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: Additive hypotensive effects may occur when phosphodiesterase-5 (PDE5) inhibitors such as tadalafil are used with alcohol, as both are mild systemic vasodilators. In clinical pharmacology studies, more subjects administered alcohol at a dose of 0.7 g/kg (equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male; consumed within 10 minutes in study subjects, providing blood alcohol levels of 0.08%) in combination with tadalafil 10 or 20 mg single doses had clinically significant decreases in blood pressure than with alcohol alone. There were reports of postural dizziness, and orthostatic hypotension was observed in some. When tadalafil 20 mg was administered with alcohol at a lower dose of 0.6 g/kg (equivalent to approximately 4 ounces of 80-proof vodka in an 80-kg male), orthostatic hypotension was not observed, dizziness occurred with similar frequency relative to alcohol alone, and the hypotensive effects of alcohol were not potentiated. Neither tadalafil nor alcohol affected the plasma concentrations of the other.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of tadalafil, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients taking tadalafil should avoid consuming large amounts of alcohol (for example, 5 units or more), which may increase the potential for orthostatic signs and symptoms including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. It may also be appropriate to avoid consuming large amounts of grapefruit juice.

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.