What medications interact with ondansetron to increase the risk of torsades de pointes?

Medications That Interact with Ondansetron to Increase Torsades de Pointes Risk

Ondansetron should not be combined with other QT-prolonging medications, particularly hydroxychloroquine (>8mg), domperidone, citalopram, antiarrhythmic drugs (sotalol, dofetilide, quinidine), antipsychotics (haloperidol, thioridazine), and certain antibiotics (erythromycin, clarithromycin), as these combinations significantly increase the risk of torsades de pointes. 1, 2

High-Risk Drug Combinations with Ondansetron

Antiarrhythmic Agents

• Class IA antiarrhythmics: Quinidine, disopyramide, and procainamide carry a 1-10% incidence of torsades de pointes and should be avoided with ondansetron 1, 2
• Class III antiarrhythmics: Sotalol, dofetilide, and ibutilide have similarly high torsades risk (1-10% incidence) and are contraindicated with ondansetron 1, 2, 3

Antimicrobial Agents

• Macrolide antibiotics: Erythromycin (especially IV) and clarithromycin significantly prolong QT interval and should not be combined with ondansetron 1, 2
• The combination is particularly dangerous because erythromycin itself can cause torsades de pointes, almost always with high doses or IV administration 1

Psychiatric Medications

• SSRIs: Citalopram and escitalopram are specifically contraindicated with ondansetron due to additive QT prolongation 1, 3
• Antipsychotics: Haloperidol, thioridazine, chlorpromazine, mesoridazine, and pimozide all prolong QT interval and increase torsades risk when combined with ondansetron 1, 2

Antiemetics and Other Agents

• Domperidone: Specifically contraindicated with ondansetron; metomimazine should be used as alternative 1
• Hydroxychloroquine: Particularly dangerous when combined with ondansetron doses >8mg, as both prolong QT interval 1, 4
• Methadone: High doses combined with ondansetron significantly increase torsades risk 1, 2

Critical Risk Factors That Amplify Drug Interactions

Electrolyte Abnormalities

• Hypokalemia (K+ <4.5 mEq/L) is the most important modifiable risk factor and dramatically increases torsades risk with ondansetron 1, 4, 2
• Hypomagnesemia compounds the arrhythmia risk, even when serum levels appear normal 1, 5, 6
• Correct potassium to 4.5-5 mEq/L and replete magnesium before administering ondansetron in high-risk patients 1, 4, 2

Patient-Specific Factors

• Female sex and advanced age significantly increase susceptibility to drug-induced torsades de pointes 1, 2
• Baseline QTc >500 ms represents absolute contraindication to ondansetron 4, 2
• Renal insufficiency increases risk, particularly with renally-cleared QT-prolonging drugs like sotalol 1, 3

Clinical Management Algorithm

Pre-Administration Assessment

• Obtain baseline ECG to measure QTc interval before ondansetron administration 4
• Review complete medication list for all QT-prolonging agents 4, 2
• Check serum potassium, magnesium, and calcium levels 4, 6
• Do not administer ondansetron if QTc ≥500 ms 4, 2

During Treatment

• Monitor cardiac rhythm via telemetry in high-risk patients (those with cardiovascular disease, multiple risk factors, or receiving other QT-prolonging drugs) 7
• QTc prolongation from ondansetron peaks at approximately 120 minutes post-administration 7
• Discontinue ondansetron immediately if QTc exceeds 500 ms during therapy 4

High-Risk Clinical Scenarios

• Heart failure patients: Ondansetron prolongs QTc by mean of 20.6 ± 20 msec in this population 7
• Acute coronary syndrome patients: QTc prolongation averages 18.3 ± 20 msec 7
• Cancer patients: Avoid combining ondansetron with tyrosine kinase inhibitors (cabozantinib, ceritinib, crizotinib, nilotinib, osimertinib, vandetanib), anthracyclines, and platinum agents that cause electrolyte disturbances 1

Common Pitfalls to Avoid

• Do not assume low doses are safe: Torsades de pointes and cardiac arrest have occurred with ondansetron 4 mg IV in patients with electrolyte abnormalities 5, 6
• Do not overlook drug-drug interactions: Even when individual drugs pose minimal risk, combinations can be lethal 1, 2
• Do not ignore electrolyte levels: Hypokalemia (3.2 mEq/L) and hypomagnesemia (1.3 mg/dL) have precipitated cardiac arrest with standard ondansetron doses 5, 6
• Do not continue ondansetron if arrhythmias develop: Immediate discontinuation, IV magnesium 1-2g, potassium repletion, and cardioversion if sustained torsades occurs 1, 2

Emergency Management of Ondansetron-Induced Torsades

• Immediate interventions: Discontinue ondansetron and all QT-prolonging agents 1, 2
• IV magnesium sulfate 2g even if serum magnesium is normal 1, 2
• Potassium repletion to 4.5-5 mEq/L 1, 2
• Temporary pacing or isoproterenol for recurrent torsades de pointes 1, 2
• Immediate cardioversion for sustained torsades de pointes 2