Voriconazole and QTc Prolongation
Yes, voriconazole can prolong the QTc interval and has been associated with serious cardiac arrhythmias including torsades de pointes, cardiac arrest, and sudden death. 1
FDA Warning and Mechanism
The FDA explicitly warns that voriconazole has been associated with QT interval prolongation on electrocardiogram, with rare cases of ventricular arrhythmias (including torsades de pointes), cardiac arrests, and sudden deaths reported during clinical development and post-marketing surveillance. 1
- In controlled studies, voriconazole caused mean QTc increases of less than 10 msec at doses up to 1600 mg, though the effect when combined with other QT-prolonging drugs remains unknown. 1
- The Infectious Diseases Society of America guidelines specifically list azole antifungals, including voriconazole, as agents that can cause QT interval prolongation, torsades de pointes, and other cardiac arrhythmias. 2
High-Risk Clinical Scenarios Requiring Extreme Caution
Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions including: 1
- Congenital or acquired QT prolongation
- Cardiomyopathy, particularly when heart failure is present
- Sinus bradycardia
- Existing symptomatic arrhythmias
- Concomitant use of medications known to prolong QT interval
Real-World Clinical Evidence
Multiple case reports and observational studies confirm clinically significant QTc prolongation with voriconazole:
- A retrospective study of 46 patients receiving concomitant voriconazole and amiodarone showed a mean QTc increase of 49.0 ms (P < 0.001), with 39.1% developing QTc ≥500 ms and 37.0% experiencing QTc increases ≥60 ms from baseline. 3
- Case reports document torsades de pointes requiring cardioversion and temporary pacemaker placement in patients receiving voriconazole, particularly those with hematological malignancies and electrolyte disturbances. 4, 5, 6
Critical Pre-Treatment and Monitoring Requirements
Before initiating voriconazole: 1
- Obtain baseline ECG to assess QTc interval
- Correct electrolyte abnormalities—rigorous attempts to normalize potassium, magnesium, and calcium are essential
- Review all concomitant medications for QT-prolonging agents
During voriconazole therapy: 2, 1
- Monitor electrolytes regularly and maintain potassium >4.0 mEq/L
- Perform serial ECG monitoring, especially in the first week of therapy
- Consider therapeutic drug monitoring to avoid excessive voriconazole concentrations, which increase arrhythmia risk 2
Drug Interactions Amplifying Risk
The IDSA guidelines emphasize that voriconazole should be used cautiously with other QT-prolonging agents, as the combined effect creates additive risk for arrhythmias. 2 Low serum potassium and concomitant "possible" QT-prolonging drugs were independently associated with QTc ≥500 ms in multivariate analysis. 3
Important Clinical Pitfall
While controlled studies showed modest QTc changes, real-world patients often have multiple confounding risk factors (cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, polypharmacy) that substantially increase arrhythmia risk. 1 The cases of torsades de pointes and cardiac arrest occurred in seriously ill patients with these compounding factors. 4, 5, 6