Cyclosporine
(Neoral^®, Sandimmune^®)

• Cyclosporine causes a 3- to 4- fold increase in bosentan steady state concentrations ( via CYP3A4).
• Bosentan decreases cyclosporine plasma concentration by ~50% (via CYP3A4).
• Concomintant administration is contraindicated

• Bosentan decreases glyburide plasma concentrations by ~40% (via CYP2C9 and CYP3A4).
• Bosentan concentrations also decrease by 30%
• Bosentan is expected to reduce plasma concentrations of other oral hypoglycemic agents predominantly metabolized by CYP2C9 or CYP3A4.
• Co-administration of glyburide & bosentan increases risk of elevated liver aminotransferases.
• Concomitant adminstration is contraindicated.

• Ketoconazole causes a 2-fold increase in bosentan plasma contraindications (via CYP3A4).
• No bosentan dose adjustment is necessary; but increased side effects should be considered.

• Bosentan decreases simvastatin plasma concentrations by ~50% (via CYP3A4)
• Bosentan is expected to decrease plasma concentrations of lovastatin, atorvastatin and other HMG-CoA reductase inhibitors metabolized via CYP3A4.
• Reduced HMG-CoA reductase inhibitor efficacy should be considered; lipid profile should be monitored; HMG-CoA reductase inhibitor dose should be adjusted accordingly.

• Bosentan is predicted to decrease levels of oral, injectable and implantable estrogen/progesterone contraceptives (via CYP3A4).
• Women should not rely on hormonal contraception alone when taking bosentan.

• Bosentan decreases plasma concentrations of S-warfarin (CYP2C9) and R-warfarin (CYP3A4) by 29 and 38%, respectively.
• Clinical experience showed no clinically relevant changes in INR.
• INR should be monitored closely.