St. John's Wort (CYP450 inducer; P-gp inducer): In an independent published study in healthy volunteers who were given multiple oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC_0-∞ was observed. In contrast, coadministration of single oral doses of St. John's Wort and voriconazole had no appreciable effect on voriconazole AUC_0-∞. Because long-term use of St. John's Wort could lead to reduced voriconazole exposure, concomitant use of voriconazole with St. John's Wort is contraindicated (see CONTRAINDICATIONS).

Carbamazepine and long-acting barbiturates (potent CYP450 inducers): Although not studied in vitro or in vivo, carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital) are likely to significantly decrease plasma voriconazole concentrations. Coadministration of voriconazole with carbamazepine or long-acting barbiturates is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - DRUG INTERACTIONS).

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg Q12h x 8 days) increased voriconazole steady state Cmax and AUC_τ by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg Q12h x 7 days to healthy subjects.

Ranitidine (increases gastric pH): Ranitidine (150 mg Q12h) had no significant effect on voriconazole Cmax and AUC_τ following oral doses of 200 mg Q12h x 7 days to healthy subjects.

Macrolide antibiotics: Coadministration of erythromycin (CYP3A4 inhibitor;1g Q12h for 7 days) or azithromycin (500 mg qd for 3 days) with voriconazole 200 mg Q12h for 14 days had no significant effect on voriconazole steady state Cmax and AUC_τ in healthy subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin or azithromycin are not known.

Effects of Voriconazole on Other Drugs

In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.

The systemic exposure of the following drugs is significantly increased or is expected to be significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus (CYP3A4 substrate): Repeat dose administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects. Coadministration of voriconazole and sirolimus is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - DRUG INTERACTIONS).

Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although not studied in vitro or in vivo, concomitant administration of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine may result in inhibition of the metabolism of these drugs. Increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of voriconazole and terfenadine, astemizole, cisapride, pimozide and quinidine is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS -DRUG INTERACTIONS).

Ergot alkaloids: Although not studied in vitro or in vivo, voriconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Coadministration of voriconazole with ergot alkaloids is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - DRUG INTERACTIONS).

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