What antifungal interacts with Prograf (tacrolimus)?

Azole Antifungals Significantly Interact with Prograf (Tacrolimus)

Azole antifungals—including voriconazole, itraconazole, posaconazole, fluconazole, and isavuconazole—all interact with tacrolimus by inhibiting CYP3A4 metabolism, causing substantial elevations in tacrolimus blood levels that require dose reduction and intensive monitoring. 1

Mechanism of Interaction

• Azole antifungals are potent inhibitors of CYP3A4 enzymes, while tacrolimus is a CYP3A4 substrate with a narrow therapeutic index 2
• This inhibition of tacrolimus metabolism leads to significantly elevated blood concentrations that can persist for days, potentially causing serious toxicity including nephrotoxicity 2, 3
• The interaction occurs through both hepatic and intestinal CYP3A4 inhibition 3

Specific Azole Interactions

Voriconazole (Strongest Interaction)

• Voriconazole causes the most pronounced interaction, requiring tacrolimus dose reduction by approximately two-thirds 4
• Blood tacrolimus levels increase 1.33 to 2.45 times baseline concentrations when combined with voriconazole 3, 5
• Voriconazole increases tacrolimus levels more markedly than fluconazole after switching to oral tacrolimus formulations 5

Fluconazole (Moderate Interaction)

• Fluconazole requires tacrolimus dose reduction by approximately one-third 4
• The FDA label confirms that fluconazole coadministration leads to increased serum tacrolimus levels 6
• Even low-dose fluconazole (100 mg every other day intravenously) can increase tacrolimus concentrations, particularly in patients with impaired renal function 3
• Fluconazole causes larger variation in tacrolimus blood levels compared to voriconazole 5

Itraconazole and Posaconazole

• These azoles also significantly interact with tacrolimus through CYP3A4 inhibition 1
• Require similar dose adjustments and monitoring as other azoles 1

Isavuconazole

• Interacts with tacrolimus via CYP3A4 inhibition 1
• Therapeutic drug monitoring may be helpful but requires further study 1

Clinical Consequences

• Nephrotoxicity is the primary concern with elevated tacrolimus levels 2
• Additional toxicities include: 3
  • Hepatotoxicity
  • Increased serum creatinine
  • Hyperglycemia
  • Potential graft rejection if tacrolimus is excessively reduced 1

Management Algorithm

Dose Adjustment Strategy

• Reduce tacrolimus dose by approximately 30-50% (two-thirds for voriconazole, one-third for fluconazole) at the time of initiating azole therapy 1, 4
• Do not wait for elevated levels to occur before adjusting the dose 1

Therapeutic Drug Monitoring Protocol

• Obtain serum trough drug levels for both the azole antifungal and tacrolimus once steady state is reached 1, 2
• Monitor tacrolimus levels daily until steady state is achieved 2
• Continue monitoring every 2-3 days until hospital discharge 2
• Monitor every 1-2 weeks in the first 1-2 months, then every 1-2 months once stable 2
• More frequent monitoring is required when initiating or discontinuing the azole, when the patient is hospitalized with complications, or when other CYP3A4-affecting medications are added or removed 2

Target Levels

• Maintain tacrolimus concentration in the therapeutic range to avoid toxic effects 3, 4
• For azoles: ensure itraconazole levels are therapeutic (≥1.0 mg/mL) but not excessive (≤10 mg/mL) 7

Special Considerations

• Patients with genetic polymorphisms affecting CYP2C19 and CYP3A4 enzymes may experience more pronounced interactions 2
• Even in the presence of renal function alteration, low doses of fluconazole can lead to increased tacrolimus concentration and adverse effects 3
• The interaction persists as long as both medications are coadministered and for several days after discontinuation due to the azoles' long half-lives 8

Common Pitfalls to Avoid

• Inadequate monitoring frequency, especially during the first week of coadministration, can lead to serious toxicity 2
• Failing to reduce tacrolimus dose preemptively when initiating azole therapy 1, 4
• Not monitoring sirolimus and cyclosporine levels when these calcineurin inhibitors are used instead of tacrolimus 1
• Overlooking the cumulative effect when patients are on multiple CYP3A4 substrates simultaneously 8
• Inadequate patient counseling about the need for frequent blood draws and potential toxicity signs 3