Drug Interactions between Omeclamox-Pak and riociguat

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 1/3 to 1/10 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.

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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.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

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