Safety of immune checkpoint inhibitors in patients aged over 80 years: a retrospective cohort study.

BACKGROUND: Immuno-oncology (IO) drugs are essential for treating various cancer types; however, safety concerns persist in older patients. Although the incidence of immune-related adverse events (irAEs) is similar among age groups, higher rates of hospitalization or discontinuation of IO therapy have been reported in older patients. Limited research exists on IO drug safety and risk factors in older adults. Our investigation aimed to assess the incidence of irAEs and identify the potential risk factors associated with their development. METHODS: This retrospective analysis reviewed the clinical data extracted from the medical records of patients aged > 80 years who underwent IO treatment at our institution. Univariate and multivariate analyses were performed to assess the incidence of irAEs. RESULTS: Our study included 181 patients (median age: 82 years, range: 80-94), mostly men (73%), with a performance status of 0-1 in 87% of the cases; 64% received IO monotherapy. irAEs occurred in 35% of patients, contributing to IO therapy discontinuation in 19%. Our analysis highlighted increased body mass index, eosinophil counts, and albumin levels in patients with irAEs. Eosinophil count emerged as a significant risk factor for any grade irAEs, particularly Grade 3 or higher, with a cutoff of 118 (/µL). The group with eosinophil counts > 118 had a higher frequency of irAEs, and Grade 3 or higher events than the group with counts ≤ 118. CONCLUSION: IO therapy is a safe treatment option for patients > 80 years old. Furthermore, patients with elevated eosinophil counts at treatment initiation should be cautiously managed.

Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system.

Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice. Methods: Based on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality. Results: The NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs. Conclusion: These findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

Determination of drug-related problems in the hematology service: a prospective interventional study.

BACKGROUND: Patients with hematological malignancies often require multidrug therapy using a variety of antineoplastic agents and supportive care medications. This increases the risk of drug-related problems (DRPs). Determining DRPs in patients hospitalized in hematology services is important for patients to achieve their drug treatment goals and prevent adverse effects. This study aims to identify DRPs by the clinical pharmacist in the multidisciplinary team in patients hospitalized in the hematology service of a university hospital in Turkey. METHODS: This study was conducted prospectively between December 2022 and May 2023 in the hematology service of Suleyman Demirel University Research and Application Hospital in Isparta, Turkey. DRPs were determined using the Pharmaceutical Care Network Europe (PCNE) 9.1 Turkish version. RESULTS: This study included 140 patients. Older age, longer hospital stay, presence of acute lymphoblastic leukemia, presence of comorbidities, higher number of medications used, and polypharmacy rate were statistically significantly higher in the DRP group than in the non-DRP group (p < 0.05). According to multivariate logistic regression analysis, the probability of DRP in patients with polypharmacy was statistically significant 7.921 times (95% CI: 3.033-20.689) higher than in patients without polypharmacy (p < 0.001).Every 5-day increase in the length of hospital stay increased the likelihood of DRP at a statistically significant level (OR = 1.476, 95% CI: 1.125-1.938 p = 0.005). In this study, at least one DRP was detected in 69 (49.3%) patients and the total number of DRPs was 152. Possible or actual adverse drug events (96.7%) were the most common DRPs. The most important cause of DRPs was drug choice (94.7%), and the highest frequency within its subcategories was the combination of inappropriate drugs (93.4%). CONCLUSIONS: This study shows the importance of including a clinical pharmacist in a multidisciplinary team in identifying and preventing DRPs in the hematology service.

[Risk factors associated to adverse drug events in hospitalized patients]. / Factores de riesgo asociados con eventos adversos a medicamentos en pacientes hospitalizados.

OBJECTIVE: To determine prevalence, causes and risk factors of ADE in hospitalized patients. METHODS: Analytical, observational, case-control study of patients with ADE. For statistical analysis, the following were calculated: percentages, frequencies, averages; odds ratio, χ2 test and multiple binary logistic regression. Data analysis was carried out with the Statistical Package, for the Social Sciences 23 program. RESULTS: A 132 patients were registered: 66 cases (26 EM and 40 RAM) and 66 controls; with average age of 35 years (SD 17.41). The prevalence of adverse drug events was 3.6%. The most frequently reported medications: antibiotics and anti-inflammatories. The frequency of adverse events by gender was: 39.3% men and 60.7% women. The services with the greatest patient care: emergencies, surgery; the most frequent route of administration: intravenous (32.3%). The main symptoms: skin. (32.3%) frequent symptoms: cutaneous. Associated symptoms RAM: type A pruritus (OR: 8.5; p = 0.001; IC95%: 0.035-0.393), type B pruritus (OR: 11; p = 0.001; CI95%: 0.021-0.368) urticaria (OR: 19; p = 0.005; IC95%: 0.007-0.412). Risk factors Associated EAM: female (OR: 2.6; p = 0.05; CI95%: 1.33-5.43), history of allergy (OR: 3.4; p = 0.033; CI95%: 1.04-8.40), prolonged hospital stays (OR: 5.4; p = 0.023; IC95%: 3.82-6.74). CONCLUSIONS: Patient safety is a priority when prescribing any drug, which represents a key point in prevention.

OBJETIVO: Determinar la prevalencia, causas y factores de riesgo asociados con eventos adversos a medicamentos en pacientes hospitalizados. MÉTODOS: Estudio de casos y controles, observacional, analítico, llevado a cabo en pacientes con eventos adversos a medicamentos. Para el análisis estadístico se calcularon: porcentajes, frecuencias, promedios; razón de momios, prueba de χ2 y regresión logística binaria múltiple. El análisis de los datos se efectuó con el programa Statistical Package, for the Social Sciencies 23. RESULTADOS: Se registraron 132 pacientes: 66 casos (26 EM y 40 RAM) y 66 controles, con edad promedio de 35 años (DS 17.41). La prevalencia de eventos adversos a medicamentos fue del 3.6%. Los medicamentos reportados con mayor frecuencia: antibióticos y antiinflamatorios. La frecuencia de eventos adversos por género fue: 39.3% hombres y 60.7% mujeres. Los servicios con mayor atención de pacientes: urgencias y cirugía; vía de administración más frecuente: intravenosa (32.3%). Los principales síntomas fueron los cutáneos. Los síntomas asociados con reacción adversa a medicamentos: prurito tipo A (RM: 8.5; p = 0.001; IC95%: 0.035-0.393), prurito tipo B (RM: 11; p = 0.001; IC95%: 0.021-0.368) urticaria (RM: 19; p = 0.005; IC95%: 0.007-0.412). Los factores de riesgo asociados con eventos adversos a medicamentos: mujer (RM: 2.6; p = 0.05; IC95%: 1.33-5.43), antecedente de alergia (RM: 3.4 p = 0.033; (IC95%: 1.04-8.40) y estancia hospitalaria prolongada (RM: 5.4; p = 0.023; IC95%: 3.82-6.74). CONCLUSIONES: La seguridad de los pacientes es una prioridad al momento de prescribir cualquier fármaco, lo que representa un punto clave en la prevención.

Gender Difference in sidE eFfects of ImmuNotherapy: a possible clue to optimize cancEr tReatment (G-DEFINER): study protocol of an observational prospective multicenter study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. AIMS: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. METHODS AND RESULTS: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. INTERPRETATION: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.

Drug-related problems in cancer patients: A systematic review.

BACKGROUND: Cancer patients are at a significantly increased risk of drug-related problems due to multiple drugs. An inclusive review of drug-related problems would offer an approach for healthcare providers to decrease the frequency of drug-related problems in cancer patients. The purpose of this study was to assess all characteristic components of drug-related problems in cancer patients, and explore actions taken to resolve the detected drug-related problems the results could be used as a baseline for epidemiology and potential related risk factors for drug-related problems in cancer patients. METHODS: The present systematic review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search consisted of studies listed from January 2015 and up to May 2023. A systematic review was carried out using an electronic database with a combination of Medical subject Headings of key words Medical Subject Heading terms. RESULTS: This evaluation included 17 studies from 11 different nations having 11 prospective and 6 retrospective studies. Pharmaceutical Care Network Europe classification system is the most commonly used to classify the drug-related problems. The prevalence of drug-related problems varied from 9.6% to 92.8%. The key predictors of the drug-related problems were age, polypharmacy, multiple comorbidities, and the stage of the disease. CONCLUSION: Drug-related problems are significantly more common among cancer patients. The age, polypharmacy, multiple comorbidities, and the stage of the malignancy all enhance the risk of acquiring drug-related problems. This review raises awareness of drug-related problems, encourages their early detection, and emphasizes the necessity for framing effective drug-related problem management strategies which will enhance patient care.

Pharmacoeconomics of medicines used for geriatric individuals in a tertiary care hospital in Delhi.

BACKGROUND OBJECTIVES: Expenditure on healthcare is a major concern in the geriatric age group. The current study was carried out to assess the expenditure patterns on medicines utilized in geriatric inpatients. METHODS: An observational study was conducted on 1000 geriatric inpatients, aged ≥60 yr, admitted to the medicine unit. Data were collected regarding demographic characteristics, prescribed medicines, expenditure incurred on medicines, appropriateness of medicines prescribed and adverse drug reactions (ADRs). Appropriateness of the prescribed medicines was determined using the American Geriatrics Society 2015 Updated Beers Criteria. RESULTS: Geriatric inpatients comprised 41.3 per cent of the total individuals admitted in the ward during the study period. A total of 8366 medicines were prescribed in 127 formulations. The total expenditure on prescribed medicines was INR 1,087,175 with a per capita expenditure of INR 1087.17. Parenteral medicines accounted for 91 per cent of the expenditure on medicines. Maximum expenditure (70%) was incurred on 11.9 per cent of the medicines prescribed. The per capita expenditure was significantly higher in individuals with comorbidities (P=0.03) and those who had a longer duration of hospital stay (P<0.0001). About 28.1 per cent prescriptions were inappropriate. ADRs (140) were observed in 139 (13.9%) inpatients. Individuals with inappropriate medicines prescriptions and ADRs had a longer duration of hospital stay and more number of medicines prescribed. INTERPRETATION CONCLUSIONS: Comorbidities, prolonged hospitalization, polypharmacy, inappropriate medicines and parenteral medicines being prescribed contribute to increased expenditure on medicines in geriatric inpatients. In view of the rising number of geriatric inpatients, there is a need to frame a drug policy for them along with surveillance of expenditure on prescribed medicines. This needs to be treated as a priority.

A Real-world Toxicity Atlas Shows that Adverse Events of Combination Therapies Commonly Result in Additive Interactions.

PURPOSE: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting. EXPERIMENTAL DESIGN: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heat maps. In addition, statistical synergy analyses were performed on the basis of BLISS independence or χ2 testing. RESULTS: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug-associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. CONCLUSIONS: Our study provides a framework for analyzing adverse events and suggests that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

Rising cases of drug-induced pulmonary fibrosis: Analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database, 2000-2022.

PURPOSE: Pulmonary fibrosis (PF) is a severe, progressive disease, which may be caused by exposure to certain medications. METHODS: We queried the U.S. FDA Adverse Event Reporting System (FAERS) from 2000 to 2022, using the search terms "pulmonary fibrosis" and "idiopathic pulmonary fibrosis" and excluded reports with patients under the age of 18 years, and patients with unknown sex or age. Reports were sorted by generic drug names, counted, and plotted over time using a best-fit trendline based on an exponential function. RESULTS: From 2000 to 2022, there were 24 095 935 adverse drug events reported in FAERS, of which 17 520 (0.07%) were reported as PF. After excluding reports containing patients with unknown age (5255, 30%), sex (122, 0.7%), and age below 18 years old (155, 0.9%), our study included 11 988 reports. The mean age of the study sample was 66.5 ± 13.1 years, and 6248 patients (52.1%) were male. Plotting the 11 988 reports by year revealed an exponential best fit line (R2 = 0.88) with a positive slope over time. The top five drug classes associated with PF were disease modifying antirheumatic drugs (DMARDs, 39.4%), antineoplastic agents (26.4%), cardiovascular agents (12.6%), corticosteroids (4.6%), and immunosuppressive agents (4.0%). CONCLUSION: A 23-year analysis of the FAERS database revealed exponentially increasing adverse event reports of PF. Significant annual increases in reporting of PF suspected with DMARDs and antineoplastic agents were identified. Our study highlights important trends, which should be used to guide PF research related to drugs of potential importance.

Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

Identification and Characterization of Immune Checkpoint Inhibitor-Induced Toxicities From Electronic Health Records Using Natural Language Processing.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their use is associated with immune-related adverse events (irAEs). Estimating the prevalence and patient impact of these irAEs in the real-world data setting is critical for characterizing the benefit/risk profile of ICI therapies beyond the clinical trial population. Diagnosis codes, such as International Classification of Diseases codes, do not comprehensively illustrate a patient's care journey and offer no insight into drug-irAE causality. This study aims to capture the relationship between ICIs and irAEs more accurately by using augmented curation (AC), a natural language processing-based innovation, on unstructured data in electronic health records. METHODS: In a cohort of 9,290 patients treated with ICIs at Mayo Clinic from 2005 to 2021, we compared the prevalence of irAEs using diagnosis codes and AC models, which classify drug-irAE pairs in clinical notes with implied textual causality. Four illustrative irAEs with high patient impact-myocarditis, encephalitis, pneumonitis, and severe cutaneous adverse reactions, abbreviated as MEPS-were analyzed using corticosteroid administration and ICI discontinuation as proxies of severity. RESULTS: For MEPS, only 70% (n = 118) of patients found by AC were also identified by diagnosis codes. Using AC models, patients with MEPS received corticosteroids for their respective irAE 82% of the time and permanently discontinued the ICI because of the irAE 35.9% (n = 115) of the time. CONCLUSION: Overall, AC models enabled more accurate identification and assessment of patient impact of ICI-induced irAEs not found using diagnosis codes, demonstrating a novel and more efficient strategy to assess real-world clinical outcomes in patients treated with ICIs.

Prevalence of urgent hospitalizations caused by adverse drug reactions: a cross-sectional study.

Adverse drug reactions account for a substantial portion of emergency hospital admissions. However, in the last decade, few studies have been conducted to determine the prevalence of hospitalization due to adverse drug reactions. Therefore, this cross-sectional study was conducted to determine the proportion of adverse drug reactions leading to emergency hospital admission and to evaluate the risk factors for these reactions. A total of 5707 consecutive patients aged > 18 years who were emergently hospitalized due to acute medical illnesses between June 2018 and May 2021 were included. Causality assessment for adverse drug reactions was performed by using the World Health Organization-Uppsala Monitoring Centre criteria. The median patient age was 78 years (IQR 63-87), and the proportion of women was 47.9%. Among all the hospitalizations, 287 (5.0%; 95% confidence interval (CI) 4.5-5.6%) were caused by 368 adverse drug reactions. The risk factors independently associated with hospitalization due to adverse drug reactions were polypharmacy (OR 2.66), age ≥ 65 years (OR 2.00), and ambulance use (OR 1.41). Given that the population is rapidly aging worldwide, further efforts are needed to minimize hospitalizations caused by adverse drug reactions.

A clinical-pharmaceutical medication reconciliation with patient interview for a medication review to identify drug-related problems in elective patients during hospital admission.

Background and aim: Drug-related problems (DRPs), e.g.drug-drug interactions (DDI), can lead to adversedrug reactions (ADRs) and thus complications during hospitalization. For this reason, such DRP, DDI and ADR should be identified and characterized as early as possible during hospital admission. We aimed to perform a clinical-pharmaceutical medication reconciliation in which patient-related information was collected and compared to drug-related information in a medication review. Investigations: During a 24-week-period, we consecutively invited patients electively admitted to Urology, Otolaryngology, Oral and Maxillofacial Surgery, General and Visceral Surgery, and Oncology Departments of a 300-bed hospital. A clinical pharmacist performed a patient interview asking for medication, ADR, and adherence. The medication reconciliation considered packages for a brown-bag analysis, medication lists, and data from the clinical information-system (CIS). In a medication review, we matched patient-related information to drug-related information from the drug label, guidelines, drug-databases and websites to identify DRPs. Results: In the study, 356 patients (median age: 58 years) taking 1,712 drugs participated. Of all patients, 7.3% reported ADR and 10.7% missing adherence. 5.3% brought packages that enabled a brown-bag analysis and 21.1% a medication list. In 76.7% of patients, information from CIS was incomplete or not up-to-date. Among the most frequently identified DRPs were "Medication without diagnosis" (31.2%) and "Inappropriate timing of administration" (11.5%). The proportion of patients affected by severe DDI ranged from 0.8%-16.6%, depending on the drug information source. Conclusions: Incomplete patient data, frequently identified DRPs and inconsistent drug-based information make pharmaceutical involvement in medication reconciliation on admission a necessity.

Development of a multidisciplinary medication management program in nursing homes: protocol for a randomized controlled trial : Multidisciplinary medication management in nursing homes.

BACKGROUND: Polypharmacy and the use of potentially inappropriate medications are common among nursing home residents and are associated with negative outcomes. Although deprescribing has been proposed as a way to curtail these problems, the best way to implement multidisciplinary comprehensive medication review and deprescribing and its real impact in specific high-risk populations, such as nursing home residents, is still unclear. This multicenter randomized controlled clinical trial aims to assess the effects of a multidisciplinary mediation management program on medication use and health problems. METHODS: A total of 1,672 residents aged ≥ 65 years from 22 nursing homes in South Korea who meet the targeted criteria, such as the use of ≥ 10 medications, are eligible to participate. The experimental group will receive a comprehensive medication review, deprescription, and multidisciplinary case conference with the help of platform. Outcomes will be measured at baseline, at the end of the intervention, as well as at 3, 6, 9, and 12 months after the end of the intervention. The primary endpoints will be the rate of adverse drug events, number of potentially inappropriate medications/potentially inappropriate medication users/two or more central nervous system drug/ central nervous system drug users, delirium, emergency department visits, hospitalization, and falls. The secondary endpoint will be the number of medications taken and polypharmacy users. DISCUSSION: Our trial design is unique in that it aims to introduce a structured operationalized clinical program focused on reducing polypharmacy and potentially inappropriate medications in a nursing home setting with large samples. TRIAL REGISTRATION: Ethical approval was granted by the public institutional review board of the Ministry of Health and Welfare (2022-1092-009). The study is also registered with the Clinical Research Information Service (Identifier: KCT0008157, Development and evaluation of a multidisciplinary medication management program in long-term care facility residents Status: Approved First Submitted Date: 2023/01/18 Registered Date: 2023/02/03 Last Updated Date: 2023/01/18 (nih.go.kr) https://cris.nih.go.kr/ ), which includes all items from the World Health Organization Trial Registration Dataset.

Analysis of drug-induced posterior reversible encephalopathy syndrome using the food and drug administration adverse drug events reporting system database.

OBJECTIVE: In this retrospective pharmacovigilance study, we gathered data on drug-induced posterior reversible encephalopathy syndrome (PRES). Our goal was to identify the primary suspect drugs in PRES by analyzing the Food and Drug Administration Adverse Events Reporting System (FAERS) database. METHODS: We identified and analyzed reports of PRES listed in the FAERS database between 2004 and 2021. Using the reporting odds ratio and 95% confidence interval, we evaluated the safety signals for each of the drugs associated with PRES. RESULTS: We reviewed 11,077 reports of adverse events corresponding to PRES. The primary suspect drug categories were antineoplastics, immunosuppressants, and glucocorticoids. PRES was 24.77% more likely to occur in females than in males. Drug-induced PRES usually occurs in individuals with cancer, those who have undergone an organ/stem cell transplant, and those with autoimmune conditions. CONCLUSION: Our results show that the drugs most commonly suspected to cause PRES were antineoplastics, immunosuppressants, and glucocorticoids. Future studies are needed to illuminate the pathophysiological alterations that underlie PRES. In the meantime, prescribers and patients should be made aware of the potential risks of PRES associated with pharmaceutical therapy, and the summaries of product characteristics for individual drugs should be updated to include this information.

Exploring the Landscape of Immune Checkpoint Inhibitor-Induced Adverse Events Through Big Data Mining of Pan-Cancer Clinical Trials.

PURPOSE: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with cancer and provided long-term durable benefit. However, ICI-treated patients develop a range of toxicities known as immune-related adverse events (irAEs), which could compromise clinical benefits from these treatments. As the incidence and spectrum of irAEs differs across cancer types and ICI agents, it is imperative to characterize the incidence and spectrum of irAEs in a pan-cancer cohort to aid clinical management. DESIGN: We queried >400 000 trials registered at ClinicalTrials.gov and retrieved a comprehensive pan-cancer database of 71 087 ICI-treated participants from 19 cancer types and 7 ICI agents. We performed data harmonization and cleaning of these trial results into 293 harmonized adverse event categories using Medical Dictionary for Regulatory Activities. RESULTS: We developed irAExplorer (https://irae.tanlab.org), an interactive database that focuses on adverse events in patients administered with ICIs from big data mining. irAExplorer encompasses 71 087 distinct clinical trial participants from 343 clinical trials across 19 cancer types with well-annotated ICI treatment regimens and harmonized adverse event categories. We demonstrated a few of the irAE analyses through irAExplorer and highlighted some associations between treatment- or cancer-specific irAEs. CONCLUSION: The irAExplorer is a user-friendly resource that offers exploration, validation, and discovery of treatment- or cancer-specific irAEs across pan-cancer cohorts. We envision that irAExplorer can serve as a valuable resource to cross-validate users' internal datasets to increase the robustness of their findings.

Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada.

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs. METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods. RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs. CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.

Development of prescribing indicators related to opioid-related harm in patients with chronic pain in primary care-a modified e-Delphi study.

BACKGROUND: Long-term opioid use is associated with dependency, addiction, and serious adverse events. Although a framework to reduce inappropriate opioid prescribing exists, there is no consensus on prescribing indicators for preventable opioid-related problems in patients with chronic pain in primary care in the UK. This study aimed to identify opioid prescription scenarios for developing indicators for prescribing opioids to patients with chronic pain in primary care. METHODS: Scenarios of opioid prescribing indicators were identified from a literature review, guidelines, and government reports. Twenty-one indicators were identified and presented in various opioid scenarios concerning opioid-related harm and adverse effects, drug-drug interactions, and drug-disease interactions in certain disease conditions. After receiving ethics approval, two rounds of electronic Delphi panel technique surveys were conducted with 24 expert panellists from the UK (clinicians, pharmacists, and independent prescribers) from August 2020 to February 2021. Each indicator was rated on a 1-9 scale from inappropriate to appropriate. The score's median, 30th and 70th percentiles, and disagreement index were calculated. RESULTS: The panel unanimously agreed that 15 out of the 21 opioid prescribing scenarios were inappropriate, primarily due to their potential for causing harm to patients. This consensus was reflected in the low appropriateness scores (median ranging from 1 to 3). There were no scenarios with a high consensus that prescribing was appropriate. The indicators were considered inappropriate due to drug-disease interactions (n = 8), drug-drug interactions (n = 2), adverse effects (n = 3), and prescribed dose and duration (n = 2). Examples included prescribing opioids during pregnancy, concurrently with benzodiazepines, long-term without a laxative prescription and prescribing > 120-mg morphine milligram equivalent per day or long-term duration over 3 months after surgery. CONCLUSIONS: The high agreement on opioid prescribing indicators indicates that these potentially hazardous consequences are relevant and concerning to healthcare practitioners. Future research is needed to evaluate the feasibility and implementation of these indicators within primary care settings. This research will provide valuable insights and evidence to support opioid prescribing and deprescribing strategies. Moreover, the findings will be crucial in informing primary care practitioners and shaping quality outcome frameworks and other initiatives to enhance the safety and quality of care in primary care settings.

Probable effects of polypharmacy and equivalent doses of psychotropic drugs on prevalence of adverse drug events among psychiatric inpatients in a general hospital in Japan.

OBJECTIVE: In psychiatry, polypharmacy or high psychotropic drug doses increase adverse drug event (ADE) prevalence. However, the full relationship between polypharmacy and ADEs is unclear, and few studies have evaluated dose equivalents for psychotropic drugs for ADEs. Thus, we conducted a retrospective analysis to clarify the effects of polypharmacy and chlorpromazine (CP)-, diazepam (DAP)-, and imipramine- equivalent doses on all ADEs in inpatients. METHODS: Psychiatric inpatients in a Japanese hospital from April 1, 2016 to March 31, 2018, were enrolled. ADE severity and causality were assessed. Multiple logistic regression analyses were performed to evaluate ADE risk factors. RESULTS: Among 462 patients analyzed, out of 471 patients enrolled, 145 (31.4%) experienced ADEs. The causality assessment determined that "possible" was 96.5%. The most common ADEs were nervous system disorders (35%). Multiple logistic regression analyses indicated an increase in ADE prevalence with the number of drugs used (≥5; p = 0.026); CP-equivalent dose (p = 0.048); and endocrine, nutritional, and metabolic disorders (p = 0.045). DAP-equivalent dose; infectious and parasitic diseases; and injury, poisoning, and consequences of other external causes decreased ADE prevalence (p = 0.047, 0.022, and 0.021, respectively). CONCLUSIONS: Avoiding polypharmacy in psychiatric inpatients and adjusting drug regimens to safe equivalent doses could reduce ADEs during hospitalization.

Monitoring of adverse drug reactions during seasonal malaria chemoprevention campaigns in children aged 3­59 months in Burkina Faso / Surveillance des effets indésirables lors des campagnes de la chimioprévention du paludisme saisonnier chez les enfants de 3-59 mois au Burkina Faso

Introduction: Seasonal malaria chemoprevention (SMC) by mass administration of sulfadoxine pyrimethamine + amodiaquine (SPAQ) reduces the burden of malaria in children aged 3­59 months. The occurrence of adverse drug reaction (ADR) may affect the success of this intervention. There are few studies of SMC adverse event surveillance in sub-Saharan Africa, particularly in Burkina Faso, a highly endemic country. Our main objective was to characterize the ADRs reported during SMC campaigns in Burkina Faso. Secondly, we evaluated the performance of the pharmacovigilance integrated into the SMC program in order to support safe administration of SMC. Method: This was a retrospective descriptive study of SMC individual case safety reports recorded in VigiBase® in Burkina Faso from 2014 to 2021. We used the P-method for the analysis of preventable serious adverse drug reactions and WHO criteria for assessing the performance of pharmacovigilance integrated into the SMC program. Results: A total of 1,105 SMC individual case safety reports were registered in VigiBase® for 23,311,453 doses of SPAQ given between 2014 and 2021. No pharmacovigilance signal was detected. The number of serious cases was 101, of which 23 (22.8%) were preventable. In 38.1% of children, the occurrence of ADRs led to discontinuation of SMC treatment. Vomiting was the most frequently reported adverse drug reaction (48.0%). The proportion of children whose treatment was discontinued due to vomiting was 42.7%, while the proportion of treatment discontinuation for other ADRs was 32.8% (p = 0.01). The SMC program contributed at 46.2% to the national pharmacovigilance database. The reporting rate was 0.03 per 1,000 exposed children in 2021. The median completeness score of the ICSRs was 0.7 (IQR: 0.5­0.7), and the median time to register the ICSRs in VigiBase® was 204 (IQR: 143­333) days. Conclusions: Post-drug administration vomiting may interfere with the purpose of SMC. Measures to manage this adverse drug reaction should be taken to improve the success of the SMC program. Based on the information on reporting time and reporting rate, spontaneous reporting should be supported by active surveillance, including cohort event monitoring, in Burkina Faso.

Introduction: La chimioprévention du paludisme saisonnier (CPS) par l'administration en masse de la sulfadoxine-pyriméthamine + amodiaquine (SPAQ) permet de réduire le fardeau du paludisme chez les enfants de 3-59 mois. La survenue d'effets indésirables (EI) pourrait nuire au succès de cette intervention. Il existe peu d'études sur la surveillance des EI de la CPS en Afrique subsaharienne et plus particulièrement au Burkina Faso, pays de forte endémicité palustre. Notre objectif principal était de caractériser les effets indésirables notifiés au cours des campagnes CPS au Burkina Faso. Secondairement, nous avons évalué la performance de la pharmacovigilance intégrée au programme de CPS dans le but de soutenir la sécurité d'administration de la CPS. Méthodes: Nous avons réalisé une analyse rétrospective à visée descriptive des rapports d'effets indésirables de la CPS enregistrés dans VigiBase® entre le 1er janvier 2014 et le 31 décembre 2021. Nous avons utilisé la P-method pour l'analyse de l'évitabilité des effets indésirables graves et les critères de l'OMS pour évaluer la performance de la pharmacovigilance intégrée au programme de CPS. Résultats: Au total, 1 105 cas individuels de rapports de sécurité de la CPS ont été analysés dans VigiBase® pour 23 311 453 doses administrées. Aucun signal de pharmacovigilance n'a été détecté. Le nombre des cas graves était de 101, dont 23 (22,8 %) évitables. Chez 38,1 % des enfants, la survenue des EI a occasionné l'arrêt de l'administration du traitement de la CPS. Le vomissement était l'effet indésirable le plus fréquemment rapporté (48,0 %). La proportion d'enfants dont le traitement a été arrêté pour motif de vomissement était de 42,7 %, tandis que la proportion d'arrêts de traitement pour les autres EI était de 32,8 % (p=0,01). La pharmacovigilance de la CPS a contribué à 46,2 % à l'alimentation de la base de données nationale de pharmacovigilance. Le taux de notification était de 0,03 pour 1 000 enfants exposés en 2021. Le score d'exhaustivité médian des rapports était de 0,7 (P25-P75 : 0,5-0,7) et le délai médian d'enregistrement des rapports dans VigiBase® était de 204 (P25-P75 : 143-333) jours. Conclusions: Les vomissements peuvent nuire à l'objectif de la CPS. Des mesures de gestion de cet effet indésirable doivent être prises pour améliorer le succès de la CPS. Au regard des informations sur le délai de notification et le taux de notification, la notification spontanée devrait être soutenue par une surveillance active, notamment une « cohort event monitoring ¼ au Burkina Faso.