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.

MONITOR: Coadministration of riociguat with proton pump inhibitors may reduce its gastrointestinal absorption. Riociguat exhibits pH-dependent solubility, with increased solubility at lower pH. According to the product labeling, administration of riociguat with omeprazole resulted in decreases of riociguat peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 30% and 25%, respectively. The Cmax and AUC of the active metabolite, M1, which has 1/3 to 1/10 the pharmacologic activity of riociguat, were not significantly affected.

MANAGEMENT: No dosage adjustment for riociguat is recommended when coadministered with proton pump inhibitors. However, patients should be monitored for potentially diminished therapeutic effects of riociguat.

Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.

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.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.