Introduction As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. Methods We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017–September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2–4.4) and gastrointestinal perforations (2.9; 1.2–7.3), tisa-cel with hepatotoxicity (2.5; 1.1–5.7) and pupil disorders (15.3; 6–39.1). Conclusions Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity.

We sought to evaluate the prescribing pattern of statins according to national and regional health policy interventions and to assess specifically the adherence to the therapy in outpatient setting in Southern Italy. A population-based study was performed on persons ≥15 years old, living in the catchment area of Caserta (Southern Italy), and registered in Arianna database between 2004 and 2010. Prevalence and incidence of new treatments with statins were calculated for each year and stratified by drug. Adherence to therapy was measured by Medication Possession Ratio. Sub-analyses by individual compound and type of cardiovascular prevention were performed. From 2004 to 2010, the one-year prevalence of statin use increased from 44.9/1,000 inhabitants to 79.8/1,000, respectively, consistently with the incidence of new use from 16.2/1,000 to 19.5/1,000, except a slight decrease after criteria reimbursement revision on 2005 (13.3/1,000). The incidence of new treatments decreased for atorvastatin, and increased for simvastatin over the study years. Overall, 43% of new users were still highly adherent to the treatment (MPR≥80%) after six months, while 26% after 4-years of follow-up. As compared with highly adherent patients, the probability to be non-adherent (MPR≤25%) at 4-years of follow-up was 26% higher for women than for men (full adj. odds ratio: 1.26; 95% CI: 1.10–1.45), and 64% higher in patients who started on primary rather than on secondary prevention (1.64; 1.29–2.07). Prevalence and incidence of statin use increased consistently with health policy interventions. Only one-fourth of patients who newly initiated a statin were adherent to the treatment after 4-year of follow-up. Since the benefits of statins in terms of cardiovascular outcome and costs are associated with their chronic use, the identification of patient-related predictors of non-adherence such as gender, primary prevention could be suitable for physicians to improve the patients' compliance.

Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings.

To describe the characteristics of pediatric adverse drug reactions (ADRs) reported in Italian spontaneous reporting database. Reports of suspected ADRs related to children and adolescents were extracted from 2001 - 2012. After exclusion of duplicates, vaccines and reports containing missing age data, the report characteristics were investigated in terms of implicated drug and adverse drug event across different age-categories. Among 123,129 selected reports, 8338 (6.8%) concerned pediatrics. Of these, 52.2% involved male patients compared to 47.5% female up to the age of 11. After the age of 11 this statistic reversed. 39.4% of pediatric reports were serious and of these, 75.2% required hospitalization mainly in very young children. Most of reports were issued by hospital physicians (61.9%), followed by pharmacists (10.1%), while reports from family pediatricians accounted for 8.1%. The most frequently implicated drug categories were anti-infectives for systemic use (44.9%), drugs for the nervous system (15.6%), and anti-inflammatory drugs (10.2%). The most frequently suspected compounds differed between children and adults and reports for the same drug were likely to be more serious in adults than in children. This ADR reporting system reflects real safety concerns for drugs used in children and emphasizes the need for stratifying analyses by age-subgroup to increase the sensitivity of signal detection procedure.

Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0–18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug [range 1–3] and 1 event [1–2] per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were ‘nervous system drugs’ (58%), ‘antineoplastics’ (32%) and ‘anti-infectives’ (25%). Most commonly reported system organ classes were ‘general’ (13%), ‘nervous system’ (12%) and ‘psychiatric’ (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.