Post-marketing safety profile of Lumacaftor/Ivacaftor in cystic fibrosis treatment: A pharmacovigilance analysis based on FAERS

Tao Wang¹Weilun Yang¹Ye Luo¹Yue Zhan¹Fan Zou²Zhiwei Cui³Yuanbo Lan^1,2,4*

• ¹Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ²Department of Tuberculosis, Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ³Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
• ⁴Guizhou Provincial Key Laboratory of Pathogenesis and Prevention of Common Chronic Diseases, Zunyi, China

Background: Lumacaftor/ivacaftor (LUM/IVA) is a CFTR modulator approved for the treatment of cystic fibrosis (CF) caused by the F508del mutation. While clinical trials have demonstrated its efficacy, the long-term safety profile remains inadequately characterized. This study aims to assess the real-world safety of LUM/IVA through a comprehensive analysis of ADEs reported in FAERS from the third quarter of 2015 to 2024. Methods: Disproportionality analysis including the ROR and BCPNN was employed to identify potential safety signals associated with LUM/IVA. Furthermore, sensitivity analyses were conducted to eliminate potential confounding arising from concomitant medication use and underlying indications. Potential risk factors for LUM/IVA-associated depression were identified through logistic regression analysis. Finally, time-to-onset (TTO) analysis was conducted to evaluate the temporal patterns of ADEs. Results: A total of 7,843 LUM/IVA-related ADE reports were extracted, spanning 27 system organ classes (SOCs). We identified 221 positive signals, with 37 signals consistent with the drug label, 61 signals might be associated with disease progression, and 123 signals not listed in the drug label. Positive signals with most reported cases included infective pulmonary exacerbations (n=1394, ROR 1201.58, IC025 9.50), hospitalization (n=841, ROR 20.07, IC025 4.13) and, dyspnoea (n=517, ROR 4.00, IC025 1.83). Unexpected signals such as depression (n=81, ROR 1.71, IC025 0.45), suicidal ideation (n=31, ROR 1.63, IC025 0.20), and hypoglycemia (n=20, ROR 2.02, IC025 0.39) were detected, highlighting previously unreported risks. Stratified analysis identified risk signals in different subgroups, such as chest discomfort in 50-100 kg subgroup. The TTO analysis revealed that the median onset of ADEs was 256 days, with most ADEs reports occurring after 360 days of treatment LUM/IVA (39.2%), Moreover, cumulative incidence varied significantly among subgroups stratified by age, dosage, and frequency of administration. Conclusion: This study provides a detailed real-world safety profile of LUM/IVA, identifying both known and unexpected adverse events. Our findings underscore the importance of continuous post-marketing surveillance and the need for updated drug label to reflect associated risks, particularly those related to psychiatric symptoms and long-term adverse effects. Personalized treatment strategies based on patient characteristics, including sex, are recommended to optimize safety during LUM/IVA therapy.