Continuing Education Activity

Aprepitant is a medication used in the management and treatment of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). It is in the neurokinin-1 antagonist class of medications. This activity outlines and reviews the indications, actions, and contraindications for aprepitant as a valuable agent in preventing and managing CINV and PONV. This activity will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients either receiving highly emetogenic chemotherapy or general anesthesia.

Objectives:

• Identify the mechanism of action of the aprepitant.
• Describe the adverse effects of aprepitant.
• Summarize appropriate monitoring of aprepitant.
• Review interprofessional team strategies for improving care coordination using aprepitant to improve outcomes.

Indications

Aprepitant (oral/intravenous) and fosaprepitant (intravenous prodrug) are indicated to prevent 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.[1]

Mechanism of Action

Aprepitant is a highly selective antagonist of the G-protein coupled neurokinin-1 receptor.[2][3][4] 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).[5][6][7]

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 attenuate the likelihood of the complex vomiting reflex initiation significantly.[8] Peripherally, neurokinin-1 receptors exist throughout the gastrointestinal tract. The binding of aprepitant to these receptors may attenuate vagal afferent signals and contribute to aprepitant's antiemetic effect.

Administration

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.[9]

• 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.[9] 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).[9][10]   

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 standard recommendation for highly emetogenic chemotherapy-induced nausea and vomiting prevention (CINV) would include a 125 mg capsule given PO one hour before administering chemotherapy on day number one, often combined with a 5-HT3 antagonist and dexamethasone.[10]

The 80 mg capsule is given 1 hour before chemotherapy on days two and three, often combined with a 5HT-3 antagonist and dexamethasone. The intravenous preparation, fosaprepitant, is administered as a one-time 150 mg dose given 30 minutes before chemotherapy. No repeat dosing is necessary when using fosaprepitant.[10] 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 to prevent 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 at high risk of nausea and vomiting or in whom the act of vomiting would jeopardize surgical repair.[11] 

The Apfel score is a validated and frequently used scoring system to predict postoperative nausea and vomiting risk.[12] 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.[11]

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.[9] 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 oral administration to pediatric patients or adults who cannot swallow capsules.

Oral suspension is the dose form of choice for pediatric patients over six months of age up to 12 years old or 30 kg. A standard 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.[13] 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 cannot tolerate PO administration and has intravenous (IV) access. The dosing of fosaprepitant is age-stratified and adjusted within the 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. Therefore, consultation with the treating oncologist and pharmacist and reviewing 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. However, literature does exist demonstrating efficacy and safety.[14]

Adverse Effects

Aprepitant and fosaprepitant are generally very well tolerated with minimal side effects. Its tolerability is comparable to other low side effect antiemetics such as single doses of ondansetron.[9] Common, less common, and rare side effects have a lower incidence when dosed at 40 mg orally once for postoperative nausea and vomiting prophylaxis than a higher dose and multiple administration chemotherapy-induced nausea and vomiting prophylaxis regimens.[15]  

• Common side effects (defined as greater than 10 percent incidence) are 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).
• 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.[16] A pregnancy test is necessary if the patient misses a menstrual cycle. 
• 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.[17][18]

Contraindications

There are few contraindications to the use of aprepitant or fosaprepitant.[17][18]

• 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 have narrow therapeutic indexes as the decreased metabolism of these medications may cause toxicity.

Monitoring

There are no recommendations for routine monitoring.

• A pregnancy test is necessary if the patient misses a menstrual cycle.[16]
• Patients taking warfarin should have an INR check at one week following single-dose aprepitant administration due to aprepitant causing increased warfarin plasma concentrations via CYP34A inhibition.[17][11]

Toxicity

Aprepitant has a very high therapeutic index. Case reports of toxicity due to overdose are sparse or non-existent. No specific antidote exists for aprepitant toxicity.

Enhancing Healthcare Team Outcomes

Chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) result in decreased patient satisfaction, increased patient stress, and potentially increased rates of admission or delayed discharge from healthcare facilities.[19][20][21] Well-tolerated new therapies are in development that is highly effective and have few side effects. Aprepitant and its IV prodrug fosaprepitant belong to a new class of antiemetics known as neurokinin-1 inhibitors. These highly selective medications bind to multiple areas in the brainstem responsible for initiating and coordinating the vomiting reflex.[5][7] Aprepitant binds to NK-1 receptors in multiple areas of the brainstem, exerting its antiemetic effect for up to 48 hours.[8][10] Aprepitant/ fosaprepitant used as monotherapy or in combination with other antiemetics can provide highly effective prophylaxis for CINV and PONV. 

Physicians, pharmacists, mid-level providers, and nursing staff working as an interprofessional team need to be aware of multiple therapies to prevent nausea and vomiting.[11][9][15] Whether in the cancer center, inpatient, or operative setting, it is the responsibility of all healthcare team members to use knowledge of antiemetic therapies to reduce rates of nausea and vomiting that can lead to adverse effects and negative patient experience. It is advisable to form interprofessional teams to develop evidence-based regimens for the prophylaxis and treatment of CINV and PONV. Including aprepitant and fosaprepitant into these regimens can lead to decreased length of hospital stay, improved patient satisfaction, and a reduction in the risk of adverse events associated with the vomiting reflex, such as poor nutrition and damage to surgical repairs.[19][20][21] 

Aprepitant and fosaprepitant are relatively novel and expensive therapies when compared to older antiemetics. Their use should be guided by risk stratification systems such as the Apfel score, Eberhart score when prescribed for postoperative nausea and vomiting, and the updated antiemetic guidelines of 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).[15][3][9][22] By evaluating individual patient's risks for the development of nausea and vomiting, both the cost/benefit ratio and risk/benefit ratios can be maximized.[22] A board-certified oncology pharmacist can work closely with oncology staff to ensure proper dosing and the lack of drug interactions when choosing chemotherapy-induced antiemetic therapy. The nursing staff should understand the interactions and adverse event profile of these drugs along with the chemotherapy to inform the rest of the team promptly should issues arise. These interprofessional strategies can maximize therapeutic outcomes while minimizing adverse events, enhancing patient results. [Level 5]