Drug Interactions between fidanacogene elaparvovec and itraconazole

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.

GENERALLY AVOID: Coadministration with other hepatotoxic agents such as alcohol may increase the risk of liver injury and decrease the therapeutic efficacy of liver-directed adeno-associated virus (AAV) vector fidanacogene elaparvovec, designed to help replace missing and coagulation factor IX. Increased transaminase levels from AAV therapy have been attributed to immune-mediated injury of transduced hepatocytes, which may decrease their therapeutic efficacy. In addition, alcohol may impact liver enzyme elevation as well as reduce the activity of coagulation factor IX. In a prospective, open-label, single-arm, multinational clinical study of adult male patients with moderately severe to severe hemophilia B (n=45) receiving a single dose of fidanacogene elaparvovec (5 x 10[11] vector genomes [vg]/kg), increased transaminase levels greater than or equal to 1.5 times baseline were reported in 29 patients. Of these patients, 28 received treatment with corticosteroids due to increased transaminases and/or a decline in factor IX activity, with a mean initiation time to corticosteroid therapy reported at 45 days.

MANAGEMENT: According to the manufacturer, for the first year after administration of fidanacogene elaparvovec, alcohol consumption should be limited.