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Health Sciences Authority
Safety Alerts

Risk of drug-induced liver injury associated with the use of pirfenidone

Audiences

Healthcare professional

Industry member

Product type

Therapeutic Products

10 December 2020

This article has been migrated from an earlier version of the site and may display formatting inconsistencies.

HSA would like to remind healthcare professionals about the risk of drug-induced liver injury (DILI) with the use of pirfenidone. This rare but potentially serious adverse event was highlighted in a Dear Healthcare Professional Letter (DHCPL) issued in November 2019 in response to overseas cases of DILI, including isolated cases with fatal outcome, reported in patients treated with pirfenidone. Healthcare professionals are advised to perform liver function tests prior to treatment initiation with pirfenidone, at regular intervals subsequently, and in the presence of clinical signs or symptoms that may indicate liver injury.

Pirfenidone (Esbriet®, Roche Singapore Pte Ltd) is an anti-fibrotic and anti-inflammatory agent. It has been registered in Singapore since 2016 and is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Overseas cases of pirfenidone-associated DILI

Pirfenidone has been known to be associated with transient and clinically silent elevation of liver enzymes, which are rarely associated with concomitant bilirubin increases. However, overseas cases of serious hepatic adverse events, including isolated cases with fatal outcome, have recently been reported in IPF patients treated with pirfenidone. Majority of the reported hepatic events occurred within the first few months of treatment. No alternative aetiologies or confounding factors were found in these reports, which were therefore deemed clinically relevant cases of DILI. In the absence of a plausible pharmacodynamic mechanism, these cases appeared to be possibly triggered by idiosyncratic reactions to pirfenidone. The frequency of clinically relevant DILI detected from post-marketing reports is estimated as rare (≥1/10,000 to <1/1,000).

Local situation and HSA’s advisory

To date, HSA has not received any local report of DILI associated with pirfenidone use. In November 2019, a DHCPL was issued by the product registrant for Esbriet® to inform healthcare professionals about this safety concern.1 The local package insert (PI) for Esbriet® has been strengthened to highlight the risk of clinically relevant DILI and recommend additional monitoring of liver function in the presence of clinical signs or symptoms suggestive of liver injury. 

Healthcare professionals are advised to perform liver function tests prior to treatment initiation with pirfenidone, and subsequently at monthly intervals for the first 6 months of treatment, and then every 3 months thereafter. In addition, liver function tests should be promptly measured in patients who report symptoms that may indicate liver injury. Recommendations on dose adjustment or discontinuation of pirfenidone therapy due to elevated liver enzymes are shown in Table 1.2

 

Table 1. Recommendations on dose adjustment or discontinuation of pirfenidone therapy due to elevated liver enzymes

Table caption

Liver enzyme elevations

Recommendations

Aminotransferase elevation >3 to <5 x ULN* without bilirubin elevation

  • Other causes should be excluded, and the patient monitored closely. Discontinuation of other medicines associated with liver toxicity should be considered

  • If clinically appropriate, the dose of pirfenidone should be reduced or interrupted

  • Once liver function tests are within normal limits, pirfenidone may be re-escalated to the recommended daily dose if tolerated

Aminotransferase elevation >3 to <5 x ULN* accompanied by hyperbilirubinemia or clinical symptoms indicative of liver injury

  • Pirfenidone should be discontinued and the patient should not be rechallenged

Aminotransferase elevation ≥5 x ULN*

 *Upper limit of normal

Healthcare professionals are also encouraged to report to HSA any suspected cases of DILI related to the use of pirfenidone.

References

  1. https://www.hsa.gov.sg/announcements/important-safety-update-on-esbriet--pirfenidone--and-drug-induced-liver-injury--dili-/

  2. Esbriet® Singapore package insert (last approved 4th May 2020).