Mental health safety profile of CFTR modulators in pediatrics and adults: insights from the French pharmacovigilance database and from VigiBase

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Abstract Rationale CFTR modulators (CFTRms) have transformed cystic fibrosis care, yet concern exists regarding their mental health safety profile. Objective To provide further information, we conducted an analysis of CFTRm-related mental health disorders using two spontaneous pharmacovigilance reporting databases in real-world settings. Methods We analyzed reports from the French Pharmacovigilance Database (FPD) and VigiBase, the WHO global individual case safety reports database. Reports recorded between 2012 and 2024 involving any CFTRm and psychiatric disorders were included. In VigiBase, we conducted a case-non case, disproportionality analysis using the Reporting Odds Ratio (ROR), overall and stratified by age group (pediatrics vs. adults) and by CFTRm type. This study was conducted in accordance with the STROBE and the READUS-PV guidelines. Results In the FPD, 116 cases were analyzed. ELX/TEZ/IVA was suspected in 98% of cases and no single case was reported with ivacaftor alone. Sleep (61%), mood (37%), and anxiety disorders (27%) were the most frequently reported, with suicidal behaviors being infrequent, including 6 suicide attempts and no completed suicide. In VigiBase (n = 3,407), sleep disorders predominated in children, whereas mood and suicidality disorders were most frequent in adolescents. The median time to onset was 60 days (Q1-Q3: 12—150 days). Mental health disorders were disproportionately reported with CFTRms, particularly ELX/TEZ/IVA, while they were not with other combination therapies, compared to other drugs in the database. Disproportionality signals were slightly stronger in pediatrics than in adults. Conclusions CFTRms, especially ELX/TEZ/IVA, are associated with increased reporting of mental health disorders, predominantly sleep and mood disorders. Pediatrics appear to be particularly affected. Prospective observational studies are warranted to confirm these findings and elucidate underlying pathophysiological mechanisms. Registration OSF: mfyx3