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 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.

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.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

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.

The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.

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.