Drug Interaction Report

MONITOR: Coadministration with bosentan may decrease the plasma concentrations of carbamazepine, phenytoin, and rifabutin. The mechanism is accelerated clearance due to induction of CYP450 3A4 and/or 2C9 by bosentan. In addition, coadministration with potent CYP450 3A4 and/or 2C9 inducers, such as carbamazepine, phenytoin, and rifabutin, 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.

MANAGEMENT: Until more information is available, the possibility of a diminished therapeutic response to bosentan should be considered when coadministered with potent CYP450 3A4 and/or 2C9 inducers, such as carbamazepine, phenytoin, and rifabutin. In contrast, drugs that are known substrates of CYP450 3A4 and/or 2C9, such as carbamazepine, phenytoin, and rifabutin, may have their plasma concentrations and effects reduced when coadministered with bosentan. Clinical and laboratory monitoring should be considered whenever bosentan and either carbamazepine, phenytoin, or rifabutin are added to or withdrawn from therapy with each other, and the dosages adjusted as necessary.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.