Drug Interaction Report

MONITOR: Coadministration with rifampin, a potent CYP450 3A4 and 2C9 inducer, may decrease the plasma concentrations and therapeutic effects of bosentan. The proposed mechanism is increased clearance due to rifampin-mediated induction of CYP450 3A4 and 2C9, the isoenzymes responsible for the metabolic clearance of bosentan. Following the first concomitant dose in healthy subjects, rifampin caused a mean 6-fold increase in bosentan trough levels. However, after 7 days of concomitant treatment with bosentan 125 mg twice daily, rifampin decreased the plasma concentrations of bosentan by 58%. It has been suggested that this decrease could achieve nearly 90% in an individual case.

MANAGEMENT: The possibility of a diminished therapeutic response to bosentan should be considered when coadministered with rifampin. Dosage adjustments as well as clinical and laboratory monitoring of bosentan should be considered whenever rifampin is added to or withdrawn from therapy. In addition, some authorities recommend monitoring liver function weekly for the first 4 weeks of concomitant use before reverting to normal monitoring.

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.