Voriconazole drug interactions

# Drug Interactions

### Effects of Other Drugs on Voriconazole
Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.
The systemic exposure to voriconazole is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:
Rifampin (potent CYP450 inducer)Rifampin (600 mg once daily) decreased the steady state Cmax and AUC of voriconazole (200 mg q12h  7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg q12h does not restore adequate exposure to voriconazole during coadministration with rifampin. Coadministration of voriconazole and rifampin is contraindicated.
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)The effect of the coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg q12h for 9 days) decreased the steady state Cmax and AUC of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg q12h for 9 days) decreased the steady state Cmax and AUC of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 8 days) by an average of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state Cmax and AUC of high-dose ritonavir in healthy subjects, steady state Cmax and AUC of low-dose ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly with oral voriconazole in healthy subjects. Coadministration of voriconazole and high-dose ritonavir (400 mg q12h) is contraindicated. Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole .
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 AUC0was observed. In contrast, coadministration of single oral doses of St. John's Wort and voriconazole had no appreciable effect on voriconazole AUC0. 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.
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 .
Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse events/toxicity:
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUC of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 hours of the last dose of fluconazole.
Cimetidine (non-specific CYP450 inhibitor and increases gastric pH)Cimetidine (400 mg q12h  8 days) increased voriconazole steady state Cmax and AUC by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg q12h  7 days to healthy subjects.
Ranitidine (increases gastric pH)Ranitidine (150 mg q12h) had no significant effect on voriconazole Cmax and AUC following oral doses of 200 mg q12h  7 days to healthy subjects.
Macrolide antibioticsCoadministration 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 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 Cmaxand 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 .
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
Ergot alkaloidsAlthough 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 .
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 q12h on day 1, 200 mg q12h 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 AUC0 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 .
Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg q12h on Day 1, then 200 mg q12h on Day 2) with a single intravenous dose of fentanyl (5 g/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 [
Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg q12h, on Day 1 followed by five doses of 200 mg q12h on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean Cmax and AUC0 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 
Cyclosporine (CYP3A4 substrate)In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg q12h for 8 days) increased cyclosporine Cmax and AUC 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
Methadone (CYP3A4, CYP2C19, CYP2C9 substrate)Repeat dose administration of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 4 days) increased the Cmax and AUC of pharmacologically active Rmethadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30100 mg QD). The Cmax and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Tacrolimus (CYP3A4 substrate)Repeat oral dose administration of voriconazole (400 mg q12h  1 day, then 200 mg q12h  6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUC 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. When initiating therapy with voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to one-third of the original dose and followed with frequent monitoring of the tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels should be carefully monitored and the dose increased as necessary
Warfarin (CYP2C9 substrate)Coadministration of voriconazole (300 mg q12h  12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects. Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended if warfarin and voriconazole are coadministered and the warfarin dose adjusted accordingly
Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates)Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of coumarin anticoagulants and therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anti-coagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly
Statins (CYP3A4 substrates)Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of statins that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin be considered during coadministration. Increased statin concentrations in plasma have been associated with rhabdomyolysis
Benzodiazepines (CYP3A4 substrates)Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 (e.g., midazolam, triazolam, and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during coadministration.
Calcium Channel Blockers (CYP3A4 substrates)Although not studied clinically, voriconazole has been shown to inhibit felodipine metabolism in vitro(human liver microsomes). Therefore, voriconazole may increase the plasma concentrations of calcium channel blockers that are metabolized by CYP3A4. Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during coadministration. Dose adjustment of the calcium channel blocker may be needed.
Sulfonylureas (CYP2C9 substrates)Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction) of the sulfonylurea dosage is recommended during coadministration.
Vinca Alkaloids (CYP3A4 substrates)Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered .
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 q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean Cmax and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean Cmax and AUC of diclofenac by 114% and 78%, respectively.
A reduction in ibuprofen and diclofenac dosage may be needed during concomitant administration with voriconazole. Patients receiving voriconazole concomitantly with other NSAIDs (e.g., celecoxib, naproxen, lornoxicam, meloxicam) that are also metabolized by CYP2C9 should be carefully monitored for NSAID-related adverse events and toxicity, and dosage reduction should be made if warranted.
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 q12h  30 days) increased Cmax and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.
Digoxin (P-glycoprotein mediated transport)Voriconazole (200 mg q12h  12 days) had no significant effect on steady state Cmax and AUC of digoxin (0.25 mg once daily for 10 days) in healthy subjects.
Mycophenolic acid (UDP-glucuronyl transferase substrate)Voriconazole (200 mg q12h  5 days) had no significant effect on the Cmax and AUC of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 g 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 Cmax and AUC 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 Cmax and AUC 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 Cmax and AUC 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. Coadministration of voriconazole and rifabutin is contraindicated .
Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:
Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)Standard doses of voriconazole and standard doses of efavirenz must not be coadministered . Steady state efavirenz (400 mg PO q24h) decreased the steady state Cmax and AUC of voriconazole (400 mg PO q12h for 1 day, then 200 mg PO q12h for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO q12h for 1 day, then 200 mg q12h for 8 days) increased the steady state Cmax and AUC of efavirenz (400 mg PO q24h 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 q12h on Days 2 to 7) with efavirenz (300 mg PO q24h on Days 17), relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg PO q12h for 2 days) or efavirenz (600 mg q24h for 9 days). Coadministration of voriconazole 400 mg q12h with efavirenz 300 mg q24h, decreased voriconazole AUC by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUC was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.
Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is increased to 400 mg q12h and the efavirenz dose is decreased to 300 mg q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer)Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state Cmax and AUC of orally administered voriconazole (200 mg q12h  14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg q12h  7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole Cmax and AUCestimates as compared to when voriconazole was given at 200 mg q12h without phenytoin.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg).
Repeat dose administration of voriconazole (400 mg q12h  10 days) increased the steady state Cmax and AUC of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUC when coadministered with voriconazole may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without voriconazole. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is coadministered with voriconazole .
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)Coadministration of omeprazole (40 mg once daily  10 days) with oral voriconazole (400 mg q12h  1 day, then 200 mg q12h  9 days) increased the steady state Cmax and AUC 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 q12h  1 day, then 200 mg  6 days) with omeprazole (40 mg once daily  7 days) to healthy subjects significantly increased the steady state Cmax and AUC 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. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half.
The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these drugs.
Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor)Coadministration of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 3 days) and oral contraceptive (Ortho-Novum1/35 consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, Q24h) to healthy female subjects at steady state increased the Cmax and AUC 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 Cmax and AUC increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related to oral contraceptives, in addition to those for voriconazole, is recommended during coadministration.
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 Cmaxand AUC following repeat dose administration (200 mg q12h for 17 days) in healthy subjects.
Repeat dose administration of voriconazole (200 mg q12h for 7 days) did not have a significant effect on steady state Cmax and AUC of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

### Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo Findings:
Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors)In vitro studies (human liver microsomes) suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and HIV protease inhibitors.
Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers)In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy male subjects suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI. Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and delavirdine).Dose adjustments are required when voriconazole is co-administered with efavirenz