The U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication regarding serious postmarketing events, including fatalities, due to drug-induced liver injury (DILI) associated with avacopan (Tavneos). This complement 5a receptor (C5aR) antagonist is indicated as an adjunctive treatment for adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. Tavneos labeling already includes hepatotoxicity as a serious adverse drug reaction (ADR), but cases of DILI and vanishing bile duct syndrome (VBDS), including fatal outcomes, are new safety concerns. Data compiled by the FDA through October 2024 identified 76 cases of DILI with reasonable evidence of a causal association with Tavneos. Furthermore, 74 of these 76 cases had a serious outcome, including 54 hospitalizations and eight deaths. The majority of cases (38 of 60 with laboratory information) had a cholestatic or mixed pattern of initial liver injury that frequently exhibited substantial increases in alkaline phosphatase (ALP) and total bilirubin. The median time-to-onset was 46 days (range, 22 to 140 days), and most cases (n=66) were reported from Japan, followed by the U.S., Europe and Canada. Seven of the 76 cases exhibited biopsy-confirmed VBDS as a complication of DILI with reasonable evidence of a causal association with Tavneos. All VBDS cases required hospitalization and three had a fatal outcome. Four of these cases had cholestatic or mixed initial liver injury and three cases had hepatocellular initial injury liver. The median time from starting Tavneos to these seven events was 46 days (range, 33 to 59 days). The Drug Safety Communication provides specific recommendations for both patients and health care professionals (HCPs) for prompt identification and management of any suspected liver injury. The FDA will continue to provide postmarketing monitoring for DILI associated with Tavneos and plans to release updates as appropriate.  

The FDA has issued a Drug Safety Communication on the potential for vitamin B6 deficiency and associated seizures linked to drugs containing carbidopa/levodopa. Carbidopa/levodopa containing products are approved to treat symptoms of Parkinson’s disease. The Agency is requiring manufacturers of these products to add a warning and make corresponding revisions to the labeling to state these risks. Due to the potential for vitamin B6 deficiency and vitamin B6 deficiency-associated seizures, HCPs are instructed to assess baseline vitamin B6 levels before initiation and regularly during treatment; patients should receive supplementation with vitamin B6 as necessary. These safety updates are based on an FDA safety review that found 14 cases of seizures associated with vitamin B6 deficiency in patients taking drugs containing carbidopa/levodopa. All cases were in patients receiving levodopa doses exceeding 1,000 mg daily, and higher doses (> 1,500 mg of levodopa) were associated with a shorter duration from initiation of therapy to identification of the deficiency. The cases occurred among patients receiving oral formulations and an enteral suspension (latency periods ranging from 23 to 132 months) with no cases reported for the combination products containing entacapone or with injectable carbidopa/levodopa products. The seizures presented most commonly as focal onset seizures with secondary generalization, as observed with vitamin B6-dependent epilepsy; however, some patients had progression to status epilepticus, demonstrating the importance of prompt identification and management. Notably, seizures associated with carbidopa/levodopa products are unresponsive to traditional anti-seizure medications but resolve following vitamin B6 administration. Additionally, the FDA notes that select anti-seizure medications can further worsen vitamin B6 deficiency, demonstrating the importance of recognizing whether the deficiency is related to carbidopa/levodopa-containing products.