Drug Interactions between Calquence and tamsulosin

GENERALLY AVOID: Consumption of grapefruit and/or grapefruit juice may increase the plasma concentrations of acalabrutinib. 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 specifically, but has been reported for other CYP450 3A4 inhibitors. When acalabrutinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 5 days) in 17 healthy subjects, acalabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9- and 5.1-fold, respectively. Physiologically based pharmacokinetic (PBPK) simulations showed that moderate CYP450 3A4 inhibitors (erythromycin, fluconazole, diltiazem) increased acalabrutinib Cmax and AUC by 2- to nearly 3-fold. In healthy subjects, administration of acalabrutinib with the moderate CYP450 3A4 inhibitors fluconazole (400 mg as a single dose) or isavuconazole (200 mg as a repeated dose for 5 days) increased acalabrutinib Cmax and AUC by 1.4- to 2-fold, while the Cmax and AUC of the active metabolite, ACP-5862, was decreased by 0.65- to 0.88-fold. 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 acalabrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and atrial fibrillation or flutter.

Food may delay the absorption of acalabrutinib, but does not appear to affect the overall extent of absorption. When a single 100 mg tablet or a 75 mg developmental formulation of acalabrutinib was administered with a high-fat, high-calorie meal (approximately 918 calories; 59 grams carbohydrate, 59 grams fat, 39 grams protein) in healthy study subjects, mean acalabrutinib Cmax was decreased by 54% and 73%, respectively, while time to reach Cmax was delayed by 1 to 2 hours compared to administration under fasted conditions. However, mean AUC was not affected.

MANAGEMENT: Acalabrutinib may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with acalabrutinib.

ADJUST DOSING INTERVAL: Food may delay the gastrointestinal absorption of tamsulosin. The time to maximum plasma concentration (Tmax) is reached by 4 to 5 hours under fasted conditions and by 6 to 7 hours when tamsulosin is administered with food. The delay in Tmax has the desirable effect of smoothing the tamsulosin plasma concentration profile, thereby reducing fluctuation of the plasma peak and trough concentrations with multiple dosing. Food may also affect the extent of absorption of tamsulosin. It has been reported that taking tamsulosin under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak plasma concentration (Cmax) compared to fed conditions. The effects of food on the pharmacokinetics of tamsulosin are consistent regardless of whether tamsulosin is taken with a light meal or a high-fat meal.

MANAGEMENT: To ensure uniformity of absorption, tamsulosin should be administered approximately one-half hour following the same meal each day.