Novel Adverse Events of Iloperidone: A Disproportionality Analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) Database.
Subeesh Viswam,Maheswari Eswaran,Singh Hemendra,Beulah Thomas Elsa,Swaroop Ann Mary
Current drug safety
BACKGROUND:The signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously". OBJECTIVE:To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). METHODOLOGY:The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal. RESULTS:The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold. CONCLUSION:Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.
DPP-4 Inhibitors and Increased Reporting Odds of Bullous Pemphigoid: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS) from 2006 to 2020.
Jedlowski Patrick M,Jedlowski Mahdieh F,Fazel Maryam T
American journal of clinical dermatology
BACKGROUND:In recent years, an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid has been detected in pharmacovigilance studies in European and Asian countries; however, no pharmacovigilance data have been published yet in the USA. OBJECTIVE:The objective of this study was to examine the relationship between bullous pemphigoid and DPP-4 inhibitors and other oral diabetes mellitus medications in the FDA Adverse Event Reporting System (FAERS). METHODS:Case/non-case analyses were performed in the FAERS using data from 2006 to 2020 to examine the reporting odds ratio (ROR) signal for bullous pemphigoid for all classes of oral diabetes medications. These analyses were performed under multiple conditions to control for bias: (1) comparison to all other drugs in the FAERS; (2) comparison to other diabetes medications; and (3) comparison to all other diabetes medications where only a single agent was implicated. RESULTS:A statistically significant ROR for bullous pemphigoid was found for DPP-4 inhibitors under all conditions: (1) 109.79 (95% confidence interval [CI] 101.61-118.62); (2) 74.46 (95% CI 60.58-91.52); and (3) 35.94 (95% CI 27.91-46.28). A larger signal was seen for non-US Food and Drug Administration (FDA)-approved (anagliptin, vildagliptin, teneligliptin) vs FDA-approved DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin), likely because of an overestimation of the ROR for non-FDA-approved drugs. The largest signal was seen under conditions 1 and 2 with vildagliptin (1) 1022.83 (95% CI 909.45-1150.35) and (2) 158.84 (95% CI 127.01-198.66) followed by anagliptin (1) 628.63 (95% CI 221.36-1785.24) and (2) 60.64 (95% CI 20.98-175.26), alogliptin, teneligliptin, linagliptin, sitagliptin, and saxagliptin. Under condition 3, the largest signal was seen with linagliptin 122.25 (95% CI 93.96-159.07). Both metformin and the sulfonylureas had a significant ROR under condition 2 [3.42 (95% CI 3.01-3.89) and 2.07 (95% CI 1.66-2.57) respectively]; however, this association was not present under condition 3 as only confounded cases occurred, and a large majority of reported cases had concurrent exposure to a DPP-4 inhibitor. CONCLUSIONS:Our findings support an association between DPP-4 inhibitors and bullous pemphigoid. This association was maintained under controls to limit bias and falsely elevated signal, including controlling for disease state and cases with multiple drug exposures. Non-FDA-approved DPP-4 inhibitors had a larger ROR compared with FDA-approved DPP-4 inhibitors, likely owing to fewer reported adverse effects overall for non-FDA-approved drugs in FAERS.
Reports of Lactic Acidosis Attributed to Metformin, 2015-2018.
Flory James H,Hennessy Sean,Bailey Clifford J,Inzucchi Silvio E
OBJECTIVE:In 2016, the U.S. Food and Drug Administration (FDA) revised metformin's label to permit use in patients with mild-moderate chronic kidney disease. We sought to determine whether this change was associated with increased reports of metformin-associated lactic acidosis (MALA) to the FDA's Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS:Publicly available FAERS reports were analyzed. RESULTS:MALA reports increased from 521 in 2015 to 1,939 in 2018. After restriction to U.S. reports, absolute and relative increase in MALA reports was less, from 111 to 243. The proportionate reporting ratio (PRR), a measure adjusted for rates of other adverse event reports, was stable. CONCLUSIONS:The increased reports deserve attention, but the PRR's stability and FAERS's known limitations, including lack of a denominator or control group, do not permit the conclusion that U.S. MALA rates have increased. Further study with more robust data sources is needed.
The risk of anaphylactic reactions to rocuronium in the United States is comparable to that of vecuronium: an analysis of food and drug administration reporting of adverse events.
Bhananker Sanjay M,O'Donnell James T,Salemi John R,Bishop Michael J
Anesthesia and analgesia
Published reports from France and Norway suggest a frequent incidence of anaphylaxis to rocuronium and have raised concerns about its safety. We hypothesized that the Food and Drug Administration Adverse Event Reporting System could be used to confirm whether there has been an unusual incidence of anaphylactic events for rocuronium in the United States (U.S.) and whether the reporting patterns differ within and outside of the U.S.. We queried the Food and Drug Administration Adverse Event Reporting System for 1999 through the first quarter of 2002 for all adverse events for the drugs rocuronium and vecuronium and then searched on the terms considered to represent possible anaphylaxis using proprietary software. We compared the frequency of these terms in data both for rocuronium and vecuronium. We then assessed the occurrence of reports of anaphylaxis-related terms in reports from the U.S. compared with reports originating outside of the U.S.. For rocuronium, the database contained 311 reports, 166 domestic and 145 from foreign sources. Fifty percent of the foreign reports contained an anaphylaxis term versus 20% of the domestic reports (P < 0.001). For vecuronium, the comparable figures were 17% and 19% (not significant) and the total number of reports was 243. The incidence of the reports containing anaphylaxis terms did not differ between vecuronium and rocuronium in the U.S. but were significantly different for foreign reports (P < 0.001). These data confirm that U.S. anesthesia providers have not observed a significant difference in anaphylactic reactions between the two commonly used intermediate-acting muscle relaxants and suggest that frequency of reports of anaphylaxis may be significantly influenced by the area from which the reports originate.
Bevacizumab and gastrointestinal perforations: a review from the FDA Adverse Event Reporting System (FAERS) database.
Wichelmann Thomas A,Abdulmujeeb Sufyan,Ehrenpreis Eli D
Alimentary pharmacology & therapeutics
BACKGROUND:Bevacizumab is used in the treatment of advanced malignancies and has a "black box" warning for gastrointestinal perforations. Despite this known side effect, there are no large descriptive series of patients who experience bevacizumab-induced gastrointestinal perforations. AIM:To review and describe post-market cases of bevacizumab-induced gastrointestinal perforation reported by healthcare professionals to the United States Food and Drug Association Adverse Event Reporting System (FAERS) database. METHODS:In total, 74 025 cases of bevacizumab-induced adverse drug reaction were reported to FAERS from January 1 2004 to July 6 2021. We identified 2874 cases of bevacizumab-induced gastrointestinal perforation. A total of 1375 cases were determined to contain complete patient demographic data after the removal of duplicates and were reviewed. Subgroup analysis was completed on gastro-oesophageal perforations given the lack of prior data. RESULTS:The average patient age was 61.9 ± 11.4 years. A total of 698 cases included descriptive locations of perforations with most occurring in the large intestine (385 cases, 55.2% of specifically described cases). Colorectal cancer was the most common indication for bevacizumab (691 cases, 50.3%) followed by ovarian cancer (197 cases, 14.3%) and non-small cell lung cancer (182 cases, 13.2%). Death was reported in 554 patients (40.3% of cases). Sixty-two cases of gastro-oesophageal perforation were identified. CONCLUSIONS:This is the largest collective descriptive study of bevacizumab-induced gastrointestinal perforations, and sheds light on this often fatal complication. We additionally identified and described a rare subgroup of patients experiencing bevacizumab-induced gastro-oesophageal perforation not previously described.
Comparing Acute Kidney Injury Reports Among Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).
Patek Taylor M,Teng Chengwen,Kennedy Kaitlin E,Alvarez Carlos A,Frei Christopher R
BACKGROUND:A study using the US FDA Adverse Event Reporting System (FAERS) found significant acute kidney injury (AKI) reporting associations with vancomycin, fluoroquinolones, penicillin combinations, and trimethoprim-sulfamethoxazole. Other antibiotics may also lead to AKI, but no study has systemically compared AKI reporting associations for many available antibiotics. OBJECTIVE:The objective of this study was to evaluate the reporting associations between AKI and many available antibiotics using FAERS. METHODS:FAERS reports from 1 January 2015 to 31 December 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify AKI cases. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the reporting associations between antibiotics and AKI were calculated. A reporting association was considered statistically significant when the lower limit of the 95% CI was > 1.0. RESULTS:A total of 2,042,801 reports (including 20,138 AKI reports) were considered. Colistin had the greatest proportion of AKI reports, representing 25% of all colistin reports. AKI RORs (95% CI) for antibiotics were, in descending order: colistin 33.10 (21.24-51.56), aminoglycosides 17.41 (14.49-20.90), vancomycin 15.28 (13.82-16.90), trimethoprim-sulfamethoxazole 13.72 (11.94-15.76), penicillin combinations 7.95 (7.09-8.91), clindamycin 6.46 (5.18-8.04), cephalosporins 6.07 (5.23-7.05), daptomycin 6.07 (4.61-7.99), macrolides 3.60 (3.04-4.26), linezolid 3.48 (2.54-4.77), carbapenems 3.31 (2.58-4.25), metronidazole 2.55 (1.94-3.36), tetracyclines 1.73 (1.26-2.36), and fluoroquinolones 1.71 (1.49-1.97). CONCLUSION:This study found 14 classes of antibiotics having significant reporting associations with AKI. Among the antibiotics evaluated in this study, colistin had the highest AKI ROR and moxifloxacin had the lowest.
A real-world disproportionality analysis of FDA Adverse Event Reporting System (FAERS) events for baricitinib.
Peng Ling,Xiao Kui,Ottaviani Silvia,Stebbing Justin,Wang Ying-Jie
Expert opinion on drug safety
BACKGROUND:Baricitinib is approved for the treatment of rheumatoid arthritis (RA). The authors retrospectively investigated adverse events (AEs) by data-mining a self-reporting database to better understand toxicities, especially since it has been used during the coronavirus disease 2019 (COVID-19) pandemic. METHODS:A reporting odds ratio (ROR) was used to detect the risk signals from the data in the US Food and Drug Administration (FDA) adverse event reporting system database (FAERS). The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). RESULTS:The search retrieved 1,598 baricitinib-associated cases within the reporting period: 86 PTs with significant disproportionality were retained. Infections including 'herpes zoster,' 'oral herpes,' and 'herpes virus infection' were found at a similar rate to those reported in trials, and such events were rare. Reports emerged for several thrombotic adverse events, while these events were also rare. Unexpected safety signals as opportunistic infections were detected. Serious outcomes as death and life-threatening outcomes accounted for 9.76% of the reported cases. CONCLUSIONS:The incidence of these AEs does not appear above the background expected. These data are consistent with routine clinical observations and suggest the importance of pharmacovigilance.
Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database.
Mikami Takahisa,Liaw Bobby,Asada Mizuho,Niimura Takahiro,Zamami Yoshito,Green-LaRoche Deborah,Pai Lori,Levy Michael,Jeyapalan Suriya
Journal of neuro-oncology
PURPOSE:To investigate the characteristics and risk factors for neurologic adverse events (AEs) induced by immune checkpoint inhibitors (ICIs). METHODS:An observational, retrospective, and pharmacovigilance study based on the FAERS database collected between January 2014 and December 2019 was conducted. ICI-related AEs were defined as adverse reactions in patients using anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab). Neurologic AEs previously reported to be associated with ICI were evaluated in the disproportionality analysis using the reporting odds ratio (ROR). RESULTS:Among 50,406 ICI-related reports, 3619 (7.2%) neurological case was found: 1985 with anti-PD-1, 372 with anti-PD-L1, 366 with anti-CTLA-4, and 896 with the combination of ICIs. In comparison to non-ICI drug use, ICI use demonstrated higher risk for neurologic complication, including hypophysitis/hypopituitarism, myasthenia gravis, encephalitis/myelitis, meningitis, Guillain-Barre syndrome, vasculitis, and neuropathy. The risk of neurologic AEs associated with ICI combination therapy was as high as or even higher than ICI monotherapy, most significantly in hypophysitis/hypopituitarism. The proportion of serious neurological events and death related to combination therapy has been decreasing in recent years. Older age, male and female sex, and metastasis were not significant risk factors for the incidence of neurologic ICI-related AEs. Patients at older age, with melanoma or non-small cell lung cancer, or on dual ICI therapy may be at higher risk of fatal neurologic AEs. CONCLUSION:ICI use is associated with a higher risk of neurological complications, with dual ICI therapy posing a higher risk, while older age, sex, or metastasis were not. Patients at older age, with certain cancer types, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.
Thromboembolic events associated with immune checkpoint inhibitors: A real-world study of data from the food and drug administration adverse event reporting system (FAERS) database.
Li Hao,Sun Ximu,Sun Dan,Zhao Jin,Xu Zhouming,Zhao Peng,Ma Zhuo,Zhang Yuhui
BACKGROUND:Although there have been a few studies reporting thromboembolic events (TEEs) in patients treated with immune checkpoint inhibitors (ICIs), the detailed profile of the TEEs and the prothrombotic effects of ICIs remain mostly unknown. METHODS:Data from January 2004 to December 2019 in the FAERS database were retrieved. We investigated the clinical characteristics of the TEEs and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare ICIs with the full database and other anti-cancer agents. RESULTS:We identified 1855 reports of TEEs associated with ICIs. Affected patients tended to be male (59.68%) and older than 65 (47.12%). The case-fatality rate of the reported TEEs was high (38%). The median time to onset (TTO) of all cases was 42 (interquartile range [IQR] 15-96) days and the median TTO of fatal cases (31 [IQR 13-73] days) was significantly shorter than non-fatal cases (50 [IQR 20-108] days, p = 0.000002). ICIs showed increased risks of VTE (ROR 2.81, 95% CI 2.69-2.95) and ATE (ROR 1.44, 95% CI 1.37-1.52) compared with the full database. Compared with protein kinase inhibitors, ICIs showed an increased risk of VTE (ROR 1.23, 95% CI 1.17-1.29), but only anti-PD-L1 showed an increased risk of cerebral ATE (ROR 1.38, 95% CI 1.08-1.76). Compared with chemotherapy, ICIs showed an increased risk of PE (ROR 1.14, 95% CI 1.07-1.21). CONCLUSIONS:Our study suggested ICIs tend to increase risks of VTE and ATE. The poor clinical outcome and early onset of these events should attract clinical attention.
Safety of SGLT2 Inhibitors: A Pharmacovigilance Study from 2013 to 2021 Based on FAERS.
Zhou Xiang,Ye Xiaofei,Guo Xiaojing,Liu Dongxu,Xu Jinfang,Hu Fangyuan,Zhai Yinghong,Gao Yongqing,Xu Xiao,Dong Ziwei,He Jia
Frontiers in pharmacology
Sodium-glucose co-transporter-2 inhibitors (SGLT2is) are widely used in clinical practice for their demonstrated cardiorenal benefits, but multiple adverse events (AEs) have been reported. We aimed to describe the distribution of SGLT2i-related AEs in different systems and identify important medical event (IME) signals for SGLT2i. Data from the first quarter (Q1) of 2013-2021 Q2 in FAERS were selected to conduct disproportionality analysis. The definition of AEs and IMEs relied on the system organ classes (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA-version 24.0). Two signal indicators, the reported odds ratio (ROR) and information component (IC), were used to estimate the association between SGLT2is and IMEs. A total of 57,818 records related to SGLT2i, with 22,537 SGLT2i-IME pairs. Most SGLT2i-related IMEs occurred in monotherapy ( = 21,408, 94.99%). Significant signals emerged at the following SOCs: "metabolism and nutrition disorders" ( = 9,103; IC025 = 4.26), "renal and urinary disorders" (3886; 1.20), "infections and infestations" (3457; 0.85). The common strong signals were observed in diabetic ketoacidosis, ketoacidosis, euglycaemic diabetic ketoacidosis and Fournier's gangrene. Unexpected safety signals such as cellulitis, osteomyelitis, cerebral infarction and nephrolithiasis were detected. Our pharmacovigilance analysis showed that a high frequency was reported for IMEs triggered by SGLT2i monotherapy. Different SGLT2is caused different types and the association strengths of IMEs, while they also shared some specific PTs. Most of the results are generally consistent with previous studies, and more pharmacoepidemiological studies are needed to validate for unexpected AEs. Based on risk-benefit considerations, clinicians should be well informed about important medical events that may be aggravated by SGLT2is.
Hypoglycemia associated with direct-acting anti-hepatitis C virus drugs: An epidemiologic surveillance study of the FDA adverse event reporting system (FAERS).
Zhou Yu,Xie Wenhuo,Zheng Chenhua,Liu Libin,Chen Zhou,Wang Xiaolu
BACKGROUND AND OBJECTIVE:Hypoglycemia induced by direct-acting antiviral agents (DAAs) for chronic hepatitis C virus (HCV) infection is a rare but potentially life-threatening adverse reaction, which led to warnings by competent authorities. We therefore aimed to examine the hypoglycemic safety signal for DAAs. METHODS:Reports to the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 1 October 2012 to 31 March 2020 were analyzed. The Medical Dictionary for Regulatory Activities was used to identify hypoglycemia cases. A case by non-case disproportionality approach was used whereby reporting odds ratio (ROR) with 95% confidence intervals (CI) were calculated. RESULTS:In HCV infection with diabetes patients, the cumulative frequency of hypoglycemic ADRs was 21.85/1000 for reports involving DAAs versus 13.50/1000 for reports involving other medications; For DAAs as a class drug, a nearly double increased reporting odds for hypoglycemia was observed (ROR: 1.63, 95% CI: 1.11-2.41). However, in DAAs subgroup analysis, only telaprevir (ROR: 1.66, 95% CI: 1.01-2.74) and elbasvir/grazoprevir (ROR: 2.25, 95% CI: 1.05-4.83) were associated with increased reporting risk of hypoglycemia during corresponding marketing period; when combined with insulins and sulfonylureas, DAAs were associated with increased reporting risk for hypoglycemia (ROR: 1.98, 95% CI: 1.36-2.88; ROR: 1.62, 95% CI: 1.06-2.48), but concomitant biguanides, dipeptidyl peptidase IV (DPP-4) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RAs) were not significant. CONCLUSIONS:This study supports the current recommendation for cautious about hypoglycemic risk relating to the use of DAAs. Treatment with DAAs and antidabetic agents (especially insulins and sulfonylureas) will increase hypoglycemia reporting risk. Physicians and pharmacists should be aware of this risk when prescribing DAAs for patients suffering from diabetes, advanced age or liver decompensation.
Severe hypoglycemia in children treated with nadolol: A case report and FDA adverse event reporting system (FAERS) database analysis.
Bergamaschi Francesco,Fumagalli Mara,Mannarino Savina,Carlucci Patrizia,Radice Sonia,Gringeri Michele,Mosini Giulia,Carnovale Carla,Battini Vera,Fabiano Valentina
International journal of clinical pharmacology and therapeutics
OBJECTIVE:We describe a case of severe hypoglycemia in a 14-month-old child as a suspected adverse drug reaction (ADR) to nadolol, and we performed an analysis of the FDA Adverse Event Reporting System (FAERS) database. Although previous reports have identified the risk of severe hypoglycemia in children during treatment with β-blockers, little is known about hypoglycemia as an ADR in infants treated with nadolol. Moreover, the pharmacodynamic and pharmacokinetic profiles of nadolol in children aged less than 1 year old are still not fully known. MATERIALS AND METHODS:We extracted all ADR reports involving nadolol from the FAERS database; in order to reduce the risk of bias, we only considered cases that exclusively reported nadolol as the suspect drug. We then selected cases of hypoglycemia in the pediatric population and conducted a manual deduplication. RESULTS:Upon FAERS database analysis, a total of 2,674 suspected ADR reports to nadolol were found. Of these, 1,950 (73%) were solely attributed to nadolol, and 63 of them were hypoglycemic events. A total of 47 reports included the relevant pediatric age (74.6%). After deduplication, we identified 25 cases (mean age: 3.65 years old); all of these reports were categorized as serious, and hospitalization was required in 15 cases. CONCLUSION:Hypoglycemia is a reported life-threatening ADR associated with nadolol, especially in infants, in whom this drug should be used with caution.
Reporting of Thromboembolic Events with JAK Inhibitors: Analysis of the FAERS Database 2010-2019.
Setyawan Juliana,Azimi Nassir,Strand Vibeke,Yarur Andres,Fridman Moshe
INTRODUCTION:A potentially elevated risk for pulmonary thrombosis with Janus kinase inhibitors (JAKinibs) was identified, as well as an increased risk for portal vein thrombosis, in ruxolitinib patients. Consequently, the objective of this investigation was to repeat a comprehensive analysis of the US FDA's Adverse Event Reporting System (FAERS) database to assess postmarketing reporting rates of thromboembolic events (TEs) in patients treated with JAKinibs. METHODS:FAERS data (1 January 2010 to 30 September 2019) were searched for reports of all FDA-approved JAKinibs across all indications. For each drug-adverse drug reaction (ADR) pair, the reporting odds ratio (ROR) [two-sided 95% confidence interval (CI)] and empirical Bayesian geometric mean (EBGM) [one-sided 95% lower bound] were calculated to detect drug-ADR pairs with higher-than-expected reporting rates within the FAERS. Significance was declared when both lower 95% CI bounds were > 1. RESULTS:Significantly elevated reporting rates of pulmonary thrombosis were evident with tofacitinib (ROR 2.36 [1.69-3.31]; EBGM 2.01 [1.53]), as was pulmonary embolism with baricitinib (ROR 12.23 [8.35-17.89]; EBGM 7.72 [3.82]) and portal vein thrombosis with ruxolitinib (ROR 4.16 [2.70-6.40]; EBGM 4.52 [3.11]). Deep vein thrombosis reports were increased with baricitinib (ROR 14.84 [9.64-22.84]; EBGM 9.49 [5.91]), as was thrombosis with ruxolitinib (ROR 1.40 [1.20-1.63]; EBGM 1.72 [1.52]). The relationship between the time of treatment initiation and event occurrence indicated that time to events occurred randomly. CONCLUSIONS:This study found significant reporting rates for TEs in patients treated with JAKinibs across brands and indications, providing additional evidence that JAKinibs may be contraindicated in patients at risk of TEs.
Signals of bleeding among direct-acting oral anticoagulant users compared to those among warfarin users: analyses of the post-marketing FDA Adverse Event Reporting System (FAERS) database, 2010-2015.
Alshammari Thamir M,Ata Sondus I,Mahmoud Mansour Adam,Alhawassi Tariq M,Aljadhey Hisham S
Therapeutics and clinical risk management
PURPOSE:To analyze and compare the signals of bleeding from the use of direct-acting oral anticoagulants (DOACs) in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database over 5 years. METHODS:Reports of bleeding and of events with related terms submitted to the FAERS between October 2010 and September 2015 were retrieved and then analyzed using the reporting odds ratio (ROR). The signals of bleeding associated with DOAC use were compared with the signals of bleeding associated with warfarin use utilizing the FAERS databases. RESULTS:A total of 1,518 reports linked dabigatran to bleeding, accounting for 2.7% of all dabigatran-related reports, whereas 93 reports linked rivaroxaban to bleeding, which accounted for 4.4% of all rivaroxaban-related reports. The concurrent proportion of bleeding-related reports for warfarin was 3.6%, with a total of 654 reports. The association of bleeding and of related terms with the use of all three medications was significant, albeit with different degrees of association. The ROR was 12.30 (95% confidence interval [CI] 11.65-12.97) for dabigatran, 15.61 (95% CI 14.42-16.90) for warfarin, and 18.86 (95% CI 15.31-23.23) for rivaroxaban. CONCLUSIONS:The signals of bleeding varied among the DOACs, and the bleeding signal was higher for rivaroxaban and lower for dabigatran compared to that for warfarin.
Vemurafenib Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Disproportionality Analysis in FAERS Database.
Neha Reddy,Beulah Elsa,Anusha Bellapu,Vasista Sharma,Stephy Chacko,Subeesh Viswam
Current reviews in clinical and experimental pharmacology
BACKGROUND:Signal strength for any drug-event combination can be determined using disproportionality analysis. Vemurafenib is a BRAF inhibitor approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of metastatic melanoma. This study aims to identify the signal strength of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with vemurafenib using disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS). METHODS:Data were obtained from the public release of data in FAERS. The case/non-case method was adopted for the analysis of the association between vemurafenib use and DRESS. The data mining algorithm used for the analysis was the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE>1, PRR≥2 was considered as positive signal strength. RESULTS:A total of 7,171 reports for DRESS have been reported in the FDA database. Amongst which, 125 reports were associated with vemurafenib. A cumulative ROR of 17.72 (95% CI 14.83; 21.18) and PRR of 17.46 (95% CI 14.65; 20.81) were observed. Combination treatment of vemurafenib with cobimetinib had a higher number of reports (100) with ROR of 103.42 (84.13- 127.14) and PRR of 94.52 (78.26- 114.15). Four deaths were reported and the non-death serious reports included hospitalization, life-threatening, disability, and other serious events with 61, 11, 2 and 39 reports, respectively. CONCLUSION:Positive signal strength was observed for vemurafenib associated DRESS. The signal strength was higher for vemurafenib in combination with cobimetinib than vemurafenib alone. Health care professionals should be cautious about encountering serious adverse events and should report such events to the regulatory authorities.
Analysis of the Association of Administration of various glucocorticoids with development of acute pancreatitis using US Food and Drug Administration adverse event reporting system (FAERS).
Nango Daisuke,Hirose Yukifumi,Goto Makoto,Echizen Hirotoshi
Journal of pharmaceutical health care and sciences
BACKGROUND:There have been debates about the association between the administration of glucocorticoids and the development of acute pancreatitis, since many anecdotal cases of this adverse event were affected either by concomitant diseases (such as systemic lupus erythematosus, SLE) that may develop acute pancreatitis without glucocorticoid treatment or by co-administered drugs with high risk for the event. The aim of the present study was to explore whether disproportionally elevated signals of developing acute pancreatitis may be detected in patients receiving glucocorticoids as compared those receiving other drugs. METHODS:We retrieved spontaneously reported cases of acute pancreatitis and clinically related adverse events (target events) from the US Food and Drug Administration Adverse Event Reporting System (FAERS) using 18 preferred terms (PTs). Target drugs studied were cortisol, cortisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, and betamethasone. After cleaning the data, we calculated reporting odds ratios (RORs) and 95% confidence intervals (CIs) of acute pancreatitis in patients who received one of the glucocorticoids. RORs were calculated for each glucocorticoid using all reported cases irrespective of reporters' judgement about the contribution of the target drugs to events [i.e., primary suspected medication (PS), secondary suspected medication (SS), concomitant medication (C) and interacting (I)] and using cases with higher certainty of contribution (PS and SS), separately. When the lower limit of 95% CI of a ROR signal exceeded 1.0, the signal was considered statistically significant. RESULTS:The RORs (95% CIs) calculated using all reported cases (PS, SS, C, and I) for cortisol (1.68; 1.43-1.98), prednisolone (1.33; 1.19-1.47), methylprednisolone (1.77; 1.55-2.02) were significant, whereas those for other target drugs were insignificant. Using the cases in which target drugs were considered to contribute the events with higher certainty (PS or SS), RORs for prednisolone (1.31; 1.10-1.55), methylprednisolone (1.62; 1.30-2.01), and dexamethasone (1.27; 1.10-1.47) were considered significant, whereas those for others were insignificant. Regarding the performance of PTs for detecting signals (RORs) associated with acute pancreatitis from FAERS database, "pancreatitis acute" gave RORs with higher significance than others, whereas more specific PTs, "haemorrhagic necrotic pancreatitis", "ischaemic pancreatitis", "pancreatic necrosis" and "pancreatitis necrotising", gave RORs with greater magnitude. CONCLUSION:The present study demonstrated that the overrepresentation of signals for acute pancreatitis may be detected for prednisolone, methylprednisolone, and some others in the FAERS database.(372 words).
Drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19: a disproportionality analysis of U.S. food and drug administration adverse event reporting system (FAERS) data.
Tang Huilin,Zhou Liyuan,Li Xiaotong,Kinlaw Alan C,Yang Jeff Y,Moon Andrew M,Barnes Edward L,Wang Tiansheng
International journal of clinical pharmacy
Background Liver injury has been documented independently in novel coronavirus disease 2019 (COVID-19) patients and patients treated with lopinavir-ritonavir. Objective to investigate the drug-induced liver injury associated with lopinavir-ritonavir among the patients with COVID-19. Methods We conducted a disproportionality analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS) between 2020Q1 and 2021Q1 to evaluate the association between lopinavir-ritonavir and risk of drug-induced liver injury (or severe drug-induced liver injury) and calculated their reporting odds ratios (RORs) with 95% confidence intervals (CIs). Results A total of 3,425 cases of drug-induced liver injury were reported in 19,782 patients with COVID-19. The ROR for drug-induced liver injury was 2.99 (2.59-3.46), 3.16 (2.68-3.73), and 5.39 (4.63-6.26) when comparing lopinavir-ritonavir with all other drugs, hydroxychloroquine/chloroquine only, and remdesivir, respectively. For severe drug-induced liver injury, RORs for lopinavir-ritonavir provided evidence of an association compared with all other drugs (3.98; 3.15-5.05), compared with hydroxychloroquine/chloroquine only (5.33; 4.09-6.94), and compared with remdesivir (3.85; 3.03-4.89). Conclusions In the FAERS, we observed a disproportional signal for drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19.
Osimertinib-Induced Cardiotoxicity: A Retrospective Review of the FDA Adverse Events Reporting System (FAERS).
OBJECTIVES:The goal of this study was to compare the risk of cardiotoxicity with osimertinib versus all other drugs and versus epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (erlotinib, afatinib, and gefitinib) in the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS), a pharmacovigilance database. BACKGROUND:Osimertinib has been shown to improve outcomes in T790M-positive non-small cell lung cancer patients who progress on EGFR-TKI therapy and in the frontline setting in EGFR mutated non-small cell lung cancer. In pivotal trials, osimertinib was associated with higher rates of cardiotoxicity compared with the control arm. METHODS:FAERS was queried for "Cardiac failure," "Electrocardiogram QT-prolonged," "Atrial Fibrillation (AF)," "Myocardial Infarction (MI)," and "Pericardial Effusion" secondary to "Osimertinib," "Erlotinib," "Afatinib," "Gefitinib," and all other drugs from 2016 to 2018. Disproportionality signal analysis was performed by calculating the reporting odds ratio (ROR) with its 95% confidence interval (CI). The ROR was considered significant when the lower limit of the 95% CI was >1.0. RESULTS:The ROR (95% CI) for cardiac failure, atrial fibrillation (AF), QT prolongation, myocardial infarction, and pericardial effusion due to osimertinib versus all other drugs in FAERS was 5.4 (4.2 to 7.1), 4.0 (2.8 to 5.8), 11.2 (7.9 to 15.8), 1.6 (0.9 to 2.6), and 8.2 (4.8 to 14), respectively. The ROR (95% CI) for cardiac failure, AF, QT prolongation, myocardial infarction, and pericardial effusion in comparing osimertinib versus other EGFR-TKIs was 2.2 (1.5 to 3.2), 2.1 (1.3 to 3.5), 6.6 (3.4 to 12.8), 1.2 (0.6 to 2.3), and 1.6 (0.8 to 3.3). CONCLUSIONS:The RORs for cardiac failure, AF, and QT prolongation were higher due to osimertinib compared with other TKIs. Electrocardiographic monitoring for QT prolongation and monitoring for signs and symptoms of heart failure should be considered in patients taking osimertinib.
Correlations Between SGLT-2 Inhibitors and Acute Renal Failure by Signal Detection Using FAERS: Stratified Analysis for Reporting Country and Concomitant Drugs.
Katsuhara Yukari,Ikeda Shunya
Clinical drug investigation
BACKGROUND:Previous studies have shown conflicting observations regarding the correlation between sodium-glucose-cotransporter-2 inhibitors (SGLT2i) and acute renal failure. Although wide use has contributed to the accumulation of safety information on SGLT2i, the examination of the countries reporting cases of SGLT2i use and influence of concomitant drugs has been insufficient in studies using spontaneous adverse event reporting databases. OBJECTIVE:We aimed to re-examine the correlation between SGLT2i and acute renal failure using the latest United States Food and Drug Administration's Adverse Event Reporting System (FAERS) records and to conduct a stratified analysis for the reporting countries (Japan or other countries), as well as the concomitant use of drugs such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) with SGLT2i. PATIENTS AND METHODS:The reporting odds ratio (ROR) and 95% confidence interval (CI) for cases recorded on FAERS from January 2013 to March 2020 were calculated. We then limited the cases to patients using SGLT2i and receiving treatment for diabetes mellitus and then calculated the ROR. A stratified analysis was performed for reporting countries (Japan or other countries), and the presence or absence of concomitant use of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) to examine their influence on the correlation between SGLT2i and acute renal failure. RESULTS:Of the 5,337,069 cases of adverse events recorded on FAERS, 410,569 were cases in which patients had received treatment for diabetes. The ROR for SGLT2i calculated from the total analysis subjects was 4.16 (95% CI 4.01-4.31), suggesting its correlation with acute renal failure. Similar results were obtained for the cases in which patients had received treatment for diabetes. However, the stratified analysis of these diabetes-treatment cases for reporting countries showed no correlation between SGLT2i and acute renal failure in cases reported in Japan with ROR 0.58 (95% CI 0.49-0.69). In contrast, a correlation was suggested in cases reported in countries other than Japan with ROR 1.91 (95% CI 1.83-1.98). Moreover, the stratified analysis for the concomitant use of an ACEi or ARB showed that the ROR tended to be low in the cases with one of these drugs. CONCLUSION:Examination with the signal detection method using FAERS suggested the correlation between SGLT2i and the onset of acute renal failure. However, when focusing on the cases reported in Japan, such a correlation was not suggested. In addition, this study indicated that the signal of acute renal failure tends to be reduced in cases with the concomitant use of either an ACEi or ARB. Through this study we suggest that patients should be closely monitored when they take SGLT2i without an ACEi or ARB.
Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: An analysis of the Food And Drug Administration Adverse Events Reporting System (FAERS).
Evoy Kirk E,Covvey Jordan R,Peckham Alyssa M,Ochs Leslie,Hultgren Kyle E
Research in social & administrative pharmacy : RSAP
BACKGROUND:Reports of gabapentinoid (gabapentin and pregabalin) misuse have increased in recent years. Pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) provides a useful examination of adverse drug event (ADE) reporting for safety signal detection. OBJECTIVE:This study was conducted to analyze epidemiological information on the nature and extent of gabapentin/pregabalin abuse utilizing the FAERS database. METHODS:A query was designed utilizing SafeRx, an indexed, searchable database of FAERS data from October 2012-December 2016. All-cause and abuse-related (including abuse/misuse/dependence/overdose events) ADE reports for gabapentin and pregabalin were isolated, as well as limited demographic data. The proportional reporting ratio (PRR) was calculated to compare signal detection. RESULTS:A total of 10,038 all-cause ADEs were reported to FAERS for gabapentin, including 576 (5.7%) abuse-related events. For pregabalin, 571 all-cause ADEs were identified, including 58 (10.2%) related to abuse. Compared to all-cause ADEs, those involved in abuse-related events were younger and more likely to be male. The PRR of pregabalin versus gabapentin abuse-related events was 1.77. CONCLUSION:Though not traditionally thought of as drugs of abuse, over 600 cases of gabapentinoid abuse were reported in the time frame analyzed, prompting the need for further study and regulatory investigation.
Injection Site Reactions in the Federal Adverse Event Reporting System (FAERS) Post-Marketing Database Vary Among Biologics Approved to Treat Moderate-To-Severe Psoriasis.
Grace Elsie,Goldblum Orin,Renda Lisa,Agada Noah,See Kyoungah,Leonardi Craig,Menter Alan
Dermatology and therapy
INTRODUCTION:Biologics used to treat moderate-to-severe plaque psoriasis may cause injection site reactions (ISRs) characterized by erythema, edema, itch, and sometimes pain. The Federal Adverse Event Reporting System (FAERS) is a repository of spontaneous post-marketing reports of adverse events (AEs) that are reported to the US Food and Drug Administration (FDA). Our objective was to perform a pharmacovigilance analysis of FAERS reports of ISRs associated with the use of subcutaneously administered biologic products approved to treat moderate-to-severe plaque psoriasis. METHODS:The products included in our assessment were adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab. Reports from the date of US approval for each biologic as treatment for plaque psoriasis through 2 years were included using the search term "injection site." RESULTS:The results show that the FAERS database contained reports of ISRs for all of the included biologics during the 2 years following FDA approval. The most common reports on ISRs were on pain, irritation, and erythema for adalimumab; reaction, pain, and erythema for etanercept; erythema, pain, and reaction for ixekizumab; bruising, pain, hemorrhage for secukinumab; and pain, induration, and swelling for ustekinumab. FAERS does not include data on total patient exposure; therefore, ISR rates could not be calculated. CONCLUSIONS:Specific ISRs varied among the biologic therapies assessed. The findings presented could be helpful when patients consider switching therapies due to ISRs. FUNDING:Eli Lilly and Company.
Use of Disproportionality Analysis to Identify Previously Unknown Drug-Associated Causes of Cardiac Arrhythmias Using the Food and Drug Administration Adverse Event Reporting System (FAERS) Database.
Moreland-Head Lindsay N,Coons James C,Seybert Amy L,Gray Matthew P,Kane-Gill Sandra L
Journal of cardiovascular pharmacology and therapeutics
INTRODUCTION:Drug-induced QT-prolongation is a well-known adverse drug reaction (ADR), however there is limited knowledge of other drug-induced arrhythmias. PURPOSE:The objective of this study is to determine the drugs reported to be associated with arrhythmias other than QT-prolongation using the FAERS database, possibly identifying potential drug causes that have not been reported previously. METHODS:FAERS reports from 2004 quarter 1 through 2019 quarter 1 were combined to create a dataset of approximately 11.6 million reports. Search terms for arrhythmias of interest were selected from the Standardized MedDRA Queries (SMQ) Version 12.0. Frequency of the cardiac arrhythmias were determined for atrial fibrillation, atrioventricular block, bradyarrhythmia, bundle branch block, supraventricular tachycardia, and ventricular fibrillation and linked to the reported causal medications. Reports were further categorized by prior evidence associations using package inserts and established drug databases. A reporting odds ratio (ROR) and confidence interval (CI) were calculated for the ADRs for each drug and each of the 6 cardiac arrhythmias. RESULTS:Of the 11.6 million reports in the FAERS database, 68,989 were specific to cardiac arrhythmias of interest. There were 61 identified medication-reported arrhythmia pairs for the 6 arrhythmia groups with 33 found to have an unknown reported association. Rosiglitazone was the most frequently medication reported across all arrhythmias [ROR 6.02 (CI: 5.82-6.22)]. Other medications with significant findings included: rofecoxib, digoxin, alendronate, lenalidomide, dronedarone, zoledronic acid, adalimumab, dabigatran, and interferon beta-1b. CONCLUSION:Upon retrospective analysis of the FAERS database, the majority of drug-associated arrhythmias reported were unknown suggesting new potential drug causes. Cardiac arrhythmias other than QTc prolongation are a new area of focus for pharmacovigilance and medication safety. Consideration of future studies should be given to using the FAERS database as a timely pharmacovigilance tool to identify unknown adverse events of medications.
Opioids and frequency counts in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database: a quantitative view of the epidemic.
Drug, healthcare and patient safety
BACKGROUND:The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the FDA through the MedWatch program. A significant number of adverse events reported in the FAERS database have been for opioid use. The objective of this study was to determine the frequency counts and associated deaths of opioid drug names in the FAERS database. METHODS:Drug data were obtained from the DRUG and OUTCOME files in the database. Drugs identified included: morphine, fentanyl, oxycodone, hydrocodone, tramadol, hydromorphone, methadone, codeine, oxymorphone, meperidine, propoxyphene, diphenoxylate, and heroin. Frequency counts and concomitant deaths of opioid drug names were determined via the MySQL database management system. RESULTS:Fifteen different opioid drugs identified in the FAERS database were associated with ADEs, including death, and 3 drugs (oxycodone, hydrocodone, fentanyl) accounted for more than half of the reports. The highest frequency count value was 158,181 for oxycodone, which represents approximately 20.2% of the frequency counts for the opioids. The lowest frequency count value was 2,161 for dextromethorphan, which represents approximately 0.3% of the total. The opioid with the highest proportion of deaths to drug count was heroin (71.8%), followed by dextromethorphan (55.6%), methadone (37.2%), morphine (26.8%), and propoxyphene (23.7%). CONCLUSION:The FAERS database represents an important source for detection and reporting of adverse drug events (ADEs), in particular the opioids and related drugs. It remains a challenge to estimate the true incidence of ADEs for this class of drugs in the general population.
Assessment of the Safety Signal for the Abuse Potential of Pregabalin and Gabapentin Using the FAERS Database and Big Data Search Analytics.
Papazisis Georgios,Spachos Dimitrios,Siafis Spyridon,Pandria Niki,Deligianni Eleni,Tsakiridis Ioannis,Goulas Antonios
Frontiers in psychiatry
The latest decade, an emerging issue has been the abuse potential of the gabapentinoids pregabalin and gabapentin. The aim of our study was to assess this safety signal combining two different methods of surveillance: search analytics big data and the FDA spontaneous reporting system database. Analysis of big data and the FAERS was used to detect pregabalin's and gabapentin's abuse potential in comparison with two controls, clonazepam and levetiracetam, and further, the correlation between these domains was investigated. Data from the United States between 2007 and 2020Q2 were analyzed. The FAERS analysis revealed the following pattern of signals: clonazepam > pregabalin ≥ gabapentin > levetiracetam, for both the primary term "drug abuse and dependence" and the secondary terms (withdrawal, tolerance, overdose). The Google domain pattern was slightly different: clonazepam ≥ gabapentin ≥ pregabalin≥ levetiracetam. A monotonic correlation was found between FAERS and Google searches for gabapentin ( = 0.558; < 0.001), pregabalin ( = 0.587; < 0.001), and clonazepam ( = 0.295; = 0.030). Our results revealed that there is preliminary evidence of a safety signal for the abuse potential of pregabalin and gabapentin. Analysis of the FAERS database, supplemented by big data search analytics, suggests that there is potential of using these methods as a supplementary tool to detect drug abuse-related safety signals in pharmacovigilance.
Emerging Causes of Drug-Induced Anaphylaxis: A Review of Anaphylaxis-Associated Reports in the FDA Adverse Event Reporting System (FAERS).
Yu Roger J,Krantz Matthew S,Phillips Elizabeth J,Stone Cosby A
The journal of allergy and clinical immunology. In practice
BACKGROUND:Drug-induced anaphylaxis is a well-known adverse drug reaction for some drug classes, but emerging drug causes of anaphylaxis and novel mechanisms may contribute in unrecognized ways. OBJECTIVE:We sought to determine the top drugs reported in association with anaphylaxis and anaphylaxis followed by death in the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS:We reviewed the publicly available FAERS database from 1999 to 2019. Using search terms "anaphylactic shock" or "anaphylactic reaction" and sorting cases by generic drug names, we counted and trended reports to FAERS in which a drug was associated with anaphylaxis or anaphylaxis followed by death. RESULTS:From 1999 to 2019, there were 17,506,002 adverse drug events reported in FAERS, of which 47,496 (0.27%) were reported as anaphylaxis. Excluding patients without age, sex, or country data, respectively, the median age of patients in reports of anaphylaxis was 52 (interquartile range: 28), 62.71% were female, and 13,899 of 34,381 (40.43%) reports were from the United States. There were 2984 of 47,496 (6.28%) reports of anaphylaxis followed by death. Top drug classes associated with anaphylaxis in FAERS were antibiotics, monoclonal antibodies (mAbs), nonsteroidal anti-inflammatory drugs, and acetaminophen. Top drug classes associated with anaphylaxis deaths were antibiotics, radiocontrast agents, and intraoperative agents. Linear regression demonstrated reports of anaphylaxis to mAbs increasing at an average rate of 0.77% of total anaphylaxis reports per year (95% confidence interval: 0.65, 0.88) from 2.00% in 1999 to 17.37% in 2019, faster than any other drug class. CONCLUSION:Antibiotics were highly reported for anaphylaxis overall and anaphylaxis followed by death. Increasing reports were noted for anaphylaxis to mAb therapies.