Drug Interaction Report

GENERALLY AVOID: Coadministration with inducers of CYP450 3A4 may significantly decrease the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. Some non-nucleoside reverse transcriptase inhibitors such as efavirenz, etravirine, and nevirapine are known inducers of CYP450 3A4. When doravirine 100 mg once daily was initiated following cessation of treatment with efavirenz 600 mg once daily in 17 study subjects, doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) decreased by an average of 35%, 62% and 85%, respectively, on the first day and 14%, 32% and 50%, respectively, 14 days later. Reduced efficacy of doravirine may occur.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, concomitant use of doravirine with efavirenz, etravirine, or nevirapine should generally be avoided.

Coadministration with tenofovir may reduce the plasma concentrations of etravirine. The mechanism of interaction has not been described. In 23 study subjects administered etravirine with tenofovir disoproxil fumarate 300 mg once a day, etravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by nearly 20% each. These changes were statistically, but not clinically, significant. Etravirine had no effect on the pharmacokinetics of tenofovir. Etravirine and tenofovir disoproxil fumarate may be coadministered without any dosage adjustments.

ADJUST DOSING INTERVAL: Coadministration with food increases the oral bioavailability of etravirine. The mechanism is unknown. Compared to administration following a meal, the systemic exposure (AUC) to etravirine was decreased by about 50% when the drug was administered under fasting conditions. The types of meal studied (ranging from 345 kilocalories containing 17 grams fat to 1160 kilocalories containing 70 grams fat) did not appear to make a difference with respect to impact on etravirine bioavailability.

MANAGEMENT: Etravirine should always be administered following a meal.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.

The recommended maximum number of medicines in the 'NNRTIs' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'NNRTIs' category:

• Delstrigo (doravirine / lamivudine / tenofovir disoproxil)
• etravirine

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.