Drug Interaction Report

MONITOR: Coadministration with inducers of uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase or UGT) enzymes may decrease the systemic exposure and effects of aprocitentan, which is primarily metabolized by UGT1A1 and UGT2B7. Some UGT inducers are associated with similar adverse effects to those of aprocitentan, such as hepatotoxicity (e.g., alcohol, carbamazepine, efavirenz, fosphenytoin, phenytoin, rifampin). It is unclear if the use of aprocitentan with these substances could increase the risk of similar adverse effects. Clinical data examining aprocitentan with inducers of UGT are not available.

MANAGEMENT: Caution and clinical monitoring for reduced efficacy may be advised if aprocitentan is used with a UGT inducer. If the UGT inducer also shares a similar adverse effect profile with aprocitentan, like hepatotoxicity, additional monitoring for the adverse effect in question may also be recommended. Additional monitoring may also be beneficial if a UGT inducer is added to or withdrawn from the patient's regimen during aprocitentan therapy.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.