Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ondansetron: Difference between pages

{{Short description|Medication to prevent nausea and vomiting}}

{{Use dmy dates|date=February 2024}}

{{Infobox drug

| verifiedrevid = 477170896

| width = 225

| alt =

| width2 = 250

| alt2 =

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Zofran, Atossa,<ref name="MedicinesFAQ_atossa_odansentron">{{cite web | title= Atossa | website= MedicinesFAQ |year = 2022 | url = https://www.medicinesfaq.com/brand/atossa | access-date = 28 August 2022 |archive-url= https://web.archive.org/web/20220828171406/https://www.medicinesfaq.com/brand/atossa |archive-date= 28 August 2022 |url-status=live }}</ref>{{Unreliable source?|date=August 2022}} others<ref name="Ondansetron international" />

| Drugs.com = {{drugs.com|monograph|ondansetron}}

| DailyMedID = Ondansetron

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Ondansetron Use During Pregnancy | website=Drugs.com | date=3 October 2019 | url=https://www.drugs.com/pregnancy/ondansetron.html | access-date=7 September 2020 | archive-date=18 September 2020 | archive-url=https://web.archive.org/web/20200918212204/https://www.drugs.com/pregnancy/ondansetron.html | url-status=live }}</ref>

| pregnancy_category=

| routes_of_administration = [[Oral administration|orally]] (by mouth), [[Rectal administration|rectal]], [[intravenous therapy|intravenous]], [[intramuscular injection|intramuscular]], [[Thin-film drug delivery|thin film]]

| class =

| ATC_prefix = A04

| ATC_suffix = AA01

| ATC_supplemental =

<!-- Legal status -->

| legal_AU_comment = <ref>{{cite web | title=Zofran Product and Consumer Medicine Information Licence | website=TGA eBS | url=http://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01055-1 | access-date=28 August 2022 | archive-date=29 August 2022 | archive-url=https://web.archive.org/web/20220829011623/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01055-1 | url-status=live }}</ref>

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Zofran Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=43116 | access-date=28 August 2022 | archive-date=29 August 2022 | archive-url=https://web.archive.org/web/20220829011237/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=43116 | url-status=live }}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK_comment = <ref>{{cite web | title=Zofran Tablets 4 mg - Summary of Product Characteristics (SmPC) | website=(emc) | date=19 January 2022 | url=https://www.medicines.org.uk/emc/product/195/smpc | access-date=28 August 2022 | archive-date=29 August 2022 | archive-url=https://web.archive.org/web/20220829011033/https://www.medicines.org.uk/emc/product/195/smpc | url-status=dead }}</ref>

| legal_US_comment = <ref name="Zofran FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{cite web|url=https://www.ema.europa.eu/documents/psusa/ondansetron-list-nationally-authorised-medicinal-products-psusa/00002217/202102_en.pdf|title=List of nationally authorised medicinal products : Active substance: ondansetron :Procedure no.: PSUSA/00002217/202102|website=Ema.europa.eu|access-date=5 March 2022}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| protein_bound = 70–76%

| metabolism = [[Liver]] ([[CYP3A4]], [[CYP1A2]], [[CYP2D6]])

| metabolites =

| onset =

| duration_of_action =

| excretion = [[Kidney]]

<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 2290

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref =

| ChEBI =

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = (''RS'')-9-Methyl-3-[(2-methyl-1''H''-imidazol-1-yl)methyl]-2,3-dihydro-1''H''-carbazol-4(9''H'')-one

| C=18 | H=19 | N=3 | O=1

| SMILES = O=C1c2c3ccccc3n(C)c2CCC1Cn4ccnc4C

| StdInChI_comment =

<!-- Definition and medical uses -->

'''Ondansetron''', sold under the brand name '''Zofran''' among others, is a medication used to prevent [[nausea]] and [[vomiting]] caused by [[Chemotherapy|cancer chemotherapy]], [[radiation therapy]], [[Migraine|migraines]] or surgery.<ref name=AHFS2016 /> It is also effective for treating [[gastroenteritis]].<ref>{{cite journal | vauthors = Schnadower D, Finkelstein Y, Freedman SB | title = Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries | journal = Current Opinion in Gastroenterology | volume = 31 | issue = 1 | pages = 1–6 | date = January 2015 | pmid = 25333367 | doi = 10.1097/mog.0000000000000132 | s2cid = 9334264 }}</ref><ref>{{cite journal | vauthors = Freedman SB, Ali S, Oleszczuk M, Gouin S, Hartling L | title = Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries | journal = Evidence-Based Child Health | volume = 8 | issue = 4 | pages = 1123–37 | date = July 2013 | pmid = 23877938 | doi = 10.1002/ebch.1932 }}</ref> It can be given [[Oral administration|orally]] (by mouth), [[intramuscular|intramuscularly]] (injection into a muscle), or [[intravenously]] (injection into a vein).<ref name=AHFS2016>{{cite web|title=Ondansetron Hydrochloride|url=https://www.drugs.com/monograph/ondansetron-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=11 February 2017|archive-url=https://web.archive.org/web/20160503132329/https://www.drugs.com/monograph/ondansetron-hydrochloride.html|archive-date=3 May 2016|url-status=live}}</ref>

<!-- Side effects and mechanism of action -->

Common [[side effect]]s include [[diarrhea]], [[constipation]], [[headache]], [[sleepiness]], and [[itchiness]].<ref name=AHFS2016 /> Serious side effects include [[QT prolongation]] and [[anaphylaxis|severe allergic reaction]].<ref name=AHFS2016 /> It appears to be safe during [[pregnancy]] but has not been well studied in this group.<ref name=AHFS2016 /> It is a [[serotonin]] [[5-HT3 antagonist|5-HT₃ receptor antagonist]].<ref name=AHFS2016 /> It does not have any effect on [[dopamine receptors]] or [[muscarinic acetylcholine receptor]]s.<ref name=Mil2012>{{cite book| veditors = Miloro M |title=Peterson's principles of oral and maxillofacial surgery.|date=2012|publisher=People's Medical Pub. House-USA|location=Shelton, CT|isbn=978-1-60795-111-7|page=86|edition=3rd|url=https://books.google.com/books?id=Gxo8AwAAQBAJ&pg=PA86|url-status=live|archive-url=https://web.archive.org/web/20160201173938/https://books.google.ca/books?id=Gxo8AwAAQBAJ&pg=PA86|archive-date=1 February 2016}}</ref>

<!-- History, society and culture -->

Ondansetron was patented in 1984 and approved for medical use in 1990.<ref>{{cite book |vauthors=FischerJ, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=448 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA448 |access-date=25 August 2020 |archive-date=12 January 2023 |archive-url=https://web.archive.org/web/20230112141709/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA448 |url-status=live }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2016 /> In 2021, it was the 79th most commonly prescribed medication in the United States, with more than 8{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Ondansetron - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ondansetron | access-date = 14 January 2024}}</ref>

==Medical uses==

Ondansetron is [[indicated]] for the prevention of [[chemotherapy-induced nausea and vomiting]] and [[postoperative nausea and vomiting]].<ref name="Zofran FDA label" /><ref>{{cite web | title=Ondansetron hydrochloride injection | website=DailyMed | date=19 October 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59c4227a-90b6-4297-aacd-05bd097010c1 | access-date=8 July 2023 | archive-date=8 July 2023 | archive-url=https://web.archive.org/web/20230708173847/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59c4227a-90b6-4297-aacd-05bd097010c1 | url-status=live }}</ref>

===Pregnancy===

Ondansetron is used [[off-label]] to treat [[morning sickness]] and [[hyperemesis gravidarum]] of [[pregnancy]]. It is typically used after other antinausea drugs have failed.<ref name="Smith, Judith A. 2011">{{cite web | vauthors = Smith JA, Refuerzo JS, Ramin SM | publisher = UpToDate | title = Treatment and outcome of nausea and vomiting of pregnancy | url = https://www.uptodate.com/contents/nausea-and-vomiting-of-pregnancy-treatment-and-outcome | url-status = live | archive-url = https://web.archive.org/web/20131203014208/http://www.uptodate.com/contents/treatment-and-outcome-of-nausea-and-vomiting-of-pregnancy | archive-date = 3 December 2013 }}</ref>

A large multi-center cohort study found no association between ondansetron exposure and fetal risk compared to other antiemetic drugs. <ref>{{cite journal | vauthors = Dormuth CR, Winquist B, Fisher A, et al. | title = Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort | journal = JAMA Netw Open | date = April 2021 | volume = 4 | issue = 4 | pages = e215329 | doi = 10.1001/jamanetworkopen.2021.5329| pmid = 33890993 | pmc = 8065380 | doi-access = free }}</ref>

===Cyclic vomiting syndrome===

Ondansetron is one of several antiemetic drugs used during the vomiting phase of [[cyclic vomiting syndrome]].<ref name="pmid18371009">{{cite journal | vauthors = Abell TL, Adams KA, Boles RG, Bousvaros A, Chong SK, Fleisher DR, Hasler WL, Hyman PE, Issenman RM, Li BU, Linder SL, Mayer EA, McCallum RW, Olden K, Parkman HP, Rudolph CD, Taché Y, Tarbell S, Vakil N | display-authors = 6 | title = Cyclic vomiting syndrome in adults | journal = Neurogastroenterology and Motility | volume = 20 | issue = 4 | pages = 269–84 | date = April 2008 | pmid = 18371009 | doi = 10.1111/j.1365-2982.2008.01113.x | url = https://deepblue.lib.umich.edu/bitstream/2027.42/72300/1/j.1365-2982.2008.01113.x.pdf | hdl = 2027.42/72300 | s2cid = 8718836 | doi-access = free | access-date = 4 November 2018 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828195918/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/72300/j.1365-2982.2008.01113.x.pdf;jsessionid=96361A3B422890FD8DAE4512F0E07713?sequence=1 | url-status = live }}</ref>

===Gastroenteritis===

Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with [[gastroenteritis]] and dehydration.<ref name="pmid16625009">{{cite journal | vauthors = Freedman SB, Adler M, Seshadri R, Powell EC | title = Oral ondansetron for gastroenteritis in a pediatric emergency department | journal = The New England Journal of Medicine | volume = 354 | issue = 16 | pages = 1698–705 | date = April 2006 | pmid = 16625009 | doi = 10.1056/NEJMoa055119 | doi-access=free | s2cid = 13712069 }}</ref> A retrospective review found it was used commonly for this purpose, being administered in over 58% of cases. Its use reduced hospital admissions, but was also associated with higher rates of return visits to the emergency department. Furthermore, people who had initially received ondansetron were more likely to be admitted on the return visit than people who had not received the drug. However, this effect may simply be due to the agent being used more frequently in people who present with more severe illness. Its use was not found to mask serious diagnoses.<ref name="pmid20031265">{{cite journal | vauthors = Sturm JJ, Hirsh DA, Schweickert A, Massey R, Simon HK | title = Ondansetron use in the pediatric emergency department and effects on hospitalization and return rates: are we masking alternative diagnoses? | journal = Annals of Emergency Medicine | volume = 55 | issue = 5 | pages = 415–22 | date = May 2010 | pmid = 20031265 | doi = 10.1016/j.annemergmed.2009.11.011 }}</ref>

=== Irritable bowel syndrome (IBS) ===

In a study of patients diagnosed as having IBS with diarrhea (IBS-D), ondansetron showed statistically significant effects on stool consistency, frequency, urgency and bloating, but not on pain scores.<ref>{{cite journal | vauthors = Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller R | display-authors = 6 | title = A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea | journal = Gut | volume = 63 | issue = 10 | pages = 1617–1625 | date = October 2014 | pmid = 24334242 | doi = 10.1136/gutjnl-2013-305989 | pmc = 4173656 }}</ref> This was confirmed in a later trial and meta-analysis<ref name="pmid36866724">{{cite journal | vauthors = Gunn D, Topan R, Barnard L, Fried R, Holloway I, Brindle R, Corsetti M, Scott M, Farmer A, Kapur K, Sanders D, Eugenicos M, Trudgill N, Whorwell P, Mclaughlin J, Akbar A, Houghton L, Dinning PG, Aziz Q, Ford AC, Farrin AJ, Spiller R | title = Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial | journal = Alimentary Pharmacology & Therapeutics | volume = 57 | issue = 11 | pages = 1258–1271 | date = June 2023 | pmid = 36866724 | doi = 10.1111/apt.17426 | url = }}</ref> and is included in international guidelines.<ref name="pmid35695704">{{cite journal | vauthors = Savarino E, Zingone F, Barberio B, Marasco G, Akyuz F, Akpinar H, Barboi O, Bodini G, Bor S, Chiarioni G, Cristian G, Corsetti M, Di Sabatino A, Dimitriu AM, Drug V, Dumitrascu DL, Ford AC, Hauser G, Nakov R, Patel N, Pohl D, Sfarti C, Serra J, Simrén M, Suciu A, Tack J, Toruner M, Walters J, Cremon C, Barbara G | title = Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility | journal = United European Gastroenterology Journal | volume = 10 | issue = 6 | pages = 556–584 | date = July 2022 | pmid = 35695704 | pmc = 9278595 | doi = 10.1002/ueg2.12259 | url = }}</ref>

==Special populations==

===Children===

Ondansetron has rarely been studied in people under 4 years of age. As such, little data is available to guide dosage recommendations.<ref name="Zofran FDA label" />

Three open non-comparative studies have been conducted to assess the safety and efficacy of ondansetron in children receiving a variety of chemotherapy regimens.

Ondansetron was well tolerated and none of the patients experienced extrapyramidal symptoms.<ref>{{Cite journal |last=Stevens |first=R F |date=1 January 1991 |title=The role of ondansetron in paediatric patients: a review of three studies |url=https://europepmc.org/article/med/1831631 |journal=European Journal of Cancer |volume=27 |issue=Suppl 1 |pages=S20–2 |issn=1879-0852 |pmid=1831631 |access-date=8 July 2023 |archive-date=8 July 2023 |archive-url=https://web.archive.org/web/20230708132048/https://europepmc.org/article/med/1831631 |url-status=live }}</ref>

==Adverse effects==

[[Headache]] is the most common [[adverse effect]].<ref name="Zofran FDA label" /> A review of use for post-operative nausea and vomiting found that for every 36 people treated, one would experience headache, which could be severe.<ref name="pmid9416710">{{cite journal | vauthors = Tramèr MR, Reynolds DJ, Moore RA, McQuay HJ | title = Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials | journal = Anesthesiology | volume = 87 | issue = 6 | pages = 1277–89 | date = December 1997 | pmid = 9416710 | doi = 10.1097/00000542-199712000-00004 | s2cid = 8049193 | doi-access = free }}</ref>

[[Constipation]], [[diarrhea]], and [[dizziness]] are other commonly reported side effects. It is broken down by the [[liver|hepatic]] [[cytochrome P450]] system and it has little effect on the [[metabolism]] of other drugs broken down by this system.<ref name="AHFS2016" />

===QT prolongation===

Use of ondansetron has been associated with prolongation of the [[QT interval]], which can lead to a potentially fatal heart rhythm known as ''[[torsades de pointes]]''. Although this may happen in any person with any formulation, the risk is most salient with the injectable (intravenous) form of the drug and increases with dose. The risk is also higher in people taking other medicines that prolong the QT interval, as well as in people with [[Long QT syndrome|congenital long QT syndrome]], [[Heart failure|congestive heart failure]], and/or [[Bradycardia|bradyarrhythmias]]. As such, single doses of injectable ondansetron should not exceed 16&nbsp;mg at one time. (Oral dosing recommendations remain intact, including the recommendation of a single 24&nbsp;mg oral dose when indicated.) Electrolyte imbalances should be corrected before the use of injectable ondansetron. People are cautioned to seek immediate medical care if symptoms such as irregular heartbeat/palpitations, shortness of breath, dizziness, or fainting occur while taking ondansetron.<ref>US Food and Drug Administration. (2012). FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Retrieved from {{cite web |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-information-regarding-qt-prolongation-ondansetron-zofran |title=FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran) |website=[[Food and Drug Administration]] |access-date=29 November 2012 |url-status=live |archive-url=https://web.archive.org/web/20121214021055/https://www.fda.gov/Drugs/DrugSafety/ucm310190.htm |archive-date=14 December 2012 }}</ref>

===Overdose===

No specific treatment is available for ondansetron overdose; people are managed with supportive measures. An antidote to ondansetron is not known.<ref name="Zofran FDA label">{{cite web | title=Zofran- ondansetron hydrochloride tablet, film coated | website=DailyMed | date=24 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=555f81bc-4ce0-4f77-b394-b974838c4440 | access-date=7 September 2020 | archive-date=6 August 2020 | archive-url=https://web.archive.org/web/20200806135119/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=555f81bc-4ce0-4f77-b394-b974838c4440 | url-status=live }}</ref>

==Pharmacology==

===Pharmacodynamics===

Ondansetron is a highly [[binding selectivity|selective]] [[5-HT3 receptor|serotonin 5-HT₃ receptor]] [[receptor antagonist|antagonist]], with low [[affinity (pharmacology)|affinity]] for [[dopamine receptor]]s. The 5-HT₃ receptors are present both [[periphery (body)|peripherally]] on [[vagus nerve|vagal nerve]] terminals and centrally in the [[chemoreceptor trigger zone]] of the [[area postrema]] in the [[medulla oblongata|medulla]]. Serotonin is released by the [[enterochromaffin cell]]s of the [[small intestine]] in response to [[chemotherapeutic agent]]s and may stimulate vagal [[afferent nerve fiber|afferent]]s (via 5-HT₃ receptors) to initiate the [[vomiting reflex]]. It is thought that ondansetron's antiemetic action is mediated mostly via antagonism of vagal afferents with a minor contribution from antagonism of [[central nervous system|central]] receptors.<ref>{{cite journal | vauthors = Browning KN | title = Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology | journal = Frontiers in Neuroscience | volume = 9 | pages = 413 | date = October 2015 | pmid = 26578870 | pmc = 4625078 | doi = 10.3389/fnins.2015.00413 | doi-access = free }}</ref> The ''R''– and ''S''–ondansetron isomers have similar potency as serotonin antagonists when tested on ''ex vivo'' rat [[vagus nerve]].<ref name="Butler-1988">{{cite journal |last1=Butler |first1=A |last2=Hill |first2=J M |last3=Ireland |first3=S J |last4=Jordan |first4=C C |last5=Tyers |first5=M B |title=Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors |journal=Br J Pharmacol |date=June 1988 |volume=94 |issue=2 |pages=397–412 |doi=10.1111/j.1476-5381.1988.tb11542.x |pmid=2969267 |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1854010/ |access-date=12 May 2024 |pmc=1854010}}</ref> However, the ''R''–ondansetron enantiomer was 7.9 times more potent as an antagonist of serotonin and [[2-methyl-5-hydroxytryptamine]] (2-methylserotonin) when tested on the longitudinal [[smooth muscle]] from guinea pig [[ileum]]. However, the guinea pig ileum test was likely not as faithful as a test of 5-HT₃ receptor antagonism, because ondansetron only partially blocked the effect of serotonin, while it completely blocked the effect of 2-methylserotonin.<ref name="Butler-1988" />

===Pharmacokinetics===

Ondansetron may have a degree of [[peripherally selective drug|peripheral selectivity]] due to binding to [[P-glycoprotein]] and efflux out of the brain at the [[blood–brain barrier]].<ref name="pmid8647944">{{cite journal | vauthors = Schinkel AH, Wagenaar E, Mol CA, van Deemter L | title = P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs | journal = Journal of Clinical Investigation| volume = 97 | issue = 11 | pages = 2517–24 | date = June 1996 | pmid = 8647944 | pmc = 507337 | doi = 10.1172/JCI118699 | url = }}</ref><ref name="pmid32017606">{{cite journal | vauthors = Kwan C, Bédard D, Frouni I, Gaudette F, Beaudry F, Hamadjida A, Huot P | title = Pharmacokinetic profile of the selective 5-HT3 receptor antagonist ondansetron in the rat: an original study and a minireview of the behavioural pharmacological literature in the rat | journal = Canadian Journal of Physiology and Pharmacology| volume = 98 | issue = 7 | pages = 431–440 | date = July 2020 | pmid = 32017606 | doi = 10.1139/cjpp-2019-0551 | s2cid = 211035717 | url = }}</ref><ref name="pmid16931690">{{cite journal | vauthors = Scott JA, Wood M, Flood P | title = The pronociceptive effect of ondansetron in the setting of P-glycoprotein inhibition | journal = Anesthesia & Analgesia| volume = 103 | issue = 3 | pages = 742–6 | date = September 2006 | pmid = 16931690 | doi = 10.1213/01.ane.0000228861.80314.22 | s2cid = 44405604 | url = | doi-access = free }}</ref> Ondansetron is marketed as a [[racemic]] mixture of ''R''–(–)–ondansetron and ''S''–(+)–ondansetron, and the two enantiomers have significantly different kinetics. In rats given 2 mg/kg intravenous doses of each enantiomer separately, ''R''–(–)–ondansetron was found to have a 37% longer half-life (''P'' < 0.05) and an 87% higher area-under-curve or AUC (''P'' < 0.01) compared to ''S''–(+)–ondansetron, indicating that the ''R'' enantiomer is metabolized more slowly.<ref name="Duan-2018">{{cite journal |last1=Duan |first1=Mingyu |last2=Zhao |first2=Qi |last3=Zhong |first3=Dafang |last4=Yuan |first4=Yue |title=Pharmacokinetics of R-(-)ondansetron compared with that of S-(+)ondansetron in rats using an LC-MS/MS method |journal=Biomed Chromatogr. |date=2018-11-08 |volume=33 |issue=3 |page=e4426 |doi=10.1002/bmc.4426 |pmid=30408206 |url=https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/epdf/10.1002/bmc.4426 |access-date=12 May 2024}}</ref> The chiral carbon in ondansetron is adjacent to a carbonyl group, so [[Enol|keto-enol]] [[tautomerism]] could theoretically lead to interconversion between the two enantiomers under physiologic conditions, if the hydrogen on the chiral carbon were removed and then replaced with opposite chirality. An experiment in rats given each enantiomer separately showed no evidence of this interconversion, the chirality was stable ''in vivo''.<ref name="Duan-2018" /> A study of 141 human patients given 4 or 8 mg of intravenous ondansetron for the prevention of post-operative nausea and vomiting also found that ''R'' and ''S''–ondansetron have different pharmacokinetic properties. Each patient was classified according to their genotype for the liver enzymes CYP2D6 and CYP3A5, and they were put on a spectrum between poor metabolizers (slow) and ultra metabolizers (fast). CYP2D6 was found to be more important for the elimination of ''S''–ondansetron, whereas CYP3A5 genotype had no impact on ''S''–ondansetron plasma levels, measured 3 hours after drug administration. CYP3A5 was more important for ''R''–ondansetron clearance, and CYP2D6 genotype had no consistent effect on plasma levels of ''R''–ondansetron at 3 hours.<ref name="Stamer-2011">{{cite journal |last1=Stamer |first1=Ulrike M |last2=Musshoff |first2=Frank |title=CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care |journal=Anesthesia and Analgesia |date=July 2011 |volume=113 |issue=1 |pages=48–54 |doi=10.1213/ANE.0b013e31821d01bc |pmid=21596874 |url=https://journals.lww.com/anesthesia-analgesia/fulltext/2011/07000/cyp2d6__and_cyp3a_dependent_enantioselective.10.aspx |access-date=12 May 2024}}</ref>

==History==

[[File:Ondansetron (1).JPG|thumb|right|A vial of Zofran 4 mg containing ondansetron for intravenous injection]]

Ondansetron (marketed under the brand name Zofran) was developed in the mid-1980s by [[GlaxoSmithKline]] in London. It was granted US patent protection in September 1987,<ref name="US4695578">{{ cite patent | country = US | number = 4695578 | status =patent | title = 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances | gdate = 22 September 1987 | fdate = 17 November 1986 | inventor = Coates IH, Bell JA, Humber DC, Ewan GB | assign1 = Glaxo Group Limited }}</ref> received a use patent June 1988,<ref name="US4753789">{{ cite patent | country = US | number = 4753789 | status =patent | title = Method for treating nausea and vomiting | gdate = 28 June 1988 | fdate = 24 June 1986 | inventor = Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA | assign1 = Glaxo Group Limited }}</ref> and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996.<ref name="US5578628">{{ cite patent | country = US | number = 5578628 | status =patent | title = Medicaments for the treatment of nausea and vomiting | gdate = 26 November 1996 | fdate = 30 March 1990 | inventor = Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA | assign1 = Glaxo Group Limited }}</ref> Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006.<ref name="url_fda_pe">{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b_06_03_OndansetronUseReview%20Cleared.pdf | title = One Year Post-Pediatric Exclusivity Post-marketing Adverse Event Review: Drug Use Data Zofran | date = 7 March 2006 | work = Memorandum | publisher = U.S. Food and Drug Administration | url-status = live | archive-url = https://web.archive.org/web/20150924170611/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b_06_03_OndansetronUseReview%20Cleared.pdf | archive-date = 24 September 2015 }}</ref> By this final year of its patent (2006), Zofran had become the 20th highest-selling brand-name drug in the United States, with sales of US$1.3 billion in the first 9 months of 2006 (80% from the US).<ref>IHS. (2006). Generics firms line up to enter Zofran market. Retrieved from {{cite web |url=https://ihsmarkit.com/country-industry-forecasting.html?id=106598562 |title=Generics Firms Line Up to Enter Zofran Market |access-date=20 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20140201231754/http://www.ihs.com/products/global-insight/industry-economic-report.aspx?id=106598562 |archive-date=1 February 2014 }}</ref> The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to [[Teva Pharmaceutical Industries|Teva Pharmaceuticals USA]] and SICOR Pharmaceuticals.<ref name="urlFDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution">{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108817.htm | title = FDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution | date = 17 December 2006 | publisher = U.S. Food and Drug Administration | url-status = dead | archive-url = https://web.archive.org/web/20140618211006/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108817.htm | archive-date = 18 June 2014 }}</ref> In 2018, [[University of São Paulo]] and Biolab were granted a patent for an [[Orodispersible tablet|orodispersible]] form of the drug.<ref>{{Cite web|title=Sabia que um remédio para enjoo traz 90% dos royalties que a USP recebe? - Agência USP de Inovação|url=http://www.inovacao.usp.br/sabia-que-um-remedio-para-enjoo-traz-90-dos-royalties-que-a-usp-recebe/|access-date=6 October 2020|language=pt-BR}}</ref>

==Society and culture==

===Publication bias===

In 1997, ondansetron was the subject of a [[meta-analysis]] case study published in the ''[[British Medical Journal]]''. Researchers examined 84 trials, with 11,980 people receiving ondansetron, published between 1991 and September 1996. Intravenous ondansetron 4&nbsp;mg versus placebo was investigated in 16 reports and three further reports which had been duplicated a total of six times. The [[number needed to treat]] (NNT) to prevent vomiting within 24 hours was 9.5, with 95% confidence interval 6.9 to 15, in the 16 nonduplicated reports. In the three duplicated reports, the NNT was significantly lower at 3.9 (3.3 to 4.8). When all 25 reports were combined, the apparent NNT improved to 4.9 (4.4 to 5.6). Inclusion of duplicate reports led to a 23% overestimation of ondansetron's antiemetic efficacy.<ref name=Tramer>{{cite journal | vauthors = Tramèr MR, Reynolds DJ, Moore RA, McQuay HJ | title = Impact of covert duplicate publication on meta-analysis: a case study | journal = BMJ | volume = 315 | issue = 7109 | pages = 635–40 | date = September 1997 | pmid = 9310564 | pmc = 2127450 | doi = 10.1136/bmj.315.7109.635 }}</ref>

In addition, the authors found the covert duplication of reports on ondansetron was not easy to detect, because of lack of cross-referencing between papers, and reports containing duplicate findings were cited in eight reviews of the drug.<ref name=Tramer /> Their analysis was a subject of an editorial in the ''[[Journal of the American Medical Association]]'' in 1999.<ref name=Rennie>{{cite journal | vauthors = Rennie D | title = Fair conduct and fair reporting of clinical trials | journal = JAMA | volume = 282 | issue = 18 | pages = 1766–8 | date = November 1999 | pmid = 10568651 | doi = 10.1001/jama.282.18.1766 }}</ref>

===Availability===

Ondansetron is a [[generic medication]] and is available in many countries under many brand names.<ref name="Ondansetron international">{{cite web | title=Ondansetron international | website=Drugs.com | date=2 September 2020 | url=https://www.drugs.com/international/ondansetron.html | access-date=2 February 2014 | archive-url=https://web.archive.org/web/20140221202123/https://www.drugs.com/international/ondansetron.html |archive-date=21 February 2014 |url-status=live }}</ref>

==References==

{{Reflist}}

{{5-HT3 antagonists}}

{{Serotonin receptor modulators}}

{{GlaxoSmithKline}}

{{Portal bar|Medicine}}

[[Category:Antiemetics]]

[[Category:5-HT3 antagonists]]

[[Category:Imidazoles]]

[[Category:Ketones]]

[[Category:Peripherally selective drugs]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]