Drug Interactions between naltrexone and valoctocogene roxaparvovec

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.

GENERALLY AVOID: Coadministration of naltrexone with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Naltrexone, especially in larger than recommended doses (more than 50 mg/day), has been associated with hepatocellular injury, hepatitis, and elevations in liver transaminases and bilirubin. Other potential causative or contributory etiologies identified include preexisting alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other hepatotoxic drugs.

MANAGEMENT: The use of naltrexone with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Periodic monitoring of hepatic function is advisable.