Drug Interaction Report

MONITOR: Coadministration with potent CYP450 3A4 and/or 2C9 inducers may decrease the plasma concentrations and therapeutic effects of bosentan. The proposed mechanism is increased clearance of bosentan by induction of CYP450 3A4 and/or 2C9, the isoenzymes responsible for the metabolic clearance of bosentan. In healthy subjects, concomitant use of rifampin initially led to a mean 6-fold increase in bosentan trough levels; however, after 7 days of concomitant use with bosentan 125 mg twice daily, rifampin decreased the plasma concentrations of bosentan by 58%. It was suggested that this decrease could achieve nearly 90% in an individual case.

MANAGEMENT: Until more information is available, the possibility of a diminished therapeutic response to bosentan should be considered when it is coadministered with a potent CYP450 3A4 and/or 2C9 inducer. Clinical and laboratory monitoring should be considered whenever a potent CYP450 3A4 and/or 2C9 inducer is added to or withdrawn from therapy, and the bosentan dosage adjusted as necessary.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.