Voriconazole (Page 10 of 15)

Letermovir (CYP2C9/2C19 inducer) –Coadministration of oral letermovir with oral voriconazole decreased the steady state C max and AUC 0-12 of voriconazole by an average of 39% and 44%, respectively [see Drug Interactions (7) ].

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

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH) –Cimetidine (400 mg every 12 hours × 8 days) increased voriconazole steady state C max 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 every 12 hours × 7 days to healthy subjects.

Ranitidine (increases gastric pH) –Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C max and AUC τ following oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Macrolide antibiotics –Coadministration of erythromycin (CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or azithromycin (500 mg every 24 hours for 3 days) with voriconazole 200 mg every 12 hours for 14 days had no significant effect on voriconazole steady state C max 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 drug is 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 [see Contraindications (4)] .

Coadministration of voriconazole with the following agents results 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 [see Drug Interactions (7)] .

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) [see Drug Interactions (7)] .

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) [see Drug Interactions (7)] .

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 [see Drug Interactions (7)] .

Methadone (CYP3A4, CYP2C19, CYP2C9 substrate) –Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the C max and AUC τ of pharmacologically active Rmethadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30–100 mg every 24 hours). The C max and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively [see Drug Interactions (7)] .

Tacrolimus (CYP3A4 substrate) –Repeat oral dose administration of voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 6 days) increased tacrolimus (0.1 mg/kg single dose) C max and AUC τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7)] .

Warfarin (CYP2C9 substrate) –Coadministration of voriconazole (300 mg every 12 hours × 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects [see Drug Interactions (7)] .

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). Voriconazole increased the mean C max and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean C max and AUC of diclofenac by 114% and 78%, respectively [see Drug Interactions (7)] .

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone (CYP3A4 substrate) –Voriconazole (200 mg every 12 hours × 30 days) increased C max and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects [see Warnings and Precautions (5.8)] .

Digoxin (P-glycoprotein mediated transport) –Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C max and AUC τ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid (UDP-glucuronyl transferase substrate) –Voriconazole (200 mg every 12 hours × 5 days) had no significant effect on the C max and AUC τ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 gram single oral dose of mycophenolate mofetil.

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin (potent CYP450 inducer) –Rifabutin (300 mg once daily) decreased the C max and AUC τ of voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state C max and AUC τ of voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily. Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the C max and AUC τ of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone [see Contraindications (4)] .

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity:

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate) –Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered [see Drug Interactions (7)] . Steady state efavirenz (400 mg PO every 24 hours) decreased the steady state C max and AUC τ of voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the steady state C max and AUC τ of efavirenz (400 mg PO every 24 hours for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy male subjects following administration of voriconazole (400 mg PO every 12 hours on Days 2 to 7) with efavirenz (300 mg PO every 24 hours on Days 1–7), relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg PO every 12 hours for 2 days) or efavirenz (600 mg every 24 hours for 9 days). Coadministration of voriconazole 400 mg every 12 hours with efavirenz 300 mg every 24 hours, decreased voriconazole AUC τ by 7% (90% CI: -23%, 13%) and increased C max by 23% (90% CI: -1%, 53%); efavirenz AUC τ was increased by 17% (90% CI: 6%, 29%) and C max was equivalent. [see Dosage and Administration (2.7), Contraindications (4) and Drug Interactions (7)] .

Phenytoin (CYP2C9 substrate and potent CYP450 inducer) –Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state C max and AUC τ of orally administered voriconazole (200 mg every 12 hours × 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hours × 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole C max and AUC τ estimates as compared to when voriconazole was given at 200 mg every 12 hours without phenytoin. [see Dosage and Administration (2.7) and Drug Interactions (7)] .

Repeat dose administration of voriconazole (400 mg every 12 hours × 10 days) increased the steady state C max and AUC τ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin C max and AUC when coadministered with voriconazole may be expected to be as high as 2 times the C max and AUC estimates when phenytoin is given without voriconazole [see Drug Interactions (7)].

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) –Coadministration of omeprazole (40 mg once daily × 10 days) with oral voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 9 days) increased the steady state C max and AUC τ of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.

Coadministration of voriconazole (400 mg every 12 hours × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state C max and AUC τ of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole [see Drug Interactions (7)] .

Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor) –Coadministration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 3 days) and oral contraceptive (Ortho-Novum1/35 ® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24 hours) to healthy female subjects at steady state increased the C max and AUC τ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole C max and AUC τ increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively [see Drug Interactions (7)] .

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir (CYP3A4 inhibitor and substrate) –Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole C max and AUC following repeat dose administration (200 mg every 12 hours for 17 days) in healthy subjects.

Repeat dose administration of voriconazole (200 mg every 12 hours for 7 days) did not have a significant effect on steady state C max and AUC τ of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

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