Substance P/Neurokinin1 Receptor Antagonists

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • October 21, 2022; September 2020; September 2018; September 2016; May 2015; August 2013; June 2013; September 2011; October 2009; February 2006; January 2006
  • Initially developed
    • Dec. 2003

1. Dosage

Current therapies for chemotherapy-induced nausea/vomiting (CINV) and post-operative nausea and vomiting (PONV) target corticosteroid, dopamine, and serotonin (5-HT3) receptors. In the central nervous system, tachykinins and neurokinins play a role in some autonomic reflexes and behaviors. Substance P and NK1 receptors control the emetic reflex, and substance P increases contractions of smooth gastrointestinal muscles leading to vasodilation1. Aprepitant is a selective human substance P/neurokinin 1 (NK1) antagonist with a high affinity for NK1 receptors and little, if any, attraction for corticosteroid, dopamine, or 5-HT3 receptors1-5. Rolapitant (Varubi®) is a selective, competitive antagonist of substance P/NK1 receptors, and it has little to no affinity for NK2 or NK3 receptors1,2,6. Combination therapy including netupitant, a substance P/NK1 antagonist and palonosetron, a selective 5-HT3 receptor antagonist (Akynzeo®), is also available. Palonosetron targets CINV in the acute phase while netupitant prevents CINV in both the acute and delayed phases1,2,7.

1.1. Adults

Aprepitant is FDA-approved for prevention of CINV due to high and moderate emetogenic agents including high dose cisplatin, as well as prevention for PONV1-4. When used to prevent CINV with highly emetogenic chemotherapy, aprepitant and rolapitant are prescribed as triple or quadruple therapy in combination with a 5-HT3 receptor antagonist, dexamethasone, and olanzapine based on product labeling, clinical trial data, as well as data from available published antiemetic guidelines8,9. Rolapitant is indicated to manage delayed CINV seen with initial and repeat courses of chemotherapy, including, but not limited to, highly emetogenic chemotherapy1,2,6. Netupitant (substance P/NK1 receptor antagonist) and palonosetron (selective 5-HT3 receptor antagonist), as combination therapy, are FDA-approved to prevent acute and delayed CINV seen with initial and repeat courses of chemotherapy, including, but not limited to, highly emetogenic chemotherapy1,2,7. Maximum recommended adult dosages for substance P/NK1 receptor antagonists are summarized in Tables 1 and 2. Dosages exceeding those listed in Tables 1 and 2 will be reviewed.

Table 1. Maximum Recommended Adult Oral Substance P/Neurokinin 1 Receptor Antagonist Monotherapy Dosages1-4,6-9
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
aprepitant (Emend®) 40 mg, 80 mg, 125 mg capsules
125 mg/5 ml oral suspension		 preventing CINV:
highly or moderately emetogenic chemotherapy:
day 1 (one hour before chemotherapy)		 125 mg/day (as capsule or suspension)*!
    preventing CINV:
highly or moderately emetogenic chemotherapy:
days 2 and 3		 80 mg/day (as capsule or suspension)+@ ¥α
    PONV:
within 3 hours of anesthesia induction		 40 mg as a single dose (as capsule)
rolapitant (Varubi®) 90 mg tablet preventing delayed CINV seen with highly emetogenic chemotherapy 180 mg as a single dose 1 to 2 hours before chemotherapy on day 1 (2 x 90 mg tablets)^!@
    preventing delayed CINV seen with non-highly emetogenic chemotherapy and combinations of anthracycline and cyclophosphamide 180 mg as a single dose 1 to 2 hours before chemotherapy on day 1 (2 x 90 mg tablets)#**α

Legend:

  • * for high and moderate emetic risk regimens, use in conjunction with a 5-HT3 receptor antagonist plus dexamethasone on day 1 (product labeling)
  • ! for high emetic risk regimens, use in conjunction with a 5-HT3 receptor antagonist, dexamethasone, and olanzapine on day 1 (guideline recommendation)8,9
  • + for high emetic risk regimens, use in conjunction with dexamethasone on days 2-3; dexamethasone monotherapy is given on day 4 (product labeling)
  • @ for high emetic risk regimens, administer dexamethasone and olanzapine on days 2-4 (guideline recommendation)8,9
  • ¥ for high emetic risk regimens containing an anthracycline combined with cyclophosphamide, dexamethasone should not be continued on days 2-4 (guideline recommendation)8,9
  • α for moderate emetic risk regimens with a known risk for delayed nausea and vomiting such as cyclophosphamide, doxorubicin, or oxaliplatin; continue dexamethasone through day 3 (guideline recommendation)8,9
  • ^ in conjunction with dexamethasone and a 5-HT3 receptor antagonist on day 1, and dexamethasone on days 2-4 (product labeling)
  • # for moderate emetic risk regimens, use in conjunction with dexamethasone and a 5-HT3 receptor antagonist on day 1. Continue 5-HT3 receptor antagonist therapy on days 2-4 (product labeling).
  • ** for high emetic risk regimens containing an anthracycline combined with cyclophosphamide, use in conjunction with a 5-HT3 receptor antagonist, dexamethasone, and olanzapine on day 1. Olanzapine monotherapy is given on days 2-4 (guideline recommendation)8,9
  • PONV = postoperative nausea and vomiting
  • CINV = chemotherapy-induced nausea and vomiting
  • PONV = postoperative nausea and vomiting
Table 2. Maximum Recommended Adult Oral Substance P/Neurokinin 1 Receptor Antagonist Combination Therapy Dosages1,2,7
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
netupitant/palonosetron (Akynzeo®) preventing acute and delayed CINV seen with chemotherapy (highly emetogenic) 300 mg netupitant/ 0.5 mg palonosetron capsules 1 capsule on day 1 (one hour before chemotherapy)**#!
  preventing acute and delayed CINV seen with chemotherapy (NOT highly emetogenic) 300 mg netupitant/ 0.5 mg palonosetron capsules 1 capsule on day 1 (one hour before chemotherapy)++ α

Legend:

  • ** in conjunction with dexamethasone 30 minutes before chemotherapy on day 1, and dexamethasone once daily on days 2-4 (product labeling)
  • # for high emetic risk regimens, use in conjunction with dexamethasone and olanzapine on day 1. Continue dexamethasone and olanzapine on days 2-4 (guideline recommendation)8,9
  • ! for high emetic risk regimens containing an anthracycline combined with cyclophosphamide, use in conjunction with dexamethasone and olanzapine on day 1. Olanzapine monotherapy is given on days 2-4 (guideline recommendation)8,9
  • ++ for regimens that are not considered high emetic risk, use in conjunction with dexamethasone 30 minutes before chemotherapy on day 1 (product labeling)
  • α for moderate emetic risk regimens with a known risk for delayed nausea and vomiting such as cyclophosphamide, doxorubicin, or oxaliplatin; continue dexamethasone through day 3 (guideline recommendation)8,9
  • CINV = chemotherapy-induced nausea and vomiting

1.2. Pediatrics

Aprepitant capsules are FDA-approved for use in children and adolescents 12 years of age and older to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately to highly emetogenic chemotherapy (includes high-dose cisplatin). Aprepitant oral suspension is FDA-approved to prevent acute and delayed nausea and vomiting seen with initial and repeat courses of highly emetogenic chemotherapy (includes high-dose cisplatin) as well as nausea and vomiting associated with moderately emetogenic chemotherapy in pediatric patients 6 months of age and to 11 years of age weighing at least 6 kg or pediatric patients of any age weighing at least 6 kg who cannot swallow capsules1-4. Rolapitant is not yet approved for use in pediatric patients, as safety and efficacy have not been established1,2,6. Combination therapy with netupitant and palonosetron is not FDA-approved in patients less than 18 years as safety and efficacy have not been established in this patient population1,2,7. Pediatric aprepitant dosages are summarized in Table 3. Aprepitant dosages exceeding these recommendations in pediatric patients will be reviewed.

Table 3. Maximum Recommended Oral Aprepitant Dosages in Pediatric Patients1-4
Treatment Indication Patient Characteristics Usual Dosage/Dosage Form Maximum Recommended Dosage
CINV: Moderate to highly emetogenic chemotherapy – day 1 6 months to less than 12 years (at least 6 kg) 3 mg/kg on day 1 (as suspension)*! 125 mg on day 1
CINV: Moderate to highly emetogenic chemotherapy – days 2 and 3 6 months to less than 12 years (at least 6 kg) 2 mg/kg on days 2 and 3 (as suspension)+! 80 mg on days 2 and 3
CINV: Moderate to highly emetogenic chemotherapy – day 1 pediatric patients any age (at least 6 kg) unable to swallow capsules 3 mg/kg on day 1 (as suspension)*! 125 mg on day 1 
CINV: Moderate to highly emetogenic chemotherapy – days 2 and 3 pediatric patients any age (at least 6 kg) unable to swallow capsules 2 mg/kg on days 2 and 3 (as suspension)+! 80 mg on days 2 and 3
moderately to highly emetogenic chemotherapy – day 1 greater than or equal to 12 years of age 125 mg on day 1 one hour before chemotherapy (as capsule)*! 125 mg on day 1
moderately to highly emetogenic chemotherapy – days 2 and 3 greater than or equal to 12 years of age 80 mg on days 2 and 3 (as capsule)+! 80 mg on days 2 and 3

Legend:

  • * in conjunction with a 5-HT3 receptor antagonist plus dexamethasone on day 1 (product labeling)
  • + in conjunction with dexamethasone on days 2-3; dexamethasone also given on day 4 (product labeling)
  • ! for moderate emetic risk regimens, a two-drug combination of a 5-HT3 receptor antagonist and dexamethasone should be offered. If a pediatric patient is unable to take dexamethasone, a two-drug combination of a 5-HT3 receptor antagonist and aprepitant should be offered (guideline recommendation)8

2. Duration of Therapy

The maximum treatment duration for aprepitant is three days per chemotherapy cycle for moderately or highly emetogenic chemotherapy regimens. The maximum treatment duration for rolapitant and netupitant/palonosetron is one day for each chemotherapy cycle. Chemotherapy regimens are administered for one to several days within a 30-day time period and repeated in cycles. The number of cycles varies based on the type of cancer being treated. Unless otherwise specified, aprepitant treatment regimens continuing for greater than three days per chemotherapy cycle and rolapitant and netupitant/palonosetron treatment regimens continuing for longer than one day per chemotherapy cycle will be reviewed for appropriateness of use.

3. Duplicative Therapy

Aprepitant is the first medication in the class of selective human substance P/NK1 antagonists. Cinvanti® (aprepitant) intravenous emulsion is indicated for use on day 1 of the chemotherapy cycle, and oral aprepitant is indicated on days two and three for moderate emetic risk chemotherapy regimens10. Fosaprepitant, the injectable aprepitant formulation, was indicated for use on day 1 of the chemotherapy cycle as the 115 mg dose with oral aprepitant administered on days 2 and 3; however, the 115 mg vial is no longer commercially available. Fosaprepitant 150 mg injection is not administered with oral aprepitant on any treatment days5. Dosage regimens incorporating concurrent use of fosaprepitant 150 mg and aprepitant will be reviewed. Concurrent administration of selective human substance P/NK1 receptor antagonists is not supported in the literature and may result in enhance adverse pharmacologic effects. Additionally, combined use of oral rolapitant or netupitant/palonosetron is not indicated and may result in increased adverse effects. Combined use of substance P/NK1 receptor antagonists or adjunctive use of oral and parenteral substance P/NK1 receptor antagonist formulations is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be monitored to identify regimens that may have clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for substance P/NK1 receptor antagonists are summarized in Table 4. Only those interactions classified as clinical significance level 1, contraindicated, or life threatening which have not been classified will be reviewed.

Table 4. Substance P/NK1 Receptor Antagonist Drug-Drug Interactions1-7
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level*
aprepitant CYP3A4 inducers (e.g., carbamazepine, rifampin) adjunctive use may induce aprepitant metabolism and potential for reduced aprepitant serum levels and decreased aprepitant efficacy; CYP3A4 inducer activity may also be reduced, as aprepitant is also a CYP3A4 inducer monitor patients for aprepitant efficacy; if needed, modify aprepitant dose or choose alternative anti-emetic without CYP3A4 inducer interaction; monitor CYP3A4 inducer activity and adjust dose as necessary moderate (DrugReax) 3-moderate (CP)
aprepitant CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, nefazodone, clarithromycin, ritonavir) combined use may result in reduced aprepitant metabolism, increased serum aprepitant levels, and the potential for adverse effects; however, aprepitant appears to be tolerated over a wide dosage range and is prescribed for short time periods clinical significance of interaction not well defined; observe patients for increased aprepitant adverse effects and adjust dose if necessary major (DrugReax) 3-moderate (CP)
aprepitant CYP3A4 substrates (e.g., aripiprazole, colchicine, diltiazem, phenytoin, ranolazine, ziprasidone) combined use may result in elevated substrate plasma levels and potential for toxicity or loss of efficacy, as aprepitant is known CYP3A4 inhibitor and inducer and may interfere with metabolism of medications metabolized by CYP3A4 use aprepitant cautiously with compounds metabolized by CYP3A4; monitor patients carefully for signs/ symptoms of substrate toxicity or loss of efficacy and adjust substrate dose as necessary major (DrugReax) 2-major, 3-moderate (CP)
aprepitant oral contraceptives (OC) adjunctive use may result in reduced OC efficacy as AUC for both estrogen and progestin components may be reduced alternative or back-up methods of contraception recommended during time that aprepitant is prescribed and for one month following last aprepitant dose moderate (DrugReax) 2-major (CP)
aprepitant pimozide (Orap®) co-use may result in elevated plasma pimozide levels and increased risk for cardiac arrhythmias, QT interval prolongation, as aprepitant inhibits CYP3A4 (enzyme for pimozide metabolism) adjunctive use contraindicated contraindicated (DrugReax) 1-severe (CP)
aprepitant phenytoin combined use may result in reduced phenytoin levels and potential loss of seizure control as aprepitant induces CYP2C9, the enzyme that metabolizes phenytoin administer cautiously together; observe for loss of seizure control moderate (DrugReax) 3-moderate (CP)
aprepitant warfarin co-administration may result in significant decreases in warfarin serum levels, INR and warfarin efficacy, as aprepitant induces CYP2C9, the enzyme involved in warfarin metabolism monitor clotting status closely within 2-week period (especially 7 to 10 days) after each 3-day chemotherapy regimen or following single-dose therapy for PONV major (DrugReax) 2-major (CP)
netupitant/palonosetron (palonosetron component) apomorphine (Apokyn®) adjunctive administration may result in hypotension and loss of consciousness due to additive hypotensive effects avoid combined use contraindicated (DrugReax) 1-severe (CP)
netupitant/palonosetron (netupitant component), rolapitant strong CYP3A4 inducers (e.g., rifampin) concurrent use may reduce netupitant, rolapitant efficacy with reduced serum levels due to CYP3A4-induced netupitant, rolapitant metabolism avoid co-administration major (DrugReax) 2-major (CP)
netupitant/palonosetron (netupitant component) CYP3A4 inhibitors combined administration with strong CYP3A4 inhibitors may increase serum netupitant levels as netupitant is metabolized by CYP3A4; netupitant is CYP3A4 inhibitor and may increase concentrations of other medications no netupitant dosage adjustment necessary due to single dose therapy; monitor for enhanced pharmacologic/ adverse effects and adjust dosages of other medications as necessary 3-moderate (CP)
netupitant/palonosetron (netupitant component) CYP3A4 substrates adjunctive use may result in enhanced substrate pharmacologic/ adverse effects as netupitant is CYP3A4 inhibitor and may increase concentrations of other medications use cautiously together; monitor for enhanced pharmacologic/ adverse effects and adjust substrate dosages as necessary moderate (DrugReax) 2-major, 3-moderate (CP)
netupitant/ palonosetron (netupitant component) flibanserin (Addyi®) combined use may lead to significant hypotension and syncope due to increased flibanserin serum levels as netupitant is moderate CYP3A4 inhibitor and flibanserin is CYP3A4 substrate avoid concurrent use for 1 week, if possible; if combined use necessary, consider CYP3A4 substrate dose reduction major (DrugReax) 1-severe (CP)
netupitant/palonosetron (palonosetron component) serotonergic agents potential for serotonin syndrome with combined therapy due to additive serotonergic effects with palonosetron monitor for signs/ symptoms of serotonin syndrome (e.g., hyperthermia, hypertension, rigidity) and discontinue combined therapy, if symptoms present major (DrugReax) 2-major (CP)
rolapitant breast cancer resistant protein (BCRP) substrates with narrow therapeutic index (e.g., methotrexate, topotecan) combined use may increase BCRP substrate levels and potential for adverse effects as rolapitant is BCRP inhibitor avoid use, if possible; if adjunctive use necessary, monitor for BCRP substrate adverse events 2-major (CP)
rolapitant p-glycoprotein substrates with narrow therapeutic index (e.g., digoxin) combined use may increase p-glycoprotein substrate levels and potential for adverse effects as rolapitant is p-glycoprotein inhibitor avoid use, if possible; if adjunctive use necessary, monitor for p-glycoprotein substrate adverse events major (DrugReax) 3-moderate (CP)
rolapitant pimozide concurrent administration may increase risk of pimozide-associated QT interval prolongation/ torsades de pointes as pimozide metabolized by CYP2D6 and rolapitant is CYP2D6 inhibitor avoid combined use, if possible; if concomitant use necessary, monitor for pimozide adverse effects major (DrugReax) 1-severe (CP)
rolapitant other CYP2D6 substrates combined use may increase CYP2D6 substrate levels and potential for adverse effects as rolapitant is CYP2D6 inhibitor use cautiously together; monitor for enhanced pharmacologic/ adverse effects and adjust substrate dosages as necessary major (DrugReax) 2-major, 3-moderate (CP)
rolapitant thioridazine combined administration may increase risk of QT interval prolongation/ torsades de pointes with thioridazine as rolapitant CYP3A4 inhibitor and thioridazine CYP3A4 substrate avoid concurrent use contraindicated (DrugReax) 1-severe (CP)

Legend:

  • *CP = Clinical Pharmacology

5. References

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 14, 2022.
  2. IMB Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed September 14, 2022.
  3. Aprepitant capsules, oral suspension (Emend®) package insert. Merck & Co., Inc., May 2022.
  4. Aprepitant oral capsules package insert. Torrent Pharmceuticals Limited. January 2022.
  5. Fosaprepitant dimeglumine for injection (Emend®) package insert. Merck & Co., Inc., May 2022.
  6. Rolapitant tablets, injectable emulsion (Varubi®) package insert. TerSera Therapeutics, LLC., August 2020.
  7. Netupitant/palonosetron capsules (Akynzeo®) package insert. Helsinn Therapeutics (U.S.), Inc., May 2022. 
  8. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: asco guideline update. Journal of Clinical Onclogy. 2020;38(24):2782-2797.
  9. National Comprehensive Cancer Network. Antiemesis (Version 2.2022). https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed September 14, 2022.
  10. Aprepitant emulsion for injection (Cinvanti®) package insert. Heron Therapeutics, Inc., March 2022.