Ondansetron

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 category	AU: B1 US: B (No risk in non-human studies)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral, rectal, IV, IM
Pharmacokinetic data
Bioavailability	~60%
Protein binding	70%-76%
Metabolism	Hepatic (CYP3A4, CYP1A2, CYP2D6)
Biological half-life	5.7 hours
Excretion	Renal
Identifiers
CAS Number	99614-02-5 Y
ATC code	A04AA01 (WHO)
PubChem	CID: 4595
IUPHAR/BPS	2290
DrugBank	DB00904 Y
ChemSpider	4434 Y
UNII	4AF302ESOS Y
KEGG	D00456 Y
ChEMBL	CHEMBL46 Y
Chemical data
Formula	C18H19N3O
Molecular mass	293.4 g/mol
SMILES O=C3c2c1ccccc1n(c2CCC3Cn4ccnc4C)C
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 Y Key:FELGMEQIXOGIFQ-UHFFFAOYSA-N Y
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Ondansetron (INN), 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, surgery and gastroenteritis.

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

It is on the World Health Organization's List of Essential Medicines, a list of medications needed in a basic health system.

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.

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.

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. Another study concluded that there is a 30% increase in major congenital malformations due to an increase in heart problems among the babies.

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

Cyclic vomiting syndrome

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

Gastroenteritis

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

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.

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.

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.

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.

Overdose

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

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, 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 US$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

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.

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

Availability

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

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. 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.

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.

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.

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 that 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.

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.

External links

• U.S. National Library of Medicine: Drug Information Portal - Ondansetron