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VFEND®Drug Interactions (voriconazole)

7 DRUG INTERACTIONS

Voriconazole is metabolized by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg every 12 hours)
Recommendations for Voriconazole Dosage Adjustment/Comments
*
Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects
Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects
Non-Nucleoside Reverse Transcriptase Inhibitors
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly ReducedContraindicated
Efavirenz (400 mg every 24 hours)
(CYP450 Induction)
Significantly ReducedContraindicated
Efavirenz (300 mg every 24 hours)
(CYP450 Induction)
Slight Decrease in AUCτWhen voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)Significantly ReducedContraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)ReducedCoadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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 ReductionContraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital)
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant ReductionContraindicated
Phenytoin*
(CYP450 Induction)
Significantly ReducedIncrease voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV 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 weighing less than 40 kg).
Letermovir
(CYP2C9/2C19 Induction)
ReducedIf concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly ReducedContraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)IncreasedMonitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives.
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)Significantly IncreasedAvoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole ExposureNo 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.
Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
*
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 every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects
Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)
§
Non-Steroidal Anti-Inflammatory Drug
Non-Nucleoside Reverse Transcriptase Inhibitors
Sirolimus*
(CYP3A4 Inhibition)
Significantly IncreasedContraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly IncreasedContraindicated
Efavirenz (400 mg every 24 hours)
(CYP3A4 Inhibition)
Significantly IncreasedContraindicated
Efavirenz (300 mg every 24 hours)
(CYP3A4 Inhibition)
Slight Increase in AUCτWhen voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours)(CYP3A4 Inhibition)No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτContraindicated because of significant reduction of voriconazole Cmax and AUCτ.
Low-dose Ritonavir (100 mg every 12 hours)Slight Decrease in Ritonavir Cmax and AUCτCoadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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.
Cisapride, Pimozide, Quinidine, Ivabradine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be IncreasedContraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes.
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be IncreasedContraindicated
Naloxegol
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse ReactionsContraindicated
Tolvaptan
(CYP3A4 Inhibition)
Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of TolvaptanContraindicated
Venetoclax
(CYP3A4 Inhibition)
Not studied In Vivo or In Vitro, but Venetoclax Plasma Exposure Likely to be Significantly IncreasedCoadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.
For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on CmaxWhen initiating therapy with VFEND 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 VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone (CYP3A4 Inhibition)IncreasedIncreased 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)IncreasedReduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary.
Alfentanil (CYP3A4 Inhibition)Significantly IncreasedAn increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary.
Oxycodone (CYP3A4 Inhibition)Significantly IncreasedIncreased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND.
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary.
NSAIDs§ including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
IncreasedFrequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus*
(CYP3A4 Inhibition)
Significantly IncreasedWhen initiating therapy with VFEND 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 VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly IncreasedFrequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)IncreasedMonitoring for adverse events related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure
Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased
No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [See Warnings and Precautions (5.8)].
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly IncreasedIf patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants
(CYP2C9/3A4 Inhibition)
Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse ReactionsDose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly IncreasedWhen initiating therapy with VFEND 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 ExposureNo dosage adjustment for indinavir when coadministered with VFEND.
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
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)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(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 IncreasedFrequent 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 IncreasedFrequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be IncreasedConcomitant administration of voriconazole and everolimus is not recommended.
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