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Background: We sought to comprehensively describe drug-related components associated with acute kidney injury (AKI) in patients with chronic kidney disease (CKD), describing the incidence of drug-related AKI, the proportion of preventable AKI, identified the various drugs potentially associated with it, explored the risk factors, and assessed the 1-year incidences of the recurrence of drug-related AKI, kidney failure, and death., Methods: CKD-REIN is a French national prospective cohort of 3033 nephrology outpatients with a confirmed diagnosis of CKD (eGFR <60 ml/min/1.73 m²). AKIs and adverse drug reactions (ADRs) were prospectively identified from hospital reports, medical records, and patient interviews. Expert nephrologists used the KDIGO criteria to adjudicate all stages of AKI, and expert pharmacologists used validated tools to adjudicate ADRs (including drug-related AKIs)., Results: Over a median [interquartile range] period of 4.9 [3.4-5.1] years, 832 cases of AKI were reported in 639 (21%) of the 3033 study participants. The drug-related component associated with AKI accounted for 236 cases, and 28% were judged to be preventable or potentially preventable. The three most frequently implicated drug classes were diuretics, renin-angiotensin system inhibitors, and contrast agents. A history of cardiovascular events, diabetes, lower levels of hemoglobin and eGFR, poor medication adherence, and ≥5 drugs taken daily were associated with a greater risk of drug-related AKI. Full recovery was not attained in 64 (27%) of the 236 cases of drug-related AKI. The 1-year cumulative incidences of recurrence of drug-related AKI, kidney replacement therapy, and death were 7%, 15%, and 11%, respectively, after the first drug-related AKI., Conclusions: Drug-related AKI is prevalent among patients with CKD. Even though a substantial proportion of these events were classified as stage 1, our findings point to a poor prognosis., Competing Interests: S.M.L., S.L., J.V., V.G.C., and J.M. have nothing to declare. Z.A.M. reports having received grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Sanofi- Genzyme, Lilly, Otsuka, AstraZeneca, Vifor and the French government, as well as fees and grants to charities from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. N.A.P. declare financial support from pharmaceutical companies integrating the public-private partnership of the CKD-REIN cohort: Fresenius Medical Care, GlaxoSmithKline (GSK), Vifor France, and Boeringher Ingelheim; all grants are made to Paris Saclay University., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Retinal vein occlusions and central retinal artery occlusions have been reported with coronavirus disease 2019 (COVID-19) vaccines. We aim to provide a descriptive analysis of cases reported in France until mid-2023, and recorded in the French pharmacovigilance database. An independent ophthalmologist reviewed all cases. We analyzed 290 cases (228 retinal vein occlusions, 58 central retinal artery occlusions, and four combinations). Retinal vein occlusions occurred with mRNA vaccines (68.0%) and adenovirus-vectored vaccines (32%), with an 11-day median onset delay. Almost half of the patients had retinal vein occlusion risk factors, mainly hypertension, and five had a positive rechallenge. Considering the lower adenovirus-vectored vaccines exposure in France, their proportion of retinal vein occlusions appears high. Among the 58 central retinal artery occlusion cases, most occurred with mRNA vaccines in patients with retinal artery occlusion risk factors (mainly hypertension), with a 17-day median onset delay. In conclusion, there was a temporal association in almost half of cases, but few cases with positive rechallenge, and many cases were confounded by risk factors (e.g., cardiovascular disorders, diabetes), which are also COVID-19 risk factors. Therefore, the risk of retinal vascular occlusion does not challenge the benefit-risk ratio of the vaccination, especially for mRNA vaccines., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Rationale & Objective: Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We comprehensively describe ADRs and assess the relationship between estimated glomerular filtration rate (eGFR) and serious ADR risk., Study Design: Prospective cohort study., Setting & Participants: 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate to advanced CKD., Predictors: Demographic and biological data (including eGFR), medication prescriptions., Outcome: ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs., Analytical Approach: Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype)., Results: During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhage (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death and 22 associated with a life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. The risk of acute kidney injury was 2.2% higher and risk of bleeding ADRs was 8% higher for each 1mL/min/1.73m 2 lower baseline eGFR., Limitations: The results cannot be extrapolated to patients who are not being treated by a nephrologist., Conclusions: ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor., Plain-Language Summary: Patients with chronic kidney disease (CKD) have complex clinical presentations, take multiple medications, and often receive inappropriate prescriptions. Using data from a large, prospective CKD cohort, we found a high incidence of serious adverse drug reactions (ADRs). The 2 most common serious ADRs were drug-induced acute kidney injury and bleeding. A large proportion of serious ADRs required hospital admission, and 11% led to death or were life threatening. Lower kidney function was a major risk factor for serious ADRs. Many of these serious ADRs were determined to be partly preventable through greater adherence to prescription guidelines. This report enhances our understanding of the potential toxicity of drugs taken by patients with moderate to advanced CKD. It emphasizes the importance of monitoring kidney function when prescribing drugs, particularly for high-risk medications such as antithrombotic agents., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Statins are recommended in kidney transplant recipients (KTRs)-a population with a high risk of major cardiovascular (CV) events. However, the literature data on the effectiveness of statins in KTRs are sparse and inconclusive. The present study's objective was to evaluate the association between statin exposure and atherosclerotic CV events in KTRs and the biochemical effectiveness of statins on the lipid profile., Methods: A total of 318 consecutive KTRs managed at a single center between 2006 and 2019 were retrospectively included. Those exposed to statins after transplantation were incident users. In all users, statins were indicated for primary CV prevention. Lipid profiles, the occurrence of any atherosclerotic CV events (stroke, myocardial infarction, other atherosclerotic CV events and atherosclerotic CV deaths) were documented comprehensively. We applied Cox models that included statin exposure as a time-dependent covariate fitted with time-varying inverse probability treatment weighting (IPTW) to assess the effectiveness of statins on atherosclerotic CV events and on all CV events. We built linear mixed models to assess the biochemical effectiveness of statins., Results: During a median (interquartile range) follow-up period of 6.0 (3.9-10.0) years, 27 atherosclerotic CV events occurred in 26 patients. In the Cox models fitted with time-varying IPTW, exposure to statins was not associated with a decrease in atherosclerotic CV events; the hazard ratio was 1.16 (95% confidence interval 0.53-2.53) (P = .700). In the linear mixed models, statin exposure was associated with significant decrease over time in triglyceride and low-density lipoprotein cholesterol concentrations (P < .001). These results were consistent when stratified for the intensity of statin therapy., Conclusion: Even though the lipid profile improved, statin exposure was not associated with a decrease in CV events in this real-life, single-center, retrospective, long-term follow-up study of a KTR cohort. Larger, controlled studies are needed to confirm or refute these results., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

As part of the COVID-19 vaccination campaign, the National Agency for the Safety of Medicines and Health Products and all 31 regional pharmacovigilance centers were mobilized in an exceptional reinforced vaccine pharmacovigilance surveillance system. Concerning adenovirus vaccines, Vaxzévria® and Jcovden®, this national system, based on the daily analysis of notified cases of adverse events, has allowed the early identification of safety signals, some of which have been validated, others still under analysis, common to mRNA vaccines or more specific of adenovirus vaccines such as Vaccine Induced Immune Thrombocytopenia. Complementing european and international actions, this follow-up has contributed to a better definition of the safety profile of these vaccines and has led to redefine the vaccine strategy in our country. Although today these two vaccines have no longer place in the national vaccine strategy, they are still used in other countries, where the experience acquired could be useful and will contribute to fuel the reflection on future therapies involving viral vectors., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: The subcutaneous (SC) route provides an alternative to the IV or oral route for drug administration in the elderly. The benefits of SC administration have been proven for hydration but are still debated for antibiotics because tolerance remains uncertain, especially in the frail geriatric population. Here, we aimed to improve current knowledge concerning the tolerance profile of ceftriaxone SC administration at both the systemic and cutaneous level, as well as in terms of pain., Patients and Methods: This was a prospective descriptive study of SC ceftriaxone tolerance in a geriatric department. We included all patients over 75 years of age who received a prescription for SC ceftriaxone in our hospital over a 5 month period., Methods: We evaluated the systemic and local tolerance of SC ceftriaxone. Nurses were asked about their perceptions concerning its use., Results: Among 117 patients, 57% presented with pain and 60% with a mild local adverse effect, such as the formation of oedema in one-third of patients, induration or transient erythema. Finally, there were no serious local adverse effects and two systemic adverse effects were observed (one diarrhoea and one Clostridioides difficile colitis). Pain was mainly related to the skin breach and oedema formation., Conclusions: We did not find any worrying signs concerning the use of SC ceftriaxone but this study shows that its wide use must consider pain management, which is often overlooked., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cases of adult-onset Still's disease (AOSD) have been reported after COVID-19 vaccination. Here we provide a comprehensive description and analysis of all cases of AOSD reported in the literature and in pharmacovigilance databases through April 2022. Disproportionality analyses of pharmacovigilance data were performed in order to further explore the association between vaccination and AOSD. We included 159 patients, 144 from the World Health Organization pharmacovigilance database and 15 from the literature. Detailed clinical characteristics were described for the cases from the literature and from the French pharmacovigilance database (n = 9). The cases of AOSD after COVID-19 vaccination concerned women in 52.2% of cases. The median age was 43.4 years. More than 80% of AOSD reports occurred during the first three weeks and concerned mostly the BNT162b2 mRNA vaccine. We identified 14.5% of disease flare with a median time-to-onset of AOSD flare-up significantly shorter than for the new onset form. More than 90% patients received steroids. Although all cases were considered serious and required hospitalization, most cases presented a favorable outcome (67.1%) with a good response to corticosteroid therapy with a mean time to recovery of 7.2 days. Disproportionality analyses suggested that AOSD was associated with COVID-19 vaccines as well as other vaccines. AOSD was nearly five times more frequently reported with COVID-19 vaccines than with all other drugs. Clinicians should be informed about the potential risk of AOSD onset or flare following COVID vaccines and the importance of its early detection to optimize its management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Published data on the safety of biologics other than tumor necrosis factor (TNF) inhibitors during pregnancy are limited., Objective: The aim was to detect pharmacovigilance signals for fetal and neonatal adverse drug reactions (ADRs) to biologics taken by pregnant women with autoimmune diseases., Methods: We performed a disproportionality analysis of the World Health Organization's VigiBase ® pharmacovigilance database from 1968 to June 1, 2021. Data were collected in June 2021. By using terms for different hierarchical levels of the Medical Dictionary for Regulatory Activities, we selected the following fetal or neonatal ADRs: stillbirth, premature birth, low birth weight, small for gestational age, and congenital malformations. The frequency of all identified ADRs for biologics of interest (adalimumab, infliximab, golimumab, certolizumab, etanercept, anakinra, canakinumab, tocilizumab, sarilumab, ustekinumab, guselkumab, secukinumab, ixekizumab, belimumab, abatacept, and rituximab) was compared with that of all other reports for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval]. Reports with known concomitant use of teratogenic drugs were excluded from the main analysis. Other analyses included ROR stratifications by therapeutic indication in the periods 1968-2021 and 2001-2021, and an analysis after excluding reports with steroids., Results: In the main analysis, the RORs were particularly high for musculoskeletal malformations with anakinra (7.18 [3.50-14.73]), canakinumab (19.54 [12.82-29.79]), and abatacept (5.09 [2.77-9.33]), and for immune system disorders with canakinumab (347.88 [217.9-555.50]) and rituximab (9.27 [2.95-29.15]). After the exclusion of reports with steroids, the ROR was significant for neonatal infections with belimumab (28.49 [5.75-141.25])., Conclusion: We identified possible associations with some adverse fetal and neonatal outcomes, suggesting that vigilance is required when prescribing certain biologics during pregnancy., (© 2022. The Author(s).)

Background: The risk of fragility fractures is high in kidney transplant recipients, and steroids are reportedly a major cause. Other drugs known to induce fragility fractures have been studied in the general population but not in kidney transplant recipients. Here, we investigated the association between exposure over time to drugs that can injure bone (namely vitamin K antagonists, insulin, loop diuretics, proton pump inhibitors, opioids, selective serotonin reuptake inhibitors, antiepileptics and benzodiazepines) and incident fractures and changes over time in T-scores in this population., Methods: A total of 613 consecutive kidney transplant recipients were included between 2006 and 2019. Drug exposures and incident fractures during the study period were comprehensively documented, and dual-energy X-ray absorptiometry was performed regularly. The data were analyzed using Cox proportional hazards models with time-dependent covariates and linear mixed models., Results: Incident fractures occurred in 63 patients, giving a fracture incidence of 16.9 per 1000 person-years. Exposures to loop diuretics [hazard ratio (95% confidence interval) 2.11 (1.17-3.79)] and opioids [5.94 (2.14-16.52)] were associated with incident fractures. Exposure to loop diuretics was associated with a decrease over time in the T-score for the lumbar spine ( P  = .022) and for the wrist ( P  = .028)., Conclusions: This study suggests that the exposure to loop diuretics and opioids increases the risk of fracture in kidney transplant recipients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Drugs constitute one of the leading causes of acute kidney injuries (AKIs) and can appear in community (CA-AKI) or hospital (HA-AKI) population. The objectives of the present study of a cohort of hospitalized patients with AKI were to describe the characteristics of drug-induced AKIs and the patients' short-term outcomes and assess risk factors for drug-induced AKIs overall, CA-AKIs, and HA-AKIs. Based on a cohort of 1557 hospitalized patients suffering from AKIs based on PMSI extraction and chart review (IRA-PMSI), drug-induced AKIs were identified by applying the Naranjo adverse drug reaction (ADR) probability scale. Multivariate logistic regression was used to identify factors associated with CA-AKIs and/or HA-AKIs. When considering the 1557 patients who experienced an AKI, 445 (28.6%) of the injuries were drug-induced (180 CA-AKIs (40.4%) and 265 HA-AKIs (59.6%)). Antibiotics, diuretics, and contrast agents were significantly more likely to be involved in HA-AKIs, whereas antineoplastic, lipid-lowering drugs, antidiabetics, and immunosuppressive were significantly more likely to be involved in CA-AKIs. Female sex (odds ratio [OR] [95%CI] = 1.3 [1.04-1.67]), chronic kidney disease (CKD) (OR = 1.8 [1.40-2.67]), and a history of ADRs of any type (OR = 1.3 [1.05-1.73]) were significant risk factors for drug-induced AKIs. CKD was a risk factor for both CA-AKI and HA-AKI. In view of the long-term impact of AKI on the kidneys and the differences between our CA-AKI and HA-AKI subgroups, our present results are interesting for optimizing treatments, limiting the occurrence of CA- and HA-AKIs and (ultimately) reducing healthcare costs., (© 2022 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Introduction: Gabapentinoids are ligands of the α2-δ subunit of voltage-gated calcium channels (Cav) that have been associated with a risk of peripheral edema and acute heart failure in connection with a potentially dual mechanism, vascular and cardiac., Objectives & Methods: All cases of peripheral edema or heart failure involving gabapentin or pregabalin reported to the French Pharmacovigilance Centers between January 1, 1994 and April 30, 2020 were included to describe their onset patterns (e.g., time to onset). Based on these data, we investigated the impact of gabapentinoids on the myogenic tone of rat third-order mesenteric arteries and on the electrophysiological properties of rat ventricular cardiomyocytes., Results: A total of 58 reports were included (gabapentin n = 5, pregabalin n = 53). The female-to-male ratio was 4:1 and the median age was 77 years (IQR 57-85, range 32-95). The median time to onset were 23 days (IQR 10-54) and 17 days (IQR 3-30) for non-cardiogenic edema and acute heart failure, respectively. Cardiogenic and non-cardiogenic peripheral edema occurred frequently after a dose escalation (27/45, 60%), and the course was rapidly favorable after discontinuation of gabapentinoid (median 7 days, IQR 5-13). On rat mesenteric arteries, gabapentinoids significantly decreased the myogenic tone to the same extent as verapamil and nifedipine. Acute application of gabapentinoids had no significant effect on Ca v 1.2 currents of ventricular cardiomyocytes., Conclusion: Gabapentinoids can cause concentration-dependent peripheral edema of early onset. The primary mechanism of non-cardiogenic peripheral edema is vasodilatory edema secondary to altered myogenic tone, independent of Ca v 1.2 blockade under the experimental conditions tested., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Acute kidney injury (AKI) has serious short- and long-term consequences. The objective of the present study of a cohort of hospitalized patients with AKI was to (i) evaluate the proportion of patients with hospital-acquired (HA) AKI and community-acquired (CA) AKI, the characteristics of these patients and the AKIs, and the short-term outcomes, and (ii) determine the performance of several ICD-10 codes for identifying AKI (both CA and HA) and drug-induced AKI., Methods: A cohort of hospitalized patients with AKI was constituted by screening hospital's electronic medical records (EMRs) for cases of AKI. We distinguished between and compared CA-AKI and HA-AKI and evaluated the proportion of AKIs that were drug-induced. The EMR data were merged with hospital billing codes (according to the International Classification of Diseases, 10th Edition (ICD-10)) for each hospital stay. The ability of ICD-10 codes to identify AKIs (depending on the type of injury) was determined by calculating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Lastly, we sought to validate specific ICD-10 codes for drug-induced AKI., Results: Of the 2473 patients included, 1557 experienced an AKI (HA-AKI: 59.3%; CA-AKI: 40.7%). Patients with CA-AKI had a better short-term outcome and a lower death rate (7.6%, vs. 20% for HA-AKI). One AKI in three was drug-induced. The combination of AKI codes had a very high specificity (94.8%), a high PPV (94.9%), a moderate NPV (56.7%) and moderate sensitivity (57.4%). The sensitivity was higher for CA-AKI (72.2%, vs. 47.2% for HA-AKI), for more severe AKI (82.8% for grade 3 AKI vs. 43.7% for grade 1 AKI), and for patients with CKD. Use of a specific ICD-10 code for drug-induced AKI (N14x) alone gave a very low sensitivity (1.8%), whereas combining codes for adverse drug reactions with AKI-specific codes increased the sensitivity., Conclusion: Our results show that the combination of an EMR-based analysis with ICD-10-based hospital billing codes gives a comprehensive "real-life" picture of AKI in hospital settings. We expect that this approach will enable researchers to study AKI in more depth., (© 2021. Italian Society of Nephrology.)

Objectives: The aims of the study were to describe medication errors (MEs) involving older adults reported to the French Medication Error Guichet and to compare them with MEs in younger adults, in each of the hospital and community settings., Methods: Retrospective secondary data analysis of MEs reported throughout 2013 to 2017 was performed. Descriptive and multivariate analyses were performed to compare actual and potential ME reports between older adults (aged ≥60 y) and younger adults (aged ≥18, <60 y)., Results: We analyzed 4979 reports. In older adults, both in hospital (n = 1329) and community (n = 1264) settings, antithrombotic agents were frequently reported in MEs and were significantly more likely to be associated with reported MEs in older adults compared with younger adults. In hospital setting, antibacterials for systemic use (adjusted odds ratio [aOR] = 1.87, 95% confidence interval [CI] = 1.19-2.93) and antineoplastic agents (aOR = 2.22, 95% CI = 1.34-3.69), whereas in community setting, psycholeptics (aOR = 1.43, 95% CI = 1.04-1.98) and drugs used in diabetes (aOR = 6.01, 95% CI = 3.21-11.2) were more likely to be associated with reported MEs in older adults. In both settings, wrong dose and wrong drug were the most frequently reported error types in older adults; however, wrong technique error type (aOR = 2.06, 95% CI = 1.30-3.28) in hospital setting and wrong patient (aOR = 2.17, 95% CI = 1.30-3.60) in community setting were more likely to be associated with reported MEs in older adults., Conclusions: We identified specific ME patterns for older adults, including antithrombotic agents in both settings; antibacterials for systemic use, antineoplastic agents, and wrong technique in hospital setting; and psycholeptics, drugs used in diabetes, and wrong patient in community setting. These findings inform future studies investigating population-specific medication safety strategies., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To determine whether the use of disease-modifying antirheumatic drugs (DMARDs) is linked to the risk of COVID-19 among patients with inflammatory rheumatic diseases (IRDs)., Methods: We performed a disproportionality analysis of the World Health Organization pharmacovigilance database between January 1, 2020, and June 10, 2020. The frequency of COVID-19 reports for all DMARD classes identified was compared with that for all other reports for all other drugs and quoted as the reporting odds ratio (ROR) (95% confidence interval [CI])., Results: Among 980,446 individual case-safety reports voluntarily recorded in the database, 398 identified COVID-19 in DMARD-treated patients with IRDs. There were 177 (44.5%) patients with rheumatoid arthritis (RA), 120 (30.1%) with ankylosing spondylitis (AS), 93 (23.4%) with psoriatic arthritis (PsA), and 8 (2.0%) with juvenile idiopathic arthritis. Most of the cases of COVID-19 occurred in patients taking anti-TNF agents (84.2%), resulting in a significant disproportionality signal (ROR [95% CI]: 8.31 [7.48-9.23]) - particularly in patients with RA, AS or PsA. A significant inverse disproportionality was found for the anti-IL-6 agent tocilizumab (ROR [95% CI]: 0.12 [0.02-0.88]) and JAK inhibitors (ROR [95% CI]: 0.33 [0.19-0.58]) in patients with RA - suggesting that these two drug classes are safer in the context of RA., Conclusion: Our results are in line with the literature on a potentially better safety profile for anti-IL-6 agents and JAK inhibitors. The WHO pharmacovigilance data suggest that COVID-19 is significantly more frequent in patients with IRDs treated with TNF inhibitors., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Background: Bone remodeling is a complex process, and many conditions (including drug exposure) lead to osteoporosis. Here, we sought to detect new disproportionality signals for drugs associated with osteoporosis., Methods: We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database through April 12, 2020. The frequency of reports on osteoporosis for all identified drug classes was compared with that for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]., Results: Of the 7,594,968 cases spontaneously recorded to VigiBase®, 4758 concerned osteoporosis. New disproportionality signals with a pharmacologically plausible mechanism were found for drugs used in neurology (levodopa (ROR [95%CI]: 10.18 [4.33-25.10]), selective serotonin agonists (4.22 [2.34-7.00]) and memantine (4.10 [1.56-8.93])), hematology (romiplostim (4.93 [1.15-21.10])), pulmonology (macitentan (3.02 [1.84-4.90])), ophthalmology (ranibizumab (3.31 [1.00-10.51])) and rheumatology (tofacitinib (3.65 [3.00-4.40])). The robustness of these new results is supported by the significant RORs for the vast majority of drugs already known to induce osteoporosis and/or increase the fracture risk, namely glucocorticoids, gonadotropin-releasing hormone analogs, anti-aromatases, androgen receptor blockers, thyroid hormones, proton pump inhibitors, thiazolidinediones, vitamin K antagonists, loop diuretics, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, and enzyme-inducing antiepileptics including barbiturates and derivatives, hydantoin derivatives, carboxamide derivatives and fatty acid derivatives., Conclusion: We established up a comprehensive list of drugs potentially associated with osteoporosis and highlighted those with pharmacologically plausible mechanisms leading to bone fragility. Our results might pave the way for additional exploration of these mechanisms., (Copyright © 2021. Published by Elsevier Inc.)

Aims: To describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease. To assess the association between renin-angiotensin system inhibitors (RASIs) and disease progression and critical outcomes., Methods and Results: All consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study. The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission. Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint. Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2. Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32-54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61-84)]. A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU. Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age. After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02-2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class. This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents., Conclusions: We highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome. Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

In this special issue, we present the main highlights of the first weeks of pharmacovigilance monitoring of coronavirus disease 2019 (COVID-19) vaccines in this unprecedented situation in France: the deployment of a vaccination during an epidemic period with the aim of vaccinating the entire population and the intense pharmacovigilance and surveillance of these vaccines still under conditional marketing authorizations. In this unprecedented situation, the cross approach and interaction between the French pharmacovigilance network and French National Agency for the Safety of Medicines and Health Products (ANSM) has been optimized to provide a real-time safety related to COVID-19 vaccines. Every week, pair of regional pharmacovigilance centers gathered safety data from the French pharmacovigilance network, to acutely expertise all the adverse drug reactions (ADRs) reported with each COVID-19 vaccine within a direct circuit with ANSM. Results of this expertise are presented and discussed with ANSM in order to raise safety signals and take appropriate measures if necessary. These reports are then published online. At the 25th of March 2021, more than 9 815 000 doses were injected and 20,265 ADRs were reported, mostly non-serious (76%). Several potential or confirmed signals were raised at the european level for those vaccines and others ADRs are under special attentions. This underlines the adaptiveness of the French pharmacovigilance system to both the identification of new patient profiles experiencing ADRs and the evolution of the vaccine strategy. Such an efficiency is necessary to manage a careful and acute surveillance of these new COVID-19 vaccines for and to face the pandemic at the same time., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: There are conflicting data on the effects of dysbiosis-inducing drugs, and especially antibiotics (ATBs), on clinical outcomes in patients treated with immune checkpoint inhibitors (ICIs). There is a particular lack of data for patients with melanoma., Methods: We performed a single-center retrospective study of the associations between ATBs and other drugs known to modify the gut microbiota (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, statins, opioids, anti-vitamin K, levothyroxine, vitamin D3, antiarrhythmics, metformin and phloroglucinol), overall survival (OS) and tumor response in consecutive cancer patients (particularly those with melanoma) treated with an ICI (ipilimumab, nivolumab or pembrolizumab) over a 9-year period., Results: A total of 372 patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Overall, 112 patients (30.1%) had received ATBs. ATB use was associated with (1) shorter OS in the study population as a whole [adjusted hazard ratio [95% confidence interval (CI)]: 1.38 (1.00-1.90), p  = 0.048] and in patients with melanoma [adjusted hazard ratio (95% CI): 2.60 (1.06-6.39), p  = 0.037], and (2) a lower response rate in the study population as a whole [8.1%, versus 31.1% in patients not treated with ATBs; adjusted odds ratio (95% CI): 6.06 (2.80-14.53), p  < 0.001] and in patients with melanoma [adjusted odds ratio (95% CI): 4.41 (1.04-22.80), p  = 0.045]. Sensitivity analyses that minimized the indication bias did not reveal an association between OS and the presence of an infection requiring ATBs (quantified as the severity of infection, hospitalization for an infection, or ICI discontinuation). Other dysbiosis-inducing drugs were not associated with a difference in OS., Conclusion: Unlike other dysbiosis-inducing drugs, ATBs were associated with poorer clinical outcomes in ICI-treated patients overall and in the subset of patients with melanoma., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID-19 are concentration-dependent. In a retrospective study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID-19 (median age: 67; males: 41 [63.1%]), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median [interquartile range]: 16,600 [11,430-20,842] ng/ml for lopinavir and 501 [247-891] ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r-treated patients with COVID-19., (© 2020 The British Pharmacological Society.)