Table 2.

Clinically Established and Other Potentially Significant Drug Interactions: Endothelin Receptor Antagonists

PAH Drug	Interacting Drug	Mechanism	Effect	Recommendation
Bosentan	Glyburide	Additive hepatotoxicity	Increased incidence of elevated aminotransferases	Contraindicated
	Hormonal contraceptives	CYP3A4 induction by bosentan, reducing plasma concentration of hormonal contraceptives	Unreliable contraception	Counsel patients to use additional method of contraception
	HMG CoA reductase inhibitors	CYP2C9 induction by bosentan, decreasing HMG CoA reductase inhibitor levels	Simvastatin levels reduce 50%	Monitor cholesterol levels
	Cyclosporine	CYP3A4 and OATP inhibition by cyclosporine, increasing bosentan concentrations CYP3A4 induction by bosentan, decreasing cyclosporine concentration	Bosentan levels increased fourfold	Contraindicated
	Amiodarone, fluconazole	CYP3A4 and CYP2C9 inhibition, increasing bosentan concentrations	Likely effect, not quantified in the literature	Not recommended
	Ketoconazole	CYP3A4 inhibition, increasing bosentan concentrations	Bosentan 125 mg twice daily administered with ketoconazole increased bosentan plasma concentration by 100%	No dose adjustment necessary; monitor for increased effects
	Ritonavir (including nirmatrelvir/ritonavir for COVID-19)	CYP3A4 inhibition, increasing bosentan concentrations	Fivefold increase in bosentan exposure	Discontinue bosentan at least 36 h before initiation of ritonavir; may resume bosentan at recommended initial dose once daily after at least 10 d after the initiation of ritonavir
	Phenytoin, rifampin	CYP3A4 and CYP2C9 induction, decreasing bosentan concentration	Rifampin decreased bosentan concentrations by more than 50%	Recommend that liver function tests be measured weekly for the first 4 w; normal liver function monitoring may be conducted subsequently
Ambrisentan	Cyclosporine	CYP3A4 and P-glycoprotein inhibition, increasing ambrisentan concentration	Twofold increase in ambrisentan exposure	Dose reduce ambrisentan to 5 mg once daily
Macitentan	Amiodarone, fluconazole	CYP3A4 and CYP2C9 inhibition, increasing macitentan concentration	Predicted to increase macitentan exposure fourfold	Macitentan increase not clinically relevant; use with caution and monitor for increased side effects
	Ketoconazole	CYP3A4 inhibition, increasing macitentan concentration	Macitentan exposure doubled	Not clinically relevant; dose adjustments not necessary
	Rifampin, carbamazepine	CYP3A4 induction, decreasing macitentan concentration	Macitentan exposure decreased by 80% when given with rifampin 600 mg daily	Avoid because of reduced efficacy; dosing recommendations not established

PAH = pulmonary arterial hypertension.