FDA Adverse Event Reporting System Reports Research Articles

META-INSTI: metabolic adverse events following integrase strand transfer inhibitor administration in spontaneous adverse event reports.

Metabolic effects of integrase strand transfer inhibitors (INSTIs) have been reported. The FDA Adverse Event Reporting System (FAERS) is a publicly available database that captures spontaneously reported adverse events. The objective of this study was to evaluate the relationship between INSTIs and metabolic adverse events using the FAERS database. FAERS data were queried from quarter 4 of 2007 through quarter 4 of 2019 and limited to adults. The Standardized MedDRA Query for 'hyperglycaemia/new-onset diabetes mellitus' (H/DM) was used to identify metabolic adverse events of interest. Weight gain was analysed as a separate event. Reporting odds ratios (RORs) and 95% CIs were calculated for the INSTI class and individual agents. Over 10.1 million FAERS reports were identified. Any INSTI was mentioned as a primary and/or secondary suspect agent in 18,400 (0.18%) reports (bictegravir: 1414 [0.01%]; dolutegravir: 7840 [0.08%]; elvitegravir: 4034 [0.04%]; raltegravir: 5551 [0.05%]). RORs (95% CI) for H/DM and weight gain for any INSTI were 1.20 (1.15-1.27) and 2.16 (1.96-2.38). For individual agents, RORs (95% CI) for H/DM and weight gain were as follows: bictegravir, 1.23 (1.10-1.37) and 6.82 (5.50-8.41); dolutegravir, 1.28 (1.19-1.39) and 1.86 (1.58-2.18); elvitegravir, 0.76 (0.56-1.02) and 1.63 (1.37-1.92); and raltegravir, 1.00 (0.90-1.11) and 3.29 (2.77-3.91). H/DM was noted in 159 bictegravir and 712 dolutegravir reports. Overall, H/DM was associated with bictegravir and dolutegravir and weight gain with all INSTIs. Clinicians should know the potential relationship between INSTIs and metabolic effects and institute appropriate monitoring. META-INSTI: Metabolic Adverse Events Following Integrase Strand Transfer Inhibitor Administration in Spontaneous Adverse Event Reports. Platform Presentation. ID Week. Virtual 2020.

Factors associated with fatal coronavirus disease 2019 infections among cancer patients in the USFDA Adverse Event Reporting System database.

Aim:To explore factors affecting coronavirus disease 2019 (COVID-19) mortality among cancer patients based on a pharmacovigilance database.Methods:US FDA Adverse Event Reporting System (FAERS) quarterly data extract files were reviewed for quarters two, three and four of 2020 (i.e., April to December). Patients with an indication related to malignancy and a reported COVID-related reaction were selected. Multivariate logistic regression analysis for factors associated with a fatal outcome was conducted.Results:A total of 2708 patients were included. The following factors were associated with fatal COVID-19 infection: older age (odds ratio [OR]: 1.03; 95% CI: 1.01–1.04), male sex (OR: 1.43; 95% CI: 1.07–1.91), non-US report source (OR: 2.46; 95% CI: 1.93–3.13), hematological malignancy (OR: 1.62; 95% CI: 1.28–2.07), potentially immunosuppressive treatment (OR: 1.83; 95% CI: 1.30–2.58) and diagnosis in quarter two versus quarter four (OR: 1.62; 95% CI: 1.27–2.07).Conclusion:Within FAERS reports, cancer patients who are older, males and receiving immunosuppressive treatment and those with hematological malignancies were at a higher risk of death because of COVID-19 infection.

Delirium Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

BackgroundErtapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime are known to be associated with delirium. Other antibiotics may also lead to delirium, but no study has systemically compared delirium associations for many available antibiotics.ObjectiveThe objective of this study was to evaluate the association between delirium and antibiotics using the FDA Adverse Event Reporting System (FAERS).MethodsFAERS reports from January 1, 2004 to December 31, 2018 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (95% CI) for the association between antibiotics and delirium were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was greater than 1.0.ResultsA total of 10,015,622 reports (including 16,982 delirium reports) were considered, after inclusion criteria were applied. Statistically significant delirium RORs (95% CI) for antibiotics were: ertapenem 21.07 (16.38–27.10), cefepime 9.8 (6.37–15.09), imipenem 9.68 (6.75–13.89), ofloxacin 7.73 (4.00–14.92), ceftazidime 6.09 (2.73–13.62), clarithromycin 5.34 (4.37–6.53), cefaclor 5.32 (1.71–16.58), ampicillin–sulbactam 4.49 (2.13–9.45), levofloxacin 4.47 (3.88–5.16), linezolid 4.33 (3.28–5.72), moxifloxacin 3.51 (2.81–4.38), azithromycin 2.76 (2.09–3.64), piperacillin–tazobactam 2.41 (1.47–3.93), trimethoprim–sulfamethoxazole 2.36 (1.61–3.47), metronidazole 1.85 (1.31–2.60), ciprofloxacin 1.83 (1.44–2.33), and cefuroxime 1.81 (1.03–3.20).ConclusionThis study found statistically significant increased risk of reporting delirium with ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, ampicillin–sulbactam, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime.

106. META-INSTI: Metabolic Adverse Events Following Integrase Strand Transfer Inhibitor Administration in Spontaneous Adverse Event Reports

BackgroundUnexpected metabolic effects of integrase inhibitors (INSTIs) have been reported in the literature. The FDA Adverse Event Reporting System (FAERS) is a publicly available database that captures spontaneously reported adverse events. Analysis of these data allows for the determination of whether rare or unknown events represent a cause for concern. The objective of this study was to evaluate the relationship between INSTIs and metabolic adverse events using the FAERS database.MethodsFAERS data were queried from quarter 4 2007 through quarter 4 2019 and limited to adults. The Standardized MedDRA Query (SMQ) for hyperglycemia/new onset diabetes mellitus (H/DM) was used to identify metabolic adverse events of interest. Weight gain was defined as increased weight or increased BMI and was analyzed as a separate event. Reporting odds ratios (ROR) and 95% Confidence Intervals (CIs) were calculated for the INSTI class and for individual agents.ResultsOver 10.1 million FAERS reports were identified. H/DM was noted in 732,591 reports (7.2%); 109,566 (1.1%) reported weight gain. Consumers (49%) and physicians (23%) were the most common reporters. The most frequent countries of occurrence were the US, Great Britain, and Japan. The mean (SD) age was 57 (17) years with 63% females. Any INSTI was mentioned as a primary and/or secondary suspect agent in 18,400 (0.18%) reports (bictegravir: 1,414 [0.01%]; dolutegravir: 7,840 [0.08%]; elvitegravir: 4,034 [0.04%]; raltegravir: 5,551 [0.05%]). RORs (95% CI) for H/DM and weight gain for any INSTI were 1.20 (1.15, 1.27) and 2.16 (1.96, 2.38). For individual agents, RORs (95% CI) for H/DM and weight gain were bictegravir: 1.23 (1.10, 1.37) and 6.82 (5.50, 8.41); dolutegravir: 1.28 (1.19, 1.39) and 1.86 (1.58, 2.18); elvitegravir: 0.76 (0.56, 1.02) and 1.63 (1.37, 1.92); raltegravir: 1.00 (0.90, 1.11) and 3.29 (2.77, 3.91). H/DM was noted in 159 bictegravir and 712 dolutegravir reports.ConclusionOverall, H/DM was associated with bictegravir and dolutegravir; weight gain was associated with all INSTIs. Clinicians should be aware of the potential relationship with INSTIs and concerning metabolic effects and institute appropriate monitoring. Future clinical studies to evaluate these findings are warranted.DisclosuresMilena M. Murray, PharmD, MSc, BCIDP, AAHIVP, Merck (Speaker’s Bureau)

1596-P: Evaluating Reports of Pancreatic Malignancy and Liraglutide: A Pharmacovigilance Study of the FDA Adverse Event Reporting System

Background: Animal studies have raised concerns about glucagon-like peptide-1 (GLP-1) receptor agonist usage and incidence of pancreatic premalignant changes. Although randomized controlled Trials (RCTs) have not described this association, smaller size and shorter duration of RCTs may limit their statistical power to find such an association. Liraglutide utilization has been increasing due to the prescribing label change and indication for cardiovascular disease. Aim: Evaluate reporting associations between pancreatic cancer and liraglutide using FDA Adverse Event Reporting System (FAERS). Methods: FAERS reports from 1 January 2004 to 31 December 2018 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify pancreatic cancer cases. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the reporting associations among liraglutide, metformin, glyburide, glipizide, and empagliflozin and pancreatic cancer were calculated. Results: A total of 10,015,622 reports were considered. Pancreatic cancer RORs (95% CI) in descending order were: Liraglutide 32.47 (30.53-34.52), metformin 6.85 (6.52-7.19), glyburide 5.24 (4.48-6.14), glipizide 3.83 (3.32-4.42), and empagliflozin 3.42 (2.50-4.67). The number of reports for pancreatic cancer increased from 2735 in 2010 to 4967 in 2018. Conclusion: Liraglutide had greater reporting associations when compared to other antidiabetes medications. Further studies are needed to determine if this signal is causal. Disclosure C.A. Alvarez: None. C. Teng: None. I. Mansi: None. Funding National Institutes of Health (K08DK101602)

Hypoglycemia Associated with Antibiotics Alone and in Combination with Sulfonylureas and Meglitinides: An Epidemiologic Surveillance Study of the FDA Adverse Event Reporting System (FAERS).

Fluoroquinolones, clarithromycin, linezolid, tigecycline, cefditoren, doxycycline, and trimethoprim-sulfamethoxazole are known to be associated with hypoglycemia, but few studies have considered concomitant glucose-lowering medications. The objective of this study was to evaluate the association between hypoglycemia and antibiotics using the US Food and Drug Administration Adverse Event Reporting System (FAERS), while accounting for concomitant glucose-lowering medications including sulfonylureas and meglitinides. FAERS reports from 1January 2004 to 31December 2017 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the association between antibiotics and hypoglycemia were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was > 1.0. A total of 2,334,959 reports (including 18,466 hypoglycemia reports) were considered, after inclusion criteria were applied. Statistically significant hypoglycemia RORs (95% CI) for antibiotics were: cefditoren 14.03 (8.93-22.03), tigecycline 3.32 (1.95-5.65), clarithromycin 2.41 (1.89-3.08), ertapenem 2.07 (1.14-3.75), moxifloxacin 2.06 (1.59-2.65), levofloxacin 1.66 (1.37-2.01), and linezolid 1.54 (1.07-2.20). After adjusting for concomitant sulfonylureas and meglitinides, the following antibiotics were still significantly associated with hypoglycemia: cefditoren 14.25 (9.08-22.39), tigecycline 3.34 (1.96-5.68), ertapenem 1.93 (1.03-3.60), and clarithromycin 1.56 (1.15-2.11). In many patients, antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides. Cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if not taken with sulfonylureas or meglitinides. The association between ertapenem and hypoglycemia has not been previously reported.

Comparing Acute Kidney Injury Reports Among Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

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. The objective of this study was to evaluate the reporting associations between AKI and many available antibiotics using FAERS. 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. 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). 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.

PDG38 PREVIOUSLY UNKNOWN RISK OF PERIPHERAL NEUROPATHY WITH CEFOXITIN AND AMIKACIN

Fluoroquinolones, nitrofurantoin, metronidazole, and linezolid are known to be associated with peripheral neuropathy. Other antibiotics may also cause peripheral neuropathy, but no study to date has systematically evaluated many available antibiotics for their association with peripheral neuropathy. Therefore, the objective of this study was to systematically evaluate the association between peripheral neuropathy and many available antibiotics using the FDA Adverse Event Reporting System (FAERS). FAERS reports from January 1, 2015 to December 31, 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify peripheral neuropathy cases. Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and peripheral neuropathy were calculated. An association was considered to be statistically significant when the lower limit of the 95%CI was greater than 1. A total of 2,042,801 reports (including 20,011 peripheral neuropathy reports) were considered, after inclusion criteria were applied. Fluoroquinolones had the greatest proportion of peripheral neuropathy reports of all antibiotics studied, representing 14% of all fluoroquinolone reports. Peripheral neuropathy RORs (95%CI) were statistically significant for (in descending order): fluoroquinolones 17.56 (16.65-18.51), cefoxitin 7.90 (3.18-19.63), nitrofurantoin 5.07 (3.39-7.58), metronidazole 3.75 (2.98-4.72), linezolid 2.96 (2.10-4.16), and amikacin 2.31 (1.09-4.89). We confirmed four known associations (fluoroquinolones, nitrofurantoin, metronidazole, and linezolid) and discovered two new associations (cefoxitin and amikacin) between antibiotics and peripheral neuropathy. Additional studies are warranted to confirm or refute these findings.

Rhabdomyolysis Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

Introduction: Daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir are known to be associated with rhabdomyolysis. Other antibiotics may also lead to rhabdomyolysis, but no study has systemically compared rhabdomyolysis associations for many available antibiotics.Objectives: The objective of this study was to evaluate the association between rhabdomyolysis and many available antibiotics using the FDA Adverse Event Report System (FAERS).Methods: FAERS reports from January 1, 2004 to December 31, 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify rhabdomyolysis cases. Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and rhabdomyolysis were calculated. An association was considered statistically significant when the lower limit of the 95%CI was greater than 1.0.Results: A total of 2,334,959 reports (including 7,685 rhabdomyolysis reports) were considered, after inclusion criteria were applied. Daptomycin had the greatest proportion of rhabdomyolysis reports, representing 5.5% of all daptomycin reports. Statistically significant rhabdomyolysis RORs (95% CI) for antibiotics were (in descending order): daptomycin 17.94 (14.08-22.85), cefditoren 8.61 (3.54-20.94), cefaclor 7.16 (2.28-22.49), erythromycin 5.93 (3.17-11.10), norfloxacin 4.50 (1.44-14.07), clarithromycin 3.95 (2.77-5.64), meropenem 3.19 (1.51-6.72), azithromycin 2.94 (1.96-4.39), cefdinir 2.84 (1.06-7.62), piperacillin-tazobactam 2.61 (1.48-4.61), trimethoprim-sulfamethoxazole 2.53 (1.52-4.21), linezolid 2.49 (1.47-4.21), ciprofloxacin 2.10 (1.51-2.92).Conclusions: This study confirms prior evidence for rhabdomyolysis associations with daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir. This study also identifies previously unknown rhabdomyolysis associations with meropenem, cefditoren, cefaclor, and piperacillin-tazobactam.

Unusual Neisseria species as a cause of infection in patients taking eculizumab

Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab. We searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018. We identified seven FAERS reports (including one case also reported in the literature) of non-meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (n = 2), N. cinerea (n = 2), N. sicca (mucosa) (n = 1), N. mucosa (n = 1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (n = 1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (n = 2) or septic shock (n = 1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics. Our search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment.

Effect of Lawyer-Submitted Reports on Signals of Disproportional Reporting in the Food and Drug Administration's Adverse Event Reporting System.

Lawyer-submitted reports may have unintended consequences on safety signal detection in spontaneous adverse event reporting systems. Our objective was to assess the impact of lawyer-submitted reports primarily for one adverse event (AE) on the ability to detect a signal of disproportional reporting for another AE for the same drug in the US FDA Adverse Event Reporting System (FAERS). FAERS reports from January 2004 to September 2015 were used to estimate yearly cumulative proportional reporting ratios (PRRs) for three known drug-AE pairs-isotretinoin-birth defects, atorvastatin-rhabdomyolysis, and rosuvastatin-rhabdomyolysis-with and without lawyer-submitted reports. Isotretinoin and atorvastatin have been the subject of high-profile tort litigation regarding other AEs. A lower bound of the 95% confidence interval (CI) of one or more based on three or more reports defined a signal. Cumulative PRRs met signaling criteria in all analyses. For isotretinoin, lawyer-submitted reports increased PRRs for birth defects before 2008, with the largest increase in 2006 (2.9 [95% CI 2.4-3.5] to 3.3 [95% CI 2.8-3.9]); lawyer-submitted reports decreased PRRs for birth defects after 2011, with the largest decrease in 2013 (2.2 [95% CI 2.0-2.5] to 1.9 [95% CI 1.7-2.1]). For atorvastatin, lawyer-submitted reports reduced PRRs for rhabdomyolysis after 2013, with the largest decrease in 2015 (18.0 [95% CI 17.1-19.1] to 15.4 [95% CI 14.5-16.2]). Lawyer-submitted reports had little impact on PRRs for rosuvastatin and rhabdomyolysis. Inclusion of lawyer-submitted reports in FAERS did not meaningfully distort known safety signals for two drugs subject to high-profile tort litigation for other AEs.