Does posaconazole (an antifungal medication) continue to prolong the QT interval in a patient with a slightly prolonged QT interval?

From the Guidelines

Posaconazole can potentially cause further QT interval prolongation in patients with an already slightly prolonged QT interval, but this effect doesn't necessarily worsen indefinitely with continued use. For patients with mild QT prolongation who require posaconazole therapy, continuation of the medication is possible with appropriate monitoring. Regular EKG monitoring (typically at baseline, after reaching steady-state concentrations, and periodically thereafter) is recommended to assess QT changes, as suggested by the 2024 guidelines on prevention and treatment of cancer-related infections 1. The risk of serious arrhythmias increases significantly when the QTc exceeds 500 ms or increases by more than 60 ms from baseline. When using posaconazole in these patients, it's essential to correct electrolyte abnormalities (particularly potassium, magnesium, and calcium), avoid other QT-prolonging medications when possible, and consider dose adjustments if significant QT prolongation occurs. Posaconazole's QT effects are dose-dependent, so therapeutic drug monitoring may help maintain effective antifungal coverage while minimizing cardiac risks. If the QT interval continues to increase to concerning levels despite these precautions, alternative antifungal therapy should be considered.

Some key points to consider when monitoring patients on posaconazole include:

• Recording a 12-lead ECG at baseline and monitoring the QT interval, corrected for heart rate with Bazett’s or Fridericia’s formula, as recommended by the 2016 ESC position paper on cancer treatments and cardiovascular toxicity 1.
• Monitoring patients with a history of QT prolongation, relevant cardiac disease, treated with QT-prolonging drugs, bradycardia, thyroid dysfunction or electrolyte abnormalities with repeated 12-lead ECG.
• Considering treatment discontinuation or alternative regimens if the QTc is >500 ms, QTc prolongation is >60 ms or dysrhythmias are encountered.
• Avoiding conditions known to provoke torsades de pointes, especially hypokalaemia and extreme bradycardia, in patients with drug-induced QT prolongation.
• Minimizing exposure to other QT-prolonging drugs in patients treated with potentially QT-prolonging chemotherapy, as also suggested by the European Journal of Heart Failure in 2017 1.

However, the most recent and highest quality study, the 2024 guidelines on prevention and treatment of cancer-related infections 1, should be prioritized when making decisions about posaconazole use and QT interval monitoring. Therefore, posaconazole can be continued in patients with a slightly prolonged QT interval, but close monitoring and precautions to minimize the risk of QT prolongation are necessary.

From the FDA Drug Label

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4

• Posaconazole and QT interval prolongation: The FDA drug label indicates that posaconazole has been associated with QT interval prolongation and torsades de pointes.
• Monitoring EKGs: While the label does not directly state that cereal EKGs should be monitored, it does recommend administering posaconazole with caution to patients with potentially proarrhythmic conditions and monitoring electrolyte disturbances, which can contribute to QT interval prolongation.
• Continuation of posaconazole: If a patient has a slightly prolonged QT interval, caution should be exercised when continuing posaconazole therapy, and the patient should be closely monitored for any signs of QT interval prolongation or torsades de pointes 2.

From the Research

Posaconazole and QT Interval Prolongation

• Posaconazole has been associated with QT interval prolongation, which can increase the risk of torsades de pointes and other cardiac arrhythmias 3.
• A case report described a patient who developed QT interval prolongation and suffered from multiple cardiac arrests after posaconazole administration 3.
• The risk of QT interval prolongation is higher in patients with underlying risk factors, such as hypokalemia, female sex, and use of other QT-prolonging medications 4, 5.

Monitoring and Management

• Close monitoring of electrocardiography (EKG) and electrolytes is necessary in patients at risk for QT interval prolongation 4, 6.
• If the QTc interval is prolonged, dose reduction or discontinuation of the offending drug should be considered, and electrolytes should be corrected as needed 4.
• Patients with a slightly prolonged QT interval should be educated to seek medical attention immediately if they experience symptoms such as palpitations, lightheadedness, or syncope 4.
• Regular EKG monitoring can help identify any changes in the QT interval and allow for prompt intervention if necessary 4, 6.

Risk Factors and Prevention

• Several risk factors can contribute to QT interval prolongation, including hypokalemia, use of diuretics, antiarrhythmic drugs, and QTc-prolonging drugs 5.
• A systematic review found very strong evidence for hypokalemia, use of diuretics, antiarrhythmic drugs, and QTc-prolonging drugs as risk factors for QTc-prolongation 5.
• Prevention of QT interval prolongation includes avoiding known risk factors, correcting electrolyte imbalances, and using non-selective beta blockers in patients with long QT syndrome 7.