Pirfenidone in Idiopathic Pulmonary Fibrosis: Expert Panel Discussion on the Management of Drug-Related Adverse Events

Abstract Background Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities. Methods Data were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age < 75 versus ≥ 75 years, by < 5 and ≥ 5 comorbidities, and by Charlson Comorbidity Index (CCI) ≤ 3 and > 3 at baseline. Results The data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and < 75 years (difference 125.2 [90.1, 160.4]) (n = 1364) (p = 0.60 for treatment-by-time-by-subgroup interaction), in patients with < 5 comorbidities (difference: 107.9 [95% CI 65.0, 150.9]) (n = 843) and ≥ 5 comorbidities (difference 139.3 [93.8, 184.8]) (n = 847) (p = 0.41 for treatment-by-time-by-subgroup interaction) and in patients with CCI score ≤ 3 (difference: 106.4 [95% CI 70.4, 142.4]) (n = 1330) and CCI score > 3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%). Conclusions Our findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy. Trial registration: ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952.

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Efficacy and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis patients: a systematic review and meta-analysis of randomised controlled trials

BMJ Open ◽

10.1136/bmjopen-2021-050004 ◽

2021 ◽

Vol 11 (12) ◽

pp. e050004

Author(s):

Wenjuan Wu ◽

Lingxiao Qiu ◽

Jizhen Wu ◽

Xueya Liu ◽

Guojun Zhang

Keyword(s):

Systematic Review ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Acute Exacerbation ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Efficacy And Safety ◽

Randomised Controlled

ObjectivesIdiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic fibrotic disease, characterised by a progressive decline in lung function and a common histological pattern of interstitial pneumonia. To analyse the efficacy and safety of pirfenidone in the treatment of IPF, a systematic review and meta-analysis was performed.DesignThis is a meta-analysis study.ParticipantsPatients were diagnosed as IPF.InterventionsUse of pirfenidone.Primary and secondary outcomeProgression-free survival (PFS), acute exacerbation and worsening of IPF and Impact on adverse events.MeasuresThe inverse variance method for the random-effects model was used to summarise the dichotomous outcomes, risk ratios and 95% CIs.ResultsA total of 9 randomised controlled trials with 1011 participants receiving pirfenidone and 912 controls receiving placebo were summarised. The pooled result suggested a statistically significant difference inall-cause mortality after pirfenidone use, with a summarised relative ratio of 0.51 (p<0.01). Longer PFS was observed in patients receiving pirfenidone compared with those who were given placebo (p<0.01). The IPF groups presented a high incidence of adverse events with a pooled relative ratio of 3.89 (p<0.01).ConclusionsPirfenidone can provide survival benefit for patients with IPF. Pirfenidone treatment was also associated with a longer PFS, a lower incidence of acute exacerbation and worsening of IPF.

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Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

Pulmonary Therapy ◽

10.1007/s41030-018-0056-8 ◽

2018 ◽

Vol 4 (1) ◽

pp. 103-114 ◽

Cited By ~ 2

Author(s):

Mark L. Wencel ◽

Tmirah Haselkorn ◽

Susan L. Limb ◽

John L. Stauffer ◽

Elizabeth Morgenthien ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Real World ◽

Practice Patterns

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Efficacy of nintedanib on acute exacerbations reported as serious adverse events in the INPULSIS trials in idiopathic pulmonary fibrosis (IPF)

Pneumologie ◽

10.1055/s-0037-1598407 ◽

2017 ◽

Vol 71 (S 01) ◽

pp. S1-S125

Author(s):

M Kreuter ◽

H Koegler ◽

M Trampisch ◽

S Geier ◽

L Richeldi

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Serious Adverse Events ◽

Acute Exacerbations

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Efficacy of low dose pirfenidone in idiopathic pulmonary fibrosis: real world experience from a tertiary university hospital

Scientific Reports ◽

10.1038/s41598-020-77837-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Myung Jin Song ◽

Sung Woo Moon ◽

Ji Soo Choi ◽

Sang Hoon Lee ◽

Su Hwan Lee ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Dose Reduction ◽

Dose Group ◽

Low Dose ◽

High Dose Group ◽

High Dose ◽

Significant Difference

AbstractPirfenidone is an antifibrotic agent that has been proven to slow down the progression of idiopathic pulmonary fibrosis (IPF). The aim of this study was to evaluate the efficacy of low-dose pirfenidone (that is, less than 1200 mg/day). We retrospectively reviewed the medical records of patients with IPF. The patients were divided into the following three groups, those who were not treated with pirfenidone (control) and those who were treated with pirfenidone at doses < 1200 mg/day (low-dose group) and ≥ 1200 mg/day (high-dose group). The adjusted mean changes in forced vital capacity (FVC) in 1 year were − 200.7, − 88.4, and − 94.7 mL in the control, low-dose, and high-dose groups (p = 0.021). The FVC declined more significantly in the control group than in the low-dose and high-dose groups. No significant difference in FVC change was observed between the low-dose and high-dose groups. Dyspepsia, anorexia, and nausea were significantly more frequent in the low-dose than in the high-dose group, suggesting that dose reduction is attributed to gastrointestinal tract-related adverse events. Dose reduction may help patients to better control gastrointestinal tract-related adverse events; continuing taking the medication at low doses is also expected to be effective in reducing the FVC decline.

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Serious adverse events in patients with idiopathic pulmonary fibrosis in the placebo arms of 6 clinical trials

Respiratory Medicine ◽

10.1016/j.rmed.2019.02.021 ◽

2019 ◽

Vol 150 ◽

pp. 120-125

Author(s):

Wim Wuyts ◽

Danielle Antin-Ozerkis ◽

J. Terrill Huggins ◽

Peter P. LaCamera ◽

Paolo Spagnolo ◽

...

Keyword(s):

Clinical Trials ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Serious Adverse Events

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Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis

European Respiratory Review ◽

10.1183/09059180.00011514 ◽

2015 ◽

Vol 24 (135) ◽

pp. 58-64 ◽

Cited By ~ 58

Author(s):

Vincent Cottin ◽

Toby Maher

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Real World ◽

Sun Exposure ◽

Progression Free Survival ◽

Primary Treatment ◽

Lung Function Decline ◽

Long Term Treatment

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, progressively destructive lung disease that culminates in respiratory failure and death. Randomised controlled trials have demonstrated that treatment of IPF patients with pirfenidone reduces lung function decline, improves progression-free survival and significantly reduces the risk of all-cause mortality at 1 year. Pirfenidone has been shown to have a favourable safety profile and was generally well tolerated over the long term in clinical trials and real-world experience. However, side-effect management is critical to help some patients remain on treatment over the long term. The primary treatment-related adverse events associated with pirfenidone therapy are gastrointestinal upset, rash and photosensitivity. Gastrointestinal events may be mitigated by ensuring that pirfenidone is taken with food, while skin symptoms may be reduced by avoiding sun exposure and frequent use of sunblock. Educating patients about the potential for these adverse events to occur and providing instructions prior to treatment to avoid adverse drug reactions are an important means of ensuring patients may derive the important benefits provided by long-term treatment with pirfenidone.

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Differential Discontinuation Profiles between Pirfenidone and Nintedanib in Patients with Idiopathic Pulmonary Fibrosis

Cells ◽

10.3390/cells11010143 ◽

2022 ◽

Vol 11 (1) ◽

pp. 143

Author(s):

Kazutaka Takehara ◽

Yasuhiko Koga ◽

Yoshimasa Hachisu ◽

Mitsuyoshi Utsugi ◽

Yuri Sawada ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Disease Progression ◽

Continuous Treatment ◽

Discontinuation Rate ◽

Antifibrotic Therapy ◽

Significant Difference ◽

One Year ◽

Observation Period

Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF treatment to prevent disease progression. However, antifibrotic treatment has considerable adverse events, and the continuation of treatment is uncertain in many cases. Therefore, we examined and compared the continuity of treatment between pirfenidone and nintedanib in patients with IPF. We retrospectively enrolled 261 consecutive IPF patients who received antifibrotic treatment from six core facilities in Gunma Prefecture from 2009 to 2018. Among them, 77 patients were excluded if the antifibrotic agent was switched or if the observation period was less than a year. In this study, 134 patients treated with pirfenidone and 50 treated with nintedanib were analyzed. There was no significant difference in patient background, discontinuation rate of antifibrotic treatment over time, and survival rate between the two groups. However, the discontinuation rate due to adverse events within one year of antifibrotic treatment was significantly higher in the nintedanib group than in the pirfenidone group (76% vs. 37%, p < 0.001). Furthermore, the discontinuation rate due to adverse events in nintedanib was higher than that of pirfenidone treatment throughout the observation period (70.6% vs. 31.2%, p = 0.016). The pirfenidone group tended to be discontinued due to acute exacerbation or transfer to another facility. The results of this study suggest that better management of adverse events with nintedanib leads to more continuous treatment that prevents disease progression and acute exacerbations, thus improving prognosis in patients with IPF.

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