Table 1.

Potentially significant drug interactions with drugs approved for PAH

PAH drug	Mechanism of interaction	Interacting drug	Interaction
Ambrisentan	?	Cyclosporine, Ketoconazole	Caution is required in the co-administration of ambrisentan with ketoconazole and cyclosporine.
Bosentan	CYP3A4 inducer	Sildenafil	Sildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustments of either drug.
	CYP3A4 substrate	Cyclosporine	Cyclosporine levels fall 50%; bosentan levels increase 4-fold. Combination contraindicated.
	CYP3A4 substrate	Erythromycin	Bosentan levels increase. May not require dose adjustment of bosentan during a short course.
	CYP3A4 substrate	Ketoconazole	Bosentan levels increase two-fold.
	CYP3A4 substrate + bile salt pump inhibitor	Glibenclamide	Increase incidence of elevated aminotransferases. Potential decrease of hypoglycaemic effect of glibenclamide. Combination contraindicated.
	CYP2C9 and CYP3A4 substrate	Fluconazole, amiodarone	Bosentan levels increase considerably. Combination contraindicated.
	CYP2C9 and CYP3A4 inducers	Rifampicin, phenytoin	Bosentan levels decrease by 58%. Need for dose adjustment uncertain.
	CYP2C9 inducer	HMG CoA reductase inhibitors	Simvastatin levels reduce 50%; similar effects likely with atorvastatin. Cholesterol level should be monitored.
	CYP2C9 inducer	Warfarin	Increase warfarin metabolism, may need to adjust warfarin dose. Intensified monitoring of warfarin recommended following initiation but dose adjustment usually unnecessary.
	CYP2C9 and CYP3A4 inducers	Hormonal contraceptives	Hormone levels decrease. Contraception unreliable.
Macitentan			To be determined.
Selexipag			To be determined.
Sildenafil67	CYP3A4 substrate	Bosentan	Sildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustments of either drug.
	CYP3A4 substrate	HMG CoA reductase inhibitors	May increase simvastatin/atorvastatin levels through competition for metabolism. Sildenafil levels may increase. Possible increased risk of rhabdomyolysis.
	CYP3A4 substrate	HIV protease inhibitors	Ritonavir and saquinovir increase sildenafil levels markedly.
	CYP3A4 inducer	Phenytoin	Sildenafil level may fall.
	CYP3A4 substrate	Erythromycin	Sildenafil levels increase. May not require dose adjustment for a short course.
	CYP3A4 substrate	Ketoconazole	Sildenafil levels increase. May not require dose adjustment.
	CYP3A4 substrate	Cimetidine	Sildenafil levels increase. May not require dose adjustment.
	cGMP	Nitrates, Nicorandil Molsidomine	Profound systemic hypotension, combination contraindicated.
Tadalafil68	CYP3A4 substrate	Bosentan	Tadalafil exposure decreases by 42%, no significant changes in bosentan levels.68 May not require dose adjustment.
	cGMP	Nitrates, Nicorandil	Profound systemic hypotension, combination contraindicated.
Riociguat69	cGMP	Sildenafil, other PDE-5 inhibitors	Hypotension, severe side effects, combination contraindicated.
	cGMP	Nitrates, Nicorandil	Profound systemic hypotension, combination contraindicated.

cGMP, cyclic guanosine monophosphate; PDE-5, phosphodiesterase type-5; ?, unknown.

See also updated official prescribing information for each compound.

Reproduced from Galiè et al.⁸ with permission from Oxford University Press.