Table 3.

Clinically Established and Other Potentially Significant Drug Interactions: NO Pathway

PAH Drug	Interacting Drug	Mechanism	Effect	Recommendation
Sildenafil	Nitrates	Additive potent vasodilation	Profound systemic hypotension	Contraindicated; if necessary, at least 24 h of separation between the last dose of sildenafil and nitrate administration is recommended
	Bosentan	CYP3A4 induction, decreases sildenafil levels; sildenafil is a substrate of CYP3A4, competing with metabolism of bosentan (also CYP3A4 substrate), resulting in increased bosentan levels	50% reduction in the serum concentration of sildenafil and 50% increase in bosentan concentration	No dose adjustments necessary; however, no benefit on exercise capacity demonstrated when used concomitantly
	Ritonavir (including Paxlovid for COVID-19)	CYP3A4 inhibition, increases sildenafil levels	Sildenafil exposure increased up to 1,000%	Contraindicated
	Cobicistat, ketoconazole	Potent CYP3A4 inhibition, increases sildenafil levels	Expect similar effects to ritonavir	Not recommended
	St. John’s wort	CYP3A4 induction, reduces sildenafil levels	Threefold increase in sildenafil clearance	Efficacy may be reduced; may consider dose increase of sildenafil under close monitoring
	Phenytoin, rifampin,	CYP3A4 induction, reduces sildenafil levels	Expect significant decreases in sildenafil levels	Not recommended; may result in near-complete clearance of sildenafil
Tadalafil	Nitrates	Additive potent vasodilation	Profound systemic hypotension	Contraindicated; if necessary, at least 48 h of separation between the last dose of sildenafil and nitrate administration is recommended
	Ketoconazole	CYP3A4 inhibition, increases tadalafil levels	Ketoconazole 400 mg daily with a single 20-mg tadalafil dose increased the tadalafil exposure by 312%; ketoconazole 200 mg daily increased tadalafil exposure by 107%	Avoid use
	Ritonavir (including Paxlovid for COVID-19)	CYP3A4 inhibition, increases tadalafil levels	Inhibits tadalafil in a time dependent manner	Avoid use of tadalafil during initiation of ritonavir; consider stopping at least 24 h before ritonavir initiation; resume tadalafil at 20 mg once daily after 1 w of ritonavir initiation
	Rifampin	CYP3A4 induction, reduces tadalafil	Tadalafil exposure reduced by 88%	Not recommended in patients taking long-term rifampin
Riociguat	Nitrates	Additive potent vasodilation	Hypotension leading to syncope	Contraindicated; data not available to decide dosing
	Antacids	Increases pH of stomach contents	Reduces solubility of riociguat up to 34%	Do not use antacids within 1 h of riociguat
	Ketoconazole	CYP3A4 and P-glycoprotein inhibition, increases riociguat levels	Riociguat exposure increased by 150%	Consider riociguat initiation dose of 0.5 mg 3 times daily
	Ritonavir (including Paxlovid for COVID-19)	CYP3A4 inhibition, increases riociguat levels	Expect similar effect to ketoconazole	Avoid interaction. Select alternative COVID-19 anti-viral.
	Tobacco smoke	CYP1A1 inducer, reduces riociguat levels	Plasma concentrations of riociguat in tobacco users are reduced by 50%-60% compared with non-tobacco users	Doses higher than 2.5 mg three times daily may be considered

NO = nitric oxide; PAH = pulmonary arterial hypertension.