drug-monograph

aprepitant / fosaprepitant

Other Names

Emend®, Emend® IV

Appearance

Aprepitant- Capsules (days 1 to 3) in various strengths

Fosaprepitant- Clear, colourless solution for injection (day 1 only)

Funding Program

ODB Limited Use

A - Drug Name

aprepitant / fosaprepitant

SYNONYM(S): Aprepitant: L-754030, MK-0869, MK-869; Fosaprepitant: MK-0517, L-785298

COMMON TRADE NAME(S): Emend®, Emend IV®

B - Mechanism of Action and Pharmacokinetics

Fosaprepitant is a prodrug of aprepitant. Aprepitant competitively binds with high affinity to the neurokinin-1 (NK₁) receptors in the brain, blocking the effect of substance P in the CNS. The relation between the clinical action of aprepitant and occupancy of NK₁ receptor is unclear. NK₁-receptor antagonists inhibit both the acute and delayed phases of cisplatin-induced emesis, and enhance the antiemetic efficacy of ondansetron (5HT3 receptor antagonist) and dexamethasone (corticosteroid).

Pivotal efficacy studies were conducted with oral aprepitant, while follow-up studies demonstrated non-inferiority for a single dose of parenteral (150mg) fosaprepitant. Clinical trials of highly emetogenic regimen used ondansetron 32mg IV which is no longer a recommended dose. For fosaprepitant, efficacy results from highly emetogenic chemotherapy were extrapolated to the moderately emetogenic chemotherapy setting.

Absorption

Oral: Yes (60 to 65%); not affected by food (aprepitant)

Distribution

Pharmacokinetics of aprepitant are non-linear and more than dose-proportional across the clinical dose range of 80mg to 125mg. Mean peak plasma concentration of aprepitant was reached at approximately 4 hours. A higher Cmax (2.6 fold) was observed with fosaprepitant 150mg as compared to oral aprepitant 125mg.

Cross blood brain barrier?

Yes (aprepitant)

PPB

> 95% (aprepitant)

Metabolism

Fosaprepitant is converted to aprepitant rapidly, within 30 minutes after the end of the infusion, in the liver or in extrahepatic tissues. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1.

Active metabolites

Yes (aprepitant: 7 weakly active metabolites)

Inactive metabolites

Unknown

Inducer of

CYP3A4 and CYP2C9 (by aprepitant)

Inhibitor of

CYP3A4 (by aprepitant – moderate; fosaprepitant single dose - weak)

Elimination

Aprepitant is eliminated primarily by metabolism. It is not renally excreted.

Half-life

(terminal) 9-13 hours (aprepitant)

Feces

86% of dose

C - Indications and Status

Health Canada Approvals:

In combination with a 5-HT₃ antagonist and dexamethasone:

for the prevention of acute and delayed nausea and vomiting due to highly emetogenic cancer chemotherapy
for the prevention of nausea and vomiting in women due to treatment with moderately emetogenic cancer chemotherapy

D - Adverse Effects

Emetogenic Potential:

Not applicable

Extravasation Potential: Irritant

Adverse effects noted below are from controlled clinical trials of aprepitant in combination with emetogenic chemotherapy, where the incidence in the aprepitant combination arm was higher (usually ≥1%) than the standard arm in at least one trial.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arrhythmia (rare)	E
	Arterial thromboembolism (rare)	E
	Hypertension (<1%)	E
	Hypotension (rare)	E
	Venous thromboembolism (rare)	E
Dermatological	Rash (may be severe)	E
Gastrointestinal	Abdominal pain (4%)	E
	Anorexia (12%)	E
	Constipation (11%)	E
	Diarrhea (10%)	E
	Dyspepsia (8%)	E
	GI perforation (perforated ulcer - rare)	E
	Nausea, vomiting (13%)	E
General	Fatigue (10%)	E
Hepatobiliary	↑ LFTs (6%)	E
Hypersensitivity	Hypersensitivity (3-4%)	I
Injection site	Injection site reaction (3%) (IV only)	I E
Metabolic / Endocrine	Hyperglycemia (diabetes - rare)	E
Musculoskeletal	Musculoskeletal pain (rare)	E
Nervous System	Cognitive disturbance (rare)	E
	Depression (rare)	E
	Dizziness (6%)	E
	Dysgeusia (rare)	E
	Neuropathy (peripheral; rare)	E
Ophthalmic	Conjunctivitis	E
Renal	Nephrotoxicity (rare)	E
	Proteinuria (6%)	E
Respiratory	Cough (rare)	E
	Dyspnea (rare)	E
	Hiccups (11%)	E
	Pneumonitis (rare)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The most common side effects for aprepitant / fosaprepitant include anorexia, nausea/vomiting (after day 5), constipation, diarrhea and hiccups.

Fosaprepitant has higher incidences of infusion site reactions, hypertension, ↑ ALT (>5x ULN) and hypersensitivity reactions when compared to aprepitant.

Serious adverse events may be more frequent in patients receiving aprepitant when CYP3A4 metabolized drugs are coadministered, including neurotoxicity with ifosfamide. (See Interactions).

A single fosaprepitant dose of 200mg had no effect on the QTc interval.

E - Dosing

Refer to protocol by which patient is being treated.

Adults:

Aprepitant / fosaprepitant must be given in combination with other antiemetic agents (corticosteroid, 5HT3 antagonist). Doses of corticosteroids, both oral and IV, need to be adjusted.

Aprepitant:
Oral: 125 mg 1 hour prior to chemotherapy treatment (Day 1)

and 80 mg once daily in the morning on Days 2 and 3.

A maximum of 3 consecutive days may be used per cycle.

Highly emetogenic regimens:

	Day 1	Day 2	Day 3	Day 4
Aprepitant	125 mg PO 1 hr pre-chemo	80 mg PO QAM	80 mg PO QAM	None
Dexamethasone*	12mg PO 30 min pre-chemo	8 mg PO QAM	8mg PO QAM	8mg PO QAM
5HT₃antagonist	Refer to product monograph for selected 5HT₃ antagonist.	None	None	None

_{*The dose of dexamethasone was amended due to drug interactions. Increasing the dose of dexamethasone is not recommended.}

Moderately emetogenic regimens:

	Day 1	Day 2	Day 3
Aprepitant	125 mg PO 1 hr pre-chemo	80 mg PO QAM	80 mg PO QAM
Dexamethasone*	12mg PO 30min pre-chemo	None	None
5HT₃ antagonist	Refer to product monograph for selected 5HT₃ antagonist.	None	None

_{*The dose of dexamethasone was amended due to drug interactions. Increasing the dose of dexamethasone is not recommended.}

Fosaprepitant:
Intravenous: 150 mg 30 minutes prior to chemotherapy (Day 1) ONLY

Highly Emetogenic Regimens:

	Day 1	Day 2	Day 3	Day 4
Fosaprepitant	150 mg IV 30 min pre-chemo	None	None	None
Dexamethasone*	12mg PO 30 min pre-chemo	8 mg PO QAM	8mg PO bid	8mg PO bid
5HT₃ antagonist	Refer to product monograph for selected 5HT₃ antagonist.	None	None	None

Moderately Emetogenic Regimens:

	Day 1 Only
Fosaprepitant	150 mg IV 30 min pre-chemo
Dexamethasone*	12mg PO 30 min pre-chemo
5HT₃ antagonist	Refer to product monograph for the selected 5HT₃ antagonist.

_{*The dose of dexamethasone was amended due to drug interactions on days 1 and 2. Increasing the dose of dexamethasone is not recommended.}

Dosage with Toxicity:

Hypersensitivity reactions: Discontinue aprepitant/fosaprepitant permanently and treat appropriately.

Dosage with Hepatic Impairment:

No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency (Child-Pugh score 5 to 9). There is no clinical data in patients with severe hepatic insufficiency (Child-Pugh score >9) and aprepitant should be used with caution in these patients.

Dosage with Renal Impairment:

No dosage adjustment is necessary. Aprepitant cannot be removed by hemodialysis.

Dosage in the elderly:

No dose adjustment is required.

Dosage based on gender:

No dose adjustment needed.

Dosage based on ethnicity:

No dose adjustment needed. No dosage adjustment needed based on BMI.

Children:

Safety and effectiveness in children have not been evaluated.

F - Administration Guidelines

Aprepitant:

Prescribed dose should be swallowed whole, once daily with or without food.
Store at room temperature in the original package.

Fosaprepitant:

Use normal saline for reconstitution and further dilution as directed. Swirl vial gently to prevent foaming. Final concentration should be approximately 1 mg/mL.
Infuse IV over 20-30 minutes, 30 minutes before chemotherapy.
Incompatible with any solutions containing divalent cations (e.g. Ca, Mg), including Lactated Ringer’s and Hartman’s solution
Unopened vials should be refrigerated (2-8°C)

G - Special Precautions

Contraindications:

Contraindicated when used with terfenadine, astemizole or cisapride, pimozide. Concurrent use may result in life-threatening reactions. (see Interactions)

Contraindicated in patients with a known hypersensitivity to aprepitant/fosaprepitant, polysorbate 80 or any ingredients in the formulation.
Fosaprepitant contains lactose and should not be used in patients with hereditary lactose or glucose/galactose disorders.

Other Warnings/Precautions:

Do not use aprepitant/fosaprepitant alone as efficacy was demonstrated in combination with other antiemetics
Use of aprepitant/fosaprepitant beyond the recommended duration is not recommended; no data are available, and the drug interaction profile may change on chronic dosing.

Other Drug Properties:

Carcinogenicity: No

Pregnancy and Lactation:

Fertility effects: No
Fetotoxicity: No
Excretion into breast milk: Documented in animals
- Aprepitant use is not recommended in pregnancy as placental transfer of this drug occurred in animals.
- Adequate (alternative/back-up) contraception must be used during treatment and for one month after the last dose (see Interactions – hormonal agents may be ineffective)

H - Interactions

The following information is derived from drug interaction studies with aprepitant, except for dexamethasone, diltiazem or midazolam (studied with both aprepitant and fosaprepitant). Similar interactions are expected with fosaprepitant, although the risk of interaction is higher with orally administered drugs than intravenous drugs.

Clinical studies suggest no clinically significant pharmacokinetic interactions with PO granisetron, IV ondansetron, PO dolasetron, docetaxel or vinorelbine. Fosaprepitant/ aprepitant appeared unlikely to interact with p-glycoprotein substrates.

AGENT	EFFECT	MECHANISM	MANAGEMENT
CYP3A4 substrates (e.g., dexamethasone, methylprednisolone, midazolam, alprazolam, etoposide, paclitaxel, vinblastine, vincristine, ifosfamide, imatinib, irinotecan)	may ↑/↓ effects of the CYP3A4 substrates; severe neurotoxicityhas been reported with ifosfamide	aprepitant is a moderate inhibitor and inducer of CYP3A4, may ↑/↓ plasma levels of CYP3A4 substrates. Fosaprepitant is a mild CYP3A4 inhibitor	Use with caution and monitor; may need to adjust dose of CYP3A4 substrates (e.g., ↓ oral dose of dexamethasone or methylprednisolone by 50%, and IV methylprednisolone by 25%)
Pimozide, astemizole, terfenadine, cisapride (CYP3A4 substrates)	↑ effect of these CYP3A4 substrates, leading to life-threatening arrhythmia	↓ metabolism lead to ↑ plasma levels of these CYP3A4 substrates	CONTRAINDICATED (see Special Precautions)
CYP 2C9 substrates (e.g., warfarin, tolbutamide, phenytoin)	↓ effect of CYP 2C9 substrates	aprepitant is a CYP2C9 inducer, may ↓ plasma levels of CYP2C9 substrates	Avoid concomitant use. If must use, monitor very closely
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit)	may ↑ aprepitant effect	↓ metabolism of aprepitant, a CYP3A4 substrate	Caution
diltiazem (moderate CYP3A4 inhibitor and substrate)	may ↑ effects of aprepitant and diltiazem	↑ plasma levels of aprepitant and diltiazem	Caution
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc)	may ↓ aprepitant effect	↑ metabolism of aprepitant, a CYP3A4 substrate	Caution
Hormone contraceptives with all routes of administration	may ↓ efficacy of hormonal contraceptives	↓ plasma levels of hormones	Alternative or backup methods of contraception should be used during aprepitant/fosaprepitant treatment and for one month following the last dose
Paroxetine	may ↓ effects of aprepitant and paroxetine	↓ plasma levels of both aprepitant and paroxetine	Caution

I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
Monitor drug-drug interactions.
Monitor drug levels (e.g., phenytoin).
INR; frequent for patients on warfarin - for 2 weeks after each 3-day cycle
Clinical toxicity assessment for GI symptoms, local toxicity, hypersensitivity reactions and respiratory effects	regular

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Supplementary Public Funding

ODB Limited Use (ODB Formulary )

aprepitant: In combination with a 5HT3 receptor antagonist and dexamethasone for highly emetogenic chemotherapy (HEC) regimens ()
aprepitant: For patients receiving moderately emetogenic chemotherapy (MEC) regimens AND who have had inadequate symptom control using a 5HT3 antagonist and dexamethasone in a previous cycle. ()

K - References

1. Product Monograph: Emend® IV (fosaprepitant). Merck Frosst Canada, Jan 22, 2014..
2. Product Monograph: Emend® (aprepitant). Merck Frosst Canada, Jan 22, 2014..
3. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol—EASE. J Clin Oncol 2011; 29: 1495-501.
4. Dando TM, Perry CM. Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs 2004; 64(7): 777-794.
5. Howell JE1, Szabatura AH, Hatfield Seung A. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract. 2008 Sep;14(3):157-62.

May 2020 archived

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

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Last Updated: July 27, 2026

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