Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of riociguat, which is partially metabolized by the isoenzyme. According to the product labeling, administration of riociguat with the moderate CYP450 3A4 inducer bosentan resulted in an approximately 30% decrease in riociguat systemic exposure (AUC). The magnitude of interaction is expected to be greater with more potent inducers.

MANAGEMENT: The potential for diminished therapeutic effects of riociguat should be considered when prescribed in combination with CYP450 3A4 inducers. No dose adjustment is necessary for concomitant use with moderate CYP450 3A4 inducers. Data are not available to guide dosing of riociguat when coadministered with potent CYP450 3A4 inducers such as carbamazepine, enzalutamide, phenobarbital, phenytoin, rifamycins, and St. John's wort. Patients should be closely monitored and alternative agents with no or minimal CYP450 3A4-inducing activity should be considered whenever possible.

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.

The recommended maximum number of medicines in the 'agents for pulmonary hypertension' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'agents for pulmonary hypertension' category:

• riociguat
• Tracleer (bosentan)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.