Serotonin 5-HT3 Receptor Antagonists for Nausea and Vomiting (oral)

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 20, 2022; September 2020; July 2018; September 2016; June 2015; October 2013; November 2011; September 2011; October 2009; December 2005; August 2003; July 2002; July 2001; August 2000; August 1999; July 1998; July 1997.
  • Initially developed
    • Sept. 1996

1.1. Adults

Serotonin 5-HT3 receptor antagonists are FDA-approved for the prevention of chemotherapy-induced nausea and vomiting (CINV), radiotherapy-induced nausea and vomiting (RINV), and post-operative nausea and vomiting (PONV)1, 2. Although not FDA-approved, these agents have also been utilized in the treatment of opioid-induced nausea, nausea and vomiting of pregnancy (hyperemesis gravidarum), and acute pediatric gastroenteritis1, 2. The American Society of Clinical Oncology (ASCO) antiemetic guidelines recommend the use of 5-HT3 receptor antagonists in conjunction with dexamethasone, a neurokinin 1 (NK1) receptor antagonist, and olanzapine to manage nausea and vomiting associated with highly emetogenic antineoplastic agents. Additionally, the guidelines recommend a 5-HT3 receptor antagonist combined with dexamethasone and a NK1 receptor antagonist for control of nausea and vomiting associated with moderately emetogenic carboplatin with an area under the curve (AUC) of greater than or equal to 4 mg/mL/min. The guidelines recommend that other antineoplastic agents with a moderate emetic risk should be managed with a two-drug combination of a 5-HT3 receptor antagonist combined with dexamethasone4. A single dose of a 5-HT3 receptor antagonist or dexamethasone is recommended for use with low emetic risk chemotherapy regimens, while no antiemetic is recommended for use with chemotherapy regimens having minimal emetic risk. ASCO also recommends 5-HT3 receptor antagonist use—often in conjunction with dexamethasone—to manage nausea and vomiting associated with minimal, low, moderate, and high emetic risk radiation therapy3, 4. A combination product containing palonosetron, a serotonin 5-HT3 receptor antagonist, and netupitant, a selective substance P selective neurokinin 1 receptor antagonist is available for use in combination with dexamethasone in adults to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of cancer therapy, including, but not limited to, highly emetogenic chemotherapy5. Recommended FDA-approved dosage regimens for the available serotonin 5-HT3 receptor antagonists are summarized in Tables 1 and 2. Dosages exceeding these recommendations will be reviewed.

Table 1. Maximum Recommended Dosage Regimens for Serotonin 5-HT3 Receptor Antagonist Monotherapy in Adults1,2,5-9
Drug Name Dosage Form/Strength Recommended Dosage Regimen - CINV Recommended Dosage Regimen - PONV Recommended Dosage Regimen - RINV
dolasetron (Anzemet®) 50 mg tablets Moderately emetogenic: 100 mg* --- ---
granisetron (generic) 1 mg tablet Moderately or highly emetogenic: 2 mg daily (as a single dose or divided by 12 hours; only on days chemotherapy given)* --- 2 mg once daily*
granisetron (Sancuso®) 3.1 mg/24 hrs transdermal patch Moderately or highly emetogenic: 3.1 mg/24 hrs (one patch) per seven days*** --- ---
  • ondansetron (generic, Zofran®)
  • ondansetron (generic, Zofran® ODT)
  • ondansetron (generic, Zofran®)
  • 4 mg, 8 mg, 24 mg tablets
  • 4 mg, 8 mg orally-disintegrating tablets
  • 4 mg/5 mL oral solution
  • Moderately emetogenic: 8 mg twice daily≠
  • Highly emetogenic: 24 mg (single dose)†
 16 mg*
  • Usual: 8 mg three times daily
  • Total body irradiation: 8 mg (on days radiotherapy given)**
  • Single high-dose fraction to the abdomen: 8 mg**††
  • Daily fractions to the abdomen: 8 mg**†††

Legend:

  • * Doses should be administered within 1 hour before chemotherapy, radiation, or induction of anesthesia
  • ** Doses should be administered within 2 hours before surgery or radiation
  • *** Patch should be applied within 24 to 48 hours before chemotherapy begins and removed a minimum of 24 hours after therapy completion; patch can be worn for up to 7 days depending on the duration of chemotherapy
  • † Doses should be given 30 minutes before the start of single-day therapy
  • ≠ First dose should be given 30 minutes before the start of chemotherapy, with a second dose 8 hours after the first dose, followed by 8 mg twice daily (every 12 hours) continued for 1 to 2 days after completion of chemotherapy
  • †† Subsequent doses should be given every 8 hours after the first dose and continued for 1 to 2 days after completion of radiotherapy
  • ††† Subsequent doses should be given every 8 hours after the first dose each day radiotherapy is given
Table 2. Maximum Recommended Oral Dosage Regimens for Serotonin 5-HT3 Receptor Antagonist Combination Therapy in Adults1,2,5
Drug Name Dosage Form/Strength Recommended Dosage Regimen - CINV Recommended Dosage Regimen - PONV Recommended Dosage Regimen - RINV
netupitant/palonosetron (Akynzeo®) 300 mg netupitant/ 0.5 mg palonosetron capsules 300 mg netupitant/ 0.5 mg palonosetron (1 capsule)*+ -- --

Legend:

  • * Doses should be administered within 1 hour before chemotherapy, radiation, or induction of anesthesia
  • + For highly emetogenic chemotherapy, given concurrently with dexamethasone on days 1-4; with moderately emetogenic chemotherapy, given concurrently with dexamethasone on day 1

1.2. Pediatrics

Table 3 summarizes the current pediatric FDA-approved indications and dosages of the available serotonin 5-HT3 receptor antagonists. Dolasetron and ondansetron are the only oral serotonin 5-HT3 receptor antagonists FDA-approved for the prevention of CINV in children 1. Currently, there are no oral 5-3 receptor antagonists approved for preventing PONV in children. Dolasetron is approved for use in children greater than 2 years of age; safety and efficacy in children less than 2 years of age have not been established 1,2,6 . Ondansetron is approved for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in children 4 years of age and older. There are no data available addressing the use of 24 mg ondansetron tablets for highly emetogenic chemotherapy in children1, 2, 9. Safety and efficacy of granisetron in children less than 18 years of age have not been established1, 2, 7, 8. Netupitant/palonosetron combination therapy is not approved in pediatric patients as safety and efficacy data are not available for this agent in this patient population1, 2, 5. No data are available evaluating serotonin 5-HT3 receptor antagonists for the use of RINV in pediatric patients.

Table 3. Maximum Recommended Oral Pediatric Dosages for Serotonin 5-HT3 Receptor Antagonists1,2,6,9
Drug Name Dosage Form/Strength Recommended Dosage Regimen - CINV Recommended Dosage Regimen - PONV Recommended Dosage Regimen - RINV
dolasetron (Anzemet®) 50 mg tablets Moderately emetogenic: 2-17 years old: 1.8 mg/kg, not to exceed 100 mg*# --- ---
  • ondansetron (generic, Zofran®)
  • ondansetron (generic, Zofran® ODT)
  • ondansetron (generic, Zofran®)
  • 4 mg, 8 mg, 24 mg tablets
  • 4 mg, 8 mg orally-disintegrating tablets
  • 4 mg/5 mL oral solution
  • Moderately emetogenic:
  • ≥12 years old: 8 mg twice daily**
  • 4-11 years old: 4 mg three times daily†
 --- ---

Legend:

  • * Doses should be administered within 1 hour before chemotherapy
  • # For children who cannot take 100 mg due to weight or ability to swallow tablets, the injection solution may be mixed into apple or apple-grape juice for oral dosing in pediatric patients
  • ** The first dose should be given 30 minutes before the start of chemotherapy, with a second dose 8 hours after the first dose, followed by 8 mg twice daily (every 12 hours) continued for 1 to 2 days after completion of chemotherapy
  • † The first dose should be given 30 minutes before the start of chemotherapy, with subsequent doses 4 and 8 hours after the first dose, followed by 4 mg three times daily (every 8 hours) continued for 1 to 2 days after completion of chemotherapy

2. Duration of Therapy

Nausea and vomiting are common side effects of cancer-chemotherapy and radiation therapy. Treatment is usually intermittent and dependent on the emetogenicity of the scheduled therapy.3,4 Patient profiles documenting the use of oral serotonin 5-HT3 receptor antagonists without concurrent antineoplastic therapy will be reviewed. Patient profiles documenting the use of more than one transdermal granisetron (Sancuso®) patch per 7 days will be reviewed. The maximum duration for most cancer chemotherapy regimens is 30 days, although some chemotherapy protocols may last longer. Radiation therapy protocols for some patients may last for six to seven weeks. Unless otherwise specified, 5-HT3 receptor antagonist treatment regimens continuing for greater than 49 days will be reviewed for appropriateness of use. Approximately one-third of surgical patients experience nausea and vomiting after receiving general anesthesia. A single dose of a serotonin 5-HT3 receptor antagonist is usually administered one to two hours before the induction of anesthesia.

3. Duplicative Therapy

The use of two or more serotonin 5-HT3 receptor antagonists concurrently is not justified due to the potentially increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). There are no additional therapeutic benefits when serotonin 5-HT3 receptor antagonists are used in combination. Patient profiles documenting receipt of multiple serotonin 5-HT3 receptor antagonists will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be reviewed to identify those drug regimens, which may result in clinically significant drug-drug interactions. The following drug-drug interactions summarized in Table 4 are considered clinically relevant for serotonin 5-HT3 receptor antagonists. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 4. Major Drug-Drug Interactions for Serotonin 5HT3 Receptor Antagonists
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level*
dolasetron, granisetron, ondansetron, palonosetron QTc interval-prolonging medications (e.g., class Ia anti-arrhythmic agents†, class III anti-arrhythmic agents††, erythromycin, gemifloxacin, ziprasidone, tricyclic antidepressants, phenothiazines, pimozide) increased risk of cardiotoxicity (QTc prolongation, torsades de pointes, cardiac arrest) due to potential for additive QT interval prolongation monitor for interaction; alternative drug therapy may be preferred contraindicated, major (DrugReax) 1-severe, 2-major (CP)
dolasetron, granisetron, ondansetron, palonosetron apomorphine potential for profound hypotension and loss of consciousness due to additive hypotensive effects avoid concurrent use contraindicated (DrugReax)  1-severe (CP)
dolasetron, granisetron, ondansetron, palonosetron serotonergic agents potential for serotonin syndrome with combined therapy due to additive serotonergic effects monitor for signs/ symptoms of serotonin syndrome (e.g., hyperthermia, hypertension, rigidity) and discontinue combined therapy, if symptoms present major (DrugReax) 2-major (CP)

Legend:

  • † Class Ia anti-arrhythmic agents include quinidine, disopyramide, procainamide
  • †† Class III anti-arrhythmic agents include amiodarone, sotalol, dofetilide 
  • * 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 8, 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 8, 2022.
  3. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017 Oct 1;35(28):3240-3261. 
  4. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. Published online July 13, 2020.
  5. Netupitant/palonosetron capsules (Akynzeo®) package insert. Helsinn Therapeutics (U.S.), Inc., June 2021. 
  6. Dolasetron mesylate tablets (Anzemet®) package insert. Validus Pharmaceuticals LLC, September 2021.
  7. Granisetron hydrochloride tablets package insert. Breckenridge Pharmaceutical, Inc., May 2022.
  8. Granisetron transdermal system (Sancuso®) package insert. Kyowa Kirin, Inc., December 2021.
  9. Ondansetron hydrochloride tablets/orally disintegrating tablets/oral solution (Zofran®, Zofran ODT®) Package Insert. Novartis Pharmaceuticals Corporation, October 2021.