Drug Interaction Report

MONITOR: Riociguat may potentiate the action of antihypertensive agents and other vasodilators including systemic phosphodiesterase (PDE) type 3 and 4 inhibitors. Symptomatic hypotension may occur. Riociguat stimulates soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system that binds with nitric oxide (NO) to catalyze the synthesis of cyclic guanosine monophosphate (cGMP). The resultant accumulation of cGMP in vascular smooth muscle cells leads to peripheral vasodilation and blood pressure decreases.

MANAGEMENT: Caution is advised if riociguat is prescribed in combination with antihypertensive agents or other vasodilators. A reduction in the starting dosage of riociguat to 0.5 mg three times a day should be considered for patients who may not tolerate the hypotensive effect of riociguat. Periodic systemic blood pressure monitoring is recommended. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, the dosage may be increased by 0.5 mg three times a day every 2 weeks as tolerated, up to a maximum of 2.5 mg three times a day. If hypotension develops at any time during treatment, the dosage should be reduced by 0.5 mg three times a day.

ADJUST DOSING INTERVAL: The bioavailability of metoprolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take metoprolol at the same time each day, preferably with or immediately following meals.

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: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.