Removing the FDA’s Boxed Hepatotoxicity Warning and Liver Function Testing Requirement for Ambrisentan
Authors: Feldman William B. , Mahesri Mufaddal , Sarpatwari Ameet , Huybrechts Krista F. , Zhu Yanmin , Hwang Catherine S. , Lii Joyce , Lee Su Been , Kattinakere Sreedhara Sushama , Toyserkani Gita A. , Zhou Esther H. , Zendel Laura , LaCivita Cynthia , Manzo Claudia , Dal Pan Gerald J. , Kesselheim Aaron S. , Bykov Katsiaryna 
Published: July 2024

Importance

Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed.

Objective

To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS.

Design, Setting, and Participants

This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases—Medicaid, Optum’s deidentified Clinformatics Data Mart, and Merative Marketscan—to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023.

Exposure

Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011.

Main Outcomes and Measures

The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1 000 000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill.

Results

A total of 10 261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11 159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, −18.2% to −8.0%) and before the first refill (26.4% absolute decrease; 95% CI, −34.4% to −18.5%) of ambrisentan but not bosentan.

Conclusions and Relevance

In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.