Ondansetron

Article Author:
Alexandria Griddine
Article Editor:
Jeffrey Bush
Updated:
1/20/2019 9:33:33 AM
PubMed Link:
Ondansetron

Indications

Nausea and vomiting are 2 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 mechanisms. There is 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.

Mechanism of Action

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.

Administration

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 QT 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.

Adverse Effects

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 QT 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 QT 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.

Contraindications

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.

Monitoring

Due to the potential for dose-dependent QT 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 QT interval. For patients without any of the risk above factors, current evidence does not demonstrate a need to pre-screen this population prior to administration of ondansetron.

Toxicity

There is no known antidote to ondansetron, and supportive measures are used for overdose.


References

Is There a Role for 5-HT<sub>3</sub> Receptor Antagonists in the Treatment of Opioid-Induced Pruritus?, Rashid S,Trivedi DD,Al-Shathir M,Moulton M,Baumrucker SJ,, The American journal of hospice & palliative care, 2017 Jan 1     [PubMed PMID: 29020799]
Comparative efficacy of ramosetron and ondansetron in preventing postoperative nausea and vomiting: An updated systematic review and meta-analysis with trial sequential analysis., Yokoi A,Mihara T,Ka K,Goto T,, PloS one, 2017     [PubMed PMID: 28977021]
Techniques for preventing hypotension during spinal anaesthesia for caesarean section., Chooi C,Cox JJ,Lumb RS,Middleton P,Chemali M,Emmett RS,Simmons SW,Cyna AM,, The Cochrane database of systematic reviews, 2017 Aug 4     [PubMed PMID: 28976555]