Abstract
BACKGROUND: Increasing global frequency of drug-induced interstitial lung disease (ILD) coincides with increasing market introduction of tyrosine kinase inhibitors (TKIs). OBJECTIVES: The aim was to detect disproportional reporting of TKI-induced ILD in the EudraVigilance post-marketing safety database and to scrutinise the prescribing information of these TKIs. METHODS: Data were gathered on the number of total and individual ILD case safety reports for each TKI marketed in the European Union (EU), together with indications and patient demographics. Information was also obtained on numbers of total and ILD reports for all drugs in the entire database, covering the period January 2002 to March 2024. Chi-squared analyses and two measures of disproportionality, the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to ascertain the ILD-inducing potential of TKIs, both as a group and with each TKI individually. The latest prescribing information for each TKI was evaluated for ILD-related information. RESULTS: TKIs were collectively associated with a significantly stronger disproportionality signal for ILD reports compared to all non-TKI drugs (p < 0.001). There was marked variation in the disproportionality of ILD reporting across the 51 TKIs studied. Potential risk factors included male gender (p < 0.001), age 65-85 years (p < 0.001) and an oncological indication (p < 0.001), particularly non-small cell lung cancer (NSCLC). Fatality rates among cases of TKI-induced ILD were 17.4% overall, 22.2% in patients with NSCLC and 11.5% in those with a non-oncological indication. The prescribing information of 11 TKIs lacked any reference to ILD despite a strong signal that indicated their potential association with ILD. CONCLUSIONS: Drug-induced ILD is emerging as an important safety issue, and physicians need to maintain a high index of suspicion of ILD in patients treated with a TKI.