Medical Dictionary For Regulatory Activities Research Articles

Safety profile of vascular endothelial growth factor receptor tyrosine-kinase inhibitors in pediatrics: a pharmacovigilance disproportionality analysis.

Introduction: existing research on children consists primarily of phase I/II clinical trials for VEGFR-TKI. System reports of safety on the use of VEGFR-TKI in pediatrics are lacking. Aim: to investigate the safety profiles of VEGFR-TKI in pediatrics via the FDA Adverse Event Reporting System (FAERS). Method: data regarding VEGFR-TKIs were extracted from the FAERS between 2004Q1 to 2022Q3 and categorized by the Medical Dictionary for Regulatory Activities (MedDRA). Population characteristics were analyzed, and reporting odds ratio (ROR) was performed to identify risk signals associated with VEGFR-TKI. Results: 53,921 cases containing 561 children were identified in the database from 18 May 2005, to 30 September 2022. Among those in the system organ class, skin, subcutaneous tissue disorders, and blood and lymphatic system disorders in pediatrics contributed to over 140 cases. Palmar-plantar eythrodysesthesia syndrome (PPES) in VEGFR-TKI presented the most significant 340.9 (95% 229.2-507.0). And pneumothorax also gave a high reporting odds ratio of 48.9 (95% 34.7-68.9). For a specific drug, musculoskeletal pain gave a ROR of 78.5 (95% 24.4-252.6) in cabozantinib and oesophagitis in lenvatinib with a ROR of 95.2 (95% 29.5-306.9). Additionally, hypothyroidism presented a high signal, especially sunitinib, with a ROR of 107.8 (95% 37.6-308.7). Conclusion: the present study explored the safety profile of VEGFR-TKI in pediatrics using the FAERS database. Multiple skin and subcutaneous tissue disorders, as well as blood and lymphatic system disorders, were common VEGFR-TKI-related AEs in system organ class. No serious hepatobiliary AEs were detected. For the specific AEs, PPES and pneumothorax were VEGFR-TKI-related AEs that presented significantly higher signals than those in the general population.

EPH47 Active Surveillance for Safety Monitoring of COVID-19 Vaccines in Saudi Arabia

It is generally accepted that the world will not return to the pre-pandemic normally situation until safe and effective vaccines become available. However, the rare and unknown adverse events following immunization (AEFIs) are not usually detected in the clinical trials. Thus, monitoring the safety of coronavirus disease of 2019 (COVID-19) vaccines in real-world population is essential. Therefore, the Saudi Food and Drug Authority (SFDA) performed a post-marketing safety surveillance of AEFIs following administration of COVID-19 vaccines. A prospective cohort study conducted and followed subjects who received COVID-19 vaccines from the first day of vaccination for seven days after the first and second doses, then biweekly for three months. All information from the vaccinee (demographic information, vaccine type and AEFIs) were collected by phone through a standardized online questionnaire. Baseline characteristics and AEFIs were analyzed descriptively by SPSS software. AEFIs classified according to medical Dictionary for Regulatory Activities (MedDRA). 544 subjects of 8867 agreed to be part of the study. Among them, 218 subjects completed the study. Out of 218, 87 (39.91%) individual received Pfizer-BioNTech vaccine, 45(20.64%) received Oxford/AstraZeneca vaccine, 5(2.3%) individual received Moderna vaccine, and 81 (37.2%) received two different COVID-19 vaccines. The reported events were categorized to system organ class (SOC) according to MedDRA. The most reported SOCs were skin and subcutaneous tissue disorders (n=66 with Pfizer-BioNTech vaccine, n=34 with Oxford/AstraZeneca vaccine, n=5 with Moderna vaccine), nervous system disorder(n=20with Pfizer-BioNTech vaccine, n=18with Oxford/AstraZeneca vaccine, n=3with Moderna vaccine) infections and infestations (n=23 with Pfizer-BioNTech vaccine, n=33 with Oxford/AstraZeneca vaccine, n=4 with Moderna vaccine), musculoskeletal and connective tissue disorders (n=53with Pfizer-BioNTech vaccine, n=46 with Oxford/AstraZeneca vaccine, n=7 with Moderna vaccine). Only 10 (4.6%) cases were serious and required medical intervention. The preliminary results shows the short-term safety profiles of included COVID-19 vaccines are acceptable in Saudi Arabia.

Hemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: A pharmacovigilance study from FDA Database.

e14684 Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat multiple cancers uncovering varieties of immune-related adverse events (irAEs). ICI-related haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome caused by exaggerated activation of macrophages and cytotoxic T cells resulting in fatal hematological toxicity and multi-organ damage. Methods: We conducted a retrospective analysis of reported cases of HLH in patients treated with checkpoint inhibitors using data from the FDA's Adverse Event Reporting System (FAERS) database from 2018 to 2022. Patients aged 18 or older were included, and cases were classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Results: Of 2,317 patients with HLH reported in the FAERS, 13.6% (315) of patients were reported to receive commonly used ICIs. With nivolumab being 44.93%%, pembrolizumab 35.87%, Ipilimumab 30.43%, and atezolizumab 15.94%. HLH among these ICI use was most commonly reported in males (65.2%) with a median age of 65. Melanoma was the most common cancer reported in this sample population. Out of the reported cases, 26% died, and 72% were males. Death was observed more in combination ICI therapy (40.73%) than in single-agent use (29.04%). Even though the most commonly reported HLH was with Nivolumab, mortality was highest with Atezolizumab use (29.55%). Conclusions: Nearly half of the patients with a diagnosis of HLH received commonly used ICIs, which points towards ICIs being one of the important risk factors for developing HLH. However, several confounders should be considered, like a cancer diagnosis, infection, and antibiotics. Further studies on ICI-induced HLH are necessary to establish its causal relationship.

Disparities in multiple myeloma: A global perspective on drug toxicity trends.

8015 Background: The FDA Adverse Event Reporting System (FAERS) is one of the largest pharmacovigilance databases containing information on adverse events (AEs) received from manufacturers, consumers and healthcare professionals. The purpose of this study is to evaluate the global disparities in multiple myeloma (MM) through data mining of FAERS. Methods: We examined AEs associated with FDA-approved MM drugs from 2003-2022 from FAERS and the Medical Dictionary for Regulatory Activities. Patient data were then stratified based on age, sex (F/M) and 6 geographical regions. We evaluated the reporting odds ratio (ROR) combined with a 95% confidence interval for the elevated incidence of AEs. Results: The data curation provided 381,378 patients with information from North America (NA), Europe (EU), Asia (AS), Africa (AF), Oceania (OC) and Latin America & the Caribbean (LA), merged from 129 countries and 27 phenotypic systems and organs categories when the number of AEs happened more than 0.1% of the total. Cardiotoxicities (n=23160) and vascular toxicities (n=26716) were seen more in NA (M) (ROR=1.16±0.02 and EU (M) (ROR=1.11± 0.03) compared to the rest of the World. Nephrotoxicity (n=17486) was reported more in AF (M) (ROR=2.92±0.41) compared to AS (M) (ROR≥1.17± 0.12), EU (M) (ROR≥1.34± 0.13) and NA (M) (ROR=1.09± 0.03). Peripheral neuropathies (n=14786) were frequent among EU (F) (ROR=1.09±0.07) and OC (M) (ROR=1.08± 0.04). Mortality was higher among AS and EU (ROR≥2.15± 0.93) compared to NA and OC. There were 18,222 secondary neoplasms in FAERS. Skin neoplasms (n=4650) more frequently occurred in OC and EU (ROR≥1.70 ±0.16). Breast neoplasms (n=694) were the highest in EU (F) (ROR=4.01+0.63) and lowest in OC (F) (ROR<1). Gastrointestinal neoplasms (n=1564) were more common among AS, EU and OC (M) with (ROR≥2.23±0.47). Lymphomas (n=542) were predominant in AS(M) (ROR=2.21±0.98) and OC (M) (ROR=3.35±2.23). Leukemias (n=3896) cases were significantly higher in EU (M) (ROR=4.08 ± 0.40) and EU (F) (3.11 ± 0.26). Respiratory tract and mediastinal neoplasms (n=796) were more common in AS, EU and OC(M) where ROR≥1.36±0.33. More phenotypic characterization are tabulated below. Conclusions: FAERS can be used to assess cancer disparity from a global perspective. Our results indicates that certain AEs are influenced by gender and geographical location. These disparities in MM AEs may be the result of factors such as genetics, dosing/regimen, comorbidities, age and sex. These variables must be investigated for improved patient care, strategies for AE reduction, mortality reduction and optimal allocation of healthcare resources. [Table: see text]

Self-reported adverse events associated with ∆8-Tetrahydrocannabinol (Delta-8-THC) Use

BackgroundThere is an expanding unregulated market for a psychotropic compound called ∆8-Tetrahydrocannabinol (delta-8-THC) that is being derived from hemp, but a summary of adverse events related to delta-8-THC has not been publicly reported.MethodsThis case series assessed adverse events reported by delta-8-THC users on the Reddit forum r/Delta8 and compared these to delta-8-THC AEs in the US Food and Drug Administration Adverse Event Reporting System (FAERS). Delta-8-THC and cannabis AEs reported in FAERS were also compared. The r/Delta8 forum was selected because it includes a large sample of 98,700 registered individuals who publicly discuss their experiences using delta-8-THC. All r/Delta8 posts were obtained from August 20, 2020, through September 25, 2022. A random sample of r/Delta8 posts was drawn (n = 10,000) and filtered for posts in which delta-8-THC users reported an adverse event (n = 335). FAERS reports that listed delta-8-THC (N = 326) or cannabis (N = 7076) as a suspect product active ingredient were obtained. Adverse events claimed to result from delta-8-THC use were coded using Medical Dictionary for Regulatory Activities to system organ class and preferred term categories.ResultsThe absolute number of delta-8-THC adverse event reports (N = 2184, 95% CI = 1949–2426) and serious adverse event reports (N = 437; 95% CI = 339–541) on r/Delta 8 were higher than the adverse event reports (N = 326) and serious adverse event reports (N = 289) to FAERS. Psychiatric disorders were the most frequently cited system organ class in r/Delta8 adverse event reports, mentioned in 41.2% (95% CI = 35.8%-46.3%) of reports, followed by respiratory, thoracic and mediastinal disorders (29.3%, 95% CI = 25.1%-34.0%) and nervous system disorders (23.3%, 95% CI = 18.5%-27.5%). Anxiety (16.4%, 95% CI = 12.8–20.6), Cough (15.5%, 95% CI = 11.9–20.0) and Paranoia (9.3%, 95% CI = 6.3–12.5) were the most frequently cited preferred terms in adverse event reports. The overall prevalence of AEs reported for cannabis and delta-8-THC on FAERS were also similar when analyzed by system organ class (Pearson’s r = 0.88).ConclusionsThe findings of this case series suggest that most of the adverse events reported by delta-8-THC users are like those reported during acute cannabis intoxication. This finding suggests that health care professionals follow similar treatment and management protocols, and that jurisdictions should clarify whether delta-8-THC can be sold as a hemp product.

Safety profile differences between salbutamol and levosalbutamol: Results from the FDA Adverse Event Reporting System

Purpose: To examine the safety profiles of salbutamol and levosalbutamol reported in the Food and Drug Administration Adverse Event Reporting System (FAERS) database. 
 Methods: Retrospective pharmacovigilance disproportionality analysis for drug-related ADRs reported in the FAERS database was performed from October 1, 2003 to March 31, 2020. The proportion of report ratio (PRR), proportional reporting ratio (PRR), and reporting odds ratio (ROR) were calculated and used for the determination of safety signals. The definition was based on system organ class (SOCs) and Standardized Medical Dictionary for Regulatory Activities Queries (SMQ) by the Medical Dictionary for Regulatory Activities (MedDRA). 
 Results: A total of 83,166 and 3,133 adverse event reports were identified for albuterol and levalbuterol, respectively, and were linked mainly with 12 SOCs, i.e., cardiac, vascular disorders, respiratory, thoracic, mediastinal disorders, and immune system disorders. The largest ROR among the 20 most frequent SMQs was asthma/bronchospasm for reports both in salbutamol group (ROR: 13.585, 95% CI: 13.254, 13.923) and levosalbutamol group (ROR: 16.225, 95% CI: 14.575, 18.063). 
 Conclusion: Data mining of the FAERS may be considered a useful approach for identifying salbutamol and levosalbutamol-related adverse events, which might provide additional information to guide their use in clinical practice.

Acute renal failure and cardiac arrhythmias associated with remdesivir use in patients with COVID-19 infections: Analysis using the US FDA adverse event reporting system.

Recently, antivirals, including remdesivir, have been repurposed to treat COVID-19 infections. Initial concerns have been raised about the adverse renal and cardiac events associated with remdesivir. This study aimed to analyse the adverse renal and cardiac events associated with remdesivir in patients with COVID-19 infections using the US FDA adverse event reporting system. A case/non-case method was used to determine adverse drug events associated with remdesivir as the primary suspect drug between January 1, 2020, and November 11, 2021, for patients with COVID-19 infections. Cases were reports for remdesivir with ≥1 ADEs as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'Renal and urinary disorders' or 'cardiac' disorders. To measure disproportionality in reporting of ADEs, frequentist approaches, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used. The empirical Bayesian Geometric Mean (EBGM) score and information component (IC) value were calculated using a Bayesian approach. A signal was defined as the lower limit of 95% confidence intervals of ROR ≥ 2, PRR ≥ 2, IC > 0, and EBGM > 1 for ADEs with ≥4 reports. Sensitivity analyses were undertaken by excluding reports for non-Covid indications and medications strongly associated with AKI and cardiac arrhythmias. In the main analysis for remdesivir use in patients with COVID-19 infections, we identified 315 adverse cardiac events comprising 31 different MeDRA PTs and 844 adverse renal events comprising 13 different MeDRA PTs. Regarding adverse renal events, disproportionality signals were noted for "renal failure" (ROR = 2.8 (2.03-3.86); EBGM = 1.92 (1.58-2.31), "acute kidney injury" (ROR = 16.11 (12.52-20.73); EBGM = 2.81 (2.57-3.07), "renal impairment" (ROR = 3.45 (2.68-4.45); EBGM = 2.02 (1.74-2.33). Regarding adverse cardiac events, strong disproportionality signals were noted for "electrocardiogram QT prolonged" (ROR = 6.45 (2.54-16.36); EBGM = 2.04 (1.65-2.51), "pulseless electrical activity" (ROR = 43.57 (13.64-139.20); EBGM = 2.44 (1.74-3.33), "sinus bradycardia" (ROR = 35.86 (11.16-115.26); EBGM = 2.82 (2.23-3.53), "ventricular tachycardia" (ROR = 8.73 (3.55-21.45); EBGM = 2.52 (1.89-3.31). The risk of AKI and cardiac arrythmias were confirmed by sensitivity analyses. This hypothesis-generating study identified AKI and cardiac arrhythmias associated with remdesivir use in patients with COVID-19 infections. The relationship between AKI and cardiac arrhythmias should be further investigated using registries or large clinical data to assess the impact of age, genetics, comorbidity, and the severity of Covid infections as potential confounders.

PO-03-238 CARDIAC ARRHYTHMIA IN THE PATIENT ON RITUXIMAB. A PHARMACOVIGILANCE STUDY FROM 2010-2022 FAERS DATABASE

Rituximab is a commonly used monoclonal antibody in most hematological diseases. Cardiac arrhythmia is one of the most common causes of morbidity and mortality in a hematological patient, given the increased cell turnover and electrolyte imbalance, especially after the treatment. Therefore, we explore potential arrhythmic complications related to the most commonly used drug. Given the high risk of cardiac complications in the age group between 65 and 85, we sought to study Rituximab’s arrhythmic complications and outcomes in this patient population. We conducted a retrospective analysis of all reported cases of arrhythmic complication in patients using Rituximab, utilizing data reported to the FDA and registered in the FDA Adverse Event Reporting System (FAERS) database over the past 12 years. We included patients between the 65 to 85 age group; these cases were identified and classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. A total of 28,595 patients aged 65 to 85 were reported to use Rituximab from 2010 to 2022. Among 2797 patients with cardiac complications, 31% (n=883) developed cardiac arrhythmias. 70% (n=619) of the reported cases were hospitalized, and 24% (n=149) died. Most deaths were in males, 60% (n=88) Fig.2. Commonly reported arrhythmia is shown in Fig1. The most frequently reported arrhythmia was atrial fibrillation at 72% (n=635), with a mortality rate of 16%. Furthermore, even incidence of ventricular arrhythmia was low at 6% (n=50), the mortality rate was high at 36%. Despite the relatively lower number (3%) of the total reported cases, the development of arrhythmia in patients using Rituximab was associated with increased hospitalization and mortality. Physicians should be aware of cardiological and rhythmic disorders for a commonly used medication like Rituximab. This might help with the early reorganization of the arrhythmia and finally improve the overall outcomes.

Abstract #1407025: Hearing-Related Adverse Events and Quality of Life Assessments in Thyroid Eye Disease Patients Treated with Teprotumumab

Hearing-related adverse events (AEs) with insulin-like growth factor-I receptor inhibitors have been reported in clinical trials. Phase 2, phase 3 (OPTIC) and OPTIC extension (OPTIC-X) controlled clinical trials included 121 teprotumumab-treated patients. Of these patients, 20 (16.5%) reported 23 AEs coded for the Ear and Labrinth category of the Medical Dictionary for Regulatory Activities. 12 (9.9%) of these 20 patients reported 13 hearing-related events (tinnitus, hearing loss/impairment, hyper/hypoacusis, autophony, eustachian tube dysfunction) with 6 (5%) considered drug-related by the investigator. 77% of the events were considered mild with none as severe. All patients with hearing-related AEs completed the 24-week study. To evaluate the Graves’ Ophthalmopathy Quality of Life (GO-QOL) scores (0 worst-100 best) in patients reporting hearing-related AEs, we examined all 12 of these patients from 3 clinical trials with teprotumumab as compared to those without hearing-related events (N=109). Of the 12 patients reporting hearing-related AEs to teprotumumab in the clinical trials, 2 reported events in both the OPTIC and OPTIC-X studies. Baseline overall GO-QOL score was similar between the 2 groups (61 for hearing AE group versus 63). Mean overall GO-QOL scores improved consistently from baseline and were similar for patients with and without hearing impairment AEs at 6, 12, and 24 weeks (4,10,15 versus 12,14,17, respectively). At Week 24 (3 weeks after final infusion of teprotumumab), the overall GO-QOL score was 76 and 80 for those with and without hearing AEs, respectively. Each patient reporting a hearing AE improved their GO-QOL score from baseline. Of patients reporting a hearing AE in 3 clinical trials with teprotumumab, none withdrew and all reported improvement in quality of life as evidenced by increased GO-QOL scores during and at the end of the study. Mean overall GO-QOL scores improved consistently from baseline manifesting large to moderate improvement in quality of life at Week 24.

Quality of MedDRA® Coding in a Sample of COVID-19 Vaccine Medication Error Data.

In recent years, there has been increasing interest from regulatory agencies and scientific organisations into the recording, coding and reporting of medication errors. Accuracy and consistency in the handling of medication error reports ensure the safety and effectiveness of medicines and provide reliable information to both healthcare professionals and patients. The authors have examined a sample of Medical Dictionary for Regulatory Activities (MedDRA®) coded reports that describe medication errors to assess the accuracy and consistency of MedDRA® coding, and to identify the main types of coding errors for the newly introduced COVID-19 vaccines. The sample of coded terms was assessed by two MedDRA® experts applying the Four Eyes Principle. It included 1500 reported terms drawn from the Uppsala Monitoring Centre database reported up to 25 August, 2021, describing medication errors for COVID-19 vaccines with their assigned MedDRA® terms. One third of the records could not be assessed because of incomplete or unclear verbatims. In one third, MedDRA® term assignments were correct, but another third of the sample was not adequately coded. The most frequent coding errors corresponded to vague MedDRA® Preferred Term assignments despite more detailed information being available in the verbatim for a more precise coding. This observation is similar to findings in the EudraVigilance database, where some of the most frequently assigned MedDRA® terms for medication errors also represent vague concepts. The findings indicate that understanding of medication error documentation and of the importance of accurate extraction of information from case narratives, as well as knowledge of MedDRA® content and coding guidelines need to be reinforced. The authors provide useful references to training opportunities and to the applicable International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-Endorsed Guides for MedDRA® users.

Data mining for signal detection of adverse events for taxanes based on the food and drug administration adverse drug events reporting system database

ABSTRACT Background This study aimed to mine and compare the positive signals of adverse drug events (ADE) in paclitaxel, docetaxel, and nab-paclitaxel to evaluate the accuracy of current drug package information inserts and enable clinicians to select the appropriate treatment. Research design and methods ADE data reported from January 2006 to December 2020 were extracted from the Food and Drug Adverse Drug Events Reporting System (FAERS) database, and the reporting odds ratio (ROR) was used to detect the risk signals of the 3 taxanes. The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). Results A total of 39,163 case reports on paclitaxel, docetaxel and nab-paclitaxel involving 25 different system organ classes (SOCs) were retrieved from the database. The ADE paclitaxel and nab-paclitaxel reports mainly focused on ‘general disorders and administration site conditions’ and the docetaxel ADE reports focused on ‘skin and subcutaneous tissue diseases.’ Among the three taxanes, nab-paclitaxel had the highest positive signal for serious adverse events. Conclusions Overall, the most common ADE signals and ADE mapping systems obtained in this study were consistent with the package inserts. However, some inconsistencies were noted. Further research is recommended to confirm some of the strong risk signals for ADEs for taxanes before updating the drug package information inserts.

Adverse Events of Abiraterone Acetate vs Enzalutamide.

This study aimed to highlight the comprehensive differences in adverse events between abiraterone and enzalutamide based on a big data data set. We downloaded adverse event data sets of abiraterone and enzalutamide from the Food and Drug Administration Adverse Event Reporting System database. We used the Medical Dictionary for Regulatory Activities to treat each adverse event as a preferred term and grouped it into the System Organ Class. Logistic regression analyses were performed to compare abiraterone and enzalutamide. In total, we extracted 59,680 data sets. After exclusion by criteria, we included 26,015 reports on enzalutamide and 7,507 on abiraterone. Enzalutamide and abiraterone presented different toxicity profiles in most System Organ Classes. Overall, the reporting odds ratio indicated a higher incidence rate of serious adverse events for abiraterone than enzalutamide. In conclusion, our findings suggest that both drugs present a discrete and nonoverlapping toxicity profile that varies by System Organ Class and patient age. This data set confirms, for the most part, what has been reported in clinical trials as well as true real-world reports.

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis.

Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also involved itself in the degradation of amyloid-β, there is an ongoing concern about the effect of sacubitril/valsartan on cognition, especially in case of long-term administration. The FDA Adverse Event Reporting System (FAERS) was mined between 2015Q3 and 2022Q4 to analyze the association between sacubitril/valsartan and adverse events (AEs) involving dementia. Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with "broad" and "narrow" preferred terms (PTs) relevant to dementia was applied to systematically search demented AE reports. The Empirical Bayes Geometric Mean (EBGM) from Multi-Item Gamma Poisson Shrinker (MGPS) and proportional reporting ratio with Chi-square (PRR, χ2 ) were used to calculate the disproportionality. We filtered the query for indication and identified 80,316 reports with heart failure indication in FAERS during the analytical period. Among all the reports, sacubitril/valsartan was listed as primary suspected or secondary suspected drug in 29,269 cases. No significantly elevated reporting rates of narrow dementia were evident with sacubitril/valsartan. The EBGM05 for narrow dementia-related AEs associated with sacubitril/valsartan was 0.88 and the PRR (χ2 ) was 1.22 (2.40). Similarly, broad demented complications were not over-reported in the heart failure patients administrated with sacubitril/valsartan (EBGM05 1.11; PRR 1.31, χ2 109.36). The number of dementia-related cases reported to FAERS generate no safety signal attributable to sacubitril/valsartan in patients with heart failure for now. Further follow-ups are still warranted to address this question.

Vulval Aphthous Ulcers in Adolescents Following COVID-19 Vaccination—Analysis of an International Case Series

To review and characterize reports of vulval aphthous ulcers (VAUs) following COVID-19 vaccination in VigiBase, the World Health Organization global database of reported potential adverse effects of medicinal products, to demonstrate the importance and power of case reports for rare suspected adverse reactions and to investigate whether they suggest a potential for COVID-19 vaccination to be a trigger METHODS: Cases reporting the Medical Dictionary for Regulatory Activities' (MedDRA) preferred term "Vulvovaginal ulceration" and related preferred terms in adolescent patients aged 12-17 years in association with any COVID-19 vaccine were extracted from VigiBase. The cases were clinically reviewed, and causality was assessed by applying the Bradford Hill criteria to the obtained case series. As of June 30th, 2022, there were 444 reports for the selected Medical Dictionary for Regulatory Activities preferred terms following COVID-19 vaccination in VigiBase. Ninety-four de-duplicated reports concerned adolescent female patients. Thirty-seven cases were clinically consistent with the diagnosis of VAU. On causality assessment, the analyzed case series fulfilled 6 of the 9 Austen Bradford Hill criteria supporting a potential causal relationship. VAUs can be perceived as a traumatic experience, especially in adolescent patients. There is, furthermore, a risk that the ulcers will be misdiagnosed, resulting in avoidable investigation and treatment burdens for patients. We communicate our findings to support the small number of published case reports and raise awareness of VAUs occurring in a temporal association with COVID-19 vaccination. Furthermore, our analysis supports observations about the value of case reports for the recognition and assessment of rare adverse events.

Assessment of adverse events for a home-use intense pulsed light hair removal device using postmarketing surveillance.

Home-use intense pulsed light (IPL) hair removal devices are convenient for consumers. Consumer safety associated with home-use IPL devices, however, remains a subject of interest. In this descriptive analysis, we assessed the most commonly reported adverse events (AEs) for a home-use IPL device from postmarketing surveillance and qualitatively compared these with AEs from clinical studies and medical device reports of home-use IPL treatments. For this analysis of voluntary reports, we queried a distributor's postmarketing database for IPL devices for the period beginning January 1, 2016, to December 31, 2021. All sources of comments, for example, phone, e-mail, company-sponsored web sites, were included in the analysis. AE data were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Also, we conducted a PubMed search to identify AE profiles from existing literature on home-use IPL devices and we searched the Manufacturer and User Facility Device Experience (MAUDE) database for reports on home-use IPL devices. These results were qualitatively compared to the data in the postmarketing surveillance database. A total of 1692 cases involving IPL were identified from voluntary reports of AEs between 2016 and 2021. The shipment-adjusted reporting rate for AE cases (number of AE cases/100,000 shipped IPL devices) was 67/100,000 during this 6-year period. The most commonly reported AEs were pain of skin 27.8% (470/1692), "thermal burn" 18.7% (316/1692), and erythema 16.0% (271/1692). Among the top 25 AEs reported, no unexpected health events were observed. The reported AEs were qualitatively similar to the pattern seen in clinical studies and the MAUDE database associated with such home-use IPL treatments. This is the first such report documenting AEs for home-use IPL hair removal from a postmarketing surveillance program. These data are supportive of the safety of such home-use low-fluence IPL technology.

Data mining and analysis for emicizumab adverse event signals based on the Food and Drug Administration Adverse Event Reporting System database.

Emicizumab is the latest treatment for patients with hemophilia A. Its safety in real-world data is limited, and regulatory agencies and clinical researchers have raised concerns about the risk of adverse events. This study aimed to detect potential adverse event signals of emicizumab using the FDA Adverse Event Reporting System (FAERS) database. Data in FAERS from the fourth quarter of 2017 to the second quarter of 2021 were searched. Cases of adverse events were extracted using the Preferred Term in the Medical Dictionary for Regulatory Activities (version 24.0). Disproportionality analysis was performed using the reporting odds ratio (ROR) and information component (IC) methods based on statistical shrinkage transformation. A total of 5,598,717 patients were included, of which 1,244 took emicizumab. A total of 703 emicizumab-related adverse event signals were mined, and 101 positive signals were detected. Haemarthrosis (ROR/ROR975/ROR025 = 155.62/184.34/131.38, IC/IC975/IC025 = 7.28/7.48/7.01), haemorrhage (ROR/ROR975/ROR025 = 71.01/81.18/62.12, IC/IC975/IC025 = 6.15/6.31/5.94), muscle haemorrhage (ROR/ROR975/ROR025 = 53.38/75.83/37.58, IC/IC975/IC025 = 5.74/6.16/5.15), traumatic haemorrhage (ROR/ROR975/ROR025 = 27.78/46.29/16.67, IC/IC975/IC025 = 4.80/5.40/3.92), haematoma (ROR/ROR975/ROR025 = 18.15/26.35/12.51, IC/IC975/IC025 = 4.18/4.63/3.55), device-related thrombosis (ROR/ROR975/ROR025 = 21.27/37.57/12.04, IC/IC975/IC025 = 4.41/5.08/3.43), and activated partial thromboplastin time prolonged (ROR/ROR975/ROR025 = 20.68/36.51/11.71, IC/IC975/IC025 = 4.37/5.04/3.39) had the strongest signal intensities. Haemorrhage, haemarthrosis, arthralgia, fall, and injection site pain were reported more frequently. This study found that mild arthralgia and injection site reaction were associated with emicizumab. Attention should also be paid to other serious adverse events related to emicizumab, such as acute myocardial infarction and sepsis, to ensure patient safety.

Analysis of the nervous system and gastrointestinal adverse events associated with solifenacin in older adults using the US FDA adverse event reporting system.

Antimuscarinics are the backbone of the pharmacological management of overactive bladder. Still, concerns have been raised over the nervous system (NS) adverse drug events (AEs) due to their dissimilarities to muscarinic receptor-subtype affinities. This study aimed to identify the nervous system and gastrointestinal adverse drug events (ADEs) associated with solifenacin use in older adults (≥65 years). A case/non-case analysis was performed on the reports submitted to the FDA Adverse Event Reporting System (FAERS) between 01/01/2004 and 30/06/2020. Cases were reports for solifenacin with ≥1 ADEs as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'nervous system' or 'gastrointestinal' disorders. Non-cases were all other remaining reports for solifenacin. The case/non-cases was compared between solifenacin and other bladder antimuscarinics. Frequentist approaches, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to measure disproportionality. The empirical Bayesian Geometric Mean (EBGM) score and information component (IC) value were calculated using a Bayesian approach. A signal was defined as the lower limit of 95% confidence intervals of ROR ≥2, PRR ≥2, IC >0, EBGM >1, for ADEs with ≥4 reports. 107 MedDRA preferred terms (PTs) comprising 970 ADE reports were retrieved for nervous system disorders associated with solifenacin. For gastrointestinal disorders, 129 MedDRA PTs comprising 1817 ADE reports were retrieved. Statistically significant results were found for 'altered state of consciousness': ROR = 9.71 (2.13-44.35), PRR = 9.69 (2.12-44.2) and IC = 1.29 (0.93-1.66). The disproportionality reporting of 'altered state of consciousness', a previously unidentified ADE, was unexpected. Further monitoring of this ADE is needed to ensure patient safety, as this could be linked to poor balance and falls in older adults.

Disproportionality analysis of quinolone safety in children using data from the FDA adverse event reporting system (FAERS).

Quinolones are widely prescribed for the treatment or prevention of infectious diseases in children. To gain further insight into quinolone-associated adverse event (AE) in children and better protect pediatric patients, continued surveillance of safety data is essential. The purpose of this study was to characterize the safety profiles of quinolone-associated AEs in children by mining the FDA adverse event reporting system (FAERS). FAERS reports from quarter 1 of 2004 to quarter 1 of 2022 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify adverse events. Reporting odds ratios (ROR) corresponding 95% confidence intervals (CIs) and information component (IC) along with 95% CIs were calculated to detect drug-AE pairs with higher-than-expected reporting rates within the FAERS from System Organ Classes (SOCs) to Preferred Terms (PTs). Reports were considered as signals if the 95% confidence interval did not contain the null value. After inclusion criteria were applied, a total of 4,704 reports associated with quinolones were considered. Most FAERS reports associated with ciprofloxacin (N = 2,706) followed by levofloxacin (N = 1,191), moxifloxacin (N = 375), oflaxacin (N = 245) and ozenoxacin (N = 187). The most common age group was 12-18 years. The median weight was 39.0 kilogram. The adverse effects of quinolones emerging for SOCs primarily included Infections and infestations, gastrointestinal symptoms, blood and lymphatic system disorders, cardiac disorders, nervous system disorders, musculoskeletal and connective tissue disorders and psychiatric disorders. The most frequently AE signals at the PT level were pyrexia (N = 236), febrile neutropenia (N = 120), off label use (N = 48), drug resistance (N = 18) and cardiac arrest (N = 22) following the use of ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, and ozenoxacin, respectively. Serious oznoxacin-associated AE signals were found and have not been documented in the package insert. They included cardiac arrest (N = 22; ROR = 19.83; IC = 3.68), overdose (N = 21; ROR = 4.98; IC = 2.07), seizure (N = 16; ROR = 6.01; IC = 2.29), small for dates baby (N = 9; ROR = 14.7; IC = 3.05), completed suicide (N = 15, ROR = 18.87; IC = 3.51), asthma (N = 9; ROR = 6.69; IC = 2.24;) and hypotension (N = 9; ROR = 3.83; IC = 1.68). This study provided additional evidence with respect to quinolones-related AEs for children. Generally, the findings of this study are compatible with AEs recorded in package inserts. The unexpected signals of ozenoxacin justify active vigilance by clinicians and timely monitoring by pharmacovigilance experts.

PS-C19-5: SAFETY PROFILES OF SACUBITRIL/VALSARTAN IN EARLY POST-MARKETING PHASE VIGILANCE FOR THE INDICATION OF CHRONIC HEART FAILURE AND HYPERTENSION

Background: The objective was to investigate and report the safety profile of Sacubitril Valsartan Sodium Hydrate (Sacubitril/Valsartan) (Entresto®) in Early Post-marketing Phase Vigilance (EPPV). Methods: In accordance with the regulation, the 6-month EPPV was conducted for the physicians or pharmacists at all medical institutions to which the drug was delivered. Safety information was collected and tabulated for the indication Chronic Heart Failure (CHF) (August 26, 2020 - February 25, 2021) and Hypertension (September 27, 2021 - March 26, 2022). The adverse drug reactions (ADRs) were classified using the basic terms of Medical Dictionary for Regulatory Activities (MedDRA). In addition, we focused on the five risks (hypotension, renal dysfunction/renal failure, hyperkalemia, angioedema, and dehydration) listed as Safety Specification in the Risk Management Plan (RMP). Results: The estimated number of patients treated with Sacubitril/Valsartan for the indication of CHF and hypertension was 24,898 and 165,000 during the data collection period. The number of ADRs were confirmed to be 850 (345 serious) for CHF and 455 (84 serious) for hypertension. No new safety findings were identified in both EPPVs. For both indications, the most common RMP-related ADRs were hypotension-related ADRs that occurred within 30 days after initiation were 87 (162 had, followed by renal dysfunction-related ADRs. Furthermore, hypotension-related ADRs were 268 (75 serious) for CHF and 93 (three serious) for hypertension. Hypotension-related ADRs that occurred within 30 days after initiation were 87 (162 had an unavailable date of onset) for CHF and 19 (71 had an unavailable date) for hypertension. Regarding renal dysfunction-related ADRs, the number of ADRs were 45 (45serious) for CHF and 19 (19serious) for hypertension. Renal dysfunction-related ADRs that occurred within 30 days after initiation were 17 (23 had an unavailable date of onset) for CHF and three (14 had an unavailable date) for hypertension. The number of hyperkalemia-related ADRs, angioedema, and dehydration were 35 (including 19 serious), five (five serious), and 25 (two serious) for CHF, and nine (five serious), four (four serious), and four (sero serious) for hypertension, respectively. Conclusion: No new safety findings were identified during the 6-month EPPV. Furthermore, there were no differences in safety profile by indication.

Analysis of Prednisolone-Induced Osteoporosis Using the Japanese Adverse Drug Event Report Database.

Osteoporosis is an adverse event of prednisolone. This study aimed to assess prednisolone-induced osteoporosis (PIO) profiles and patient backgrounds by analyzing data from the Japanese Adverse Drug Event Report (JADER) database. The current study focused only on orally administered prednisolone. PIO was defined using preferred terms from the Medical Dictionary for Regulatory Activities. Reporting odds ratio (ROR) at 95% confidence interval (CI) and the time-to-onset profile of PIO were used to evaluate adverse events. The RORs (95% CI) of the female and male subgroups were 4.73 (4.17-5.38) and 2.49 (2.06-3.00), respectively. The analysis of time-to-onset profiles demonstrated that the median values (interquartile range: 25.0-75.0%) of PIO were 136 (74.0-294.0). The prednisolone treatment duration was significantly longer in the PIO patient group than in the non-PIO patient group. The findings suggest that patients with rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome receiving prednisolone have different age-related PIO profiles. Our results suggest that longer prednisolone treatment duration and larger cumulative dose might be risk factors of PIO. The potential risk for PIO should not be overlooked, and careful observation is recommended.