Drug Interaction Report

MONITOR: Coadministration of riociguat with anticoagulant, antiplatelet, or other antithrombotic therapy may increase the risk of bleeding. Patients with pulmonary hypertension have an underlying risk for respiratory tract bleeding, which can be further exacerbated by riociguat and use of antithrombotic agents, particularly in the presence of additional risk factors such as recent episodes of serious hemoptysis (including those managed by bronchial arterial embolization) or concomitant prostacyclin use (e.g., epoprostenol, iloprost, and treprostinil) due to their inhibitory effect on platelet aggregation. In clinical trials, serious bleeding occurred in 2.4% and hemoptysis in 1% of patients taking riociguat compared to 0% of placebo patients. The proposed mechanism for the bleeding risk associated with riociguat is unknown. However, an in vitro study indicates that riociguat may inhibit von Willebrand factor elongation and platelet adhesion on the surface of pulmonary artery endothelial cells.

MANAGEMENT: Bleeding risk should be carefully evaluated before initiating riociguat in patients on antithrombotic therapy. Close clinical and laboratory monitoring for bleeding complications is recommended if concomitant use is required. Some authorities recommend avoiding riociguat in patients with a history of serious hemoptysis or who have previously undergone bronchial arterial embolization.

ADJUST DOSE: Smoking may decrease the plasma concentrations of riociguat. The proposed mechanism is induction of the CYP450 1A1-mediated metabolism of riociguat by polycyclic aromatic hydrocarbons present in cigarette smoke. CYP450 1A1 is responsible for the formation of the major active metabolite, M1, which has just 1/3 to 1/10 the pharmacologic activity of riociguat. According to the product labeling, plasma concentrations of riociguat are reduced by 50% to 60% in smokers compared to nonsmokers.

MANAGEMENT: Patients should be advised to stop smoking. Riociguat dosages higher than 2.5 mg three times a day may be considered in cigarette smokers, if tolerated, to match the exposure seen in nonsmoking patients. However, safety and effectiveness of higher dosages have not been established. A dosage reduction should be considered in patients who stop smoking during treatment with riociguat. The tablet form of riociguat can generally be taken with or without food. Some authorities recommend not to switch between fed and fasted riociguat intake because of increased peak plasma levels of riociguat in the fasting compared to the fed state.