Potentially significant drug interactions with pulmonary arterial hypertension(PAH)-targeted therapies
| PAH drug | Mechanism of interaction | Interacting drug | Interaction |
| Ambrisentan | ? | CyclosporineKetoconazole | 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 fourfold. 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 indicated. | |
| CYP2C9 and CYP3A4 substrate | Fluconazole, amiodarone | Bosentan levels considerably increase. Combination potentially 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 | Increases warfarin metabolism, may need to adjust warfarin dose. Intensified monitoring of warfarin recommended following initiation but dose adjustment usually necessary. | |
| CYP2C9 and CYP3A4 inducers | Hormonal contraceptives | Hormone levels decrease. Contraception unreliable. | |
| Sitaxentan | CYP2C9 inhibitor | Warfarin | Inhibits warfarin metabolism, warfarin dose needs to be reduced by 80% when initiating sitaxentan and INR monitoring intensified. |
| ? inhibition of OATP transporter | Cyclosporine | Increases sitaxen levels; combination contraindicated. | |
| Sildenafil | CYP3A4 substrate | Bosentan | Sildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustment 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. Sildenafil dose adjustments are usually required. | |
| 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 | NitratesNicorandil | Profound systemic hypotension, combination contraindicated. | |
| Tadalafil | CYP3A4 substrate | Bosentan | Tadafil plasma levels decrease by 42%, no significant changes in bosentan levels. May not require dose adjustment. |
| cGMP | NitratesNicorandil | Profound systemic hypotension, combination contraindicated. |
HMG CoA: 3-hydroxy-3-methylglutary coenzyme A; OATP: organic anion transporter proteins; cGMP: cyclic guanosine monophosphate. The table is adapted from National Pulmonary Hypertension Centres of the UK and Ireland, “Consensus Statement on the Management of Pulmonary Hypertension in Clinical Practice in the UK and Ireland” 180, wih permmission from the publisher.