SIGNAL regarding the use of nintedanib and the occurrence of ischemic colitis, according to the WHO global database VigiBase

Nintedanib is a small-molecule protein kinase inhibitor intended for the treatment of idiopathic pulmonary fibrosis in adults.

Statistical screening of VigiBase, the WHO global database, revealed an increased disproportionality score for the nintedanib-colitis combination. A review of the published literature and further investigation made it possible to refine the clinical manifestation of the adverse reaction from the nonspecific term “colitis” to the more specific “ischemic colitis”. Causality was assessed using the Bradford Hill criteria. The causal relationship of this signal is considered justified, since early detection of ischemia can prevent gastrointestinal perforation.

Given that the most common gastrointestinal adverse reaction for nintedanib is diarrhea, which may be a symptom of ischemic colitis, it is considered important to inform healthcare professionals of the need to exclude ischemia before recommending symptomatic treatment of diarrhea with loperamide.

Reports in VigiBase

The nintedanib-colitis combination with the drug-ADR was identified as a statistical signal during analysis of VigiBase, the WHO global database, in December 2018. The initial case series included 25 cases, which on review described either various specific types of colitis, such as ischemic or inflammatory, or were not specified. Given that nintedanib acts on the VEGF receptor, it was decided to investigate the association between nintedanib and the more specific term “ischemic colitis”.

Conclusions

VigiBase analysis revealed a signal of disproportionate reports of colitis following the use of nintedanib, which is a low-molecular-weight tyrosine kinase inhibitor. Given that nintedanib blocks VEGF receptors, the initial signal was further investigated in VigiBase and refined to the more specific clinical event “ischemic colitis.” The case series supporting this signal consists of 10 cases, including “colitis,” “ischemic colitis,” “intestinal ischemia,” and “intestinal infarction.” Evaluation of nintedanib and ischemic colitis demonstrated that the data supporting the Bradford Hill criteria led to the conclusion of a reasonable possibility of a causal relationship between nintedanib and ischemic colitis.

It is considered appropriate to add “ischemic colitis” to the instructions for medical use of nintedanib. In addition, given that the most common gastrointestinal adverse reaction is diarrhea, which may be a symptom of ischemic colitis, it is important to inform healthcare professionals about excluding ischemia before the recommended symptomatic treatment of diarrhea with loperamide.

Link to the VigiBase website – https://vigilyze.who-umc.org/