Drug Interaction Report

MONITOR: Sapropterin may potentiate the hypotensive effects of vasodilators, including phosphodiesterase-5 (PDE5) inhibitors and drugs that affect nitric oxide-mediated vasodilation. Theoretically, the additive effects on vasodilation could lead to a reduction in blood pressure, although combined use of these medications has not been evaluated in humans. In animal studies, no effect on blood pressure was observed during coadministration of these agents.

MANAGEMENT: Caution is advised if sapropterin is used in combination with vasodilators, including topical drugs. Patients should be advised to contact their physician if they experience signs of hypotension such as dizziness, fainting, tachycardia, and headache.

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.

ADJUST DOSING INTERVAL: Food increases the gastrointestinal absorption of sapropterin.

MANAGEMENT: Sapropterin should be administered with food, preferably at the same time each day. Sapropterin tablets should be dissolved in 4 to 8 ounces (120 to 240 mL) of water or apple juice and taken within 15 minutes of dissolution.