Ondansetron (INN), originally marketed under the brand name Zofran, is a serotonin5-HT3 receptor antagonist used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.
Trials in emergency department settings support the use of ondansetron to reduce vomiting associated with gastroenteritis and dehydration. 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.
Ondansetron has rarely been studied in patients under 4 years of age. As such, there is little data to guide dosage recommendations.
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.
Poor 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.
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.
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.
There is no specific treatment for ondansetron overdose; patients are managed with supportive measures. An antidote to ondansetron is not available.
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.
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, received a use patent June 1988, and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996. Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006. 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 USD $1.3 billion in the first 9 months of 2006 (80% from the US). The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.
Society and culture
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.
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. Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.
Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease. 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.
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.
Researchers at the Stanford University School of Medicine have demonstrated that ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions. Unlike the existing treatments methadone and buprenorphine, it is not itself an opioid. Additionally, it does not require continued supervision like treatment with clonidine.
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.HTR3A which codes for the 5-HT3 receptor emerged as the primary candidate, which suggested 5-HT3 antagonist ondansetron as a possible treatment. The researchers were then able to show using an acute morphine administration model the efficacy in withdrawal symptom control in humans.
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.
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^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 Med55 (5): 415–22. doi:10.1016/j.annemergmed.2009.11.011. PMID20031265.
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^ abcdefGlaxoSmithKline. "Zofran". Prescribing Information. U.S. Food and Drug Administration.
^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
^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
^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