Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C8 may increase the plasma concentrations of treprostinil, which is primarily metabolized by the isoenzyme. Coadministration of the potent CYP450 2C8 inhibitor gemfibrozil (600 mg twice daily) with oral treprostinil (treprostinil diolamine) in healthy adults resulted in a doubling of both the systemic exposure (AUC) and peak plasma concentration (Cmax) of treprostinil. However, it has not been determined if the safety and efficacy of treprostinil administered parenterally (e.g., subcutaneously, intravenously, via inhalation) are altered by this interaction.

MANAGEMENT: Pharmacologic response to treprostinil should be monitored more closely whenever a CYP450 2C8 inhibitor is added to or withdrawn from therapy, and the treprostinil dosage adjusted as necessary. Patients starting on oral treprostinil who are already on a CYP450 2C8 inhibitor should use a lower starting dose of 0.125 mg twice daily and titrate in 0.125 mg twice daily increments, not more frequently than every 3 to 4 days. If a CYP450 2C8 inhibitor is started during therapy with treprostinil, patients should be advised to notify their physician if they experience excessive adverse effects of treprostinil such as headache, dizziness, lightheadedness, flushing, diarrhea, edema, and unusual bleeding or bruising. Abrupt cessation of a CYP450 2C8 inhibitor should be avoided where possible due to the potential of worsening pulmonary arterial hypertension symptoms.