Drug Interactions between propranolol and Quviviq

ADJUST DOSING INTERVAL: The bioavailability of propranolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take propranolol at the same time each day, preferably with or immediately following meals.

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.

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.