Drug Interactions between amoxicillin / clarithromycin / vonoprazan and rifabutin

GENERALLY AVOID: The coadministration of clarithromycin and rifabutin at normally recommended dosages has been reported to have resulted in significantly altered pharmacokinetics for both drugs. In a study of 34 clinically stable subjects with advanced HIV infection (CD4 less than 200 cells/mm3), the addition of rifabutin in patients stabilized on clarithromycin therapy slowly decreased the clarithromycin area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) up to an average of 44% and 41%, respectively, at the end of 4 weeks of combination therapy. In patients stabilized on rifabutin therapy, the addition of clarithromycin significantly increased rifabutin AUC and Cmax after the first dose. After 4 weeks, average increases of 99% and 69%, respectively, were reported. This bidirectional interaction is consistent with rifabutin's cumulative inducing effect over time on the CYP450 enzymatic pathway as well as clarithromycin's immediate inhibiting effect on the pathway. In the study, the combination was tolerated by more than 90% of the patients. However, 66% of them experienced gastrointestinal problems including nausea, vomiting and diarrhea. An increased incidence of uveitis has also been reported with this combination. In addition, the combination of clarithromycin and rifampin 600 mg/day (with multiple other drugs) decreased clarithromycin serum levels by approximately 90%. Other macrolide antibiotics may interact in a similar manner with rifamycins.

MANAGEMENT: Some authorities recommend that this combination be avoided since it may result in decreased efficacy of the macrolide and increased rifamycin toxicity (e.g., neutropenia, uveitis). If coadministration cannot be avoided, patients should be monitored for rifamycin toxicity such as leukopenia, uveitis, arthralgias and skin discoloration. Some authorities recommend discontinuing erythromycin during and two weeks after treatment with CYP 450 3A4 inducers. Further dosage adjustments may be necessary.

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vonoprazan, which is metabolized by the isoenzyme. When coadministered with potent CYP450 3A4 inducers, vonoprazan systemic exposure (AUC) is predicted to decrease by 80%. Reduced efficacy of vonoprazan may occur.

MANAGEMENT: According to the manufacturer, concomitant use of vonoprazan with potent CYP450 3A4 inducers should be avoided.

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.