Drug Interactions between bosentan and sildenafil

ADJUST DOSE: Coadministration of bosentan and sildenafil may result in increased bosentan plasma concentrations and decreased sildenafil plasma concentrations, without providing any clinically significant benefits in some patients with pulmonary arterial hypertension (PAH). The mechanisms are sildenafil-mediated inhibition of bosentan's metabolism via CYP450 3A4 and 2C9, and bosentan-mediated induction of sildenafil's metabolism via these same isoenzymes. Coadministration of oral sildenafil (80 mg three times daily) at steady state with bosentan (125 mg twice daily) at steady state over 6 days in healthy adult volunteers decreased the systemic exposure (AUC) and peak plasma concentration (Cmax) of sildenafil by 62.6% and 55.4%, respectively. The combination also led to an increase in bosentan's AUC and Cmax of approximately 50% and 42%, respectively. Despite these changes in concentration, clinically significant changes in blood pressure (supine and standing) were not documented. Similar effects on AUC and Cmax have also been observed at lower doses of oral sildenafil (20 mg three times daily) and bosentan (62.5 mg to 125 mg twice daily). However, in a population pharmacokinetic analysis of data from adult PAH patients on background bosentan therapy (62.5 mg to 125 mg twice daily), coadministration of oral sildenafil (20 mg three times a day, steady state levels) was reported to increase the AUC of bosentan by only 20%. This was less than that observed in healthy individuals on higher doses of oral sildenafil (80 mg three times daily). In a clinical study in adult patients (n=103) with PAH on stable bosentan (62.5 mg to 125 mg twice daily), no benefits were observed with the addition of oral sildenafil (20 mg three times daily) compared to bosentan alone. In fact, patients with PAH associated with connective tissue disease (CTD) on the combination were observed to have a reduction from baseline in the distance they could walk in 6 minutes when compared to placebo (-18.32 m versus 17.5 m, respectively). Clinical data are not available for pediatric patients nor for those using sildenafil for erectile dysfunction.

MANAGEMENT: In adult patients being treated for PAH, the dose of sildenafil may need to be increased when initiating bosentan according to the manufacturer for sildenafil. Conversely, if a moderate CYP450 3A4 inducer like bosentan is discontinued, the dose of sildenafil should be reduced to 20 mg orally three times daily. The labeling for some bosentan products does not consider the changes in bosentan's or sildenafil's AUC to be clinically significant and does not recommend adjusting the dose of sildenafil when it is combined with bosentan. Some authorities suggest avoiding this combination in patients with PAH associated with CTD. Patients using sildenafil for erectile dysfunction should be monitored closely and may require a dose adjustment of sildenafil if bosentan is initiated or discontinued during treatment. Dosing should be guided by the patient's symptoms, ability to tolerate each medication, and recommendations provided in the product labeling. The possibility of reduced therapeutic efficacy of sildenafil and prolonged and/or increased pharmacologic effects of bosentan, including serious adverse effects such as hepatotoxicity, should be considered. All patients should be advised to seek medical attention if they experience signs and symptoms of hepatotoxicity, such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and/or jaundice.