Vertex Updates Warnings Section of Trikafta Label

Vertex Pharmaceuticals has updated the Warnings and Precautions section of the label for Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) to reflect postmarketing data of liver failure as a result of therapy.

The FDA approved Trikafta in October 2019 to treat cystic fibrosis in patients aged 12 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which represents 90% of the cystic fibrosis population. In January 2021, the FDA approved the therapy to treat patients with cystic fibrosis who have other mutations, and in June the FDA approved for patients between 6 years and 11 years.

At the time of approval, the safety profile was based on data from 510 patients in two trials. Serious adverse events included rash and flu. At that time, the label warned of elevated liver function tests (transaminases and bilirubin), as well as use at the same time with other products that are inducers or inhibitors of another liver enzyme called Cytochrome P450 3A4.

The label was updated following postmarketing reports of liver injury in a small number of patients, including a report of liver failure leading to transplantation in one patient with pre-existing cirrhosis and portal hypertension, a spokesperson for Vertex said in an email to Formulary Watch.

“The existing warning for elevated transaminases in the Trikafta label was updated to reflect the postmarketing data and include a caution for use in patients with preexisting advanced liver disease. The positive risk/benefit profile of Trikafta is unchanged,” the spokesperson said.

The Warnings and Precautions section of the label now reads:

“Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving Trikafta. Avoid use of Trikafta in patients with preexisting advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment.

“Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with Trikafta. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of preexisting liver disease.”

In August 2021, the company released data from the third phase 3 study of Trikafta. In this study, 258 patients were randomized to receive Trikafta or to remain on their prior regimen of ivacaftor or tezacaftor/ivacaftor for eight weeks. The results show clinically meaningful improvements in pulmonary function, sweat chloride, and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores.

Cystic fibrosis is a rare genetic disease is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. It is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene.

It occurs in 1 in 2,500 to 3,500 white newborns. Cystic fibrosis is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans.