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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 Interactio ns,
PRECAUTIONS - Drug Interactions).
3. PRECAUTIONS
Table 8 and Table 9 in Drug Interactions
were revised to include information concerning ritonavir and efavirenz.
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Office of Special Health Issues
Food and Drug Administration
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