Nausea and vomiting are two of the most common presenting complaints seen by emergency department physicians and primary care physicians on a daily basis. Ondansetron is one of the medications most commonly used for empiric treatment. It appears on the World Health Organization’s (WHO) List of Essential Medicines, which is a list of medications that are considered to be the most effective and safe with regards to meeting the most important needs in a health system. Other antiemetics that appear on this list with ondansetron include dexamethasone and metoclopramide. In 2006 (the last year of its patent), the brand-name version of ondansetron was the 20th highest-selling brand-name drug in the United States, and its popularity continues today. Ondansetron has extreme utility as an antiemetic drug, and it is effective against nausea and vomiting of various etiologies. Common uses of ondansetron include the prevention of chemotherapy-induced and radiation-induced nausea and vomiting, the prevention of postoperative nausea and vomiting (PONV), and off-label use for the prevention of nausea and vomiting associated with pregnancy. It is considered first-line therapy for the treatment of chemotherapy-induced and radiation-induced nausea and vomiting. Although the drug works particularly well for these indications, it has very little effects on nausea and vomiting caused by motion sickness, which is mediated by different control centers and pathophysiologic mechanisms. There are limited data available from pediatric populations. Aside from the indications mentioned above, one unique indication that ondansetron has within pediatric populations is the acute treatment of Cyclic Vomiting Syndrome although there is very little information available on the efficacy in this disease.
Ondansetron is a selective 5-HT3 serotonin-receptor antagonist used for its antiemetic properties. It is 1 of 4 FDA-approved 5-HT3 serotonin-receptor antagonists used to combat nausea and vomiting, with the others including granisetron, dolasetron, and the second-generation drug, palonosetron. Ondansetron acts both centrally and peripherally to prevent and treat nausea and vomiting. Central effects are mediated by the antagonism of 5HT-3 serotonin receptors in the area postrema. The area postrema, which is located on the floor of the fourth ventricle contains the “chemoreceptor trigger zone.” This zone senses neurotransmitters like serotonin, toxins, and other signals, and plays a role in mediating the sensation of nausea and subsequent vomiting. Ondansetron also has effects peripherally by acting on the vagus nerve. It acts on the 5-HT3 receptors that can be found at the vagus nerve terminals. Within the GI tract, the vagus nerve can sense nausea and vomiting triggers, such as stomach irritants, and it forms synapses within the nucleus tractus solitarius of the brainstem, another region important in vomiting. The peripheral actions of ondansetron are thought to be the predominant mechanism for its antiemetic effects. It is metabolized primarily by the cytochrome P450 system of the liver.
Routes of administration include oral, intramuscular (IM), and intravenous (IV). Oral formulations are available in dissolving tablet and soluble film forms. When administered orally, ondansetron tablets should be administered 1 to 2 hours before radiotherapy, 30 minutes before chemotherapy, and an hour before anesthesia induction. Oral and IV formulations have been shown to have similar efficacy for the treatment of emetogenic chemotherapy. Dosing varies depending on the route of administration and cause of the symptoms, although 16 mg per dose IV is the maximum recommended single dose due to the risk for QTc elongation and arrhythmias. Standard oral dosing includes 8 mg every 12 hours, and 4 mg IV is common as the prophylactic dose to prevent postoperative nausea and vomiting. No dosage adjustments are necessary for IV or oral administration in patients with renal impairment. The same holds true for patients with mild to moderate hepatic impairment, but in patients with severe hepatic impairment, the maximum daily dosing is reduced to 8 mg IV or 8 mg orally. Pediatric dosing is weight-based at 0.15 mg/kg per dose with a maximum of 16 mg per dose.
The most commonly reported side effects (occurring in more than 10% of adults) include a headache, fatigue, dry mouth, malaise, and constipation. Some less common effects range from central nervous system (CNS) manifestations, such as drowsiness and sedation to local injection site reactions and pruritus. A transient increase in liver function tests has been reported as well. Although typically clinically insignificant, ECG interval changes such as QTc elongation can be seen. These changes typically take place within 1 to 2 hours after administration with a return to baseline within 24 hours. As with any medication that causes QTc elongation, there is a concern for Torsade de Pointes and other arrhythmias. IV administration is where the greatest risk lies. Because of this risk, single doses greater than 16 mg IV are not recommended per the FDA. Serotonin syndrome is another reported risk that may occur when taking ondansetron, although the greatest risk exists when it is taken in conjunction with other serotonergic medications.
Ondansetron is contraindicated in patients with hypersensitivity to the drug or any components of it. It is also contraindicated in patients currently taking apomorphine. Concomitant use of ondansetron and apomorphine can lead to profound hypotension and loss of consciousness, with ondansetron enhancing the hypotensive effects of apomorphine. Patients with phenylketonuria (PKU) should be cautious, as the dissolving tablet formulation can contain phenylalanine. It is considered pregnancy risk-factor category B and should only be used when other medications have been trialed and failed for the treatment of pregnancy-associated nausea and vomiting and hyperemesis gravidarum. Antihistamines, like diphenhydramine and meclizine, and dopamine antagonists, like metoclopramide and promethazine should be considered in this patient population prior to using ondansetron. Pregnancy category B drugs are medications that have failed to demonstrate a risk to the fetus in animal reproductive studies and no adequate trials in human pregnant women exist or drugs that have shown adverse effects in animal trials but adequate studies in pregnant women have failed to show a risk to the fetus in any trimester.
Due to the potential for dose-dependent QTc interval elongation, the FDA recommends ECG monitoring along with potassium and magnesium monitoring in particularly susceptible populations, such as the elderly or other at-risk groups. These at-risk groups include patients with electrolyte abnormalities such as hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients on other medications that may prolong the QTc interval. For patients without any of the risk above factors, current evidence does not demonstrate a need to pre-screen this population prior to the administration of ondansetron.
There is no known antidote to ondansetron, and supportive measures are used for overdose.
Ondansetron is a widely prescribed medication for nausea and vomiting from a variety of causes. The drug is relatively safe but prescribers including nurse practitioners, primary care providers, internists, surgeons, and emergency department physicians need to monitor the drug in certain populations. Due to the potential for dose-dependent QTc interval elongation, the FDA recommends ECG monitoring along with potassium and magnesium monitoring in particularly susceptible populations, such as the elderly or other at-risk groups. These at-risk groups include patients with electrolyte abnormalities such as hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients on other medications that may prolong the QTc interval. For patients without any of the risk above factors, current evidence does not demonstrate a need to pre-screen this population prior to the administration of ondansetron.
|||Liu Y,Li XJ,Liang Y,Kang Y, Pharmacological Prevention of Postoperative Delirium: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Evidence-based complementary and alternative medicine : eCAM. 2019; [PubMed PMID: 31001357]|
|||Castrén S,Mäkelä N,Alho H, Selecting an appropriate alcohol pharmacotherapy: review of recent findings. Current opinion in psychiatry. 2019 Apr 9; [PubMed PMID: 30973369]|
|||Shinohara M,Shinohara M,Zhao J,Fu Y,Liu CC,Kanekiyo T,Bu G, 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway. International journal of molecular sciences. 2019 Mar 25; [PubMed PMID: 30934555]|
|||Zheng W,Cai DB,Zhang QE,He J,Zhong LY,Sim K,Ungvari GS,Ning YP,Xiang YT, Adjunctive ondansetron for schizophrenia: A systematic review and meta-analysis of randomized controlled trials. Journal of psychiatric research. 2019 Mar 5; [PubMed PMID: 30878789]|
|||Kaplan YC,Richardson JL,Keskin-Arslan E,Erol-Coskun H,Kennedy D, Use of ondansetron during pregnancy and the risk of major congenital malformations: A systematic review and meta-analysis. Reproductive toxicology (Elmsford, N.Y.). 2019 Mar 5; [PubMed PMID: 30849498]|
|||Fernandes FM,da Silva Paulino AM,Sedda BC,da Silva EP,Martins RR,Oliveira AG, Assessment of the risk of QT-interval prolongation associated with potential drug-drug interactions in patients admitted to Intensive Care Units. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. 2019 Feb; [PubMed PMID: 30766434]|
|||Patel P,Paw Cho Sing E,Dupuis LL, Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis. Expert opinion on drug safety. 2019 Feb; [PubMed PMID: 30640557]|
|||Romano C,Dipasquale V,Scarpignato C, Antiemetic Drug Use in Children: What the Clinician Needs to Know. Journal of pediatric gastroenterology and nutrition. 2019 Apr; [PubMed PMID: 30540713]|
|||Balayla J, Comment on: Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2018 Dec; [PubMed PMID: 30361157]|
|||Sridharan K,Sivaramakrishnan G, Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials. The journal of maternal-fetal [PubMed PMID: 30173590]|