Drug Interactions between Intuniv and sildenafil

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.

GENERALLY AVOID: Coadministration with grapefruit juice may slightly increase the oral bioavailability and delay the onset of action of sildenafil. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a randomized, crossover study with 24 healthy male volunteers, ingestion of 250 mL of grapefruit juice one hour before and concurrently with a 50 mg dose of sildenafil increased the mean area under the plasma concentration-time curve (AUC) of sildenafil and its pharmacologically active N-desmethyl metabolite by 23% and 24%, respectively, compared to water. Peak plasma concentrations (Cmax) were unaltered, but the time to reach sildenafil Cmax was prolonged by 0.25 hour. The observed increase in sildenafil bioavailability is unlikely to be of clinical significance in most individuals. However, pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability and may be significant in the occasional susceptible patient. Indeed, one subject in the study had a 2.6-fold increase in sildenafil concentrations.

MANAGEMENT: It may be advisable to avoid administration of sildenafil with grapefruit juice to prevent potential toxicity and delay in onset of action.