What are the side effects of excessive Zofran (ondansetron) use?

Side Effects of Excessive Ondansetron (Zofran) Use

Excessive ondansetron use primarily causes QT interval prolongation, severe constipation, and in pediatric overdoses can trigger serotonin syndrome with potentially serious neurological manifestations. 1

Documented Overdose Effects

Cardiovascular Complications

• QT prolongation is dose-dependent and clinically significant, with documented cases showing vasovagal episodes and transient second-degree heart block when 32 mg was infused over 4 minutes 1
• Hypotension and syncope (faintness) occurred in a patient taking 48 mg of oral ondansetron 1
• The FDA label specifically warns about QT prolongation risk, though research shows mean prolongation of 16-20 msec with standard 4 mg doses 1, 2, 3

Gastrointestinal Effects

• Severe constipation is a hallmark of ondansetron excess, documented in a patient receiving 72 mg intravenously as a single dose 1
• Constipation is common even at therapeutic doses and is specifically mentioned as a side effect when used for irritable bowel syndrome 4
• Increased stool volume and diarrhea paradoxically occur in some patients, particularly children with gastroenteritis 4, 5

Neurological and Systemic Effects (Pediatric Overdose)

Pediatric cases exceeding 5 mg/kg have resulted in serotonin syndrome, presenting with: 1

• Somnolence and agitation
• Tachycardia and tachypnea
• Hypertension with flushing
• Mydriasis (dilated pupils) and diaphoresis (sweating)
• Myoclonic movements and horizontal nystagmus
• Hyperreflexia and seizures
• Some cases required intubation, though complete recovery occurred within 1-2 days without long-term sequelae 1

Rare but Serious Effects

• "Sudden blindness" (amaurosis) lasting 2-3 minutes was documented in one patient receiving 72 mg intravenously 1
• Transient elevations in liver function tests can occur 6
• Headache is a common adverse effect even at therapeutic doses 6

Clinical Context and Risk Factors

Drug Interactions Amplifying Risk

• Increased QT prolongation risk when combined with: tyrosine kinase inhibitors, doxorubicin, serotonin reuptake inhibitors, and hydroxychloroquine 7
• Baseline ECG should be obtained in patients with cardiac risk factors before initiating treatment 7

Special Population Considerations

• Elderly patients show reduced clearance and increased elimination half-life, particularly those over 75 years, though no specific dose adjustment is recommended in the FDA label 1
• Patients with severe hepatic impairment (Child-Pugh ≥10) should not exceed 8 mg total daily dose due to significantly prolonged half-life 1
• No dose adjustment needed for renal impairment, though experience beyond first-day administration is limited 1

Management of Overdose

No specific antidote exists for ondansetron overdose—management is entirely supportive 1:

• Monitor cardiac rhythm and vital signs
• Provide respiratory support if needed (intubation may be required in severe pediatric cases)
• Treat seizures if they occur
• Ensure adequate hydration to prevent complications from severe constipation
• All documented cases resolved completely with supportive care 1

Common Pitfalls to Avoid

• Do not assume ondansetron is completely benign simply because it lacks the extrapyramidal side effects of older antiemetics like metoclopramide 6
• Avoid prescribing multiple doses without considering cumulative QT effects, especially in patients on other QT-prolonging medications 7, 3
• In children under 6 months, ondansetron should not be used for food protein-induced enterocolitis syndrome 7
• Be cautious with oral contraceptive efficacy—ondansetron delays gastric emptying and may reduce absorption of oral hormonal contraceptives, requiring alternative contraception methods for 4 weeks after initiation and dose escalation 8