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Aprepitant

Pronunciation

(ap RE pi tant)

Index Terms

  • L 754030
  • MK 869

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Emend: 40 mg, 80 mg, 125 mg, 80 mg & 125 mg

Brand Names: U.S.

  • Emend

Pharmacologic Category

  • Antiemetic
  • Substance P/Neurokinin 1 Receptor Antagonist

Pharmacology

Prevents acute and delayed vomiting by inhibiting the substance P/neurokinin 1 (NK1) receptor; augments the antiemetic activity of 5-HT3 receptor antagonists and corticosteroids to inhibit acute and delayed phases of chemotherapy-induced emesis.

Distribution

Vd: ~70 L; crosses the blood-brain barrier

Metabolism

Extensively hepatic via CYP3A4 (major); CYP1A2 and CYP2C19 (minor); forms 7 metabolites (weakly active)

Excretion

Primarily via metabolism

Time to Peak

Plasma: Pediatric: Capsule: ~4 hours; Suspension ~6 hours; Adults: 40 mg: ~3 hours; 125 mg followed by 80 mg for 2 days: ~4 hours

Half-Life Elimination

Terminal: ~9 to 13 hours

Protein Binding

>95%

Special Populations: Renal Function Impairment

Following a single oral aprepitant 240 mg dose in patients with severe renal impairment (CrCl <30 mL/minute) and end stage renal disease requiring hemodialysis, the AUC of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32% compared with healthy subjects. In patients with ESRD undergoing hemodialysis, the AUC of total aprepitant decreased by 42% and Cmax decreased by 32%. Hemodialysis conducted 4 or 48 hours after aprepitant dosing had no significant impact on aprepitant pharmacokinetics.

Special Populations: Hepatic Function Impairment

Following oral administration of aprepitant 125 mg on day 1 and 80 mg once daily on days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC of aprepitant was 11% lower on day 1 and 36% lower on day 3 compared with healthy subjects; in patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of aprepitant was 10% higher on day 1 and 18% higher on day 3. These differences are not considered clinically meaningful.

Special Populations: Elderly

Following oral administration of aprepitant 125 mg on day 1 and 80 mg once daily on days 2 through 5, the AUC of aprepitant was 21% higher on day 1 and 36% higher on day 5; the Cmax was 10% higher on day 1 and 24% higher on day 5. These differences are not considered clinically meaningful.

Special Populations: Gender

Following a single oral aprepitant dose ranging from 40 to 375 mg, the AUC was 14% higher and the Cmax was 22% higher in women (compared to males); the half-life of aprepitant is 25% lower in females; the Tmax occurs at approximately the same time. These differences are not considered clinically meaningful.

Special Populations: Race

Following a single oral aprepitant dose ranging from 40 to 375 mg, the AUC of aprepitant was ~42% higher and the Cmax was ~29% higher in Hispanic patients compared to Caucasians (there was no difference in AUC and Cmax between Black patients and Caucasians). The AUC of aprepitant was ~62% higher and the Cmax was ~41% higher in Asian patients compared to Caucasians. These differences are not considered clinically meaningful.

Special Populations Note

Obesity: In patients with BMI ranging from 18 to 36 kg/m2, for every 5 kg/m2 increase in BMI, the AUC and Cmax of aprepitant decreased by 11%. These differences are not considered clinically meaningful.

Use: Labeled Indications

Prevention of chemotherapy-induced nausea and vomiting:

Prevention of acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy (initial and repeat courses; in combination with other antiemetics) in patients ≥12 years (capsules) and in patients ≥6 months (oral suspension).

Prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (initial and repeat courses; in combination with other antiemetics) in patients ≥12 years (capsules) and in patients ≥6 months (oral suspension).

Postoperative nausea and vomiting: Prevention of postoperative nausea and vomiting (PONV) in adults.

Limitations of use: Aprepitant has not been studied for the management of existing nausea and vomiting. Chronic, continuous administration is not recommended (has not been studied and chronic use may alter aprepitant’s drug interaction profile).

Contraindications

Hypersensitivity to aprepitant or any component of the formulation; concurrent use with pimozide

Canadian labeling: Additional contraindications (not in US labeling): Concurrent use with astemizole, cisapride, or terfenadine.

Dosing: Adult

Prevention of chemotherapy-induced nausea/vomiting:

Manufacturer's labeling:

Prevention of acute and delayed nausea/vomiting associated with highly-emetogenic chemotherapy:

Capsules: 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)

Suspension: Adults unable to swallow capsules: Oral: 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:

Capsules: 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)

Suspension: Adults unable to swallow capsules: Oral: 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; Basch, 2011): 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 (MASCC) and European Society of Medical Oncology (ESMO) (Roila, 2010): 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 day 1 only [AC regimen])

Prevention of postoperative nausea/vomiting (PONV): Oral: 40 mg within 3 hours prior to anesthesia induction

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Manufacturer's labeling:

Prevention of acute and delayed nausea/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 <12 years (and ≥6 kg) and patients (any age and ≥6 kg) unable to swallow capsules: Oral: 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 [reduce dexamethasone dose to 50% of recommended dose])

Prevention of nausea/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 <12 years (and ≥6 kg) and patients (any age and ≥6 kg) unable to swallow capsules: Oral: 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 [reduce dexamethasone dose to 50% of recommended dose])

Pediatric guideline recommendations: Prevention of nausea/vomiting associated with highly-emetogenic chemotherapy: Pediatric Oncology Group of Ontario (POGO): Children ≥12 years and Adolescents: Oral: 125 mg prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (Dupuis 2013). The antiemetic regimen also includes a 5-HT3 antagonist and dexamethasone.

Dosing: Renal Impairment

No dosage adjustment necessary.

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

Dosing: Hepatic Impairment

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.

Reconstitution

Suspension: Aprepitant for oral suspension is packaged as a kit, with a 1 mL and a 5 mL oral dosing dispenser, one cap, one mixing cup, and the aprepitant pouch. Fill mixing cup with room temperature drinking water, using the 5 mL dosing dispenser, measure 4.6 mL of water from the mixing cup and discard unused water from cup. Add the 4.6 mL water back to the empty cup. Shake content of aprepitant pouch to bottom of pouch and pour entire contents of pouch into mixing cup, add lid and snap shut. Mix suspension by gently swirling 20 times, then gently invert cup 5 times (to avoid foaming, do not shake vigorously). This results in a 25 mg/mL cloudy pink to light pink suspension. If clumps are present, repeat mixing by gently swirling 20 times and gently inverting 5 times. If foam is present, wait for foam to disappear. Measure calculated dose into oral dosing dispenser (use the 1 mL dispenser if dose is ≤1 mL and the 5 mL dispenser if dose is >1 mL). If dose is <1 mL, round to nearest 0.1 mL; if dose is >1 mL, round to the nearest 0.2 mL. Make sure all air is removed from dispenser and dispenser contains the prescribed dose. Place cap on dispenser until it clicks. Discard mixing cup and any suspension remaining in cup. Refer to manufacturer's instructions for further preparation details.

Extemporaneously Prepared

A 20 mg/mL oral aprepitant suspension may be prepared with capsules and a 1:1 combination of Ora-Sweet and Ora-Plus (or Ora-Blend). Empty the contents of four 125 mg capsules into a mortar and reduce to a fine powder (process will take 10-15 minutes). Add small portions of vehicle and mix to a uniform paste. Add sufficient vehicle to form a liquid; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 25 mL. Label "shake well" and "refrigerate". Stable for 90 days refrigerated.

Dupuis LL, Lingertat-Walsh K, and Walker SE, "Stability of an Extemporaneous Oral Liquid Aprepitant Formulation," Support Care Cancer, 2009, 17(6):701-6.19043742

A suspension for oral administration is commercially available.

Administration

Capsules: Swallow whole.

Prevention of chemotherapy-induced nausea/vomiting: Administer with or without food. First dose should be given 1 hour prior to chemotherapy; subsequent doses should be given 1 hour prior to chemotherapy or in the morning (if no chemotherapy is administered on days 2 and 3).

Oral suspension: Dose should be prepared by a health care provider and dispensed to patient or caregiver in an oral dispenser. Administer by placing the dispenser in the patient’s mouth along the inner cheek and slowly dispensing the medicine.

Prevention of postoperative nausea/vomiting: Administer within 3 hours prior to induction; follow health care provider instructions about food/drink restrictions prior to surgery.

Storage

Capsules: Store at room temperature of 20°C to 25°C (68°F to 77°F).

Oral suspension: Store unopened pouch at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Store in the original container. Do not open pouch until ready to use. Once prepared, if suspension is not used immediately, store refrigerated (between [2°C to 8°C/36°F to 46°F]) for up to 72 hours. When ready to use, the mixture may be kept at room temperature (between [20°C to 25°C/68°F to 77°F]) for up to 3 hours.

Drug Interactions

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Astemizole: Aprepitant may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cisapride: Aprepitant may increase the serum concentration of Cisapride. Avoid combination

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Contraceptives (Estrogens): Aprepitant may decrease the serum concentration of Contraceptives (Estrogens). Management: Use of a non-hormone-based contraceptive is recommended. Consider therapy modification

Contraceptives (Progestins): Aprepitant may decrease the serum concentration of Contraceptives (Progestins). Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification

Corticosteroids (Systemic): Aprepitant may increase the serum concentration of Corticosteroids (Systemic). Management: No dose adjustment is needed for single 40 mg aprepitant doses. For other regimens, reduce oral dexamethasone or methylprednisolone doses by 50%, and IV methylprednisolone doses by 25%. Antiemetic regimens containing dexamethasone reflect this adjustment. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inducers (Strong) may increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Aprepitant. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Aprepitant. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Aprepitant. Avoid combination

CYP3A4 Substrates: Aprepitant may increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diclofenac (Systemic): CYP2C9 Inducers (Strong) may decrease the serum concentration of Diclofenac (Systemic). Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Canadian labeling recommends an initial 50% reduction in guanfacine dose with further dose titration as needed. However, US labeling does not call for any specific guanfacine dose reduction with this combination. Monitor therapy

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: Aprepitant may increase the serum concentration of Ifosfamide. Specifically, concentrations of the toxic metabolites of ifosfamide may increase. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PARoxetine: May decrease the serum concentration of Aprepitant. Aprepitant may decrease the serum concentration of PARoxetine. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Aprepitant may increase the serum concentration of Pimozide. Avoid combination

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Sirolimus: Aprepitant may increase the serum concentration of Sirolimus. Monitor therapy

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Terfenadine: Aprepitant may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

TOLBUTamide: Aprepitant may decrease the serum concentration of TOLBUTamide. Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Warfarin: Aprepitant may decrease the serum concentration of Warfarin. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

Adverse reactions may be reported in combination with other antiemetic agents. As reported for highly emetogenic cancer chemotherapy or moderately emetogenic cancer chemotherapy, unless otherwise noted as reported for postoperative nausea and vomiting (PONV).

>10%:

Central nervous system: Fatigue (adults: 13%; children & adolescents: 5%)

Hematologic & oncologic: Neutropenia (children & adolescents: 13%; adults: <3%)

0.5% to 10%:

Cardiovascular: Hypotension (PONV: 6%), bradycardia (PONV: <3%), flushing (<3%), palpitations (<3%), peripheral edema (<3%), syncope (PONV: <3%)

Central nervous system: Headache (children & adolescents: 9%), dizziness (<3% to 5%), anxiety (<3%), hypoesthesia (PONV: <3%), hypothermia (PONV: <3%), malaise (<3%), peripheral neuropathy (<3%), abnormal behavior (children & adolescents: 2%), agitation (children & adolescents: 2%)

Dermatologic: Alopecia (<3%), hyperhidrosis (<3%), skin rash (<3%), urticaria (<3%)

Endocrine & metabolic: Dehydration (≤3%), decreased serum albumin (PONV: <3%), decreased serum potassium (PONV: <3%), decreased serum sodium (<3%), hot flash (<3), hypokalemia (<3%), hypovolemia (PONV: <3%), increased serum glucose (PONV: <3%), weight loss (<3%)

Gastrointestinal: Constipation (PONV: 9%), diarrhea (6% to 9%), dyspepsia (≤7%), abdominal pain (≤6%), hiccups (4% to 5%), decreased appetite (<3% to 5%), dysgeusia (<3%), eructation (<3%), flatulence (<3%), gastritis (<3%), gastroesophageal reflux disease (<3%), nausea (<3%), vomiting (<3%), xerostomia (<3%)

Genitourinary: Proteinuria (<3%)

Hematologic & oncologic: Decreased hemoglobin (children & adolescents: 5%), decreased white blood cell count (≤4%), anemia (<3%), febrile neutropenia (<3%), hematoma (PONV: <3%), thrombocytopenia (<3%)

Hepatic: Increased serum ALT (3%), increased serum alkaline phosphatase (<3%), increased serum AST (<3%), increased serum bilirubin (PONV: <3%)

Infection: Candidiasis (<3%), postoperative infection (PONV: <3%)

Neuromuscular & skeletal: Weakness (≤7%), musculoskeletal pain (<3%)

Renal: Increased blood urea nitrogen (<3%)

Respiratory: Cough (<3% to 5%), dyspnea (<3%), hypoxia (PONV: <3%), oropharyngeal pain (<3%), pharyngitis (<3%), respiratory depression (PONV: <3%)

Miscellaneous: Wound dehiscence (PONV: <3%)

<0.5% (Limited to important or life-threatening): Anaphylaxis, angioedema, hypersensitivity reaction, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions, including anaphylactic reactions have been reported.

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. Due to a risk of significantly increased pimozide plasma concentrations and potential for QT prolongation, concurrent use with pimozide is contraindicated. Other CYP3A4-mediated drug interactions may occur. In patients receiving concurrent warfarin, a clinically significant decrease in INR or prothrombin time (PT) may occur; monitor INR/PT for 2 weeks (particularly at 7 to 10 days) following aprepitant administration.

Special populations:

• Pediatrics: For prevention of chemotherapy-induced nausea and vomiting, use is not recommended in pediatric patients weighing <6 kg. Not approved for prevention of postoperative nausea and vomiting in children.

Monitoring Parameters

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

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. 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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, diarrhea, lack of appetite, abdominal pain, hiccups, constipation, headache, or heartburn. Have patient report immediately to prescriber signs of infection, severe dizziness, passing out, dry mouth, dry eyes, thirsty, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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