Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Global Pharmacovigilance Data

Abstract

Introduction: The safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) have been characterized using data from clinical trials. Methods: We further characterized the safety and tolerability of nintedanib in patients with IPF in clinical practice using the global pharmacovigilance database. The database included spontaneously reported adverse events and data collected via solicited reporting in patients treated with nintedanib from 15 October 2014 to 15 October 2018. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated on the basis of sales data. Results: Cumulative exposure to nintedanib was estimated as 60,107 patient-years. Diarrhea was the most frequent event (301.6 events per 1000 patient-years). Most (97.0%) diarrhea events were non-serious. The median (25th, 75th percentile) time to onset of the first diarrhea event was 60 (11, 182) days. Elevated liver enzyme or bilirubin levels were reported at a rate of 31.5 events per 1000 patient-years. Bleeding was reported at a rate of 36.8 events per 1000 patient-years; 81.0% of events were non-serious. Major cardiovascular adverse events were reported at a rate of 13.4 events per 1000 patient-years and myocardial infarction at a rate of 4.3 events per 1000 patient-years. Gastrointestinal perforation was reported at a rate of 1.0 event per 1000 patient-years. Conclusions: On the basis of pharmacovigilance data collected over 4 years, the safety profile of nintedanib in patients with IPF was consistent with that observed in clinical trials and described in the product label, with no new safety concerns observed. Joseph A. Lasky and Gerard J. Criner contributed equally to this article.

Nintedanib: A Review in Fibrotic Interstitial Lung Diseases

“…In INSTAGE, nintedanib had a similar AE profile to that in the INPULSIS trials in patients with milder disease (albeit with a higher frequency of serious AEs) and AEs led to permanent discontinuation of nintedanib in 19% of patients who received nintedanib plus placebo [34]. Global pharmacovigilance data for nintedanib in the treatment of IPF collected over 4 years (estimated cumulative exposure to nintedanib of 60,107 PY) were consistent with the safety profile established in clinical trials [55].…”

“…GI AEs were the most frequently reported AEs in clinical trials and global pharmacovigilance data. In the latter, diarrhoea had an incidence rate of 301.6 events/1000 PY and most events of diarrhoea were non-serious (97%) [ 55 ]. GI perforation was rare, occurring at a rate of 1.0 event/1000 PY [ 55 ].…”

“…In the latter, diarrhoea had an incidence rate of 301.6 events/1000 PY and most events of diarrhoea were non-serious (97%) [ 55 ]. GI perforation was rare, occurring at a rate of 1.0 event/1000 PY [ 55 ]. Diarrhoea should be managed with adequate hydration and antidiarrhoeal medication (e.g.…”

“…Drug-induced liver injury, while uncommon, has been associated with nintedanib [ 37 , 51 , 58 ]. In global pharmacovigilance data, elevated liver enzyme or bilirubin levels occurred at a rate of 31.5 events/1000 PY, with a median time to first onset of 60 days [ 55 ]. Liver enzyme and bilirubin elevations were typically reversible with dose interruption or reduction in clinical trials [ 37 , 51 ].…”

“…The incidence of serious bleeding events was similar between treatment groups (1.3% vs 1.4%) [ 54 ]. Bleeding occurred at a rate of 36.8 events/1000 PY in global pharmacovigilance data, with the majority of bleeding events being non-serious (81%) and the most frequently reported type of bleeding event being epistaxis (25% of events) [ 55 ].…”