Drug Interaction Report

MONITOR: Coadministration with daridorexant may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) efflux transporter and/or the CYP450 3A4 isoenzyme. The mechanism is inhibition of CYP450 3A4 and P-gp mediated drug efflux by daridorexant. Substrates of P-gp and/or CYP450 3A4 that are also inhibitors of CYP450 3A4 may also increase the plasma concentrations of daridorexant, a CYP450 3A4 substrate. When co-administered with daridorexant 50 mg, the systemic exposure (AUC) and peak plasma concentration (Cmax) of dabigatran etexilate, a sensitive P-gp substrate, increased by 42% and 29%, respectively, suggesting mild P-gp inhibition. Likewise, the AUC and Cmax of midazolam, a sensitive CYP450 3A4 substrate, increased by 42% and 13%, respectively, in subjects receiving 50 mg of daridorexant. However, the pharmacokinetics of midazolam were not affected by 25 mg of daridorexant.

MANAGEMENT: Caution is advised when daridorexant is used with drugs that are substrates of P-gp and/or CYP450 3A4, particularly those with a narrow therapeutic index, as well as with CYP450 3A4 substrates that are also CYP450 3A4 inhibitors (e.g., ethinyl estradiol, hydroxychloroquine, nicardipine, nifedipine). Pharmacologic response to the coadministered P-gp and/or CYP450 3A4 substrate(s) and daridorexant should be monitored more closely whenever daridorexant is added to or withdrawn from therapy. Individual product labeling for the CYP450 3A4 and/or P-gp substrate(s) should be consulted for further guidance.

GENERALLY AVOID: Coadministration with inhibitors of P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) may increase the plasma concentrations of bictegravir. According to the product labeling, bictegravir is a substrate of both P-gp and BCRP; however, the extent to which each enzymatic pathway contributes to the metabolic clearance of bictegravir has not been reported.

MANAGEMENT: The use of bictegravir with P-gp and/or BCRP inhibitors should generally be avoided. If concomitant use is required, caution and close clinical and laboratory monitoring, including renal function, are recommended. Dosage adjustments may be required whenever a P-gp and/or BCRP inhibitor is added to or withdrawn from therapy.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of daridorexant, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. Per physiologically based pharmacokinetic (PBPK) analysis, concomitant use of itraconazole, a potent CYP450 3A4 inhibitor, increased daridorexant systemic exposure (AUC) by more than 400%. When a 25 mg daridorexant dose was coadministered with multiple 240 mg doses of diltiazem, a moderate CYP450 3A4 inhibitor, daridorexant peak plasma concentration (Cmax) and AUC increased by 1.4- and 2.4-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to daridorexant may increase the risk of adverse reactions such as central nervous system (CNS) depression, sleep paralysis, hallucinations, complex sleep behaviors, worsening of depression or suicidal ideation, or headache.

After administration of a high-fat, high-calorie meal, daridorexant Cmax decreased by 16% (no effect on AUC) and the time to maximum concentration (Tmax) was delayed by 1.3 hours.

GENERALLY AVOID: Alcohol may potentiate the pharmacologic effects of daridorexant. Coadministration of daridorexant (50 mg) with alcohol led to additive effects on psychomotor performance. Use in combination may result in an increased risk of complex sleep-related behaviors (e.g., "sleep driving"), additive central nervous system (CNS) depression, and/or impairment of psychomotor performance.

MANAGEMENT: Consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with daridorexant should generally be avoided. Some authorities suggest avoiding grapefruit or grapefruit juice consumption specifically in the evening. Patients should avoid the consumption of alcohol during treatment with daridorexant. The manufacturer makes no recommendation regarding administration with food; however, the time to sleep onset may be delayed if taken with or soon after 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.