FDA Safety Warning: Avacopan and Serious Liver Injury Save

Yesterday the FDA issued a Drug Safety Communication alerting patients and health care professionals about postmarketing identification of serious (drug induced) liver injury (DILI), including fatal cases, associated with the use of avacopan (Tavneos) in patients with ANCA- associated vasculitis (AAV). 

Hepatotoxicity with avacopan was previously identified as a potential serious adverse event (SAE) with avacopan and is described in product labeling.  This new report describes cases of VBDS and DILI cases with fatal outcomes. Vanishing bile duct syndrome (VBDS), is characterized by progressive destruction and disappearance of the bile ducts and may lead to permanent liver damage. VBDS may manifest as jaundice, itchiness, and tiredness.  

FDA is continuing to monitor postmarketing cases of DILI, including VBDS.

Avacopan was approved October 2021, and is used together with glucocorticoids and other standard-of-care medications to treat adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). While avacopan does not eliminate the need of glucocorticoid use, it may be steroid-sparing.  

Health Care Professionals using avacaopan should: 

• Conduct liver panel testing every 2 weeks in the 1st month of treatment, monthly for the next 5 months, and then as clinically indicated.   
• Promptly discontinue avacopan if LFTs are elevated:
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is >3 times the upper limit of normal (ULN)
  • Alkaline phosphatase (ALP) is >2 times the ULN;
  • Patients present with symptomatic cholestasis (jaundice or pruritus)

If liver test abnormalities or symptoms of liver injury do not improve, patients should be referred to a hepatologist for further evaluation. 

As of October 9, 2024, FDA identified 76 cases of DILI with a causal association with avacopan use; 74 of these reported a serious outcome, including hospitalization (n=54) and death (n=8). In 60 cases labs revealed the liver injury pattern was mostly (n=38) cholestatic or mixed (elevations in ALP and total bilirubin). 

The median t ime-to-onset of DILI was 46 days (range 22 to 140 days). Most cases (n=66) were reported from Japan, followed by the United States (n=5), Europe (n=4), and Canada (n=1). 

Of the 76 liver injury cases, 7 reported biopsy-confirmed VBDS as a complication of DILI with reasonable evidence of a causal association with avacopan use. All were hospitalized (n=7), of which 3 had a fatal outcome. The initial pattern of liver injury was cholestatic or mixed in 4 cases and hepatocellular in 3 cases. The median time from avacopan initiation to DILI onset among the 7 cases was 46 days (range 33 to 59 days). Similarly, these cases were mostly from Japan (n=6) and Canada (n=1). 

FDA is continuing to monitor postmarketing cases of DILI, including VBDS, involving avacopan and will provide updates as appropriate.