Drug Interaction Report

Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations of ensifentrine. According to the prescribing information, ensifentrine's primary routes of metabolism are oxidative (hydroxylation and O-demethylation) followed by conjugation. Additionally, in vitro data indicates ensifentrine is predominantly metabolized by CYP450 2C9, and to a lesser extent by CYP450 2D6. When ensifentrine (3 mg single dose) was coadministered with the CYP450 2C9 inhibitor fluconazole (200 mg twice daily) to 28 healthy volunteers, ensifentrine systemic exposure (AUC) increased by 1.6-fold and peak plasma concentration (Cmax) increased by 1.4-fold. The increase in ensifentrine exposure by fluconazole was not considered clinically relevant.

MONITOR: Two cases have been reported in which patients on sulfamethoxazole-trimethoprim therapy, after consuming beer, reported flushing, heart palpitations, dyspnea, headache, and nausea (disulfiram - alcohol type reactions). First-generation sulfonylureas have been reported to cause facial flushing when administered with alcohol by inhibiting acetaldehyde dehydrogenase and subsequently causing acetaldehyde accumulation. Since sulfamethoxazole is chemically related to first-generation sulfonylureas, a disulfiram-like reaction with products containing sulfamethoxazole is theoretically possible. However, pharmacokinetic/pharmacodynamic data are lacking and in addition, the two reported cases cannot be clearly attributed to the concomitant use of sulfamethoxazole-trimethoprim and alcohol.

MANAGEMENT: Patients should be alerted to the potential for this interaction and although the risk for this interaction is minimal, caution is recommended while taking sulfamethoxazole-trimethoprim concomitantly with alcohol.