Drug Interactions

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of Tacrolimus are recommended when concomitant use of the following drugs with Tacrolimus is initiated or discontinued [see Drug Interactions (7)].

Telaprevir: In a single dose study in 9 healthy volunteers, coadministration of Tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the Tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to Tacrolimus alone [see Drug Interactions (7.3)].

Boceprevir: In a single dose study in 12 subjects, coadministration of Tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased Tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to Tacrolimus alone [see Drug Interactions (7.3)].

Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of Tacrolimus with nelfinavir increased blood concentrations of Tacrolimus significantly and, as a result, a reduction in the Tacrolimus dose by an average of 16-fold was needed to maintain mean trough Tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of Tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.3)].

Rifampin: In a study of 6 normal volunteers, a significant decrease in Tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in Tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.7)].

Magnesium-aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, co-administration of Tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean Tacrolimus AUC and a 10% decrease in the mean Tacrolimus Cmax relative to Tacrolimus administration alone [see Drug Interactions (7.10)].

Ketoconazole: In a study of 6 normal volunteers, a significant increase in Tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of Tacrolimus during ketoconazole administration was significantly decreased compared to Tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of Tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients [see Drug Interactions (7.4)].

Voriconazole (see complete prescribing information for VFEND®): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased Tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.4)].

Posaconazole (see complete prescribing information for Noxafil®): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased Tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.4)].