What are the potential interactions between voriconazole (antifungal) and tacrolimus (immunosuppressant)?

Voriconazole and Tacrolimus Drug Interaction Management

Voriconazole significantly increases tacrolimus blood levels by inhibiting CYP3A4 metabolism, requiring a reduction of tacrolimus dose to one-third of the original dose and mandatory therapeutic drug monitoring to prevent toxicity. 1, 2

Mechanism of Interaction

• Voriconazole is a potent inhibitor of CYP3A4 enzymes, while tacrolimus is a CYP3A4 substrate with a narrow therapeutic index 3
• This interaction results in a 2-fold increase in tacrolimus Cmax and 3-fold increase in AUC when coadministered 1
• The inhibition of tacrolimus metabolism leads to significantly elevated blood concentrations that can persist for days, potentially causing serious toxicity 3

Clinical Consequences of Interaction

• Elevated tacrolimus levels can cause:
  • Nephrotoxicity (primary concern) 1, 3
  • Neurotoxicity including tremors, paresthesias, headache, mental status changes 2
  • Hyperkalemia 2
  • Hypertension 2
  • QT interval prolongation and potential cardiac arrhythmias 2
  • Myocardial hypertrophy 2

Management Recommendations

Initial Dose Adjustment

• When initiating voriconazole in patients already on tacrolimus:
  • Reduce tacrolimus dose to one-third of the original dose immediately 1
  • Some cases may require even greater dose reductions (up to two-thirds reduction) due to the potent inhibitory effect 4
  • The standard one-third dose reduction may not be sufficient in all patients 5

Therapeutic Drug Monitoring (TDM)

• Obtain serum trough drug levels for both voriconazole and tacrolimus once steady state is reached 3
• Monitor tacrolimus levels:
  • Daily until steady state is achieved 3
  • Every 2-3 days until hospital discharge 3
  • Every 1-2 weeks in the first 1-2 months 3
  • Every 1-2 months once stable 3
• More frequent monitoring is required when:
  • Initiating or discontinuing voriconazole 1
  • Patient is hospitalized with complications 3
  • Other medications affecting CYP3A4 are added or removed 3

Laboratory Monitoring

• Monitor renal function closely (creatinine, BUN) 3, 2
• Check serum potassium and glucose levels regularly 3, 2
• Monitor CBC to detect bone marrow suppression 3
• Consider ECG monitoring for QT interval prolongation 2

Discontinuation Protocol

• When voriconazole is discontinued, tacrolimus levels should be frequently monitored 1
• Tacrolimus dose will need to be gradually increased back to the pre-voriconazole dose 1
• Be vigilant for subtherapeutic tacrolimus levels after voriconazole discontinuation 6

Special Considerations

• The interaction may be more pronounced in patients with genetic polymorphisms affecting CYP2C19 and CYP3A4 enzymes 3
• Three-way interactions can occur with other medications:
  • Flucloxacillin can induce metabolism of both voriconazole and tacrolimus, requiring higher doses of both drugs during coadministration 6
  • When flucloxacillin is discontinued while voriconazole and tacrolimus are continued, supra-therapeutic tacrolimus levels can occur 6

Common Pitfalls to Avoid

• Failing to reduce tacrolimus dose before initiating voriconazole therapy 5
• Using a standard one-third dose reduction formula without individualized TDM 5, 4
• Inadequate monitoring frequency, especially during the first week of coadministration 3
• Not adjusting tacrolimus dose when voriconazole is discontinued 1
• Overlooking the potential for hyponatremia when these drugs are coadministered 7