Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 1A1 may theoretically increase the plasma concentrations of riociguat, which is partially metabolized by the isoenzyme to its main active metabolite (1/10th to 1/3rd the pharmacologic activity of riociguat). Increased levels of riociguat may increase the risk for hypotension.

MANAGEMENT: Caution is advised if riociguat is prescribed in combination with an inhibitor of CYP450 1A1. Blood pressure should be monitored, and a dose reduction of riociguat should be considered if necessary.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailabilities of both elvitegravir and tenofovir. When a single dose of cobicistat/elvitegravir/emtricitabine/tenofovir (trade name Stribild) was given with a light meal (approximately 373 kcal; 20% fat), mean elvitegravir and tenofovir systemic exposures (AUCs) increased by 34% and 24%, respectively, relative to fasting conditions. When administered with a high-fat meal (approximately 800 kcal; 50% fat), the mean AUC of elvitegravir and tenofovir increased by 87% and 23%, respectively, relative to fasting conditions. The alterations in mean AUCs of cobicistat and emtricitabine were not clinically significant with either the light or high-fat meal.

MANAGEMENT: Cobicistat/elvitegravir/emtricitabine/tenofovir as a fixed-dose preparation should be administered once daily with food. Elvitegravir as a single-ingredient preparation should also be administered once daily with food.

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.