Effects of Other Drugs on Darifenacin
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. Darifenacin exposure following 30 mg once daily at steady state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg.
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) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). In a drug interaction study, when a 7.5 mg once-daily dose of ENABLEX was given to steady state and coadministered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n=10) and 55.4 ng/mL for one PM subject (n=1). Mean AUC increased to 143 and 939 ng.h/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of ENABLEX was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n=3) and one PM subject (n=1), respectively. Mean AUC increased to 1110 and 931 ng.h/mL for EMs and for one PM subject, respectively.
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.
Effects of Darifenacin on Other Drugs
In Vitro Studies: Based on in vitro human microsomal studies, ENABLEX is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations.
In Vivo Studies: The potential for clinical doses of ENABLEX to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies.
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 (see PRECAUTIONS, Drug Interactions).
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. This was accompanied by a 3.6-fold increase in the mean Cmax and AUC of desipramine, the active metabolite of imipramine.
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.
Darifenacin (10 mg t.i.d.) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinylestradiol.
Other Drugs: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was coadministered with darifenacin (30 mg daily) at steady state. Standard therapeutic prothrombin time monitoring for warfarin should be continued.
Routine therapeutic drug monitoring for digoxin should be continued. Darifenacin (30 mg daily) coadministered with digoxin (0.25 mg) at steady state resulted in a 16% increase in digoxin exposure.
The effect of six-day treatment of 15-mg and 75-mg ENABLEX on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65. Subjects included 18% PMs and 82% EMs. The QT interval was measured over a 24-hour period both predosing and at steady state. The 75-mg ENABLEX dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor. At the doses studied, ENABLEX did not result in QT/QTc interval prolongation at any time during the steady state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15-mg and 75-mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the Phase II/III clinical studies, the change in median HR following treatment with ENABLEX was no different from placebo.