant dimeglumine followed by aprepitant, or the 3-day oral aprepitant regimen.1,6,12,16 Because of weak inhibition of CYP3A4 associated with single 40-mg doses of aprepitant, dosage adjustments of corticosteroids are not required when used concomitantly with this aprepitant regimen.1,6

Digoxin

Pharmacokinetic interaction unlikely.1,4,12,16

Diltiazem

Potential pharmacokinetic interaction (increased plasma aprepitant and diltiazem concentrations), but no clinically important changes in ECG, heart rate, or blood pressure were observed in one study with oral aprepitant.1,4,16 The manufacturer recommends caution when aprepitant is used concomitantly with diltiazem.1,12

In studies with fosaprepitant dimeglumine, a small but clinically meaningful decrease in diastolic blood pressure and a small but possibly clinically meaningful decrease in systolic blood pressure were reported.12 However, no clinically important changes in heart rate or PR interval beyond those induced by diltiazem were reported.12

Docetaxel

Pharmacokinetic interaction unlikely when administered with the 3-day aprepitant regimen (consisting of 125 mg on day 1 followed by 80 mg on days 2 and 3).1,6,12

Midazolam

Potential pharmacokinetic interaction (altered plasma midazolam concentrations).1,4 Dosage adjustment for IV midazolam may be necessary when administered concomitantly with the 3-day oral aprepitant regimen.1 Consider the potential effect of increased benzodiazepine plasma concentrations when midazolam is used concomitantly with the 3-day regimen of aprepitant or fosaprepitant followed by aprepitant.1,4,12,16

Increase in plasma midazolam concentrations not considered clinically important when concomitantly administered with a single dose of fosaprepitant 100 mg or aprepitant 40 mg.1,6,12

Oral Contraceptives

Potential pharmacokinetic interaction (decreased plasma steroid concentrations).1,4 Use alternative or additional contraceptive methods during fosaprepitant and aprepitant treatment and for 1 month following the last dose.1,4,6,12,16

Paroxetine

Potential pharmacokinetic interaction (decreased plasma aprepitant and paroxetine concentrations.1,4

Vinorelbine

Pharmacokinetic interaction unlikely when administered with the 3-day aprepitant regimen (consisting of 125 mg on day 1 followed by 80 mg on days 2 and 3).1,12

Warfarin

Potential pharmacokinetic interaction (decreased plasma S -warfarin concentrations).1,4 Monitor prothrombin time closely for 2 weeks (particularly 7-10 days) after initiation of fosaprepitant followed by aprepitant, the 3-day oral aprepitant regimen, or aprepitant 40 mg as a single dose.1,4,6,12,16

Description

Fosaprepitant dimeglumine, a prodrug of aprepitant, is rapidly (within 30 minutes of infusion completion) converted in hepatic and extrahepatic tissues to aprepitant, a selective, high-affinity antagonist at substance P/neurokinin 1 (NK₁) receptors.1,3,4,7,12,13,16 Aprepitant crosses the blood-brain barrier and occupies NK₁ receptors in the brain.1,3,4 The drug acts in the CNS to inhibit emesis induced by cytotoxic chemotherapy, including both the acute and delayed emesis induced by cisplatin therapy.1,3,4 Studies indicate that aprepitant augments the antiemetic activity of ondansetron and dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.1,3,4

Aprepitant is extensively metabolized to weakly active metabolites by the cytochrome P-450 (CYP) enzyme system, principally by CYP3A4, and to a lesser extent by CYP1A2 and CYP2C19.1,16 Aprepitant is both a moderate inhibitor and an inducer of CYP3A4;1,4 the drug also is an inducer of CYP2C9.1,4

Advice to Patients

Importance of reading the fosaprepitant and aprepitant patient information provided by the manufacturer before beginning therapy and rereading each time the prescription is renewed.1,2,12

Importance of using fosaprepitant and aprepitant only as directed by the clinician.1,2,12

Advise patients that aprepitant may be taken with or without food.2

Importance of taking first oral aprepitant (125-mg) dose 1 hour before initiation of antineoplastic chemotherapy.1,2

Importance of taking aprepitant (40-mg) dose within 3 hours prior to induction of anesthesia for prevention of postoperative nausea and vomiting.1

Importance of discontinuing aprepitant and promptly contacting a clinician if symptoms of an allergic reaction occur.2,12,17

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,2 Importance of women using alternative or additional contraceptive methods during fosaprepitant or aprepitant use (and for 1 month after last dose) if oral contraceptives are being taken.1,2,12

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products.1,2,12 Importance of closely monitoring prothrombin time in patients receiving chronic warfarin therapy during the 2 weeks (particularly 7-10 days) after initiation of the 3-day regimen of fosaprepitant followed by aprepitant or the 3-day oral aprepitant regimen for each antineoplastic chemotherapy cycle, or administration of aprepitant for prevention of postoperative emesis.1,2,12

Importance of informing patients of other important precautionary information.1,12 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Merck. Emend^® (aprepitant) capsules prescribing information. Whitehouse Station, NJ; 2008 Apr.

2. Merck. Emend (aprepitant) capsules patient information. Whitehouse Station, NJ; 2008Apr.

3. Sorbera LA, Castaner J, Bayes M at al. Aprepitant and L-758298. Drugs Fut . 2002; 27:211-22.

4. Merck. Emend^® (aprepitant) product information form for the American Hospital Formulary Service. 2003.

5. Merck. Dear pharmacist letter regarding Emend^® (aprepitant). 2003 Apr.

6. Merck, Whitehouse Station, NJ: Personal communication.

7. 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. [PubMed 16717289]

8. Hesketh PJ, Grunberg SM, Gralla RJ et al. 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. [PubMed 14559886]

9. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer . 2003; 97:3090-8. [PubMed 12784346]

11. Warr DG, Hesketh PJ, Gralla RJ. et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol . 2005; 23:2822-30. [PubMed 15837996]

12. Merck. Emend^® (fosaprepitant dimeglumine) for injection prescribing information. Whitehouse Station, NJ; 2009 Feb.

13. Lasseter KC, Gambale J, Jin B et al. Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects. J Clin Pharmacol . 2007; 47:834-40. [PubMed 17525168]

14. Diemunsch P, Gan TJ, Philip BK et al. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind Phase III trial in patients undergoing open abdominal surgery. Br J Anesth . 2007; 99:202-11.

15. Gan TJ, Apfel CC, Kovac A et al. A randomized, double-blind comparison of the NK₁ antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Anal . 2007; 104:1082-9.

16. Navari RM. Fosaprepitant (MK-0517): a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Opin. Investig. Drugs . 2007; 16:1977-85.

17. Merck. Emend (fosaprepitant dimeglumine) for injection patient information. Whitehouse Station, NJ; 2009 Feb.

18. Merck., Whitehouse Station, NJ: Personal communication.

19. Basch E, Prestrud AA, Hesketh PJ et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol . 2011; 29:4189-98. [PubMed 21947834][PubMedCentral]

20. Hesketh PJ, Bohlke K, Lyman GH et al. Antiemetics: American Society of Clinical Oncology focused guideline update. J Clin Oncol . 2016; 34:381-6. [PubMed 26527784]