Drug Interactions between sildenafil and voxelotor

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may significantly increase the plasma concentrations and effects of sildenafil, which is primarily metabolized by the isoenzyme. Pharmacokinetic studies have been conducted in healthy male volunteers using erectile dysfunction dosing for sildenafil. When administered to volunteers on the moderate to strong CYP450 3A4 inhibitors erythromycin (500 mg twice daily) or un-boosted saquinavir (1200 mg three times daily), each at steady state, the systemic exposure (AUC) of oral sildenafil (100 mg) increased by approximately 182% and 210%, respectively. Similarly, sildenafil's AUC increased by approximately 2-fold in volunteers who received a single dose of the moderate CYP450 3A4 inhibitor ciprofloxacin (500 mg) followed 2 hours later by a single oral dose of sildenafil (50 mg). An analysis of population pharmacokinetic data from clinical trials in adult pulmonary hypertension patients indicated a reduction in sildenafil's clearance of approximately 30% when it was coadministered with moderate CYP450 3A4 inhibitors. This analysis found a wide concentration range for oral sildenafil, as a dosage of 80 mg three times a day led to a systemic exposure of sildenafil that was 5 times greater than the standard 20 mg three times daily dose. This wide range may therefore cover the potential increased exposure from coadministration with CYP450 3A4 inhibitors less potent than ketoconazole, itraconazole, and ritonavir. Pharmacokinetic models predict that this interaction may be more significant for oral rather than intravenous (IV) formulations of sildenafil, due at least partly to effects from first pass metabolism. However, one physiologically-based pharmacokinetic model used to analyze the effects of IV fluconazole on IV sildenafil predicted an increase in sildenafil's AUC of 2.11-fold in adults and 2.82-fold in infants.

MANAGEMENT: Caution and close clinical monitoring are advised if sildenafil is coadministered with a moderate CYP450 3A4 inhibitor. The severity of this interaction may be increased in the presence of renal and/or hepatic dysfunction, potentially requiring dosage adjustments. When used in the treatment of pulmonary arterial hypertension in adults, some authorities recommend considering a dose reduction for sildenafil to 20 mg oral (10 mg IV) twice daily in the presence of a 3A4 inhibitor like erythromycin. For erectile dysfunction, the US labeling recommends considering a starting dose of 25 mg in patients taking erythromycin or stronger CYP450 3A4 inhibitors. The labeling for the CYP450 3A4 inhibitor should also be consulted as some may have additional recommendations or guidance, such as specific information on the potency of the CYP450 3A4 inhibitor and how long the inhibition may persist after the last dose of the inhibitor. Regardless of indication, all patients should be advised to promptly notify their physician if they experience serious side effects from sildenafil such as pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, low blood pressure, sudden decrease or loss of hearing, visual disturbances, syncope, or prolonged erection (greater than 4 hours).