Drug Interaction Report

MONITOR: Coadministration with other hepatotoxic agents may increase the risk of liver injury and decrease the therapeutic efficacy of valoctocogene roxaparvovec, a liver-directed adeno-associated virus (AAV) vector designed to help replace missing coagulation factor VIII. Most of the patients treated with valoctocogene roxaparvovec in clinical studies experienced ALT elevations, presumably due to immune-mediated injury of transduced hepatocytes, which may decrease the therapeutic efficacy of valoctocogene roxaparvovec. In a clinical trial of adults with severe hemophilia (n=134) receiving a single dose of valoctocogene roxaparvovec (6 x 10[13] vector genomes [vg]/kg), 107 patients (96%) experienced increased ALT levels greater than or equal to 1.5 times baseline or greater than the upper limit of normal (ULN), while 12 patients (9%) experienced increased ALT levels greater than 5 to 20 times ULN. Some of the ALT elevations were associated with decreased factor VIII activity. Most patients treated with valoctocogene roxaparvovec required immunosuppressive medications, including corticosteroids, to control elevations in transaminases and prevent loss of transgene expression.

MANAGEMENT: The risk of additive hepatotoxicity and decreased therapeutic efficacy of valoctocogene roxaparvovec should be considered after coadministration with other hepatotoxic agents. Alternative treatment may be required if an interaction is suspected. Monitoring of ALT and factor VIII activity levels (e.g., weekly to every 2 weeks for the first month) is recommended when a new medication is started following valoctocogene roxaparvovec administration.

CONTRAINDICATED: Coadministration with inhibitors of CYP450 1A2 such as caffeine may significantly increase the plasma concentrations of fezolinetant, which is primarily metabolized by the isoenzyme. The interaction has not been studied with caffeine but has been reported for other CYP450 1A2 inhibitors. Consumption of caffeine-containing food or beverages (e.g., chocolate, coffee, cola drinks, energy drinks, tea) could result in an interaction with fezolinetant. In clinical drug interaction studies, coadministration of the potent CYP450 1A2 inhibitor fluvoxamine increased the peak plasma concentration (Cmax) and systemic exposure (AUC) by 80% and 840%, respectively. Likewise, the moderate CYP450 1A2 inhibitor, mexiletine, is predicted through physiologically based pharmacokinetic (PBPK) modeling to increase the Cmax and AUC of fezolinetant by 40% and 360%, respectively. The weak CYP450 1A2 inhibitor cimetidine is also predicted via PBPK to increase the Cmax and AUC of fezolinetant by 30% and 100%, respectively.

MANAGEMENT: Concomitant use of fezolinetant with CYP450 1A2 inhibitors such as caffeine, including caffeine-containing food or beverages, is considered contraindicated.

GENERALLY AVOID: Coadministration with other hepatotoxic agents such as alcohol may increase the risk of liver injury and decrease the therapeutic efficacy of valoctocogene roxaparvovec, a liver-directed adeno-associated virus (AAV) vector designed to help replace missing coagulation factor VIII. Most of the patients treated with valoctocogene roxaparvovec in clinical studies experienced ALT elevations, presumably due to immune-mediated injury of transduced hepatocytes, which may decrease the therapeutic efficacy of valoctocogene roxaparvovec. In a clinical trial of adults with severe hemophilia (n=134) receiving a single dose of valoctocogene roxaparvovec (6 x 10[13] vector genomes [vg]/kg), 107 patients (96%) experienced increased ALT levels greater than or equal to 1.5 times baseline or greater than the upper limit of normal (ULN), while 12 patients (9%) experienced increased ALT levels greater than 5 to 20 times ULN. Some of the ALT elevations were associated with decreased factor VIII activity, and some were attributed to alcohol consumption. Most patients treated with valoctocogene roxaparvovec required immunosuppressive medications, including corticosteroids, to control elevations in transaminases and prevent loss of transgene expression.

MANAGEMENT: After administration of valoctocogene roxaparvovec, alcohol consumption should be avoided for at least 1 year and limited thereafter.