Ondansetron

Last updated

Ondansetron
Ondansetron skeletal.svg
Ondansetron 3D.png
Clinical data
Trade names Zofran, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a601209
License data
Pregnancy
category
Routes of
administration 		By mouth, rectal, intravenous, intramuscular, thin film
Drug class
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~60%
Protein binding 70–76%
Metabolism Liver (CYP3A4, CYP1A2, CYP2D6)
Elimination half-life 5.7 hours
Excretion Kidney
Identifiers
  • (RS)-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4(9H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.918 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C18H19N3O
Molar mass 293.370 g·mol−1
3D model (JSmol)
  • O=C1c2c3ccccc3n(C)c2CCC1Cn4ccnc4C
  • 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 Yes check.svgY
  • Key:FELGMEQIXOGIFQ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by chemotherapy, radiation therapy, migraines, or surgery. [8] It is also effective for treating gastroenteritis. [9] [10] It can be given orally (by mouth), intramuscularly (injection into a muscle), or intravenously (injection into a vein). [8]

Contents

Common side effects include diarrhea, constipation, headache, sleepiness, and itchiness. [8] Serious side effects include QT prolongation and severe allergic reaction. [8] It appears to be safe during pregnancy but has not been well studied in this group. [8] It is a serotonin 5-HT3 receptor antagonist. [8] It does not have any effect on dopamine receptors or muscarinic acetylcholine receptors. [11]

Ondansetron was patented in 1984 and approved for medical use in 1990. [12] It is on the World Health Organization's List of Essential Medicines. [13] It is available as a generic medication. [8] In 2022, it was the 61st most commonly prescribed medication in the United States, with more than 10 million prescriptions. [14] [15]

Medical uses

Ondansetron is indicated for the prevention of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. [6] [16]

Pregnancy

Ondansetron is used off-label to treat morning sickness and hyperemesis gravidarum of pregnancy. It is typically used after other antiemetic drugs have failed. [17]

A large multi-center cohort study found no association between ondansetron exposure and fetal risk compared to other antiemetics. [18]

Cyclic vomiting syndrome

Ondansetron is one of several antiemetics used during the vomiting phase of cyclic vomiting syndrome. [19]

Gastroenteritis

Trials in emergency department settings support the use of ondansetron to abort vomiting episodes associated with gastroenteritis and dehydration. [20] 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. [21] 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. [22]

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. [23] This was confirmed in a later trial and meta-analysis [24] and is included in international guidelines. [25]

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. [6]

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. [26]

Adverse effects

Headache is the most common adverse effect. [6] 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. [27]

Constipation, diarrhea, and dizziness are other commonly reported side effects. 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. [8]

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, 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. [28]

Overdose

No specific treatment is available for ondansetron overdose; people are managed with supportive measures. An antidote to ondansetron is not known. [6]

Pharmacology

Pharmacodynamics

Ondansetron is a highly selective serotonin 5-HT3 receptor antagonist, 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 in the medulla. 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 thought that ondansetron's antiemetic action is mediated mostly via antagonism of vagal afferents with a minor contribution from antagonism of central receptors. [29] The R– and S–ondansetron isomers have similar potency as serotonin antagonists when tested on ex vivo rat vagus nerve. [30] 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 from guinea pig ileum. 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. [30]

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. [31] [32] [33] Ondansetron is marketed as a racemic 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. [34] 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. [34] 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. [35]

History

A vial of Zofran 4 mg containing ondansetron for intravenous injection Ondansetron (1).JPG
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 U.S. patent protection in September 1987, [36] received a use patent June 1988, [37] and was approved by the U.S. Food and Drug Administration (FDA) in January 1991. It was granted another divisional patent in November 1996. [38] Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006. [39] 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). [40] 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. [41]

In December 2012, the FDA announced that the 32 mg, 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. [42]

In 2018, University of São Paulo and Biolab were granted a patent for an orodispersible form of the drug. [43]

Society and culture

Publication bias

In 1997, ondansetron was the subject of a meta-analysis 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 (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. [44]

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. [44] Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999. [45]

Availability

Ondansetron is a generic medication and is available in many countries under many brand names. [1]

Related Research Articles

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 be used for severe cases of gastroenteritis, especially if the patient is dehydrated.

<span class="mw-page-title-main">Tramadol</span> Opioid pain medication

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Metoclopramide</span> Medication

Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.

<span class="mw-page-title-main">Granisetron</span> Serotonin 5-HT3 antiemetic

Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the post-anesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.

<span class="mw-page-title-main">Domperidone</span> Peripheral D2 receptor antagonist

Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis. It raises the level of prolactin in the human body and is used off label to induce and promote breast milk production. It may be taken by mouth or rectally.

<span class="mw-page-title-main">Aprepitant</span> Chemical compound

Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting and to prevent postoperative nausea and vomiting. It may be used together with ondansetron and dexamethasone. It is taken by mouth or administered by intravenous injection.

<span class="mw-page-title-main">Nabilone</span> Synthetic cannabinoid

Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.

<span class="mw-page-title-main">Dolasetron</span> Pharmaceutical drug

Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

<span class="mw-page-title-main">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride, sold under the brand names Solian and Barhemsys, is a medication used in the treatment of schizophrenia, acute psychotic episodes, depression, and nausea and vomiting. It is specifically used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; at low doses by mouth to treat depression; and at higher doses by mouth to treat psychosis.

<span class="mw-page-title-main">Busulfan</span> Chemical compound

Busulfan is a chemotherapy drug in use since 1959. It is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.

<span class="mw-page-title-main">Droperidol</span> Antidopaminergic drug

Droperidol is an antidopaminergic drug used as an antiemetic and as an antipsychotic. Droperidol is also often used as a rapid sedative in intensive-care treatment, and where "agitation aggression or violent behavior" are present.

<span class="mw-page-title-main">Palonosetron</span> Pharmaceutical drug

Palonosetron, sold under the brand name Aloxi, is a medication used for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is a 5-HT3 antagonist.

5-HT<sub>3</sub> antagonist Anti-nausea group of medications

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

<span class="mw-page-title-main">Metopimazine</span> Chemical compound

Metopimazine, sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. It is marketed in Europe, Canada, and South America. As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.

<span class="mw-page-title-main">Azasetron</span> Chemical compound

Azasetron is an antiemetic which acts as a 5-HT3 receptor antagonist, pKi = 9.27 It is used in the management of nausea and vomiting induced by cancer chemotherapy (such as cisplatin chemotherapy). Azasetron hydrochloride is given in a usual dose of 10 mg once daily by mouth or intravenously. It is approved for marketing in Japan, and marketed exclusively by Torii Pharmaceutical Co., Ltd. under the trade names "Serotone I.V. Injection 10 mg" and "Serotone Tablets 10 mg". Pharmacokinetics data from S. Tsukagoshi.

<span class="mw-page-title-main">Levosulpiride</span> Dopamine antagonist medication

Levosulpiride, sold under the brand names Dislep and Sulpepta among others, is a dopamine antagonist medication which is used in the treatment of psychotic disorders like schizophrenia, major depressive disorder, nausea and vomiting, and gastroparesis. It is taken by mouth.

<span class="mw-page-title-main">Vortioxetine</span> Serotonin modulator antidepressant

Vortioxetine, sold under the brand name Trintellix and Brintellix among others, is an antidepressant of the serotonin modulator and stimulator (SMS) class. Its effectiveness is viewed as similar to that of other antidepressants. It is taken orally.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.

<span class="mw-page-title-main">Rolapitant</span> Pharmaceutical drug

Rolapitant (INN, trade name Varubivə-ROO-bee in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor). It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.

References

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  36. ↑ USpatent 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 22 September 1987, assigned to Glaxo Group Limited
  37. ↑ USpatent 4753789,Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA,"Method for treating nausea and vomiting",issued 28 June 1988, assigned to Glaxo Group Limited
  38. ↑ USpatent 5578628,Tyers MB, Coates IH, Humber DC, Ewan GB, Bell JA,"Medicaments for the treatment of nausea and vomiting",issued 26 November 1996, assigned to Glaxo Group Limited
  39. ↑ "One Year Post-Pediatric Exclusivity Post-marketing Adverse Event Review: Drug Use Data Zofran" (PDF). Memorandum. U.S. Food and Drug Administration. 7 March 2006. Archived (PDF) from the original on 24 September 2015.
  40. ↑ IHS. (2006). Generics firms line up to enter Zofran market. Retrieved from "Generics Firms Line Up to Enter Zofran Market". Archived from the original on 1 February 2014. Retrieved 20 January 2014.
  41. ↑ "FDA Approves First Generic Ondansetron Tablets, Orally Disintegrating Tablets and Oral Solution" (Press release). U.S. Food and Drug Administration. 17 December 2006. Archived from the original on 18 June 2014.
  42. ↑ "FDA Drug Safety Communication: Updated information on 32 mg intravenous ondansetron (Zofran) dose and pre-mixed ondansetron products". U.S. Food and Drug Administration (FDA). Archived from the original on 13 December 2019. Retrieved 12 December 2012.
  43. ↑ "Sabia que um remédio para enjoo traz 90% dos royalties que a USP recebe? - Agência USP de Inovação" (in Brazilian Portuguese). Retrieved 6 October 2020.
  44. 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.
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