Posaconazole and QTc Prolongation

Mechanism and Risk

• Posaconazole can cause QTc prolongation through direct effects, particularly with higher serum levels achieved with delayed-release tablet formulations, and through inhibition of CYP3A4 enzyme, which can increase plasma concentrations of other QTc-prolonging medications when co-administered 1, 2, 3, 4
• 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 National Comprehensive Cancer Network recommends caution when administering posaconazole to patients with potentially proarrhythmic conditions, and notes that posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval 1, 2

Risk Factors for QTc Prolongation with Posaconazole

• Patients with electrolyte disturbances, concomitant use of other QTc-prolonging medications, and certain chemotherapeutic agents are at higher risk of QTc prolongation with posaconazole 1, 2
• Higher serum concentrations of posaconazole, particularly with the delayed-release tablet formulation, also increase the risk of QTc prolongation 3, 4

Monitoring Recommendations

• The National Comprehensive Cancer Network and Clinical Infectious Diseases societies recommend therapeutic drug monitoring (TDM) for posaconazole to avoid excessive serum concentrations, especially with the delayed-release tablet formulation 1, 4

Alternative Options

• Isavuconazonium sulfate may be considered as an alternative to posaconazole for patients at high risk of QTc prolongation, as it has been associated with dose-dependent QTc shortening rather than prolongation 1, 2
• Echinocandins may also be considered as they do not have significant QTc effects 3

Common Pitfalls

• Failing to recognize the additive effect of multiple QTc-prolonging medications when used with posaconazole, and not monitoring electrolyte levels or considering drug-drug interactions through CYP3A4 inhibition, can increase the risk of QTc prolongation 1, 2
• Overlooking the higher risk of QTc prolongation with the delayed-release tablet formulation that achieves higher serum concentrations can also lead to adverse outcomes 3, 4