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Aprepitant
Indications
Aprepitant (oral/intravenous) and fosaprepitant (intravenous prodrug) are indicated to prevent nausea and vomiting in cancer patients. Initially, the development of aprepitant was for the prevention of chemotherapy-induced nausea and vomiting(CINV); currently, its use and indications have since expanded to include post-operative nausea and vomiting(PONV). Aprepitant now has FDA approval for both indications.[1][2][3]
Research suggests that aprepitant may have antiproliferative, anti-angiogenic, and antimetastatic effects.[4][5] Studies indicate that aprepitant may also be used for chronic refractory pruritus(Non-FDA approved). However, extensive research is required to prove its efficacy and safety in randomized controlled trials (RCTs) for the abovementioned indications.[6][7]
Mechanism of Action
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Mechanism of Action
Aprepitant is a highly selective antagonist of the G-protein coupled neurokinin-1 receptor.[8][9][10] 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).[11][12][13]
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.[14] Peripherally, neurokinin-1(NK-1) receptors exist throughout the gastrointestinal tract. The binding of the aprepitant to NK-1 receptors may attenuate vagal afferent signals and contribute to the antiemetic effect. The suggested mechanism for the antipruritic effect is the antagonism of substance P, an endogenous ligand of the NK1 receptor.[6]
Pharmacokinetics
Absorption: Aprepitant shows nonlinear pharmacokinetics. The bioavailability of the aprepitant decreases with increasing dose, with the mean oral bioavailability of the aprepitant being 67% for the 80 mg aprepitant and 59% for the 125 mg aprepitant capsules. The time to peak plasma concentration(Tmax) is approximately four hours.[15]
Distribution: Aprepitant has high plasma protein binding (approximately 95%) and a high volume of distribution at a steady state(Vss) of 70 L.
Metabolism: Aprepitant undergoes hepatic metabolism by P450 CYP3A4 and CYP2C9 and CYP1A2 (minor), CYP2C19 (minor). Major metabolites are N- and O-dealkylation products which are pharmacologically inactive. It is important to recognize that aprepitant is a dose-dependent inhibitor and inducer of CYP3A4.[16]
Excretion: Metabolites of aprepitant are excreted approximately 50% in urine and 50% in feces. There is minimal renal excretion of the parent drug.[17]
Administration
Adult Patients
Chemotherapy-Induced Nausea and Vomiting (CINV)
Chemotherapy agents are broadly divided into five emetogenic levels. Each level states the expected frequency of emesis if the patient receives no prophylactic antiemetic.[16]
- 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.[16] 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).[16][18]
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 a 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 one, often combined with a 5-HT3 antagonist and dexamethasone.[18]
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.[18] 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.[19]
The Apfel score is a validated and frequently used scoring system to predict postoperative nausea and vomiting risk.[20] Antiemetic regimens that include aprepitant can be prescribed based on the calculated risk. Fosaprepitant has not yet received an indication for postoperative nausea and vomiting though future use in NPO patients is under exploration. It is expected to have similar efficacy to an equipotent dose of aprepitant.[19]
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.[16] 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.[21] Similar to adults, aprepitant often gets combined with a weight-based dose of ondansetron and dexamethasone on both days.
Fosaprepitant may be substituted for 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)
FDA has not approved aprepitant and fosaprepitant for the indication of prophylaxis of anesthesia-induced postoperative nausea and vomiting in the pediatric population. However, literature does exist demonstrating efficacy and safety.[22]
Use in Specific Patient Populations
Patients with Hepatic Impairment: No dose adjustment is necessary for mild to moderate hepatic impairment. Use caution in severe hepatic impairment(Child-Pugh score>9).
Patients with Renal Impairment: No dosage adjustment of aprepitant is necessary for patients with renal impairment or patients with ESRD undergoing hemodialysis.[16]
Pregnancy Considerations: The review suggests that aprepitant can be safely used during the first trimester of pregnancy. Aprepitant is a former FDA category drug B.[23] Risk-benefit evaluation should be considered, and clinicians should participate in shared decision-making.[24]
Breastfeeding Considerations: There is a lack of clinical data regarding the use of aprepitant during breastfeeding. Clinicians should consider the developmental and health benefits of breastfeeding, the mother’s clinical need for the aprepitant, and possible adverse drug reactions from the aprepitant on the breastfed infant.
Adverse Effects
Aprepitant and fosaprepitant are generally very well tolerated with minimal side effects. They are well tolerated like other antiemetics(with low adverse event profile), such as single doses of ondansetron.[16] 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.[25]
- A systematic review of 17 RCTs suggested that adverse drug reactions such as hiccups, fatigue, asthenia, and serious infections were reported in patients receiving aprepitant.[26]
- Common side effects (defined as > 10 percent incidence) are headache, fatigue, anorexia, constipation, diarrhea, nausea, and hiccups.
- 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.
- 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.
- 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. A pregnancy test is necessary if the patient misses a menstrual cycle.[27]
Drug-Drug Interactions
- Aprepitant is a dose-dependent inhibitor and inducer of the cytochrome P450 CYP3A4 family of enzymes. Aprepitant also induces CYP2C9. Any medication or substance metabolized by this pathway may be affected, resulting in clinically appreciable effects. Commonly cited interactions include benzodiazepines, warfarin, ketoconazole, and dexamethasone. A dose reduction in dexamethasone is recommended when coadministered with aprepitant or fosaprepitant.[28][29]
- Oxycodone is also metabolized by CYP3A4 to its active metabolite oxymorphone and can lead to increased exposure of oxymorphone when administered with aprepitant. Hence it is important to monitor patients closely during concurrent therapy. There is also an impact of aprepitant on hormonal contraceptives due to CYP3A4 induction, which can lead to oral contraceptive failure. Patients should be advised to use an alternative method of contraception. Quetiapine is a CYP3A4 substrate; increased plasma levels of quetiapine are seen when coadministered with aprepitant.[30]
Contraindications
Few contraindications exist to the use of aprepitant or fosaprepitant.[28][29]
- Prior hypersensitivity reactions and the co-administration of pimozide or cisapride are the commonly cited drug reactions of pimozide. Pimozide is a CYP3A4 substrate, and inhibition of CYP3A4 by aprepitant can increase plasma levels of pimozide, increasing the risk of QT prolongation.[6]
- Relative contraindications 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.[27]
- Patients taking warfarin should have an INR check one week following single-dose aprepitant administration due to aprepitant causing increased warfarin plasma concentrations via CYP34A inhibition.[28][19]
- Monitor the quality of life and clinical response to the aprepitant using a modified functional living index-emesis (FLIE) or functional living index-emesis (FLIE) score.[31][32][33]
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.[34] Serum aminotransferase elevations occur in 6% of treated patients, but clinically apparent liver injury is rare.[35] There is a case report of ifosfamide-induced encephalopathy associated with aprepitant. Encephalopathy reversed with supportive treatment and discontinuation of aprepitant.[36] The retrospective case series examined the long-term daily administration of aprepitant for intractable nausea and vomiting in children in palliative care settings. In contrast with the routine regimen, the mean number of days of aprepitant treatment was 36.5 days (6 to 84 days). No adverse event was observed even after prolonged administration establishing the safety profile of the aprepitant.[37] In the case of an overdose, institute supportive care and consult a medical toxicologist or poison control center.[38]
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 admission rates or delayed discharge from healthcare facilities.[39] Well-tolerated, highly effective, novel therapies are in development with 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.[11][13] Aprepitant binds to NK-1 receptors in multiple areas of the brainstem, exerting its antiemetic effect for up to 48 hours.[14][18] Aprepitant/ fosaprepitant used as monotherapy or in combination with other antiemetics can provide highly effective prophylaxis for CINV and PONV. CINV refractory to all medical therapies, including aprepitant, needs further evaluation and workup for intestinal obstruction, CNS metastases, and electrolyte abnormalities.[40]
Clinicians (MD, DO, NP, PA), pharmacists, and nursing staff working as an interprofessional team must be aware of multiple therapies to prevent nausea and vomiting.[19][16][25] 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 experiences. 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 reduced risk of adverse events associated with the vomiting reflex, such as poor nutrition and damage to surgical repairs.[41][42] This may require consulting with a specialized pharmacology pharmacist who can communicate with the rest of the team regarding appropriate dosing, check for interactions, advise the nursing staff on administration, and be available for additional input during post-administration monitoring. Nurses will want to reach out to the ordering clinician if they note any adverse events or changes in patient status.
Aprepitant and fosaprepitant are relatively novel and expensive therapies 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).[25][9][16][43] By evaluating individual patients' risks for the development of nausea and vomiting, the cost/benefit ratio and risk/benefit ratios can be maximized.[43] As mentioned, a board-certified oncology pharmacist can work closely with the oncology staff to ensure proper dosing and the lack of drug interactions when choosing chemotherapy-induced antiemetic therapy. The nursing staff should promptly understand the interactions and adverse event profile of these drugs and the chemotherapy to inform the rest of the team should issues arise. These interprofessional strategies can maximize therapeutic efficacy, minimize adverse events and optimize patient outcomes related to aprepitant therapy. [Level 5]
References
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