| ⚠️ Key Safety Summary: Read This First On March 31, 2026, the FDA issued a Drug Safety Communication identifying 76 cases of drug-induced liver injury (DILI) linked to Tavneos (avacopan), including 8 deaths and 54 hospitalizations. Seven biopsy-confirmed cases involved vanishing bile duct syndrome (VBDS), a potentially irreversible liver condition, and 3 of those were fatal. Median time from starting Tavneos to liver injury onset: 46 days. Most cases occurred within 60 days. Updated monitoring requirements: Patients on Tavneos should have liver function tests every 2 weeks for the first month, then monthly for 5 months. Discontinue immediately if ALT/AST exceed 3 times the upper limit of normal (ULN) or ALP exceeds 2 times ULN. Critical context: The FDA had already requested in January 2026 that Amgen voluntarily withdraw Tavneos from the U.S. market. Amgen refused. The drug remains available. |
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This story is more complicated than a standard FDA drug safety alert. Tavneos (avacopan) was already under significant regulatory pressure when the March 31, 2026 safety communication was issued, and understanding why the drug is still on the market requires knowing the full context, not just the liver injury numbers.
The liver injury signal is real and serious. Eight people have died. But the situation patients and clinicians are navigating is also one in which a manufacturer has declined a federal request to remove a drug from shelves, both U.S. and European regulators are reviewing the integrity of the clinical trial data that supported the drug’s original approval, and a major watchdog organization is publicly challenging the FDA’s failure to escalate. All of this is happening while people with a serious, life-threatening autoimmune disease continue to be treated with, and in some cases depend on, the drug in question.
Here is the whole picture.
The Disease Tavneos Treats: ANCA-Associated Vasculitis
ANCA-associated vasculitis (AAV) is a group of rare autoimmune diseases in which the body’s immune system attacks and destroys small-to-medium blood vessels throughout the body. The two forms Tavneos is approved to treat are granulomatosis with polyangiitis (GPA, formerly called Wegener’s granulomatosis) and microscopic polyangiitis (MPA).
These are serious diseases. Untreated or inadequately managed, they can destroy kidney function, damage the lungs, and be fatal. The standard treatment for decades has involved high-dose glucocorticoids (steroids) combined with immunosuppressants such as cyclophosphamide or rituximab. These regimens work, but carry significant toxicity of their own. Chronic steroid use is associated with infection, bone loss, diabetes, and cardiovascular disease. Any therapy that could reduce steroid burden while maintaining disease control represents a genuine clinical advance.
Avacopan works by blocking the complement C5a receptor, which plays a role in driving neutrophil-mediated inflammation in AAV. The ADVOCATE Phase 3 trial showed it could achieve non-inferior remission rates compared with prednisone tapering at week 26, and superior sustained remission at week 52, with significantly less glucocorticoid exposure. Published in the New England Journal of Medicine in 2021, those results drove FDA approval. That is a clinically meaningful result for a disease where the side effects of standard treatment are themselves a major burden.
The Liver Injury Signal: What the Data Shows
Hepatotoxicity, meaning drug-induced liver injury, was not a surprise finding with avacopan. It was identified in premarket clinical trials and included in the drug’s prescribing information as a warning from the time of approval in 2021. In the ADVOCATE trial itself, 5.4% of patients in the avacopan arm experienced serious adverse events related to liver function, compared with 3.6% in the prednisone arm.
What changed, and what the March 31, 2026 safety communication addresses, are two new and more severe categories of concern that emerged in the postmarketing period:
| Category | Number of Cases | Outcomes |
|---|---|---|
| All DILI cases (reasonable causal evidence) | 76 total | 74 serious outcomes |
| Hospitalizations | 54 | — |
| Deaths | 8 | All fatal by definition |
| Cholestatic or mixed injury pattern | 38 of 60 with lab data | Elevated ALP + bilirubin |
| Biopsy-confirmed VBDS | 7 | All hospitalized; 3 fatal |
| Median time to onset | 46 days | Range: 22 to 140 days |
| Cases from Japan | 66 of 76 | Largest concentration globally |
Source: FDA Drug Safety Communication. March 31, 2026.
| What is vanishing bile duct syndrome (VBDS)? VBDS is a rare and serious condition in which the small bile ducts inside the liver are progressively destroyed. Bile, the digestive fluid produced by the liver, can no longer drain properly, leading to a backup of bile acids in the liver and bloodstream. It is called “vanishing” because on liver biopsy, the small intrahepatic bile ducts that are normally present in portal tracts have disappeared. The resulting damage can be permanent and may eventually progress to cirrhosis or liver failure if not caught early. VBDS is most commonly caused by drug-induced liver injury, immune-mediated disorders, infections, and malignancy. It is distinctly different from the transient transaminase elevations seen in many drug reactions. It is a structural injury to the bile duct architecture itself. Clinically, patients typically present with jaundice (yellowing of skin or eyes), pruritus (intense itching that is often worse at night), and fatigue. In the avacopan VBDS cases, the majority occurred within 60 days of starting treatment. |
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Why Are 87% of Cases From Japan?
The geographic concentration of DILI and VBDS cases is one of the most striking features of this safety signal. Of 76 total DILI cases, 66 were reported from Japan, approximately 87%. Of the 7 biopsy-confirmed VBDS cases, 6 were from Japan.
Amgen has noted that VBDS cases from Japan primarily involved patients aged 65 and older. Several factors may contribute to the geographic pattern, none of which are definitively established:
Pharmacogenomic differences: Japanese patients may have different expression profiles or activity levels for the drug-metabolizing enzymes responsible for avacopan clearance, potentially altering hepatic drug exposure.
AAV epidemiology: MPA is substantially more prevalent in Japan than GPA compared with Western countries, and the two conditions may involve different baseline inflammatory profiles affecting hepatic susceptibility.
Concomitant medications: Patients in Japan may more frequently receive certain co-medications. Antibiotics such as trimethoprim/sulfamethoxazole, commonly given as infection prophylaxis in immunocompromised patients, have themselves been associated with DILI and may interact synergistically.
Post-marketing surveillance intensity: Japan has a notably rigorous pharmacovigilance system, and some of the apparent geographic concentration may reflect more systematic case capture rather than true biological difference.
Age and comorbidity profile: The older age of most Japanese VBDS cases may reflect a population with greater baseline hepatic vulnerability.
A case report published in Annals of Internal Medicine: Clinical Cases documented VBDS in a 74-year-old patient with MPA treated with avacopan, with a Naranjo Adverse Drug Reaction score of 6 (probable causality). That report noted the importance of monitoring compliance: in that case, liver enzyme testing had been inadvertently delayed, which may have contributed to the severity of the injury. It also noted that prior DILI episodes may increase vulnerability to subsequent drug-related liver injury.
The Bigger Story: FDA Requested Withdrawal. Amgen Said No.
The March 31 safety communication cannot be read in isolation. Six weeks earlier, on January 16, 2026, the FDA had privately requested that Amgen voluntarily withdraw Tavneos from the U.S. market. Amgen disclosed this publicly in February, and on January 28 formally informed the FDA it would not comply.
The FDA’s withdrawal request cited two concerns. The first was hepatotoxicity, specifically the emerging DILI and VBDS signal that became the subject of the March safety communication. The second was a data integrity issue: the FDA raised questions about a process followed by ChemoCentryx (the original developer) to re-adjudicate primary endpoint results for 9 of the 331 patients in the ADVOCATE trial, the sole pivotal study supporting avacopan’s approval.
| What was the ADVOCATE endpoint re-adjudication controversy? The ADVOCATE trial used the Birmingham Vasculitis Activity Score (BVAS) to assess disease activity. The primary endpoint was remission (BVAS = 0) at week 26. After investigators originally scored certain patients, a post-hoc adjudication committee reviewed and changed the scores for 9 patients. The FDA first raised concerns about this process during the original 2021 review, and the FDA advisory committee vote on avacopan’s approval was close. These disputes were later publicly aired in a civil investor lawsuit (Amgen won in August 2025) and triggered the EMA’s January 2026 safety review of avacopan in Europe. The ADVOCATE re-adjudication issue is about whether the efficacy data supporting avacopan’s approval was handled appropriately, specifically whether changing endpoint scores for 9 patients affected the trial’s outcome assessment in ways that could have influenced regulatory decisions. |
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Amgen’s response has been consistent: the company maintains that Tavneos has a favorable benefit-risk profile, that liver toxicity is a known and labeled risk, and that more than 7,000 patients have been treated with it since approval. The company has indicated it submitted a proposed label update to the FDA in 2024 to add VBDS to the prescribing information, a request that was still pending at the time of the March 31, 2026 safety communication.
It is also contextually relevant that Tavneos generated $459 million in sales in 2025, growing 62% year-over-year, making it one of Amgen’s fastest-growing products. That commercial context is not dispositive in evaluating Amgen’s position, but it is part of the full picture of why a voluntary withdrawal request would face resistance.
Dr. Robert Steinbrook, Health Research Group Director at Public Citizen, stated in a formal release on March 31, 2026 that if the FDA in January 2026 requested that avacopan be voluntarily withdrawn from the U.S. market, the agency needed to explain publicly why it had not made that request publicly, and why the prescribing information did not yet include a boxed warning for the risk of fatal liver disease. He characterized these as urgent questions for the FDA to answer.
That criticism represents a legitimate and so far unanswered question about regulatory transparency. The FDA’s standard tools when a company declines voluntary withdrawal are limited: the agency can initiate mandatory withdrawal proceedings, but these require formal regulatory steps and take time, and no such proceedings have been announced.
For Patients Currently Taking Tavneos
If you are taking Tavneos for ANCA-associated vasculitis, the most important message is this: do not stop the medication on your own without speaking to your rheumatologist first. Stopping avacopan abruptly without a transition plan in a patient with active GPA or MPA could allow disease flare, which carries its own serious risks including kidney damage.
| Symptoms of liver injury: seek care immediately if you develop any of these Unusual fatigue or weakness that is more than your baseline; nausea or vomiting without another clear cause; itching (pruritus), especially if persistent or worse at night; yellowing of your skin or the whites of your eyes (jaundice); light-colored or pale stools; dark, tea-colored urine; pain or swelling in the upper right abdomen. These symptoms can appear within the first six weeks of treatment. Do not wait for your next scheduled appointment. Contact your provider the same day. |
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If you have concerns about whether to continue Tavneos given the safety communication, that conversation belongs with your rheumatologist specifically. The benefit-risk calculation is individual: it depends on your disease severity, how well your vasculitis is controlled, your liver function baseline, and whether alternative regimens are viable for your situation. The Vasculitis Foundation has issued a patient-facing update on this situation and is a good resource for community support and current information.
Adverse events should be reported to FDA MedWatch at 1-800-332-1088 or online at fda.gov/safety/medwatch.
For Clinicians: Monitoring Protocol and Decision Framework
The FDA’s updated monitoring recommendations are specific and represent an intensification of the original labeling:
| Time Period | Monitoring Frequency | Action Threshold |
|---|---|---|
| First month of treatment | Every 2 weeks | Discontinue if ALT/AST greater than 3 times ULN, or ALP greater than 2 times ULN |
| Months 2 to 6 | Monthly | Same thresholds; monitor for new symptoms |
| After 6 months | As clinically indicated | Remain vigilant for late-onset cases |
| Any time | Immediately on symptoms | Jaundice or pruritus: discontinue and refer to hepatology |
Key clinical judgment points for prescribers:
The DILI pattern in most cases is cholestatic or mixed, characterized by elevated alkaline phosphatase (ALP) and total bilirubin rather than isolated transaminase elevation. This pattern can progress more insidiously than hepatocellular injury. Do not wait for transaminase elevation alone to act.
VBDS is a structural, potentially irreversible injury. If a patient develops jaundice or persistent pruritus, discontinue avacopan promptly and refer to hepatology without waiting to see if liver enzymes normalize on repeat testing.
Prior DILI episodes from any cause may increase susceptibility to subsequent drug-induced liver injury. Take a thorough medication and hepatic history before initiating avacopan.
The median onset of 46 days means the highest-risk window falls exactly in the first two months. The biweekly monitoring in month one is not optional in the current regulatory and clinical context.
Document your monitoring compliance carefully. The published VBDS case report noted that a two-week delay in scheduled liver monitoring may have contributed to injury severity in that patient.
For patients with uncontrolled disease where avacopan provides meaningful clinical benefit, the benefit-risk calculation may still favor continuation with rigorous monitoring. For patients in stable remission or with other viable options, the calculus is different. Consult ACR vasculitis guidelines and consider hepatology co-management when initiating or continuing therapy given the current safety signal.
What Happens Next
EMA review
The European Medicines Agency launched a review of avacopan in January 2026, citing concerns about data integrity in the ADVOCATE trial. The EMA will evaluate all available evidence to determine whether the handling of trial data affects the overall benefit-risk profile of avacopan for European patients. That review is ongoing.
FDA mandatory withdrawal authority
When a pharmaceutical company declines a voluntary withdrawal request, the FDA can initiate mandatory withdrawal proceedings under 21 U.S.C. §355(e), but this requires a formal process that includes opportunity for hearing. The FDA has not announced it is pursuing this path for avacopan. Whether and when the agency escalates remains an open question.
Label update (pending)
Amgen submitted a proposed label update in 2024 to add VBDS to the prescribing information. As of the March 31, 2026 safety communication, that label change had not yet been approved. The current label includes a hepatotoxicity warning but does not specifically mention VBDS by name.
Boxed warning
Public Citizen has called for a boxed warning, the FDA’s strongest label alert, reserved for serious or life-threatening risks, for fatal liver disease associated with avacopan. The current label does not carry a boxed warning for hepatotoxicity. Given eight confirmed deaths, the question of whether the FDA will move in this direction in any eventual label update bears watching.
For related coverage of how FDA regulatory tools, including drug safety communications, mandatory withdrawal authority, and label change procedures, work in practice, see our earlier post on what the FDA’s contrasting decisions on camizestrant and vepdegestrant reveal about regulatory evidence standards.
If you are a patient or caregiver navigating this situation:
The Vasculitis Foundation is actively tracking developments and providing patient-centered guidance on the Tavneos situation. The American College of Rheumatology maintains current treatment guidelines for AAV. Adverse events can be reported directly to the FDA MedWatch system at 1-800-332-1088 or online.
Sources
FDA Drug Safety Communication: FDA Identifies Cases of Serious Liver Injury in Patients Taking Tavneos (avacopan). March 31, 2026. fda.gov.
Tavneos original FDA approval: FDA approves avacopan for ANCA-associated vasculitis. October 7, 2021. fda.gov.
Amgen prescribing update: Important Update Regarding TAVNEOS (avacopan). Amgen. April 2026.
ADVOCATE Phase 3 trial: Jayne DRW, Merkel PA, Schall TJ, Bekker P. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021;384:599-609.
ADVOCATE trial registration: NCT02994927. ClinicalTrials.gov.
Withdrawal controversy: Medscape. What’s at Issue in the FDA’s Request to Withdraw Avacopan? February 23, 2026.
Medscape alert coverage: Medscape. FDA Issues Alert on Liver Injuries Linked to Vasculitis Drug, Following Withdrawal Request. March 31, 2026.
Amgen refusal: Pharmaphorum. Amgen baulks at FDA request to withdraw Tavneos. February 2026.
Public Citizen statement: Public Citizen. FDA’s Avacopan Alert Raises More Questions Than It Answers. March 31, 2026.
Vasculitis Foundation patient update: Important Information for the Vasculitis Community Regarding TAVNEOS (avacopan). vasculitisfoundation.org. April 2026.
The Rheumatologist: Kaufman MB. Avacopan Under Scrutiny by FDA, EMA Due to Data Concerns. February 21, 2026. the-rheumatologist.org.
ACR vasculitis guidelines: American College of Rheumatology. Guidelines for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. rheumatology.org.
MedWatch adverse event reporting: FDA MedWatch Safety Reporting Portal. fda.gov/safety/medwatch.
Patient resources: Vasculitis Foundation | American College of Rheumatology | FDA MedWatch | NIAMS Vasculitis Information
| Disclaimer: Health Evidence Digest provides general information about drug safety communications and health research for educational purposes. This content is not a substitute for professional medical advice, diagnosis, or treatment. Patients should not make changes to their medication without consulting their healthcare provider. All clinical decisions should account for individual patient circumstances, disease severity, and current treatment guidelines. |
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