Drug Interactions between conivaptan and macitentan / tadalafil

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of macitentan, which is primarily metabolized by the isoenzyme. In ten healthy subjects, administration of a single 10 mg oral dose of macitentan on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure (AUC) compared to administration alone. Additionally, there was a 26% reduction in the AUC of the active metabolite, which has been reported to be approximately 5-fold less potent than macitentan in vitro, but whose systemic exposure in human is 2.5-fold higher than that of macitentan. The clinical significance of these changes has not been established. Macitentan was well tolerated with or without ketoconazole in the study, and there were no relevant differences in safety parameters between the treatments.

MANAGEMENT: According to the product labeling, concomitant use of macitentan with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. Alternative treatment options for pulmonary arterial hypertension are recommended when potent CYP450 3A4 inhibitors are needed as part of HIV treatment.

GENERALLY AVOID: Coadministration with conivaptan may significantly increase the plasma concentrations of phosphodiesterase-5 (PDE5) inhibitors. The mechanism is conivaptan inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these agents. Although the interaction has not been specifically studied, high plasma levels of PDE5 inhibitors (e.g., due to high doses or interaction with other potent 3A4 inhibitors such as protease inhibitors) have been associated with increased PDE5 adverse effects such as headache, flushing, dyspepsia, rhinitis, visual disturbances, hypotension, and even death. In pharmacokinetic studies with other drugs that are primarily metabolized by CYP450 3A4 such as midazolam, simvastatin, and amlodipine, conivaptan has increased systemic exposure (AUC) by 2- to 3-fold.

MANAGEMENT: Use of PDE5 inhibitors should preferably be avoided in patients treated with conivaptan. Patients currently using PDE5 inhibitors should consider an interruption during administration of conivaptan, and allow an appropriate amount of time following completion of conivaptan therapy before resuming these medications.