| Common types of azole drug interactions | Examples (see important note below) | Approach to management |
Inhibition of metabolism of coadministered drug by azole leading to increased serum concentrations of coadministered drug - Combined use of fluconazole, posaconazole, voriconazole, or itraconazole with medicines that are highly dependent upon CYP3A metabolism for clearance and have a narrow therapeutic index can result in toxicity of coadministered drug(s).
- Combined use of fluconazole with medicines that are highly dependent upon CYP2C9/CYP2C19 metabolism for clearance and have a narrow therapeutic index can result in toxicity of coadministered drug(s).
| - Apixaban, conivaptan, cyclosporine, dronedarone, everolimus, lovastatin, methadone, rivaroxaban, simvastatin, sirolimus, tacrolimus, and vincristine are examples of medicines that are dependent upon CYP3A for clearance; interaction of these drugs with azoles can result in elevated serum concentrations leading to toxic levels.
- Warfarin is an example of a medicine that is dependent upon CYP2C9 for clearance, and interaction of warfarin with fluconazole can result in elevated INR and an increased risk of pathologic bleeding.
| - When appropriate non-interacting alternatives are readily available, consider modifying treatment to avoid combined use of CYP3A substrate with fluconazole, posaconazole, voriconazole, or itraconazole.
- Example: Substitute a non-interacting statin (eg, fluvastatin, rosuvastatin) for an interacting statin (lovastatin, simvastatin).
- In patients receiving immunosuppressants, monitor immunosuppressant concentrations and signs of toxicity. Substantial, including preemptive, dose reduction of immunosuppressant may be needed. Some combinations are considered contraindicated; refer to appropriate topic reviews for detail.
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Induction of azole metabolism leading to decreased azole serum concentrations - Combined use of voriconazole, posaconazole, isavuconazole, or itraconazole with medicines that are potent inducers of CYP metabolism can result in subtherapeutic azole serum concentrations and therapeutic failure of antifungal treatment.
| - Rifampin (rifampicin), enzyme-inducing antiseizure medications (eg, carbamazepine, phenobarbital, phenytoin), and St. John's wort are examples of drugs that induce metabolism of azoles.*
- Although ritonavir is a CYP3A inhibitor, it acts as an inducer of voriconazole metabolism and can result in decreased voriconazole concentrations.
| - Combined use of strong inducers of CYP with voriconazole, posaconazole, isavuconazole, or itraconazole should generally be avoided. Some combinations are considered contraindicated; others may be managed by therapeutic drug monitoring and dose adjustment.
- Combined use with fluconazole may warrant an increase in fluconazole dose.¶
- Enzyme induction can require up to two weeks to achieve maximum effect and persists for up to two weeks after discontinuation of the interacting medication. However, clinically significant effects can occur within hours to days of starting a CYP inducer.
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Inhibition of azole metabolism leading to increased azole serum concentrations - Combined use of voriconazole with medicines that are potent inhibitors of CYP2C9/CYP2C19 may result in elevated concentrations of voriconazole and potential toxicity.
- Combined use of itraconazole or isavuconazole with medicines that are potent inhibitors of CYP3A may result in elevated serum concentrations of these azoles and potential toxicity.
| - Fluconazole and fluvoxamine are examples of drugs that inhibit CYP2C9/CYP2C19 metabolism of voriconazole; toxicity might include central nervous system adverse effects.
- Clarithromycin, cobicistat, and ritonavir are examples of drugs that inhibit CYP3A* metabolism of isavuconazole and itraconazole; toxicity might include altered QTc interval.
| - Combined use of voriconazole with strong CYP2C9/CYP2C19 inhibitors should be undertaken with caution.
- Combined use of strong inhibitors of CYP3A with itraconazole or isavuconazole should generally be avoided. Some combinations are considered contraindicated; others may be managed by therapeutic drug monitoring and dose adjustment.
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