702. Hepatic Safety Among Patients Treated with Anti-Fungal Triazole Agent Posaconazole: Characterization of Adverse events in a Manufacturer’s Safety Database

Abstract

BackgroundSecond-generation triazoles including posaconazole are highly efficacious for the prophylaxis and salvage treatment of life-threatening invasive fungal diseases. All triazoles have been associated with hepatic adverse events (AEs), which may affect their clinical use; however, risk factors for those AEs are poorly defined.MethodsReports of hepatobiliary AEs for posaconazole from clinical trials and post-market use in our company’s global safety database were reviewed to characterize concomitant medical conditions and drug exposure.ResultsAs of 2018, 444 cases of hepatic AEs were reported; 139 (31%) led to discontinuation of posaconazole. Most hepatic AEs had a time to onset >20 days (55.5%). The most frequent AEs reported (per Medical Dictionary for Regulatory Activities) were: Hyperbilirubinaemia (17%); Hepatotoxicity (13.5%); Hepatic function abnormal (11.5%); and Hepatocellular injury (11.3%). Most patients were adults (18–64 years old) (65%). Hematological malignancy (128 cases, 29%) and hematopoietic stem cell transplant (91 cases, 20%) were leading concurrent medical conditions. Notably, 75% of the cases reported exposure to other drugs (often multiple ones) with known risks for drug-induced liver injury (DILI, e.g., acetaminophen, cytarabine, cyclosporine). Among 139 cases in which posaconazole treatment was discontinued due to hepatic AEs, 6 of the 20 most frequently used co-medications (used by >4.5% of the cases) were classified by the FDA in its DILIRank as “Most-DILI-Concern” (resulting in drug withdrawal, or prominent labeling for severe DILI risk in boxed warning or warnings and precautions), and 7 were “Less-DILI-concern” drugs (DILI risk language in warnings and precautions or adverse reactions). Similarly, of the top 35 concomitant medications for the entire group, 9 are classified as “Most-DILI-Concern” and 12 are “Less-DILI Concern” drugs.ConclusionThe use of concomitant medications with known risks for hepatic injury appears to be an important contributor to the development of hepatotoxicity in patients treated with posaconazole. Co-administration of these drugs with anti-fungal triazole agents such as posaconazole, when needed, will continue to be carefully monitored.Disclosures All authors: No reported disclosures.