Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. In 10 study subjects, administration of a single 100 mg dose of doravirine with the potent CYP450 3A4 inducer rifampin (600 mg once daily) decreased doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) by an average of 57%, 88% and 97%, respectively, compared to administration of doravirine alone. When doravirine was administered with the moderate CYP450 3A4 inducer rifabutin (300 mg once daily) in 12 study subjects, doravirine Cmax did not change, but AUC and C24hr decreased by an average of 50% and 68%, respectively. In addition, when doravirine 100 mg once daily was initiated following cessation of treatment with efavirenz (600 mg once daily) in 17 study subjects, doravirine Cmax, AUC, and C24hr decreased by an average of 35%, 62% and 85%, respectively, on the first day and 14%, 32% and 50%, respectively, 14 days later. Although coadministration of doravirine with other moderate CYP450 3A4 inducers has not been evaluated, reduced efficacy of doravirine may occur. The extent to which other, less potent CYP450 3A4 inducers may affect doravirine is unknown.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, concomitant use of doravirine with moderate CYP450 3A4 inducers should generally be avoided. If coadministration is necessary, some authorities recommend that the doravirine dose be increased to 100 mg twice daily (approximately 12 hours apart) (UK).

MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.