Ondansetron

Ondansetron (INN)
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, others
AHFS/Drugs.com monograph
MedlinePlus a601209
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 Oral, rectal, IV, IM
Pharmacokinetic data
Bioavailability ~60%
Protein binding 70%-76%
Metabolism Liver (CYP3A4, CYP1A2, CYP2D6)
Biological half-life 5.7 hours
Excretion Kidney
Identifiers
CAS Number 99614-02-5 YesY
ATC code A04AA01
PubChem CID 4595
IUPHAR/BPS 2290
DrugBank DB00904 YesY
ChemSpider 4434 YesY
UNII 4AF302ESOS YesY
KEGG D00456 YesY
ChEMBL CHEMBL46 YesY
Chemical data
Formula C18H19N3O
Molar mass 293.4 g/mol
  (verify)

Ondansetron, marketed under the brand name Zofran, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery.[1] It is also useful in gastroenteritis.[2][3] It has little effect on vomiting caused by motion sickness.[4] It can be given by mouth, by injection into a muscle or into a vein.[1]

Common side effects include diarrhea, headache, sleepiness, and itchiness. Serious side effects include QT prolongation and severe allergic reaction. It appears to be safe during pregnancy but has not been well studied in this group. It is a serotonin 5-HT3 receptor antagonist.[1] It does not have any effect on dopamine receptors or muscarinic receptors.[5]

Ondansetron was first used medically in 1990.[6] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[7] It is available as a generic medication.[1] The wholesale cost of the injectable form is about 0.10 to 0.76 USD per dose.[8] In the United States it costs about 1.37 USD per tablet.[1]

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.[9]

Cancer treatment

The 5-HT3 receptor antagonists are the primary drugs 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 of other drugs have failed.[10]

Animal reproduction studies have not shown evidence of harm to the baby or impairment of fertility with use of high daily doses of ondansetron. A study of over 600,000 pregnancies in Denmark found that ondansetron 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.[11] Other studies concluded that there is an increase in major congenital malformations due to an increase in heart problems among the babies.[12][13]

Ondansetron is in pregnancy category B in the US.[14] It is not known if ondansetron is excreted in breast milk.[14]

Cyclic vomiting syndrome

Ondansetron is one of several antiemetic agents used during the vomiting phase of cyclic vomiting syndrome.[15]

Gastroenteritis

Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration.[16] 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 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.[17]

Special populations

Children

Ondansetron has rarely been studied in patients under 4 years of age. As such, little data are available to guide dosage recommendations.[14]

Elderly

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.[14]

Poor liver function

The maximum recommended dose 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 rate as in healthy patients. The concentration of Zofran in body tissues as opposed to plasma is also higher than in healthy patients.[14]

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. Anecdotally, ototoxicity has also been reported if injected too quickly.

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 torsades 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.[18]

Overdose

No specific treatment is available for ondansetron overdose; patients are managed with supportive measures. An antidote to ondansetron is not known.[14]

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.

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,[19] received a use patent June 1988,[20] and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996.[21] Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006.[22] 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).[23] The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.[24]

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 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 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.[25]

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.[25] Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.[26]

Availability

Ondansetron is a generic drug and is available in many countries under many brand names.[27]

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.[28] 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.[29][30]

Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease.[31] 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

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 5-HTTLPR region of the serotonin transporter gene (SLC6A4), who showed no improvement over placebo. The effect of Ondansetron on the dual diagnosis of alcohol abuse and bipolar disorder is being studied in depth in the psychoneuroendocrine group at Ut Southwestern in Dallas, TX. [32][33][34][35]

Ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions.[36] Unlike the existing treatments methadone and buprenorphine, it is not itself an opioid.[36] Additionally, it does not require continued supervision like treatment with clonidine.[36]

The original experiment used mice that were injected with increasing doses of morphine, assayed with naloxone, and then underwent haplotypic analysis to isolate a gene candidate.[37] HTR3A which codes for the 5-HT3 receptor emerged as the primary candidate, which suggested 5-HT3 antagonist ondansetron as a possible treatment.[37] The researchers were then able to show using an acute morphine administration model the efficacy in withdrawal symptom control in humans.[37]

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.[38]

References

  1. 1 2 3 4 5 "Ondansetron Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Jan 2016.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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 9781607951117.
  6. ↑ Sneader, Walter (2005). Drug discovery : a history (Rev. and updated ed.). Chichester: Wiley. p. 217. ISBN 9780471899792.
  7. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  8. ↑ "Ondansetron". International Drug Price Indicator Guide. Retrieved 26 January 2016.
  9. ↑ 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.
  10. ↑ Smith JA, Refuerzo JS, Ramin SM. "Treatment and outcome of nausea and vomiting of pregnancy". UpToDate.
  11. ↑ 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.
  12. ↑ Koren, G (December 2014). "Treating morning sickness in the United States--changes in prescribing are needed". American Journal of Obstetrics and Gynecology 211 (6): 602–6. doi:10.1016/j.ajog.2014.08.017. PMID 25151184.
  13. ↑ Danielsson, Bengt; Wikner, Birgitta Norstedt; Källén, Bengt (2014-12-01). "Use of ondansetron during pregnancy and congenital malformations in the infant". Reproductive Toxicology (Elmsford, N.Y.) 50: 134–137. doi:10.1016/j.reprotox.2014.10.017. ISSN 1873-1708. PMID 25450422.
  14. 1 2 3 4 5 6 GlaxoSmithKline. "Zofran" (PDF). Prescribing Information. U.S. Food and Drug Administration.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ "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.
  23. ↑ 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
  24. ↑ "FDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution". News Release. U.S. Food and Drug Administration. 2006-12-17.
  25. 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.
  26. ↑ 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.
  27. ↑ Drugs.com. Ondansetron international page from drugs.com Retrieved February 2, 2014
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ "Ondansetron for Bipolar Disorder Outpatients". January 21, 2015. Retrieved 2016-02-15.
  34. ↑ Johnson, Bankole A.; Seneviratne, Chamindi; Wang, Xin-Qun; Ait-Daoud, Nassima; Li, Ming D. (2013-09-01). "Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT(3) antagonist ondansetron". The American Journal of Psychiatry 170 (9): 1020–1031. doi:10.1176/appi.ajp.2013.12091163. ISSN 1535-7228. PMC 3809153. PMID 23897038.
  35. ↑ Johnson, B. A.; Roache, J. D.; Javors, M. A.; DiClemente, C. C.; Cloninger, C. R.; Prihoda, T. J.; Bordnick, P. S.; Ait-Daoud, N.; Hensler, J. (2000-08-23). "Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial". JAMA 284 (8): 963–971. ISSN 0098-7484. PMID 10944641.
  36. 1 2 3 "Stanford scientists identify drug to treat opioid addiction". 17 Feb 2009. Retrieved 19 Feb 2009.
  37. 1 2 3 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.
  38. ↑ Generali JA, Cada DJ (August 2009). "Ondansetron: postanesthetic shivering" (PDF). Hospital Pharmacy 44 (8): 670–1. doi:10.1310/hpj4408-670.

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