Pirfenidone (Esbriet): risk of serious liver injury; updated advice on liver function testing
Serious liver injury has been reported during treatment with pirfenidone in the first year after initiation, including 2 cases with a fatal outcome. Measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels before starting pirfenidone treatment, monthly for the first 6 months of treatment, and then every 3 months thereafter. Follow new guidance on testing liver function promptly in patients who report symptoms or have clinical signs that might indicate they have liver injury and adjust the dose or discontinue treatment according to new recommendations.
Advice for healthcare professionals:
- serious cases of drug-induced liver injury, including liver failure, have been reported in patients treated with pirfenidone; cases have been estimated to be of uncommon frequency but 2 reports worldwide had a fatal outcome
- continue to monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels before initiation, at monthly intervals during the first 6 months of treatment and every 3 months thereafter
- advise patients to seek medical help immediately if they have signs and symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice
- perform prompt clinical evaluation and measure liver function in patients who report symptoms that may indicate liver injury
- in the event of significant elevation of liver enzymes or clinical signs and symptoms of liver injury, adjust the dose of pirfenidone or discontinue treatment (see table for new guidance)
- monitor closely for signs of toxicity if pirfenidone is being used concomitantly with inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone (see table)
- report suspected adverse reactions associated with pirfenidone to the Yellow Card scheme
Review of reports of severe liver injury
Pirfenidone (brand name Esbriet) is an anti-fibrotic and anti-inflammatory agent indicated for the treatment of idiopathic pulmonary fibrosis. Pirfenidone is known to commonly cause elevation of liver transaminases (ALT and AST), with associated concomitant increases in bilirubin in rare cases.
A recent European review of safety data identified severe cases of drug-induced liver injury associated with pirfenidone reported post-marketing, including isolated cases with a fatal outcome. Reported events included hepatitis, liver injury, and liver failure.
Reports of serious liver injury are considered to be uncommon (may occur in between 1 in 100 and 1 in 1000 people who take pirfenidone) and the benefit-risk profile of pirfenidone in the approved indications remains favourable. Although the aetiology is unclear, idiosyncratic reactions may underlie the occurrence of drug-induced liver injury following treatment with pirfenidone.
New advice to minimise risk
Following the findings of the review, existing warnings for the potential for hepatotoxicity in the product information will be strengthened to include the risk of clinically relevant drug-induced liver injury with pirfenidone. While the recommendation for liver function monitoring before and during treatment has not changed, new advice will be added to minimise risk in patients taking pirfenidone.
New warnings in the summary of product characteristics will ask for prompt liver function testing in patients who report symptoms or have clinical signs that might indicate liver injury, and adjustment of the dose of pirfenidone or discontinuation of treatment if necessary – see Table.
A letter has been sent to prescribers to advise them of this information and updates have been made to the educational materials and the prescriber checklist to reflect the new advice. A targeted questionnaire has also been introduced, which will be used by the marketing authorisation holder for pirfenidone to follow-up with healthcare professionals to obtain further details of reported cases of serious hepatic reactions.
Details of fatal reports
Two fatal cases consistent with drug-induced liver injury were reported in the literature in association with pirfenidone.[footnote 1] [footnote 2] These events of drug-induced liver injury and subsequent liver failure occurred at 1 month and 12 months after initiation of treatment with pirfenidone.
In the first case, the patient presented with acute liver failure and grade 3 hepatic encephalopathy, accompanied by elevated liver function test results, jaundice, and altered mental state.[footnote 1] Pirfenidone was withdrawn but the patient, who had no other apparent causes for acute liver failure, subsequently had organ failure and died. Post-mortem liver biopsy revealed findings consistent with drug-induced liver injury.
In the second fatal case, the patient developed elevated transaminases after 1 year of pirfenidone treatment and 3 days after starting concomitant treatment with esomeprazole.[footnote 2] Despite discontinuation of both medicines, the patient was hospitalised with jaundice, pruritus, nausea, and fatigue accompanied by further increase in transaminases. Liver biopsy indicated drug-induced liver injury and the patient died from sepsis, lactic acidosis, and multiorgan failure. Esomeprazole is a known substrate for cytochrome P450 enzymes that are important in pirfenidone metabolism, and the authors of the study hypothesise that this could lead to a potential drug-drug interaction.[footnote 2]
Recommended liver monitoring
Perform liver function tests (ALT, AST, and bilirubin) before initiating treatment with pirfenidone, and subsequently at monthly intervals for the first 6 months. and then every 3 months thereafter.
Clinically evaluate and perform liver function tests in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
In the event of significant elevation of liver aminotransferases or clinical signs and symptoms of hepatic injury, adjust the dose or discontinue treatment according to the below guidance.
Dose adjustments due to liver enzyme abnormalities
The dose adjustments due to liver enzyme abnormalities or clinical signs and symptoms have been updated in the product information and the new recommendations are recorded in the table below.
Table – Laboratory value of aminotransferases by upper level normal (ULN) and actions to take
| 3–5-times ULN without bilirubin elevation |
|---|
| Exclude other causes |
| Monitor the patient closely |
| Consider discontinuing other medicines associated with liver toxicity |
| Consider possible drug interactions if the patient is taking inhibitors of CYP isoenzymes involved in the metabolism of pirfenidone – for example, fluvoxamine (CYP1A2), amiodarone (CYP1A2 and CYP2C9), chloramphenicol (CYP2C19), and fluoxetine (CYP2D6) |
| Reduce or interrupt the dose of pirfenidone if clinically appropriate |
| Re-escalate pirfenidone to the recommended daily dose if tolerated once liver function tests are within normal limits |
| 3–5-times ULN accompanied by hyperbilirubinaemia or clinical signs or symptoms indicative of liver injury |
|---|
| Permanently discontinue pirfenidone therapy; do not reinitiate treatment |
| Higher than 5-times ULN |
|---|
| Permanently discontinue pirfenidone therapy; do not reinitiate treatment |
Further information on hepatic risks
During clinical development of pirfenidone, an increased cumulative incidence of hepatic treatment-emergent adverse events was observed; most of which were laboratory abnormalities without clinical signs and symptoms. Pirfenidone is contraindicated in patients with severe or end-stage hepatic disease.
Report suspected reactions on a Yellow Card
Please continue to report suspected adverse drug reactions (ADRs) to the Yellow Card scheme. Reporting suspected ADRs, even those known to occur, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
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the Yellow Card app; download from the Apple App Store or Google Play Store
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some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, treatment dates, and product brand name.
Article citation: Drug Safety Update volume 14, issue 4: November 2020: 2.
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Verma N and others. ‘Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini-review of the literature’. Hepatol Commun 2017; volume 2: pages 142–147. ↩ ↩2
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Benesic A and others. ‘Acute liver failure during pirfenidone treatment triggered by co-medication with esomeprazole’. Hepatology 2019; volume 70: pages 1869–71. ↩ ↩2 ↩3
Updates to this page
Last updated 16 November 2020 + show all updates
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Added to DSU November
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First published.