Aprepitant (oral) and fosaprepitant (intravenous prodrug) are indicated for the prevention of nausea and vomiting. Initially, the development of aprepitant was for the prevention of chemotherapy-induced nausea and vomiting, but its use and indications have since expanded to include post-operative nausea and vomiting. Aprepitant now has FDA approval for both indications. 

Aprepitant is a highly selective antagonist of the G-protein coupled neurokinin-1 receptor.[1][2][3] Neurokinin-1 receptors are present in both the central and peripheral nervous systems. Their primary ligand is substance P, a nociceptive neurotransmitter. The areas in the brainstem thought to play critical roles in the vomiting reflex are the central pattern generator, the nucleus tractus solitarius (NTS), and area postrema (AP).[4][5][6] Central neurokinin-1 receptors are found throughout these regions, allowing widespread binding of aprepitant in these critical regions. By acting as a competitive antagonist in these regions, aprepitant is thought to greatly attenuate the likelihood of initiation of the complex vomiting reflex.[7] Peripherally, neurokinin-1 receptors exist throughout the gastrointestinal tract. Binding of aprepitant to these receptors may attenuate vagal afferent signals and contribute to aprepitant's antiemetic effect.

Adult Patients

Chemotherapy-Induced Nausea and Vomiting (CINV)

Chemotherapy agents broadly divide into five emetogenic levels.  Each level states the expected frequency of emesis if the patient receives no prophylactic antiemetic.[8]

High – over 90 percent risk of emesis

Moderate – over 30 and up to 90 percent risk of emesis

Low – 10 to 30 percent risk of emesis

Minimal – under10 percent risk of emesis

The Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) make antiemetic therapy based guidelines based on the risk of emesis.[8] An (NK-1) receptor antagonist is recommended in combination with a 5-HT3 receptor antagonist (e.g., ondansetron) and a glucocorticoid (often dexamethasone) for highly emetogenic chemotherapy (HECT) and moderately emetogenic chemotherapy (MECT).[8][9]   

Aprepitant is available as a capsule for PO administration in 40 mg, 80 mg, and 125 mg strengths. It is also available in a prodrug preparation known as fosaprepitant for intravenous administration. Fosaprepitant comes in powder form for reconstitution in 150 mg/ vial strength.  A common recommendation for highly emetogenic chemotherapy-induced nausea and vomiting prevention (CINV) would include a 125 mg capsule given PO one hour before the administration of chemotherapy on day number one often combine with a 5-HT3 antagonist and dexamethasone.[9] The 80 mg capsule is given 1 hour before chemotherapy on days two and three again, often combine with a 5HT-3 antagonist and dexamethasone.  The intravenous preparation, fosaprepitant, is administered as a one-time 150 mg dose given 30 minutes prior to chemotherapy.  No repeat dosing is necessary when using fosaprepitant.[9] It bears mentioning that multiple dosing regimens exist based on the prescribed chemotherapy regimen and institutional practices. Consultation with the treating oncologist and pharmacist, as well as up to date reference literature, is recommended. 

Postoperative nausea and vomiting (PONV) and Post-discharge nausea and vomiting (PDNV)

Aprepitant 40 mg capsule is administered PO within three hours of induction for the prevention of anesthesia-induced postoperative nausea and vomiting.  Due to its increased cost compared with other antiemetics used in anesthesia practice, its use should only be for patients who are at high risk of nausea and vomiting or in whom the act of vomiting would jeopardize surgical repair.[10]  The Apfel score is a validated and frequently used scoring system for the prediction of postoperative nausea and vomiting risk.[10][11] Antiemetic regimens that include aprepitant can be prescribed based on the risk calculated risk.  Fosaprepitant has not yet received an indication for postoperative nausea and vomiting though future use in NPO patients is under exploration. If used, it would likely have similar efficacy to an equipotent dose of aprepitant.[10]

Pediatric Patients

Chemotherapy-Induced Nausea and Vomiting (CINV)

Oral capsules may be used in the same manner as adult patients if the pediatric patient is greater than 12 years of age or under the age of 12 and greater than 30 kg.[8] Aprepitant is available for oral suspension prepared by mixing the contents of one pouch of powder with 4.6 ml of water. The resulting suspension yields a 25 mg/ml strength for PO administration to pediatric patients or adults who cannot swallow capsules. For pediatric patients greater than six months of age up to 12 years old or 30 kg, the oral suspension is the dose form of choice. A common regimen for highly emetogenic chemotherapy is a dose of 3 mg/kg PO 1 hour before chemotherapy on day one and 2 mg/kg PO 1 hour before chemotherapy on day 2.[12] Similar to adults, aprepitant often gets combined with a weight-based dose of ondansetron and dexamethasone on both days. Fosaprepitant may be substituted for the oral suspension if the patient is unable to tolerate PO administration and has intravenous (IV) access. The dosing of fosaprepitant is age-stratified and adjusted within age group depending on whether it is used as a monotherapy or combined with dexamethasone and a 5HT-3 antagonist. It is worth noting that multiple dosing regimens exist based on the prescribed chemotherapy regimen and institutional practices just as in adults. Consultation with the treating oncologist and pharmacist, as well as up to date reference literature, is recommended.

Postoperative nausea and vomiting (PONV) and post-discharge nausea and vomiting (PDNV)

Aprepitant and fosaprepitant have not received FDA approval for the indication of prophylaxis of anesthesia-induced postoperative nausea and vomiting in the pediatric population, though literature does exist demonstrating efficacy and safety.[13]

Aprepitant and fosaprepitant are generally very well tolerated with minimal side effects. It tolerability is comparable to other low side effect antiemetic such as single doses of ondansetron.[8] Common, less common, and rare side effects have a lower incidence when dosed at 40 mg PO once for postoperative nausea and vomiting prophylaxis when compared to a higher dose and multiple administration chemotherapy-induced nausea and vomiting prophylaxis regimens.[14]  

Common side effects (defined as greater than 10 percent incidence) headache, fatigue, anorexia, constipation, diarrhea, nausea, and hiccups (EMEND, 2013).

Less common side effects (defined as 1 to 10 percent incidence) include dizziness, insomnia, bradycardia, hypotension, pharyngolaryngeal pain, mucosal inflammation, stomatitis, dyspepsia, anemia, neutropenia, hot flash, pruritus, dehydration, and fever (EMEND, 2013).

Rare side effects (defined as less than one percent incidence) include candidiasis, staphylococcal infection, febrile neutropenia, weight gain, polydipsia, disorientation, euphoria, vivid dreams, cognitive disorder, lethargy, somnolence, conjunctivitis, cough, acid reflux, epigastric discomfort, malaise, and chills (EMEND, 2013).

Aprepitant is a dose-dependent inhibitor and inducer of the cytochrome P450 CYP3A4 family of enzymes. Any medication or substance metabolized by this pathway may be affected, resulting in clinically appreciable effects. Commonly cited interactions include benzodiazepines, warfarin, ketoconazole, oral hormonal contraceptives, and dexamethasone. A dose reduction in dexamethasone is recommended when coadministered with aprepitant or fosaprepitant.[15][16] Patients taking oral contraceptive medications should use a backup means of contraception or abstain from sexual activity to reduce the chances of an unplanned pregnancy.[17] A pregnancy test is necessary if the patient misses a menstrual cycle. 

There are few contraindications to the use of aprepitant or fosaprepitant.  Hypersensitivity, severe prior reaction, and the co-administration of pimozide or cisapride are the commonly cited ones. Relative contraindications would include medications that get metabolized via CYP3A4 metabolism and that have narrow therapeutic indices as the decreased metabolism of these medications may cause toxicity.[15][16]