Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4. Consequently, plasma concentrations of substances metabolized by these isoenzymes will be decreased when Bosentan is co-administered. The possibility of altered efficacy of medicinal products metabolized by these isoenzymes should be considered. The dosage of these products may need to be adjusted after initiation, dose change or discontinuation of concomitant Bosentan treatment.
Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of Bosentan (see Ketoconazole). The influence of CYP2C9 inhibitors on Bosentan concentration has not been studied. The combination should be used with caution.
Fluconazole and other inhibitors of both CYP2C9 and CYP3A4: Co-administration with Fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of Bosentan. The combination is not recommended. For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as Ketoconazole, Itraconazole or Ritonavir) and a CYP2C9 inhibitor (such as Voriconazole) with Bosentan is not recommended.
Cyclosporine A: Co-administration of Bosentan and cyclosporine A (a calcineurin inhibitor) is contraindicated (see Contraindication). When co-administered, initial trough concentrations of Bosentan were approximately 30-fold higher than those measured after Bosentan alone. At steady state, Bosentan plasma concentrations were 3- to 4-fold higher than with Bosentan alone. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of Bosentan into hepatocytes by cyclosporine. The blood concentrations of Cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by Bosentan.
Tacrolimus, Sirolimus: Co-administration of Tacrolimus or Sirolimus and Bosentan has not been studied in man but co-administration of Tacrolimus or Sirolimus and Bosentan may result in increased plasma concentrations of Bosentan in analogy to co-administration with cyclosporine A. Concomitant Bosentan may reduce the plasma concentrations of Tacrolimus and Sirolimus. Therefore, concomitant use of Bosentan and Tacrolimus or Sirolimus is not advisable. Patients in need of the combination should be closely monitored for adverse events related to Bosentan and for Tacrolimus and Sirolimus blood concentrations.
Glibenclamide: Co-administration of Bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of Glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of the hypoglycemic effect. The plasma concentrations of Bosentan were also decreased by 29%. In addition, an increased incidence of elevated aminotransferase may be observed in patients receiving concomitant therapy. Both Glibenclamide and Bosentan inhibit the bile salt export pump, which could explain the elevated aminotransferases. This combination should not be used. No drug-drug interaction data are available with the other sulfonylureas.
Rifampicin: Co-administration of Bosentan 125 mg twice daily with Rifampicin, a potent inducer of CYP2C9 and CYP3A4 for 7 days, will decrease the plasma concentrations of Bosentan by 58%, and this decrease could achieve almost 90% in an individual case. As a result, a significantly reduced effect of Bosentan is expected when it is co-administered with Rifampicin. Concomitant use of Rifampicin and Bosentan is not recommended. Data on other CYP3A4 inducers, e.g. Carbamazepine, Phenobarbital, Phenytoin and St. John's Wort are lacking, but their concomitant administration is expected to lead to reduced systemic exposure to Bosentan. A clinically significant reduction of efficacy cannot be excluded.
Lopinavir + Ritonavir (and other Ritonavir-boosted protease inhibitors): Co-administration of Bosentan 125 mg twice daily and Lopinavir + Ritonavir 400 + 100 mg twice daily for 9.5 days will result in initial trough plasma concentrations of Bosentan that were approximately 48-fold higher than those measured after Bosentan administered alone. On day 9, plasma concentrations of Bosentan were approximately 5-fold higher than with Bosentan administered alone. Inhibition by Ritonavir of transport protein-mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of Bosentan, most likely causes this interaction. When administered concomitantly with Lopinavir + Ritonavir, or other Ritonavir-boosted protease inhibitors, the patient's tolerability of Bosentan should be monitored.
After co-administration of Bosentan for 9.5 days, the plasma exposures to Lopinavir and Ritonavir may be decreased to a clinically non-significant extent (by approximately 14% and 17%, respectively). However, full induction by Bosentan might not have been reached and a further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similar effects would be expected with other Ritonavir-boosted protease inhibitors (see Precautions).
Other antiretroviral agents: No specific recommendation can be made with regard to other available antiretroviral agents due to the lack of data. Due to the marked hepatotoxicity of Nevirapine, which could add to Bosentan liver toxicity, this combination is not recommended.
Hormonal contraceptives: Co-administration of Bosentan 125 mg twice daily for 7 days with a single dose of oral contraceptive containing Norethisterone 1 mg + Ethinyl estradiol 35 mcg decreased the AUC of Norethisterone and Ethinyl estradiol by 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormone-based contraceptives alone, regardless of the route of administration (i.e. oral, injectable, transdermal or implantable forms), are not considered as reliable methods of contraception (see Precautions and Use in Pregnancy & lactation).
Warfarin: Co-administration of Bosentan 500 mg twice daily for 6 days may decrease the plasma concentrations of both S-Warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29% and 38%, respectively. Concomitant administration of Bosentan with Warfarin in patients with PAH may not result in clinically relevant changes in International Normalized Ratio (INR) or Warfarin dose. No dose adjustment is needed for Warfarin and similar oral anticoagulant agents when Bosentan is initiated, but intensified monitoring of INR is recommended, especially during Bosentan initiation and the up-titration period.
Simvastatin: Co-administration of Bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of Simvastatin (a CYP3A4 substrate) and its active β-hydroxy acid metabolite by 34% and 46%, respectively. The plasma concentrations of Bosentan were not affected by concomitant Simvastatin. Monitoring of cholesterol levels and subsequent dosage adjustment should be considered.
Ketoconazole: Co-administration for 6 days of Bosentan 62.5 mg twice daily with Ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of Bosentan approximately 2-fold. No dose adjustment of Bosentan is considered necessary. Although not demonstrated through in vivo studies, similar increases in Bosentan plasma concentrations are expected with the other potent CYP3A4 inhibitors (such as Itraconazole or Ritonavir). However, when combined with a CYP3A4 inhibitor, patients who are poor metabolizers of CYP2C9 are at risk of increases in Bosentan plasma concentrations that may be of higher magnitude, thus leading to potential harmful adverse events.
Epoprostenol: Combination of Bosentan and Epoprostenol may indicate that after both single- and multiple-dose administration, the Cmax and AUC values of Bosentan is similar in patients with or without continuous infusion of Epoprostenol (see Pharmacology under Actions).
Sildenafil: Co-administration of Bosentan 125 mg twice daily (steady state) with Sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days may result in a 63% decrease in the Sildenafil AUC and a 50% increase in the Bosentan AUC. Caution is recommended in the case of co-administration.
Tadalafil: Bosentan (125 mg twice daily) reduced Tadanafil (40 mg once per day) systemic exposure by 42% and Cmax by 27% following multiple dose co-administrations. Tadalafil did not affect the exposure (AUC and Cmax) of Bosentan or its metabolites.
Digoxin: Co-administration for 7 days of Bosentan 500 mg twice daily with Digoxin decreased the AUC, Cmax and Cmin of Digoxin by 12%, 9% and 23%, respectively. The mechanism for this interaction may be induction of P-glycoprotein. This interaction is unlikely to be of clinical relevance.
Pediatric population: Interaction studies have only been performed in adults.