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Background: People with gender dysphoria are treated with hormone therapy for gender reassignment. The indication of this therapy was initially for the opposite sex, and information on potential adverse drug reaction (ADR) is lacking. Objective: To describe ADR associated with gender transition medication in transgender individuals reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data from the FAERS database up to June 2023 were examined, focusing on reports of gender transition medication use in the context of gender dysphoria. The ADRs were categorized using the Medical Dictionary for Regulatory Activities at both Preferred Term and System Organ Class (SOC) levels. Descriptive statistics summarized report counts, medication types, indications, and ADR severity. Results: For individuals assigned female at birth undergoing gender transition to male (transgender men), 82 reports (230 ADRs) were analyzed, with an average age of 29.5 years. Transgender hormonal therapy was cited in 72% of reports, predominantly from the United States (67.1%). A striking 88% were categorized as serious ADRs, primarily SOC injury, poisoning, and procedural complications (26.5%), followed by psychiatric disorders (14.8%) and nervous system disorders (12.2%). Among those assigned sex male at birth transitioning to female (transgender women) (81 reports, 237 ADRs), mean age was 33.3 years, with 58% indicating use for gender dysphoria. A significant proportion (53.6%) were serious ADRs, primarily SOC: injury, poisoning, and procedural complications (26.6%). Conclusions and Relevance: The FAERS data reveal significant ADRs in transgender individuals using hormone therapy, sometimes unintended for their recipient gender. Population-level studies are crucial to enhance transgender health care. Spontaneous surveillance databases like FAERS illuminate off-label ADRs, urging health care providers to approach hormone therapies with informed caution. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the current knowledge and experiences of consumers in Australia on adverse drug reaction (ADR) reporting and their reasons for reporting or not reporting ADRs, with a focus on the use of digital tools for ADR reporting. Methods: A cross-sectional online survey was conducted among adults who had taken medicine in Australia. A structured questionnaire with multiple choice or Likert scale responses with an option for participants to provide free-text responses and pretested for face validity was used. Consumer characteristics, knowledge, and ADR reporting practices were analyzed using descriptive statistics and the chi-square test or Fisher's exact test. Results: A total of 544 survey responses were included in the analysis. The majority of respondents were women (68%), and 22% were aged between 65 and 74 years. Fifty-eight percent (n = 317) of respondents knew that they could report ADRs to either the Therapeutic Goods Administration (TGA), state or territory government health department, or healthcare professionals. Three-quarters (n = 405) of respondents stated that they had experienced an ADR; of these, 36% reported an ADR to either the TGA, state or territory government health department, or healthcare professionals. Among those who reported ADRs, 58% were unaware that they could use digital tools to report ADRs. The main reason for not reporting was that they did not think the ADR was serious enough to report (39%). Conclusion: Over half of consumers knew that they could report ADR; however, improved consumer awareness about using digital tools for ADR reporting and increased ADR reporting is needed. [ABSTRACT FROM AUTHOR]

Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system. The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates. After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64–1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21–4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20–2.71). These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to perform a nationwide analysis of medication errors (MEs) from hospitals using national reporting system data and to compare the ME patterns among different age groups. Methods: We analyzed medication‐related incidents in acute care hospitals reported to the Korean Patient Safety Reporting and Learning System (KOPS), which is a patient safety reporting system, from July 2016 to December 2020. The stages of the medication use process, type of errors, medication class involved in MEs, and degree of harm were analyzed. Results: Among a total of 5071 medication‐related incidents, 37.7% (1911 cases) were incidents that caused patient harm and 1.2% caused long‐term, permanent, and fatal harm. The proportion of medication‐related incidents that resulted in harm was the highest among the <1‐year‐old age group (67 cases, 51.5%), followed by the elderly (≥ 65 years) (828 cases, 40.9%). The cases leading to patient death were most frequently reported in patients aged ≥65 years. Medication‐related incidents occurred mainly in the administration stage (2954 cases, 58.3%), and wrong dose was the most frequently reported ME type. The most prevalent medication class occurring in the 20–64‐year age group (256 cases, 11.7%) was 'antibacterials for systemic use', whereas 'contrast media' (236 cases, 11.6%) and 'blood substitutes and perfusion solutions' (98 cases, 19.3%) were the most prevalent drug classes in the ≥65‐ and <20‐year‐old age groups, respectively. Conclusions: It is necessary to establish guidelines for the prevention of medication‐related incidents according to the medication use process and patient age group. [ABSTRACT FROM AUTHOR]

IntroductionSystematic collection of diverse adverse events during herbal medicine administration is crucial. The Korea Adverse Event Reporting System (KAERS) compiles spontaneously reported adverse event data for medicinal products including herbal medicines. This study focused on extracting and analyzing adverse event data specifically related to herbal medicine products from the KAERS database.MethodsIndividual case safety reports (ICSRs) encompassing 84 types of herbal medicine products, identified by item codes from 2012 to 2021, were extracted from the KAERS database. Descriptive statistics were employed to analyze the characteristics of the extracted reports, and adverse event information was systematically categorized and analyzed based on the MedDRA System Organ Class and preferred term classification.ResultsIn total, 1,054 ICSRs were extracted, with some documenting multiple adverse events in a single ICSR, resulting in 1,629 extracted adverse events. When categorized by the MedDRA System Organ Class, gastrointestinal disorders were the most prevalent (28.7%), followed by skin and subcutaneous tissue disorders (20.1%). Based on the preferred terms, the most frequently reported adverse events were diarrhea (5.8%), urticaria (5.3%), pruritus (4.7%), rash (4.4%), and abdominal discomfort (4.2%). The most frequently reported herbal medicines were Bangpungtongseong-san (297 cases), Kyeongok-go (144 cases), and Eunkyo-san (108 cases).ConclusionSpontaneously reported adverse events associated with herbal medicine products were systematically documented using the KAERS database. This study, which focused on voluntarily reported adverse reactions, underscores the need for additional research to estimate the incidence rate of adverse events and assess causality.

Chimeric antigen receptor (CAR) T-cell therapy presents a promising treatment for hematologic malignancies, displaying high efficacy but not being exempt from toxicity. In this observational study, we assessed adverse events (AEs) reported to the Food and Drug Adverse Event Reporting System (FAERS) including any of the six approved CAR T-cell therapies. A total of 5249 reports mentioning a CAR T-cell as a suspect product were retrieved from the FAERS database, containing a total of 24333 AEs, of which 3236 (13.3%) were cytopenias. The highest number of AEs mentioned by the report was observed for tisagenlecleucel (mean = 6.7), with the lowest for ciltacabtagene (mean = 1.3). Among all reports, hematopoietic leukopenia was the most frequently reported AEs (n = 1386, 5.7%), with hematopoietic erytropenia the least reported (n = 291, 1.2%). Tisagenlecleucel showed a high reporting odds ratio for hematopoietic erythropenia (27.28, 95%CI 14.04–53.00), leukopenia (4.04, 95%CI 3.52–4.64), and thrombocytopenia (4.01, 95%CI 3.19–5.03). Cytopenias represent one of the most frequently reported AEs in FAERS, a CAR T-cell therapy is indicated, with haematopoetic leukopenia being the most common. When comparing different CAR-T cell therapies, the cytopenias' reporting odds ratio was particularly high for tisagenlecleucel, especially in relation to hematopoietic erythropenia. [ABSTRACT FROM AUTHOR]

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Abstract Objective To evaluate the risk of myasthenia gravis (MG) associated with immune checkpoint inhibitors (ICI). Methods Adverse event (AE) reports related to MG, myasthenic syndrome, and MG crisis for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab in the US FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2022 were collected. The proportional reporting odds ratio (PRR) method was used to evaluate the correlation between the six drugs and the three AEs. Statistical significance was defined as having reports ≥3, PRR ≥ 2, and chi‐square (χ2) ≥ 4. Results A total of 36, 78, 276, 380, 5, and 53 AE reports were collected for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For myasthenic syndrome, the PRR values reflecting the correlation with the drugs were 27.83 (χ2 = 102.66), 26.20 (χ2 = 235.67), 44.17 (χ2 = 1313.98), 32.09 (χ2 = 1229.54), 21.31 (χ2 = 151.15), and 0 for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG, the PRR values reflecting the correlation with the drugs were 24.21 (χ2 = 682.04), 18.34 (χ2 = 900.27), 39.32 (χ2 = 7945.15), 26.93 (χ2 = 6636.45), 14.73 (χ2 = 566.47), and 15.69 (χ2 = 54.77) for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG crisis, there were no data for durvalumab, atezolizumab, avelumab, and ipilimumab; the PRR values reflecting the correlation with the drugs were 16.54 (χ2 = 225.23) and 9.20 (χ2 = 119.14) for pembrolizumab and nivolumab, respectively. All six drugs were statistically correlated with their corresponding AEs. Conclusions ICI may lead to ICIs‐associated MG during therapy. Analysis of FAERS data identified signals for AEs of MG with ICI regimens. Practitioners should consider the factors that may increase the likelihood of MG. The findings support a continued surveillance and risk factor identification.

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.

AIMS: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). METHODS AND RESULTS: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P

A 66-year-old woman, ex-smoker, diagnosed with hypertension, hypercholesterolemia, asthma, anxiety and migraine, who presented pruritus and urticaria, was given Medication Review with Follow-Up Service (MRF). She was taking 5 medications. After the review of the pharmacotherapy and conducting an in-depth interview, the presence of pruritus and urticaria was determined as a Negative Outcomes Releated to Medicines (NOM) and a Drug Related Problem (DRP) derived from the use of Rosuvastatin/Ezetimibe, and a possible DRPs of probability of adverse effects and prescription error. It was proposed to the patient to suspend the treatment and a referral was made to the Primary Care Physician (PCP) by means of a referral report that was submitted by the patient at the medical appointment to assess a pharmacological alternative to treat hypercholesterolemia. The proposal was accepted by the PCP. A follow-up of the case was carried out, which allowed verifying the resolution of the DRPs and NOMs detected, achieving an improvement in the patient's health and favoring adherence to treatment. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the risk of myasthenia gravis (MG) associated with immune checkpoint inhibitors (ICI). Methods: Adverse event (AE) reports related to MG, myasthenic syndrome, and MG crisis for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab in the US FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2022 were collected. The proportional reporting odds ratio (PRR) method was used to evaluate the correlation between the six drugs and the three AEs. Statistical significance was defined as having reports ≥3, PRR ≥ 2, and chi‐square (χ2) ≥ 4. Results: A total of 36, 78, 276, 380, 5, and 53 AE reports were collected for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For myasthenic syndrome, the PRR values reflecting the correlation with the drugs were 27.83 (χ2 = 102.66), 26.20 (χ2 = 235.67), 44.17 (χ2 = 1313.98), 32.09 (χ2 = 1229.54), 21.31 (χ2 = 151.15), and 0 for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG, the PRR values reflecting the correlation with the drugs were 24.21 (χ2 = 682.04), 18.34 (χ2 = 900.27), 39.32 (χ2 = 7945.15), 26.93 (χ2 = 6636.45), 14.73 (χ2 = 566.47), and 15.69 (χ2 = 54.77) for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG crisis, there were no data for durvalumab, atezolizumab, avelumab, and ipilimumab; the PRR values reflecting the correlation with the drugs were 16.54 (χ2 = 225.23) and 9.20 (χ2 = 119.14) for pembrolizumab and nivolumab, respectively. All six drugs were statistically correlated with their corresponding AEs. Conclusions: ICI may lead to ICIs‐associated MG during therapy. Analysis of FAERS data identified signals for AEs of MG with ICI regimens. Practitioners should consider the factors that may increase the likelihood of MG. The findings support a continued surveillance and risk factor identification. [ABSTRACT FROM AUTHOR]

Purpose: Studies on the detection of COVID‐19 vaccine signals in South Korea are insufficient. Therefore, to investigate adverse events (AEs) that might be associated with COVID‐19 vaccines, signals were detected using spontaneous reports from South Korea. We compared the signals with the vaccine insert lists of the regulators in the four countries. Methods: Spontaneous reports from 62 sites were collected by the National Medical Center between January 2013 and May 2022. A descriptive analysis of AEs associated with COVID‐19 vaccines (Pfizer, Moderna, AstraZeneca, and Janssen) was performed, and the proportional reporting ratio, reporting odds ratio, and information component were calculated. We performed five analyses, with five cases and one control group. Results: During the study period, 68 355 cases were reported, of which 12 485 were COVID‐19 vaccine AEs. Injection site pain (2198 cases, 17.6%), myalgia (1552 cases, 12.4%), headache (1145 cases, 9.2%), pyrexia (1003 cases, 8.0%), and fatigue (735 cases, 5.9%) were frequently reported. When comparing all COVID‐19 vaccines with other viral vaccines, 20 signals were detected, of which cachexia, dyspepsia, abdominal discomfort, and mood swings were not listed on the vaccine inserts in all four countries. Overall, 20, 17, 29, and 9 signals were detected in vaccines developed by Pfizer, Moderna, AstraZeneca, and Janssen, respectively. Conclusions: Based on a disproportionate analysis of COVID‐19 vaccine AEs using spontaneous reports from South Korea, different signals were detected for each vaccine manufacturer. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is an emerging global public health threat. One of the main drivers of this threat is the inappropriate use of antibiotics. In Sri Lanka, antibiotic consumption is increasing, but little is known locally about how patients perceive antibiotics. We conducted a qualitative study to gain a better understanding of the knowledge, perceptions, and attitudes of patients regarding antibiotics and antibiotic resistance. Semi-structured interviews involving 18 patients with lower respiratory tract infection (LRTI) admitted to a large, public tertiary care hospital in southern Sri Lanka were conducted. Interviews were analyzed to identify themes regarding the patients' knowledge of LRTI etiology and treatment, perceptions and attitudes toward LRTI treatment, including antibiotics, and patient-physician communication. Most patients mentioned multiple care visits and the use of multiple pharmaceuticals prior to admission. Patients sought a quick resolution to their ailments and frequently visited several private physicians to obtain a satisfying answer. Self-medication was also common. Patients reused prescriptions for antibiotics, kept antibiotics for later use after prematurely stopping their course of treatment, and bought over-the-counter antibiotics. Patients' knowledge of disease etiology and antibiotics was poor. Only a few patients were aware of antibiotic resistance. Despite the desire to receive more information regarding disease and treatment, patient-provider communication was limited and mainly confined to prescription instructions. This qualitative study performed in Sri Lanka suggests that inappropriate use of antibiotics is a multifactorial problem. To improve antibiotic use, a multifactorial approach that includes educating the public, increasing awareness among physicians, and implementing systems-level changes to restrict access to antibiotics is urgently needed.

3,4-Methylenedioxymethamphetamine (MDMA) is currently being evaluated by the Food and Drug Administration (FDA) for the treatment of post-traumatic stress disorder (PTSD). If MDMA is FDA-approved it will be important to understand what medications may pose a risk of drug-drug interactions. The goal of this study was to evaluate the risks due to MDMA ingestion alone or in combination with other common medications and drugs of abuse using the FDA drug safety surveillance data. To date, nearly one thousand reports of MDMA use have been reported to the FDA. The majority of these reports include covariates such as co-ingested substances and demographic parameters. Univariate and multivariate logistic regression was employed to uncover the contributing factors to the reported risk of death among MDMA users. Several drug classes (MDMA metabolites or analogs, anesthetics, muscle relaxants, amphetamines and stimulants, benzodiazepines, ethanol, opioids), four antidepressants (bupropion, sertraline, venlafaxine and citalopram) and olanzapine demonstrated increased odds ratios for the reported risk of death. Future drug-drug interaction clinical trials should evaluate if any of the other drug-drug interactions described in our results actually pose a risk of morbidity or mortality in controlled medical settings.

Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.

BackgroundWomen experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs.MethodsSearches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased.ResultsFor most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88% of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29% of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs CONCLUSIONS: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.

This study aimed to determine the type of drugs reported as suspected of causing severe supraventricular arrhythmias from the Spanish Human Pharmacovigilance System database. A total of 1053 reports were analysed, of which 526 (50%) were on men and 516 (49%) were on women. The most affected age group was the over-65s, with 593 reports (56%). Of the 1613 drugs, those belonging to the cardiovascular system (ATC Group C) were the most numerous (414 reports, 26%), with digoxin being the most frequent drug (49 reports, 12%). Other common groups were antiinfectives for systemic use (ATC Group J; 306 reports, 19%), antineoplastic and immunomodulating agents (ATC Group L; 198 reports, 12%), and nervous system drugs (ATC Group N; 185 reports, 11%). The most common supraventricular arrhythmia was atrial fibrillation (561 reports, 51%). Regarding outcomes, 730 (66%) patients recovered, 76 (7%) did not recover, 25 (3%) recovered but with sequelae, and 23 (2%) resulted in death. This study revealed that certain drugs have reported to be associated more frequently to supraventricular arrhythmias as serious adverse reactions, especially in the older population. Proper clinical management and effective strategies to ensure medication appropriateness should always be considered to improve patient safety when prescribing drugs. [ABSTRACT FROM AUTHOR]

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system. [ABSTRACT FROM AUTHOR]

Purpose: Fluoropyrimidines are anticancer drugs and can cause hyperammonemia both intravenously and orally. Renal dysfunction may interact with fluoropyrimidine to cause hyperammonemia. We performed quantitative analyses of hyperammonemia using a spontaneous report database to examine the frequency of intravenously and orally administered fluoropyrimidine, the reported frequency of fluoropyrimidine-related regimens, and fluoropyrimidine's interactions with chronic kidney disease (CKD). Methods: This study used data collected between April 2004 and March 2020 from the Japanese Adverse Drug Event Report database. The reporting odds ratio (ROR) of hyperammonemia was calculated for each fluoropyrimidine drug and was adjusted for age and sex. Heatmaps depicting the use of anticancer agents in patients with hyperammonemia were drawn. The interactions between CKD and the fluoropyrimidines were also calculated. These analyses were performed using multiple logistic regression. Results: Hyperammonemia was observed in 861 of the 641,736 adverse events reports. Fluorouracil was the most frequent drug associated with hyperammonemia (389 cases). The ROR of hyperammonemia was 32.5 (95% CI 28.3–37.2) for intravenously administered fluorouracil, 4.7 (95% CI 3.3–6.6) for orally administered capecitabine, 1.9 (95% CI 0.87–4.3) for tegafur/uracil, and 2.2 (95% CI 1.5–3.2) for orally administered tegafur/gimeracil/oteracil. Calcium levofolinate, oxaliplatin, bevacizumab, and irinotecan were the most frequently reported agents in cases of hyperammonemia with intravenously administered fluorouracil. The coefficient of the interaction term between CKD and fluoropyrimidines was 1.12 (95% CI 1.09–1.16). Conclusion: Hyperammonemia cases were more likely to be reported with intravenous fluorouracil than orally administered fluoropyrimidines. Fluoropyrimidines might interact with CKD in hyperammonemia cases. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate reporting of surgical complications and other adverse events in clinical research articles describing soft tissue and oncologic surgery in dogs and cats.Study designSystematic literature review.SampleEnglish-language articles describing soft tissue and oncologic surgeries in client-owned dogs and cats published in peer-reviewed journals from 2013 to 2016.MethodsCAB, AGRICOLA, and MEDLINE databases were searched for eligible articles. Article characteristics relevant to complications were abstracted and summarized, including reported events, definitions, criteria used to classify events according to severity and time frame, and relevant citations.ResultsOne hundred fifty-one articles involving 10 522 animals were included. Canine retrospective case series of dogs predominated. Ninety-two percent of articles mentioned complications in study results, but only 7.3% defined the term complication. Articles commonly described complications according to time frame and severity, but terminology and classification criteria were highly variable, conflicting between studies, or not provided. Most (58%) reported complications could have been graded with a published veterinary adverse event classification scheme, although common intraoperative complications were notable exceptions.ConclusionDefinitions and criteria used to classify and report soft tissue and oncologic surgical complications are often absent, incomplete, or contradictory among studies.Clinical significanceLack of consistent terminology contributes to inadequate communication of important information about surgical complications. Standardization of terminology and consistency in severity scoring will improve comparative evaluation of clinical research results.

Background: Medication errors can result in adverse drug events (ADEs) and cause considerable patient harm. Limited data are available from Saudi Arabia and the Middle East regarding the prevalence of preventable adverse drug events (pADEs) in primary care settings. Objectives: To estimate the period prevalence of pADEs and assess the medication error severity in primary care setting in Saudi Arabia. Methods: This retrospective study is a continuation of a previous study where 117 of 2000 adult patients managed at the Family Medicine clinics of King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, were identified to have had least one medication error in the past 15 months. The electronic health records of these 117 patients were analyzed for a 3-month post-medication error period to explore the presence of pADE. Medication errors were categorized according to the National Coordinating Council for Medication Error Reporting and Prevention index (NCC MERP) and the occurrence of pADE was assessed using the NCC MERP scheme. Results: Of the included 117 patients, 9 (7.7% [95% confidence interval (CI): 2.79–12.59]) experienced pADE (Category E), while 108 (92.3% [95% CI: 87.97–98.35]) did not (Category C). All patients who experienced pADE were using over-the-counter medications and were on polypharmacy. Outcomes 2a and 2b (asthma and β-blocker) accounted for two and four cases, respectively, while Outcomes 6 (warfarin and international normalized ratio), 7 (lithium and lithium level), 16 (new oral anti-coagulant or warfarin and antiplatelet), and 17 (acetylsalicylic acid [aspirin] and antiplatelet) each accounted for one case. Conclusions: This study provides the period prevalence of patients with pADEs from Family Medicine clinics at a major tertiary hospital of Saudi Arabia, and highlights the need for a multicenter study of clinically important medication errors at the prescribing and monitoring stages for the development of quality improvement programs.

A quantitative descriptive study based on Brazilian Active Pharmacovigilance of Dolutegravir (DTG) Project was performed to describe the adverse drug reactions (ADRs) to DTG reported and to evaluate the noncompleteness of data from DTG active pharmacovigilance in Brazil. ADRs and clinical and individual data were obtained from information from the Pharmacovigilance Questionnaire from April 2017 to August 2019. The reported ADRs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). In the evaluated period, 249,066 individuals using DTG participated in the active pharmacovigilance of DTG, with 3472 (1.39%) reporting ADRs at least once. A total of 6312 ADRs were reported, of which 57.56% were persistent and 81.46% were not serious according to the individuals' reports. Most of the reported ADRs were gastrointestinal, neurological and psychiatric. ADRs related to neural tube defects and serious neuropsychiatric ADRs have been reported. Completion of more than half of the fields in the Pharmacovigilance Questionnaire was excellent. The frequency of ADR was low in relation to the number of people living with HIV (PLHIV) using DTG in Brazil, which suggests good tolerability and safety of DTG. The DTG active pharmacovigilance database in Brazil showed good data completeness. [ABSTRACT FROM AUTHOR]

The close contact between patients and community pharmacists, along with the extensive geographical distribution of pharmacies in Portugal, offer exceptional conditions to detect and report adverse drug reactions (ADR). This study aimed to evaluate the motivation and knowledge of spontaneous reporting of ADR by community pharmacists of Porto, Portugal. Secondly, we aimed to generate real-world evidence on the main factors determining ADR report and at raising potential alternatives to the current reporting procedure in community pharmacy. We performed a descriptive, cross-sectional, observational, anonymous web survey-based study. Between April and July 2021, a web survey was implemented, targeting community pharmacists in the Porto district, Portugal. We validated 217 surveys from pharmacists. Regular notifiers seem to be more familiarised than non-regular notifiers with the Portuguese Pharmacovigilance System (PPS), with the Portal RAM for reporting suspected ADR, and with the update of the concept of ADR. Moreover, regular notifiers seem to be more proactive with their care in questioning patients about ADR and have more self-knowledge to identify suspected ADR. Conversely, non-regular notifiers, seem to be more reluctant to be judged by their ADR reporting activities. Respondents suggested to simplify and optimise the reporting process (31% of the suggestions), or to integrate a reporting platform into the pharmacy's software (27%). This study identified opportunities to promote the ADR reporting process by community pharmacists, namely receiving feedback from the PPS on the reported case and its regulatory implications, implementing training programs in pharmacovigilance, and creating solutions to simplify the reporting process. [ABSTRACT FROM AUTHOR]

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system.Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients’ hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals.Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug’s SmPC and in 1 case the risk prevention material was updated.Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Proton-pump inhibitors, PPIs, are considered effective therapy for stomach acid suppression due to their irreversible inhibition of the hydrogen/potassium pump in the gastric parietal cells. They are widely prescribed and are considered safe for over-the-counter use. Recent studies have shown an association between PPI use and Alzheimer dementia, while others have disputed that connection. We analyzed over ten million United States Food and Drug Administration Adverse Event Reporting System reports, including over forty thousand reports containing PPIs, and provided evidence of increased propensity for memory impairment among PPI reports when compared to histamine-2 receptor antagonist control group. Furthermore, we found significant associations of PPI use with a wide range of neurological adverse reactions including, migraine, several peripheral neuropathies, and visual and auditory neurosensory abnormalities.

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organizations pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.

Abstract Background Pharmacovigilance may be defined as the continuous monitoring of the reaction between a drug agent or combination of drugs a patient took and steps taken to prevent any associated risk. Clinical trials conducted before drug approval cannot uncover every aspect of the health hazards of approved drugs. People with carefully selected characteristics are monitored for the safety and efficacy of the drug; hence, common adverse drug reactions (ADRs) following proper use of the medication can be detected. This calls for continuous monitoring of drugs to report any undocumented ADRs during the clinical trial. The study aimed to assess the knowledge, practice, and barriers to pharmacovigilance among nurses at a teaching hospital. Methods The study was a descriptive cross-sectional study, and a stratified sampling technique was used to select 125 nurses within the three units: medical, surgical, and pediatric wards. A structured questionnaire was developed and used for data collection based on the study's objectives and reviewed literature. Results The majority (67.2%) of the respondents were females, and 32.8% were males. Most (71.2%) of the nurses had low knowledge of ADR reporting procedures. Also, 84.8% of the nurses knew the purpose of reporting ADRs. The purpose of ADR reporting, as perceived by respondents, was to identify safe drugs (80.8%) and calculate the incidence of ADR (75.2%). Additionally, among the nurses who reported having nursed a patient with ADRs, 52.54% stated they reported the case, while 47.46% did not report it. The most cited reason for not reporting ADRs was that nurses considered the reaction normal and commonly associated with that medicine (35.7%). In comparison, 28.5% of the nurses said they did not know they were supposed to report the adverse drug reaction. There was no statistically significant difference between ranks of nurses, ward, attending in-service training, and pharmacovigilance practice. Conclusion In conclusion, nurses in this study had inadequate knowledge of pharmacovigilance and its reporting procedure. The study found that most nurses fear that reporting ADRs may be wrong because most of the nurses in the study did not have any form of pharmacovigilance training.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs. METHODS: In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHOs global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC025 is the lower end of the IC 95% credibility interval, and an IC025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540. FINDINGS: We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC025 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC025 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC025 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC025 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC025 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ2 test for overall subgroup comparison, p80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p

Introduction: Because patients and patient organizations want to strengthen their role in the care pathway and drug evaluation and in order to improve pharmacovigilance activities, European competent authorities implemented regulations to allow direct reporting of adverse drug reactions related to medicinal products by patients in 2012. Objectives: To describe evolution and analyze determinants of patient reporting activity in France in order to assess patient involvement in pharmacovigilance. Method: Using the French national pharmacovigilance database, univariate and multivariate analyses were performed to compare the characteristics of adverse drug reaction (ADR) reports from patients and healthcare professionals (HCP) between 2011 and 2020. The relationship between regional patient ADR report activity and regional care provision and socio-professional characteristics was analyzed using the principal component analysis. Results: A significant and higher increase in ADR reports over time from patients (r = 0.89, p < 0.001) compared to HCP (r = 0.27, p = 0.002) has been observed. Patient ADR report activities compared to HCP concerned more women (80% vs. 55%, p < 0.001), younger age classes (p < 0.001), reporting through web portal (83% vs. 17%, p < 0.001), and less serious events (26% vs. 63%, p < 0.001). In the principal component analysis, regional patient reporting activity was related to socio-professional categories, age classes, and densities of hospital beds and physicians. Conclusion: Our results confirm an increasing involvement of patients in ADR report activities. The determinants of patient reporting activities are not only related to drug and medical factors but also to social factors. Digital tools may also play a role in health democracy in pharmacovigilance. [ABSTRACT FROM AUTHOR]

Purpose: A cornerstone of treatment for many cancers is the administration of platinum-based chemotherapies and/or ionizing radiation, which can be ototoxic. An accurate ototoxicity risk assessment would be useful for counseling, treatment planning, and survivorship follow-up in patients with cancer. Methods: This systematic review evaluated the literature on predictive models for estimating a patient's risk for chemotherapy-related auditory injury to accelerate development of computational approaches for the clinical management of ototoxicity in cancer patients. Of the 1195 articles identified in a PubMed search from 2010 forward, 15 studies met inclusion for the review. Conclusions: All but 1 study used an abstraction of the audiogram as a modeled outcome; however, specific outcome measures varied. Consistently used predictors were age, baseline hearing, cumulative cisplatin dose, and radiation dose to the cochlea. Just 5 studies were judged to have an overall low risk of bias. Future studies should attempt to minimize bias by following statistical best practices including not selecting multivariate predictors based on univariate analysis, validation in independent cohorts, and clearly reporting the management of missing and censored data. Future modeling efforts should adopt a transdisciplinary approach to define a unified set of clinical, treatment, and/or genetic risk factors. Creating a flexible model that uses a common set of predictors to forecast the full post-treatment audiogram may accelerate work in this area. Such a model could be adapted for use in counseling, treatment planning, and follow-up by audiologists and oncologists and could be incorporated into ototoxicity genetic association studies as well as clinical trials investigating otoprotective agents. Implications for Cancer Survivors: Improvements in the ability to model post-treatment hearing loss can help to improve patient quality of life following cancer care. The improvements advocated for in this review should allow for the acceleration of advancements in modeling the auditory impact of these treatments to support treatment planning and patient counseling during and after care. [ABSTRACT FROM AUTHOR]

Background: Medication errors can result in adverse drug events (ADEs) and cause considerable patient harm. Limited data are available from Saudi Arabia and the Middle East regarding the prevalence of preventable adverse drug events (pADEs) in primary care settings. Objectives: To estimate the period prevalence of pADEs and assess the medication error severity in primary care setting in Saudi Arabia. Methods: This retrospective study is a continuation of a previous study where 117 of 2000 adult patients managed at the Family Medicine clinics of King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, were identified to have had least one medication error in the past 15 months. The electronic health records of these 117 patients were analyzed for a 3-month post-medication error period to explore the presence of pADE. Medication errors were categorized according to the National Coordinating Council for Medication Error Reporting and Prevention index (NCC MERP) and the occurrence of pADE was assessed using the NCC MERP scheme. Results: Of the included 117 patients, 9 (7.7% [95% confidence interval (CI): 2.79–12.59]) experienced pADE (Category E), while 108 (92.3% [95% CI: 87.97–98.35]) did not (Category C). All patients who experienced pADE were using over-the-counter medications and were on polypharmacy. Outcomes 2a and 2b (asthma and β-blocker) accounted for two and four cases, respectively, while Outcomes 6 (warfarin and international normalized ratio), 7 (lithium and lithium level), 16 (new oral anti-coagulant or warfarin and antiplatelet), and 17 (acetylsalicylic acid [aspirin] and antiplatelet) each accounted for one case. Conclusions: This study provides the period prevalence of patients with pADEs from Family Medicine clinics at a major tertiary hospital of Saudi Arabia, and highlights the need for a multicenter study of clinically important medication errors at the prescribing and monitoring stages for the development of quality improvement programs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. METHODS: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed. RESULTS: SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p

Antibacterial drugs are a widely used drug class due to the frequency of infectious diseases globally. Risks knowledge should ground these medicines' selection. Data mining in large databases is essential to identify early safety signals and to support pharmacovigilance systems. We conducted a cross-sectional study to assess adverse drug events related to antibiotics reporting between December 2018 and December 2021 in the Brazilian database (Vigimed/VigiFlow). We used the Reporting Odds Ratio (ROR) disproportionality analysis method to identify disproportionate reporting signals (SDR), referring to statistical combinations between drugs and adverse events. Vancomycin was the most reported antibiotic (n = 1,733), followed by ceftriaxone (n = 1,277) and piperacillin and tazobactam (n = 1,024). We detected 294 safety signals related to antibacterials. We identified azithromycin leading in the number of safety signals (n = 49), followed by polymyxin B (n = 25). Of these, 95 were not provided for in the drug label and had little or no reports in the medical literature. Three serious events are associated with ceftazidime and avibactam, a new drug in the Brazilian market. We also found suicide attempts as a sign associated with amoxicillin/clavulanate. Gait disturbance, a worrying event, especially in the elderly, was associated with azithromycin. Our findings may help guide further pharmacoepidemiologic studies and monitoring safety signals in pharmacovigilance. [ABSTRACT FROM AUTHOR]

Objective: Adverse Drug Reactions (ADR) add a significant clinical and economic burden to the healthcare system of a country. We present an overview of the different approaches of ADR reporting systems worldwide and their evolution over time. Methods: A systematic review of the literature was made based on PubMed and the Cochrane database of systematic reviews. The articles searched for included original articles, WHO and FDA reports and institute of medicine reports. Summary: Reporting ADRs is the cornerstone of detecting uncommon ADRs once the drugs are on the market. In many countries, ADR reporting is regulated by national regulatory bodies and various methods are employed to report ADRs. Direct reporting by healthcare professionals has been adopted by many developed and developing countries. With emerging new technologies in the field of medicine, there is a great potential to develop better ADR reporting systems in the countries where they have poor reporting. Conclusion: Development and acquisition of newer technologies to promote ADR monitoring and reporting is a necessity for an effective pharmacovigilance system in a country. [ABSTRACT FROM AUTHOR]

Marketing-authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post-authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry-sponsored PASS that did not render a conclusion. We conducted a thematic analysis of study limitations extracted from assessment reports and study reports finalized by the Pharmacovigilance Risk Assessment Committee between 2018 and 2021. In 39 (61.0%) of the PASS a conclusion on RMM effectiveness was drawn, where 25 (39.0%) PASS was inconclusive. Most PASS had a cross-sectional design with surveys as primary data sources (73.4% and 65.6% respectively). Four main themes emerged: (i) survey-specific limitations, (ii) limitations specifically related to secondary use of data, (iii) general limitations related to study design, and (iv) limitations not related to study design. In general, frequently reported limitations were survey-related, such as selection bias or information bias. Interestingly, well-known study limitations related to secondary use of data such as missing or misclassification of data were more often presented in inconclusive compared with conclusive PASS. Given that about 40% of PASS did not allow a conclusion on RMM effectiveness, our results suggest prioritization for strategies to mitigate limitations related to the secondary use of data at the protocol stage, for example, through feasibility assessments. Although many databases may have incomplete registration of some variables, feasibility testing prior to conducting a PASS could contribute to meeting study objectives and concluding on RMM effectiveness., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Propofol is an ultra-fast-acting intravenous anesthetic, which is rapidly metabolized primarily into inactive compounds in the live and then excreted in the urine. The purpose of this study is to explore the risk signals of propofol based on the US FDA Adverse Event Reporting System database. The risk signals of propofol-related adverse reactions in adverse event (AE) reports from 2004 to 2021 in the US FAERS were mined using ratio-report method (ROR) and the ratio-report ratio method (PRR) methods. We screened out 1651 pairs AE reports using propofol as primary suspect (PS) drugs. ROR, PRR, BCPNN and MGPS methods were used to calculate respectively, there are 363 positive preferred terms (PT) signals with 9549 cases. Among them, the top 3 adverse reactions associated with using propofol from the FAERS database were anaphylactic shock, hypotension and propofol infusion syndrome. The top 3 systems of the body associated with adverse reaction of propofol from the FAERS database were General disorders, Cardiac disorders and administration site conditions and Respiratory, thoracic and mediastinal disorders. The top 4 indication of using propofol from the FAERS database, including anaesthesia, induction of anaesthesia, sedation, general anaesthesia. There are many adverse reactions that are not included in the drug insert of propofol and involve a wide range of organs and/or systems. Caution should be exercised in the clinical use of propofol.

While some literature has provided limited information about the potential cardiovascular risk and immune-related adverse events (irAEs) risk associated with PD-1/PD-L1 inhibitors in the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC), the exact relevance is still uncertain. To assess the pharmacovigilance (PV), constituent ratio, severity, and reaction outcomes of major adverse cardiovascular events (MACE) and immune-related adverse events (irAEs) related to PD-1/PD-L1 inhibitors for HNSCC reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed reports of cardiovascular adverse events and irAEs associated with drug therapy for HNSCC submitted to FAERS from the 1st quarter 2015 to the 3rd quarter of 2023. Three PD-1/PD-L1 inhibitors were identified: nivolumab, pembrolizumab and durvalumab. Our primary composite endpoint was the PV of MACE and irAEs related to PD-1/PD-L1 inhibitors in the treatment of HNSCC, and the secondary endpoint was PV of other cardiovascular events. The software implemented was STATA 17.0 MP. 19,372 suspected drug-adverse event reports related to drug treatment in patients with HNSCC were identified, of which 916 reports were cardiovascular events, including 555 reports of MACE and 361 reports of other cardiovascular events. The PV signal regarding MACE was detected in durvalumab (PRR  = 2.12, 95% CI: 1.24-3.61; χ2  = 7.71; ROR  = 2.19, 95% CI: 1.24-3.86; IC  = 1.01; IC025  = 0.07) but not in nivolumab and pembrolizumab. The constituent ratio of MACE in all adverse events caused by nivolumab (OR  = 0.38, 95% CI: 0.19-0.73) and pembrolizumab (OR  = 0.48, 95% CI: 0.23-0.99) was significantly decreased, compared with durvalumab. A PV signal about other cardiovascular events was detected in durvalumab (PRR  = 3.04, 95% CI: 1.73-5.31; χ2  = 16.13; ROR  = 3.15, 95% CI: 1.74-5.70; IC  = 1.46; IC025  = 0.48), but it was not detected in nivolumab or pembrolizumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR  = 0.25, 95% CI: 0.13-0.48) and pembrolizumab (OR  = 0.40, 95% CI: 0.20-0.80) was significantly decreased, compared with durvalumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR  = 0.61, 95% CI: 0.38-0.99) was significantly decreased, compared with pembrolizumab. There were 40 cases of hypertension. A PV signal about hypertension was detected in pembrolizumab (PRR  = 3.72, 95% CI: 1.87-7.43; χ2  = 15.99; ROR  = 3.75, 95% CI: 1.87-7.51; IC  = 1.53, IC025  = 0.45), but it was not detected in nivolumab. The constituent ratio of hypertension in all adverse events caused by nivolumab (OR  = 0.09, 95% CI: 0.09-0.39) was significantly decreased, compared with pembrolizumab. There were 737 cases of irAEs. A PV signal about irAEs was detected in nivolumab (PPR  = 1.27, 95% CI: 1.05-1.53; χ2  = 6.38; ROR  = 1.28, 95% CI: 1.06-1.56; IC  = 0.29, IC025  = -0.00) and pembrolizumab (PPR  = 2.20, 95% CI: 1.79-2.71; χ2  = 56.55; ROR  = 2.31, 95% CI: 1.84-2.88; IC  = 1.03; IC025  = 0.68), but it was not detected in durvalumab. The constituent ratio of irAEs in all adverse events caused by nivolumab (OR  = 0.58, 95% CI: 0.44-0.76) significantly decreased, compared with pembrolizumab. By comparing the PV signals, constituent ratio, severity, and reaction outcome of the three drugs, we suppose that nivolumab can be used as the safest PD-1/PD-L1 inhibitor for HNSCC., (© 2024. The Author(s).)

Tolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04). A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs. 32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes., (© 2024. The Author(s).)

Lutetium-177( 177 Lu)-PSMA-617 has been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our main objective is to elucidate the association between 177 Lu-PSMA-617 and reported adverse events (AEs) in the FDA Adverse Event Reporting System (FAERS) database. Relevant information regarding 177 Lu-PSMA-617 usage and reports of AEs was extracted from the FAERS database. The Empirical Bayes Geometric Mean (EBGM), Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) with their 95% confidence intervals (CI) were calculated using four algorithms of disproportionality analysis. The pharmacovigilance signals deemed significant across the four algorithms were considered associated with drug use. We collected 6266 unique reports related to 177 Lu-PSMA-617 usage from the FAERS database. Compared to other drugs, 177 Lu-PSMA-617 usage was associated with a higher risk of anemia, platelet count decreased, and pancytopenia. In addition to hematologic AEs, consistent high signals were observed for AEs such as dry mouth, laboratory test abnormal, and general physical health deterioration. The analysis based on mCRPC treatment drugs showed that full blood count decreased, general physical health deterioration, and laboratory test abnormal continued to exhibit significant signals. Furthermore, the number of AEs reports for 177 Lu-PSMA-617 decreased over time, with most reports occurring within one month after drug administration. Our study compiled AEs associated with 177 Lu-PSMA-617 in real-world drug usage and highlighted its propensity for specific AEs in the context of mCRPC treatment. These findings will contribute to enhancing our clinical experience with this medication., (© 2024. The Author(s).)

Neutropenia is a rare complication of drug therapy and is usually underdiagnosed. Cefoperazone/sulbactam is a combination of broad-spectrum antibacterial agents. Data on cefoperazone/sulbactam-induced neutropenia are limited. Herein, we report the case of a 35 year-old female patient who was admitted to the hospital due to an appendiceal abscess. After anti-infective treatment with cefoperazone/sulbactam, the patient developed neutropenia on day 4. After discontinuing treatment with cefoperazone/sulbactam, the patient's white blood cells and neutrophils gradually returned to normal. Hence, clinicians should monitor changes in neutrophil count during cefoperazone/sulbactam therapy and provide timely treatment., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Immune checkpoint inhibitors (ICIs) have become an important treatment modality for various malignancies. Due to excessive inflammatory and immune responses, immune-related adverse events (irAEs), such as rash, pruritis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism and fatigue, can occur. Acquired immune thrombocytopenia is a rare irAE that can lead to severe low platelet counts and hemorrhage. A retrospective observational analysis was conducted on data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We searched for all reports recorded in the FAERS covering the period from 2011 Q1 to 2023 Q4 for target agents. Signal analysis was performed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) algorithm. Nonparametric tests were used to compare the time to onset of thrombocytopenia-associated fractures between different regimens. There were 404 reports of immune thrombocytopenia in the FAERS database. Immune thrombocytopenia was associated with all ICIs except tremelimumab, and signals were detected by all 4 methods. The median time to the onset of immune thrombocytopenia caused by PD-1, PD-L1 and CTLA-4 inhibitors was 47 days (range: 21-139.2), 21 days (range: 13-131) and 9 days (range: 7-27), respectively. The Weibull shape parameter test revealed that pembrolizumab-, durvalumab-, and ipilimumab-induced thrombocytopenia had a random failure-type profile, and nivolumab- and atezolizumab-induced thrombocytopenia were characterized by an early failure-type profile. There was a significant reporting signal of ICI-induced thrombocytopenia associated with most ICIs. Immune thrombocytopenia has a greater incidence in males, elderly individuals and Asian populations, and PD-1 inhibitors were the most common cause. Clinicians should be aware of the signs of potential serious adverse events., (© 2024. The Author(s).)

Congenital anomalies of the external ear can have a significant impact on a child's development and quality of life. While genetic factors play a crucial role in the etiology of these anomalies, environmental factors such as drug exposure during pregnancy may also contribute to their occurrence. This study aims to investigate the association between drug exposure and congenital anomalies of the external ear using data from an adverse drug reaction report database. Using OpenVigil 2.1, we queried the FAERS database to retrieve adverse event reports from the first quarter of 2004 to the first quarter of 2024. To identify relevant cases, we used Medical Dictionary for Regulatory Activities terms focusing on congenital anomalies of the external ear. Drug generic names were sourced from the DrugBank database. To assess safety signals and rank drugs by their signal strength, we conducted a disproportionality analysis, generating reporting odds ratios (ROR) and proportional reporting ratios (PRR). A total of 20,754,281 AE reports were identified in the FAERS database from Q1 2004 to Q1 2024, of which 1763 were related to congenital anomalies of the external ear. Valproic acid (122 cases) was associated with the most cases, followed by mycophenolate mofetil (105 cases) and lamotrigine (65 cases). According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were primidone (ROR: 397.05, 95% CI 147.21, 1070.9; PRR: 388.71, 95% CI 145.89, 1035.7), valproic acid (ROR: 239.46, 95% CI 123.75, 463.37; PRR: 236.42, 95% CI 123.82, 451.43), tapazole (ROR: 198.35, 95% CI 63.49, 619.67; PRR: 196.25, 95% CI 62.97, 611.67), nevirapine (ROR: 138.24, 95% CI 82.9, 230.51; PRR: 137.23, 95% CI 82.44, 228.44), and sebivo (ROR: 117.1, 95% CI 48.51, 282.67; PRR: 116.37, 95% CI 48.17, 281.12). This study identified several drugs significantly associated with congenital anomalies of the external ear in the FAERS database using disproportionality analysis. The findings can help healthcare professionals better recognize and manage drug-induced congenital anomalies of the external ear, particularly when prescribing high-risk medications. Further research is needed to elucidate the mechanisms underlying these associations and develop strategies for preventing and mitigating drug-induced congenital anomalies of the external ear., (© 2024. The Author(s).)

Background: Adverse drug reaction (ADR) reporting systems are critical for monitoring and managing drug safety. However, various factors influence the willingness to use these systems. This study aimed to investigate the willingness to use ADR reporting systems through an integrated model of the Technology Acceptance Model (TAM) and Task-Technology Fit (TTF) theory, conducting a multicentre qualitative study from the user's perspective., Methods: This study used qualitative research methods, including in-depth interviews with clinicians, nurses, pharmacists and administrators who reported ADRs through the National Adverse Drug Reaction Monitoring System (NADRMS) and the China Hospital Pharmacovigilance System (CHPS). The interviews were audio-recorded, transcribed verbatim and analysed using QDA Miner software for data management and thematic analysis., Results: Eighteen healthcare workers from five healthcare organisations participated in the study. They found the ease of use and usefulness of the current NADRMS and CHPS to be acceptable. The essential technical requirements identified included accuracy, standardisation, timeliness and confidentiality. However, challenges such as inaccurate information capture, unstable interfacing with medical record systems, low reporting efficiency and lack of data sharing were highlighted. Overall, front-line healthcare workers exhibited a generally negative attitude towards using NADRMS and CHPS, driven more by necessity than preference. Factors influencing their willingness to use these systems included ease of use, practicality, risk perception and social impact, with varying attitudes and requirements observed between user groups., Conclusion: This study provides practical recommendations that can be readily implemented to enhance the effectiveness and sustainability of ADR reporting systems. While front-line users in China acknowledged the systems' ease of use and usefulness, they also noted significant gaps in technological adaptation. They expressed the need for improvements in data openness and sharing, accessibility and system intelligence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Post-licensure vaccine safety surveillance of adverse events following immunisation is critical to ensure public safety and confidence in vaccines. This paper aims to describe the governance structure and data linkage methodology behind the establishment of the largest linked vaccine safety surveillance data resource in Australia - The Vaccine Safety Health Link (VSHL)., Methods: The Vaccine Safety Health Link contains linked records from the Australian Immunisation Register with records from hospital, perinatal, mortality, and notifiable disease datasets in near real-time. Linkage is done by the Centre for Victorian Data Linkage who receive the datasets in an identifiable format which then undergo standardisation, enrichment, linkage, quality assurance and de-identification, prior to being supplied for analysis., Results: The VSHL data resource allows sensitive and rapid analysis of a broad spectrum of suspected adverse events to ensure the safety of all vaccines administered. It is also used to refute spurious concerns where no associations are found, upholding trust, and maintaining vaccine confidence., Conclusions: The Vaccine Safety Health Link's surveillance design complements existing vaccine safety surveillance methods. Challenges encountered and lessons learnt using Vaccine Safety Health Link would benefit linkage projects globally., Implications for Public Health: In its first two years, The Vaccine Safety Health Link has been used for 14 vaccine safety investigations. Studies into these conditions would not have otherwise been possible. The Vaccine Safety Health Link also partners with the Global Vaccine Data Network™ for approved collaborative studies with a combined population of over 300 million people., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This article reflects on the 2010 pharmacovigilance legislation of the European Union (EU). Its legislative aim of better patient and public health protection through new responsibilities for pharmaceutical companies and regulatory bodies is considered to have been achieved and is well supported by the good pharmacovigilance practices 'EU-GVP'. For future progress, we set out a vision for high-quality pharmacovigilance in a world of ongoing medical, technological and social changes. To deliver this vision, four principles are proposed to guide actions for further progressing the EU pharmacovigilance system: synergistic interactions with healthcare systems; trustworthy evidence for regulatory decisions; adaptive process efficiency; and readiness for emergency situations (the 'STAR principles'). Like a compass, these principles should guide actions for building capacity, technology and methods; improving regulatory processes; and expanding policies, frameworks and research agendas. Fit for the future, the EU system should achieve further improved outputs in terms of safe, effective and trusted use of medicines and positive health outcomes within patient-centred healthcare., (© 2024. The Author(s).)

Introduction: Despite the public health success of vaccination, there is an ongoing need to build public confidence in vaccines and improve systems to monitor safety while maintaining data security and patient privacy. African countries face multiple challenges in establishing systems for vaccine pharmacovigilance as was demonstrated during COVID-19 mass vaccination. We provide a framework for the development of pharmacovigilance using the COVID-19 vaccination rollout as an exemplar., Areas Covered: We describe the pre-COVID-19 vaccine pharmacovigilance systems in Southern Africa and propose improvements based on our experience of COVID-19 vaccine rollout in South Africa where we implemented systems to evaluate real-world safety and effectiveness of COVID-19 vaccinations. By conducting a PubMed review of the literature on pharmacovigilance with a focus on Africa and from guidance emanating from the World Health Organization (WHO), we evaluate challenges and opportunities to improve pharmacovigilance in our setting., Expert Opinion: There are ongoing efforts to improve pharmacovigilance on the African continent with improved coordination at a national level with the support of the WHO, the national regulatory authorities, and national departments of health. COVID-19 vaccine rollout provided an opportunity to improve pharmacovigilance by integrating national vaccine platforms with active and passive surveillance including hospital and death registries.

Background: Bempedoic acid exhibits promising potential in hyperlipidemia therapy and preventing cardiovascular events. However, investigations into its adverse drug reactions remain scant. This study seeks to utilize data mining techniques with the FDA Adverse Event Reporting System (FAERS) database to assess adverse drug events (ADEs) linked to bempedoic acid., Methods: Based on the drug's market release timeline, we extracted data from the FAERS database covering the fourth quarter of 2020 through the fourth quarter of 2023 for disproportionality analysis., Results: This study gathered a total of 5,797,543 adverse event case reports, of which 735 were linked to bempedoic acid. These reports covered 19 System Organ Classes (SOCs) and 22 Preferred Terms (PTs). Predominantly, the musculoskeletal and nervous systems were implicated in these adverse events. By conducting PT-level screening, various signals for ADEs were detected, including myalgia (ROR 30.33, PRR 28.51, IC 4.83, EBGM 28.47), arthralgia (n = 34, ROR 6.34, PRR 6.09, IC 2.61, EBGM 6.09), tendon disorders (ROR 99.57, PRR 98.75, IC 6.62, EBGM 98.28), and dizziness (ROR 3.18, PRR 3.13, IC 1.65, EBGM 3.13). Particularly noteworthy was the hypertensive crisis (ROR 28.63, PRR 28.51, IC 4.83, EBGM 28.47), which exhibited a robust signal strength, an observation previously unreported in clinical studies and drug labeling., Conclusion: While our results are largely consistent with the drug's specifications, several new adverse reaction signals, such as hypertensive crisis, have not been previously documented. Therefore, further investigations are necessary to assess these unlabeled adverse reactions, offering crucial support for the clinical utilization of bempedoic acid., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)