Does Voriconazole Cause Hypokalemia?
Yes, voriconazole causes hypokalemia, though it is an uncommon adverse effect that requires monitoring and correction of electrolyte disturbances prior to and during therapy. 1
Evidence from FDA Drug Labeling and Guidelines
The FDA drug label explicitly states that electrolyte disturbances such as hypokalemia should be corrected prior to initiation of and during voriconazole therapy, and patient management should include laboratory evaluation throughout treatment. 1
The Infectious Diseases Society of America guidelines note that hypokalemia is among the multiple confounding risk factors that can contribute to serious cardiac complications in patients taking voriconazole, including ventricular arrhythmias such as torsade de pointes, cardiac arrest, and sudden death. 2
Itraconazole, another azole antifungal in the same class, is documented to cause hypokalemia as one of its most observed transient reactions. 2 This suggests a class effect among azole antifungals.
Clinical Evidence and Incidence
Recent prospective real-world data demonstrates that hypokalemia occurs in 18% of patients receiving voriconazole, with 81.2% developing hypokalemia within 14 days and 56.2% within the first week of treatment. 3
Risk Factors for Voriconazole-Induced Hypokalemia
The following independent risk factors increase the likelihood of developing hypokalemia:
- Female sex - Women have significantly higher rates of hypokalemia compared to men. 3
- Intravenous voriconazole administration - IV formulation carries higher risk than oral administration. 3
- Combined use of antibiotics - Concurrent antibiotic therapy increases hypokalemia risk. 3
- Higher voriconazole N-oxide to parent drug ratio (CN/C0) - Elevated metabolite levels correlate with increased hypokalemia risk. 3
Mechanism and Nephrotoxicity
Voriconazole's adverse effects involve multiple segments of the nephron, particularly the proximal tubule, medullary thick ascending limb, and collecting duct, causing loss of potassium and magnesium and backdiffusion of hydrogen ions. 4
The mechanism may also involve azole-induced interference with adrenal steroid biosynthesis, potentially leading to aldosterone deficiency, though this is more clearly established with other azoles. 5
Severe Complications
Hypokalemia from voriconazole can lead to life-threatening complications, including hypokalemic rhabdomyolysis with muscle weakness, inability to walk, and typical ECG changes. 6 This represents a severe but uncommon complication that requires prompt recognition and intervention.
The cardiac risks are particularly concerning, as hypokalemia combined with voriconazole's direct effects on QT interval prolongation creates a dangerous synergistic risk for fatal arrhythmias. 2
Monitoring Recommendations
Check serum potassium levels before starting voriconazole and monitor regularly throughout therapy, with increased frequency in high-risk patients (females, IV administration, concurrent antibiotics). 1, 3
Monitor most closely during the first two weeks of therapy, when the majority of hypokalemia cases develop. 3
Therapeutic drug monitoring of voriconazole levels is useful to evaluate for potential toxicity and should be considered in patients developing electrolyte abnormalities. 7
Clinical Pitfall
While hyperkalemia has been reported in rare cases with voriconazole (particularly when drug-drug interactions cause extremely elevated voriconazole levels or when combined with calcineurin inhibitors in transplant patients), 5, 8 hypokalemia is the more common electrolyte disturbance and the one specifically highlighted in FDA labeling and guidelines. 1