What are the indications, dosing regimens (including for chemotherapy, postoperative nausea, pregnancy, and pediatrics), contraindications, and major drug interactions of Zofran (ondansetron)?

Zofran (Ondansetron): Clinical Guide

Indications

Ondansetron is FDA-approved for prevention of chemotherapy-induced nausea and vomiting (CINV), radiation-induced nausea and vomiting (RINV), and postoperative nausea and vomiting (PONV). 1, 2 It is also widely used off-label for nausea and vomiting of pregnancy, though this remains an off-label indication. 3, 4

Approved Uses:

• Chemotherapy-induced nausea/vomiting (acute and delayed phases) 1, 5
• Radiation-induced nausea/vomiting (particularly upper abdominal or total body irradiation) 5, 6
• Postoperative nausea/vomiting (prophylaxis and treatment) 2

Off-Label Use:

• Nausea and vomiting of pregnancy/hyperemesis gravidarum 1, 3, 4

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Dosing Regimens

Chemotherapy-Induced Nausea and Vomiting

For highly emetogenic chemotherapy, administer 8 mg IV over 15 minutes given 30 minutes before chemotherapy, or 24 mg orally as a single dose. 5, 6

Acute Phase (Day 1):

• Standard IV dose: 8 mg IV over 15 minutes, 30 minutes before chemotherapy 1, 5, 6
• Oral alternative: 24 mg orally as a single dose 30 minutes before chemotherapy (superior to divided dosing) 5
• Maximum single IV dose: Do not exceed 16 mg due to QT prolongation risk 5

Delayed Phase (Days 2-3):

• Continue 8 mg orally every 12 hours for up to 2-3 days after chemotherapy 5, 6

Breakthrough Nausea:

• Give 16 mg IV as a single PRN dose, with maximum total dose of 24 mg in 24 hours 5
• If nausea persists, add metoclopramide 20-30 mg orally from a different drug class 5, 6

Combination Therapy (Essential for Highly Emetogenic Chemotherapy):

Ondansetron monotherapy is inadequate—always combine with dexamethasone and an NK₁ antagonist (aprepitant) to achieve 73-86% complete response rates. 5, 6

• Day 1: Ondansetron 8 mg + dexamethasone 12 mg + aprepitant 125 mg 5, 6
• Reduce dexamethasone dose by 40-50% when using with aprepitant due to CYP3A4 interactions 1, 5, 6
• Ondansetron plus dexamethasone is significantly more effective than ondansetron alone 5, 2

Radiation-Induced Nausea and Vomiting

• For upper abdominal radiation or total body irradiation: 8 mg orally 2-3 times daily during treatment 5, 6
• Efficacy: Ondansetron 8 mg three times daily provided complete control in 67% vs 45% with placebo 5, 6
• Adding dexamethasone 4 mg daily provides modest additional benefit 5

Postoperative Nausea and Vomiting

• Prophylaxis: 8 mg IV over 15 minutes before anesthesia induction 2
• Treatment: 8 mg IV for established postoperative nausea/vomiting 2
• Ondansetron is more effective than droperidol or metoclopramide for PONV 2

Pregnancy (Off-Label)

Ondansetron, metoclopramide, and steroids are considered safe for chemotherapy-induced nausea during pregnancy, with ondansetron being the preferred 5-HT3 antagonist. 1

• Dosing: Standard doses (8 mg orally or IV) can be used 1
• Safety profile: Small absolute risk increase for cleft palate (0.03%) and ventricular septal defects (0.3%) 1, 3
• Timing consideration: Risk is primarily with first-trimester exposure 3, 4
• Steroid preference in pregnancy: Use methylprednisolone or prednisolone (NOT dexamethasone or betamethasone due to 100% placental passage) 1
• Avoid steroids before 10 weeks gestation due to oral cleft risk 1

Pediatric Dosing

While specific pediatric dosing was not extensively covered in the provided guidelines, ondansetron is used in children with dosing typically weight-based (consult pediatric-specific guidelines for exact dosing). 1

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Contraindications and Precautions

Major Contraindications:

• Concomitant use with apomorphine (profound hypotension and loss of consciousness) 7
• Known hypersensitivity to ondansetron or other 5-HT3 antagonists 7

QT Prolongation Risk:

The 32 mg IV dose is associated with significant QT prolongation and should be avoided; standard 8 mg doses carry minimal risk. 5, 6, 7

• High-risk dose: 32 mg IV (no longer recommended) 7
• Standard doses (8 mg): Minimal QT prolongation concern 5, 6, 7
• Use caution in patients with: Congenital long QT syndrome, electrolyte abnormalities (hypokalemia, hypomagnesemia), congestive heart failure, or concurrent QT-prolonging medications 7

Hepatic Impairment:

• Severe hepatic impairment: Dosage reduction may be necessary (maximum 8 mg daily) due to decreased clearance 8
• Mild-moderate impairment: No adjustment typically needed 8

Renal Impairment:

• No dosage adjustment required (only 5% renal excretion) 8

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Major Drug Interactions

CYP3A4 Interactions:

• Aprepitant (NK₁ antagonist): Reduces dexamethasone clearance; decrease dexamethasone dose by 40-50% when combined 1, 5, 6
• Other CYP3A4 inducers/inhibitors: May alter ondansetron metabolism, though clinically significant interactions are uncommon 1, 8

QT-Prolonging Medications:

• Avoid concurrent use with: Class IA antiarrhythmics (quinidine, procainamide), Class III antiarrhythmics (amiodarone, sotalol), certain antipsychotics, and macrolide antibiotics 7

Chemotherapeutic Agents:

• No significant pharmacokinetic interactions with chemotherapy agents 8

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Managing Refractory Cases

Before treating breakthrough emesis, assess for non-chemotherapy causes: electrolyte abnormalities, brain metastases, bowel obstruction, or other GI abnormalities. 5, 6

Stepwise Approach:

1. Increase ondansetron: 16 mg IV as single PRN dose 5
2. Add dopamine antagonist: Metoclopramide 20-30 mg orally 5, 6
3. Consider antacid therapy: PPIs or H2 blockers (patients may confuse heartburn with nausea) 5, 6
4. For anticipatory/anxiety-related vomiting: Add lorazepam or alprazolam 0.25-0.5 mg orally 3 times daily 5, 6
5. Switch 5-HT3 antagonist: Consider granisetron or palonosetron if ondansetron fails 6

Special Consideration for Elderly:

• Benzodiazepines: Start with lower doses (0.25 mg 2-3 times daily) due to increased sensitivity 5

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Pharmacokinetics

• Bioavailability: 60% oral (due to first-pass metabolism) 8
• Time to peak: 0.5-2 hours after oral administration 8
• Volume of distribution: ~160L (widely distributed) 8
• Protein binding: 70-76% 8
• Elimination half-life: 3.8 ± 1 hours 8
• Metabolism: 95% hepatic (CYP3A4, CYP2D6, CYP1A2); metabolites inactive 8
• Excretion: 5% renal 8

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Common Pitfalls and Caveats

• Monotherapy failure: Never use ondansetron alone for highly emetogenic chemotherapy—combination with dexamethasone and aprepitant is mandatory 5, 6
• Delayed nausea: Ondansetron monotherapy is inadequate for delayed cisplatin-induced nausea; combination therapy required 2
• Timing matters: Administer at least 30 minutes before chemotherapy for optimal effect 5, 8
• Pregnancy counseling: Discuss small absolute risks (cleft palate, cardiac defects) versus benefits of treating severe NVP/hyperemesis 1, 3
• Avoid high-dose IV: Never exceed 16 mg single IV dose due to QT prolongation 5, 7
• Assess underlying causes: Rule out metabolic, structural, or CNS causes before escalating antiemetic therapy 5, 6