Back To Search Results

Antiemetics, Selective 5-HT3 Antagonists

Editor: John V. Ashurst Updated: 4/19/2024 2:50:13 PM

Indications

The 5-HT3 receptor antagonists available on the US market include dolasetron, granisetron, palonosetron, and ondansetron.[1] Dolanestron, granisetron, and ondansetron are first-generation 5-HT3 receptor antagonists. Palonosetron is a second-generation 5-HT3 receptor antagonist.[2] Tropisetron and ramosetron are not available in the US.[1] 

Serotonin binding to 5-HT3 receptors triggers nausea and vomiting.[3] Serotonin 5-hydroxytryptamine-3 (5-HT3) receptor antagonists exert their activity on receptors located peripherally on gastrointestinal (GI) vagal nerve terminals and centrally in the chemoreceptor trigger zone (CTZ).[4] 

Chemotherapy-induced nausea and vomiting (CINV) may be acute or delayed.[5] Acute CINV usually starts within 2 hours of chemotherapy administration and may last up to 24 hours. Delayed CINV starts 24 hours or more and lasts up to 5 days after chemotherapy administration.[5][6] Breakthrough CINV starts 5 days after chemotherapy administration.[7] Serotonin can trigger acute CINV.[5] Therefore, All 5-HT3 receptor antagonists are effective in preventing acute CINV.[8] Other neurotransmitters may be involved in the pathophysiology of delayed CINV, which explains the limited efficacy of 5-HT3 receptor antagonists in preventing delayed CINV.[5] However, ondansetron and palonosetron prevent delayed CINV in addition to acute CINV.[8][9] Palonosetron is more effective than ondansetron in preventing delayed CINV.[8] Granisetron extended-release subcutaneous formulation is indicated for acute and delayed CINV.[10] Granisetron extended-release subcutaneous formulation is associated with less unscheduled rescue hydration to treat breakthrough CINV compared to palonosetron.[11]

FDA-Approved Indications

Prevention of chemotherapy-induced nausea and vomiting and radiation-induced nausea and vomiting

  • Dolanestron
  • Granisetron
  • Ondansetron
  • Palonosetron [1]

The manufacturer's labeling for dolasetron, granisetron (excluding extended-release subcutaneous formulation), or ondansetron does not specify if the indication is to prevent acute or delayed CINV. Palonosetron's manufacturer labeling specifies its indication to prevent acute and delayed CINV.[8] Granisetron (extended-release subcutaneous) is indicated for the prevention of acute and delayed CINV.[11]

Prevention of postoperative nausea and vomiting

  • Granisetron
  • Ondansetron
  • Palonosetron [1]

Off-label Uses

Ondansetron is used to treat nausea and vomiting associated with pregnancy, but data to support its safety is limited.[12] The risk of fetal cleft palate is increased 2-fold with the use of ondansetron in the first trimester.[13]

Mechanism of Action

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Mechanism of Action

Gastric irritation or cellular damage triggers the intestinal release of 5-HT, which binds to 5-HT3 receptors in the GI tract. The activation of the 5-HT3 receptors triggers nausea and vomiting.[1] Serotonin 5-HT3 receptor antagonists inhibit the activation of the 5-HT3 receptors peripherally and centrally, resulting in antiemetic effects.[1] Palonosetron has a higher binding affinity to the 5-HT3 receptors than the first-generation 5-HT3 receptor antagonists.[3] Additional receptors that trigger nausea and vomiting include dopamine D2 receptors, muscarinic M1 cholinergic receptors, histamine H1 receptors, cannabinoid receptors, and neurokinin-1 (NK1) receptors. Therefore, 5-HT3 receptor antagonists do not treat all causes of emesis. Antiemetics with different mechanisms of action target the other receptors.[1]

Pharmacokinetics

Absorption: Ondansetron, granisetron, and dolasetron have a rapid and complete absorption following oral administration.[14][15][16]

Distribution: Ondansetron has a wide volume of distribution and is about 70% bound to plasma proteins.[14] Granisetron has a high volume of distribution.[15]

Metabolism: Different enzymes of the CYP-450 enzyme system metabolize each of the 5-HT3 receptor antagonists.[3] Patients with high CYP2D6 enzyme activity are less responsive to 5-HT3 receptor antagonists. Ondansetron undergoes hepatic metabolism by CYP3A4, CYP2D6, and CYP1A2. Granisetron undergoes first-pass metabolism by CYP2D6.[3] Ondansetron and granisetron have a bioavailability of 60%.[14][15] The bioavailability of ondansetron in cancer patients is slightly higher.[14][15] Smoking induces the metabolism of granisetron.[17] Dolasetron is a prodrug that undergoes hepatic metabolism to an active metabolite, hydrodolasetron.[16][18] Hydrodolasetron undergoes metabolism by CYP 2D6.[3] Polanosetron undergoes hepatic metabolism and has a bioavailability of about 97% after oral administration.[19]

Elimination: Ondansetron undergoes extensive hepatic metabolism to inactive metabolites.[14] The elimination half-life for ondansetron is about 4 hours. Granisetron undergoes 12% renal excretion.[15] The elimination half-life for granisetron is about 4 to 6 hours. Dolasetron has a half-life of less than 10 minutes, while hydrodolasetron has a half-life of about 7 hours.[3] Unchanged dolasetron undergoes less than 1% excretion in the urine.[16] Polanosetron is longer acting than the first-generation 5-HT3 receptor antagonists and has an elimination half-life of about 40 hours.[19][3] Polanosetron undergoes about 80% renal excretion, with 40% of the drug being excreted unchanged.

Administration

5-HT3 receptor antagonists come in various formulations, offering multiple administration routes.[20] These include oral tablets, orally disintegrating tablets, oral soluble film, oral solution, intramuscular (IM) injection, intravenous (IV) injection, subcutaneous (SubQ) injection, and transdermal patch.[21][22] Palonosetron comes in an IV formulation. Ondansetron is available as oral tablets, orally disintegrating tablets, an oral solution, and IV and IM formulations. Dolasetron comes in an oral tablet and IV solution. Granisetron is available as an oral tablet, oral solution, transdermal patch, an IV formulation, and extended-release SubQ injection. The extended-release subcutaneous formulation of granisetron is long-acting and provides a therapeutic drug concentration for up to 5 days post-injection and is effective for delayed CINV, in addition to acute CINV.[10]

Common dosing and administration regimens for adults include, but are not limited to:

  • Ondansetron: 
    • For nausea and vomiting prophylaxis, chemotherapy-related:
      • IV: (moderately to highly emetogenic chemo): 0.15 mg/kg/dose (maximum 16 mg/dose) every 4 hours for 3 doses.[23] Treatment should be initiated 30 minutes before chemotherapy.
      • PO: (highly emetogenic chemo): 24 mg once 30 minutes before chemotherapy; ODT dose forms should not be chewed or crushed.
      • PO: (moderately emetogenic chemo): 8 mg every 8 hours for 2 doses, then 8 mg every 12 hours until 1 or 2 days after chemotherapy completion. Chemotherapy should be started 30 minutes before. Again, ODT dosage forms should not be cut, crushed, or chewed.
    • Nausea and vomiting prophylaxis, post-operative: 4 mg intramuscularly (IM) or intravenously (IV) for 1 dose.[24]
    • Nausea and vomiting prophylaxis, radiotherapy-related (total body): 8 mg PO for 1 dose, given 1 to 2 hours before each therapy fraction; ODT dosage forms should not be cut, crushed, or chewed.[25]
  • Granisetron:
    • Nausea and vomiting prophylaxis, chemotherapy-related: 10 μg/kg IV 30 minutes before chemotherapy; oral dose within 1 hour before chemo. Alternately, 2 mg PO once or 1 mg PO every 12 hours for 2 doses.[15] Granisetron should only be administered on the days of chemotherapy
    • Nausea and vomiting prophylaxis, radiotherapy-related: 2 mg orally for a single dose; treatment should be started within 1 hour of radiotherapy.[26]
    • Nausea and vomiting prophylaxis, post-operative: 5-20 μg/kg IV as a single dose administered at the end of surgery.[27]
  • Palonosetron:
    • Nausea and vomiting prevention, chemotherapy-related: 0.25 mg IV for 1 dose, started 30 minutes before chemotherapy.[28]
    • Nausea and vomiting prophylaxis, post-operative: 0.075 mg IV for a single dose, started immediately before anesthesia induction.[29]

The American Society of Clinical Oncology (ASCO) guidelines suggest administering granisetron extended-release subcutaneous injection or granisetron transdermal patch to patients undergoing a multiday chemotherapy cycle instead of administering a 5-HT3 receptor antagonist each day of the multiday cycle.[30]

Special Patient Populations

Hepatic impairment: Ondansetron requires dosage adjustment in patients with severe hepatic impairment.[14] Palonosetron, dolasetron, and granisetron do not require a hepatic dosage adjustment

Renal adjustment: Ondansetron, palonosetron, and dolasetron do not require renal dosage adjustment. Granisetron requires renal dosage adjustment and is contraindicated in patients with a creatinine clearance of less than 30 mL/min.

Pregnancy considerations: Ondansetron for nausea and vomiting: 4 mg PO every 8 hours in pregnant women who are not dehydrated or 8 mg IV every 12 hours to be infused over 15 minutes.[31]

Older patients: Ondansetron does not require dosage adjustment in older adults.[14]

Adverse Effects

The serotonin 5-HT3 receptor antagonists share a similar safety and tolerability profile.[32]

Most Common Adverse Reactions [1][33]

  • Headache (9% to 27%)
  • Fatigue (9% to 13%)
  • Malaise (9% to 13%)
  • Constipation (6% to 11%)

One Percent to 10%

Drowsiness, sedation, dizziness, agitation, anxiety, paresthesia, the sensation of cold, pruritus, skin rash, diarrhea, gynecologic disease, urinary retention, transient increase (greater than 2-fold) of serum aminotransferases, injection site reaction, hypoxia, fever.[34]

5-HT3 receptor antagonists carry a risk of dose-dependent QT prolongation.[35] The Food and Drug Administration (FDA) issued a warning about the risk of QT prolongation associated with a single dose of 32 mg intravenous (IV) ondansetron.[35] Most published literature shows that the risk of QT prolongation with 5-HT3 antagonists is clinically insignificant in healthy patients. A review of several studies conducted on healthy patients concludes that dolasetron carries the highest risk of QT prolongation, followed by ondansetron and then granisetron.[36] Further studies are needed to determine the cardiovascular safety of 5-HT3 antagonists in patients with cancer, polypharmacy, and other cardiotoxic medications.[36] Experts recommend using the antiemetic agent with the least known QT prolongation, such as polanosetron, in patients at risk of QT prolongation.[3]

Pregnancy

5-HT3 receptor antagonists are FDA pregnancy category B. Available human studies examining early pregnancy conclude there is not a high risk of congenital malformations. There is a small increased risk of septal defects and cleft palate. Animal studies show no increased risk during early pregnancy. The presence or absence of 5-HT3 receptor antagonists in breast milk has not been established. The American Academy of Obstetrics and Gynecology (ACOG) guidelines provide a treatment algorithm for nausea and vomiting in pregnancy. Ondansetron can be added for patients who remain symptomatic despite the use of a pyridoxine/doxylamine combination along with adjunct therapy.[37] In patients without dehydration, the ACOG guideline recommends oral ondansetron. In patients with dehydration receiving IV fluid replacement, the ACOG guideline recommends IV ondansetron.

Drug-Drug Interactions

The 5-HT3 receptor antagonists are metabolized by different isoenzymes of the cytochrome P450 (CYP450) system.[38][39][40] Therefore, these drugs will likely interact with many prescription or over-the-counter medications and supplements. The clinical significance of the 5-HT3 drug-drug interactions is uncertain because studies are limited.[18] An in-vitro study showed that ketoconazole inhibits the metabolism of granisetron.[18] Granisetron does not inhibit CYP450 enzymes. Ondansetron is metabolized by CYP3A4, CYP2D6, and CYP1A2 enzymes. Therefore, medications that induce or inhibit these CYP450 isoenzymes alter the metabolism of ondansetron. However, ondansetron dosage adjustment is not recommended. Dolasetron is a prodrug activated by CYP450 enzymes in the liver.[18] Drug interactions with commonly used chemotherapy drugs are not clinically significant. The manufacturer of dolasetron does not recommend dosage adjustments. The World Health Organization (WHO), the Food and Drug Administration (FDA), and Health Canada (HC) requested that manufacturers of 5-HT3 receptor antagonists include the risk of serotonin syndrome in drug labeling.[41] However, there is insufficient evidence that administering 5-HT3 receptor antagonists with other serotonergic drugs contributes to the development of serotonin syndrome. The first-generation 5-HT3 receptor antagonists, dolasetron, ondansetron, granisetron, and tropisetron, may cause QT prolongation.[42] Palonosetron does not cause a clinically significant QT prolongation.

Contraindications

The major relative contraindications include the following:

  • Hypersensitivity to 5-HT3 receptor antagonists or any formulation components due to cross-reactivity concerns.
  • Concomitant use with apomorphine due to concern for a decreased level of consciousness and hypotension.[43]

Box Warnings

The 5-HT3 receptor antagonist labeling includes a warning about the risk of serotonin syndrome in combination with other serotonergic drugs. However, the evidence is limited.[41] The 5-HT3 receptor antagonists are associated with a varying level of QT prolongation based on the agent.[2] Ondansetron ODT contains a small amount of phenylalanine. Patients with phenylketonuria cannot metabolize phenylalanine.[44]

Monitoring

Baseline ECG for at-risk patient populations should be obtained, and sodium, potassium, calcium, and magnesium serum levels should be monitored.[45]

Arrhythmia

5-HT3 receptor antagonists have been associated with cardiac arrhythmia.[46] The risk of arrhythmia with 5-HT3 receptor antagonists increases with the concomitant use of other QT-prolonging agents, intravenous route of administration, and patients with a significant medical history.[47] Healthcare professionals should use 5-HT3 receptor antagonists with caution in patients with a history of congenital long QT syndrome, ventricular arrhythmias, cardiac disease, electrolyte abnormalities, or concomitant cardiotoxic chemotherapy.

Serotonin Syndrome

Evidence is insufficient to conclude that 5-HT3 receptor antagonists contribute to the development of serotonin syndrome.[41] However, the World Health Organization (WHO), the US Food and Drug Administration (FDA), and Health Canada suggest a risk of serotonin syndrome by using 5-HT3 receptor antagonists in combination with other serotonergic drugs. The package inserts for the 5-HT3 receptor antagonist require healthcare professionals to monitor patients for signs of serotonin syndrome.[41] Signs and symptoms include mental status changes, autonomic instability, tachycardia, labile blood pressure, diaphoresis, flushing, neuromuscular changes, GI symptoms, and seizures.[48] If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonists and initiate supportive management.

Constipation

Constipation is a commonly reported adverse effect with all formulations of 5-HT3 receptor antagonists.[49] Therefore, healthcare professionals should closely monitor patients at risk of intestinal obstruction.[46]

Toxicity

Overdose is rare, and there is no fatal dose yet established. 5-HT3 receptor antagonists have a broad therapeutic index with mild side effects that occur infrequently. There is no antidote for 5-HT3 receptor antagonists.[50] Therefore, the healthcare team treats patients with supportive therapy, such as IV fluid resuscitation and norepinephrine infusions. In a case report of intentional granisetron overdose, the patient presented with significant hemodynamic instability, characterized by hypotension and ECG changes.[50]

Enhancing Healthcare Team Outcomes

Nausea and vomiting can negatively impact a patient's health and quality of life, especially when induced by cancer treatment. CINV is associated with increased healthcare costs.[51] An interdisciplinary team can ensure that antiemetic guidelines are appropriately followed. Physicians, physician assistants, and nurse practitioners can identify patient-specific factors that increase the risk of CINV, such as female gender, age less than 50 years, and anxiety.[52] Nurses can assess patient history to anticipate nausea and vomiting and advocate to premedicate patients. Pharmacists can identify the emetogenic risk of cancer medications, identify drug interactions and adverse effects, and recommend the appropriate monitoring parameters.[53] An interdisciplinary team can work together to ensure patients understand the antiemetic role of 5-HT3 receptor antagonists in preventing CINV. This will help increase adherence when the healthcare team prescribes additional doses of 5-HT3 receptor antagonists for the patient to take at home.[54]

References


[1]

Machu TK. Therapeutics of 5-HT3 receptor antagonists: current uses and future directions. Pharmacology & therapeutics. 2011 Jun:130(3):338-47. doi: 10.1016/j.pharmthera.2011.02.003. Epub 2011 Feb 26     [PubMed PMID: 21356241]

Level 3 (low-level) evidence

[2]

Tricco AC, Soobiah C, Antony J, Hemmelgarn B, Moher D, Hutton B, Straus SE. Safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery and chemotherapy: protocol for a systematic review and network meta-analysis. Systematic reviews. 2013 Jun 28:2():46. doi: 10.1186/2046-4053-2-46. Epub 2013 Jun 28     [PubMed PMID: 23810058]

Level 1 (high-level) evidence

[3]

Smith HS, Cox LR, Smith EJ. 5-HT3 receptor antagonists for the treatment of nausea/vomiting. Annals of palliative medicine. 2012 Jul:1(2):115-20. doi: 10.3978/j.issn.2224-5820.2012.07.07. Epub     [PubMed PMID: 25841471]


[4]

Lummis SC. 5-HT(3) receptors. The Journal of biological chemistry. 2012 Nov 23:287(48):40239-45. doi: 10.1074/jbc.R112.406496. Epub 2012 Oct 4     [PubMed PMID: 23038271]


[5]

Rapoport BL. Delayed Chemotherapy-Induced Nausea and Vomiting: Pathogenesis, Incidence, and Current Management. Frontiers in pharmacology. 2017:8():19. doi: 10.3389/fphar.2017.00019. Epub 2017 Jan 30     [PubMed PMID: 28194109]


[6]

Navari RM, Aapro M. Antiemetic Prophylaxis for Chemotherapy-Induced Nausea and Vomiting. The New England journal of medicine. 2016 Apr 7:374(14):1356-67. doi: 10.1056/NEJMra1515442. Epub     [PubMed PMID: 27050207]


[7]

Navari RM. Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea and Vomiting. BioMed research international. 2015:2015():595894. doi: 10.1155/2015/595894. Epub 2015 Sep 3     [PubMed PMID: 26421294]


[8]

Gralla R, Lichinitser M, Van Der Vegt S, Sleeboom H, Mezger J, Peschel C, Tonini G, Labianca R, Macciocchi A, Aapro M. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Annals of oncology : official journal of the European Society for Medical Oncology. 2003 Oct:14(10):1570-7     [PubMed PMID: 14504060]

Level 1 (high-level) evidence

[9]

Rao KV, Faso A. Chemotherapy-induced nausea and vomiting: optimizing prevention and management. American health & drug benefits. 2012 Jul:5(4):232-40     [PubMed PMID: 24991322]


[10]

Ottoboni T, Gelder MS, O'Boyle E. Biochronomer™ technology and the development of APF530, a sustained release formulation of granisetron. Journal of experimental pharmacology. 2014:6():15-21. doi: 10.2147/JEP.S68880. Epub 2014 Dec 9     [PubMed PMID: 27186139]


[11]

Barnes M, Calcanes G, Mosier MC, Vacirca J, Malik Z. Granisetron Extended-Release Subcutaneous Injection versus Palonosetron Infusion for CINV Prevention: Cost Comparison of Unscheduled Hydration. American health & drug benefits. 2021 Dec:14(4):133-139     [PubMed PMID: 35261717]


[12]

Koren G. Motherisk update. Is ondansetron safe for use during pregnancy? Canadian family physician Medecin de famille canadien. 2012 Oct:58(10):1092-3     [PubMed PMID: 23064917]


[13]

Anderka M, Mitchell AA, Louik C, Werler MM, Hernández-Diaz S, Rasmussen SA, National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth defects research. Part A, Clinical and molecular teratology. 2012 Jan:94(1):22-30. doi: 10.1002/bdra.22865. Epub 2011 Nov 19     [PubMed PMID: 22102545]


[14]

Roila F, Del Favero A. Ondansetron clinical pharmacokinetics. Clinical pharmacokinetics. 1995 Aug:29(2):95-109     [PubMed PMID: 7586904]

Level 3 (low-level) evidence

[15]

Spartinou A, Nyktari V, Papaioannou A. Granisetron: a review of pharmacokinetics and clinical experience in chemotherapy induced - nausea and vomiting. Expert opinion on drug metabolism & toxicology. 2017 Dec:13(12):1289-1297. doi: 10.1080/17425255.2017.1396317. Epub 2017 Oct 27     [PubMed PMID: 29057666]

Level 3 (low-level) evidence

[16]

Boxenbaum H, Gillespie T, Heck K, Hahne W. Human dolasetron pharmacokinetics: II. Absorption and disposition following single-dose oral administration to normal male subjects. Biopharmaceutics & drug disposition. 1993 Mar:14(2):131-41     [PubMed PMID: 8453023]


[17]

Corrigan BW, Nicholls B, Thakrar B, Lam R, Grosse C, Alianti J, Palmer JL. Heterogeneity in systemic availability of ondansetron and granisetron following oral administration. Drug metabolism and disposition: the biological fate of chemicals. 1999 Jan:27(1):110-2     [PubMed PMID: 9884318]


[18]

Blower PR. 5-HT3-receptor antagonists and the cytochrome P450 system: clinical implications. Cancer journal (Sudbury, Mass.). 2002 Sep-Oct:8(5):405-14     [PubMed PMID: 12416899]


[19]

Chen R, Wang H, Zhong W, Chessari S, Lanzarotti C, Bernareggi A, Hu P. Pharmacokinetics and safety evaluation of oral Palonosetron in Chinese healthy volunteers: A phase 1, open-label, randomized, cross-over study. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2021 May 1:160():105752. doi: 10.1016/j.ejps.2021.105752. Epub 2021 Feb 10     [PubMed PMID: 33581259]

Level 1 (high-level) evidence

[20]

Paul M, Callahan R, Au J, Kindler CH, Yost CS. Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors. Anesthesia and analgesia. 2005 Sep:101(3):715-721. doi: 10.1213/01.ANE.0000160531.65953.77. Epub     [PubMed PMID: 16115980]

Level 3 (low-level) evidence

[21]

National Comprehensive Cancer Network (NCCN). NCCN antiemesis guidelines emphasize 'delayed' emesis, new 5-HT3 inhibitors, and NK-1 blockers. The journal of supportive oncology. 2004 Jul-Aug:2(4):366     [PubMed PMID: 15357520]


[22]

Hargreaves AC, Gunthorpe MJ, Taylor CW, Lummis SC. Direct inhibition of 5-hydroxytryptamine3 receptors by antagonists of L-type Ca2+ channels. Molecular pharmacology. 1996 Nov:50(5):1284-94     [PubMed PMID: 8913360]


[23]

Hainsworth JD, Hesketh PJ. Single-dose ondansetron for the prevention of cisplatin-induced emesis: efficacy results. Seminars in oncology. 1992 Dec:19(6 Suppl 15):14-9     [PubMed PMID: 1485176]


[24]

Kovac AL, O'Connor TA, Pearman MH, Kekoler LJ, Edmondson D, Baughman VL, Angel JJ, Campbell C, Jense HG, Mingus M, Shahvari MB, Creed MR. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. Journal of clinical anesthesia. 1999 Sep:11(6):453-9     [PubMed PMID: 10526822]

Level 1 (high-level) evidence

[25]

Henriksson R, Lomberg H, Israelsson G, Zackrisson B, Franzén L. The effect of ondansetron on radiation-induced emesis and diarrhoea. Acta oncologica (Stockholm, Sweden). 1992:31(7):767-9     [PubMed PMID: 1476756]


[26]

Lanciano R, Sherman DM, Michalski J, Preston AJ, Yocom K, Friedman C. The efficacy and safety of once-daily Kytril (granisetron hydrochloride) tablets in the prophylaxis of nausea and emesis following fractionated upper abdominal radiotherapy. Cancer investigation. 2001:19(8):763-72     [PubMed PMID: 11768028]


[27]

Mikawa K, Takao Y, Nishina K, Shiga M, Maekawa N, Obara H. Optimal dose of granisetron for prophylaxis against postoperative emesis after gynecological surgery. Anesthesia and analgesia. 1997 Sep:85(3):652-6     [PubMed PMID: 9296425]

Level 2 (mid-level) evidence

[28]

Shah A, DeGroot T, Apseloff G. Pharmacokinetic evaluation and safety profile of a 15-minute versus 30-second infusion of palonosetron in healthy subjects. Journal of clinical pharmacology. 2006 Oct:46(10):1139-45     [PubMed PMID: 16988202]


[29]

Kim HJ, Ahn E, Choi GJ, Kang H. Comparison of the Effectiveness of Palonosetron and Ramosetron in Preventing Postoperative Nausea and Vomiting: Updated Systematic Review and Meta-Analysis with Trial Sequential Analysis. Journal of personalized medicine. 2022 Dec 29:13(1):. doi: 10.3390/jpm13010082. Epub 2022 Dec 29     [PubMed PMID: 36675743]

Level 1 (high-level) evidence

[30]

Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Lyman GH. Antiemetics: ASCO Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 Aug 20:38(24):2782-2797. doi: 10.1200/JCO.20.01296. Epub 2020 Jul 13     [PubMed PMID: 32658626]


[31]

Erick M, Cox JT, Mogensen KM. ACOG Practice Bulletin 189: Nausea and Vomiting of Pregnancy. Obstetrics and gynecology. 2018 May:131(5):935. doi: 10.1097/AOG.0000000000002604. Epub     [PubMed PMID: 29683896]


[32]

Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer investigation. 2000:18(2):163-73     [PubMed PMID: 10705879]

Level 2 (mid-level) evidence

[33]

Roila F, Tonato M, Basurto C, Bracarda S, Sassi M, Lupattelli M, Picciafuoco M, Ballatori E, Del Favero A. Ondansetron. European journal of cancer (Oxford, England : 1990). 1993:29A Suppl 1():S16-21     [PubMed PMID: 8427720]


[34]

Piechotta V, Adams A, Haque M, Scheckel B, Kreuzberger N, Monsef I, Jordan K, Kuhr K, Skoetz N. Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis. The Cochrane database of systematic reviews. 2021 Nov 16:11(11):CD012775. doi: 10.1002/14651858.CD012775.pub2. Epub 2021 Nov 16     [PubMed PMID: 34784425]

Level 1 (high-level) evidence

[35]

Singh K, Jain A, Panchal I, Madan H, Gupta A, Sharma A, Gupta S, Kostojchin A, Singh A, Sandhu IS, Mittal J, Bhogal L, Kolli ST, Bejugam VR, Chaturvedi S, Bhalla A, Piplani S. Ondansetron-induced QT prolongation among various age groups: a systematic review and meta-analysis. The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology. 2023 Jul 3:75(1):56. doi: 10.1186/s43044-023-00385-y. Epub 2023 Jul 3     [PubMed PMID: 37395900]

Level 1 (high-level) evidence

[36]

Keefe DL. The cardiotoxic potential of the 5-HT(3) receptor antagonist antiemetics: is there cause for concern? The oncologist. 2002:7(1):65-72     [PubMed PMID: 11854548]


[37]

Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstetrics and gynecology. 2018 Jan:131(1):e15-e30. doi: 10.1097/AOG.0000000000002456. Epub     [PubMed PMID: 29266076]


[38]

Bloomer JC, Baldwin SJ, Smith GJ, Ayrton AD, Clarke SE, Chenery RJ. Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron. British journal of clinical pharmacology. 1994 Dec:38(6):557-66     [PubMed PMID: 7888294]


[39]

Sanwald P, David M, Dow J. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. Drug metabolism and disposition: the biological fate of chemicals. 1996 May:24(5):602-9     [PubMed PMID: 8723743]


[40]

Dixon CM, Colthup PV, Serabjit-Singh CJ, Kerr BM, Boehlert CC, Park GR, Tarbit MH. Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug metabolism and disposition: the biological fate of chemicals. 1995 Nov:23(11):1225-30     [PubMed PMID: 8591723]


[41]

Rojas-Fernandez CH. Can 5-HT(3) Antagonists Really Contribute to Serotonin Toxicity? A Call for Clarity and Pharmacological Law and Order. Drugs - real world outcomes. 2014 Dec:1(1):3-5     [PubMed PMID: 27747475]


[42]

Yavas C, Dogan U, Yavas G, Araz M, Ata OY. Acute effect of palonosetron on electrocardiographic parameters in cancer patients: a prospective study. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2012 Oct:20(10):2343-7. doi: 10.1007/s00520-011-1348-9. Epub 2011 Dec 15     [PubMed PMID: 22170340]


[43]

Martirosov KS, Grigor'ev IuG, Zorin VV, Borovkov MV. [Comparative experimental study of antiemetic action of latranum in radiation-induced vomiting and vomiting caused by apomorphine]. Radiatsionnaia biologiia, radioecologiia. 2003 Jan-Feb:43(1):60-4     [PubMed PMID: 12677660]

Level 3 (low-level) evidence

[44]

van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet journal of rare diseases. 2017 Oct 12:12(1):162. doi: 10.1186/s13023-017-0685-2. Epub 2017 Oct 12     [PubMed PMID: 29025426]


[45]

Etchegoyen CV, Keller GA, Mrad S, Cheng S, Di Girolamo G. Drug-induced QT Interval Prolongation in the Intensive Care Unit. Current clinical pharmacology. 2017:12(4):210-222. doi: 10.2174/1574884713666180223123947. Epub     [PubMed PMID: 29473523]


[46]

Cohen R, Shlomo M, Dil DN, Dinavitser N, Berkovitch M, Koren G. Intestinal obstruction in pregnancy by ondansetron. Reproductive toxicology (Elmsford, N.Y.). 2014 Dec:50():152-3. doi: 10.1016/j.reprotox.2014.10.014. Epub 2014 Oct 24     [PubMed PMID: 25461913]

Level 3 (low-level) evidence

[47]

Freedman SB, Uleryk E, Rumantir M, Finkelstein Y. Ondansetron and the risk of cardiac arrhythmias: a systematic review and postmarketing analysis. Annals of emergency medicine. 2014 Jul:64(1):19-25.e6. doi: 10.1016/j.annemergmed.2013.10.026. Epub 2013 Dec 4     [PubMed PMID: 24314899]

Level 1 (high-level) evidence

[48]

Gillman PK. CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology (Oxford, England). 2011 Mar:25(3):429-36. doi: 10.1177/0269881109359098. Epub 2010 Feb 8     [PubMed PMID: 20142303]

Level 3 (low-level) evidence

[49]

Garsed K,Chernova J,Hastings M,Lam C,Marciani L,Singh G,Henry A,Hall I,Whorwell P,Spiller R, A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014 Oct;     [PubMed PMID: 24334242]

Level 1 (high-level) evidence

[50]

Rochford M, Kiernan TJ, Aziz A. Dolasetron overdose resulting in prolonged QTc interval and severe hypotension: a case report and literature review. Emergency medicine journal : EMJ. 2007 Jul:24(7):515-7     [PubMed PMID: 17582056]

Level 3 (low-level) evidence

[51]

Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2011 Jan:19(1):131-40. doi: 10.1007/s00520-009-0797-x. Epub 2010 Jan 26     [PubMed PMID: 20101417]


[52]

Sekine I, Segawa Y, Kubota K, Saeki T. Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer science. 2013 Jun:104(6):711-7. doi: 10.1111/cas.12146. Epub 2013 Apr 16     [PubMed PMID: 23480814]


[53]

McCullough SW. Chemotherapy-induced nausea and vomiting: roles of pharmacists and formulary decision makers. The American journal of managed care. 2017 Sep:23(14 Suppl):S266-S271     [PubMed PMID: 28978207]


[54]

Smith C, Smith M, Cunningham R, Davis S. Recent Advances in Antiemetics: New Formulations of 5-HT3 Receptor Antagonists in Adults. Cancer nursing. 2020 Jul/Aug:43(4):E217-E228. doi: 10.1097/NCC.0000000000000694. Epub     [PubMed PMID: 30688665]

Level 3 (low-level) evidence