Posaconazole and QTc Prolongation
Yes, posaconazole can cause QTc prolongation and has been associated with cases of torsades de pointes. 1, 2
Mechanism and Risk
Posaconazole, like other azole antifungals, has been clearly documented to cause QTc prolongation through several mechanisms:
- Direct QTc prolongation effects have been reported with posaconazole, particularly with the higher serum levels achieved with delayed-release tablet formulations 1
- Inhibition of CYP3A4 enzyme, which can increase plasma concentrations of other QTc-prolonging medications when co-administered 1
- Posaconazole is also an inhibitor of gastric P-glycoprotein, which can increase systemic levels of drugs affected by this transport system 1
Clinical Evidence and FDA Warnings
The FDA label for posaconazole specifically warns about QTc prolongation:
- Cases of torsades de pointes have been reported in patients taking posaconazole 2
- Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval (e.g., pimozide and quinidine) 2
- The FDA recommends administering posaconazole with caution to patients with potentially proarrhythmic conditions 2
Risk Factors for QTc Prolongation with Posaconazole
The risk of QTc prolongation and subsequent arrhythmias is heightened in patients with:
- Electrolyte disturbances (especially potassium, magnesium, and calcium abnormalities) 1, 2
- Concomitant use of other QTc-prolonging medications (e.g., fluoroquinolones, macrolides, ondansetron) 1
- Certain chemotherapeutic agents (e.g., nilotinib, panobinostat) 1
- Higher serum concentrations of posaconazole, particularly with the delayed-release tablet formulation 1
Monitoring Recommendations
When using posaconazole, clinicians should:
- Monitor and correct electrolyte disturbances before and during posaconazole therapy 2
- Consider baseline and follow-up ECGs in high-risk patients 2
- Avoid co-administration with other drugs known to prolong QTc interval and metabolized through CYP3A4 2
- Consider therapeutic drug monitoring (TDM) for posaconazole to avoid excessive serum concentrations, especially with the delayed-release tablet formulation 1
Case Reports
There have been documented cases of serious cardiac events associated with posaconazole:
- A case report described multiple cardiac arrests after posaconazole administration in an immune-compromised septic patient, with episodes of polymorphic ventricular tachycardia (torsades de pointes) that degenerated to ventricular fibrillation 3
Alternative Options
For patients at high risk of QTc prolongation requiring antifungal therapy:
- Isavuconazonium sulfate may be considered as an alternative, as it has been associated with dose-dependent QTc shortening rather than prolongation 1
- Echinocandins may be considered as they do not have significant QTc effects 1
Common Pitfalls
- Failing to recognize the additive effect of multiple QTc-prolonging medications when used with posaconazole 1
- Not monitoring electrolyte levels, which can exacerbate QTc prolongation 2
- Overlooking drug-drug interactions through CYP3A4 inhibition, which can increase levels of other QTc-prolonging drugs 1
- Not considering the higher risk of QTc prolongation with the delayed-release tablet formulation that achieves higher serum concentrations 1