Spontaneous Reports Research Articles

Integrating electronic health records with other data sources for postmarket drug safety signal identification: a review

Electronic health records (EHRs) have emerged as resources for both the identification of adverse drug events (ADEs) and general population health surveillance, however questions remain around how best to utilize EHR data for drug safety signal identification. While the majority of signal identification research has utilized spontaneous reports and health insurance claims, these data also have limitations. Pharmacovigilance approaches combining EHR data with other data sources have the potential to address many of the shortcomings of individual sources. This mini-review seeks to provide an overview of some of the recent research leveraging EHR data in combination with spontaneous reports, claims data, and other pharmacovigilance data sources for drug safety signal identification. Studies have shown that combining EHR data with these and other sources is often beneficial compared to the use of a single source alone, however the synergism or friction introduced is insufficiently explored in current literature. Our review explores how EHR data benefits signal identification when used in combination with other sources, what methods have been applied, and what considerations have previously been noted. Finally, we identify gaps in current research and highlight important considerations for future work using multiple real world data sources for drug safety surveillance.

Impact of multifaceted interventions on the knowledge, attitude, and practice of adverse drug reactions reporting among healthcare workers in Vietnam: a comparative intervention study

BackgroundKnowledge, attitude, and practice of Adverse Drug Reactions (ADRs) and ADRs reporting among healthcare workers were related to the quality and ADRs reporting rate. The aim of this study was to evaluate the effectiveness of the multifaceted interventions on knowledge, attitude, and practice (KAP) of healthcare workers and to compare the proportion of spontaneous ADRs reports at the study center, before and after instituting multifaceted interventions.MethodsA comparative intervention study was conducted among healthcare workers at the hospital. The participants were asked to complete a questionnaire before and after instituting the multifaceted interventions to assess the KAP of ADRs and their reporting. The impact of the multifaceted interventions was assessed by comparing their correct responses to the KAP questions and the proportion of spontaneous ADRs reports before and after the interventions. The pre- and post-intervention scores for KAP questions were compared usingMcNemar test by R Language.Results388 healthcare workers completed the study. The proportion of participants qualified for ADRs reporting increased significantly, from 73.5% (pre–intervention) to 99.2% (post–intervention) for knowledge scores, from 70.6% to 91.8% for attitude scores, and from 81.4% to 97.2% for practice scores (p < 0.001). Similarly, the number of spontaneous ADRs reports increased by 31% after 3 months of interventions.ConclusionMultifaceted interventions instituted at the study center improved the knowledge, attitude, and practice of health workers towards ADRs and spontaneous reporting. It would be beneficial to implement such interventions in other hospitals in Vietnam.

Crowdsourcing Adverse Events Associated With Monoclonal Antibodies Targeting Calcitonin Gene-Related Peptide Signaling for Migraine Prevention: Natural Language Processing Analysis of Social Media.

Clinical trials demonstrate the efficacy and tolerability of medications targeting calcitonin gene-related peptide (CGRP) signaling for migraine prevention. However, these trials may not accurately reflect the real-world experiences of more diverse and heterogeneous patient populations, who often have higher disease burden and more comorbidities. Therefore, postmarketing safety surveillance is warranted. Regulatory organizations encourage marketing authorization holders to screen digital media for suspected adverse reactions, applying the same requirements as for spontaneous reports. Real-world data from social media platforms constitute a potential venue to capture diverse patient experiences and help detect treatment-related adverse events. However, while social media holds promise for this purpose, its use in pharmacovigilance is still in its early stages. Computational linguistics, which involves the automatic manipulation and quantitative analysis of oral or written language, offers a potential method for exploring this content. This study aims to characterize adverse events related to monoclonal antibodies targeting CGRP signaling on Reddit, a large online social media forum, by using computational linguistics. We examined differences in word frequencies from medication-related posts on the Reddit subforum r/Migraine over a 10-year period (2010-2020) using computational linguistics. The study had 2 phases: a validation phase and an application phase. In the validation phase, we compared posts about propranolol and topiramate, as well as posts about each medication against randomly selected posts, to identify known and expected adverse events. In the application phase, we analyzed posts discussing 2 monoclonal antibodies targeting CGRP signaling-erenumab and fremanezumab-to identify potential adverse events for these medications. From 22,467 Reddit r/Migraine posts, we extracted 402 (2%) propranolol posts, 1423 (6.33%) topiramate posts, 468 (2.08%) erenumab posts, and 73 (0.32%) fremanezumab posts. Comparing topiramate against propranolol identified several expected adverse events, for example, "appetite," "weight," "taste," "foggy," "forgetful," and "dizziness." Comparing erenumab against a random selection of terms identified "constipation" as a recurring keyword. Comparing erenumab against fremanezumab identified "constipation," "depression," "vomiting," and "muscle" as keywords. No adverse events were identified for fremanezumab. The validation phase of our study accurately identified common adverse events for oral migraine preventive medications. For example, typical adverse events such as "appetite" and "dizziness" were mentioned in posts about topiramate. When we applied this methodology to monoclonal antibodies targeting CGRP or its receptor-fremanezumab and erenumab, respectively-we found no definite adverse events for fremanezumab. However, notable flagged words for erenumab included "constipation," "depression," and "vomiting." In conclusion, computational linguistics applied to social media may help identify potential adverse events for novel therapeutics. While social media data show promise for pharmacovigilance, further work is needed to improve its reliability and usability.

Using Multiple Drug Similarity Networks to Promote Adverse Drug Event Detection

The occurrence of an adverse drug event (ADE) has become a serious social concern of public health. Early detection of ADEs can lower the risk of drug safety as well as the expense of the drug. While post-market spontaneous reports of ADEs remain a cornerstone of pharmacovigilance, most existing signal detection algorithms rely on substantial accumulated data, limiting their applicability to early ADE detection when reports are scarce. To address this issue, we propose a label propagation model for generating enhanced drug safety signals using multiple drug features. We first construct multiple drug similarity networks using a range of drug features. We then calculate initial drug safety signals using conventional signal detection algorithms. These original signals are subsequently propagated across each drug similarity network to obtain enhanced drug safety signals. We evaluate our proposed model using two common signal detection algorithms on data from the FDA Adverse Event Reporting System (FAERS). Results demonstrate that enhanced drug safety signals with pre-clinical information outperform the standard safety signal detection algorithms on early ADE detection. In addition, we systematically evaluate the performance of different drug similarities against different types of ADEs. Furthermore, we have developed a web interface (http://drug-drug-sim.aimedlab.net/) to display our multiple drug similarity scores, facilitating access to this valuable resource for drug safety monitoring.

Patient-initiated follow-up supported by asynchronous telemedicine versus usual care in spondyloarthritis (TeleSpA-study): a randomised controlled trial of clinical and cost-effectiveness.

With rising health-care expenditures and workforce shortages, sustainable alternatives to traditional outpatient follow-up strategies are required to optimise care efficiency. We aimed to investigate the cost-effectiveness and clinical effectiveness of patient-initiated follow-up (PIFU) supported by asynchronous telemedicine for patients with spondyloarthritis compared with usual care in daily practice. TeleSpA was a multicentre, pragmatic, open-label, randomised controlled trial. Patients with spondyloarthritis and stable disease were randomly assigned (1:1) to either the PIFU and asynchronous telemedicine group or usual care group. All patients received a scheduled outpatient visit at baseline and after 1 year. Patients were monitored remotely at 6 months (PIFU and asynchronous telemedicine) or at the discretion of the treating rheumatologist (usual care). The primary outcome was the number of rheumatology visits within a 1-year period. A trial-based 1-year health-economic evaluation from a Dutch health-care perspective (only including health-care costs) and societal perspective (also including travel costs and work productivity losses), per the Dutch guidelines was used to estimate cost-effectiveness. The safety analysis was done in the intention-to-treat population and was based on spontaneous reports of adverse events and serious adverse events or as observed by the research team. The primary analysis was in the intention-to-treat population. Individuals with relevant lived experience were involved in the study design. This trial was registered with the Dutch National Trial Register (NL71041.068.19) and ClinicalTrials.gov (NCT04673825) and is completed. Between Dec 2, 2020, and June 20, 2022, 200 patients were randomly assigned to PIFU and asynchronous telemedicine (n=100) or usual care (n=100). 79 (40%) of 200 participants were women, 121 (60%) were men, and the mean age was 55·0 years (SD 11·9). After 1 year, the mean number of rheumatology visits was 1·9 (SD 1·5) for the PIFU and asynchronous telemedicine group and 2·6 (1·3) in the usual care group (mean difference -0·7 [95% CI -1·0 to -0·3]; 25·4% reduction; p<0·0001). PIFU and asynchronous telemedicine was cost-effective from a health-care perspective, saving health-care costs (-€180 [95% CI -921 to 560]) without a loss in quality-adjusted life-years (0·004 [95 % CI -0·022 to 0·030]). Seven non-trial-related adverse events occurred in the PIFU and asynchronous telemedicine group and eight in usual care group (including one death). PIFU and asynchronous telemedicine resulted in significant and clinically meaningful reductions in rheumatology visits. This was not at the expense of health outcomes and saved health-care costs. Dutch Arthritis Society.

Osteonecrosis of the jaw in patients with clear cell renal cell carcinoma treated with targeted agents: a case series and large-scale pharmacovigilance analysis.

To optimize the use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for cancer patients, we characterized and evaluated ONJ related to TKIs and ICIs by analyzing a public database and reviewing the relevant literature. TKIs and ICIs are limited to drugs that treat renal cancer recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Kidney Cancer. We described a case series of patients experiencing ONJ while on TKIs or ICIs. We also analyzed spontaneous reports submitted to the FAERS in an observational and retrospective manner between January 2004 and December 2022. Selecting ONJ' adverse events to TKIs and ICIs. Associations between TKIs, ICIs and ONJ were assessed using reporting odds ratios (ROR), drug interaction signals based on the Ω shrinkage measure. 29 patients with ONJ events while on TKIs and ICIs were included in our case series. 240 were related to ONJ AEs. Specifically, 32.1% ICSRs were linked to sunitinib, 16.7% to lenvatinib, 12.9% to pazopanib, 12.5% to nivolumab, 10.0% to axitinib, 5.4% to sorafenib, 5.0% to pembrolizumab, 4.2% to cabozantinib, and 1.3% to ipilimumab. More ICSRs were generally seen in male and reported in Europe. The median age was 63years. Renal cancer and lung cancer was the most common indication for TKIs and ICIs, respectively. Excluding missing data, the prevalence of mortality was highest for sunitinib-related ONJ ICSRs (18.5%), followed by sorafenib-related ONJ ICSRs (15.4%). With the criteria of ROR, sunitinib and lenvatinib were significantly associated with ONJ AEs. With the criteria of Ω, nivolumab + cabozantinib was significantly associated with ONJ AEs. TKIs and ICIs have been reported to have significant ONJ side effects. Patients and physicians need to recognize and monitor these potentially fatal adverse events.

The Association Between Dextromethorphan/Bupropion with Alcohol and Substance Misuse: Reports to the Food and Drug Administration Adverse Event Reporting System (FAERS).

Dextromethorphan/bupropion (DXM/BUP) received Food and Drug Administration (FDA) approval for the treatment of adults with major depressive disorder (MDD) in August 2022. This combination is not known to have abuse liability and is not currently scheduled by the Drug Enforcement Administration (DEA). Notwithstanding, dextromethorphan is a drug of abuse. Herein, we sought to determine whether DXM/BUP has alcohol and/or substance misuse liability. We evaluated spontaneous reports of terms such as "alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse" in the FDA Adverse Event Reporting System (FAERS). The FAERS is a spontaneous reporting database of adverse events submitted to the FDA. We performed a comparative assessment of the alcohol and/or substance misuse liability of DXM/BUP since its market authorization in August 2022, using acetaminophen as the control. Dextromethorphan served as the upper-bound reference point. Our findings showed that, since August 2022, dextromethorphan had a significant reporting odds ratio (ROR) for "drug abuse." In contrast, DXM/BUP did not have a significant ROR for any of the categories of alcohol and/or substance misuse evaluated. Limitations of our findings derive largely from the limitations of the FAERS and its data capture method. The absence of alcohol or substance misuse reported to the FAERS with DXM/BUP accords with the lack of evidence of abuse liability prior to FDA approval and its non-scheduling by the DEA.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: A replication study using reports to the World Health Organization pharmacovigilance database (VigiBase®)

IntroductionReports of suicidality associated with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been reported to the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). We previously reported an increased reporting odds ratio (ROR) of some measures of suicidality with semaglutide and liraglutide using the FDA Adverse Event Reporting System (FAERS). Notwithstanding the increased ROR, causality between GLP-1 RAs exposure and any aspect of suicidality is not established. Research design and methodsThe analysis herein aims to extend a previous analysis of the FAERS by evaluating the ROR for suicidality reported to the World Health Organization (WHO) Pharmacovigilance Database (VigiBase). We aimed to characterize the ROR of suicidality associated with GLP-1 RAs, as extrapolated from spontaneous reports. As per our previous report, the ROR was considered significant when the lower limit of the 95 % confidence (CI) was >1.0. ResultsWe searched VigiBase reports from inception to January 2024. The RORs for suicidal ideation were significantly increased for semaglutide (5.82), liraglutide (4.03) and tirzepatide (2.25). For “depression/suicidal”, the ROR was significantly increased for semaglutide (14.74) and liraglutide (5.86); and for suicidal behaviour, the ROR was significantly increased for semaglutide (6.52) and liraglutide (3.90). However, for suicide attempts, the ROR was significantly decreased for semaglutide (0.11), dulaglutide (0.075), exenatide (0.047) and liraglutide (0.15). For completed suicide, the ROR was also significantly decreased for semaglutide (0.01), dulaglutide (0.003), exenatide (0.002) and liraglutide (0.008). ConclusionUnlike our previous report with FAERS, a mixed pattern of ROR emerged in the WHO VigiBase with respect to suicidality and exposure to select GLP-RAs. Causation between GLP-1 RA exposure and suicidality (either increased or decreased) cannot be ascertained from ROR data.

Integration of FAERS, DrugBank and SIDER Data for Machine Learning-based Detection of Adverse Drug Reactions

AbstractTraditionally, disproportionality analysis (DPA) methods are employed for signal detection in pharmacovigilance, but these methods utilize only a limited portion of the data available from spontaneous event reports (SERs). This research aims to enhance signal detection by applying machine learning (ML) methods that can leverage additional data. We create a dataset by integrating SER data from the FDA Adverse Event Reporting System (FAERS) with biological and chemical data from DrugBank, and information on known adverse drug reactions (ADRs) from Side Effect Resource (SIDER). The known ADRs from SIDER are used to label the dataset for ML training. Using the AutoML library TPOT, ML models are trained on this dataset. Our findings indicate that ML models, even when trained with the same features as DPA methods, achieve higher recall and precision. Moreover, incorporating additional features related to drugs and events significantly boosts the performance of ML models. Analysis using the explainable AI (XAI) technique SHAP reveals that the drug name, event name, and fifth-level ATC code are the most influential features for model predictions. These ML models offer a promising alternative or supplement to conventional DPA methods for signal detection in pharmacovigilance.

Adverse Event Profile of First-line Drugs for Treating Patent Ductus Arteriosus in Neonates: A Disproportionality Analysis Study of USFDA Adverse Event Reporting System.

Acetaminophen, ibuprofen, and indomethacin are widely used as first-line drugs for patent ductus arteriosus (PDA) closure in preterm neonates. However, their relative safety profiles remain unclear. Adverse event reports related to the first-line drugs used in PDA and neonates in general were retrieved from the US Food and Drug Authority (FDA) Adverse Event Reporting System. Deduplicated reports were analyzed using proportional reporting ratios and reporting odds ratios to identify disproportionality safety signals between drugs. A total of 969 unique reports related to the first-line drugs used in PDA and 499 reports in the neonatal period were included. Acetaminophen signals primarily involved the liver, while ibuprofen and indomethacin signals pertained to gastrointestinal, renal, vascular, and mortality outcomes. Higher occurrences of death were reported with indomethacin and ibuprofen compared with acetaminophen. This first comparison of PDA drug safety profiles from spontaneous reports highlights some differences, with acetaminophen potentially conferring a safer adverse effect profile overall. While limitations include missing data and reporting biases, the signals warrant further validation. Given its comparable efficacy to ibuprofen, as demonstrated in other studies, acetaminophen has the potential to be preferred as an initial medical therapy for PDA.

Medication Errors Associated with the Use of Levofloxacin: An Analysis of the National Database of Spontaneous Reports

Medication Errors Associated with the Use of Levofloxacin: An Analysis of the National Database of Spontaneous Reports

Suicidal behaviour and CFTR modulators: A case series and WHO database disproportionality analysis

BackgroundA highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database. MethodsFirst, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect. ResultsFour cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt. ConclusionsETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation.

Influence of loop diuretics on denosumab-induced hypocalcaemia in osteoporosis: a retrospective observational analysis

BackgroundWe examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion.MethodsJapanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level < 8.5 mg/dL) using multivariate logistic regression analysis. We compared differences in corrected calcium levels (ΔCa = nadir-baseline).ResultsA significant signal for hypocalcaemia was detected (Reporting odds ratio = 865.8, 95% confidence interval [95% CI]: 596.8 to 1255.9, p < 0.0001). Among 164 patients (hypocalcaemia, 12%), loop diuretics have a significant association with hypocalcaemia (odds ratio [OR] = 6.410, 95% CI: 1.005 to 40.90, p = 0.0494). However, hypocalcaemia was found to be lower in high corrected calcium levels at baseline (OR = 0.032, 95% CI: 0.005 to 0.209, p < 0.0001) and calcium and vitamin D supplementation (OR = 0.285, 95% CI: 0.094 to 0.868, p = 0.0270). In the non-hypocalcaemia, ΔCa decreased significantly in the denosumab plus loop diuretics than in the denosumab alone (-0.9 [-1.3 to -0.7] mg/dL vs. -0.5 [-0.8 to -0.3] mg/dL, p = 0.0156). However, ΔCa remained comparable in the hypocalcaemia despite loop diuretics co-administration (-1.0 [-1.2 to -0.8] mg/dL vs. -0.8 [-1.5 to -0.7] mg/dL, p = 0.7904).ConclusionsLoop diuretics may predispose to developing denosumab-induced hypocalcaemia.

Regional diversity in drug-induced lung diseases among the USA, European Union, and Japan.

Drug-induced lung disease (DILD) is a considerable and potentially fatal adverse event with poorly understood risk factors. Large-scale, data-driven analyses investigating regional discrepancies in DILD incidence are lacking. The aim of this study was to investigate the potential association among DILD prevalence, regional differences and other factors based on large-scale data base. This retrospective observational study analyzed spontaneous adverse event reports from the FDA Adverse Event Reporting System (FAERS) database between January 2010 and December 2020. Regional disparities in DILD incidence were assessed among reports from the United States of America (USA), the European Union (EU), and Japan (JP). Using multivariate logistic regression accounting for age, sex, and reporting years, we calculated the reporting odds ratios (RORs) with 95% confidence intervals. Subgroup analyses were performed for different types of anticancer agents, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and cytotoxic agents. Regional differences in RORs were observed for anticancer drugs in reports from JP and the EU compared with those from the USA (JP, ROR 4.432; EU, ROR 1.291) and for non-anticancer drugs (JP, ROR 3.481; EU, ROR 1.086). Significantly higher RORs were observed for all anticancer drug regimens reported in JP than in the USA (TKIs, ROR 3.274; ICIs, ROR 2.170; ADCs, ROR 2.335; cytotoxic agents, ROR 3.989). The EU reports exhibited higher RORs for TKIs and cytotoxic agents than the USA reports, with no significant differences in ICIs or ADCs (TKIs, ROR 1.679; ICIs, ROR 1.041; ADCs, ROR 1.046; cytotoxic agents, ROR 1.418). The prevalence of DILD in JP, the EU, and the USA differed. These findings have important implications in evaluating the safety profiles of drugs and patient safety in drug development and clinical practice. This study is the first to identify regional differences in DILDs using a large global database.

Safety and Efficacy of Mirtazapine Compared to Sertraline in Hemodialysis Patients with Major Depressive Disorder: A Randomized Controlled Clinical Trial

Background: This study aimed to compare the efficacy and tolerability of mirtazapine and sertraline in moderately depressed patients undergoing chronic hemodialysis therapy. Methods: In this double-blind clinical study, 54 hemodialysis patients diagnosed with moderate to severe depression, scoring greater than 18 on the Beck Depression Inventory, version II (BDI-II), were randomly assigned to receive 12 weeks of treatment with either mirtazapine (15mg/day) plus placebo or sertraline (50 mg/day) plus placebo. Efficacy outcomes were assessed by evaluating changes in baseline BDI-II scores, as well as rates of response and remission at weeks 2, 4, 8, and 12 of treatment. The impact of the antidepressant treatment on the patient’s health-related quality of life was also assessed at the end of the treatment phase, with ratings ranging from 0 (the worst impact) to 10 (the best impact). Safety and tolerability of the study medications were monitored using an antidepressant side effect checklist and through spontaneous participant reports. Both efficacy and tolerability analyses were conducted on the intent-to-treat sample. The p-values less than 0.01 based on Bonferroni's multiple-testing correction method were considered statistically significant. Results: The mixed models for repeated measures analysis revealed a significant time effect on depression symptoms (p &lt; 0.001), indicating improvement in both treatment groups over the study period. However, the treatment effect was not significant (p = 0.160), suggesting no overall difference in depressive symptoms between groups. The interaction between time and treatment was significant (p = 0.020), indicating varying changes in depressive symptoms over time between treatment groups. At week two, patients receiving mirtazapine had a lower mean BDI-II score than those receiving sertraline (15.62±5.24 versus 18.92±5.03), but the difference between the groups was not statistically significant (p-value = 0.022). Subsequent assessments at weeks 4, 8, and 12 showed comparable mean BDI-II scores between both treatment groups. Furthermore, at all assessment points, the rate of responders (≥50% reduction in BDI-II total score from baseline) and the rate of remitters (BDI-II total score of &lt;10) were similar between the treatment groups. However, mirtazapine- treated patients scored higher in assessing the overall impact of the treatment on their quality of life compared to the sertraline-treated group (7.40±1.18 versus 6.51±1.15 p-value = 0.007). Regarding safety and tolerability, although there were differences in the pattern of adverse effects between the treatment groups, the proportion of patients experiencing at least one adverse effect and the rate of dropouts were similar between the two groups, indicating comparable tolerability for both medications. Conclusion: Our results suggest that the efficacy and tolerability of mirtazapine are equivalent to those of sertraline in treating moderate depression in hemodialysis patients. However, mirtazapine appears to have a more favorable effect on patients' health-related quality of life compared to sertraline. Trial Registration: The trial was registered at the Iranian Registry of Clinical Trials (https://www. irct.ir/trial/66756, identifier code: IRCT20120215009014N445). Registration date: 2022-11-09.

ORENITRAM’s decadal journey: unveiling safety profiles and adverse event through a real-world pharmacovigilance study of FAERS events

ABSTRACT Background ORENITRAM, an oral treprostinil formulation, was approved in 2013 for pulmonary arterial hypertension (PAH) treatment, necessitating ongoing safety monitoring. Research design and methods This retrospective analysis used FDA Adverse Event Reporting System data from Q4 2013 to Q4 2023, employing disproportionality analysis and the reporting odds ratio (ROR) to identify adverse events (AEs) linked with ORENITRAM. Results Out of 15,660,695 reports, ORENITRAM was the primary suspect in 10,125 cases. We identified 174 significant adverse events across 27 organ systems, with notable issues like pulmonary edema, ascites, and ventricular fibrillation. Females reported more AEs (75.6%) than males (24.0%), suggesting potential metabolic differences. AEs were most common within 30 days of starting treatment or after one year. Conclusions The study indicates significant safety issues with ORENITRAM, including serious unexpected events such as pulmonary edema, ascites, and ventricular fibrillation. These findings highlight the necessity for careful clinical monitoring and effective risk management, particularly with observed gender differences in AE profiles. The study’s retrospective nature and reliance on spontaneous reports may affect result generalizability.

Safety profile of levonorgestrel intrauterine system: Analysis of spontaneous reports submitted to FAERS

The levonorgestrel-releasing intrauterine system (LNG-IUS) is an established, long-acting contraceptive option. With the widespread use of the LNG-IUS, drug-reported adverse events (AEs) have also garnered significant attention. In this study, we conducted a real-world analysis using the FDA's Adverse Event Reporting System (FAERS) database to assess the incidence of AEs associated with LNG-IUS use. Data from FAERS spanning from 2004Q1 to 2024Q1 were reviewed, with a focus on reports in which LNG-IUS was the primary suspected and secondary suspect drug. Signal detection was carried out utilizing Standardized MedDRA Queries (SMQ) and Preferred Terms (PT), with reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) employed to identify Signals of Disproportionate Reporting (SDR) for AEs. A positive SDR was defined when all three methods indicated significance. Analysis of 13 SMQs revealed notable SDRs in ear and eye disorders, cardiac arrhythmias, and lipodystrophy. Of the 61 suspected SDRs identified at the PT level, nearly half were not previously documented in labeling. Key potential signals of AEs associated with LNG-IUS use included increased heart rate, papilledema, idiopathic intracranial hypertension, cervical dysplasia, ruptured ovarian cyst, and uterine embedment and perforation. The findings underscore the importance of signal detection using FAERS data for identifying safety concerns related to LNG-IUS. Long-term observational studies are warranted to confirm and further elucidate these potential safety signals.

Ocular adverse events associated with platins: a disproportionality analysis of pharmacovigilance data and extensive systematic review of case reports

ABSTRACT Background Anti-cancer drugs, particularly platinum-based chemotherapy drugs, have been showing ocular adverse events (OAEs) in patients undergoing chemotherapy, which is concerning due to the potential impact on patient’s quality of life and the ability to continue effective cancer treatment. Research design and methods A retrospective case/non-case study was conducted using spontaneous reports on OAEs by platins from the FDA Adverse Event Reporting System (FAERS) database. A disproportionality analysis was performed by calculating the Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and the Information Component (IC) to identify OAE signals for platinum-based chemotherapy drugs. In parallel, a review of case reports for OAEs from platins was conducted by a systematic literature search in PubMed and Google Scholar. Results Using disproportionality analysis, 69 signals were identified for platinum-based chemotherapy drugs and OAEs (carboplatin: 42, oxaliplatin: 16, cisplatin: 11). Choroidal infarction [PRR = 215.1; χ2 = 4527.1; lower bound (LB) ROR = 140.7; IC025 = 5.1] and orbital hemorrhage [PRR = 120.0; χ2 = 300.5; LB ROR = 35.1; IC025 = 1.3] were the strong signals identified for carboplatin. Optic disc hyperemia [PRR = 208.2; χ2 = 742.5; LB ROR = 74.1; IC025 = 2.2] and blindness cortical [PRR = 23.7; χ2 = 382.5; LB ROR = 14.8; IC025 = 3.1] were the signals identified for oxaliplatin and cisplatin, respectively. A total of 32 case reports of OAEs from platinum-based chemotherapy drugs were identified through a systematic search in PubMed and Google Scholar, strengthening the association. Conclusion The study revealed a potential risk of OAEs when using platinum-based chemotherapy drugs as an anticancer medication.

Safety assessment of brexanolone in the FAERS database: real adverse event analysis and discussion of side effects

ABSTRACT Background Postpartum depression (PPD) is linked to hormonal changes. Brexanolone, the first FDA-approved drug for PPD, is a potential treatment. This study analyzes Brexanolone’s safety using the FAERS database, highlighting its adverse effects and potential risk factors. Methods We analyzed FAERS data from Q3 2019 to Q3 2023, evaluating adverse reactions to Brexanolone. The analysis includes demographics, reporting regions, reporter identities, and types of adverse reactions. Results Most reports are from the United States, with consumers and physicians as primary reporters. Adverse reactions mainly involve severe systemic diseases, administration site reactions, injuries, intoxication, operational complications, and mental disorders. Specific adverse reactions include incorrect drug monitoring, PPD, intrusive thoughts, delayed treatment efficacy, sedation complications, product discontinuation, misuse, infusion site leakage and pain, and medication errors. Conclusion The study confirms known safety information about Brexanolone and provides comprehensive data for medical practices and public health decisions. However, relying on spontaneous reports may introduce biases and incomplete information. Continued monitoring and reporting of adverse reactions to newer drugs like Brexanolone remain crucial.

Adverse Event Profiles of the Third-Generation Aromatase Inhibitors: Analysis of Spontaneous Reports Submitted to FAERS.

The third-generation aromatase inhibitors (AIs), represented by letrozole, anastrozole, and exemestane, have been used as a standard first-line adjuvant therapy for postmenopausal breast cancer patients with positive hormone receptor. However, their safety in the real world has not been systematically analyzed. We used the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to investigate adverse event (AE) profiles of the three AIs, covering the period from Q1 2004 to Q3 2023. The time-to-event onset profiles and cumulative incidence were analyzed by Weibull shape parameter test and Kaplan-Meier method, respectively. The disproportionality analysis was utilized to assess drug toxicity risk. Based on the FAERS database, 18,035, 8242, and 7011 reports listing letrozole, anastrozole, and exemestane as primary suspected drugs were extracted, respectively. AEs associated with anastrozole displayed the latest onset (p < 0.0001); meanwhile, WSP test showed that all three AIs had early failure-type profiles. At the preferred term level, we acquired 95, 59, and 42 significant signals associated with letrozole, anastrozole, and exemestane, which involved 18, 13, and 15 system organ classes, respectively. The three AIs all reported that their strongest AE signal was trigger finger. Neutropenia was the most frequent AE for letrozole, while the highest occurrences of anastrozole and exemestane were arthralgia. We also found that interstitial lung disease, a rare but serious AE, showed strong signal intensity in all three AIs. Additionally, letrozole was also associated with lots of other rare but serious AEs in hematologic, respiratory, and hepatic systems, which were not recorded in the instructions. Our analysis of safety warning signals of the third-generation AIs from the FAERS database provided reference for clinical safe and rational drug use.