MHRA Highlights Liver Injury Risk with Combination Therapy for Cystic Fibrosis

Pavankumar Kamat

February 22, 2022

The Medicines and Healthcare products Regulatory Agency (MHRA) has issued a drug safety update highlighting the risk of serious liver injury following treatment with a combination therapy for cystic fibrosis.

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

There is a potential risk of serious liver injury characterised by elevations in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin in patients receiving Kaftrio–Kalydeco combination.

Elevations in ALT and AST are considered clinically significant if they are five times the upper limit of normal (ULN) without increase in bilirubin levels or more than three times the ULN with bilirubin more than twice the ULN.

Safety Data Findings

A recent European review of safety data identified a post-marketing report of liver failure which necessitated liver transplantation in a patient receiving Kaftrio–Kalydeco combination. The patient had pre-existing cirrhosis and portal hypertension. Additionally, two more cases of serious liver injury were identified in adults with a history of liver disease.

Between October 2020 and December 12, 2021, the MHRA received 22 reports of serious liver disorders and 54 reports of abnormal findings on liver function tests among patients receiving Kaftrio–Kalydeco combination in the UK.

Advice for Clinicians

Clinicians should assess serum levels of total bilirubin, ALT and AST before starting treatment with Kaftrio–Kalydeco combination and subsequently every 3 months during the first year of treatment. Patients with a history of liver disease or a history of elevated transaminases need to be monitored more frequently.

Clinicians should use the combination cautiously in patients with an advanced pre-existing liver condition such as cirrhosis or portal hypertension and its use in this population is only justified if the benefits are likely to outweigh the risks. Such patients would require close monitoring.

Immediate clinical assessment and liver function testing is warranted for patients reporting symptoms suggestive of liver injury. Treatment discontinuation is advisable if there is significant elevation of liver enzymes or clinical signs and symptoms of hepatic damage.

Any suspected adverse drug reaction should be promptly reported to the Yellow Card Scheme.

The Summaries of Product Characteristics and Patient Information Leaflets for both Kaftrio and Kalydeco are being updated to reflect the risk of drug-induced liver injury associated with the combination.


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