(April 24, 2023)

 
Ondansetron is a selective serotonin receptor antagonist (5HT-3) with proven antiemetic properties, used in both children and adults to treat nausea and vomiting caused by a variety of conditions; such as chemotherapy, gastroenteritis, migraine, traumatic brain injury, etc. (3, 5, 17).

• Its use in the ED has increased significantly in the past decade (22), due to its effectiveness and fewer adverse effects than other antiemetic drugs. 

• Usually ondansetron is considered a first-line antiemetic for most patients in the ED (4).

• Disintegrating tablets offer a practical advantage over other antiemetic formulations because they are easier to administer. 

• When using multiple doses of ondansetron, a major concern is the risk of QT interval prolongation and subsequent potential arrhythmia. Patients with a history of prolonged QT interval or those at risk for it should be closely monitored.

Adult dose for nausea and/or vomiting
4 to 8mg PO or IV.

• Repeat every 4-8 hours if necessary.

• A maximum cumulative daily dose of 24mg may be a conservative approach for ensuring safety.

Adult dose for nausea and/or vomiting
4 to 8mg PO or IV.

• Repeat every 4-8 hours if necessary.

• There is conflicting data to establish a maximum daily dose. A maximum cumulative daily dose of 24mg may be a conservative approach for ensuring safety.

• Since 2010, the US FDA has backed down from the previously approved 32mg individual dose for safety concerns.

Pediatric dose for nausea and/or vomiting (13)
0.15mg/kg PO, IV

• Repeated every 8 hours if necessary

• According to usual pediatric practice and guidelines, and for ensuring safety, EMDrugs recommends a maximum of 8mg per dose (cumulative daily dose of 24mg) in children ≥54kg.

• US-FDA labeled (26)

  • Chemotherapy and radiation-induced nausea and vomiting prophylaxis

  • Postoperative nausea and/or vomiting prophylaxis

• Non-labeled

  • Other causes of nausea and/or vomiting prophylaxis

  • Pregnancy-associated nausea and vomiting prophylaxis

• Adults:

  • The use of ondansetron in adults in the emergency department is a topic that lacks significant research, with only a few studies available (7, 16).

  • The efficacy of ondansetron and droperidol in the ED has also been recently studied, with similar results for the treatment of nausea (25). 

  • Ondansetron is usually accepted and used as a first line treatment for acute nausea and vomiting in the ED (4).

• Pediatrics: 

  • Multiple studies support the efficacy of ondansetron to treat gastroenteritis induced nausea and vomiting (3, 5, 17). 

  • For the outcomes of cessation of vomiting within one hour it has an NNT of 4, and for avoiding immediate hospitalization an NNT of 15 (19). 

  • Its efficacy and costs have also been extensively reviewed (17, 20), and the Canadian Paediatric Society recommends its usage for gastroenteritis (13).

• Vomiting is a complex process coordinated by a central emesis center in the mid-brainstem. This center, which receives input from the chemoreceptor trigger zone, vagus nerve, splanchnic afferent nerves, cerebral cortex, and the vestibular apparatus (4).

• Numerous classes of antiemetic drugs are available, which work by inhibiting the neurotransmitter receptors involved in the mechanism of nausea and vomiting. 

• These drugs are categorized based on their primary action; some of them can also affect multiple receptors.

• The vomiting reflex mainly involves five neurotransmitter receptor sites (4, 18): 

1. Dopamine (D2)

• Metoclopramide, domperidone

• Droperidol, olanzapine, haloperidol

• Benzodiazepines (indirectly)

2. Histamine (H1)

• Diphenhydramine, meclizine, dimenhydrinate, promethazine

3. Muscarinic (M1)

   • Scopolamine

4. Serotonin (5 HT-3)

• Ondansetron, granisetron, metoclopramide

• Corticosteroids (dexamethasone)

5. Substance P (NK 1)(not used in emergency medicine)

   • Aprepitant, etc

Although nausea and vomiting are common, there are few studies comparing antiemetic drugs for specific disorders. Most studies have focused on patients undergoing chemotherapy. As a result, drug selection in many situations is based on empirical evidence, preferred routes of administration, and safety considerations.

• Mechanism of action (9)

• Ondansetron is a selective antagonist of the 5HT-3 receptor, which is primarily located in the brainstem Area Postrema or Chemoreceptor Zone (CCR). This receptor responds to the neurotransmitter serotonin and plays a key role in the development of nausea and vomiting. By blocking the 5HT-3 receptor in the CCR, ondansetron can reduce the activity of neurons that mediate these symptoms, and this is the primary mechanism by which it exerts its antiemetic effects.

• While 5HT-3 receptors are also present in the peripheral nervous system (PNS) along the gastrointestinal tract, the blockade of these receptors by ondansetron does not typically affect gastrointestinal motility. However, the stimulation of these receptors in the gut can increase intestinal motility and lead to diarrhea and other gastrointestinal symptoms.
  
  

• Pharmacology for a single bolus/tablet administration (1, 7)

• Onset of action:

  • PO: 30+ min

  • No data for orally disintegrating tablets

  • IV:  5 min

• Bioavailability (PO): 50-70%.

• Time to peak plasma concentration (PO): 0.5h-1.5h.

• Duration of action: 4-8h

• Elimination half-life: 3-4h Adults, 5h or more in elderly patients.

• Plasma protein binding 73-76%

• No renal adjustment needed

• Hepatic adjustment:

  • Mild to moderate: no adjustment needed.

  • Severe liver failure: maximum daily dose of 8mg

• Older adult:

  • Maximum daily dose of 16mg for risk of QT prolongation.

1. Adverse effects

• QT prolongation (2, 7, 8, 15, 21):

  • Ondansetron may cause QT interval prolongation due to the blockade of voltage-dependent Na+ and K+ channels. Multiple studies have shown that these changes are transitory and usually resolve within 8 hours. Although these studies have demonstrated statistically significant changes in the QT interval, they have not shown any clinical relevance. Some of the studies were conducted in healthy volunteers, while others were conducted in cancer patients receiving chemotherapy or surgical patients, but none have been conducted in patients with cardiovascular disease.

  • In 2012, the FDA issued a safety warning regarding the premixed ondansetron 32 mg, as it was associated with a high risk of QT prolongation. QT prolongation can occur within 5 minutes of administration and persist for up to 2 hours.

    • Granisetron and Dolasetron are also 5HT-3 receptor selective antagonists. They were also included in these studies, and also have a block effect on  Na+ and K+ voltage dependent channels, increasing the risk of QRS widening and QT prolongation.

  • Despite the risk of QT prolongation associated with the use of ondansetron, it remains a first-line medication for the management of nausea and vomiting in the emergency department. It is important to consider other factors that may prolong QT interval, but routine ECG is generally not recommended in healthy patients or those with few risk factors. Nonetheless, clinicians should remain vigilant for any signs of adverse effects and monitor patients closely while on this medication. Ultimately, the benefits of ondansetron in treating nausea and vomiting often outweigh the potential risks, making it a valuable tool in the management of patients in the emergency setting.
    
    

• Headache:
  It is the most common adverse effect associated with the use of ondansetron. It typically appears within minutes of administration, and repetitive doses have been reported to increase its intensity and duration. Risk factors have been identified, such as personal or familial history of migraine or repetitive ondansetron doses. Ondansetron-associated migraine has also been reported in both adult and pediatric populations.
  
  

• Constipation:
  Constipation has been reported in some cases associated with the use of ondansetron, possibly due to its PNS block of the 5HT3 receptor, resulting in decreased intestinal motility. Rare cases of intestinal obstruction have also been reported.
  
  

• Hypersensitivity reactions:
  Ranging from mild to moderate, hypersensitivity reactions have been reported with the use of ondansetron, such as urticaria, angioedema, and even anaphylaxis. Management of these conditions should be addressed by local protocols.
  
  

2. Warning/Precautions

• Serotonin toxicity (6)
  Ondansetron, as a 5HT3 antagonist, increases serotonin levels in the synaptic cleft. Its concomitant use with other serotonergic agents such as SSRIs, TCAs, MAOIs, first-generation antipsychotic drugs, opioids (such as fentanyl and tramadol), lithium, and other drugs that increase serotonin levels could increase the risk of serotonin toxicity. Among these drugs, MAOIs pose the highest risk, as they block and inhibit the reuptake of serotonin, which can lead to dangerous levels of serotonin accumulation.

3. Drug interactions
   QT prolonging drugs: patients with concomitant use of QT prolonging drugs such as antidepressants, antipsychotics, antiarrhythmics, opioids, and some antibiotics are at increased risk of QT prolongation and ventricular arrhythmias.

Pregnancy risk classification

• AU TGA pregnancy category: B1

• US FDA pregnancy category: B
  
  

Lactation (23)

• Ondansetron is considered as a drug with very low risk for the nursing infant by e-lactancia.org. 

• Its high volume of distribution and short half-life make it unlikely that it will be excreted in breast milk in significant quantities.

• No problems have been reported in infants of mothers treated with ondansetron

Comments: 

• Conflicting data exist regarding the association between ondansetron use during pregnancy and cardiac malformations and palate/oral cleft (10). A recent study showed no association between ondansetron use in the first trimester of pregnancy and cardiac malformations but suggested a small increase in the number of oral/palate clefts (11). However, extensive and recent literature reviews have not found a clear association with oral/palate cleft (12, 14). Although some studies have shown an increased risk of congenital malformations with ondansetron use,  recent data have found no increase in the risk of cardiac defects or in overall malformations in ondansetron-exposed patients (24).

• Women should still be informed about the available data, and the use of ondansetron before 10 weeks of gestation should be individualized, taking into account the risks and benefits.

• EMCases: Episode 19 Part 2: Pediatric Gastroenteritis, Constipation and Bowel Obstruction (2012)

• The NNT: Ondansetron (Zofran) for Pediatric Gastroenteritis (2020)

• RebelEM: Association of Maternal First-Trimester Ondansetron Use with Cardiac Malformations and Oral Clefts in Newborns (2020)

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