Ivacaftor, tezacaftor, elexacaftor (Kaftrio▼) in combination with ivacaftor (Kalydeco): risk of serious liver injury; updated advice on liver function testing

Cases of serious liver injury with elevated transaminases and bilirubin have been reported during treatment with Kaftrio–Kalydeco combination therapy. In all patients, measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels before starting treatment, every 3 months during the first year of treatment, and annually thereafter.

From:
Medicines and Healthcare products Regulatory Agency
Published
15 February 2022
Therapeutic area:
Respiratory disease and allergy

Advice for healthcare professionals:

  • cases of serious liver injury characterised by concomitant elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin have been reported with ivacaftor/tezacaftor/elexacaftor (Kaftrio) in combination with ivacaftor (Kalydeco)
  • one case of serious liver injury in a patient with pre-existing cirrhosis and portal hypertension resulted in liver failure requiring liver transplantation
  • measure total bilirubin levels in addition to ALT and AST levels before initiating treatment, every 3 months during the first year of treatment, and annually thereafter; consider more frequent monitoring for patients with a history of liver disease or a history of transaminase elevations
  • use with caution in patients with advanced pre-existing liver disease (for example, cirrhosis or portal hypertension) and only if the benefits are expected to outweigh the risks; if used, these patients should be closely monitored
  • perform prompt clinical evaluation and measure liver function in patients who report symptoms that may indicate liver injury
  • discontinue treatment in the event of significant elevation of liver enzymes (see criteria below) or clinical signs and symptoms of liver injury; following resolution of liver abnormalities, consider the benefits and risks before resuming treatment
  • report any suspected adverse reactions associated with Kaftrio▼ in combination with ivacaftor (Kalydeco) to the Yellow Card scheme

Advice for healthcare professionals to give to patients and carers:

  • Kaftrio and Kalydeco are medicines used in cystic fibrosis to help breathing by improving lung function
  • these medicines can affect the liver in some patients; a few patients on Kaftrio and Kalydeco combination therapy have developed severe liver problems – in isolated cases, a liver transplant could be needed
  • blood tests to check your liver function are needed before your treatment starts, every 3 months for the first year, and then once a year after this; you might need more frequent tests if you have had liver problems or high liver enzymes in the past
  • talk to your doctor straight away if you have signs of liver problems, such as pain in the upper right area of your stomach, yellowing of your skin or the white part of your eyes, loss of appetite, nausea or vomiting, or dark urine

Kaftrio–Kalydeco combination therapy and liver injury

Ivacaftor/elexacaftor/tezacaftor (Kaftrio▼) is indicated in a combination regimen with ivacaftor (Kalydeco) for the treatment of cystic fibrosis in patients aged 6 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Cystic fibrosis can lead to liver fibrosis and liver cirrhosis, and elevations in ALT and AST are common. Elevated transaminases have also been observed in patients treated with Kaftrio–Kalydeco combination therapy. Regular monitoring of liver function, including transaminases, has been advised since authorisation.

A recent European review of safety data identified a case of liver failure leading to liver transplantation in a patient taking Kaftrio–Kalydeco combination. This case was reported post-marketing in an adult patient with pre-existing cirrhosis and portal hypertension. The review also identified 2 other cases of serious liver injury in adult patients with no prior history of liver disease. These patients had elevations in transaminases and total bilirubin, and the patients were hospitalised with jaundice.

It is not possible to estimate the frequency of reports of serious liver injury or bilirubin elevations. The mechanism underlying liver injury following treatment is also unknown.

In the UK, from October 2020 and up to 12 December 2021, the Yellow Card scheme has received 22 reports of serious liver disorders and 54 reports of abnormal liver test results (6 with concomitant bilirubin elevations) associated with Kaftrio–Kalydeco combination therapy.[footnote 1] As for all medicines, the MHRA will keep reports of suspected serious adverse drug reactions under close review.

New advice to minimise risk of liver injury

Following the findings of the European review, existing warnings on hepatotoxicity in the product information for Kaftrio and Kalydeco have been strengthened to include the risk of clinically relevant drug-induced liver injury with Kaftrio–Kalydeco combination therapy.

The recommendations for liver function monitoring before and during treatment, which already included regular assessment of ALT and AST, have been strengthened to include advice to measure total bilirubin concomitantly. The advice that more frequent monitoring should be considered in patients with a history of transaminase elevations has been extended to include also patents with pre-existing liver disease.

In patients with pre-existing advanced liver disease (for example, cirrhosis, portal hypertension) Kaftrio–Kalydeco combination therapy should be used with caution and only if the benefits are expected to outweigh the risks. If these patients receive combination therapy, they should be closely monitored after the initiation of treatment.

Advice in cases of significant liver enzyme abnormalities

If aminotransferases are more than 5-times upper limit of normal (ULN) without bilirubin elevation or more than 3-times ULN with bilirubin more than 2-times ULN:

  • interrupt treatment dosing
  • monitor aminotransferases and bilirubin until within normal limits
  • following resolution, consider the benefits and risks of resuming treatment

Reminder of advice for hepatic impairment

Ivacaftor, tezacaftor, and elexacaftor are extensively metabolised by the cytochrome P450 system in the liver. For patients with moderate hepatic impairment (Child-Pugh Class B), the use of Kaftrio–Kalydeco combination therapy should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If this is the case, the combination should be used with caution at a reduced dose as advised in the Summary of Product Characteristics. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. It is recommended that patients with severe hepatic impairment should not be treated with Kaftrio.

Report suspected reactions on a Yellow Card

Kaftrio is a black triangle medicine and all suspected adverse drug reactions should be reported to the Yellow Card scheme.

Report electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 15, issue 7: February 2022: 3.

  1. In interpreting these data, caution should be exercised as the data may not be complete, and the reporting rates and the information provided within the reports can be influenced by many factors. Reporters are asked to submit Yellow Card reports even if they only have a suspicion that the medicine may have caused the adverse drug reaction. ↩

Updates to this page

Published 15 February 2022
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