ESBRIET (pirfenidone) and the Risk of Drug-Induced Liver Injury

Starting date:
September 14, 2020
Posting date:
September 14, 2020
Type of communication:
Dear Healthcare Professional Letter
Subcategory:
Drugs
Source of recall:
Health Canada
Issue:
Important Safety Information, Product Safety
Audience:
Healthcare Professionals, Hospitals
Identification number:
RA-73905

Last updated:

Audience

Healthcare professionals including respirologists, prescribing physicians, emergency room physicians, and selected pharmacists.

Key messages

  • Drug-induced liver injury (DILI) in the form of transient and clinically silent elevations in transaminases has been commonly reported in patients treated with ESBRIET (pirfenidone). In rare cases, DILI has been associated with serious clinical consequences including isolated cases with fatal outcome.
  • Healthcare professionals are advised to:
    • perform liver function tests (ALT, AST, and bilirubin) before initiating treatment with ESBRIET, subsequently at monthly intervals for the first 6 months, and then every 3 months thereafter.
    • promptly measure liver function tests in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
    • consider discontinuation or dose adjustments in the event of liver enzyme elevation (see Table in the Information for healthcare professionals section).
    • not use ESBRIET in patients with severe hepatic impairment or end-stage liver disease.
    • use ESBRIET with caution in patients with pre existing mild to moderate hepatic impairment (Child-Pugh Class A and B).
  • The Canadian Product Monograph (CPM) for ESBRIET has been updated to include this new safety information.

   

Issue

Drug-induced liver injury (DILI) in the form of transient and clinically silent elevations in transaminases has been commonly reported in patients treated with ESBRIET. Rare DILI cases have been associated with serious clinical consequences including isolated cases with fatal outcome.

Products affected

ESBRIET®, pirfenidone hard capsules (267 mg) and pirfenidone film-coated tablets (267 mg and 801 mg).

Background information

ESBRIET (pirfenidone) is an anti-fibrotic and anti-inflammatory agent indicated for the treatment of idiopathic pulmonary fibrosis (IPF) in adults.

Serious hepatic adverse events including isolated cases with fatal outcome have recently been reported in the post-market setting in IPF patients treated with ESBRIET. The majority of the reported hepatic events occurred within the first 6 months of treatment. No alternative etiologies or confounding factors could be found in these reports, which were therefore deemed clinically relevant cases of DILI. In the absence of a plausible pharmacodynamic mechanism, these cases appear possibly triggered by idiosyncratic reactions to pirfenidone.

Who is affected

Information for consumers

ESBRIET (also known as pirfenidone) is a prescription medicine used to treat idiopathic pulmonary fibrosis (IPF) in adults. IPF is a condition in which the tissue in the lungs becomes scarred over time, making it difficult to breathe.

In some patients, ESBRIET has been associated with drug-induced liver injury (DILI), which can be serious and life-threatening.

Before taking ESBRIET, patients should talk to their healthcare professional if they have, or have had, liver problems. ESBRIET may cause liver problems and other abnormal blood test results. Patients with severe or end-stage liver disease should not use ESBRIET. ESBRIET should be used with caution and careful monitoring in patients with mild or moderate liver issues. Before and during treatment, patients should have blood tests done to check their liver function.

If patients experience signs of liver injury such as, tiredness, yellowing of the skin or eyes, dark urine, abdominal pain, nausea, vomiting, or loss of appetite, they need to stop taking ESBRIET and seek immediate medical attention.

Patients should discuss any questions or concerns about this information with their healthcare professional.

Information for healthcare professionals

Healthcare professionals are advised to:

  • perform liver function tests (ALT, AST, and bilirubin) before initiating treatment with ESBRIET, subsequently at monthly intervals for the first 6 months, and then every 3 months thereafter.
  • promptly measure liver function tests in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
  • not use ESBRIET in patients with severe hepatic impairment or end-stage liver disease.
  • use ESBRIET with caution in patients with pre existing mild to moderate hepatic impairment (Child-Pugh Class A and B).

Healthcare professionals are reminded to adjust or discontinue ESBRIET therapy in patients with confirmed elevations in ALT, AST or bilirubin as indicated in the table below:

LABORATORY VALUES/
SIGNS OR SYMPTOMS OF LIVER INJURY
ACTION
ALT and/or AST elevation to
>3 to <5 times ULN* without hyperbilirubinemia
  • Confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely.
  • As clinically appropriate, ESBRIET can be continued at the recommended dose, reduced or temporarily discontinued.
  • Once ALT and AST levels have resolved, ESBRIET may be re-escalated to the recommended daily dose and continued, if tolerated and the patient should be monitored closely.
ALT and/or AST elevation to
>3 to <5 times ULN* with clinical signs or symptoms indicative of liver injury OR hyperbilirubinemia (excluding patients with known predominantly unconjugated hyperbilirubinemia, e.g., Gilbert’s syndrome)
  • ESBRIET should be discontinued promptly.
  • The patient should be monitored closely until resolution of elevated ALT, AST, bilirubin, and symptoms.
  • The patient should NOT be re-challenged with ESBRIET.
ALT and/or AST elevation to ≥5 times ULN* regardless of the level of serum bilirubin
  • ESBRIET should be discontinued promptly.
  • The patient should be monitored closely until resolution of elevated ALT, AST, and bilirubin.
  • The patient should not be re-challenged with ESBRIET.

*the upper limit of normal

Action taken by Health Canada

Health Canada, in collaboration with Hoffmann-La Roche Limited, has updated the Warnings and Precautions, Adverse Reactions (Post-Market Adverse Drug Reactions) and Dosage and Administration sections of the Canadian Product Monograph (CPM) for ESBRIET to include this new safety information.

Health Canada is communicating this important safety information to healthcare professionals and Canadians via the Recalls and Safety Alerts Database on the Healthy Canadians Web Site. This communication will be further distributed through the MedEffect™ e-Notice email notification system as well as through social media channels, including LinkedIn and Twitter.

Report health or safety concerns

Health Canada’s ability to monitor the safety of marketed health products depends on healthcare professionals and consumers reporting adverse reactions and medical device incidents. Any case of DILI or other serious or unexpected side effects in patients receiving ESBRIET should be reported to Hoffmann-La Roche Limited or Health Canada.

Hoffmann-La Roche Limited
Drug Safety Department
7070 Mississauga Road
Mississauga, Ontario, L5N 5M8
Toll free: 1-888-762-4388
Fax: 905-542-5864
E-mail: mississauga.drug_safety@roche.com

To correct your mailing address or fax number, contact Hoffmann-La Roche Limited.

You can report any suspected adverse reactions associated with the use of health products to Health Canada by:

  • Calling toll-free at 1-866-234-2345; or
  • Visiting MedEffect Canada's Web page on Adverse Reaction Reporting for information on how to report online, by mail or by fax.

For other health product inquiries related to this communication, please contact Health Canada at:
Marketed Health Products Directorate
E-mail: hc.mhpd-dpsc.sc@canada.ca
Telephone: 613-954-6522
Fax: 613-952-7738

Original signed by

Loredana Regep, MD
Vice President, Medical & Regulatory Affairs
Hoffmann-La Roche Limited