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Clinical and laboratory monitoring should be considered whenever a potent CYP450 3A4 and/or 2C9 inducer is added to or withdrawn from therapy, and the bosentan dosage adjusted as necessary.

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.