Ondansetron

Ondansetron
Names
Trade namesZofran, Zuplenz, Ondisolv, others
IUPAC name
  • (RS)-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4(9H)-one
Clinical data
Drug classSerotonin 5-HT3 receptor antagonist[1]
Main usesNausea, vomiting[1]
Side effectsDiarrhea, constipation, headache, sleepiness, itchiness[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
    Routes of
    use    		By mouth, rectal, intravenous therapy (IV), intramuscular injection (IM), thin film
    Defined daily dose16 mg[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa601209
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability~60%
    Protein binding70–76%
    MetabolismLiver (CYP3A4, CYP1A2, CYP2D6)
    Elimination half-life5.7 hours
    ExcretionKidney
    Chemical and physical data
    FormulaC18H19N3O
    Molar mass293.370 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C1c2c3ccccc3n(C)c2CCC1Cn4ccnc4C
    InChI
    • InChI=1S/C18H19N3O/c1-12-19-9-10-21(12)11-13-7-8-16-17(18(13)22)14-5-3-4-6-15(14)20(16)2/h3-6,9-10,13H,7-8,11H2,1-2H3 checkY
    • Key:FELGMEQIXOGIFQ-UHFFFAOYSA-N checkY

    Ondansetron, marketed under the brand name Zofran, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery.[2] It is also effective for treating gastroenteritis.[4][5] It is ineffective for treating vomiting caused by motion sickness.[6] It can be given by mouth or by injection into a muscle or into a vein.[2]

    Common side effects include diarrhea, constipation, headache, sleepiness, and itchiness.[2] Serious side effects include QT prolongation and severe allergic reaction.[2] It appears to be safe during pregnancy but has not been well studied in this group.[2] It is a serotonin 5-HT3 receptor antagonist.[2] It does not have any effect on dopamine receptors or muscarinic receptors.[7]

    Ondansetron was patented in 1984 and approved for medical use in 1990.[8] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[2] The wholesale cost of the injectable form in the developing world is about US$0.10 to US$0.76 per dose.[10] In the United States it costs about US$1.37 per tablet.[2] In 2017, it was the 83rd most commonly prescribed medication in the United States, with more than nine million prescriptions.[11][12]

    Medical uses

    Although an effective antiemetic agent, the high cost of brand-name ondansetron initially limited its use to controlling postoperative nausea and vomiting and chemotherapy-induced nausea and vomiting.[13]

    Cancer treatment

    The 5-HT3 receptor antagonists are the primary medications used to treat and prevent chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting.

    Postoperative

    A number of medications including ondansetron appear to be effective in controlling postoperative nausea and vomiting. It is more effective than metoclopramide, and less sedating than cyclizine or droperidol.

    Pregnancy

    Ondansetron is used off-label to treat morning sickness and hyperemesis gravidarum of pregnancy. It is typically used after trials if other drugs have failed.[14]

    There appears to be a low risk of harm to the baby with use during pregnancy, though there may be an increase in heart problems among the babies.[15][16]

    Ondansetron is in pregnancy category B in the US.[17] It is not known if ondansetron is excreted in breast milk.[17]

    Cyclic vomiting syndrome

    Ondansetron is one of several antiemetic drugs used during the vomiting phase of cyclic vomiting syndrome.[18]

    Gastroenteritis

    Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration.[19] 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.[20]

    Dosage

    The defined daily dose is 16 mg by mouth, by injection, or rectally.[3] In adults it may be used as 4 mg three times per day.[1] In children the dose is 0.1 mg/kg up to three times per day.[1]

    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.[17]

    Elderly

    It is not necessary to adjust the dosage for people under 75 years of age. The use of ondansetron has not been studied in people older than 75 years of age, and it is not known if dosage should be adjusted for this group.[17]

    Poor liver function

    The maximum recommended dose for people with severe liver function impairment is 8 mg/day. In these people, ondansetron is cleared from the body at half to one-third the rate as in healthy people. The concentration of ondansetron in body tissues as opposed to plasma is also higher than in healthy people.[17]

    Side effects

    Headache is the most common side effect.[21] 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.[22]

    Constipation, diarrhea, and dizziness are other commonly reported side effects.[2] It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system. Anecdotally, ototoxicity has also been reported if injected too quickly.[2]

    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 congenital long QT syndrome, congestive heart failure, and/or bradyarrhythmias. 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.[23]

    Overdose

    No specific treatment is available for ondansetron overdose; people are managed with supportive measures. An antidote to ondansetron is not known.[17]

    Pharmacodynamics

    Ondansetron is a highly specific and selective serotonin 5-HT3 receptor antagonist, with low affinity for dopamine receptors. The 5-HT3 receptors are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema in the medulla. Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (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 receptors.[24]

    History

    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,[25] received a use patent June 1988,[26] and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996.[27] Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006.[28] 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).[29] The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.[30]

    Society and culture

    Cost

    The wholesale cost of the injectable form in the developing world is about US$0.10 to US$0.76 per dose.[10] In the United States it costs about US$1.37 per tablet.[2] In 2017, it was the 83rd most commonly prescribed medication in the United States, with more than nine million prescriptions.[11][12]

    • Ondansetron costs (US)
      Ondansetron costs (US)
    • Ondansetron prescriptions (US)
      Ondansetron prescriptions (US)

    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 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.[31]

    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.[31] Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.[32]

    Availability

    Ondansetron is a generic drug and is available in many countries under many brand names.[33] Brands include Zofran and Zuplenz.

    Routes

    It can be given by mouth, as a tablet or orally disintegrating tablet, or by injection into a muscle or into a vein.[2]

    Research

    Psychiatric disorders

    A 2006 double-blind, randomized controlled trial indicated ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. The study found the combination to significantly improve negative schizophrenia symptoms, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.[34] An earlier, smaller, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia, and the study patients also showed significant improvement in the disease's symptoms.[35][36]

    Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease.[37] Its apparent benefits despite a lack of any significant antagonistic properties at dopamine receptors or the 5-HT2A receptor raises interesting questions about the etiology of psychosis.

    Substance use

    There is tentative evidence that it may be useful in decreasing the desired effects of alcohol.[38] There is also some tentative evidence in those who are addicted to stimulants.[39]

    Postanesthetic shivering

    Two small, placebo-controlled trials have been conducted to assess the efficacy of ondansetron for postanesthetic shivering, a common occurrence after surgery. Ondansetron was found to be as effective as pethidine (meperidine, Demerol) when given as a single intravenous dose before anesthesia.[40]

    References

    1. 1 2 3 4 "ONDANSETRON injectable - Essential drugs". medicalguidelines.msf.org. Archived from the original on 28 August 2021. Retrieved 4 September 2020.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Ondansetron Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on May 3, 2016. Retrieved February 11, 2017.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 18 October 2020. Retrieved 4 September 2020.
    4. ↑ 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. PMID 25333367.
    5. ↑ 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: A Cochrane Review Journal. 8 (4): 1123–37. doi:10.1002/ebch.1932. PMID 23877938.
    6. ↑ Sutton, M; Mounsey, AL; Russell, RG (15 July 2012). "FPIN's Clinical Inquiries. Treatment of motion sickness". American Family Physician. 86 (2): 192–5. PMID 22962932.
    7. ↑ Miloro, ed. by Michael (2012). Peterson's principles of oral and maxillofacial surgery (3rd ed.). Shelton, CT: People's Medical Pub. House-USA. p. 86. ISBN 978-1-60795-111-7. Archived from the original on 2016-02-01.
    8. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 448. ISBN 9783527607495. Archived from the original on 2019-12-22. Retrieved 2019-02-28.
    9. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    10. 1 2 "Ondansetron". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 26 January 2016.
    11. 1 2 "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 11 April 2020.
    12. 1 2 "Ondansetron - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 11 April 2020.
    13. ↑ Cooke, C. E.; Mehra, I. V. (1994). "Oral ondansetron for preventing nausea and vomiting". American Journal of Hospital Pharmacy. 51 (6): 762–771. PMID 8010314.
    14. ↑ Smith JA, Refuerzo JS, Ramin SM. "Treatment and outcome of nausea and vomiting of pregnancy". UpToDate. Archived from the original on 2013-12-03.
    15. ↑ Carstairs, SD (May 2016). "Ondansetron Use in Pregnancy and Birth Defects: A Systematic Review". Obstetrics and Gynecology. 127 (5): 878–83. doi:10.1097/AOG.0000000000001388. PMID 27054939.
    16. ↑ Committee on Practice Bulletins-Obstetrics (2018-01-01). "Acog Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy". Obstetrics & Gynecology. 131 (1): e15–e30. doi:10.1097/AOG.0000000000002456. ISSN 0029-7844. PMID 29266076.
    17. 1 2 3 4 5 6 GlaxoSmithKline. "Zofran" (PDF). Prescribing Information. U.S. Food and Drug Administration. Archived (PDF) from the original on 2013-12-03.
    18. ↑ 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 (April 2008). "Cyclic vomiting syndrome in adults" (PDF). Neurogastroenterol. Motil. 20 (4): 269–84. doi:10.1111/j.1365-2982.2008.01113.x. hdl:2027.42/72300. PMID 18371009. Archived from the original on 2021-08-28. Retrieved 2018-11-04.
    19. ↑ Freedman SB, Adler M, Seshadri R, Powell EC (April 2006). "Oral ondansetron for gastroenteritis in a pediatric emergency department" (PDF). N. Engl. J. Med. 354 (16): 1698–1705. doi:10.1056/NEJMoa055119. PMID 16625009.
    20. ↑ 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?". Ann Emerg Med. 55 (5): 415–22. doi:10.1016/j.annemergmed.2009.11.011. PMID 20031265.
    21. ↑ "DailyMed - ONDANSETRON HYDROCHLORIDE - ondansetron hydrochloride injection, solution". dailymed.nlm.nih.gov. Archived from the original on 2018-02-23. Retrieved 2018-02-22.
    22. ↑ Efficacy, dose-response, and safety of ondansetron in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Tramèr MR, Reynolds DJ, Moore RA, McQuay HJ. Anesthesiology. 1997 Dec;87(6):1277-89.
    23. ↑ US Food and Drug Administration. (2012). FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Retrieved from "Archived copy". Archived from the original on 2012-12-14. Retrieved 2012-11-29.{{cite web}}: CS1 maint: archived copy as title (link)
    24. ↑ Browning, KN (29 October 2015). "Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology". Frontiers in Neuroscience. 9: 413. doi:10.3389/fnins.2015.00413. PMC 4625078. PMID 26578870.
    25. ↑ 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 1987-09-22, assigned to Glaxo Group Limited 
    26. ↑ US patent 4753789, Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA, "Method for treating nausea and vomiting", issued 1988-06-28, assigned to Glaxo Group Limited 
    27. ↑ US patent 5578628, Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA, "Medicaments for the treatment of nausea and vomiting", issued 1996-11-26, assigned to Glaxo Group Limited 
    28. ↑ "One Year Post-Pediatric Exclusivity Post-marketing Adverse Event Review: Drug Use Data Zofran" (PDF). Memorandum. U.S. Food and Drug Administration. 2006-03-07. Archived (PDF) from the original on 2015-09-24.
    29. ↑ IHS. (2006). Generics firms line up to enter Zofran market. Retrieved from "Archived copy". Archived from the original on 2014-02-01. Retrieved 2014-01-20.{{cite web}}: CS1 maint: archived copy as title (link)
    30. ↑ "FDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution". News Release. U.S. Food and Drug Administration. 2006-12-17. Archived from the original on 2014-06-18.
    31. 1 2 Tramèr MR, Reynolds DJ, Moore RA, McQuay HJ (September 1997). "Impact of covert duplicate publication on meta-analysis: a case study". BMJ. 315 (7109): 635–40. doi:10.1136/bmj.315.7109.635. PMC 2127450. PMID 9310564. Archived from the original on 2013-12-03.
    32. ↑ Rennie D (November 1999). "Fair conduct and fair reporting of clinical trials". JAMA. 282 (18): 1766–8. doi:10.1001/jama.282.18.1766. PMID 10568651.
    33. ↑ Drugs.com. Ondansetron international page from drugs.com Archived 2014-02-21 at the Wayback Machine Retrieved February 2, 2014
    34. ↑ Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ (2006). "Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study". Schizophrenia Research. 88 (1–3): 102–10. doi:10.1016/j.schres.2006.07.010. PMID 16959472.
    35. ↑ Zullino DF, Eap CB, Voirol P (2001). "Ondansetron for tardive dyskinesia". Am J Psychiatry. 158 (4): 657–8. doi:10.1176/appi.ajp.158.4.657-a. PMID 11282718.
    36. ↑ Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD (February 2000). "Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia". Am J Psychiatry. 157 (2): 287–9. doi:10.1176/appi.ajp.157.2.287. PMID 10671405. Archived from the original on 2007-08-11. Retrieved 2007-09-22.
    37. ↑ Zoldan J, Friedberg G, Livneh M, Melamed E (1995). "Psychosis in advanced Parkinson's disease: treatment with ondansetron, a 5-HT3 receptor antagonist". Neurology. 45 (7): 1305–8. doi:10.1212/WNL.45.7.1305. PMID 7617188.
    38. ↑ Miller, PM; Book, SW; Stewart, SH (2011). "Medical treatment of alcohol dependence: a systematic review". International Journal of Psychiatry in Medicine. 42 (3): 227–66. doi:10.2190/pm.42.3.b. PMC 3632430. PMID 22439295.
    39. ↑ Lee, TH; Szabo, ST; Fowler, JC; Mannelli, P; Mangum, OB; Beyer, WF; Patkar, A; Wetsel, WC (1 July 2012). "Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy". Drug and Alcohol Dependence. 124 (1–2): 11–8. doi:10.1016/j.drugalcdep.2012.01.021. PMC 3500569. PMID 22356892.
    40. ↑ Generali JA, Cada DJ (August 2009). "Ondansetron: postanesthetic shivering" (PDF). Hospital Pharmacy. 44 (8): 670–1. doi:10.1310/hpj4408-670. Archived (PDF) from the original on 2011-07-10.
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