What are the cardiovascular side effects of Fluconazole (antifungal medication)?

Cardiovascular Side Effects of Fluconazole

Fluconazole causes QT interval prolongation and can lead to torsade de pointes (TdP), a potentially fatal ventricular arrhythmia, particularly in patients with risk factors such as electrolyte abnormalities, structural heart disease, or concurrent use of other QT-prolonging medications. 1

Mechanism of Cardiotoxicity

• Fluconazole prolongs the QT interval by inhibiting the Rectifier Potassium Channel current (IKr), which delays cardiac repolarization. 1
• This mechanism is similar to other azole antifungals, though fluconazole's cardiotoxic effects can occur even at standard therapeutic doses. 2

Primary Cardiovascular Adverse Effects

QT Prolongation and Arrhythmias

• The most significant cardiovascular side effect is QT interval prolongation, which can progress to torsade de pointes, ventricular arrhythmias, cardiac arrest, and sudden cardiac death. 1
• Post-marketing surveillance has documented rare cases of QT prolongation and TdP in patients receiving fluconazole. 1
• Case reports demonstrate TdP occurring even with low-dose fluconazole (200 mg/day), with complete resolution upon drug discontinuation. 2, 3
• Pediatric patients are also at risk, with documented cases of TdP in children treated with fluconazole. 4

Prevalence

• In a prospective study of 170 patients receiving ciprofloxacin and fluconazole combination therapy, QTc prolongation occurred in 4.7% of patients, with a mean QTc increase of 10.7 ms. 5
• This prevalence is relatively low compared to the general population (5-11%), though serious arrhythmias remain a critical concern. 5

High-Risk Patient Populations

Patients at increased risk for life-threatening ventricular arrhythmias and TdP include those with: 1

• Hypokalemia or other electrolyte abnormalities (hypomagnesemia, hypocalcemia) 1, 4
• Advanced cardiac failure or structural heart disease 1
• History of cardiotoxic chemotherapy or cardiomyopathy 6
• Baseline QTc prolongation (>500 msec represents significant risk) 3
• Renal dysfunction (impairs fluconazole clearance, increasing drug exposure) 1, 3
• Congenital Long-QT Syndrome 4

Critical Drug Interactions Increasing Cardiac Risk

Amiodarone

• Concomitant administration of fluconazole with amiodarone significantly increases QT prolongation risk and has resulted in sudden cardiac arrest. 1, 7
• Caution is mandatory if co-administration is necessary, particularly with high-dose fluconazole (800 mg). 1
• This combination should be avoided when possible. 7

Erythromycin and Macrolides

• Co-administration of fluconazole and erythromycin has the potential to increase cardiotoxicity risk (prolonged QT interval, TdP) and sudden cardiac death; this combination should be avoided. 1
• The mechanism involves both pharmacokinetic interactions (CYP3A4 inhibition) and additive pharmacodynamic effects on cardiac repolarization. 6

Other QT-Prolonging Medications

• Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor and a strong CYP2C19 inhibitor, which can increase plasma concentrations of other QT-prolonging drugs. 1
• Drugs with narrow therapeutic windows metabolized through these pathways require careful monitoring. 1
• The enzyme-inhibiting effect persists 4-5 days after fluconazole discontinuation due to its long half-life. 1

Specific Drug Interactions

• Domperidone: Combined use intensifies proarrhythmic effects, particularly in patients with renal dysfunction. 3
• Quinolones (ciprofloxacin): Additive QT prolongation effects, though overall prevalence remains relatively low. 5
• Other medications: Calcium channel blockers, HMG-CoA reductase inhibitors, and various cardiovascular agents may have increased toxicity when combined with fluconazole. 1

Clinical Monitoring Recommendations

• Serial electrocardiographic monitoring should be considered when fluconazole is administered to patients at risk for ventricular arrhythmias. 2
• Monitor for symptoms including dizziness, syncope, palpitations, or seizures. 1
• Correct electrolyte abnormalities (particularly potassium and magnesium) before and during fluconazole therapy. 4
• If QTc interval exceeds 500 msec, strongly consider discontinuing fluconazole or switching to an alternative antifungal agent. 3

Important Clinical Caveats

• Most reported cases of serious arrhythmias involved patients with multiple confounding risk factors, though fluconazole alone can cause TdP even in the absence of other identifiable risk factors. 1, 2
• Complete resolution of arrhythmias typically occurs within days of fluconazole discontinuation (usually within 6 days). 2
• The risk exists across all age groups, including pediatric patients. 4
• Fluconazole should be administered with extreme caution to patients with potentially proarrhythmic conditions. 1