What is the cardiac QT prolongation risk of co-administering two doses of Fluconazole (Diflucan) with Escitalopram (Lexapro)?

From the Guidelines

The combination of two doses of fluconazole with escitalopram carries a relatively low but still present risk of QT prolongation, and it is recommended to monitor patients closely for symptoms like dizziness, palpitations, or syncope, especially in those with pre-existing cardiac conditions or electrolyte abnormalities. This risk occurs because both medications can independently prolong the QT interval, and fluconazole also inhibits CYP3A4 and CYP2C19, which metabolize escitalopram, potentially increasing escitalopram blood levels 1. According to the European Heart Journal, if the QT-interval or QTc reaches a length >500 ms or increases by >60 ms compared with baseline, treatment with the particular drug should be ceased or dose reduced 1.

Key Considerations

• The risk of QT prolongation is higher in patients with pre-existing cardiac conditions, electrolyte abnormalities (especially hypokalemia or hypomagnesemia), or those taking other QT-prolonging medications 1.
• It is essential to obtain a baseline ECG before starting treatment and monitor for symptoms like dizziness, palpitations, or syncope 1.
• If possible, consider alternative antifungal options that don't interact with escitalopram, and if the combination is necessary, use the lowest effective dose of both medications and limit fluconazole to just two doses to minimize the risk of clinically significant QT prolongation 1.
• The British Thoracic Society guidelines also highlight the risk of QT prolongation with azole antifungals, such as fluconazole, and recommend avoiding coadministration with other QT-prolonging medications for more than 14 days 1.

Recommendations

• Monitor patients closely for symptoms of QT prolongation, such as dizziness, palpitations, or syncope.
• Obtain a baseline ECG before starting treatment and monitor for changes in the QT interval.
• Consider alternative antifungal options that don't interact with escitalopram.
• Use the lowest effective dose of both medications and limit fluconazole to just two doses to minimize the risk of clinically significant QT prolongation.

From the FDA Drug Label

General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsade de pointes. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline.

The cardiac QT prolongation risk of 2 doses of fluconazole with escitalopram is not directly addressed in the label. However, fluconazole is known to cause QT prolongation. Additionally, concomitant administration of fluconazole with other medications that may prolong the QT interval (such as amiodarone) may increase this risk. Escitalopram is not explicitly mentioned in the label as a medication that interacts with fluconazole to increase the risk of QT prolongation. Caution should be exercised when administering fluconazole to patients with potentially proarrhythmic conditions 2.

From the Research

Cardiac QT Prolongation Risk

The risk of cardiac QT prolongation is a significant concern when administering certain medications, including fluconazole and escitalopram.

• Fluconazole has been shown to prolong the QT interval, with a study demonstrating a significant QT prolongation after application of fluconazole in female rabbits 3.
• Escitalopram has also been found to cause QT prolongation, with a study showing that the maximum upper bound 95% confidence interval for the ΔΔQTcI of escitalopram was 10.5 ms, with a mean estimate of 6.9 ms 4.

Interaction between Fluconazole and Escitalopram

There is limited information available on the specific interaction between fluconazole and escitalopram in terms of cardiac QT prolongation risk.

• However, it is known that the concurrent use of multiple medications that can prolong the QT interval may increase the risk of torsades de pointes, a life-threatening arrhythmia 5, 6.
• A study on the management of long QT syndrome highlights the importance of considering patient-specific risk factors, including age, sex, and electrolyte imbalances, when administering medications that can prolong the QT interval 7.

Risk Assessment and Management

To minimize the risk of cardiac QT prolongation when administering 2 doses of fluconazole with escitalopram, it is essential to:

• Monitor the patient's QT interval closely 3, 6.
• Be aware of potential drug interactions that may increase the risk of QT prolongation 5.
• Consider patient-specific risk factors, such as age, sex, and electrolyte imbalances 7.
• Adjust the dosage or discontinue the medication if necessary to prevent QT prolongation 6.