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Labeling changes for Voriconazole (VFEND) antifungal, when coadministered with efavirenz or ritonavir

Please note that the following changes have been made to the label for Voriconazole (VFEND)
triazole antifungal agent, to include drug interaction information when coadministered with efavirenz or ritonavir.

1. CLINICAL PHARMACOLOGY

  • The following paragraph was added to Drug Interactions, Effects of Other Drugs on Voriconazole:
    Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Ritonavir (400 mg Q12h for 9 days) decreased the steady state Cmax and AUCt of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied. Repeat oral administration of voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) did not have a significant effect on steady state Cmax and AUCt of ritonavir following repeat dose administration (400 mg Q12h for 9 days) in healthy subjects.
    Coadministration of voriconazole and ritonavir (400 mg Q12h) is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions).
  • The following paragraph was added to Drug Interactions, Two-Way Interactions:
    Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate): Steady state efavirenz (400 mg PO QD) decreased the steady state Cmax and AUCt of voriconazole (400 mg PO Q12h for 1 day, then 200 mg PO Q12h for 8 days) by an average of 61% and 77%, respectively, in healthy subjects. Voriconazole at steady state (400 mg PO Q12h for 1 day, then 200 mg Q12h for 8 days) increased the steady state Cmax and AUCt of efavirenz (400 mg PO QD for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.
    Coadministration of voriconazole and efavirenz is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions).
  • The following paragraph was modified in Drug Interactions, Two-Way Interactions:
    Other Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) (CYP3A4 substrates, inhibitors or CYP450 inducers): In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by an NNTRI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy volunteers suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI. Efavirenz and voriconazole coadministration is contraindicated (see CLINICAL PHARMACOLOGY - Drug Interactions, CONTRAINDICATIONS,
    PRECAUTIONS - Drug Interactions). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g. nevirapine and delavirdine) (see PRECAUTIONS - Drug Interactions).

2. CONTRAINDICATIONS

  • The following paragraphs were added to this section:

Coadministration of VFEND with ritonavir (400 mg Q12h) is contraindicated because ritonavir (400 mg Q12h) significantly decreases plasma voriconazole concentrations in healthy subjects. The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

Coadministration of VFEND with efavirenz is contraindicated because efavirenz significantly decreases voriconazole plasma concentrations while VFEND also significantly increases efavirenz plasma concentrations (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

 

3. PRECAUTIONS

  • Table 8 and Table 9 in Drug Interactions were revised to include information concerning ritonavir and efavirenz.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration