Overview

Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) indicated for the treatment of idiopathic pulmonary fibrosis in adults. Nintedanib targets three key receptors including the vascular endothelial growth factor receptors (VEGFR 1-3), fibroblast growth factor receptors (FGFR 1-3) and platelet derived growth factor receptors (PDGFR).¹

Ischaemic colitis is caused by insufficient blood flow to the large intestine which results in mucosal ulceration, inflammation and haemorrhage. Its causes can either be physiological (hypotension, secondary to embolus or thrombosis) or iatrogenic secondary to medicines or surgery. The clinical manifestations of ischaemic colitis are diarrhoea, colicky abdominal pain, and rectal bleeding. Complications resulting from ischaemic colitis include obstruction, necrosis, and perforation.² 

Background

In February 2020, the National Pharmaceutical Regulatory Agency (NPRA) received a safety issue notification from Boehringer Ingelheim Sdn. Bhd. regarding a signal assessment of ischaemic colitis associated with nintedanib use. This assessment was published in the World Health Organisation (WHO) Pharmaceuticals Newsletter in December 2019.

Based on WHO’s signal assessment, the biologic plausibility of an association between nintedanib and ischaemic colitis is based on its inhibitory action of the vascular endothelial growth factor (VEGF)-receptor. VEGF mediates multiple functions within the vascular system, including endothelial cell proliferation, vascular permeability, vasodilation, and the mediation of the release of nitric oxide. VEGF inhibition therefore leads to vasoconstriction, and this could be a factor to the occurrence of ischaemic colitis.²

Looking at all the available evidence, the WHO assessment concluded that there is a reasonable possibility of a causal relationship between nintedanib and ischaemic colitis.

Adverse Drug Reaction (ADR) Reports:

To date, NPRA has received 36 reports with 88 adverse events suspected to be related to nintedanib. The most commonly reported ADR were diarrhoea, vomiting, appetite lost, decreased weight and transaminitis. No event on ischaemic colitis has been reported locally.³

Advice for Healthcare Professionals:

• While NPRA is still reviewing this safety issue, be aware that there have been post-marketing ADR reports of ischaemic colitis associated with nintedanib use.
• Be alert that that diarrhoea could be a symptom of ischaemic colitis. Rule it out prior to recommending symptomatic treatment for diarrhoea, in patients on nintedanib.
• Report all adverse events suspected to be related to the use of nintedanib to NPRA.

References:

1. Nintedanib local product package insert (Last revision date: September 2019).
2. World Health Organisation (2019). WHO Pharmaceuticals Newsletter No. 6: Nintedanib and ischaemic colitis.
3. The Malaysian Adverse Reactions Database, NPRA [Accessed: April 2020].

DISCLAIMER:

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.