Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

caused by

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

radiation therapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a therapy, treatment using ionizing radiation, generally provided as part of treatment of cancer, cancer therapy to either kill or control the growth of malignancy, malignant cell (biology), ...

, migraines, or

surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...

. It is also effective for treating

gastroenteritis Gastroenteritis, also known as infectious diarrhea, is an inflammation of the Human gastrointestinal tract, gastrointestinal tract including the stomach and intestine. Symptoms may include diarrhea, vomiting, and abdominal pain. Fever, lack of ...

. It can be given orally (by mouth), intramuscularly (injection into a muscle), or

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

(injection into a vein). Common

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s include

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, sleepiness, and itchiness. Serious side effects include QT prolongation and severe allergic reaction. It appears to be safe during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

but has not been well studied in this group. It is a

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT₃ receptor antagonist. It does not have any effect on dopamine receptors or

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

and therefore does not cause akathisia. Ondansetron was patented in 1984 and approved for medical use in 1990. It is on the World Health Organization's List of Essential Medicines. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2022, it was the 61st most commonly prescribed medication in the United States, with more than 10million prescriptions.

Medical uses

Ondansetron is indicated for the prevention of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting.

Pregnancy

Ondansetron is used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

to treat morning sickness and hyperemesis gravidarum of

. It is typically used after other

antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...

drugs have failed. A large multi-center cohort study found no association between ondansetron exposure and fetal risk compared to other antiemetics.

Cyclic vomiting syndrome

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

Gastroenteritis

Trials in emergency department settings support the use of ondansetron to abort vomiting episodes associated with

and

dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...

. A randomized controlled trial using a single dose of oral ondansetron in children with presumably viral gastroenteritis found it to be highly effective in stopping vomiting and increasing the effectiveness of oral rehydration therapy, thereby significantly increasing patient satisfaction. Only 16 of the 123 children treated with ondansetron vomited in the following 6 hours. A retrospective review found that ondansetron was used commonly for vomiting due to gastroenteritis, 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.

Irritable bowel syndrome (IBS)

In a study of patients diagnosed as having IBS with diarrhea (IBS-D), ondansetron showed statistically significant effects on stool consistency, frequency, urgency and bloating, but not on pain scores. This was confirmed in a later trial and meta-analysis and is included in international guidelines.

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. Three open non-comparative studies have been conducted to assess the safety and efficacy of ondansetron in children receiving a variety of chemotherapy regimens. Ondansetron was well tolerated and none of the patients experienced extrapyramidal symptoms.

Adverse effects

Headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

is the most common

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...

. 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.

Constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

, and

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

are other commonly reported side effects. It is broken down by the

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

system and it has little effect on the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

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 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 Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...

, 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.

Overdose

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

Pharmacology

Pharmacodynamics

Ondansetron is a highly selective serotonin 5-HT₃ receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

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 The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its role to detect circulating chemical messengers in the blood and tra ...

in the medulla. Serotonin is released by the

enterochromaffin cell Enterochromaffin (EC) cells (also known as Kulchitsky cells) are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal r ...

s of the

small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

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. The ''R''– and ''S''–ondansetron isomers have similar potency as serotonin antagonists when tested on ''ex vivo'' rat

vagus nerve The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...

. However, the ''R''–ondansetron enantiomer was 7.9 times more potent as an antagonist of serotonin and 2-methyl-5-hydroxytryptamine (2-methylserotonin) when tested on the longitudinal

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

from guinea pig

ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may ...

. However, the guinea pig ileum test was likely not as faithful as a test of 5-HT₃ receptor antagonism, because ondansetron only partially blocked the effect of serotonin, while it completely blocked the effect of 2-methylserotonin.

Pharmacokinetics

Ondansetron may have a degree of peripheral selectivity due to binding to P-glycoprotein and efflux out of the brain at the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. Ondansetron is marketed as a

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

mixture of ''R''–(–)–ondansetron and ''S''–(+)–ondansetron, and the two enantiomers have significantly different kinetics. In rats given 2 mg/kg intravenous doses of each enantiomer separately, ''R''–(–)–ondansetron was found to have a 37% longer half-life (''P'' < 0.05) and an 87% higher area-under-curve or AUC (''P'' < 0.01) compared to ''S''–(+)–ondansetron, indicating that the ''R'' enantiomer is metabolized more slowly. The chiral carbon in ondansetron is adjacent to a carbonyl group, so keto-enol tautomerism could theoretically lead to interconversion between the two enantiomers under physiologic conditions, if the hydrogen on the chiral carbon were removed and then replaced with opposite chirality. An experiment in rats given each enantiomer separately showed no evidence of this interconversion, the chirality was stable ''in vivo''. A study of 141 human patients given 4 or 8 mg of intravenous ondansetron for the prevention of post-operative nausea and vomiting also found that ''R'' and ''S''–ondansetron have different pharmacokinetic properties. Each patient was classified according to their genotype for the liver enzymes CYP2D6 and CYP3A5, and they were put on a spectrum between poor metabolizers (slow) and ultra metabolizers (fast). CYP2D6 was found to be more important for the elimination of ''S''–ondansetron, whereas CYP3A5 genotype had no impact on ''S''–ondansetron plasma levels, measured 3 hours after drug administration. CYP3A5 was more important for ''R''–ondansetron clearance, and CYP2D6 genotype had no consistent effect on plasma levels of ''R''–ondansetron at 3 hours.

History

Ondansetron (marketed under the brand name Zofran) was developed in the mid-1980s by

GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...

in London. It was granted U.S. patent protection in September 1987, received a use patent June 1988, and was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(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 U.S. FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals. In December 2012, the FDA announced that the 32mg, single intravenous (IV) dose of ondansetron was being withdrawn from U.S. market because of the potential for serious cardiac issues from prolonged QT interval. In 2018,

University of São Paulo The Universidade de São Paulo (, USP) is a public research university in the Brazilian state of São Paulo, and the largest public university in Brazil. The university was founded on 25 January 1934, regrouping already existing schools in ...

and Biolab were granted a patent for an orodispersible form of the drug.

Society and culture

Publication bias

In 1997, ondansetron was the subject of a

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

case study. 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 The number needed to treat (NNT) or number needed to treat for an additional beneficial outcome (NNTB) is an epidemiology, epidemiological measure used in communicating the effectiveness of a health-care intervention, typically a treatment with me ...

(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 ''JAMA'' (''The Journal of the American Medical Association'') is a peer-reviewed medical journal published 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of ...

'' in 1999.

Availability

Ondansetron is a

and is available in many countries under many brand names.

Research

Ondansetron may be useful in the treatment of nausea and vomiting that can sometimes be induced by certain

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

References

{{Authority control Antiemetics Peripherally selective drugs World Health Organization essential medicines Withdrawn drugs Wikipedia medicine articles ready to translate 5-HT3 antagonists Imidazoles Ketones Tetrahydrocarbazoles