DARIFENACIN METABOLISM IS PRIMARILY MEDIATED BY THE CYTOCHROME P450 ENZYMES CYP2D6 AND CYP3A4. THEREFORE, INDUCERS OF CYP3A4 OR INHIBITORS OF EITHER OF THESE ENZYMES MAY ALTER DARIFENACIN PHARMACOKINETICS.
CYP2D6 INHIBITORS: NO DOSING ADJUSTMENTS ARE RECOMMENDED IN THE PRESENCE OF CYP2D6 INHIBITORS.
CYP3A4 INHIBITORS: THE DAILY DOSE OF ENABLEX SHOULD NOT EXCEED 7.5 MG WHEN COADMINISTERED WITH POTENT CYP3A4 INHIBITORS (E.G., KETOCONAZOLE, ITRACONAZOLE, RITONAVIR, NELFINAVIR, CLARITHROMYCIN AND NEFAZODONE)
NO DOSING ADJUSTMENTS ARE RECOMMENDED IN THE PRESENCE OF MODERATE CYP3A4 INHIBITORS (E.G., ERYTHROMYCIN, FLUCONAZOLE, DILTIAZEM AND VERAPAMIL). THE MEAN CMAX AND AUC OF DARIFENACIN FOLLOWING 30 MG ONCE-DAILY DOSING AT STEADY STATE WERE 128% AND 95% HIGHER, RESPECTIVELY, IN THE PRESENCE OF ERYTHROMYCIN. COADMINISTRATION OF FLUCONAZOLE AND DARIFENACIN 30 MG ONCE DAILY AT STEADY STATE INCREASED DARIFENACIN CMAX AND AUC BY 88% AND 84%, RESPECTIVELY.
THE MEAN CMAX AND AUC OF DARIFENACIN FOLLOWING 30 MG ONCE DAILY AT STEADY STATE WERE 42% AND 34% HIGHER, RESPECTIVELY, IN THE PRESENCE OF CIMETIDINE, A MIXED CYP P450 ENZYME INHIBITOR.
CYP2D6 SUBSTRATES: CAUTION SHOULD BE TAKEN WHEN ENABLEX IS USED CONCOMITANTLY WITH MEDICATIONS THAT ARE PREDOMINANTLY METABOLIZED BY CYP2D6 AND WHICH HAVE A NARROW THERAPEUTIC WINDOW, SUCH AS FLECAINIDE, THIORIDAZINE AND TRICYCLIC ANTIDEPRESSANTS.
THE MEAN CMAX AND AUC OF IMIPRAMINE, A CYP2D6 SUBSTRATE, WERE INCREASED 57% AND 70%, RESPECTIVELY, IN THE PRESENCE OF STEADY-STATE DARIFENACIN 30 MG ONCE DAILY.
CYP3A4 SUBSTRATES: DARIFENACIN (30 MG DAILY) COADMINISTERED WITH A SINGLE ORAL DOSE OF MIDAZOLAM 7.5 MG RESULTED IN A 17% INCREASE IN MIDAZOLAM EXPOSURE.