What is ondansetron used for. How does ondansetron work to prevent nausea and vomiting. What are the FDA-approved indications for ondansetron. What are the off-label uses of ondansetron. How is ondansetron absorbed and metabolized in the body.

Overview of Ondansetron and Its Importance in Healthcare

Ondansetron is a widely used medication that plays a crucial role in managing nausea and vomiting across various medical scenarios. As a selective 5-HT3 serotonin receptor antagonist, it has earned its place on the World Health Organization’s List of Essential Medicines, highlighting its significance in global healthcare systems.

First introduced to the market under the brand name Zofran, ondansetron has maintained its popularity even after patent expiration. In 2006, it ranked as the 20th highest-selling brand-name drug in the United States, a testament to its efficacy and widespread use.

FDA-Approved Indications for Ondansetron

The U.S. Food and Drug Administration (FDA) has approved ondansetron for several specific uses:

• Prevention of chemotherapy-induced nausea and vomiting (CINV)
• Prevention of radiation-induced nausea and vomiting
• Prevention of postoperative nausea and vomiting (PONV)

Is ondansetron considered a first-line treatment for chemotherapy-induced nausea and vomiting? Yes, ondansetron is widely recognized as a first-line therapy for both chemotherapy-induced and radiation-induced nausea and vomiting due to its effectiveness and safety profile.

Off-Label Uses of Ondansetron

While not FDA-approved for these purposes, ondansetron is often used off-label in several situations:

• Prevention of nausea and vomiting associated with pregnancy
• Acute treatment of cyclic vomiting syndrome in pediatric populations
• Management of severe refractory diarrhea associated with neuroendocrine tumors (carcinoid syndrome)

It’s important to note that while ondansetron is effective against various types of nausea and vomiting, it has minimal efficacy in treating motion sickness-induced nausea. This limitation is due to the distinct control centers and pathophysiological mechanisms involved in motion sickness.

Mechanism of Action: How Ondansetron Works

Understanding the mechanism of action of ondansetron is crucial for healthcare providers to appreciate its efficacy in various clinical scenarios. Ondansetron exerts its antiemetic effects through both central and peripheral actions:

Central Effects

Ondansetron’s central effects are primarily mediated by antagonizing 5-HT3 serotonin receptors in the area postrema. This region, located on the floor of the fourth ventricle, contains the “chemoreceptor trigger zone” – a key area in sensing neurotransmitters, toxins, and other signals that can induce nausea and vomiting.

Peripheral Effects

The peripheral actions of ondansetron, which are considered the predominant mechanism for its antiemetic effects, involve:

• Acting on 5-HT3 receptors located at vagus nerve terminals
• Modulating the vagus nerve’s ability to sense nausea and vomiting triggers within the gastrointestinal tract
• Influencing synapses within the nucleus tractus solitarius of the brainstem, another critical region in the vomiting reflex

How does ondansetron’s dual action contribute to its effectiveness? By targeting both central and peripheral pathways involved in nausea and vomiting, ondansetron provides comprehensive antiemetic coverage, making it effective against various types of nausea and vomiting.

Pharmacokinetics of Ondansetron

Understanding the pharmacokinetics of ondansetron is essential for optimizing its use in clinical practice. Let’s explore the key aspects of how ondansetron is processed in the body:

Absorption

Ondansetron is rapidly absorbed from the gastrointestinal tract after oral administration. Key points about its absorption include:

• Peak plasma concentration (Tmax) is reached approximately 1.5 hours after an 8 mg single oral dose
• Absolute bioavailability after oral administration is about 60% (range: 50%-70%)
• Lower bioavailability is attributed to first-pass metabolism in the liver

Does the bioavailability of ondansetron change with increasing doses? Yes, the systemic bioavailability of ondansetron increases nonlinearly with increasing doses from 8 mg to 64 mg. This nonlinear increase is due to saturation of the first-pass metabolism at higher doses.

Special Populations

Interestingly, the bioavailability of ondansetron is significantly higher in patients with cancer, ranging from 85% to 87%. This increased bioavailability in cancer patients may be due to alterations in metabolism or absorption associated with their condition.

Clinical Applications and Dosing Considerations

Ondansetron’s versatility makes it a valuable tool in various clinical settings. Here’s an overview of its applications and dosing considerations:

Chemotherapy-Induced Nausea and Vomiting (CINV)

For CINV, ondansetron is typically administered before chemotherapy and continued for 1-2 days after treatment. Dosing may vary based on the emetogenic potential of the chemotherapy regimen:

• Highly emetogenic chemotherapy: 8 mg IV or oral, given 30 minutes before chemotherapy, followed by 8 mg oral twice daily for 1-2 days post-chemotherapy
• Moderately emetogenic chemotherapy: 8 mg oral twice daily for 1-2 days, starting 30 minutes before chemotherapy

Postoperative Nausea and Vomiting (PONV)

For PONV prevention, ondansetron is typically given as a single dose before anesthesia induction:

• Adults: 4 mg IV given slowly over 2-5 minutes
• Pediatric patients (4-18 years): 4 mg oral or IV

Radiation-Induced Nausea and Vomiting

For patients undergoing radiotherapy, especially to the upper abdomen:

• 8 mg oral given 1-2 hours before each fraction of radiotherapy

How should ondansetron dosing be adjusted for patients with hepatic impairment? In patients with moderate to severe hepatic impairment, the total daily dose of ondansetron should not exceed 8 mg due to reduced clearance and increased half-life of the drug.

Adverse Effects and Safety Considerations

While ondansetron is generally well-tolerated, healthcare providers should be aware of potential adverse effects and safety considerations:

Common Side Effects

• Headache (reported in up to 27% of patients)
• Constipation (10-11%)
• Diarrhea (7-9%)
• Fatigue (8-13%)
• Dizziness (5-10%)

Serious Adverse Effects

Although rare, some serious adverse effects have been reported:

• QT interval prolongation: This can potentially lead to Torsades de Pointes, a life-threatening arrhythmia
• Serotonin syndrome: Especially when used in combination with other serotonergic drugs
• Hypersensitivity reactions: Including anaphylaxis in rare cases

What precautions should be taken for patients with a history of cardiac arrhythmias? Patients with a history of cardiac arrhythmias or those at risk for QT prolongation should be monitored closely when receiving ondansetron, and ECG monitoring may be warranted in high-risk patients.

Drug Interactions and Contraindications

Understanding potential drug interactions and contraindications is crucial for safe and effective use of ondansetron:

Drug Interactions

• CYP3A4 inducers (e.g., rifampicin): May decrease ondansetron plasma concentrations
• CYP3A4 inhibitors (e.g., ketoconazole): May increase ondansetron plasma concentrations
• Serotonergic drugs (e.g., SSRIs, SNRIs): Increased risk of serotonin syndrome
• QT-prolonging drugs: Additive effect on QT interval prolongation

Contraindications

Ondansetron is contraindicated in the following situations:

• Known hypersensitivity to ondansetron or any component of the formulation
• Concomitant use with apomorphine (due to reports of profound hypotension and loss of consciousness)

Are there any specific considerations for using ondansetron in pregnancy? While ondansetron is often used off-label for pregnancy-associated nausea and vomiting, its use during pregnancy should be carefully considered. Some studies have suggested a possible small increase in the risk of certain birth defects, particularly when used in the first trimester. The benefits and risks should be carefully weighed for each individual patient.

Role of the Interprofessional Team in Ondansetron Therapy

Effective use of ondansetron in clinical practice often requires a collaborative effort from an interprofessional healthcare team. Here’s how different team members contribute to optimizing ondansetron therapy:

Physicians

• Assess the need for antiemetic therapy and prescribe ondansetron appropriately
• Consider patient-specific factors such as medical history, concurrent medications, and risk factors for adverse effects
• Monitor treatment efficacy and adjust dosing as needed

Pharmacists

• Review prescriptions for appropriate dosing, potential drug interactions, and contraindications
• Provide medication counseling to patients, including information on proper administration and potential side effects
• Collaborate with physicians to optimize antiemetic regimens, especially in complex cases like chemotherapy-induced nausea and vomiting

Nurses

• Administer ondansetron as prescribed, particularly in inpatient or infusion center settings
• Monitor patients for efficacy and adverse effects, reporting any concerns to the prescribing physician
• Provide patient education on ondansetron use and management of nausea and vomiting

Oncology Team

• Develop and implement antiemetic protocols for various chemotherapy regimens
• Assess and manage chemotherapy-induced nausea and vomiting, adjusting antiemetic regimens as needed
• Provide ongoing support and education to patients undergoing chemotherapy

How can effective communication within the interprofessional team improve ondansetron therapy outcomes? Regular team meetings, clear documentation, and open channels of communication allow for prompt addressing of patient concerns, optimization of antiemetic regimens, and early identification of potential adverse effects, ultimately leading to improved patient care and outcomes.

Future Directions and Research in Antiemetic Therapy

As our understanding of nausea and vomiting mechanisms continues to evolve, so does the landscape of antiemetic therapy. Here are some areas of ongoing research and potential future directions:

Novel Drug Formulations

Researchers are exploring new formulations of ondansetron and other antiemetics to improve efficacy and patient convenience:

• Extended-release formulations for longer-lasting effect
• Transdermal patches for patients unable to tolerate oral medications
• Nasal sprays for rapid onset of action

Combination Therapies

Investigating the synergistic effects of combining ondansetron with other antiemetics or supportive medications:

• Ondansetron plus NK1 receptor antagonists for enhanced CINV control
• Combination with non-pharmacological interventions like acupressure or ginger supplements

Personalized Medicine Approaches

Exploring genetic and metabolic factors that influence individual response to ondansetron:

• Pharmacogenomic studies to identify genetic markers of efficacy or adverse effects
• Development of predictive models for optimal antiemetic regimens based on patient characteristics

Expanded Indications

Investigating the potential use of ondansetron in other conditions associated with nausea and vomiting:

• Chronic nausea of unknown etiology
• Gastroparesis
• Cyclic vomiting syndrome in adults

What role might artificial intelligence play in optimizing antiemetic therapy in the future? AI algorithms could potentially analyze large datasets of patient characteristics, treatment regimens, and outcomes to develop personalized antiemetic protocols, predict high-risk patients for nausea and vomiting, and suggest optimal dosing strategies for ondansetron and other antiemetics.

As research in these areas progresses, healthcare providers can look forward to more tailored and effective approaches to managing nausea and vomiting across various clinical scenarios. The continued evolution of ondansetron use and the development of novel antiemetic strategies promise to further improve patient care and quality of life for those suffering from nausea and vomiting.

Ondansetron – StatPearls – NCBI Bookshelf

Continuing Education Activity

Ondansetron is one of the medications most commonly used for the empiric treatment of nausea and vomiting. Ondansetron has excellent 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, and off-label use for the prevention of nausea and vomiting associated with pregnancy. However, it is not effective for motion sickness-induced nausea. This activity will cover the mechanism of action, pharmacology, adverse event profiles, eligible patient populations, contraindications, and monitoring. It also highlights the interprofessional team’s role in managing patients needing ondansetron therapy.

Objectives:

• Identify the antiemetic mechanism of action of ondansetron.

• Outline the approved and off-label indications for using ondansetron.

• Summarize the adverse event profile of ondansetron.

• Review the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with ondansetron.

Access free multiple choice questions on this topic.

Indications

Nausea and vomiting are common complaints seen by emergency department physicians and primary care clinicians daily.[1] Ondansetron is on the World Health Organization’s (WHO) List of Essential Medicines, a list of medications considered effective and safe in meeting the essential needs of a health care 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 widespread utility as an antiemetic drug and is effective against nausea and vomiting of various etiologies.

The FDA-approved indications include the prevention of chemotherapy-induced nausea and vomiting(CINV), radiation-induced nausea and vomiting, and the prevention of postoperative nausea and vomiting (PONV).[2] It is considered first-line therapy for the treatment of chemotherapy-induced and radiation-induced nausea and vomiting.[3][4]

Off-label use for the prevention of nausea and vomiting associated with pregnancy. Ondansetron has minimal efficacy against nausea and vomiting caused by motion sickness, mediated by different control centers and pathophysiologic mechanisms. There are limited data available from pediatric populations. Ondansetron is used in pediatric populations for the acute treatment of cyclic vomiting syndrome; however, there is little information available on the efficacy of this disease.[5] Ondansetron is used off-label for severe refractory diarrhea associated with neuroendocrine tumors (carcinoid syndrome). [6]

Mechanism of Action

Ondansetron is a selective 5-HT3 serotonin-receptor antagonist used for its antiemetic properties. It is one of the four FDA-approved 5-HT3 serotonin-receptor antagonists used to combat nausea and vomiting, including granisetron, dolasetron, and the second-generation drug, palonosetron.[7]

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, located on the fourth ventricle floor, 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 works on the 5-HT3 receptors that can be found at the vagus nerve terminals. The vagus nerve can sense nausea and vomiting triggers within the GI tract, such as stomach irritants. 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.[8][9]

Pharmacokinetics

Absorption: Ondansetron undergoes rapid absorption from the GI tract, and the peak plasma concentration (Tmax) is approximately 1.5 hours after an 8 mg single oral dose. The absolute bioavailability of ondansetron after oral administration is approximately 60%(50%-70%). The lower bioavailability is attributed to first-pass metabolism. The systemic bioavailability of ondansetron increases nonlinearly with increasing doses from 8 mg, 16 mg, 32 mg, and 64 mg because of saturation of the first-pass metabolism. The bioavailability of ondansetron is significantly higher in patients with cancer (85% to 87%) than in healthy individuals (50%-70%), possibly due to alterations in metabolism.

Distribution: Ondansetron and its metabolites are extensively distributed in tissues. The apparent volume of distribution(Vd) at a steady state is approximately 1.8 L/kg. Ondansetron crosses the blood-brain barrier to a lower extent, with the CSF concentration only about 10%-15% of the plasma concentration in human volunteers. Adenosine binding cassette subfamily 1(ABCB1) is a drug efflux transporter known to transport ondansetron across the blood-brain barrier, thus limiting its accumulation in the CNS. In a patient with decreased activity of ABCB1, the concentration of ondansetron in the brain increases and improves efficacy.[10]

Metabolism: The liver is the primary site of metabolism. The primary mechanism of metabolism is oxidation. 8-hydroxy ondansetron represents the major metabolite (40%), followed by 7-hydroxy ondansetron (< 20%) and 6-hydroxy ondansetron (<5%). Minor metabolism also occurs via N-demethylation to yield N-demethyl ondansetron. The active metabolite of ondansetron is  8-hydroxy ondansetron which is rapidly metabolized to glucuronide and sulfate conjugates in the liver, resulting in low blood concentrations and, thus, a very small contribution to ondansetron’s antiemetic activity. Cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4, are involved in the metabolism of ondansetron. In humans, CYP1A1/2 plays the most crucial role, while CYP2D6 plays a minor role in the metabolism of ondansetron. The role of CYP3A4 is important at higher concentrations of ondansetron.[11]

Excretion: Hepatic metabolism accounts for nearly 95% of ondansetron clearance, and less than 5% is excreted unchanged in the urine. The clearance and elimination half-life of ondansetron vary according to age. The elimination half-life after an 8 mg oral or intravenous dose is approximately 3-4 h in adults, but on average, it is 5.5 hours in the elderly. Clearance ranges from 0.381 L/h/kg to 0.262 L/h/kg, depending on age. In adults, clearance is 0.351 5L/h/kg. The clearance per body weight is higher in younger children. However, the clearance is decreased in infants due to the underdeveloped cytochrome P450 enzyme system.[12]

Administration

Routes of administration include oral, intramuscular (IM), and intravenous (IV). Oral formulations are available in dissolving tablet and soluble film forms. 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 treating emetogenic chemotherapy.

Dosing varies depending on the route of administration and the etiology. However, 16 mg per dose IV is the maximum recommended single dose due to the risk for QTc prolongation and arrhythmias. Standard dosing to prevent postoperative nausea and vomiting includes 8 mg every 12 hours orally or 4 mg given intravenously. No dosage adjustments are necessary for IV or oral administration in patients with renal impairment. The same holds for patients with mild to moderate hepatic impairment, but the maximum daily dosing is reduced to 8 mg IV or 8 mg orally in patients with severe hepatic impairment. Pediatric dosing is weight-based at 0.15 mg/kg per dose, with a maximum of 16 mg per dose.

Use in Specific Patient Populations

Patients with Hepatic Impairment: No dose adjustments of ondansetron are necessary for mild to moderate hepatic impairment. In patients with severe hepatic impairment, clearance of ondansetron is reduced; the volume of distribution and the plasma half-life is increased. Consequently, ondansetron should be used with caution, and the maximum recommended daily intravenous dose isis reduced to 8 mg.[11]

Patients with Renal Impairment: No dosage adjustments are necessary for IV or oral administration in patients with renal impairment.[11]

Pregnancy Considerations: Ondansetron is a former FDA  “Pregnancy Category B” drug. It should only be used when other medications have been trialed and failed to treat pregnancy-associated nausea, vomiting, and hyperemesis gravidarum.[8] According to ACOG(The American College of Obstetricians and Gynecologists) guidelines, pyridoxine alone or combined with doxylamine is the preferred pharmacological therapy for nausea and vomiting. However, in refractory cases with persistent symptoms, ondansetron, 4 mg orally every 8 hours, may be considered(if there is no dehydration).[13] A possible association between ondansetron use in the first trimester and cleft palate has been reported. Electrolyte and electrocardiogram monitoring are suggested in patients treated with ondansetron having risk factors for arrhythmia, such as a family history of prolonged QT interval, heart failure, and electrolyte disturbances.[14] Recommendations for pregnant women with gynecological cancer suggest that 5HT-3 antagonists (including ondansetron ) can be used as supportive medication.[15]

Breastfeeding Considerations: In a pharmacokinetic study, the relative infant exposure to ondansetron is less.[16] Ondansetron is commonly used for nausea during and after a cesarean section, usually in doses of 4 to 8 mg intravenously. Using ondansetron during cesarean section does not affect the onset of breastfeeding. No adverse drug reactions have been reported in infants. Additionally, ondansetron is indicated for use in infants as young as one month. No specific precautions are required.[17]

Adverse Effects

The most commonly reported side effects (occurring in more than 10% of adults) include headaches, 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.[18][19] A transient increase in liver function tests has been reported as well. The pattern of liver enzyme elevation is normally hepatocellular, with rare cases of clinically apparent acute liver injury or jaundice.[20]

Although typically clinically insignificant, EKG interval changes such as QTc elongation can be seen. These changes typically occur within 1 to 2 hours after administration, returning to baseline within 24 hours. As with any medication that causes QTc elongation, there is a concern for Torsade de Pointes and other arrhythmias. [21] IV administration has a higher risk for arrhythmias; consequently, the FDA does not recommend a single dose greater than 16 mg IV.[22] Isolated cases of sinus bradycardia and asystole have also been reported.[23] Cases of intestinal obstruction due to impaired gut motility have been reported.[24] Stevens-Johnson syndrome has been reported in patients with multiple comorbidities.[25]

Drug-Drug Interactions

Concurrent administration of pimozide with ondansetron should be avoided due to the risk of QTc prolongation.[26] Amiodarone may also prolong the QTc interval; hence administration with ondansetron requires monitoring.[27] There is a risk of serotonin syndrome when taking ondansetron in conjunction with other serotonergic medications.[28][26]

Contraindications

Ondansetron is contraindicated in patients with hypersensitivity to the drug or any components of it.[29] Severe hypersensitivity reactions, including anaphylaxis, have been reported.[30][31] Ondansetron 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.[32] Patients with phenylketonuria (PKU) should be cautious, as the dissolving tablet formulation can contain phenylalanine, leading to irreversible neurological damage in PKU patients.[33]

Monitoring

Due to the potential for dose-dependent QTc interval elongation, the FDA recommends EKG monitoring along with potassium and magnesium in 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.[22][34] 

Pregnant patients should be monitored for adverse fetal outcomes associated with ondansetron therapy.[35][36][37] Current evidence does not suggest routine EKG and electrolyte monitoring for ondansetron without known risk factors.  Monitoring should be done in high-risk patients receiving ondansetron intravenously.[23][35]

Toxicity

There is no known antidote to ondansetron, and supportive measures are used for overdose. A case report describes an ondansetron overdose in an infant presenting with seizures, QTc prolongation, hepatotoxicity, and serotonin syndrome. The patient required endotracheal intubation, supportive care, and lorazepam for seizures.[38]

Enhancing Healthcare Team Outcomes

Ondansetron is a widely prescribed medication for nausea and vomiting from various 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 specific populations. Due to the potential for dose-dependent QTc interval prolongation, clinicians should monitor EKG, potassium, and magnesium levels in a susceptible population. It includes the elderly or patients with electrolyte abnormalities such as hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients on other medications that may prolong the QTc interval. Current evidence does not demonstrate a need to pre-screen this population before administering ondansetron for patients without any of the above risk factors.

An interprofessional team approach is critical for diagnosing and managing symptoms, treating patients with nausea and vomiting, and managing the adverse effects of the treatments. Clinicians (MDs, DOs, NPs, PAs) usually prescribe ondansetron for labeled indications. Oncologist consultation is necessary for CINV. Pharmacists should ensure proper dose, perform medication reconciliation and consult prescribers about any concerns. Nursing staff should monitor patients administering medicine and inform clinicians of any side effects observed. Emergency department physicians should rapidly stabilize the patient in case of arrhythmia. Severe cases may require consultation with an intensivist and MICU/IMC level of care. Medical toxicologist consultation may become necessary in the overdose. If the overdose is intentional, psychiatric consultation is essential. An interprofessional team approach would maximize the efficacy and minimize potential adverse drug reactions for the patients requiring ondansetron, resulting in better patient outcomes. [Level 5] A prospective study involving 789 patients demonstrated that an interprofessional team approach among clinicians, residents, clinical pharmacists, and oncologists reduced potential medication errors, eventually enhancing patient safety. [Level 3]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Furyk JS, Meek RA, Egerton-Warburton D. Drugs for the treatment of nausea and vomiting in adults in the emergency department setting. Cochrane Database Syst Rev. 2015 Sep 28;2015(9):CD010106. [PMC free article: PMC6517141] [PubMed: 26411330]

2.

Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Somerfield MR, Lyman GH. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Oct 01;35(28):3240-3261. [PubMed: 28759346]

3.

Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Lyman GH. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797. [PubMed: 32658626]

4.

Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, Jin Z, Kovac AL, Meyer TA, Urman RD, Apfel CC, Ayad S, Beagley L, Candiotti K, Englesakis M, Hedrick TL, Kranke P, Lee S, Lipman D, Minkowitz HS, Morton J, Philip BK. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg. 2020 Aug;131(2):411-448. [PubMed: 32467512]

5.

Dicato MA, Freeman AJ. Experience with ondansetron in chemotherapy- and radiotherapy-induced emesis. Eur J Anaesthesiol Suppl. 1992 Nov;6:19-24. [PubMed: 1425621]

6.

Kiesewetter B, Raderer M. Ondansetron for diarrhea associated with neuroendocrine tumors. N Engl J Med. 2013 May 16;368(20):1947-8. [PubMed: 23675671]

7.

Ye JH, Ponnudurai R, Schaefer R. Ondansetron: a selective 5-HT(3) receptor antagonist and its applications in CNS-related disorders. CNS Drug Rev. 2001 Summer;7(2):199-213. [PMC free article: PMC6741689] [PubMed: 11474424]

8.

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. Reprod Toxicol. 2019 Jun;86:1-13. [PubMed: 30849498]

9.

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 Opin Drug Saf. 2019 Feb;18(2):97-110. [PubMed: 30640557]

10.

He H, Yin JY, Xu YJ, Li X, Zhang Y, Liu ZG, Zhou F, Zhai M, Li Y, Li XP, Wang Y, Zhou HH, Liu ZQ. Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting. Clin Ther. 2014 Aug 01;36(8):1242-1252.e2. [PubMed: 25012726]

11.

Christofaki M, Papaioannou A. Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting. Expert Opin Drug Metab Toxicol. 2014 Mar;10(3):437-44. [PubMed: 24471415]

12.

Rajawat GS, Belubbi T, Nagarsenker MS, Abrahamsson B, Cristofoletti R, Groot DW, Langguth P, Parr A, Polli JE, Mehta M, Shah VP, Tajiri T, Dressman J. Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron. J Pharm Sci. 2019 Oct;108(10):3157-3168. [PubMed: 31181225]

13.

Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstet Gynecol. 2018 Jan;131(1):e15-e30. [PubMed: 29266076]

14.

Pasternak B, Svanström H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23. [PubMed: 23445092]

15.

Amant F, Berveiller P, Boere IA, Cardonick E, Fruscio R, Fumagalli M, Halaska MJ, Hasenburg A, Johansson ALV, Lambertini M, Lok CAR, Maggen C, Morice P, Peccatori F, Poortmans P, Van Calsteren K, Vandenbroucke T, van Gerwen M, van den Heuvel-Eibrink M, Zagouri F, Zapardiel I. Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting. Ann Oncol. 2019 Oct 01;30(10):1601-1612. [PubMed: 31435648]

16.

Job KM, Dallmann A, Parry S, Saade G, Haas DM, Hughes B, Berens P, Chen JY, Fu C, Humphrey K, Hornik C, Balevic S, Zimmerman K, Watt K. Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk. Clin Pharmacol Ther. 2022 May;111(5):1111-1120. [PMC free article: PMC10267851] [PubMed: 35076931]

17.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): May 15, 2022. Ondansetron. [PubMed: 29999857]

18.

Khan RB. Migraine-type headaches in children receiving chemotherapy and ondansetron. J Child Neurol. 2002 Nov;17(11):857-8. [PubMed: 12585731]

19.

Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller R. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014 Oct;63(10):1617-25. [PMC free article: PMC4173656] [PubMed: 24334242]

20.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jan 15, 2018. Serotonin 5-HT3 Receptor Antagonists. [PubMed: 31643518]

21.

Patel E, Rosemond D, Afzal A. Ondansetron induced torsades de pointes. Clin Case Rep. 2019 Aug;7(8):1557-1558. [PMC free article: PMC6692972] [PubMed: 31428390]

22.

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 Pharm J. 2019 Feb;27(2):229-234. [PMC free article: PMC6362170] [PubMed: 30766434]

23.

Rapp JH, Yuen M, Abraham T. Bradycardia After Intravenous Ondansetron with Asystole on Rechallenge: A Case Report. Hosp Pharm. 2015 Nov;50(10):918-921. [PMC free article: PMC5057199] [PubMed: 27729680]

24.

Cohen R, Shlomo M, Dil DN, Dinavitser N, Berkovitch M, Koren G. Intestinal obstruction in pregnancy by ondansetron. Reprod Toxicol. 2014 Dec;50:152-3. [PubMed: 25461913]

25.

Cokan A, Gavrić Lovrec V, Takač I. A Case of Stevens-Johnson Syndrome in Recurrent Late-Stage Ovarian Cancer Patient after Management of Chronic Pain with Elastomeric Pump. Curr Oncol. 2021 Aug 03;28(4):2928-2932. [PMC free article: PMC8395433] [PubMed: 34436022]

26.

Cada DJ, Leonard J, Baker DE. Netupitant/Palonosetron. Hosp Pharm. 2015 Apr;50(4):310-25. [PMC free article: PMC4589884] [PubMed: 26448661]

27.

Moffett PM, Cartwright L, Grossart EA, O’Keefe D, Kang CS. Intravenous Ondansetron and the QT Interval in Adult Emergency Department Patients: An Observational Study. Acad Emerg Med. 2016 Jan;23(1):102-5. [PubMed: 26720490]

28.

Guo MH, Monir RL, Wright A, Holland NP. Case of Serotonin Syndrome Initially Presenting as Diffuse Body Pain. Am J Case Rep. 2018 Oct 15;19:1227-1231. [PMC free article: PMC6196581] [PubMed: 30318504]

29.

Leung J, Guyer A, Banerji A. IgE-mediated hypersensitivity to ondansetron and safe use of palonosetron. J Allergy Clin Immunol Pract. 2013 Sep-Oct;1(5):526-7. [PubMed: 24565629]

30.

Sapkota K, Bhagat R. Fatal anaphylaxis to intravenous ondansetron: A case report. Clin Case Rep. 2021 May;9(5):e04110. [PMC free article: PMC8122120] [PubMed: 34026152]

31.

Goyal P, Paramesh K, Puranik S, Proctor M, Sanghvi M. Delayed diagnosis of anaphylaxis secondary to ondansetron: A case report. Eur J Anaesthesiol. 2016 Feb;33(2):146-7. [PubMed: 26555872]

32.

Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson’s Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs. 2019 Sep;33(9):905-918. [PMC free article: PMC6776563] [PubMed: 31473980]

33.

Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015 Oct;4(4):304-17. [PMC free article: PMC4728993] [PubMed: 26835392]

34.

Fiedrich E, Sabhaney V, Lui J, Pinsk M. Assessment of ondansetron-associated hypokalemia in pediatric oncology patients. ISRN Oncol. 2012;2012:798239. [PMC free article: PMC3459247] [PubMed: 23050164]

35.

Romano C, Dipasquale V, Scarpignato C. Antiemetic Drug Use in Children: What the Clinician Needs to Know. J Pediatr Gastroenterol Nutr. 2019 Apr;68(4):466-471. [PubMed: 30540713]

36.

Balayla J. Comment on: Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review. J Obstet Gynaecol Can. 2018 Dec;40(12):1567-1568. [PubMed: 30361157]

37.

Sridharan K, Sivaramakrishnan G. Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials. J Matern Fetal Neonatal Med. 2020 Apr;33(8):1405-1411. [PubMed: 30173590]

38.

George M, Al-Duaij N, O’Donnell KA, Shannon MW. Obtundation and seizure following ondansetron overdose in an infant. Clin Toxicol (Phila). 2008 Dec;46(10):1064-6. [PubMed: 18803119]

Disclosure: Alexandria Griddine declares no relevant financial relationships with ineligible companies.

Disclosure: Jeffrey Bush declares no relevant financial relationships with ineligible companies.

Ondansetron – StatPearls – NCBI Bookshelf

Continuing Education Activity

Ondansetron is one of the medications most commonly used for the empiric treatment of nausea and vomiting. Ondansetron has excellent 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, and off-label use for the prevention of nausea and vomiting associated with pregnancy. However, it is not effective for motion sickness-induced nausea. This activity will cover the mechanism of action, pharmacology, adverse event profiles, eligible patient populations, contraindications, and monitoring. It also highlights the interprofessional team’s role in managing patients needing ondansetron therapy.

Objectives:

• Identify the antiemetic mechanism of action of ondansetron.

• Outline the approved and off-label indications for using ondansetron.

• Summarize the adverse event profile of ondansetron.

• Review the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with ondansetron.

Access free multiple choice questions on this topic.

Indications

Nausea and vomiting are common complaints seen by emergency department physicians and primary care clinicians daily.[1] Ondansetron is on the World Health Organization’s (WHO) List of Essential Medicines, a list of medications considered effective and safe in meeting the essential needs of a health care 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 widespread utility as an antiemetic drug and is effective against nausea and vomiting of various etiologies.

The FDA-approved indications include the prevention of chemotherapy-induced nausea and vomiting(CINV), radiation-induced nausea and vomiting, and the prevention of postoperative nausea and vomiting (PONV).[2] It is considered first-line therapy for the treatment of chemotherapy-induced and radiation-induced nausea and vomiting.[3][4]

Off-label use for the prevention of nausea and vomiting associated with pregnancy. Ondansetron has minimal efficacy against nausea and vomiting caused by motion sickness, mediated by different control centers and pathophysiologic mechanisms. There are limited data available from pediatric populations. Ondansetron is used in pediatric populations for the acute treatment of cyclic vomiting syndrome; however, there is little information available on the efficacy of this disease. [5] Ondansetron is used off-label for severe refractory diarrhea associated with neuroendocrine tumors (carcinoid syndrome).[6]

Mechanism of Action

Ondansetron is a selective 5-HT3 serotonin-receptor antagonist used for its antiemetic properties. It is one of the four FDA-approved 5-HT3 serotonin-receptor antagonists used to combat nausea and vomiting, including granisetron, dolasetron, and the second-generation drug, palonosetron.[7]

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, located on the fourth ventricle floor, 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 works on the 5-HT3 receptors that can be found at the vagus nerve terminals. The vagus nerve can sense nausea and vomiting triggers within the GI tract, such as stomach irritants. 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.[8][9]

Pharmacokinetics

Absorption: Ondansetron undergoes rapid absorption from the GI tract, and the peak plasma concentration (Tmax) is approximately 1.5 hours after an 8 mg single oral dose. The absolute bioavailability of ondansetron after oral administration is approximately 60%(50%-70%). The lower bioavailability is attributed to first-pass metabolism. The systemic bioavailability of ondansetron increases nonlinearly with increasing doses from 8 mg, 16 mg, 32 mg, and 64 mg because of saturation of the first-pass metabolism. The bioavailability of ondansetron is significantly higher in patients with cancer (85% to 87%) than in healthy individuals (50%-70%), possibly due to alterations in metabolism.

Distribution: Ondansetron and its metabolites are extensively distributed in tissues. The apparent volume of distribution(Vd) at a steady state is approximately 1.8 L/kg. Ondansetron crosses the blood-brain barrier to a lower extent, with the CSF concentration only about 10%-15% of the plasma concentration in human volunteers. Adenosine binding cassette subfamily 1(ABCB1) is a drug efflux transporter known to transport ondansetron across the blood-brain barrier, thus limiting its accumulation in the CNS. In a patient with decreased activity of ABCB1, the concentration of ondansetron in the brain increases and improves efficacy.[10]

Metabolism: The liver is the primary site of metabolism. The primary mechanism of metabolism is oxidation. 8-hydroxy ondansetron represents the major metabolite (40%), followed by 7-hydroxy ondansetron (< 20%) and 6-hydroxy ondansetron (<5%). Minor metabolism also occurs via N-demethylation to yield N-demethyl ondansetron. The active metabolite of ondansetron is  8-hydroxy ondansetron which is rapidly metabolized to glucuronide and sulfate conjugates in the liver, resulting in low blood concentrations and, thus, a very small contribution to ondansetron’s antiemetic activity. Cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4, are involved in the metabolism of ondansetron. In humans, CYP1A1/2 plays the most crucial role, while CYP2D6 plays a minor role in the metabolism of ondansetron. The role of CYP3A4 is important at higher concentrations of ondansetron.[11]

Excretion: Hepatic metabolism accounts for nearly 95% of ondansetron clearance, and less than 5% is excreted unchanged in the urine. The clearance and elimination half-life of ondansetron vary according to age. The elimination half-life after an 8 mg oral or intravenous dose is approximately 3-4 h in adults, but on average, it is 5.5 hours in the elderly. Clearance ranges from 0.381 L/h/kg to 0.262 L/h/kg, depending on age. In adults, clearance is 0.351 5L/h/kg. The clearance per body weight is higher in younger children. However, the clearance is decreased in infants due to the underdeveloped cytochrome P450 enzyme system.[12]

Administration

Routes of administration include oral, intramuscular (IM), and intravenous (IV). Oral formulations are available in dissolving tablet and soluble film forms. 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 treating emetogenic chemotherapy.

Dosing varies depending on the route of administration and the etiology. However, 16 mg per dose IV is the maximum recommended single dose due to the risk for QTc prolongation and arrhythmias. Standard dosing to prevent postoperative nausea and vomiting includes 8 mg every 12 hours orally or 4 mg given intravenously. No dosage adjustments are necessary for IV or oral administration in patients with renal impairment. The same holds for patients with mild to moderate hepatic impairment, but the maximum daily dosing is reduced to 8 mg IV or 8 mg orally in patients with severe hepatic impairment. Pediatric dosing is weight-based at 0.15 mg/kg per dose, with a maximum of 16 mg per dose.

Use in Specific Patient Populations

Patients with Hepatic Impairment: No dose adjustments of ondansetron are necessary for mild to moderate hepatic impairment. In patients with severe hepatic impairment, clearance of ondansetron is reduced; the volume of distribution and the plasma half-life is increased. Consequently, ondansetron should be used with caution, and the maximum recommended daily intravenous dose isis reduced to 8 mg.[11]

Patients with Renal Impairment: No dosage adjustments are necessary for IV or oral administration in patients with renal impairment.[11]

Pregnancy Considerations: Ondansetron is a former FDA  “Pregnancy Category B” drug. It should only be used when other medications have been trialed and failed to treat pregnancy-associated nausea, vomiting, and hyperemesis gravidarum.[8] According to ACOG(The American College of Obstetricians and Gynecologists) guidelines, pyridoxine alone or combined with doxylamine is the preferred pharmacological therapy for nausea and vomiting. However, in refractory cases with persistent symptoms, ondansetron, 4 mg orally every 8 hours, may be considered(if there is no dehydration).[13] A possible association between ondansetron use in the first trimester and cleft palate has been reported. Electrolyte and electrocardiogram monitoring are suggested in patients treated with ondansetron having risk factors for arrhythmia, such as a family history of prolonged QT interval, heart failure, and electrolyte disturbances.[14] Recommendations for pregnant women with gynecological cancer suggest that 5HT-3 antagonists (including ondansetron ) can be used as supportive medication.[15]

Breastfeeding Considerations: In a pharmacokinetic study, the relative infant exposure to ondansetron is less.[16] Ondansetron is commonly used for nausea during and after a cesarean section, usually in doses of 4 to 8 mg intravenously. Using ondansetron during cesarean section does not affect the onset of breastfeeding. No adverse drug reactions have been reported in infants. Additionally, ondansetron is indicated for use in infants as young as one month. No specific precautions are required.[17]

Adverse Effects

The most commonly reported side effects (occurring in more than 10% of adults) include headaches, 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.[18][19] A transient increase in liver function tests has been reported as well. The pattern of liver enzyme elevation is normally hepatocellular, with rare cases of clinically apparent acute liver injury or jaundice.[20]

Although typically clinically insignificant, EKG interval changes such as QTc elongation can be seen. These changes typically occur within 1 to 2 hours after administration, returning to baseline within 24 hours. As with any medication that causes QTc elongation, there is a concern for Torsade de Pointes and other arrhythmias. [21] IV administration has a higher risk for arrhythmias; consequently, the FDA does not recommend a single dose greater than 16 mg IV.[22] Isolated cases of sinus bradycardia and asystole have also been reported.[23] Cases of intestinal obstruction due to impaired gut motility have been reported.[24] Stevens-Johnson syndrome has been reported in patients with multiple comorbidities.[25]

Drug-Drug Interactions

Concurrent administration of pimozide with ondansetron should be avoided due to the risk of QTc prolongation.[26] Amiodarone may also prolong the QTc interval; hence administration with ondansetron requires monitoring.[27] There is a risk of serotonin syndrome when taking ondansetron in conjunction with other serotonergic medications.[28][26]

Contraindications

Ondansetron is contraindicated in patients with hypersensitivity to the drug or any components of it.[29] Severe hypersensitivity reactions, including anaphylaxis, have been reported.[30][31] Ondansetron 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.[32] Patients with phenylketonuria (PKU) should be cautious, as the dissolving tablet formulation can contain phenylalanine, leading to irreversible neurological damage in PKU patients.[33]

Monitoring

Due to the potential for dose-dependent QTc interval elongation, the FDA recommends EKG monitoring along with potassium and magnesium in 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.[22][34] 

Pregnant patients should be monitored for adverse fetal outcomes associated with ondansetron therapy.[35][36][37] Current evidence does not suggest routine EKG and electrolyte monitoring for ondansetron without known risk factors.  Monitoring should be done in high-risk patients receiving ondansetron intravenously.[23][35]

Toxicity

There is no known antidote to ondansetron, and supportive measures are used for overdose. A case report describes an ondansetron overdose in an infant presenting with seizures, QTc prolongation, hepatotoxicity, and serotonin syndrome. The patient required endotracheal intubation, supportive care, and lorazepam for seizures.[38]

Enhancing Healthcare Team Outcomes

Ondansetron is a widely prescribed medication for nausea and vomiting from various 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 specific populations. Due to the potential for dose-dependent QTc interval prolongation, clinicians should monitor EKG, potassium, and magnesium levels in a susceptible population. It includes the elderly or patients with electrolyte abnormalities such as hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients on other medications that may prolong the QTc interval. Current evidence does not demonstrate a need to pre-screen this population before administering ondansetron for patients without any of the above risk factors.

An interprofessional team approach is critical for diagnosing and managing symptoms, treating patients with nausea and vomiting, and managing the adverse effects of the treatments. Clinicians (MDs, DOs, NPs, PAs) usually prescribe ondansetron for labeled indications. Oncologist consultation is necessary for CINV. Pharmacists should ensure proper dose, perform medication reconciliation and consult prescribers about any concerns. Nursing staff should monitor patients administering medicine and inform clinicians of any side effects observed. Emergency department physicians should rapidly stabilize the patient in case of arrhythmia. Severe cases may require consultation with an intensivist and MICU/IMC level of care. Medical toxicologist consultation may become necessary in the overdose. If the overdose is intentional, psychiatric consultation is essential. An interprofessional team approach would maximize the efficacy and minimize potential adverse drug reactions for the patients requiring ondansetron, resulting in better patient outcomes. [Level 5] A prospective study involving 789 patients demonstrated that an interprofessional team approach among clinicians, residents, clinical pharmacists, and oncologists reduced potential medication errors, eventually enhancing patient safety. [Level 3]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Furyk JS, Meek RA, Egerton-Warburton D. Drugs for the treatment of nausea and vomiting in adults in the emergency department setting. Cochrane Database Syst Rev. 2015 Sep 28;2015(9):CD010106. [PMC free article: PMC6517141] [PubMed: 26411330]

2.

Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Somerfield MR, Lyman GH. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Oct 01;35(28):3240-3261. [PubMed: 28759346]

3.

Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Lyman GH. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797. [PubMed: 32658626]

4.

Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, Jin Z, Kovac AL, Meyer TA, Urman RD, Apfel CC, Ayad S, Beagley L, Candiotti K, Englesakis M, Hedrick TL, Kranke P, Lee S, Lipman D, Minkowitz HS, Morton J, Philip BK. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg. 2020 Aug;131(2):411-448. [PubMed: 32467512]

5.

Dicato MA, Freeman AJ. Experience with ondansetron in chemotherapy- and radiotherapy-induced emesis. Eur J Anaesthesiol Suppl. 1992 Nov;6:19-24. [PubMed: 1425621]

6.

Kiesewetter B, Raderer M. Ondansetron for diarrhea associated with neuroendocrine tumors. N Engl J Med. 2013 May 16;368(20):1947-8. [PubMed: 23675671]

7.

Ye JH, Ponnudurai R, Schaefer R. Ondansetron: a selective 5-HT(3) receptor antagonist and its applications in CNS-related disorders. CNS Drug Rev. 2001 Summer;7(2):199-213. [PMC free article: PMC6741689] [PubMed: 11474424]

8.

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. Reprod Toxicol. 2019 Jun;86:1-13. [PubMed: 30849498]

9.

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 Opin Drug Saf. 2019 Feb;18(2):97-110. [PubMed: 30640557]

10.

He H, Yin JY, Xu YJ, Li X, Zhang Y, Liu ZG, Zhou F, Zhai M, Li Y, Li XP, Wang Y, Zhou HH, Liu ZQ. Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting. Clin Ther. 2014 Aug 01;36(8):1242-1252.e2. [PubMed: 25012726]

11.

Christofaki M, Papaioannou A. Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting. Expert Opin Drug Metab Toxicol. 2014 Mar;10(3):437-44. [PubMed: 24471415]

12.

Rajawat GS, Belubbi T, Nagarsenker MS, Abrahamsson B, Cristofoletti R, Groot DW, Langguth P, Parr A, Polli JE, Mehta M, Shah VP, Tajiri T, Dressman J. Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron. J Pharm Sci. 2019 Oct;108(10):3157-3168. [PubMed: 31181225]

13.

Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstet Gynecol. 2018 Jan;131(1):e15-e30. [PubMed: 29266076]

14.

Pasternak B, Svanström H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23. [PubMed: 23445092]

15.

Amant F, Berveiller P, Boere IA, Cardonick E, Fruscio R, Fumagalli M, Halaska MJ, Hasenburg A, Johansson ALV, Lambertini M, Lok CAR, Maggen C, Morice P, Peccatori F, Poortmans P, Van Calsteren K, Vandenbroucke T, van Gerwen M, van den Heuvel-Eibrink M, Zagouri F, Zapardiel I. Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting. Ann Oncol. 2019 Oct 01;30(10):1601-1612. [PubMed: 31435648]

16.

Job KM, Dallmann A, Parry S, Saade G, Haas DM, Hughes B, Berens P, Chen JY, Fu C, Humphrey K, Hornik C, Balevic S, Zimmerman K, Watt K. Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk. Clin Pharmacol Ther. 2022 May;111(5):1111-1120. [PMC free article: PMC10267851] [PubMed: 35076931]

17.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): May 15, 2022. Ondansetron. [PubMed: 29999857]

18.

Khan RB. Migraine-type headaches in children receiving chemotherapy and ondansetron. J Child Neurol. 2002 Nov;17(11):857-8. [PubMed: 12585731]

19.

Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller R. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014 Oct;63(10):1617-25. [PMC free article: PMC4173656] [PubMed: 24334242]

20.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jan 15, 2018. Serotonin 5-HT3 Receptor Antagonists. [PubMed: 31643518]

21.

Patel E, Rosemond D, Afzal A. Ondansetron induced torsades de pointes. Clin Case Rep. 2019 Aug;7(8):1557-1558. [PMC free article: PMC6692972] [PubMed: 31428390]

22.

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 Pharm J. 2019 Feb;27(2):229-234. [PMC free article: PMC6362170] [PubMed: 30766434]

23.

Rapp JH, Yuen M, Abraham T. Bradycardia After Intravenous Ondansetron with Asystole on Rechallenge: A Case Report. Hosp Pharm. 2015 Nov;50(10):918-921. [PMC free article: PMC5057199] [PubMed: 27729680]

24.

Cohen R, Shlomo M, Dil DN, Dinavitser N, Berkovitch M, Koren G. Intestinal obstruction in pregnancy by ondansetron. Reprod Toxicol. 2014 Dec;50:152-3. [PubMed: 25461913]

25.

Cokan A, Gavrić Lovrec V, Takač I. A Case of Stevens-Johnson Syndrome in Recurrent Late-Stage Ovarian Cancer Patient after Management of Chronic Pain with Elastomeric Pump. Curr Oncol. 2021 Aug 03;28(4):2928-2932. [PMC free article: PMC8395433] [PubMed: 34436022]

26.

Cada DJ, Leonard J, Baker DE. Netupitant/Palonosetron. Hosp Pharm. 2015 Apr;50(4):310-25. [PMC free article: PMC4589884] [PubMed: 26448661]

27.

Moffett PM, Cartwright L, Grossart EA, O’Keefe D, Kang CS. Intravenous Ondansetron and the QT Interval in Adult Emergency Department Patients: An Observational Study. Acad Emerg Med. 2016 Jan;23(1):102-5. [PubMed: 26720490]

28.

Guo MH, Monir RL, Wright A, Holland NP. Case of Serotonin Syndrome Initially Presenting as Diffuse Body Pain. Am J Case Rep. 2018 Oct 15;19:1227-1231. [PMC free article: PMC6196581] [PubMed: 30318504]

29.

Leung J, Guyer A, Banerji A. IgE-mediated hypersensitivity to ondansetron and safe use of palonosetron. J Allergy Clin Immunol Pract. 2013 Sep-Oct;1(5):526-7. [PubMed: 24565629]

30.

Sapkota K, Bhagat R. Fatal anaphylaxis to intravenous ondansetron: A case report. Clin Case Rep. 2021 May;9(5):e04110. [PMC free article: PMC8122120] [PubMed: 34026152]

31.

Goyal P, Paramesh K, Puranik S, Proctor M, Sanghvi M. Delayed diagnosis of anaphylaxis secondary to ondansetron: A case report. Eur J Anaesthesiol. 2016 Feb;33(2):146-7. [PubMed: 26555872]

32.

Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson’s Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs. 2019 Sep;33(9):905-918. [PMC free article: PMC6776563] [PubMed: 31473980]

33.

Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015 Oct;4(4):304-17. [PMC free article: PMC4728993] [PubMed: 26835392]

34.

Fiedrich E, Sabhaney V, Lui J, Pinsk M. Assessment of ondansetron-associated hypokalemia in pediatric oncology patients. ISRN Oncol. 2012;2012:798239. [PMC free article: PMC3459247] [PubMed: 23050164]

35.

Romano C, Dipasquale V, Scarpignato C. Antiemetic Drug Use in Children: What the Clinician Needs to Know. J Pediatr Gastroenterol Nutr. 2019 Apr;68(4):466-471. [PubMed: 30540713]

36.

Balayla J. Comment on: Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review. J Obstet Gynaecol Can. 2018 Dec;40(12):1567-1568. [PubMed: 30361157]

37.

Sridharan K, Sivaramakrishnan G. Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials. J Matern Fetal Neonatal Med. 2020 Apr;33(8):1405-1411. [PubMed: 30173590]

38.

George M, Al-Duaij N, O’Donnell KA, Shannon MW. Obtundation and seizure following ondansetron overdose in an infant. Clin Toxicol (Phila). 2008 Dec;46(10):1064-6. [PubMed: 18803119]

Disclosure: Alexandria Griddine declares no relevant financial relationships with ineligible companies.

Disclosure: Jeffrey Bush declares no relevant financial relationships with ineligible companies.

Use of ondansetron in the treatment of children with cancer

Supportive care

Trademarks:

Zofran®

Other names:

Ondansetron Hydrochloride

Often used for:

treatment of nausea and vomiting

Ondansetron is a drug that is used to prevent and treat nausea and vomiting during chemotherapy and radiation therapy, as well as in the postoperative period.

The rate of breakdown of ondansetron in the body may vary. This is determined by the activity of an enzyme called P450 2D6 (CYP2D6). Genetic analysis may be required to determine the quality of the enzymes in a particular patient. The drug may not be effective enough if the rate of breakdown of ondansetron in the patient’s body is higher than normal.

This drug is usually taken 30 minutes before chemotherapy starts.

Oral administration in the form of tablets or absorbable films or tablets

Oral liquid form

Administered intravenously (by drip or injection) in liquid form

• Headache
• Abdominal pain
• Dizziness
• Diarrhea
• Constipation
• Rash
• Increased fatigue or general weakness
• Blurred vision
• Alarm
• Disorders of the heart
• Liver disorders

The listed side effects are not observed in all patients who are prescribed ondansetron. The most common side effects are highlighted in bold, but others are not excluded. Report all possible side effects to your doctor or pharmacist.

Be sure to discuss these and other recommendations with your doctor or pharmacist.

Home use of ondansetron:

• Non-absorbable tablets should be swallowed whole. Do not crush or chew before taking.
• Resorbable tablets or films hold on tongue until completely dissolved. They should not be chewed or swallowed with water or other liquid. Hands must be dry when handling the preparation.
• When taking ondansetron in liquid form, measure the dosage using the measuring device included in the kit.
• Take your dose as soon as possible if you miss it. Do not do this only if there is little time left until the next appointment. In no case do not double the dose at the next dose!
• Store at room temperature. Ondansetron for intravenous administration should be stored in the refrigerator.
• Do not use an expired drug.
• Follow the instructions for disposal of the drug.

Additional information about ondansetron

• Cytochrome P450 2D6 (CYP2D6) and drugs

More about ondansetron

Ondansetron PJSC SPC “Borshchagovsky CPP”

• Pharmacological properties
• Indications Ondansetron
• Application of Ondansetron
• Contraindications
• Side effects
• Special instructions
• Interactions
• Overdose
• Storage conditions
• Diagnosis
• Recommended alternatives
• Trade names

Pharmacodynamics. Antiemetic. The mechanism of action is due to a competitive highly selective blockade of central and peripheral 5HT ₃ serotonin receptors (receptors of the trigger zone, vomiting center). Suppresses the gag reflex, eliminating and preventing nausea when using cytotoxic chemotherapeutic agents, radiation therapy, in the postoperative period. With repeated use, it slows down peristalsis and the passage of contents through the intestines.

Pharmacokinetics. When administered intravenously at a dose of 0.15 mg/kg of body weight to adults under the age of 75 years, C _max in blood plasma averages about 100 ng/ml, in persons over the age of 75 years – 170 ng/ml . With an IV infusion of 32 mg for 15 minutes, C _max reaches 264 ng / ml. With intramuscular injection C _max of ondansetron in blood plasma (about 25 ng / ml) is noted 10 minutes after injection.

When taken orally, the drug is well absorbed in the gastrointestinal tract, bioavailability is about 60% due to the effect of the first passage through the liver. C _max of ondansetron in plasma is reached after 1.5–1.7 hours. Eating prolongs the absorption period by 17% without affecting C _max . Binding to plasma proteins – 70-76%.

The main part of the administered dose (85–90%) is hydroxylated in the liver with the participation of cytochrome P450 to indole ring compounds, and then conjugated with glucuronic and sulfuric acids. The total volume of distribution is 1.9 l / kg of body weight, T _½ , depending on age, is 3.5–5.5 h, the total clearance is 5.9ml/(min kg). The drug is excreted from the body by the kidneys, while 5% of the administered dose is excreted unchanged. The pharmacokinetic parameters of ondansetron do not change with repeated use.

In children, as well as in persons with liver damage, the total clearance decreases, in elderly patients, T _½ and the total clearance of the drug increase. In patients with moderate renal insufficiency (creatinine clearance – 15-60 ml / min), systemic clearance and volume of distribution of ondansetron are reduced, resulting in a clinically insignificant small increase in T _½ drug. In women, C _max and the bioavailability of the drug are higher, and the clearance and volume of distribution are lower than in men.

prevention and management of nausea and vomiting during cytotoxic chemotherapy (initial and repeated courses, including high dose cisplatin) and radiotherapy (whole body irradiation, partial single high dose or daily abdominal irradiation) in oncology. Prevention and elimination of nausea and vomiting in the postoperative period in general surgery, ophthalmology, etc.

Tablets

When carrying out cytostatic therapy, the dosing regimen is set individually, depending on the severity of the emetic reaction.

Moderate emetogenic chemotherapy and radiotherapy

Adults and children over 12 years of age by mouth: Initially 8 mg 1 to 2 hours before anticancer therapy, followed by another 8 mg 8 to 12 hours later. To prevent late or prolonged nausea and vomiting after the first 24 hours, the use of the drug should be continued at 8 mg every 12 hours. With partial high-dose irradiation of the abdominal region, 8 mg every 8 hours is prescribed. The drug is taken during the entire course of chemotherapy and radiation therapy, as well as 1-2 days (if necessary – 3-5 days) after its completion.

Highly emetogenic chemotherapy

Adults and children over 12 years of age are given ondansetron 24 mg orally (simultaneously with dexamethasone phosphate) 1 to 2 hours before starting chemotherapy. For the prevention of late vomiting in the following days, 8 mg 2 times a day during the entire course of chemotherapy, as well as 5 days after its completion.

In case of chemotherapy in children aged 4-12 years, oral is prescribed: initially 4 mg 3 times a day (30 minutes before the start of the course, then after 4 and 8 hours). To prevent late vomiting, 4 mg is prescribed every 8 hours 1-2 days, then 4 mg 2 times a day during the entire course, as well as 5 days after its completion.

Postoperative nausea and vomiting

Adults and children over 12 years of age are given 16 mg 1 hour before anesthesia. Children under the age of 12 are not prescribed.

The maximum daily dose of ondansetron is 32 mg, for patients with severe hepatic impairment – 8 mg.

Injection solution

Injection solution may be administered IM or IV as a single slow injection or by infusion. To prepare the ondansetron solution for infusion, you can use 0. 9% sodium chloride solution, 5% glucose solution, Ringer solution. Solution of ondansetron for infusion administration is prepared immediately before administration; however, if necessary, it can be stored until fully used for no more than 24 hours at a temperature of 2–8 °C. During the infusion, protection from light is not required (under normal lighting).

Emethogenic chemotherapy and radiotherapy

Adults use 8 mg IV solution slowly immediately before chemotherapy.

Highly emetogenic chemotherapy

• a single dose of 8-32 mg given IV slowly immediately before chemotherapy; when administered at a dose above 8 mg, ondansetron must be dissolved in 50-100 ml of 0.9% sodium chloride solution or other compatible solution for intravenous administration and an infusion should be carried out for at least 15 minutes;

• 8 mg IV slowly immediately prior to chemotherapy, then 2 slow IV doses of 8 mg 2 to 4 hours apart or IV drip at 1 mg/hour for 24 hours.

The choice of dosing regimen is set individually depending on the severity of the emetogenic effect.

Children can be given as a single IV dose of 5 mg/m ² immediately prior to chemotherapy.

Postoperative nausea and vomiting

Adults: may be given 4 mg as a slow IV or IM injection during induction of anesthesia. To eliminate the development of postoperative nausea and vomiting, a single injection of 4 mg intramuscularly or intravenously is recommended.

Children: may be given at a dose of 0.1 mg/kg (maximum 4 mg) IV slowly before, during, or after initiation of anesthesia to prevent postoperative nausea and vomiting. To eliminate the development of postoperative nausea and vomiting, a single dose of 0.1 mg/kg (maximum 4 mg) intramuscularly or intravenously is recommended.

hypersensitivity to drug components; the period of pregnancy (especially the first trimester) and breastfeeding; insufficiency of liver function, surgical operations on the abdominal cavity; the drug is not prescribed to children under the age of 4 years during chemotherapy and radiation therapy; during anesthesia, tablets cannot be prescribed to children under the age of 12 years; injection solution – up to 2 years.

from the side of the central nervous system: headache, dizziness, temporary impairment of visual acuity (with rapid intravenous administration), spontaneous movement disorders, seizures, depression of the central nervous system, paresthesia, weakness, extrapyramidal symptoms, syncope;

from the side of the cardiovascular system: feeling of heat and flushing to the face, arrhythmia, tachycardia or bradycardia, arterial hypo- or hypertension;

from the digestive system: constipation, diarrhea, hiccups, dry mouth, transient increase in aminotransferase activity, liver failure;

allergic reactions: urticaria, bronchospasm, in isolated cases – anaphylactic reactions;

others: cough, chest pain (anginal type), redness and burning at the injection site.

Breast-feeding should be discontinued during treatment with Ondansetron.

For parenteral use of the drug in patients with moderate and severe hepatic impairment, it is not recommended to exceed a dose of 8 mg / day.

In case of a very severe vomiting reaction as a result of chemotherapy, the effectiveness of the drug can be increased by a single intravenous administration of corticosteroids (for example, 20 mg of dexamethasone sodium phosphate) before starting chemotherapy.

Use with caution in patients with a history of hypersensitivity reactions to other selective serotonin 5HT ₃ receptor antagonists. With caution and under close medical supervision, the drug is used in the treatment of patients with signs of subacute intestinal obstruction.

Simultaneous use of inhibitors of microsomal hepatic enzymes of the cytochrome P450 system may increase T _½ and reduce the overall clearance of the drug.

With special use with inducers of microsomal hepatic enzymes of the P450 cytochrome system (barbiturates, carbamazepine, karizu, glutetimide, Griseoofulvin, nitrogen oxide, papaverine, phenylbutazone, phenytoine, hydrantoins, rifampicin, tolbutamide, it is possible to reduce the clinical efficiency of the drug. that.

The drug in the form of an infusion solution at a concentration of ondansetron 16-160 mcg / ml (8 mg / 500 ml – 8 mg / 50 ml) can be administered through a Y-shaped catheter in combination with the following drugs:

• cisplatin up to 0.48 mg/mL for 1-8 hours;

• carboplatin at a concentration of 0.18-9.90 mg / ml for 10-60 minutes;

• fluorouracil at concentrations up to 0.8 mg/ml at a rate of at least 20 ml/h, bearing in mind that higher concentrations of fluorouracil may cause precipitation of ondansetron;

• etoposide at a concentration of 0.14-0.25 mg/ml for 30-60 minutes;

• ceftazidime 0.025-2 g, diluted with water for injection according to manufacturer’s recommendations, as an IV bolus injection over 5 minutes;

• cyclophosphamide 0.1-1 g, diluted with water for injection according to manufacturer’s recommendations, as an IV bolus injection over 5 minutes;

• doxorubicin 10-100 mg, diluted with water for injection according to manufacturer’s recommendations, as an IV bolus injection over 5 minutes;

• Dexamethasone 20 mg IV slowly over 2-5 minutes in combination with ondansetron 8-32 mg in 50-100 ml solution.