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