Table 3.

Mechanisms of voriconazole drug interactions and recommendations for its use (Muijsers et al 2002; Venkataramanan et al 2002; Johnson and Kauffman 2003; Purkins et al 2003; Groll et al 2004; Klasko 2005)

Drug	Mechanism	Results/Drug plasma exposure	Recommendation
Astemizole, terfenadine, quinidine, dofetilide	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma concentrations of astemizole.	Contraindicated. An increased risk of cardiotoxicity (QT prolongation, torsade de pointes, cardiac arrest).
Azithromycin	Azithromycin inhibits CYP450 metabolism of voriconazole (unclear).	↑ voriconazole Cmax (8%) and AUC (1%).	No adjustment of voriconazole dose.
Barbiturates	Barbiturates inhibit CYP450 metabolism of voriconazole.	Systemic exposure to voriconazole significantly reduced.	Contraindicated.
Benzodiazepines	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma exposure.	Frequent monitoring for adverse events and toxicity (prolonged sedation). Dose adjustment of benzodiazepine may be necessary.
Calcium channel blockers	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma concentrations of calcium channel blockers.	Frequent monitoring for adverse events and toxicity. Dose adjustment of calcium channel blockers.
Carbamazepine	Carbamazepine inhibits CYP450 metabolism.	↓ systemic exposure of voriconazole.	Contraindicated.
Cyclosporine	Voriconazole inhibits CYP3A4 metabolism.	↑ AUC cyclosporine ˜70%	↓ cyclosporine dose by 50%.Monitor cyclosporine levels and signs of toxicity.
		↑ cyclosporine trough levels by 2.5.
Digoxin	Voriconazole inhibits CYP3A4 metabolism.	↑ digoxin Cmax (10%) and AUC (1%).	No dose adjustment recommended.
Ergot alkaloids	Voriconazole inhibits CYP.	Likely to be increased (based on available data; not studied).	Contraindicated.
Erythromycin	Erythromycin and voriconazole inhibit their CYP3A4 metabolism.	↑ plasma concentrations of voriconazole (Cmax 8% and AUC 1%) and erythromycin.	No adjustment of voriconazole dose. Monitor patients for signs.
HMG-CoA reductase inhibitors (statins)	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma exposure of HMG-CoA reductase inhibitors (in vitro studies).	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dose may be necessary.
Imatinib	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma exposure of imatinib.	Monitor for signs of imatinib dose-related adverse events (fluid retention/water gain, nausea and vomiting, neutropenia).
Indinavir HIV protease inhibitors	Indinavir inhibits CYP450 metabolism of voriconazole.	↑ voriconazole Cmax (2%) and AUC (7%).	No dose adjustment required for indinavir. Frequent monitoring for adverse events related to other HIV protease inhibitors.
	Voriconazole inhibits	↑ voriconazole exposure.
	CYP3A4 metabolism of indinavir.	↑ indinavir Cmax (9%) and AUC (11%).
NNRTIs	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma exposure (in vitro studies).	Frequent monitoring for adverse events and toxicity related to NNRTIs.
Omeprazole	Competitive inhibition of omeprazole and voriconazole metabolim by CYP2C19 and CYP3A4.	↑ voriconazole Cmax (15%) and AUC (41%).	Reduce omeprazole dose by 50% when starting voriconazole. No change in voriconazole dose.
		↑ omeprazole Cmax (3.8-fold) and AUC (2.2-fold).
		↑ exposure to voriconazole and omeprazole.
Phenytoin	Voriconazole inhibits CYP2C9 metabolism of phenytoin.	↑ phenytoin Cmax (67%) and AUC (81%).	Monitor phenytoin levels and phenytoin-related adverse events. Adjust voriconazole dose to 5 mg/kg intravenously or to 400 mg orally, twice daily.
	Phenytoin induces CYP3A4 metabolism of voriconazole.	↓ voriconazole Cmax (51%) and AUC (31%).
Prednisolone	Competitive inhibition of CYP3A4.	- prednisolone Cmax (11%) and AUC (34%). Slight accumulation of voriconazole.	No dose adjustment required.
Rifabutin	Rifabutin induces CYP450 metabolism of voriconazole.	↓ voriconazole Cmax (66%) and AUC (79%)	Contraindicated.
	Voriconazole inhibits CYP3A4 metabolism of rifabutin.	↓ rifabutin Cmax (69%) and AUC (78%).	If benefits of co-administration outweigh risks, adjust voriconazole dose to 5 mg/kg intravenously or to 400 mg orally, twice daily.
Rifampin	Rifampin induces CYP450 metabolism of voriconazole.	↓ voriconazole Cmax (92%) and AUC (96%).	Contraindicated.
Sirolimus	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma concentrations of sirolimus.	Contraindicated.
Sulfonylureas (tolbutamida, glipizide, glyburide)	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma concentrations of sulfonylureas.	Frequent monitoring of blood glucose and appropriate adjustment of the sulfonylurea dose.
Tacrolimus	Voriconazole inhibits CYP3A4 metabolism (dose dependent).	↑ tacrolimus Cmax (2.2-fold) and AUC (3.2-fold).	Reduce tacrolimus dose by a third when starting voriconazole.
			Monitor plasma levels frequently.
Vinca alkaloids (vincristine, vinblastine, vinorelbine)	Voriconazole inhibits CYP3A4 metabolism.	↑ plasma concentrations of vinca alkaloids.	Dose adjustment of vinca alkaloids.
Warfarin oral anticoagulants	Voriconazole inhibits CYP3A4 metabolism.	↑ warfarin effect	Monitor prothrombin time.
		(↑ prothrombin time).	Adjust warfarin dose if necessary. Increased risk of bleeding.

Abbreviations: NNRTIs, nonnucleoside reverse transcriptase inhibitor; AUC, area under the curve; C_max, maximum concentration; CY, cytochrome.