The safety of nintedanib for the treatment of interstitial lung disease: A systematic review and meta-analysis of randomized controlled trials

Abstract

Introduction Nintedanib can inhibit processes involved in the progression of fibrosis and can reduce the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic-interstitial lung disease (fibrotic-ILDs). Although the adverse events associated with nintedanib in IPF patients are well known, its safety in other fibrotic-ILD patients remained unclear. Methods We searched PubMed, EMBASE, Cochrane CENTRAL and Cochrane CDSR for randomized controlled studies which compared nintedanib with a placebo in ILD patients. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs) for adverse events using the DerSimonian–Laird random-effects model. Results Six studies with a total of 2,583 patients were included in the meta-analysis. The pooled estimates showed that patients treated with nintedanib had a significantly higher likelihood of having any adverse events (OR = 2.39; 95% CI = 1.71–3.36) or adverse events leading to treatment discontinuation (OR = 1.73; 95% CI = 1.34–2.25). However, they had trend to lower likelihood of having fatal adverse events (OR = 0.69; 95% CI = 0.41–1.14) compared with the placebo group. Use of nintedanib was positively associated with diarrhea (OR = 5.96; 95% CI = 4.35–8.16), nausea (OR = 3.00; 95% CI = 1.93–4.66), vomiting (OR = 3.22; 95% CI = 2.17–4.76) and weight loss (OR = 3.38; 95% CI = 1.1.76–6.47). Whereas, patients treated with nintedanib were less likely to have a cough (OR = 0.73; 95% CI = 0.56–0.96) and dyspnea (OR = 0.70; 95% CI = 0.53–0.94). Conclusions Compared to a placebo, nintedanib was associated with a higher risk of adverse events, especially for diarrhea, nausea, vomiting and weight loss, but it was also associated with a lower risk of cough and dyspnea in IPF and fibrotic-ILD patients.

Fatty acid nitroalkene reversal of established lung fibrosis

“…Nintendanib inhibits NFκB, Smad3, STAT3 and multiple MAPK: Akt, ERK1/2, p38 MAPK signaling [ [148] , [149] , [150] ]. Both of these drugs can slow clinical IPF progression, do not reverse this process and have dose-limiting side effects, the latter possibly due to drug-protein adduct accumulation due to the irreversible nature of α,β−unsaturated carbonyl-protein derivatives [ 4 , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] ]. NO 2 -OA is shown herein to limit the same pro-inflammatory and pro-fibrotic pathways, as well as being a strong inducer of PPARγ and Nrf2-regulated anti-inflammatory and anti-fibrotic responses [ 28 , 72 , 73 , [120] , [121] , [122] , 124 , 125 ].…”

“…Pirfenidone induces adverse gastrointestinal tract responses (up to 68% incidence), anorexia (up to 16%) and skin irritation (up to 38%) [ 4 , [11] , [12] , [13] , [14] ]. Similarly, nintedanib induces gastrointestinal tract symptoms (up to 80% incidence), anorexia (up to 45%), headache (up to 13%), liver enzyme elevation (up to 13%) and fatigue (up to 11%) [ [15] , [16] , [17] , [18] ]. Consequently, a large proportion of IPF patients require dose reduction and treatment discontinuation due to the adverse side effects of both drugs [ 13 , 14 , 17 , 19 , 20 ].…”

“…Similarly, nintedanib induces gastrointestinal tract symptoms (up to 80% incidence), anorexia (up to 45%), headache (up to 13%), liver enzyme elevation (up to 13%) and fatigue (up to 11%) [ [15] , [16] , [17] , [18] ]. Consequently, a large proportion of IPF patients require dose reduction and treatment discontinuation due to the adverse side effects of both drugs [ 13 , 14 , 17 , 19 , 20 ]. Pirfenidone and nintedanib also have substantial monthly US healthcare costs of $11,272 and $11,987 per patient, respectively [ 21 ].…”

Pharmacological treatment for connective tissue disease-associated interstitial lung involvement: Protocol for an overview of systematic reviews and meta-analyses

“…We intend to categorize adverse events according to the classification outlined in the Medical Dictionary for Regulatory Activities (MedDRA) coding ( https://www.meddra.org/ ) and previous studies [ 43 ]. If data will be inadequately reported according to this categorization, then the primary investigators will be conducted to obtain the missing results.…”

The effect of additional antimicrobial therapy on the outcomes of patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis

“…These two agents have obtained approval from the United States (US) Food and Drug Administration for the treatment of IPF and are widely used in the European Union (EU) and other countries worldwide. However, their usefulness may be limited by their high cost and difficult to tolerate toxicity [ 9 – 11 ].…”