ONDASENTRON

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