Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of guanfacine, which is primarily metabolized by the isoenzyme. Rifampin, a potent CYP450 3A4 inducer, has been reported to decrease guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) by 54% and 70%, respectively. A computer simulation suggests that efavirenz, a moderate CYP450 3A4 inducer, would reduce guanfacine Cmax and AUC by a similar magnitude.

MANAGEMENT: The possibility of diminished therapeutic response to guanfacine should be considered during coadministration with CYP450 3A4 inducers. Pharmacologic response to guanfacine should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of guanfacine. The risk of adverse reactions such as hypotension, bradycardia, and sedation may increase. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Ketoconazole, a potent CYP450 3A4 inhibitor, has been reported to increase guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 2- and 3-fold, respectively. A computer simulation suggests that fluconazole, a moderate CYP450 3A4 inhibitor, would increase guanfacine Cmax and AUC by about 1.5- and 2-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.

GENERALLY AVOID: Alcohol may enhance the sedative and hypotensive effects of guanfacine.

GENERALLY AVOID: Administration of extended-release guanfacine with a high-fat meal may increase the bioavailability of guanfacine. When a single 4 mg dose of extended-release guanfacine was administered to adult volunteers with a high-fat breakfast, mean guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 75% and 40%, respectively, compared to dosing in a fasted state.

MANAGEMENT: Patients treated with guanfacine should avoid consumption of grapefruit and grapefruit juice. In addition, it is preferable to avoid or limit the use of alcohol during treatment. Patients should be advised against driving or operating hazardous machinery until they know how the medication affects them. The extended-release formulation of guanfacine should not be taken together with a high-fat meal.

MONITOR: Isolated case reports have suggested that the ingestion of alcohol during griseofulvin therapy may rarely cause disulfiram-like reactions, flushing, tachycardia, or increased effects of alcohol. The mechanism is unknown.

MANAGEMENT: Patients should be advised of the possibility of increased adverse effects or a disulfiram-like reaction.