Drug Interactions between efavirenz and valoctocogene roxaparvovec

ADJUST DOSING INTERVAL: Administration with food increases the plasma concentrations of efavirenz and may increase the frequency of adverse reactions. According to the product labeling, administration of efavirenz capsules (600 mg single dose) with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with mean increases of 39% and 51% in efavirenz peak plasma concentration (Cmax) and 22% and 17% in systemic exposure (AUC), respectively, compared to administration under fasted conditions. For efavirenz tablets, administration of a single 600 mg dose with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) resulted in a 79% increase in mean Cmax and a 28% increase in mean AUC of efavirenz relative to administration under fasted conditions.

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of efavirenz. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

MANAGEMENT: Efavirenz should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms such as dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations, although they often resolve on their own after the first 2 to 4 weeks of therapy . Patients should be advised of the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs, and to avoid driving or operating hazardous machinery until they know how the medication affects them.

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.