Potentially significant drug interactions with PAH targeted therapies
| PAH drug | Mechanism of interaction | Interacting drug | Interaction |
|---|---|---|---|
| Ambrisentan | ? | Cyclosporine ketoconazole | Caution is required in the coadministration 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 twofold | |
| 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 contraindicate | |
| 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 unnecessary | |
| CYP2C9 and CYP3A4 inducers | Hormonal contraceptives | Hormone levels decrease. Contraception unreliable | |
| Macitentan | To be determined | ||
| Selexipag | To be determined | ||
| Sildenafil85 | 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 | |
| Tadalafil86 | CYP3A4 substrate | Bosentan | Tadalafil exposure decreases by 42%, no significant changes in bosentan levels.44 May not require dose adjustment |
| cGMP | Nitrates Nicorandil | Profound systemic hypotension, combination contraindicated | |
| Riociguat47 | cGMP | Sildenafil | Hypotension, severe side effects, combination contraindicated |
| cGMP | Nitrates Nicorandil | Profound systemic hypotension |
Adapted from National Pulmonary Hypertension Centres of the UK and Ireland.87
Note that most of the listed RCT data were derived from studies in adults with PAH. Healthcare providers must obtain valid information on the approval of any of the listed medications for use in paediatric PAH in the according country.
cGMP, cyclic guanosine monophosphate; PAH, pulmonary arterial hypertension; RCT, randomised controlled trial.