Is it safe to administer voriconazole and fluconazole (antifungal medications) together?

Concurrent Administration of Voriconazole and Fluconazole is Not Recommended

Voriconazole and fluconazole should not be administered together due to significant pharmacokinetic interactions that substantially increase voriconazole exposure and associated toxicity risk. 1, 2

FDA-Labeled Drug Interaction

The FDA labels for both medications explicitly address this interaction:

• Fluconazole increases voriconazole exposure dramatically: Concurrent administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) with fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) increased voriconazole Cmax by 57% and AUC by 79% in healthy subjects 1

• The interaction persists even with dose adjustments: A follow-on clinical study involving 8 healthy subjects demonstrated that reducing the dosing and/or frequency of either agent did not eliminate or diminish this effect 1

• FDA recommendation is clear: "Concomitant administration of voriconazole and fluconazole at any dose is not recommended" 1, 2

Mechanism of Interaction

The interaction occurs through CYP2C19 inhibition 3:

• Fluconazole inhibits CYP2C19, CYP2C9, and CYP3A4 enzymes, which are responsible for voriconazole metabolism 1
• This inhibition is particularly significant in CYP2C19 extensive metabolizers, where fluconazole increased voriconazole AUC by 178% 3
• CYP2C19 poor metabolizers are less affected, as their voriconazole pharmacokinetics remain relatively unchanged with fluconazole co-administration 3

Sequential Use Considerations

If switching from fluconazole to voriconazole, close monitoring is essential for at least 24-36 hours 1, 2, 3:

• The FDA label recommends "close monitoring for adverse events related to voriconazole if voriconazole is used sequentially after fluconazole, especially within 24 hours of the last dose of fluconazole" 1

• Pharmacokinetic modeling predicts significant residual interaction when voriconazole is started after fluconazole cessation 3:

  • 6 hours after last fluconazole dose: voriconazole AUC increased by 51%
  • 12 hours after: increased by 41%
  • 24 hours after: increased by 28%
  • 36 hours after: increased by 14%

• Practical recommendation: Wait at least 24-36 hours after the last fluconazole dose before initiating voriconazole, with careful monitoring for voriconazole-related adverse events 3

Clinical Context from Guidelines

While guidelines do not specifically address concurrent use (as it is contraindicated), they do provide context for sequential azole therapy 4:

• For salvage therapy in cryptococcal disease, guidelines mention using voriconazole (200-400 mg twice daily orally) or posaconazole after fluconazole failure, but emphasize this should occur after reinduction therapy and susceptibility testing 4
• The sequential use implies discontinuation of the first agent before starting the second 4

Safety Monitoring

If voriconazole must be used after recent fluconazole exposure, monitor for 5, 1:

• Visual disturbances (occur in ~30% of voriconazole patients) 6
• Hepatotoxicity (elevated transaminases in up to 20%) 5, 6
• Skin reactions including photosensitivity 5, 6
• QTc prolongation, especially with other QT-prolonging drugs 5

Bottom Line

Never administer voriconazole and fluconazole simultaneously. If transitioning from fluconazole to voriconazole, allow at least 24-36 hours after the last fluconazole dose and implement intensive monitoring for voriconazole toxicity during the first several days of therapy. 1, 2, 3