Drug Interactions between riociguat and vericiguat

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.

ADJUST DOSING INTERVAL: Administration of vericiguat with food reduces its pharmacokinetic variability and increases its exposure. Vericiguat is less soluble at neutral pH than at acidic pH. Administration of vericiguat with a high-fat, high-calorie meal or low-fat, high-carbohydrate meal increased time to reach peak plasma concentration (Tmax) from about 1 hour (fasted) to about 4 hours (fed) and increased vericiguat systemic exposure (AUC) by 19% and peak plasma concentration (Cmax) by 9% for the 5 mg tablet and by 44% (AUC) and 41% (Cmax) for the 10 mg tablet as compared with the fasted state. Concurrent treatment with drugs that increase gastric pH, such as proton pump inhibitors or antacids, decrease vericiguat AUC by about 30%. Co-treatment with drugs that increase gastric pH did not affect vericiguat exposure in patients with heart failure when vericiguat was taken as directed with food.

MANAGEMENT: Administer vericiguat with food to ensure maximal exposure and decrease pharmacokinetic variability.