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Voriconazole: Drug Interactions

Voriconazole, a triazole antifungal agent, is a synthetic derivative of fluconazole. Like other azole antifungal agents, voriconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased permeability, secondary metabolic effects, and growth inhibition. Although the exact mechanism of action of voriconazole has not been fully determined, the drug inhibits cytochrome P-450-dependent sterol 14-a-demethylase in susceptible fungi, which leads to accumulation of C-14-methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.

Voriconazole is active in vitro against Aspergillus fumigatus, A. flavus, A. niger, and A. terreus. The drug also has variable activity in vitro against Scedosporium apiospermum and Fusarium spp., including F. solani.

Voriconazole has been active in vivo in normal and immunocompromised guinea pigs with established systemic A. fumigatus infections, prolonging survival and reducing fungal burden in the animals’ organs.

Voriconazole: Drug Interactions

The pharmacokinetics of voriconazole are similar following IV or oral administration. Voriconazole exhibits nonlinear, dose-dependent pharmacokinetics, apparently because of saturable first-pass metabolism or systemic clearance. In vitro studies indicate that voriconazole is extensively metabolized in the liver by cytochrome P-450 (CYP) isoenzymes 2C19, 2C9, and 3A4.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) isoenzymes 2C19, 2C9, or 3A4 may increase or decrease plasma voriconazole concentrations, respectively. Voriconazole and its major metabolite inhibit the metabolic activity of CYP isoenzymes 2C19, 2C9, and 3A4 and may increase plasma concentrations of other drugs metabolized by these hepatic enzymes.

Rifampin and Rifabutin

Potential pharmacokinetic interaction (decrease in plasma voriconazole concentrations and/or increase in plasma rifabutin concentrations). Concomitant use of rifampin or rifabutin with voriconazole is contraindicated.

Voriconazole: Drug Interactions

Drugs that Prolong the QT Interval

Potential pharmacokinetic interaction with CYP3A4 substrates that prolong the QT interval (e.g., terfenadine [no longer commercially available in the US], astemizole [no longer commercially available in the US], cisapride, pimozide, quinidine).

Potential increase in plasma concentrations of the concomitantly administered CYP3A4 substrate, which can result in QT interval prolongation and rarely, torsades de pointes. Concomitant use of these drugs with voriconazole is contraindicated.

Immunosuppressants

Potential pharmacokinetic interaction (increase in plasma concentrations of sirolimus, cyclosporine, or tacrolimus). Concomitant use of sirolimus with voriconazole is contraindicated. When initiating voriconazole therapy in patients currently receiving cyclosporine or tacrolimus, dosage of cyclosporine or tacrolimus should be reduced by one-half or one-third, respectively. When voriconazole is discontinued, plasma concentrations of cyclosporine or tacrolimus should be monitored frequently and the dosage of these drug adjusted as necessary.

Ergot Alkaloids

Potential pharmacokinetic interaction (increase in plasma concentrations of ergot alkaloid). Concomitant use of ergot alkaloids (e.g., ergotamine, dihydroergotamine) with voriconazole is contraindicated.

Carbamazepine and Barbiturates

Potential pharmacokinetic interaction (decrease in plasma voriconazole concentrations) with carbamazepine or long-acting barbiturates (e.g., phenobarbital, mephobarbital). Concomitant use of carbamazepine or long-acting barbiturates with voriconazole is contraindicated.

Phenytoin

Potential pharmacokinetic interaction (decreased plasma voriconazole concentrations and/or increased plasma phenytoin concentrations). When phenytoin and voriconazole are used concomitantly, IV maintenance dosage of voriconazole should be increased to 5 mg/kg every 12 hours and oral maintenance dosage increased to 400 mg every 12 hours in patients weighing 40 kg or more or 200 mg every 12 hours in those weighing less than 40 kg. Plasma phenytoin concentrations should be monitored frequently and the patient observed for potential phenytoin adverse effects.

HIV Protease Inhibitors

Potential pharmacokinetic interaction. Potential increase in plasma voriconazole concentrations with concomitant use of certain HIV protease inhibitors (e.g., ritonavir, saquinavir, amprenavir). Potential increase in plasma concentrations of certain HIV protease inhibitors (e.g., saquinavir, amprenavir, nelfenavir). Monitor patient for manifestations of voriconazole or HIV protease inhibitor toxicity. No pharmacokinetic interaction observed between indinavir and voriconazole.

Nonnucleoside Reverse Transcriptase Inhibitors

Potential pharmacokinetic interaction. Potential increase in plasma concentrations of nonnucleoside reverse transcriptase inhibitor (NNRTI). Plasma voriconazole concentrations may be increased (e.g., with concomitant use of delaviridine or efavirenz) or decreased (e.g., with concomitant use of efavirenz or nevirapine). Monitor patient for manifestations of voriconazole or NNRTI toxicity, as well as for clinical response to voriconazole.

Coumarin Anticoagulants

Potential pharmacokinetic interaction (increased prothrombin time). Monitor prothrombin time closely if coumarin anticoagulants (e.g., warfarin) are used concomitantly with voriconazole; reduction of anticoagulant dosage may be necessary.

Voriconazole: Drug Interactions

Proton-Pump Inhibitors

Potential pharmacokinetic interaction (increased plasma concentrations of omeprazole and voriconazole) with omeprazole. In patients currently receiving omeprazole in dosages of 40 mg or more daily, reduce omeprazole dosage by one-half when voriconazole therapy is initiated. Potential increase in plasma concentrations of other proton-pump inhibitors that are metabolized by CYP2C19 isoenzyme.

Benzodiazepines

Potential pharmacokinetic interaction (increased plasma benzodiazepine concentrations) with benzodiazepines that are metabolized by CYP3A4 isoenzyme (e.g., midazolam, triazolam, alprazolam). Monitor patient for manifestations of benzodiazepine toxicity and adjust benzodiazepine dosage as necessary.

Antilipemic Agents

Potential pharmacokinetic interaction (increased plasma concentrations of antilipemic agent) with HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by CYP3A4 isoenzyme (e.g., lovastatin). Monitor patient for manifestations of statin toxicity and adjust statin dosage as necessary.

Voriconazole: Drug Interactions

Calcium-Channel Blocking Agents

Potential pharmacokinetic interaction (increased plasma concentrations of calcium-channel blocker) with calcium-channel blocking agents that are metabolized by CYP3A4 isoenzyme (e.g., felodipine). Monitor patient for manifestations of calcium-channel blocker toxicity and adjust dosage as necessary.

Sulfonylurea Antidiabetic Agents

Potential pharmacokinetic interaction (increased plasma concentrations of antidiabetic agent) with sulfonylurea antidiabetic agents (e.g., tolbutamide, glipizide, glyburide). Monitor blood glucose concentrations and monitor patient for signs and symptoms of hypoglycemia; adjust dosage of antidiabetic agent as necessary.

Voriconazole: Drug Interactions

Vinca Alkaloids

Potential pharmacokinetic interaction (increased plasma concentrations of vinca alkaloid). Monitor patient for manifestations of vinca alkaloid toxicity (i.e., neurotoxicity) and adjust dosage as necessary.

Advice to Patients

Importance of taking oral voriconazole at least 1 hour before or 1 hour after meals. Possibility of visual changes, including blurred vision and photophobia. Avoid driving, operating machinery, or performing hazardous tasks if visual changes occur; importance of not driving at night while taking voriconazole. Importance of avoiding exposure to strong, direct sunlight during voriconazole therapy. Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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