Voriconazole (Page 11 of 19)

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 every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the C max 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 (4) and Warnings and Precautions (5.13)] .

Cisapride, Pimozide and Quinidine (CYP3A4 Substrates)

Although not studied in vitro or in vivo , concomitant administration of voriconazole with 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, cisapride, pimozide and quinidine is contraindicated [see Contraindications (4) and Warnings and Precautions (5.13)] .

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 (4) and Warnings and Precautions (5.13)] .

Naloxegol (CYP3A4 Substrate)

Although not studied in vitro or in vivo , voriconazole may increase the plasma concentration of naloxegol and precipitate opioid withdrawal symptoms. Coadministration of voriconazole with naloxegol is contraindicated [see Contraindications (4) and Warnings and Precautions (5.13)] .

Everolimus (CYP3A4 Substrate, P-gp Substrate)

Although not studied in vitro or in vivo , voriconazole may increase plasma concentrations of everolimus, which could potentially lead to exacerbation of everolimus toxicity. Currently there are insufficient data to allow dosing recommendations in this situation. Therefore, co-administration of voriconazole with everolimus is not recommended [see Drug Interactions (7)] .

Coadministration of voriconazole with the following agents results in increased exposure or is expected to result in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil (CYP3A4 Substrate)

Coadministration of multiple doses of oral voriconazole (400 mg every 12 hours on day 1, 200 mg every 12 hours on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC 0-∞ and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone. An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting during co-administration of voriconazole and alfentanil was also observed. Reduction in the dose of alfentanil or other opiates that are also metabolized by CYP3A4 (e.g., sufentanil), and extended close monitoring of patients for respiratory and other opiate-associated adverse events, may be necessary when any of these opiates is coadministered with voriconazole [see Warnings and Precautions (5.13)] .

Fentanyl (CYP3A4 Substrate)

In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 μg/kg) resulted in an increase in the mean AUC 0-∞ of fentanyl by 1.4-fold (range 0.81- to 2.04-fold). When voriconazole is co-administered with fentanyl IV, oral or transdermal dosage forms, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and fentanyl dosage should be reduced if warranted [see Warnings and Precautions (5.13)] .

Oxycodone (CYP3A4 Substrate)

In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C max and AUC 0–∞ of oxycodone by 1.7- fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range 1.4- to 2.5-fold). Voriconazole also increased the visual effects (heterophoria and miosis) of oxycodone. A reduction in oxycodone dosage may be needed during voriconazole treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended [see Warnings and Precautions (5.13)] .

Cyclosporine (CYP3A4 Substrate)

In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cyclosporine C max and AUC τ an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as compared to when cyclosporine was administered without voriconazole. When initiating therapy with voriconazole in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be reduced to one-half of the original dose and followed with frequent monitoring of the cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine levels should be frequently monitored and the dose increased as necessary[see Warnings and Precautions (5.13)] .

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