Table 4 Prohibited treatments or those requiring close monitoring

Prohibited treatments

Risks

Cyclosporine A

Major risk of increasing residual plasma levels of bosentan following transport protein inhibition of bosentan in hepatocytes

Major risk of decreasing plasma concentrations of cyclosporine with reduction in its efficacy and therefore its immunosuppressive activity

Glibenclamide

Major risk of increasing risk of elevation of liver enzymes

General corticosteroid therapy

Risk of interfering with potential efficacy of bosentan

Amiodarone

Drug giving NAAION-like picture

CYP 3A4- and 2 C9 2C19-inhibitor drugs

Risk of increasing plasma bosentan concentrations

CYP 3A4-, 2C9-inductor drugs

Risk of decreasing plasma bosentan concentrations

Protease- and ritonavir-inhibitor drugs

Risk of increasing plasma bosentan concentrations

Nevirapine

Pronounced hepatotoxicity that can potentially cumulate with that of bosentan.

Not recommended

Close monitoring required

Anti-coagulants (warfarin and other antivitamin Ks)

INR (3–4 days after beginning of treatment, after each dosage modification and after discontinuation of bosentan treatment) during treatment initiation and/or dosage increase

Hormonal contraceptives (oestrogen/progestin combination and progestin-only pills)

Risk of reducing efficacy

Sildenafil intake

Discontinuation of this drug should be discussed with the patient to be included in the protocol, especially since sildenafil is suspected of being associated with NAAION onset.

Immunosuppressors (tacrolimus and sirolimus)

Bosentan lead to increase in the concentration of tacrolimus and sirolimus