A real-world study of antifibrotic drugs-related adverse events based on the United States food and drug administration adverse event reporting system and VigiAccess databases

Objectives: This study aims to investigate adverse events (AEs) and adverse drug reactions (ADRs) associated with pirfenidone and nintedanib, two antifibrotic drugs used to treat idiopathic pulmonary fibrosis (IPF). Methods: Reporting odds ratio (ROR) and proportional reporting ratio (PRR) analyses were conducted to assess the association between these drugs and signals at both the preferred term (PT) and system organ class (SOC) levels. Results: 55,949 reports for pirfenidone and 35,884 reports for nintedanib were obtained from the FAERS database. The VigiAccess database provided 37,187 reports for pirfenidone and 23,134 reports for nintedanib. Male patients and individuals over the age of 65 were more likely to report AEs. Gastrointestinal disorders emerged as the most significant signal at SOC level for both drugs. Furthermore, nausea, diarrhoea, and decreased appetite were observed at the PT level. We further identified notable signals, including hemiplegic migraine for pirfenidone and asthenia, constipation, and flatulence for nintedanib, which were previously unknown or underestimated ADRs. Conclusion: This study has identified AEs and ADRs associated with pirfenidone and nintedanib, confirming that the majority of the corresponding label information indicates relative safety. However, it is essential to take unexpected risk signals seriously, necessitating further research to manage the safety profiles of these drugs.


Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease (ILD) characterized by the excessive development of fibrotic tissue in the lungs, leading to impaired respiratory function, an increased risk of respiratory failure, and complications causing mortality (Lederer and Martinez, 2018).Globally, IPF affects approximately 3 million individuals, with a median survival ranging from 2 to 3 years (Quinn et al., 2019).Despite extensive research efforts, the exact etiology of IPF remains elusive (Podolanczuk et al., 2023).Nonpharmacologic interventions are pivotal in improving the overall wellbeing and quality of life for IPF patients, enabling them to lead healthier lives (Liu et al., 2022).Moreover, among the limited treatment options currently available, nintedanib and pirfenidone, two antifibrotic drugs, are recommended as first-line treatment for IPF due to their promise in slowing progression, preserving lung function, and improving patient outcomes (Flaherty et al., 2018).
Pirfenidone exerts regulatory effects on fibrogenic growth factors, particularly transforming growth factor (TGF)-β1.It mitigates fibroblasts proliferation and differentiation, as well as the synthesis of collagen, fibronectin, and other extracellular matrix (ECM) components (Ruwanpura et al., 2020).Clinical evidence shows that pirfenidone can reduce the decline in forced vital capacity (FVC) and improve progression-free survival in IPF patients (Takehara et al., 2023).Firstly approved for IPF treatment in Japan, pirfenidone has gained clinical recognition in America and Europe.Nintedanib, a triple angiokinase inhibitor, is another disease-modifying therapy approved for the treatment of IPF.It targets key fibrogenesis pathways, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) signaling (Flaherty et al., 2019).Clinical trials, such as INPULSIS trials, have demonstrated that nintedanib reduces the annual decline in FVC and slows IPF progression, leading to its first approval as a treatment option for IPF in the United States in 2014 (Crestani et al., 2019).
However, despite their therapeutic benefits, drugs can pose unforeseen harm in the form of adverse events (AEs), affecting effects of drug, prognosis and patients outcome (Feagins et al., 2023).In addition, adverse drug reactions (ADRs), defined as the unexpected and harmful response that occur during drug administration, should also be taken seriously (Basile et al., 2023).Pirfenidone administration has been linked to gastrointestinal symptoms, skin rashes and significant liver function abnormalities, necessitating regular monitoring (Lancaster et al., 2017).Moreover, the occurrence of ADRs related to pirfenidone demonstrates a dosedependent relationship and can be ameliorated through adjustments in mode and dose of administration (Kang et al., 2023).The reported common ADRs associated with nintedanib were diarrhea, bronchitis, nasopharyngitis, and cough (Li et al., 2023).Tthe occurrence of these ADRs in hospitalized patients not only imposes financial burden but also prolongs their hospital stay, and in severe cases, poses lifethreatening risks.Therefore, it is crucial for clinicians to have a thorough understanding of these potential ADRs, as close monitoring and prompt management can help mitigate the impact of these ADRs.
While clinical trials play a crucial role in establishing the efficacy of novel medications and identifying common ADRs, they may not capture all real-world scenarios due to the potential for rare and severe events that may only emerge after widespread administration of the drug in clinical settings.Fortunately, these limitations could be solved with the emergence of pharmacovigilance (PV) analysis, which involves monitoring and evaluating the safety profile of pharmaceutical products.Data sources such as the FDA Adverse Event Reporting System (FAERS) and the World Health Organization's VigiAccess database enable the collection, analysis, and assessment of ADRs and other medication-related safety issues on a population level (Rong et al., 2023).
In the present study, we conducted a statistical analysis of the data obtained from the FAERS and VigiAccess databases to identify the AEs and ADRs signals associated with pirfenidone and nintedanib.In addition, we categorized AEs for both drugs and compared the risk of ADRs between them.These findings provide valuable insights into the safety of clinical medication and support evidence-based decision-making in drug selection.

Data source
OpenVigil 2.1 (https://openvigil.sourceforge.net/),a widelyused online tool in pharmacovigilance research, was utilized for data mining and pharmacovigilance data analysis (Böhm et al., 2023).In this study, we employed this online tool to retrieve data from the FAERS database, covering the period from 1 January 2015, to 1 January 2023 for pirfenidone and nintedanib, in accordance with their approval dates.Various pharmaproduct names of pirfenidone (such as "esbriet", "pirfenidone aet", "pirfenidone axunio", "pirfenidone viatris", "truemed group llc") and "ofev" or "vargatef" for nintedanib were used as search terms.Only primary suspect roles were considered for the analysis.Furthermore, VigiAccess database, a valuable resource for healthcare professionals and researchers, was also utilized to search for data related to these two drugs.

Data standardization
AEs documented in the FAERS database underwent systematic categorization and encoding using the Medical Dictionary for The ROR (A) and PRR (B) disproportionality analysis of signals at PTs level associated with pirfenidone in the FAERS database.ROR, reporting odds ratio; PRR, proportional reporting ratio; PTs, preferred terms; FAERS, Food and Drug Administration Adverse Event Reporting System; 95% CI, 95% credibility interval.
Regulatory Activities (MedDRA) terminology.Each individual record was assigned a preferred term (PT), which can be further categorized into various systems based on the System Organ Class (SOC).

Statistical analysis
Disproportionality analysis, a data mining algorithm known for its high sensitivity and effectiveness in mitigating various biases, was extensively employed in the global monitoring of ADRs.Each signal identified through this approach represents a statistical association between a specific drug and an AE.For our study, a combination of proportional reporting ratio (PRR) (Evans et al., 2023) and reporting odds ratio (ROR) (Rothman et al., 2023), both known for their heightened sensitivity, were utilized in our signal mining process.The screening criteria for PRR included: N ≥ 3; χ2≥4; PRR≥2.As for ROR, N ≥ 3 and a lower limit of 95% CI > 1 was set as criteria.AEs that met both PRR and ROR criteria underwent further analysis.The ROR (A) and PRR (B) disproportionality analysis of signals at PTs level associated with nintedanib in the FAERS database.ROR, reporting odds ratio; PRR, proportional reporting ratio; PTs, preferred terms; FAERS, Food and Drug Administration Adverse Event Reporting System; 95% CI, 95% credibility interval.

Characteristic analysis of AE reports
The characteristic results were depicted in Figure 1.The FAERS database contained a total of 55,949 AE reports associated with pirfenidone and 35,884 reports associated with nintedanib, surpassing the corresponding figures reported in the VigiAccess database (37,187 and 23,134).Furthermore, male patients predominated over females for both drugs in both databases (Pirfenidone: 60.09% vs 36.73% in the FAERS database; 63.36% vs 33.45% in the VigiAccess database, Nintedanib: 55.98% vs 38.66% in the FAERS database; 59.17% vs 34.94% in the VigiAccess database).Concerning age distribution in the FAERS database, patients over the age of 65 were more likely to reporting AE, constituting 29.88% (16,716) for pirfenidone and 56.65% (20,330) for nintedanib.Similar results were shown in the VigiAccess database (14,409, 38.75%; 13,245, 57.25%).However, more than half of cases (20,047, 53.91%) lacked age information for pirfenidone.The main reporting continent was the Americas for both drugs in both databases.Among all cases, the most severe outcome was hospitalization (10,869, 19.43% for pirfenidone; 17,433, 48.58% for nintedanib).Additionally, AE reports for these drugs showed an increasing trend over the years.

Signal detection at PT level
A combination of PRR and ROR algorithms was utilized to analyze AEs and assess their adherence to various screening criteria.In the FAERS database, a total of 150 PTs (Supplementary Table S1) related to pirfenidone was screened, and the top 20 PTs, presented in Figure 2 3).In the VigiAccess database, the top 20 PTs were ranked by case numbers.The top five PTs for pirfenidone were death (case number: 6,240), nausea (case numbers: 5,013), fatigue (case number: 3,760), decreased appetite (case number: 3,733), and diarrhoea (case number: 2,895) (Table 1).The top five PTs for nintedanib were diarrhoea (case numbers: 9,676), nausea (case number: 3,770), weight decreased (case number: 2,888), decreased appetite (case number: 2,671), and vomiting (case number: 2,302) (Table 1).

Discussion
Pirfenidone and nintedanib are major therapeutic agents for IPF patients, having demonstrated their efficacy and safety through rigorous clinical trials (Justet et al., 2023).However, there's a limited number of post-marketing and pharmacovigilance studies that offer insights into their long-term safety profiles and comprehensive guidelines.Given that "a one-size-fits-all approach" to the management of IPF is not currently suitable, the drugs should be decided with optimal consideration of interindividual differences to maximize effectives and minimize side-effects (Karampitsakos et al., 2023a).In this study, we analyzed and compared the AEs induced by these two drugs using data from the FAERS and VigiAccess databases in the real-world practice.This analysis aims to assist clinicians in managing these drugs more effectively for IPF patients.
In our analysis, we found that male patients or those over 65 accounted for a large part of AE reports in both databases.This is consistent with previous studies, indicating that older age and male gender are risk factors for IPF (Zhao et al., 2023).The higher incidence in males might be due to factors like smoking or occupational exposures.Hence, it is crucial for clinicians to be particularly attentive when administering pirfenidone or nintedanib to elderly males, given their heightened susceptibility to AEs.Moreover, hospitalization was the most severe outcome for both pirfenidone (10,869, 19.43%) and (nintedanib) (17,433, 48.58%).In 10%-20% of hospitalized patients, ADRs pose unexpected risks to patients, affecting their prognosis and increasing their financial burden (Staniszewka, 2020).In this study, therefore, we aim to identify the ADRs of these two drugs and offer guidance on their prevention or control, especially for the new and unexpected ADRs.
Both pirfenidone and nintedanib have been linked to several ADRs.Pirfenidone is mainly associated with gastrointestinal disorders, skin rashes or photosensitivity, while nintedanib is tied to gastrointestinal disorders, bleeding, cardiovascular events and myocardial infarction (Petnak et al., 2023;Rogliani et al., 2023).For reminding us that we should not only focus on respiratory system but also pay attention to cardiovascular and digestive systems in the administration of nintedanib.In the VigiAccess database, gastrointestinal disorders, including nausea, vomiting and diarrhoea, account for majority ADRs of reports, which are consistent with clinical trials (Song et al., 2019).Hence, Supportive care, including antiemetic or antidiarrheal therapy, must be prepared for patients with high risk potential of gastrointestinal disorders.Additionally, more attention should be paid to signals that were rarely mentioned in these drugs labels.Hemiplegic migraine occurred with the use of pirfenidone, and asthenia, constipation, as well as flatulence occurred with the use of nintedanib.Among these, only asthenia has been reported in patients with advanced solid tumors or lung adenocarcinoma (Bahleda et al., 2015;Riudavets et al., 2021).Recent studies found that IPF patients exhibit an approximately five-fold elevated susceptibility to developing lung cancer compared with the general population, and those with coexisting IPF and lung cancer experience a markedly diminished overall survival rate compared with IPF patients without lung cancer (Karampitsakos et al., 2023b;Karampitsakos et al., 2023c).Therefore, the role of antifibrotics compounds plus antitumor drugs in IPF patients with lung cancer should be explored.In a  et al., 2022).In another study, pembrolizumab, the PD-1 inhibitor, was found to exert therapeutic effect in bleomycin-induced pulmonary fibrosis (Karampitsakos et al., 2023d).More clinical trials are imperative to find the potential of ADRs in the use of antifibrotic and antitumor medications.The high prevalence of depression in IPF patients receiving antifibrotic drugs, which reduce the quality of life, should also be noted (Tzouvelekis et al., 2020).Furthermore, in combined use of pirfenidone and nintedanib, no relevant pharmacokinetic drug-drug interaction was found, which needs further study to assess the efficiveness and safety of this combination compared to monotherapy in IPF patients (Richeldi et al., 2019).

Limitations
It is important to acknowledge the limitations in this study.First, the major is the issue of underreporting of AEs by healthcare professionals, leading to incomplete data and an inaccurate representation of the true safety profile of drug.Second, the quality of data in pharmacovigilance databases can exhibit variations that hinder the analysis and interpretation of safety signals.Third, pharmacovigilance data often lacks comprehensive information about confounding factors that could contribute to AEs.Therefore, it is important to consider these limitations when interpreting pharmacovigilance data and making decisions regarding drug and risk management.However, this study succeeded in identifying previous unknown or underestimated risk

Conclusion
Our analysis provides valuable insights into the safety profiles of pirfenidone and nintedanib in real-world practice.The findings emphasize the importance of monitoring and managing specific ADRs, highlighting the ongoing need for pharmacovigilance efforts to improve patient safety, medical decision-making and effectiveness of drug therapy.

SOC name
Case number PT Percentage (%)

FIGURE 1
FIGURE 1Characteristic analysis of AE reports in the FAERS and VigiAccess databases.

TABLE 1
The signals of AEs of pirfenidone and nintedanib at the PT level in the VigiAccess database.

TABLE 2
The signals of AEs of pirfenidone at the SOC level in the FEARS database.
Abbreviations: AEs, adverse events; SOC, system organ class; FAERS, food and drug administration adverse event reporting system; PT, preferred term.transplant, which also indicates that professional caregivers should pay more attention to the pulmonary protection.Other uncommon signals are paroxysmal arrhythmia, cholelithotomy, aortic valve calcification, haemorrhoids, and hepatic cirrhosis, cystitis,

TABLE 3
The signals of AEs of nintedanib at the SOC level in the FEARS database.

TABLE 4
The signals of AEs of pirfenidone at the SOC level in the VigiAccess database.These findings offer an opportunity to assess ADRs that may remain undetected during pre-approval clinical trials, which typically involve a limited number of patients.