Drug Interactions between avanafil and givinostat

GENERALLY AVOID: Additive hypotensive effects may occur when phosphodiesterase-5 (PDE5) inhibitors 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. Administration of avanafil 200 mg with alcohol at a dose of 0.5 g/kg (equivalent to approximately 3 ounces of 80-proof vodka in a 70-kg male; consumed within 15 minutes in study subjects, providing blood alcohol levels of 0.057%) resulted in additional maximum supine systolic/diastolic blood pressure decreases of 3.5/4.5 mm Hg and additional maximum pulse rate increase of 9.3 bpm compared to alcohol alone, but did not cause orthostatic hypotension or dizziness. The plasma concentrations of alcohol were not affected. Sildenafil 50 mg and vardenafil 20 mg reportedly did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08% and in healthy volunteers administered alcohol at a dose of 0.5 g/kg, respectively. Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of avanafil, 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 avanafil should avoid consuming large amounts of alcohol, 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. Some authorities advise that grapefruit juice should be avoided within 24 hours prior to taking avanafil.

ADJUST DOSING INTERVAL: Food increases the systemic exposure of givinostat. An open-label, randomized, crossover, single dose food effect study conducted in 12 healthy males used givinostat liquid filled capsules. Subjects received a single oral dose of givinostat (100 mg) in the fasting state or after a high-fat standard meal, with a washout period of at least 1 week in between. The high-fat standard meal resulted in an increase in systemic exposure (AUC) and maximum plasma concentration (Cmax) of about 40% and 23%, respectively, when compared to the fasted state. Additionally, the time to maximum concentration (Tmax) was delayed slightly from 2 to 3 hours.

MANAGEMENT: Givinostat should be administered with food to increase its absorption. In the case of the oral suspension, this can also help mask its bitter taste.