Drug Interaction Report

GENERALLY AVOID: Theoretically, proton pump inhibitors may decrease the gastrointestinal absorption of enteric-coated naproxen, which requires an acidic environment for dissolution. The proposed mechanism is an increase in gastric pH (i.e. decreased gastric acidity) induced by proton pump inhibitors. In patients treated with proton pump inhibitors, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered.

MANAGEMENT: Concomitant use of these drugs is generally not recommended.

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.

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.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.