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and/or CYP450 3A4 substrate(s) and daridorexant should be monitored more closely whenever daridorexant is added to or withdrawn from therapy.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: Use of alcohol or products containing alcohol during nitroimidazole therapy may result in a disulfiram-like reaction in some patients. There have been a few case reports involving metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have questioned the disulfiram-like properties of metronidazole. One study found neither elevations in blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects who received placebo.

MANAGEMENT: Because clear evidence is lacking concerning the safety of ethanol use during nitroimidazole therapy, patients should be apprised of the potential for interaction and instructed to avoid alcoholic beverages and products containing alcohol or propylene glycol while using oral, intravenous, or vaginal preparations of a nitroimidazole. Alcoholic beverages should not be consumed for up to 3 days after completion of systemic nitroimidazole 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.