What is the interaction between fluconazole and tacrolimus (tacrolimus is an immunosuppressant)

Fluconazole-Tacrolimus Drug Interaction

Fluconazole significantly increases tacrolimus blood concentrations by inhibiting CYP3A4 metabolism, requiring preemptive dose reduction of tacrolimus by approximately one-third to one-half before initiating fluconazole, with intensive therapeutic drug monitoring to prevent nephrotoxicity and other serious adverse effects. 1

Mechanism of Interaction

• Fluconazole inhibits CYP3A4, the primary enzyme responsible for tacrolimus metabolism, though it is the weakest CYP3A4 inhibitor among azole antifungals 2
• The interaction is dose-dependent and more pronounced at fluconazole doses ≥200 mg daily 2
• Fluconazole may increase serum concentrations of orally administered tacrolimus up to 5-fold due to inhibition of intestinal CYP3A4 metabolism 1
• Tacrolimus is also a substrate of P-glycoprotein, adding complexity to the drug interaction 2

Clinical Consequences

• Elevated tacrolimus levels are directly associated with nephrotoxicity, which is the primary concern 1
• Case reports document tacrolimus concentration increases ranging from 1.33 to 2.45 times baseline values when combined with fluconazole 3
• One case report showed a 125% increase (18.4 ng/mL) and 212% increase (25.4 ng/mL) in tacrolimus blood concentration after fluconazole initiation 4
• Another case demonstrated a 9.1-fold increase in dose-normalized tacrolimus trough level with fluconazole coadministration 5
• Adverse effects include hepatotoxicity, increased serum creatinine, and hyperglycemia in all affected patients 3

Preemptive Dose Adjustment Strategy

Before initiating fluconazole, reduce tacrolimus dose by one-third to one-half to prevent supratherapeutic levels. 6

• The FDA label states that dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration 1
• A retrospective study of 109 kidney transplant recipients found that tacrolimus dose should be reduced by one-third before combination with fluconazole 6
• Even with dose reduction by two-thirds, patients may still experience elevated tacrolimus concentrations, particularly those with pre-existing renal impairment 3
• No significant pharmacokinetic changes occur when tacrolimus is given intravenously, so this interaction primarily affects oral tacrolimus 1

Therapeutic Drug Monitoring Protocol

Monitor tacrolimus trough levels daily initially, then every 2-3 days until stable, with target therapeutic range of 5-15 ng/mL for stable transplant recipients. 7

• Obtain baseline tacrolimus trough level before initiating fluconazole 7
• Check tacrolimus levels daily during the first week of fluconazole coadministration 8
• Transition to every 2-3 days once toxicity resolves and therapeutic range is re-established 7
• Continue weekly monitoring, then every 1-2 weeks once stable 7
• Monitor renal function, electrolytes, glucose, CBC, blood pressure, and liver function tests at least weekly during acute management 7

Route of Administration Considerations

• Oral fluconazole has a more significant impact on tacrolimus levels than intravenous fluconazole 5
• Even low-dose intravenous fluconazole (100 mg every other day) can increase tacrolimus concentrations by 1.33 times, particularly in patients with pre-existing renal impairment 3
• Intravenous fluconazole inhibits only hepatic CYP3A4, while oral fluconazole inhibits both intestinal and hepatic CYP3A4 as well as P-glycoprotein 3

After Fluconazole Discontinuation

Return tacrolimus to the original dose gradually after fluconazole discontinuation, with close monitoring for subtherapeutic levels. 4

• One case required 161 days after fluconazole discontinuation before tacrolimus dosing stabilized, still requiring a 26% reduction from baseline 5
• Another case returned to therapeutic range within 8 days of fluconazole withdrawal with 50% dose reduction, then required return to initial dose after fluconazole cessation 4
• The interaction effects may persist for days after fluconazole discontinuation due to its long half-life 8

Critical Pitfalls to Avoid

• Never fail to reduce tacrolimus dose preemptively before starting fluconazole - waiting for elevated levels to occur before adjusting risks nephrotoxicity 7
• Do not assume intravenous fluconazole is safe - even low doses can cause clinically significant interactions, especially in patients with renal impairment 3
• Avoid inadequate monitoring frequency - daily monitoring is essential during the first week of coadministration 8
• Do not overlook genetic polymorphisms - CYP3A5 6986 A>G and ABCB1 3435 C>T screening may help predict interaction magnitude and facilitate dose adjustment 5

Comparison with Other Azoles

• Fluconazole is the weakest CYP3A4 inhibitor among azoles, making it preferable when azole therapy is needed in transplant recipients 2
• Voriconazole requires tacrolimus dose reduction by two-thirds, compared to one-third for fluconazole 6
• The American Heart Association recommends that combination of tacrolimus with fluconazole may be considered, unlike stronger azoles which should be avoided 2