Effect of Other Drugs on Voriconazole Pharmacokinetics

* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to    healthy subjects

† Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h    for at least 2 days voriconazole to healthy subjects

‡ Non-Nucleoside Reverse Transcriptase Inhibitors

Drug/Drug Class (Mechanism of Interaction by the Drug)

Voriconazole Plasma Exposure (Cmax and AUCτafter 200 mg q12h)

Recommendations for Voriconazole Dosage Adjustment/Comments

Rifampin* and Rifabutin* (CYP450 Induction)

Significantly Reduced

Contraindicated

Efavirenz† (CYP450 Induction)

Significantly Reduced

When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h

High dose Ritonavir (400 mg q12h)† (CYP450 Induction)

Significantly Reduced

Contraindicated

Low dose Ritonavir (100 mg q12h)† (CYP450 Induction)

Reduced

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

Carbamazepine (CYP450 Induction)

Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction

Contraindicated

Long-acting Barbiturates (CYP450 Induction)

Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction

Contraindicated

Phenytoin* (CYP450 Induction)

Significantly Reduced

Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)

St. John’s Wort (CYP450 inducer; P-gp inducer)

Significantly Reduced

Contraindicated

Oral Contraceptives†

containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)

Increased

Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives

Fluconazole†

CYP2C9, CYP2C19 and CYP3A4 Inhibition)

Significantly Increased

Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.

Other HIV Protease Inhibitors

(CYP3A4 Inhibition)

In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure

No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors

Other NNRTIs‡

(CYP3A4 Inhibition or CYP450 Induction)

In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to voriconazole

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)

Careful assessment of voriconazole effectiveness

Effect of Voriconazole on Pharmacokinetics of Other Drugs

* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects

† Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects

‡ Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 mg to 100 mg QD)

§ Non-Steroidal Anti-Inflammatory Drug

¶ Non-Nucleoside Reverse Transcriptase Inhibitors

Drug/Drug Class (Mechanism of Interaction by Voriconazole)

Drug Plasma Exposure (C_max and AUCτ )

Recommendations for Dosage Adjustment/Comments

Sirolimus* (CYP3A4 Inhibition)

Significantly Increased

Contraindicated

Rifabutin* (CYP3A4 Inhibition)

Significantly Increased

Contraindicated

Efavirenz† (CYP3A4 Inhibition)

Significantly Increased

When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h

High dose Ritonavir (400 mg q12h)† (CYP3A4 Inhibition) Low dose Ritonavir (100mg q12h)†

No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ

Contraindicated because of significant reduction of voriconazole Cmax and AUCτ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole

Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased

Contraindicatedbecause of potential for QT prolongation and rare occurrence of Torsades de pointes

Ergot Alkaloids (CYP450 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased

Contraindicated

Cyclosporine* (CYP3A4 Inhibition)

AUC_τ Significantly Increased; No Significant Effect on C_max

When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.

Methadone‡ (CYP3A4 Inhibition)

Increased

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.

Fentanyl (CYP3A4 Inhibition)

Increased

Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary.

Alfentanil (CYP3A4 Inhibition)

Significantly Increased

Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary

Oxycodone (CYP3A4 Inhibition)

Significantly Increased

Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary

NSAIDs§ including: ibuprofen and diclofenac (CYP2C9 Inhibition)

Increased

Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed

Tacrolimus* (CYP3A4 Inhibition)

Significantly Increased

When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.

Phenytoin* (CYP2C9 Inhibition)

Significantly Increased

Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.

Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)†

Increased

Monitoring for adverse events related to oral contraceptives is recommended during coadministration.

Warfarin* (CYP2C9 Inhibition)

Prothrombin Time Significantly Increased

Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.

Omeprazole* (CYP2C19/3A4 Inhibition)

Significantly Increased

When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose 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 other proton pump inhibitors.

Other HIV Protease Inhibitors (CYP3A4 Inhibition)

In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)

MNo dosage adjustment for indinavir when coadministered with voriconazole

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors

Other NNRTIs¶ (CYP3A4 Inhibition)

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to NNRTI

Benzodiazepines (CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.

HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.

Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.

Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased

Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.

Vinca Alkaloids (CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased

Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.