Ondansetron

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Ondansetron
Systematic (IUPAC) name
(RS)-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4(9H)-one
Clinical data
Trade names Zofran Ondisolv
AHFS/Drugs.com monograph
MedlinePlus a601209
Pregnancy cat. B1 (AU) B (US)
Legal status Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes Oral, rectal, IV, IM
Pharmacokinetic data
Bioavailability ~60%
Protein binding 70%-76%
Metabolism Hepatic (CYP3A4, CYP1A2, CYP2D6)
Half-life 5.7 hours
Excretion Renal
Identifiers
CAS number 99614-02-5 YesY
ATC code A04AA01
PubChem CID 4595
IUPHAR ligand 2290
DrugBank DB00904
ChemSpider 4434 YesY
UNII 4AF302ESOS YesY
KEGG D00456 YesY
ChEMBL CHEMBL46 YesY
Chemical data
Formula C18H19N3O 
Mol. mass 293.4 g/mol
 YesY (what is this?)  (verify)

Ondansetron (INN), originally marketed under the brand name Zofran, is a serotonin 5-HT3 receptor antagonist used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.

It has little effect on vomiting caused by motion sickness [citation needed], and does not have any effect on dopamine receptors or muscarinic receptors. [citation needed]

Medical uses

Although an effective anti-emetic agent, the high cost of brand-name ondansetron initially limited its use to controlling postoperative nausea and vomiting (PONV) and chemotherapy-induced nausea and vomiting (CINV).[1]

Cancer treatment

The 5-HT3 receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting (CINV) and radiotherapy-induced nausea and vomiting (RINV).

Post-operative

A number of medications including ondansetron appear to be effective in controlling post-operative nausea and vomiting (PONV). It is unclear if it is better than or worse than other agents like droperidol, metoclopramide, or cyclizine.[2]

Pregnancy

Ondansetron is used off-label to treat morning sickness and hyperemesis gravidarum of pregnancy. It is typically used after trials of other drugs have failed.[3]

Cyclic vomiting syndrome

Ondansetron is one of several anti-emetic agents used during the vomiting phase of cyclic vomiting syndrome.[4]

Gastroenteritis

Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration.[5] A retrospective review found that 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 ED. Furthermore, patients who had initially received ondansetron were more likely to be admitted on the return visit than patients who had not received the drug. However, this effect may simply be due to the agent being used more frequently in patients who present with more severe illness. Its use was not found to mask serious diagnoses.[6]

Adverse effects

Ondansetron is a well-tolerated drug with few side effects. Constipation, dizziness and headache are the most commonly reported side effects associated with its use. 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.

QT prolongation

Use of ondansetron has been associated with prolongation of the QT interval, which can lead to the potentially fatal heart rhythm known as Torsade de Pointes. Although this may happen in any patient 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 patients taking other medicines that prolong the QT interval, as well as in patients 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. Patients are cautioned to seek immediate medical care if symptoms such as irregular heartbeat/palpitations, shortness of breath, dizziness, or fainting occur while taking ondansetron.[7]

Overdose

There is no specific treatment for ondansetron overdose; patients are managed with supportive measures. An antidote to ondansetron is not available.[8]

Pharmacodynamics

Ondansetron is a highly specific and selective serotonin 5-HT3 receptor antagonist and 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. 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 not certain whether ondansetron's antiemetic action is mediated centrally, peripherally, or in both sites.

Special populations

Pregnancy

Animal reproduction studies have not shown evidence of harm to the fetus or impairment of fertility with use of high daily doses of ondansetron. Additionally, a cohort study of over 600,000 pregnancies in Denmark found that ondansetron administration during pregnancy was not associated with a significantly increased risk of spontaneous abortion, stillbirth, major birth defect, preterm birth, low birth weight, or small for gestational age.[9] Ondansetron is in pregnancy category B in the US.[8]

Nursing mothers

It is not known if ondansetron is excreted in breast milk.[8]

Pediatric use

Ondansetron has rarely been studied in patients under 4 years of age. As such, there is little data to guide dosage recommendations.[8]

Geriatric use

It is not necessary to adjust the dosage for elderly patients under 75 years of age. The use of Zofran has not been studied in patients older than 75 years of age, and it is not known if dosage should be adjusted for these patients.[8]

Patients with impaired liver function

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

History

A vial of 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,[10] received a use patent June 1988,[11] and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996.[12] Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006.[13] By this final year of its patent (2006), Zofran had become the 20th highest-selling brand-name drug in the United States, with sales totaling USD $1.3 billion (80% from the US).[14] The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.[15]

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 patients 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 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 non-duplicated reports. In the three duplicated reports, the NNT was significantly lower at 3.9 (3.3 to 4.8) with P<0.00001. When all 25 reports were combined the apparent number needed to treat improved to 4.9 (4.4 to 5.6). Inclusion of duplicate reports led to a 23% overestimation of ondansetron's antiemetic efficacy.[16]

In addition, the authors found that the covert duplication of reports on ondansetron was not easy to detect, because of lack of cross-referencing between papers, and that reports containing duplicate findings were cited in eight reviews of the drug.[16] Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.[17]

Society and culture

Brand names[18]

Australia

  • Onsetron
  • Zofran

Bangladesh

  • Emizof
  • Anset
  • Emetron
  • Emistat
  • Emiston
  • Ofran
  • Onaserone
  • Onasia
  • Oncodex
  • Onsat
  • Osetron
  • Seton
  • Zofra
  • Zofra ODT

Brazil

  • Ansentron
  • Modifical
  • Nausedron
  • Ontrax
  • Vonau
  • Zofran

Canada

  • Zofran
  • Zofran ODT

China

  • Aoyimai
  • An Si Xin
  • Di Li Xin
  • En Fu De
  • En Nuo Ping
  • Fu Mi Ting
  • Kang Da Li Te
  • Lu Wei Sen
  • Ou Bei
  • Shi Tai
  • Wei Ze
  • Yi Feng
  • Yi Shu Ning
  • Zofran

Germany

  • axisetron
  • axisetron lingual
  • cellondan
  • cellondan lingual
  • Sigondan
  • Zofran
  • Zofran Zydis Lingual

India

  • Adom-O
  • Afon
  • Domi-UP
  • Doran-O
  • Emeset
  • Emigo
  • Emitus
  • Emtron
  • Flatron
  • Glendan
  • Lupisetron
  • Lupisetron Plus
  • Naucid
  • Novatron
  • Nuset
  • Ond
  • Ond-R
  • Ondai
  • Ondanz
  • Ondar
  • Onsett
  • Onstal
  • Onstar
  • Oset
  • Osetron
  • Periset
  • Rulcer-ON
  • Speronden
  • Supracetron
  • Vomikind
  • Vomipra
  • Vomiven
  • Vomiven-P
  • Vomiz
  • Vona
  • Vorast
  • Zondan
  • Zordil

Indonesia

  • Cedantron
  • Dantroxal
  • Entron

Ireland

  • Emizof
  • Ondran
  • Zofran

Japan

  • Emizof
  • Zofran
  • Zofran Zydis

Mexico

  • Amal
  • Dosartron
  • Frynyvom
  • Lartron
  • Nalisen
  • Zofran

New Zealand

  • Zofran
  • Zofran Zydis

Philippines

  • Emistop
  • Emodan
  • Nozuca
  • Zofan

Russia

  • Emizof
  • Emetron
  • Osetron
  • Setronon
  • Zofran

United Kingdom

  • Ondemet
  • Zofran

United States

  • Zofran
  • Zofran ODT
  • Zuplenz

Vietnam

  • Emeset
  • Prezinton 8
  • Onfran

Research

Psychiatric disorders

A 2006 double-blind, randomized controlled trial indicated that 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.[19] 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.[20][21]

Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease.[22] 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.

Hewlett and others found that the treatment of obsessive compulsive disorder with Ondansetron 1 mg three times daily was associated with a significant decrease in the Yale Brown Obsessive Compulsive scores in a small (n=8), 8-week, open-label study.[23]

Substance use

Ondansetron lowers the cravings for alcohol, especially in early-onset alcoholics. In one cognitive-behavioral therapy study, ondansetron patients with early-onset alcoholism had fewer drinks per day and reported more days without drinking at all, as compared to the other groups in the study. Also of note, individuals with the LL genotype show significant improvements in alcohol misuse when treated with ondansetron, compared with individuals with the other genotypes of the 5HTTLPR polymorphism, who showed no improvement over placebo.[24][25][26]

Researchers at the Stanford University School of Medicine have demonstrated that ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions.[27] Unlike the existing treatments methadone and buprenorphine, it is not itself an opioid.[27] Additionally, it does not require continued supervision like treatment with clonidine.[27]

The original experiment used mice who were injected with increasing doses of morphine, assayed with naloxone and then underwent haplotypic analysis to isolate a gene candidate.[28] HTR3A which codes for the 5-HT3 receptor emerged as the primary candidate, which suggested 5-HT3 antagonist ondansetron as a possible treatment.[28] The researchers were then able to show using an acute morphine administration model the efficacy in withdrawal symptom control in humans.[28]

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 IV dose before anesthesia.[29]

References

  1. ↑ 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. 
  2. ↑ Carlisle JB, Stevenson CA (2006). "Drugs for preventing postoperative nausea and vomiting". Cochrane Database Syst Rev (3): CD004125. doi:10.1002/14651858.CD004125.pub2. PMID 16856030. 
  3. ↑ Smith JA, Refuerzo JS, Ramin SM. "Treatment and outcome of nausea and vomiting of pregnancy". UpToDate. 
  4. ↑ 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". Neurogastroenterol. Motil. 20 (4): 269–84. doi:10.1111/j.1365-2982.2008.01113.x. PMID 18371009. 
  5. ↑ Freedman SB, Adler M, Seshadri R, Powell EC (April 2006). "Oral ondansetron for gastroenteritis in a pediatric emergency department". N. Engl. J. Med. 354 (16): 1698–705. doi:10.1056/NEJMoa055119. PMID 16625009. 
  6. ↑ 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. 
  7. ↑ US Food and Drug Administration. (2012). FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 GlaxoSmithKline. "Zofran". Prescribing Information. U.S. Food and Drug Administration. 
  9. ↑ Pasternak B, Svanström H, Hviid A (February 2013). "Ondansetron in pregnancy and risk of adverse fetal outcomes". N. Engl. J. Med. 368 (9): 814–23. doi:10.1056/NEJMoa1211035. PMID 23445092. 
  10. ↑ 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 
  11. ↑ 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 
  12. ↑ 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 
  13. ↑ "One Year Post-Pediatric Exclusivity Post-marketing Adverse Event Review: Drug Use Data Zofran". Memorandum. U.S. Food and Drug Administration. 2006-03-07. 
  14. ↑ IHS. (2006). Generics firms line up to enter Zofran market. Retrieved from http://www.ihs.com/products/global-insight/industry-economic-report.aspx?id=106598562
  15. ↑ "FDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution". News Release. U.S. Food and Drug Administration. 2006-12-17. 
  16. ↑ 16.0 16.1 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. 
  17. ↑ 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. 
  18. ↑ Drugs.com. (n.d.). Ondansetron. Retrieved February 2, 2014, from http://www.drugs.com/international/ondansetron.html
  19. ↑ 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. 
  20. ↑ 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. 
  21. ↑ 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. 
  22. ↑ 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. 
  23. ↑ Hewlett WA, Schmid SP, Salomon RM (2003). "Pilot trial of ondansetron in the treatment of 8 patients with obsessive compulsive disorder". J Clin Psychiatry 64 (9): 1025–30. doi:10.4088/JCP.v64n0907. PMID 14628977. 
  24. ↑ "Ondansetron can prevent alcohol craving". June 11, 2006. Retrieved 2007-11-05. 
  25. ↑ Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB (1994). "Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence". Alcohol Clin Exp Res 18 (4): 879–85. doi:10.1111/j.1530-0277.1994.tb00054.x. PMID 7978099. 
  26. ↑ "Genes Predict Success of Ondansetron Treatment for Alcoholism". January 25, 2011. Retrieved 2011-01-25. 
  27. ↑ 27.0 27.1 27.2 "Stanford scientists identify drug to treat opioid addiction". 17 FEB 2009. Retrieved 19 FEB 2009. 
  28. ↑ 28.0 28.1 28.2 Chu LF, Liang DY, Li X, Sahbaie P, D'arcy N, Liao G, Peltz G, David Clark J (March 2009). "From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics". Pharmacogenet. Genomics 19 (3): 193–205. doi:10.1097/FPC.0b013e328322e73d. PMC 2730361. PMID 19214139. 
  29. ↑ Generali JA, Cada DJ (August 2009). "Ondansetron: postanesthetic shivering". Hospital Pharmacy 44 (8): 670–1. doi:10.1310/hpj4408-670. 

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