Drug Interactions between ombitasvir / paritaprevir / ritonavir and Omeclamox-Pak

ADJUST DOSE: Coadministration with ritonavir may increase the plasma concentrations of clarithromycin. The mechanism is ritonavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic conversion of clarithromycin to 14-hydroxyclarithromycin. In 22 healthy volunteers, administration of clarithromycin (500 mg every 12 hours) with ritonavir (200 mg every 8 hours) for 4 days increased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of clarithromycin by 31%, 77% and 180%, respectively, compared to administration without ritonavir. The formation of 14-hydroxyclarithromycin was nearly completely inhibited, as indicated by a 100% decrease in Cmax, AUC, and Cmin in the presence of ritonavir. In contrast, clarithromycin had only minor effects on the pharmacokinetics of ritonavir.

MANAGEMENT: When coadministered with ritonavir, the clarithromycin dose should not exceed 1 g/day. In addition, the clarithromycin dosage should be reduced by 50% in patients with moderate renal impairment (CrCl 30 to 60 mL/min) and 75% in patients with more severe renal impairment (CrCl below 30 mL/min).

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MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of paritaprevir, which is primarily metabolized by the isoenzyme. In 12 study subjects, ketoconazole 400 mg given once daily increased single-dose paritaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 37% and 98%, respectively. The risk of hyperbilirubinemia may be increased, as paritaprevir can cause elevations in indirect (unconjugated) bilirubin via inhibition of OATP1B1/1B3.

MANAGEMENT: Caution is advised if paritaprevir is prescribed in combination with potent CYP450 3A4 inhibitors. Patients should be monitored for signs and symptoms of hepatotoxicity (i.e., ALT and bilirubin elevations).

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MONITOR: Coadministration with ombitasvir/paritaprevir/ritonavir plus dasabuvir may decrease the plasma concentrations of omeprazole. The proposed mechanism of interaction is CYP450 2C19 induction by ritonavir. In 11 study subjects, administration of omeprazole 40 mg once daily in combination with once daily doses of ombitasvir/paritaprevir/ritonavir (25 mg/150 mg/100 mg) plus twice daily doses of dasabuvir resulted in approximately 38% decreases in both mean omeprazole peak plasma concentration (Cmax) and systemic exposure (AUC). The pharmacokinetics of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not significantly altered. This interaction may also be expected with the other proton pump inhibitors, which are also CYP450 2C19 substrates; however, data are lacking.

MANAGEMENT: Patients should be monitored for potentially diminished efficacy of omeprazole during coadministration with ombitasvir/paritaprevir/ritonavir plus dasabuvir. The dosage of omeprazole may be increased in patients whose symptoms are not well controlled; however, some authorities suggest that the dosage of omeprazole should be limited to 40 mg/day.

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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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