Trials in emergency department settings support the use of ondansetron to abort vomiting episodes associated withgastroenteritis anddehydration.[20] A randomized controlled trial using a single dose of oral ondansetron in children with presumably viral gastroenteritis found it to be highly effective in stopping vomiting and increasing the effectiveness of oral rehydration therapy, thereby significantly increasing patient satisfaction. Only 16 of the 123 children treated with ondansetron vomited in the following 6 hours.[21] A retrospective review found that ondansetron was used commonly for vomiting due to gastroenteritis, 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.[22]
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.[23] This was confirmed in a later trial and meta-analysis[24] and is included in international guidelines.[25]
Ondansetron has rarely been studied in people under 4 years of age. As such, little data is available to guide dosage recommendations.[6]
Three open non-comparative studies have been conducted to assess the safety and efficacy of ondansetron in children receiving a variety of chemotherapy regimens.[26]
Ondansetron was well tolerated and none of the patients experienced extrapyramidal symptoms.[27]
Headache is the most commonadverse effect.[6] 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.[28]
Use of ondansetron has been associated with prolongation of theQT interval, which can lead to a potentially fatal heart rhythm known astorsades 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 withcongenital long QT syndrome,congestive heart failure, and/orbradyarrhythmias. As such, single doses of injectable ondansetron should not exceed 16 mg at one time. (Oral dosing recommendations remain intact, including the recommendation of a single 24 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.[29]
In 2012, theWorld Health Organization[30] &Food and Drug Administration,[31] andHealth Canada in 2014,[32] released reports and added aboxed warning, that stated use of ondansetron in conjunction withserotonergic drugs (SSRIs,SNRIs,MAOIs &TCAs) had been linked to rare cases ofserotonin syndrome.[33] Although some members of the scientific and medical community believe these reports were released without substantive evidential foundation, and that the studies cited by the FDA, WHO and HC were flawed. Claiming there is no clear and convincing evidence that ondansetron is capable of causing serotonin syndrome, nor any well documented cases where serotonin syndrome could be definitively linked to ondansetron use with a serotonergic drug, leading to needless avoidance of ondansetron for patients taking SSRIs, SNRIs and tricyclics.[33]
Ondansetron is a highlyselectiveserotonin 5-HT3 receptorantagonist, with lowaffinity fordopamine receptors. The 5-HT3 receptors are present bothperipherally onvagal nerve terminals and centrally in thechemoreceptor trigger zone of thearea postrema in themedulla. Serotonin is released by theenterochromaffin cells of thesmall intestine in response tochemotherapeutic agents and may stimulate vagalafferents (via 5-HT3 receptors) to initiate thevomiting reflex. It is thought that ondansetron's antiemetic action is mediated mostly via antagonism of vagal afferents with a minor contribution from antagonism ofcentral receptors.[34] TheR– andS–ondansetron isomers have similar potency as serotonin antagonists when tested onex vivo ratvagus nerve.[35] However, theR–ondansetron enantiomer was 7.9 times more potent as an antagonist of serotonin and2-methyl-5-hydroxytryptamine (2-methylserotonin) when tested on the longitudinalsmooth muscle from guinea pigileum. 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.[35]
Ondansetron may have a degree ofperipheral selectivity due to binding toP-glycoprotein and efflux out of the brain at theblood–brain barrier.[36][37][38] Ondansetron is marketed as aracemic mixture ofR–(–)–ondansetron andS–(+)–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 toS–(+)–ondansetron, indicating that theR enantiomer is metabolized more slowly.[39] The chiral carbon in ondansetron is adjacent to a carbonyl group, soketo-enoltautomerism 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 stablein vivo.[39] 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 thatR andS–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 ofS–ondansetron, whereas CYP3A5 genotype had no impact onS–ondansetron plasma levels, measured 3 hours after drug administration. CYP3A5 was more important forR–ondansetron clearance, and CYP2D6 genotype had no consistent effect on plasma levels ofR–ondansetron at 3 hours.[40]
A vial of Zofran 4 mg containing ondansetron for intravenous injection
Ondansetron (marketed under the brand name Zofran) was developed in the mid-1980s byGlaxoSmithKline in London. It was granted U.S. patent protection in September 1987,[41] received a use patent June 1988,[42] and was approved by the U.S.Food and Drug Administration (FDA) in January 1991. It was granted another divisional patent in November 1996.[43] Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006.[44] 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).[45] The first generic versions were approved by the U.S. FDA in December 2006, with marketing approval granted toTeva Pharmaceuticals USA and SICOR Pharmaceuticals.[46]
In December 2012, the FDA announced that the 32mg, single intravenous (IV) dose of ondansetron was being withdrawn from U.S. market because of the potential for serious cardiac issues from prolonged QT interval.[47]
In 1997, ondansetron was the subject of ameta-analysis case study. Researchers examined 84 trials, with 11,980 people receiving ondansetron, published between 1991 and September 1996. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports and three further reports which had been duplicated a total of six times. Thenumber 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.[49]
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.[49] Their analysis was a subject of an editorial in theJournal of the American Medical Association in 1999.[50]
^Schnadower D, Finkelstein Y, Freedman SB (January 2015). "Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries".Current Opinion in Gastroenterology.31 (1):1–6.doi:10.1097/mog.0000000000000132.PMID25333367.S2CID9334264.
^Freedman SB, Ali S, Oleszczuk M, Gouin S, Hartling L (July 2013). "Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries".Evidence-Based Child Health.8 (4):1123–37.doi:10.1002/ebch.1932.PMID23877938.
^World Health Organization (2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Sturm JJ, Hirsh DA, Schweickert A, Massey R, Simon HK (May 2010). "Ondansetron use in the pediatric emergency department and effects on hospitalization and return rates: are we masking alternative diagnoses?".Annals of Emergency Medicine.55 (5):415–22.doi:10.1016/j.annemergmed.2009.11.011.PMID20031265.
^Gunn D, Topan R, Barnard L, Fried R, Holloway I, Brindle R, et al. (June 2023). "Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial".Alimentary Pharmacology & Therapeutics.57 (11):1258–1271.doi:10.1111/apt.17426.PMID36866724.
^Kwan C, Bédard D, Frouni I, Gaudette F, Beaudry F, Hamadjida A, et al. (July 2020). "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".Canadian Journal of Physiology and Pharmacology.98 (7):431–440.doi:10.1139/cjpp-2019-0551.PMID32017606.S2CID211035717.
^abDuan M, Zhao Q, Zhong D, Yuan Y (March 2019). "Pharmacokinetics of R-(-)ondansetron compared with that of S-(-)ondansetron in rats using an LC-MS/MS method".Biomedical Chromatography.33 (3) e4426.doi:10.1002/bmc.4426.PMID30408206.
^Stamer UM, Lee EH, Rauers NI, Zhang L, Kleine-Brueggeney M, Fimmers R, et al. (July 2011). "CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care".Anesthesia and Analgesia.113 (1):48–54.doi:10.1213/ANE.0b013e31821d01bc.PMID21596874.
^US patent 4695578, Coates IH, Bell JA, Humber DC, Ewan GB, "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", issued 22 September 1987, assigned to Glaxo Group Limited
^US patent 4753789, Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA, "Method for treating nausea and vomiting", issued 28 June 1988, assigned to Glaxo Group Limited
^US patent 5578628, Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA, "Medicaments for the treatment of nausea and vomiting", issued 26 November 1996, assigned to Glaxo Group Limited
^Rossi GN, Hallak JE, Bouso Saiz JC, Dos Santos RG (June 2022). "Safety issues of psilocybin and LSD as potential rapid acting antidepressants and potential challenges".Expert Opinion on Drug Safety.21 (6):761–776.doi:10.1080/14740338.2022.2066650.PMID35426754.
^Glennon RA, Dukat M (May 2023). "Quipazine: Classical hallucinogen? Novel psychedelic?".Australian Journal of Chemistry.76 (5):288–298.doi:10.1071/CH22256.ISSN0004-9425.
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