Drug Interaction Report

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 or moderate to potent inhibitors of P-glycoprotein (P-gp) or breast cancer resistant protein (BCRP) may increase the plasma concentrations of riociguat, which is partially metabolized by CYP450 3A and also a substrate of the P-gp and BCRP efflux transporters. Increased levels of riociguat may increase the risk for hypotension. When riociguat was administered with ketoconazole, a potent CYP450 3A4 inhibitor that also inhibits P-gp and BCRP, riociguat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 1.5- and 2.5-fold, respectively. The Cmax and AUC of the active metabolite, M1, which has 1/10th to 1/3rd the pharmacologic activity of riociguat, were reduced by approximately 50% and 25%, respectively. Administration with the potent CYP450 3A4 inhibitor clarithromycin increased the AUC of riociguat by about 30%. The Cmax and AUC of M1 were not significantly altered (i.e., <20% increase).

MANAGEMENT: Caution is advised when riociguat is prescribed with potent CYP450 3A4 inhibitors or moderate to potent P-gp or BCRP inhibitors. Patients should be monitored for signs and symptoms of hypotension, and the dosage of riociguat adjusted if necessary.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ceritinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ceritinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death. Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ceritinib. The mechanism of interaction is unknown. Compared to the fast state, administration of a single 500 mg dose of ceritinib with a high-fat meal (approximately 1000 calories; 58 grams of fat) increased ceritinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 41% and 73%, respectively, and administration with a low-fat meal (approximately 330 calories; 9 grams of fat) increased ceritinib Cmax and AUC by 43% and 58%, respectively. A dose of 600 mg or higher taken with a meal is expected to produce systemic exposure exceeding that from a 750 mg dose taken in the fasted state, which may lead to increased adverse effects.

MANAGEMENT: Patients treated with ceritinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ceritinib should be administered on an empty stomach (i.e., avoid administration within 2 hours of a meal).

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.