Ondansetron - Drug Monograph

Introduction

Ondansetron is a selective serotonin 5-HT₃ receptor antagonist that has revolutionized the management of nausea and vomiting. First approved by the FDA in 1991, it has become a cornerstone therapy for chemotherapy-induced, radiotherapy-induced, and postoperative nausea and vomiting. This monograph provides a comprehensive overview of ondansetron's pharmacology, clinical applications, and safety profile.

Mechanism of Action

Ondansetron exerts its antiemetic effects by selectively blocking serotonin 5-HT₃ receptors in the chemoreceptor trigger zone (CTZ) located in the area postrema of the medulla oblongata and on vagal nerve terminals in the gastrointestinal tract. By antagonizing these receptors, ondansetron prevents serotonin binding and subsequent activation of the vomiting reflex pathway. Unlike older antiemetics, it does not block dopamine receptors, resulting in a favorable side effect profile without extrapyramidal symptoms.

Indications

• Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy
• Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy
• Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction, or daily fractions to the abdomen
• Prevention of postoperative nausea and vomiting (PONV)
• Treatment of postoperative nausea and vomiting

Dosage and Administration

• Chemotherapy-induced nausea/vomiting: 8-24 mg orally 30 minutes before chemotherapy; or 0.15 mg/kg IV (maximum 16 mg) 30 minutes before chemotherapy
• Radiotherapy-induced nausea/vomiting: 8 mg orally three times daily
• Postoperative nausea/vomiting: 4-8 mg orally or IV 1 hour before anesthesia induction or at end of surgery

• Chemotherapy-induced: 0.15 mg/kg IV (maximum 16 mg) or weight-based oral dosing
• Postoperative: 0.1 mg/kg IV (maximum 4 mg)

• Hepatic impairment: Maximum daily dose 8 mg
• Renal impairment: No dosage adjustment required
• Elderly: No dosage adjustment required

Available formulations include oral tablets, orally disintegrating tablets, oral solution, and intravenous injection.

Pharmacokinetics

• Absorption: Oral bioavailability approximately 60%; Tmax 1.5-2 hours
• Distribution: Volume of distribution approximately 160 L; 70-76% plasma protein bound
• Metabolism: Extensive hepatic metabolism primarily via cytochrome P450 enzymes (CYP1A2, CYP2D6, CYP3A4)
• Elimination: Half-life 3-6 hours; excreted primarily in urine (44-60%) as metabolites

Contraindications

• Hypersensitivity to ondansetron or any component of the formulation
• Concomitant use with apomorphine due to risk of profound hypotension and loss of consciousness
• Patients with congenital long QT syndrome

Warnings and Precautions

• QT prolongation: Dose-dependent QT interval prolongation has been observed. Use with caution in patients with risk factors for QT prolongation
• Serotonin syndrome: Cases have been reported, particularly with concomitant serotonergic drugs
• Hypersensitivity reactions: Including anaphylaxis, bronchospasm, and urticaria
• Masking of progressive ileus: May obscure diagnosis of intestinal obstruction
• Phenylketonuria: Orally disintegrating tablets contain phenylalanine

Drug Interactions

• Drugs that prolong QT interval: Increased risk of torsades de pointes (antiarrhythmics, antipsychotics, antibiotics)
• Serotonergic drugs: Increased risk of serotonin syndrome (SSRIs, SNRIs, tramadol)
• CYP enzyme inducers/inhibitors: May alter ondansetron concentrations (rifampin, carbamazepine, fluoxetine)
• Apomorphine: Contraindicated due to risk of hypotension

Adverse Effects

• Headache (16-25%)
• Constipation (9-11%)
• Diarrhea (5-8%)
• Fatigue (5-8%)
• Dizziness (4-7%)

• QT prolongation and torsades de pointes
• Anaphylaxis and hypersensitivity reactions
• Serotonin syndrome
• Extrapyramidal symptoms (rare)
• Transient visual disturbances

Monitoring Parameters

• Efficacy: Control of nausea and vomiting
• ECG monitoring in patients with risk factors for QT prolongation
• Signs and symptoms of hypersensitivity reactions
• Electrolyte imbalances (potassium, magnesium)
• Signs of serotonin syndrome (agitation, hyperreflexia, clonus)
• Bowel function in patients at risk for intestinal obstruction

Patient Education

• Take medication as prescribed, usually 30 minutes before chemotherapy or surgery
• Orally disintegrating tablets should be placed on tongue and allowed to dissolve
• Report any signs of allergic reaction (rash, itching, swelling)
• Be aware of potential side effects, especially headache and constipation
• Inform healthcare providers of all medications being taken
• Seek immediate medical attention for irregular heartbeat, dizziness, or fainting
• Do not drive or operate machinery if experiencing dizziness

References

1. FDA Prescribing Information: Zofran (ondansetron) 2. Roila F, et al. Ann Oncol. 2016;27(suppl 5):v119-v133. 3. Gan TJ, et al. Anesth Analg. 2014;118(1):85-113. 4. Grunberg SM, et al. Support Care Cancer. 2004;12(8):570-574. 5. Trammel M, et al. Am J Health Syst Pharm. 2013;70(1):34-42. 6. NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 2.2023. 7. ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm. 2023;80(5):276-299.