Does fluconazole (an antifungal medication) affect the QTc (corrected QT) interval?

From the Guidelines

Fluconazole may cause QTc prolongation, particularly at higher doses or when combined with other QT-prolonging medications, and caution is warranted in patients with pre-existing cardiac conditions or electrolyte abnormalities. According to the most recent study 1, fluconazole, like other azoles, can cause QTc prolongation, which may lead to ventricular tachyarrhythmias. The study highlights the importance of considering potential drug-drug interactions, especially with medications that are metabolized by the cytochrome P450 3A4 isoenzyme, as these can increase the risk of QTc prolongation.

For patients taking typical doses of fluconazole (50-400mg daily), QTc monitoring is not routinely required, but baseline ECG and electrolyte monitoring should be considered for high-risk patients or those on doses exceeding 400mg daily. The QT-prolonging effect of fluconazole occurs due to its inhibition of the hERG potassium channels in cardiac cells, which can interfere with cardiac repolarization 1. Additionally, fluconazole's potent CYP3A4 inhibition may increase plasma concentrations of other QT-prolonging medications, potentially creating additive effects.

It is essential to note that the risk of QTc prolongation is not limited to fluconazole alone but can also be exacerbated by the combination of azoles and other drugs, such as fluoroquinolones, macrolides, or ondansetron, as well as some chemotherapies 1. In patients who develop QTc prolongation while on fluconazole, dose reduction, drug discontinuation, or switching to an alternative antifungal with less QT effect should be considered, depending on the clinical situation and degree of prolongation.

The measurement of QTc interval is crucial, and a normal QTC is 0.46 second in women and 0.45 second in men, with a QTC of 0.50 second or more indicating a higher risk for torsades de pointes 1. However, it is essential to consider the limitations of QTc interval monitoring, including the lack of consensus on measurement techniques and the potential for overcorrection or undercorrection of the QT interval at different heart rates 1.

In clinical practice, the Bazett's formula (QTC = QT interval divided by the square root of the R-R interval) is commonly used to correct the QT interval for heart rate, but its adequacy has been questioned, and other correction formulas may be used depending on the specific clinical situation 1. Ultimately, the decision to monitor QTc interval and manage potential QTc prolongation should be individualized based on the patient's underlying risk factors, concomitant medications, and clinical presentation.

From the FDA Drug Label

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). During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsade de pointes. 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.

Fluconazole and QTc: Fluconazole can cause QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). There have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole, especially those with hypokalemia and advanced cardiac failure. The concomitant use of fluconazole and erythromycin can increase the risk of cardiotoxicity and sudden heart death 2.

From the Research

Fluconazole and QTc Interval Prolongation

• Fluconazole has been associated with QTc interval prolongation, which can increase the risk of torsades de pointes (TdP) 3, 4, 5.
• The risk of QTc prolongation is higher when fluconazole is used in combination with other drugs that can prolong the QTc interval, such as levofloxacin 3, 6, 7.
• Studies have shown that the prevalence of QTc prolongation in patients using fluconazole and other QTc-prolonging drugs is relatively low, ranging from 4.7% to 22.3% 6, 7.
• Risk factors for QTc prolongation in patients using fluconazole include hypokalemia, left-ventricular ejection fraction of <55%, and exposure to multiple drugs with the potential to prolong the QTc interval 7.

Mechanism of QTc Prolongation

• Fluconazole has been shown to impair human ether-a-go-go-related gene (hERG) protein trafficking, which can lead to QTc interval prolongation 5.
• The inhibition of hERG protein trafficking by fluconazole can result in a longer QT interval and increased arrhythmia occurrence 5.

Clinical Implications

• Patients initiated on fluconazole should be closely monitored for QTc-interval prolongation, particularly if they are also using other QTc-prolonging drugs 3, 4.
• The use of fluconazole in patients with baseline QT prolongation should be avoided, and alternative treatments should be considered 3, 4.
• Routine ECG monitoring in patients on fluconazole therapy may not be necessary, given the relatively low prevalence of QTc prolongation 6.