Aprepitant

A04A - Antiemetics and antinauseants ATC A04AD12 Small molecule approved 2003 Oral Parenteral First-in-class

JFDA label: Emend

Mechanism of Action

Antagonist of Substance-P receptor — Neurokinin 1 receptor antagonist

Target	Action	Gene / class
Substance-P receptor efficacy	ANTAGONIST	TACR1

Indications

Approved

IV (Cinvanti)
Oral(Emend oral)
Postoperative nausea and vomiting
Prevention of chemotherapy-induced nausea and vomiting

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Concurrent use with astemizole, cisapride, or terfenadine Absolute
Hypersensitivity to aprepitant or any component of the formulation Absolute
concurrent use with pimozide Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Very Common bradycardia, dizziness, alopecia, decreased serum albumin, diarrhea, dyspepsia, abdominal pain, hiccups, decreased appetite, decreased white blood cell count, anemia, increased serum alkaline phosphat · Hypotension

Nervous system disorders (1)

Very Common Fatigue

Blood and lymphatic system disorders (1)

Very Common Neutropenia (children & adolescents: 13%; adults: 1% to 10%:

Musculoskeletal and connective tissue disorders (2)

Very Common musculoskeletal pain (Renal: Increased blood urea nitrogen (Respiratory: Cough (Miscellaneous: Wound dehiscence (PONV: · Weakness

Dosing

Source: Lexicomp

Note: Dosing is for aprepitant (Emend Oral and Cinvanti IV); refer to the fosaprepitant monograph for Emend IV dosing. Prevention of chemotherapy-induced nausea and vomiting: Manufacturer's labeling: Prevention of acute and delayed nausea/vomiting associated with highly-emetogenic chemotherapy: IV: 130 mg ~30 minutes prior to chemotherapy on day 1 (in combination with a 5-HT3 antagonist antiemetic on day 1 only and oral dexamethasone on days 1 to 4). Oral: Capsules: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic on day 1 and dexamethasone on days 1 to 4) Suspension: Adults unable to swallow capsules: 3 mg/kg (maximum: 125 mg/dose) 1 hour prior to chemotherapy on day 1, followed by 2 mg/kg (maximum: 80 mg/dose) once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic on day 1 and dexamethasone on days 1 to 4) Prevention of nausea/vomiting associated with moderately-emetogenic chemotherapy: IV: 100 mg ~30 minutes prior to chemotherapy on day 1 (in combination with oral aprepitant 80 mg on days 2 and 3, a 5-HT3 antagonist antiemetic on day 1 only and dexamethasone on day 1 only). Oral: Capsules: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic and dexamethasone on day 1) Suspension: Adults unable to swallow capsules: 3 mg/kg (maximum: 125 mg/dose) 1 hour prior to chemotherapy on day 1, followed by 2 mg/kg (maximum: 80 mg/dose) once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic and dexamethasone on day 1) Guideline recommendations: Prevention of nausea/vomiting associated with highly-emetogenic chemotherapy (including anthracycline and cyclophosphamide [AC] regimens): Oral: American Society of Clinical Oncology (ASCO [Hesketh 2017]): 125 mg prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic on day 1 and dexamethasone on days 1 to 4 or days 1 to 3) Multinational Association of Supportive Care in Cancer and European Society of Medical Oncology (MASCC/ESMO [Roila 2016]): 125 mg prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with dexamethasone and a 5-HT3 antagonist antiemetic on day 1, followed by dexamethasone for 3 to 4 more days Prevention of postoperative nausea and vomiting (PONV): Oral: 40 mg within 3 hours prior to anesthesia induction

(For additional information see "Aprepitant: Pediatric drug information") Manufacturer's labeling: Prevention of acute and delayed nausea and vomiting associated with highly-emetogenic chemotherapy: Capsules: Children ≥12 years, and Adolescents: Oral: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic on day 1 and dexamethasone on days 1 to 4 [reduce dexamethasone dose to 50% of recommended dose]) Suspension: Infants ≥6 months (and ≥6 kg), Children 3 antagonist antiemetic on day 1 and dexamethasone on days 1 to 4 [reduce dexamethasone dose to 50% of recommended dose]) Prevention of nausea and vomiting associated with moderately-emetogenic chemotherapy: Capsules: Children ≥12 years, and Adolescents: Oral: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT3 antagonist antiemetic and dexamethasone on day 1 [reduce dexamethasone dose to 50% of recommended dose]) Suspension: Infants ≥6 months (and ≥6 kg), Children 3 antagonist antiemetic and dexamethasone on day 1 [reduce dexamethasone dose to 50% of recommended dose]) Pediatric Oncology Group of Ontario (POGO) guidelines: Recommended antiemetic regimen combinations in pediatric patients ≥6 months receiving chemotherapy agents that do not potentially interact with aprepitant (Dupuis 2013; Patel 2017): High emetogenic risk: Aprepitant (oral), plus ondansetron or granisetron or palonosetron, plus dexamethasone. High emetogenic risk and cannot receive corticosteroids (due to contraindications): Aprepitant (oral) plus palonosetron. Moderate emetogenic risk and cannot receive corticosteroids (due to contraindications): Aprepitant (oral) plus ondansetron or granisetron or palonosetron. Infants ≥6 months, Children, and Adolescents: Oral: 3 mg/kg (maximum dose: 125 mg) on day 1 prior to chemotherapy, followed by 2 mg/kg (maximum dose: 80 mg) once daily on days 2 and 3.

Refer to adult dosing.

No dosage adjustment necessary. ESRD undergoing dialysis: No dosage adjustment necessary. Aprepitant is not removed by hemodialysis (

Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): Use with caution; no data available; may require additional monitoring for adverse reactions.

Warnings & Precautions

Source: Lexicomp

Hypersensitivity

Hypersensitivity reactions, including anaphylactic reactions, have been reported with fosaprepitant or oral aprepitant. Symptoms have included flushing, erythema, dyspnea, hypotension, and syncope. Monitor for hypersensitivity reaction during and following infusion; if a reaction occurs, discontinue infusion and manage appropriately. Do not re-initiate aprepitant IV if hypersensitivity symptoms occur during the initial infusion. Disease-related concerns:

Hepatic impairment

Use with caution in patients with severe hepatic impairment (Child-Pugh class C); has not been studied. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. A clinically significant decrease in INR or prothrombin time (PT) may occur with concurrent warfarin therapy; monitor INR/PT for 2 weeks (particularly at 7 to 10 days) following aprepitant administration in each chemotherapy cycle. Special populations:

Pediatrics

For prevention of chemotherapy-induced nausea and vomiting, use is not recommended in pediatric patients weighing Dosage form specific issues:

Aprepitant IV

The IV aprepitant formulation is an emulsion which also contains the excipients alcohol, egg lecithin, soybean oil, and sucrose.

Pregnancy & Lactation

Pregnancy

Adverse events were not observed in animal reproduction studies. The injection formulation contains ethanol; use should be avoided in females who are pregnant. Efficacy of hormonal contraceptive may be reduced during and for 28 days following the last aprepitant dose; alternative or additional effective methods of contraception should be used both during treatment with fosaprepitant or aprepitant and for at least 1 month following the last fosaprepitant/aprepitant dose.

Lactation

It is not known if aprepitant is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. The injection formulation contains ethanol.

Monitoring

Clinical pearl	In patients receiving concurrent warfarin, monitor INR/PT for 2 weeks (particularly at 7 to 10 days) following aprepitant administration; monitor for signs/symptoms of hypersensitivity reaction.

Chemistry & Properties

Formula	C23H21F7N4O3
Molecular weight	534.43 g/mol
IUPAC name	3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,4-dihydro-1,2,4-triazol-5-one
CAS	170729-80-3
PubChem CID	135413536
InChIKey	`ATALOFNDEOCMKK-OITMNORJSA-N`
logP	4.95 (XLogP 4.2)
Polar surface area	83.24 Å²
H-bond acceptors / donors	5 / 2
Drug-likeness (QED)	0.44
Lipinski violations	1

SMILES

C[C@@H](O[C@H]1OCCN(Cc2n[nH]c(=O)[nH]2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP3A4	Inhibitor	IC₅₀ 0.024629860647679767 µM
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
NK1 receptor (TACR1)	Antagonist	pKi 10.1

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acalabrutinib	major
Alfentanil	major
Astemizole	major
Avanafil	major
Avapritinib	major
Benzhydrocodone	major
Bosutinib	major
Brexpiprazole	major
Brigatinib	major
Butorphanol	major
Cilostazol	major
Cisapride	major
Cobimetinib	major
Colchicine	major
Deflazacort	major
Eliglustat	major
Encorafenib	major
Entrectinib	major
Eplerenone	major
Everolimus	major
Fentanyl	major
Flibanserin	major
Guanfacine	major
Halofantrine	major
Hydrocodone	major
Ibrutinib	major
Ivabradine	major
Ivacaftor	major
Ivosidenib	major
Lemborexant	major
Levacetylmethadol	major
Lomitapide	major
Lonafarnib	major
Lumateperone	major
Lurasidone	major
Lurbinectedin	major
Naloxegol	major
Neratinib	major
Olaparib	major
Oliceridine	major

Showing 40 of 100+.

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Emend combo	Capsule 1 Cap (125 mg) + 2 Cap (80 mg)	2 cap	Adatco Drug Store	—
Enevom 125mg Hard capsules	Capsule 125 mg	1 cap	MS PHARMA/JORDAN	—
Enevom 80mg & 125mg Hard capsules(80mg(2caps)+125mg(1cap)	Capsule 80+125 mg/1BOX	3 cap	ms pahrma - Jordan	—
Enevom 80mg Hard capsules	Capsule 80 mg	1 cap	ms pahrma - Jordan	—