Drug Interaction Report

MONITOR: Coadministration with danicopan may increase the plasma concentrations of drugs that are substrates of the efflux transporters breast cancer resistance protein (BCRP) and/or P-glycoprotein (P-gp). The proposed mechanism involves decreased clearance due to inhibition of BCRP and P-gp by danicopan. In clinical drug interaction studies, when subjects were coadministered the BCRP substrate rosuvastatin (single 20 mg dose) with danicopan at steady state (200 mg three times daily for 4 days), the peak plasma concentration (Cmax) and systemic exposure (AUC) of rosuvastatin increased by 3.3-fold and 2.2-fold, respectively. In addition, when the P-gp substrate fexofenadine (single 180 mg dose) was coadministered with danicopan (150 mg three times daily for 4 days), the peak plasma concentration (Cmax) and systemic exposure (AUC) of fexofenadine increased by 1.4-fold and 1.6-fold, respectively. Similarly, when subjects were coadministered the P-gp substrate tacrolimus (single 2 mg dose) with danicopan (200 mg three times daily for 5 days), the Cmax and AUC of tacrolimus increased by 1.1-fold and 1.5-fold, respectively.

MANAGEMENT: Caution and clinical monitoring are recommended if danicopan is coadministered with drugs that are substrates of the transporters BCRP and/or P-gp, particularly sensitive substrates, or those with a narrow therapeutic range. Dosage adjustments as well as closer clinical and laboratory monitoring for the development of adverse effects may be appropriate for some drugs whenever danicopan is added to or withdrawn from therapy. Individual product labeling should be consulted for further guidance.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lurasidone. 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. When a single 10 mg dose of lurasidone was administered with the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 5 days), lurasidone peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 6.9- and 9.0-fold, respectively, compared to administration alone. The AUC of lurasidone's active metabolite increased by 6-fold. Another potent CYP450 3A4 inhibitor, posaconazole, has been reported to increase lurasidone AUC by approximately 4.5-fold. When a single 20 mg dose of lurasidone was administered with the moderate CYP450 3A4 inhibitor diltiazem (extended release formulation 240 mg/day for 5 days), lurasidone Cmax and AUC increased by 2.1- and 2.2-fold, respectively, while the AUC of the active metabolite increased by 2.4-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.

GENERALLY AVOID: Alcohol may potentiate some of the central nervous system and hypotensive effects of lurasidone. Use in combination may result in increased sedation, dizziness, hypotension, and impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of lurasidone. According to the product labeling, lurasidone mean Cmax and AUC were increased approximately 3-fold and 2-fold, respectively, when administered with food relative to under fasting conditions. Lurasidone AUC was not affected by meal size (in the range of 350 to 1000 calories) or fat content. In clinical studies, lurasidone was administered with food.

MANAGEMENT: Patients treated with lurasidone should avoid consumption of grapefruit and grapefruit juice as well as alcohol. Lurasidone should be taken with food (at least 350 calories).