A Real-World Pharmacovigilance Study of Cilostazol Based on the Food and Drug Administration Adverse Event Reporting System: A Cross-Sectional Disproportionality Analysis.

Remimazolam is a new ultra-short-acting benzodiazepine used in anaesthesia, valued for its rapid metabolism and reversibility. Despite its growing clinical use, a comprehensive assessment of its real-world safety profile remains essential. To evaluate the postmarketing safety of remimazolam using adverse event (AE) data from the US and Japanese pharmacovigilance databases. Retrospective analysis of AEs associated with remimazolam using disproportionality analysis techniques. FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report database (JADER) from January 2020 to December 2023. Patients who experienced remimazolam-related AEs reported in the FAERS and JADER databases. Identification of significant AEs using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network and multiitem gamma Poisson shrinker. Categorisation of AEs using the 'Important Medical Event Terms List' (IME) list (version 26.1). We identified 199 remimazolam-related reports (69 from FAERS, 130 from JADER) revealing 20 significant AEs. Key findings include previously unlabelled serious AEs such as cardiac, cardio-respiratory, and respiratory arrests; nine events classified as Important Medical Events, including hypotension and anaphylaxis; four AEs not included in current Food and Drug Administration (FDA) labelling; and low-frequency but clinically significant off-label events including arrhythmias and postoperative delirium. While remimazolam shows a generally acceptable safety profile, our pharmacovigilance analysis identified serious unlabelled reactions requiring clinical vigilance. Practice recommendations include judicious administration with balanced crystalloids and comprehensive cardiorespiratory monitoring. Future research should address prospective surveillance of rare serious events, optimal administration protocols to prevent vascular occlusions and investigation of anaphylactic reactions. Not applicable.

A Real-World Disproportionality Analysis of FDA Adverse Event Reporting System(FAERS) Event for Belatacept.

Dacomitinib, a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor that was approved for the treatment of non-small cell lung cancer in 2018, has limited real-world safety data. This study investigates dacomitinib-associated adverse events (AEs) using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database.We conducted a retrospective analysis of the FAERS database, extracting dacomitinib-related reports from 2018 Q3 to 2024 Q3. To assess the association between dacomitinib and AEs, we employed multiple disproportionality analyses, including the reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker.From the FAERS database, we analyzed 10,869,881 case reports, identifying 594 dacomitinib-related AEs. Among these, 56 significant PTs were retained based on the four algorithms. Common AEs included diarrhoea (ROR 4.40), rash (ROR 6.40), paronychia (ROR 347.91), mouth ulcers (ROR 32.24), dermatitis acneiform (ROR 58.79), palmar-plantar erythrodysaesthesia (ROR 16.08), liver injury (ROR 5.56), and pulmonary fibrosis (ROR 9.75), aligning with the drug label. In addition, some unanticipated major AEs were detected, including cholestasis (ROR 6.12), cholelithiasis (ROR 6.56), an increase in blood pressure (ROR 6.85), an elevation in heart rate (ROR 4.91), a decline in red blood cell count (ROR 5.95), a decrease in hemoglobin (ROR 5.95), the presence of pericardial effusion (ROR 5.59), white matter lesions (ROR 98.11), and cerebral atrophy (ROR 56.69). All reported RORs for the identified AEs were statistically significant, as defined by a lower limit of the 95% confidence interval that exceeded 1.This study systematically evaluates AEs associated with dacomitinib, confirming its known safety profiles and identifying some emerging safety concerns in real-world settings. These findings provide crucial insights for clinicians and pharmacists to better manage dacomitinib's safety profile.

ObjectivePaliperidone palmitate is a second-generation antipsychotic that has undergone extensive investigation in clinical trials. However, real-world studies assessing its safety in large populations are lacking. As such, this study aimed to comprehensively evaluate real-world adverse drug events (ADEs) linked to paliperidone palmitate by employing data mining techniques on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database.MethodsThe study retrieved ADE reports from the FAERS database covering the period from 2009 through the third quarter of 2024, and from the JADER database covering the period from 2013 through the second quarter of 2024. Utilizing disproportionality analyses such as the reporting odds ratios (ROR), proportional reporting ratios (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item Poisson shrinkage (MGPS), significant associations between ADEs and paliperidone palmitate were evaluated.ResultsA total of 27,672 ADE reports related to paliperidone palmitate were identified in FAERS, with 285 significantly disproportionate preferred terms (PTs) identified by all four algorithms. Paliperidone palmitate-associated ADEs encompassed 27 System Organ Classes (SOCs). The top three PTs with the highest reported cases were off-label use, drug ineffective, and hospitalization. Common ADEs included increased blood prolactin, galactorrhea, and schizophrenia, which was consistent with drug label. Noteworthy, unexpected signals not listed in the drug label were also identified, such as psychosexual disorders, prolactin-producing pituitary tumors, suicide attempt, and sudden death. The median onset time for all ADEs was 40 days. Furthermore, gender-based difference in risk signals was detected. Females are more likely to experience elevated blood prolactin and weight increase, whereas males are more prone to sexual dysfunction. Among the 1,065 ADE reports from the JADER database, we identified 51 positive signals, 35 of which overlapped with those found in FAERS, including schizophrenia, hyperprolactinemia, and erectile dysfunction.ConclusionThe study findings from two independent databases serve as crucial references for ensuring the safe of paliperidone palmitate. Additionally, the gender-specific monitoring references provided can enhance clinical surveillance efforts and facilitate more effective risk identification.

This study aims to investigate the occurrence of adverse events associated with topiramate by analyzing data from the FDA Adverse Event Reporting System. The goal is to provide a basis for the safe clinical use of topiramate. Adverse event data from the FDA Adverse Event Reporting System, from its inception through the first quarter of 2024, were extracted. Signal detection was conducted using three methods: the reporting odds ratio, the medicines and healthcare products regulatory agency method, and the Bayesian confidence propagation neural network. Adverse events were statistically analyzed according to the preferred term and system organ class classifications from the Medical Dictionary for Regulatory Activities version 27.0. Positive signals were then compared against the drug label and the Important Medical Event list. A total of 12,168 adverse event reports involving topiramate as the primary suspect were analyzed, resulting in the extraction of 244 positive signals across 15 system organ classes. Among these, 21 signals were identified as serious adverse reactions not included in the drug label, encompassing 5 system organ classes. Notable signals included hypospadias, spina bifida, abortion spontaneous, renal tubular dysfunction, uveitis, retinal detachment, and choroidal effusion. Additionally, signals such as osmotic demyelination syndrome and Arnold-Chiari malformation were identified as requiring further monitoring. This study identified several unexpected and serious adverse reaction signals that align with previously reported cases. These findings underscore the need for ongoing study, focused attention, and vigilant monitoring during the clinical use of topiramate.

Background and purpose: Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment (TRT). Herein, we investigated long-standing controversies about the association between TRT and major adverse cardiovascular events (MACEs), based on real world adverse event (AE) reports, registered in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Publicly available FAERS data from 1 January 2004 to 31 December 2022 were retrieved from the Food and Drug Administration (FDA) website. The data mining protocol including the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) was applied to analyze overreporting caused by risk factors and MACEs, including TRT, morbidities, and ages. The ROR and the BCPNN were also applied to investigate the annually developing trend of pharmacovigilance (PV) signals in the real world, retrospectively. Results: A total of 3,057 cases referring to MACEs, with a median age of 57 years old (yo), were identified from 28,921 cases of testosterone users. MACEs related to PV signals have emerged since 2014, including cardiac death, non-fatal myocardial infarction, and non-fatal stroke. Myocardial infarction (MI) (ROR: 9.46; IC025: 3.08), acute myocardial infarction (AMI) (ROR: 16.20; IC025: 3.72), ischemic cardiomyopathy (ROR: 11.63; IC025: 2.20), and cardiomyopathy (ROR: 5.98; IC025: 1.96) were the most significant signals generated, and weaker signals included cardiac failure acute (ROR: 4.01; IC025: 0.71), cardiac arrest (ROR: 1.88; IC025: 0.56), and ventricular fibrillation (VF) (ROR: 2.38; IC025: 0.38). The time-to-onset (TTO) of MACEs was calculated with a median of 246 days for AMI. Conclusion: For myocardial infarction and cardiomyopathy, TRT statistically tended to increase the risk of MACEs, while for cardiac arrhythmia, cardiac failure, and stroke, TRT demonstrated beneficial effects among the population with morbidities, such as testosterone deficiency (TD), diabetes mellitus (DM), and hypertension. MACEs were rare but led to serious outcomes including significant increase in death and disability. Since 2018, and before 2014, reports referring to TRT associated with MACEs were relatively scarce, which indicated that there might be a considerable number of cases that went unrecorded, due to neglection. Health workers and testosterone users might pay more attention to testosterone-induced MACEs.

Temsirolimus is a mammalian target of rapamycin inhibitor primarily used to treat not only various types of renal carcinoma, but also various types of lymphomas and other tumors. However, its real-world safety profile remains inadequately characterized. By analyzing the Food and Drug AdministrationAdverse Event Reporting System (FAERS) database, we identified risk signals associated with temsirolimus adverse reactions and gained valuable insights for clinical decision-making and risk management. We extracted temsirolimus-related reports of adverse events (AEs) from FAERS across 68 quarters (Q2 2007-Q2 2024) and analyzed the demographic characteristics. Disproportionality analyses-including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM)-were conducted to evaluate the association between temsirolimus and adverse events. When a signal simultaneously meets the threshold criteria of all four algorithms, it is considered a significantly positive signal. We compared the significant positive signals obtained with those in the drug label and ultimately identified new adverse reactions that had not been discovered. We extracted 2,929 adverse event reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) database in which temsirolimus was identified as the "primary suspect"drug. Through disproportionality analysis, we identified 128 preferred terms (PTs) associated with temsirolimus across 17 organ systems. The significant adverse reactions consistent with the drug label were observed, including hypersensitivity/infusion reactions, liver injury, hyperglycemia/insulin resistance, infections, interstitial lung disease, hyperlipidemia, intestinal perforation, renal failure, wound complications, and intracranial hemorrhage. Additionally, the new positive signals not documented in the drug label were identified, including dehydration, pleural effusion, cardiac failure, and ascites. Our findings are basically consistent with prior clinical studies, and the new potential adverse events (AEs) associated with temsirolimus were identified. These insights contribute to ongoing pharmacovigilance efforts, enhancing safety monitoring and optimizing clinical application.

BackgroundLumacaftor/ivacaftor (LUM/IVA) is a CFTR modulator approved for the treatment of cystic fibrosis (CF) caused by the F508del mutation. While clinical trials have demonstrated its efficacy, the long-term safety profile remains inadequately characterized. This study aims to assess the real-world safety of LUM/IVA through a comprehensive analysis of adverse drug events (ADEs) reported in the U. S. FDA Adverse Event Reporting System (FAERS) from the third quarter of 2015 to 2024.MethodsDisproportionality analysis including the reporting odds ratio (ROR) and Bayesian confidence Propagation Neural Network (BCPNN) was employed to identify potential safety signals associated with LUM/IVA. Furthermore, sensitivity analyses were conducted to eliminate potential confounding arising from concomitant medication use and underlying indications. Potential risk factors for LUM/IVA-associated depression were identified through logistic regression analysis. Finally, time-to-onset (TTO) analysis was conducted to evaluate the temporal patterns of ADEs.ResultsA total of 7,843 LUM/IVA-related ADE reports were extracted, spanning 27 system organ classes (SOCs). We identified 221 positive signals, with 37 signals consistent with the drug label, 61 signals might be associated with disease progression, and 123 signals not listed in the drug label. Positive signals with most reported cases included infective pulmonary exacerbations (n = 1,394, ROR 1201.58, IC025 9.50), hospitalization (n = 841, ROR 20.07, IC025 4.13) and, dyspnoea (n = 517, ROR 4.00, IC025 1.83). Unexpected signals such as depression (n = 81, ROR 1.71, IC025 0.45), suicidal ideation (n = 31, ROR 1.63, IC025 0.20), and hypoglycemia (n = 20, ROR 2.02, IC025 0.39) were detected, highlighting previously unreported risks. Stratified analysis identified risk signals in different subgroups, such as chest discomfort in 50–100 kg subgroup. The TTO analysis revealed that the median onset of ADEs was 256 days, with most ADEs reports occurring after 360 days of treatment LUM/IVA (39.2%), Moreover, cumulative incidence varied significantly among subgroups stratified by age, dosage, and frequency of administration.ConclusionThis study provides a detailed real-world safety profile of LUM/IVA, identifying both known and unexpected adverse events. Our findings underscore the importance of continuous post-marketing surveillance and the need for updated drug label to reflect associated risks, particularly those related to psychiatric symptoms and long-term adverse effects. Personalized treatment strategies based on patient characteristics, including sex, are recommended to optimize safety during LUM/IVA therapy.

Vortioxetine is an antidepressant approved for the treatment of major depressive disorder (MDD). Given its widespread post-marketing clinical use, it is essential to explore its real-world safety. Reports were extracted from the FDA Adverse Event Reporting System (FAERS) from the third quarter of 2013 to the first quarter of 2025. Four disproportionality analysis methods, commonly used in pharmacovigilance to evaluate the relative reporting frequency of adverse events (AEs), were employed to identify AE signals associated with vortioxetine. These included the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrink (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN). The median was used to describe the time to onset (TTO) of AEs, and Weibull distribution was employed to assess the trend of AE occurrence over time. In addition, sensitivity analyses were conducted to ensure the robustness of the findings. A total of 13,613 individual case safety reports (ICSRs) involving 34,156 AEs were analyzed. Females accounted for 60.9% of the reports, while males represented 26.5%. The median age of patients was 42 years (interquartile range: 26-59 years), with most cases (34.1%) in the 18-65 age group. The United States contributed the highest proportion of reports (77.4%). Common AEs included nausea (n = 2042, ROR = 5.11, PRR = 4.86, EBGM = 4.85, IC = 2.28), anxiety (n = 781, ROR = 5.3, PRR = 5.2, EBGM = 5.18, IC = 2.37 ), vomiting (n = 773, ROR = 3.23, PRR = 3.17, EBGM = 3.17, IC = 1.66), headache (n = 670, ROR = 1.96, PRR = 1.94, EBGM = 1.94, IC = 0.96), and somnolence (n = 212, ROR = 2, PRR = 1.99, EBGM = 1.99, IC = 0.99). Notably, several AEs not listed on the drug label, such as tinnitus (n = 79, ROR = 3.24, PRR = 3.24, EBGM = 3.23, IC = 1.69), urinary retention (n = 62, ROR = 3.57, PRR = 3.57, EBGM = 3.56, IC = 1.83), prolonged QT interval (n = 62, ROR = 3.14, PRR = 3.13, EBGM = 3.13, IC = 1.64), and restless legs syndrome (n = 48, ROR = 5.08, PRR = 5.08, EBGM = 5.06, IC = 2.34) were also identified. Most AEs occurred within the first month of treatment, with a median onset time of 15 days. Sensitivity analyses confirmed the consistency of these findings. This study provides new insights into the safety of vortioxetine and offers preliminary safety evidence. In addition, the findings may inform updates to prescribing information and guide post-marketing safety surveillance. However, the spontaneous nature of the FAERS database precludes establishing a causal relationship between vortioxetine and the reported AEs. Further prospective studies are needed to validate our findings.

Donepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy. We retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age. Of the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18years, 16 in patients between 18 and 65years, and 113 in patients older than 65years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment. Our study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.

This study utilizes data from the FDA Adverse Event Reporting System (FAERS) to identify and compare adverse events (AEs) signals related to hepatobiliary disorders associated with triazole antifungal agents (TAAs), aiming to inform clinical selection and risk assessment of these drugs. AE reports related to TAAs submitted to the FAERS database from 2004Q1 to 2024Q4 were collected. Data mining was performed using multiple signal detection methods, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN). The incidence of hepatobiliary-related AEs associated with the five TAAs was highest among individuals aged 45-64. Compared with other TAAs, the proportion of adverse events occurring in children is higher with voriconazole. For AEs related to voriconazole and isavuconazole, the proportion of males is higher than that of females, whereas for others, the proportion of male and female patients is roughly equal. Based on the prescribing information for each drug, a total of 11 novel AEs were identified across all TAAs, including hepatolysis (ROR = 11.73, PRR = 11.71), vanishing bile duct syndrome (ROR = 26.95, PRR = 26.94), hepatic fibrosis (ROR = 3.6, PRR = 3.6), venoocclusive liver disease (ROR = 7.6, PRR = 7.59), hepatosplenomegaly (ROR = 5.17, PRR = 5.17), hepatorenal syndrome (ROR = 4.85, PRR = 4.85), hepatic cysts (ROR = 6.59, PRR = 6.59), hepatomegaly (ROR = 3.5, PRR = 3.5), mixed liver injury (ROR = 7.71, PRR = 7.71), steatohepatitis (ROR = 22.49, PRR = 22.48), and hepatorenal failure (ROR = 11.02, PRR = 11.02). This study analyzed the clinical traits of hepatobiliary adverse event reports related to triazole antifungal agents, conducted a detailed comparative analysis of PT, and identified 11 novel PTs not mentioned in the drug labeling, such as vanishing bile duct syndrome, steatohepatitis, and hepatolysis. Clinicians should be alert to these novel risks and strengthen liver function monitoring during the clinical use of these drugs.

Drug-induced hypogonadism is an underrecognized but significant adverse effect of various medications, contributing to male sexual dysfunction and infertility. Despite its clinical significance, comprehensive studies systematically identifying high-risk drugs remain limited. This study aimed to investigate the potential drugs associated with hypogonadism from FDA Adverse Event Reporting System. This study analyzed adverse drug events reported from FDA Adverse Event Reporting System covering the period from the first quarter of 2004 to the third quarter of 2024. Cases related to hypogonadism were identified using standardized Medical Dictionary for Regulatory Activities preferred terms. Disproportionality analyses were conducted using the reporting odds ratio and the Bayesian confidence propagation neural network. Drugs were classified according to Anatomical Therapeutic Chemical classification system and clinical applications. This study utilized FDA Label to determine whether adverse drug events related to male hypogonadism are mentioned on their labels. We identified 10 classes including 42 drugs that showed positive signals for both reporting odds ratio and Bayesian confidence propagation neural network: anesthetics and analgesics, psychiatric and neurological medications, antineoplastic agents, urological medications, hormonal agents, cardiovascular medications, gastrointestinal medications, bone metabolism modifiers, antiretroviral agents, and other drugs. According to the Bayesian confidence propagation neural network algorithm, 6 drugs were considered to have a high risk of causing hypogonadism, and 11 drugs had medium risk. In addition, 20 drugs did not mention adverse drug events related to male hypogonadism, of which 3 were identified as high risk using the Bayesian confidence propagation neural network algorithm. This research summarized a list of potential drugs associated with hypogonadism. A clear understanding of the risk and frequency of drug-induced hypogonadism can reduce the likelihood of patients developing the condition.

To explore adverse event (AE) signals of Ceftazidime/avibactam (CZA) based on the FDA Adverse Event Reporting System (FAERS) database. AE reports primarily associated with CZA were retrieved from the FAERS database from the second quarter of 2015 to the second quarter of 2023. Signal detection was conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) methods. A total of 750 AEs reports with CZA as the preferred suspected drug were obtained, identifying 66 preferred terms (PTs) involving 24 system organ classes (SOCs). Besides, the AEs already mentioned in the drug label, this study also revealed some new, clinically valuable potential AEsignals, such as Cholestasis (n = 14, ROR 29.39, PRR 29.15, IC 3.34, EBGM 29.11), Drug-induced liver injury (n = 8, ROR 9.05, PRR 9.01, IC 2.25, EBGM 9.01), Hepatocellular injury (n = 7, ROR 13.90, PRR 13.84, IC 2.41, EBGM 13.63), Haemolytic anaemia (n = 5, ROR 24.29, PRR 24.22, IC 2.42, EBGM 40.53), etc. Additionally, AE signals with higher intensity were identified, such as Hypernatraemia (n = 5, ROR 40.73, PRR 40.61, IC 2.31, EBGM 24.19), Toxic epidermal necrolysis (n = 4, ROR 11.58, PRR 11.55, IC 1.89, EBGM 11.54). Therefore, special vigilance for these potential AEs is warranted when using CZA clinically. This study highlights the potential AEs and risks associated with the clinical use of CZA, particularly the risks related to Cholestasis, Drug-induced liver injury, Haemolytic anaemia, Hypernatraemia, and Toxic epidermal necrolysis.

ObjectiveLaronidase is the first drug of enzyme replacement therapy approved for the treatment of mucopolysaccharidosis type I (MPS I). However, its adverse events (AEs) have not been investigated in real - world settings. The aim of this study was to investigate AEs associated with laronidase using the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsData for laronidase were acquired from the FAERS database covering Q1 2004 through Q4 2024. The Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS) were employed to identify potential safety signals.ResultsA total of 3,677 adverse event reports associated with laronidase were identified in the FAERS from 2004 to 2024. The results revealed that common AEs of laronidase such as pyrexia [n = 465, ROR = 6.23 (5.68–6.83)], pneumonia [n = 223, ROR = 3.22 (2.82–3.68)], cough [n = 167, ROR = 2.78 (2.38–3.23)], influenza [n = 114, ROR = 4.95 (4.12–5.95)], urticaria [n = 106, ROR = 2.99 (2.47–3.62)], disease progression [n = 101, ROR = 3.95 (3.25–4.81)]. Furthermore, we detected probable unexpected AEs like seizures [n = 75, ROR = 3.1 (2.47–3.89)], hydrocephalus [n = 60, ROR = 50.47 (39.1–65.14)], blindness [n = 44, ROR = 5.02 (3.73–6.75)], glaucoma [n = 32, ROR = 7.56 (5.34–10.69)]. Laronidase -induced adverse reactions involved 27 System Organ Class (SOC). No significant difference in AEs was observed between sexes for laronidase. Most AEs (n = 763) emerged more than 360 days following laronidase treatment.ConclusionOur study has identified AEs associated with laronidase that could provide support for clinical monitoring and risk identification of laronidase.

To date, only two drugs, pirfenidone and nintedanib, are approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). In addition, very few studies have reported on the safety profile of either drug in large populations. This study aims to identify and compare adverse drug events (ADEs) associated with pirfenidone and nintedanib in real-world settings by analyzing data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). In addition, we utilized data from the Japanese Adverse Drug Event Report (JADER) database for external validation. The ADE reports on both drugs from 2014 Q3 to 2024 Q2 in FAERS and from 2008 Q1 to 2024 Q1 in JADER were collected. After deduplication, Bayesian and non-Bayesian methods for disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multiple Gamma Poisson Shrinkers (MGPS), were used for signal detection. Additionally, time to onset (TTO) analysis were performed. In total, 35,804 and 20,486 ADE reports were identified from the FAERS database for pirfenidone and nintedanib, respectively. At the system organ class (SOC) level, both drugs have a positive signal value for "gastrointestinal disorders," "respiratory, thoracic, and mediastinal disorders," and "metabolism and nutrition disorders." Other positive signals for pirfenidone include "general disorders and administration site conditions," and "skin and subcutaneous tissue disorders," while for nintedanib, they were "investigations," "infections and infestations," and "hepatobiliary disorders." Some positive signals were consistent with the drug labels, including nausea, decreased appetite, and weight decreased identified in pirfenidone, as well as diarrhea, decreased appetite, abdominal pain upper, and epistaxis identified in nintedanib. We also identified unexpected signals not listed on the drug label, such as decreased gastric pH, and pneumothorax for pirfenidone, and constipation, flatulence for nintedanib. The median onset time for ADEs was 146 days for pirfenidone and 45 days for nintedanib, respectively. Although the two antifibrotics differed in the proportion of periods in which the ADEs occurred, these ADEs were likely to continue even after a year of treatment. In the external validation of JADER, the number of reports for pirfenidone and nintedanib were 265, and 1,327, respectively. The disproportionality analysis at the SOC and preferred term (PT) levels supports the FAERS results. This study systematically investigates and compares the ADEs and their onset times at the SOC and specific PT levels for pirfenidone and nintedanib. Our results provide valuable pharmacological insights for the similarities and differences between the safety profiles of the two drugs and highlight the importance of monitoring and managing the toxicity profile associated with antifibrotic drugs.