Glucagon-like Peptide-1 Receptor Agonists and Suicidal Ideation: Analysis of Real-Word Data Collected in the European Pharmacovigilance Database.

BACKGROUND: A potential risk of suicide associated with liraglutide or semaglutide treatments has recently emerged. Therefore, we decided to investigate the reporting probability of suicidal events among glucagon-like peptide-1 receptor agonists (GLP-1 RAs). METHODS: A retrospective pharmacovigilance study of the European Pharmacovigilance database was conducted for the period from 1 January 2018 to 10 July 2023. Disproportionality analyses (reporting odds ratio, ROR) were performed to assess the reporting probability of suicidal events among GLP-1 RAs. RESULTS: A total of 230 reports of suicidal events were identified. The most reported GLP-1 RA was liraglutide (38.3%), followed by semaglutide (36.5%) and dulaglutide (16.1%). The most reported events were suicidal ideation (65.3%) and suicide attempt (19.5%). Disproportionality analysis found a higher reporting probability of suicidal events for semaglutide than dulaglutide (ROR, 2.05; 95%CI, 1.40-3.01) and exenatide (ROR, 1.81; 95%CI, 1.08-3.05). In the same way, liraglutide was associated with a higher reporting probability of suicidal events than dulaglutide (ROR, 3.98; 95%CI, 2.73-5.82) and exenatide (ROR, 3.52; 95%CI, 2.10-5.92). On the contrary, a lower reporting probability was found for semaglutide than liraglutide (ROR, 0.51; 95%CI, 0.38-0.69). CONCLUSIONS: Suicidal events were mostly reported with semaglutide and liraglutide, which were also associated with significantly higher reporting probabilities compared to other GLP1 RAs. Although this study provides the reporting frequencies of suicide-related events with GLP-1 RAs, establishing causality requires further investigation, which will probably be addressed by the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency in the future.

Disease-Modifying Therapies (DMTs) in Pregnant and Lactating Women with Multiple Sclerosis: Analysis of Real-World Data from EudraVigilance Database.

(1) Background: The purpose of study was to compare the safety profile of glatiramer with natalizumab, alemtuzumab and ocrelizumab in pregnant and lactating women affected by multiple sclerosis (MS). (2) Methods: Individual case safety reports (ICSRs) were retrieved from the European spontaneous reporting system database (EudraVigilance). The reporting odds ratios (RORs) were computed to compare the reporting probability of events between natalizumab, alemtuzumab and ocrelizumab vs. glatiramer. (3) Results: A total of 1236 ICSRs reporting at least one DMT as a suspected drug were selected. More adverse drug reactions (ADRs) unrelated to pregnancy and breastfeeding (n = 1171; 32.6%) were reported than ADRs specific to pregnancy and breastfeeding (n = 1093; 30.4%). The most frequently reported unrelated ADR was MS relapse. Alemtuzumab and natalizumab seem to have a lower reporting probability of MS relapse compared to glatiramer (ROR 0.17, 95% CI 0.07-0.45 and ROR 0.34, 95% CI 0.20-0.57). Among pregnancy- and breastfeeding-related ADRs, the first most reported event was spontaneous abortion (n = 321; 8.9%). Natalizumab and ocrelizumab were associated with a higher reporting probability of spontaneous abortion compared to glatiramer (ROR 2.22, 95% CI 1.58-3.12; ROR 2.18, 95% CI 1.34-3.54, respectively), while alemtuzumab had a lower reporting frequency (ROR 0.32, 95% CI 0.17-0.60). (4) Conclusions: This study did not suggest any strong or new insights for DMTs in this special subpopulation. However, further studies need to be performed.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and the reporting of falls and fractures: an european pharmacovigilance analysis.

Background: The risk of falls and bone fractures with sodium-glucose co-transporter-2 (SGLT2) inhibitors has been characterized by conflicting evidence. Therefore, we decided to investigate the reporting probability of falls and fractures by comparing SGLT2 inhibitors with DPP4 inhibitors. Methods A retrospective, pharmacovigilance study of the European database of Individual Case Safety Reports (ICSRs) was conducted. Disproportionality analyses (Reporting Odds Ratio, ROR) were conducted to compare the reporting probability of falls or fracture between treatments. Results A total of 507 ICSRs reporting at least one fall or fracture with SGLT2 inhibitors were identified. The most reported SGLT2 inhibitor was canagliflozin (N = 188; 36.9%), followed by empagliflozin (N = 176; 34.5%), and dapagliflozin (N = 143; 28.0%). A total of 653 events related to fall or bone fracture were reported. Fall was the most reported event (N = 333; 51.0%). Among fractures (N = 320; 49.0%), the most reported were foot fractures (N = 40; 6.1%) and hip fractures (N = 32; 4.9%). SGLT2 inhibitors were associated with a lower reporting probability of fall than DPP4 inhibitors (ROR, 0.66; 95%CI, 0.57-0.78). The lower reporting probability of fall was also observed when the single SGLT2 inhibitor was compared to DPP4 inhibitors: dapagliflozin (ROR, 0.67; 95%CI, 0.53-0.83), canagliflozin (ROR, 0.56; 95%CI, 0.45-0.70), and empagliflozin (ROR, 0.77; 95%CI, 0.63-0.94). For fractures, canagliflozin showed a slightly significant increased reporting when compared with DPP4 inhibitors (not confirmed in the sensitivity analysis), whereas all other comparison showed no statistically significant difference. Conclusion SGLT2 inhibitors were associated with a lower reporting probability of fall than DPP4 inhibitors, in accordance with the reassuring evidence about the safety profile of these drugs. Future researches will help to confirm their long-term safety profile.

Retrospective Analysis of a Real-Life Use of Tixagevimab-Cilgavimab plus SARS-CoV-2 Antivirals for Treatment of COVID-19.

Tixagevimab-cilgavimab is effective for the treatment of early COVID-19 in outpatients with risk factors for progression to severe illness, as well as for primary prevention and post-exposure prophylaxis. We aimed to retrospectively evaluate the hospital stay (expressed in days), prognosis, and negativity rate for COVID-19 in patients after treatment with tixagevimab-cilgavimab. We enrolled 42 patients who were nasal swab-positive for SARS-CoV-2 (antigenic and molecular)-both vaccinated and not vaccinated for COVID-19-hospitalized at the first division of the Cotugno Hospital in Naples who had received a single intramuscular dose of tixagevimab-cilgavimab (300 mg/300 mg). All patient candidates for tixagevimab-cilgavimab had immunocompromised immune systems either due to chronic degenerative disorders (Group A: 27 patients) or oncohematological diseases (Group B: 15 patients). Patients enrolled in group A came under our observation after 10 days of clinical symptoms and 5 days after testing positivite for COVID-19, unlike the other patients enrolled in the study. The mean stay in hospital for the patients in Group A was 21 ± 5 days vs. 25 ± 5 days in Group B. Twenty patients tested negative after a median hospitalization stay of 16 days (IQR: 18-15.25); of them, five (25%) patients belonged to group B. Therefore, patients with active hematological malignancy had a lower negativization rate when treated 10 days after the onset of clinical symptoms and five days after their first COVID-19 positive nasal swab.

Thromboembolic Events after COVID-19 Vaccination: An Italian Retrospective Real-World Safety Study.

INTRODUCTION: Real-world safety studies can provide important evidence on the thromboembolic risk associated with COVID-19 vaccines, considering that millions of people have been already vaccinated against COVID-19. In this study, we aimed to estimate the incidence of thromboembolic events after COVID-19 vaccination and to compare the Oxford-AstraZeneca vaccine with other COVID-19 vaccines. METHODS: We conducted a retrospective real-world safety study using data from two different data sources: the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza, RNF) and the Campania Region Health system (Sistema INFOrmativo saNità CampanIA, SINFONIA). From the start date of the COVID-19 vaccination campaign (27 December 2021) to 27 September 2022, information on COVID-19 vaccinations and thromboembolic events were extracted from the two databases. The reporting rate (RR) and its 95% confidence interval (95%CI) of thromboembolic events for 10,000 doses was calculated for each COVID-19 vaccine. Moreover, the odds of being vaccinated with the Oxford-AstraZeneca vaccine vs. the other COVID-19 vaccines in cases with thromboembolic events vs. controls without thromboembolic events were computed. RESULTS: A total of 12,692,852 vaccine doses were administered in the Campania Region, of which 6,509,475 (51.28%) were in females and mostly related to the Pfizer-BioNtech vaccine (65.05%), followed by Moderna (24.31%), Oxford-AstraZeneca (9.71%), Janssen (0.91%), and Novavax (0.02%) vaccines. A total of 641 ICSRs with COVID-19 vaccines and vascular events were retrieved from the RNF for the Campania Region, of which 453 (70.67%) were in females. Most ICSRs reported the Pfizer-BioNtech vaccine (65.05%), followed by Oxford-AstraZeneca (9.71%), Moderna (24.31%), and Janssen (0.91%). A total of 2451 events were reported in the ICSRs (3.8 events for ICSRs), of which 292 were thromboembolic events. The higher RRs of thromboembolic events were found with the Oxford-AstraZeneca vaccine (RR: 4.62, 95%CI: 3.50-5.99) and Janssen vaccine (RR: 3.45, 95%CI: 0.94-8.82). Thromboembolic events were associated with a higher likelihood of exposure to the Oxford-AstraZeneca vaccine compared to Pfizer-BioNtech (OR: 6.06; 95%CI: 4.22-8.68) and Moderna vaccines (OR: 6.46; 95%CI: 4.00-10.80). CONCLUSION: We observed a higher reporting of thromboembolic events with viral-vector-based vaccines (Oxford-AstraZeneca and Janssen) and an increased likelihood of being exposed to the Oxford-AstraZeneca vaccine compared to the mRNA vaccines (Pfizer-BioNtech and Moderna) among thromboembolic cases.

Which is the top player for the cardiovascular safety? ibrutinib vs. obinutuzumab in CLL.

Introduction: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is authorized for the treatment of chronic lymphocytic leukemia (CLL). This study aims to explore the cardiac safety profile of ibrutinib in comparison with obinutuzumab. Methods: A retrospective pharmacovigilance study was conducted on data retrieved from the European pharmacovigilance database (Eudravigilance) from 1 January 2014 to 30 September 2022. To compare the reporting frequency of cardiovascular events among ibrutinib, obinutuzumab, and the combination of both. Results: A total of 2 291 CV cases were retrieved, of which 1965 were related to ibrutinib, 312 to obinutuzumab, and 14 to the combination. Most cases referred to patients aged ≥65 years (N = 1,454; 63.47%) and male (N = 1,497; 65.34%). Most cases were serious (N = 2,131; 93.02%). The most reported events were: atrial fibrillation (N = 913; 31.31%) and haemorrhage (N = 201; 6.89%). A higher reporting frequency of CV events was found when ibrutinib was compared to obinutuzumab (ROR, 3.22; 95% CI, 2.89-3.60) or combination (ROR, 1.77; 95% CI, 1.11-2.83). A lower reporting was observed when obinutuzumab was compared to combination (ROR, 0.55; 95% CI, 0.34-0.88). Discussion: A higher reporting frequency of CV events in patients exposed to ibrutinib in comparison with obinutuzumab was found. Further studies are needed to better explore the safety of ibrutinib.

Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.

OBJECTIVE: To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. DESIGN: Nationwide cohort study. SETTING: Denmark through national registries. PARTICIPANTS: All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065). MAIN OUTCOME MEASURE: A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism. RESULTS: Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception. CONCLUSIONS: NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.

What Is the Role of Nutraceutical Products in Cancer Patients? A Systematic Review of Randomized Clinical Trials.

Chemotherapy represents the main pharmacological cancer treatment. Recently, positive effects emerged with the combination of anticancer therapy and nutraceutical products. The aim of this systematic review is to collect and synthesize the available scientific evidence regarding the potential effects of nutraceuticals on cancer cells. A systematic literature search of randomized clinical trials of nutraceutical products in patients with cancer published up to 15 December 2022 was conducted using three data sources: Embase, PubMed, and Web of Science. The effect of high-dose isoflavone supplements on prostate cancer resulted in stabilization or reduction of PSA concentrations in 50% of isoflavone group patients six months after treatment. High doses of vitamin D supplementation plus chemotherapy in patients with advanced or metastatic colorectal cancer showed a median PFS of 13.0 months (95% CI, 10.1-14.7 months) for 49 patients. The effect of vitamin D supplementation on markers of inflammatory level and antioxidant capacity in women with breast cancer showed a significant increase in serum vitamin D concentration (28 ± 2.6 to 39 ± 3.5; p = 0.004) after 8 weeks of treatment. In conclusion, nutraceutical supplements represent a potentially growing sector and can be utilized in medical treatment or nutrition to provide integrated medical care.

COVID-19 Vaccines and Atrial Fibrillation: Analysis of the Post-Marketing Pharmacovigilance European Database.

Atrial fibrillation (AF) has been described in COVID-19 patients. Recently, some case reports and US pharmacovigilance analyses described AF onset as a rare adverse event following COVID-19 vaccination. The possible correlation is unclear. We systematically analyzed the reports of AF related to COVID-19 vaccines collected in the European pharmacovigilance database, EudraVigilance (EV), from 2020 to November 2022. We carried out descriptive and disproportionality analyses. Moreover, we performed a sensitivity analysis, excluding the reports describing other possible alternative AF causes (pericarditis, myocarditis, COVID-19, or other drugs that may cause/exacerbate AF). Overall, we retrieved 6226 reports, which represented only 0.3% of all those related to COVID-19 vaccines collected in EV during our study period. AF reports mainly referred to adults (in particular, >65 years old), with an equal distribution in sex. Reports were mainly related to tozinameran (54.04%), elasomeran (28.3%), and ChAdOx1-S (14.32%). The reported AF required patient hospitalization in 35% of cases and resulted in a life-threatening condition in 10% of cases. The AF duration (when reported) was highly variable, but the majority of the events had a short duration (moda = 24 h). Although an increased frequency of AF reporting with mRNA vaccines emerges from our study, other investigations are required to investigate the possible correlation between COVID-19 vaccination and the rare AF occurrence.

The efficacy and the safety of eltrombopag in pediatric patients with severe aplastic anemia: a systematic review.

Background: Acquired aplastic anemia (AAA) in pediatric patients is a rare disorder characterized by hypocellular bone marrow and pancytopenia. Eltrombopag, an oral thrombopoietin receptor agonist, provides a hematologic improvement in adults with severe aplastic anemia (SAA) refractory to immunosuppressive therapy (IST). The association of ELT and IST was approved by the US Food and Drug Administration (FDA) for adults and children ≥2 years of age as a first-line treatment for SAA. However, the effects of ELT on pediatric patients with SAA remain controversial and limited. Methods and findings: We conducted a systematic review of the most recent literature from Pubmed, Web of Science, and Embase, published up to 20th December 2022, in order to evaluate the available evidence on the efficacy and safety of ELT added to IST for the treatment of SAA in the pediatric population. Conclusion: Eltrombopag added to the IST has shown a good safety profile, without manifestations of excessive toxic effects, although not all the results obtained from our studies support the addition of ELT to the IST in the first-line treatment of children with SAA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022325859.

Do immune checkpoint inhibitors share the same pharmacological feature in the risk of cardiac arrhythmias?

BACKGROUND: Despite the available evidence showing an association between cardiac arrhythmia and Immune Checkpoint Inhibitors (ICIs), few studies have compared this risk between ICIs. OBJECTIVES: We aim to evaluate Individual Case Safety Reports (ICSRs) of ICIs-induced cardiac arrhythmias and compare the reporting frequency of cardiac arrhythmias among ICIs. METHODS: ICSRs were retrieved from the European Pharmacovigilance database (Eudravigilance). ICSRs were classified based on the ICI reported (pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab, cemiplimab, and dostarlimab). If more than one ICI was reported, the ICSR was classified as a combination of ICIs. ICSRs of ICI-related arrhythmias were described and the reporting frequency of cardiac arrhythmias was assessed by applying the reporting odds ratio (ROR) and its 95 % confidence interval (95 %CI). RESULTS: A total of 1262 ICSRs were retrieved, of which 147 (11.65 %) were related to combinations of ICIs. A total of 1426 events of cardiac arrhythmias were identified. The three most reported events were atrial fibrillation, tachycardia, and cardiac arrest. Ipilimumab was associated with a reduced reporting frequency of cardiac arrhythmias compared to all other ICIs (ROR 0.71, 95 %CI 0.55-0.92; p = 0.009). Anti-PD1 was associated with a higher reporting frequency of cardiac arrhythmias than anti-CTLA4 (ROR 1.47, 95 %CI 1.14-1.90; p = 0.003). CONCLUSION: This study is the first comparing ICIs for the risk of cardiac arrhythmias. We found that ipilimumab was the only ICI associated with a reduced reporting frequency. Further high-quality studies are needed to confirm our results.

Decolonization of drug-resistant Enterobacteriaceae carriers: A scoping review of the literature.

The ESCMID-EUCIC guideline on decolonization of multidrug-resistant Gram-negative bacteria carriers does not recommend routine decolonization and highlights the necessity of well-powered and designed randomized clinical trials. Based on this limited evidence, we decided to conduct a scoping review with the aim of describing and discussing the last published studies investigating the efficacy and safety of decolonization therapies in drug-resistant Enterobacteriaceae carriers. Studies published in PubMed from January 1, 2017 to December 28, 2021 were retrieved. A PICO (population, intervention, comparator, outcome) framework was used for article selection as follows: Population defined as any patient of any age in any setting with screening sample yielding for drug-resistant Enterobacteriaceae; Intervention defined as any decolonization; Controls defined as patients receiving no intervention (spontaneous decolonization) or a different decolonization therapy; Outcomes defined as a microbiological, clinical, epidemiological and adverse event. A total of 679 records were initially identified, of which 647 were excluded because they were not related to decolonization therapies. Other 18 records were excluded because not related to our aims, target bacteria, or study design. A total of 12 clinical studies were included, of which 4 were randomized clinical trials and 8 were non-randomized studies. The majority of studies evaluated selective decontamination of the digestive tract or selective oropharyngeal decontamination regimens. Selected studies were characterized by high heterogeneity. Further high-quality studies with proper design and sample size calculation are warranted.

The Safety Profile of COVID-19 Vaccines in Patients Diagnosed with Multiple Sclerosis: A Retrospective Observational Study.

In the current COVID-19 pandemic, patients diagnosed with multiple sclerosis (MS) are considered to be one of the highest priority categories, being recognized as extremely vulnerable people. For this reason, mRNA-based COVID-19 vaccines are strongly recommended for these patients. Despite encouraging results on the efficacy and safety profile of mRNA-based COVID-19 vaccines, to date, in frail populations, including patients diagnosed with MS, this information is rather limited. We carried out a retrospective observational study with the aim to evaluate the safety profile of mRNA-based COVID-19 vaccines by retrieving real-life data of MS patients who were treated and vaccinated at the Multiple Sclerosis Center of the Hospital A.O.R.N. A. Cardarelli. Three-hundred and ten medical records of MS patients who received the first dose of the mRNA-based COVID-19 vaccine were retrieved (63% female; mean age: 45.9 years). Of these patients, 288 also received the second dose. All patients received the Pfizer-BioNTech vaccine. Relapsing-Remitting Multiple Sclerosis (RRSM) was the most common form of MS. The Expanded Disability Status Scale (EDSS) values were <3.0 in 70% of patients. The majority of patients received a Disease Modifying Therapy (DMT) during the study period, mainly interferon beta 1-a, dimethyl fumarate, and natalizumab and fingolimod. Overall, 913 AEFIs were identified, of which 539 were after the first dose of the vaccine and 374 after the second dose. The majority of these AEFIs were classified as short-term since they occurred within the first 72 h. The most common identified adverse events were pain at injection site, flu-like symptoms, and headache. Fever was reported more frequently after the second dose than after the first dose. SARS-CoV-2 infection occurred in 3 patients after the first dose. Using historical data of previous years (2017−2020), the relapses' rate during 2021 was found to be lower. Lastly, the results of the multivariable analysis that assessed factors associated with the occurrence of AEFIs revealed a statistical significance for age, sex, and therapy with ocrelizumab (p < 0.05). In conclusion, our results indicated that Pfizer-BioNTech vaccine was safe for MS patients, being associated with AEFIs already detected in the general population. Larger observational studies with longer follow-up and epidemiological studies are strongly needed.

Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary.

A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors might be effective alone or in combination with any other drugs. This therapeutic class currently includes five agents: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. SGLT2 inhibitors prevent the renal reabsorption of filtered glucose and sodium by blocking the SGLT2 co-transporters in the proximal convoluted renal tubule, facilitating glucose excretion in the urine (glycosuria) and lowering blood glucose levels. SGLT2 inhibitors have also shown to have pleiotropic effects and determine cardiovascular and renal prevention, thus leading to an extension of their therapeutic indication to include the heart failure. Despite their clinical benefits, warnings about adverse events have been implemented by Regulatory Agencies in the product's information since their introduction to the market. In particular, SGLT2 inhibitors have shown a strong impact on a high number of risk factors. They can cause hypoglycaemia, hypotension, lower limb amputation, fractures, genito-urinary infections, and diabetic ketoacidosis with different frequencies of onset. Despite some of these events are rare, they can lead to serious and dangerous complications, highlighting the importance of a strict monitoring of patients. Overall, SLGT-2 inhibitors are effective antidiabetic drugs with favorable advantages in renal and cardiovascular protection, and with a generally well-tolerated safety profile. This review aims to summarize the safety profile of SGLT2 inhibitors available in the market.

Maternal, fetal and neonatal outcomes among pregnant women receiving COVID-19 vaccination: The preg-co-vax study.

Introduction: Although the European Medicines Agency (EMA) encourage coronavirus disease 2019 (COVID-19) vaccination in pregnant women, the scientific evidence supporting the use of COVID-19 vaccines during pregnancy is still limited. Aim: We aimed to investigate adverse events following immunization (AEFI) with COVID-19 vaccines during pregnancy. Methods: We retrieved Individual Case Safety Reports (ICSRs) related to the use of COVID-19 vaccines during pregnancy from the EudraVigilance database for the year 2021. We analyzed AEFI related to the mother and fetus/newborn. The reporting odds ratio (ROR) was computed to compare the reporting probability of spontaneous abortion between COVID-19 vaccines. Results: During the study period, among 1,315,315 ICSRs related to COVID-19 vaccines, we retrieved 3,252 (0.25%) reports related to the use in pregnancy. More than half (58.24%) of ICSRs were submitted by non-healthcare professionals. Although the majority (87.82%) of ICSRs concerned serious AEFI, their outcomes were mostly favorable. In this study, 85.0% of total ICSRs referred to pregnant women (n = 2,764), while 7.9% referred to fetuses/newborns (n = 258). We identified 16,569 AEFI. Moreover, 55.16% were AEFI not related to pregnancy (mostly headache, pyrexia, and fatigue), while 17.92% were pregnancy-, newborn-, or fetus-related AEFI. Among pregnancy-related AEFI, the most reported was spontaneous abortion. Messenger RNA (mRNA) vaccines had a lower reporting probability of spontaneous abortion than viral vector-based vaccines (ROR 0.80, 95% CI 0.69-0.93). Moderna and Oxford-AstraZeneca vaccines had a higher reporting probability of spontaneous abortion (ROR 1.2, 95% CI 1.05-1.38 and ROR 1.26, 95% CI 1.08-1.47, respectively), while a lower reporting probability was found for Pfizer-BioNTech vaccine compared with all other COVID-19 vaccines (ROR 0.73, 95% CI 0.64-0.84). In addition, 5.8% of ICSRs reported a fatal outcome. Conclusions: No strong insight of unknown AEFI associated with COVID-19 vaccination in pregnant women was observed. Considering the high risk associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, our analysis suggests that the benefits of COVID-19 vaccines during pregnancy outweigh the possible risks. However, it is important to continue monitoring the safety profile of COVID-19 vaccines in this subpopulation.

Capillary leak syndrome following COVID-19 vaccination: Data from the European pharmacovigilance database Eudravigilance.

Capillary leak syndrome (CLS) emerged as new adverse event after immunization (AEFI) associated to COVID-19 vaccination. CLS is a rare condition characterized by increased capillary permeability, resulting in hypoalbuminemia, hypotension, and edema mainly in the upper and lower limbs. Our pharmacovigilance study aims to evaluate the CLS onset following receipt of COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) compared to viral vector vaccines (Ad26.COV2-S and ChAdOx1-SARS-COV-2). We carried a cross-sectional study using all Individual Case Safety Reports (ICSRs) reporting a COVID-19 vaccine as suspected drug and CLS as AEFI, which were collected in the pharmacovigilance database EudraVigilance from January 1st, 2021, to January 14th, 2022. We applied the Reporting Odds Ratio (ROR) 95% CI for the disproportionality analysis. During our study period, CLS was described as AEFI in 84 out of 1,357,962 ICRs reporting a vaccine COVID-19 as suspected drug and collected in the EV database. Overall, the ICSR reported by CLS were mainly related to the viral vector COVID-19(ChAdOx1-SARS-COV-2 = 36; Ad26.COV2-S = 9). The mRNA COVID-19 vaccines were reported in 39 ICSRs (BNT162b2 =33; mRNA-1273 =6). Majority of ICSRs were reported by healthcare professionals (71.4%). Majority of the patients were adult (58.3%) and the female gender accounted in more than 65% of ICSRs referred both to classes vaccines. In particular, women were more represented in ICSRs referred to mRNA-1273 (83.3%) and to ChAdOx1-SARS-COV-2 (72.2%). The CLS outcome was more frequently favorable in mRNA ICSRs (33,3%) than the viral vector ones (13.3%). Among the ICSRs reporting CLS with unfavorable outcome, we found also 9 fatal cases (BNT162b2 = 1; ChAdOx1-SARS-COV-2 = 4; Ad26.COV2-S = 4). From disproportionality analysis emerged a lower CLS reporting probability after vaccination with mRNA vaccines compared to viral vector-based ones (ROR 0.5, 95% CI 0.3-0.7; p <0.001).Our findings, even if subject to the limitations of spontaneous reporting systems, suggest a small but statistically significant safety concern for CLS following receipt of COVID-19 viral vector vaccines, in particular with Ad26.COV2-S. Cytokine-release following T-cell activation could be involved in CLS occurrence, but a precise mechanism has been not yet identified. COVID-19 vaccines remain attentive as possible triggers of CLS.

The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis.

Background: Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that has proven efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Despite its efficacy, it has also been associated with the development of potentially serious adverse events such as the cytokine release syndrome (CRS) and neurologic events. The present meta-analysis aimed to assess the safety profile of blinatumomab in terms of serious adverse events, CRS, and neurologic events (such as seizure and encephalopathy) in pediatric patients with B-cell ALL. Methods and findings: A systematic review was conducted in Pubmed up to December 10, 2021 to retain pediatric clinical trials on blinatumomab. A random effect meta-analysis approach was used. This study followed the PRISMA statement. Four out of the 255 initial references were selected, of which 2 were phase 1/2 clinical trials and 2 phase 3 clinical trials. Blinatumomab was associated with a lower risk of serious adverse events (Risk ratio RR, 0.56; 95% CI, 0.32-0.99), febrile neutropenia (RR, 0.13; 95% CI, 0.06-0.26), infection (RR, 0.40; 95% CI, 0.29-0.56), and grade ≥ 3 adverse events (RR, 0.79; 95% CI, 0.67-0.93) compared to chemotherapy. No difference in the risk of CRS (RR, 8.37; 95% CI, 0.27-260.97) and seizure (RR, 6.43; 95% CI, 0.79-53.08) was observed between groups, while for encephalopathy a higher risk was associated with blinatumomab compared to chemotherapy (RR, 8.90; 95% CI, 1.08-73.29). Conclusion: Our data support the good safety profile of bliantumomab in treating pediatric patients with B-ALL.

European Safety Analysis of mRNA and Viral Vector COVID-19 Vaccines on Glucose Metabolism Events.

Few data have been published on the effects of impaired glucose metabolism induced by COVID-19 vaccines. We decided to perform a study to describe Individual Case Safety Reports (ICSRs) of impaired glucose metabolism events reported in the European database (Eudravigilance, EV). ICSRs were retrieved from the online website of Eudravigilance. The reporting odds ratios (ROR) were computed to assess the reporting frequency for COVID-19 mRNA vaccines compared to COVID-19 viral vector-based vaccines. A total of 3917 ICSRs with a COVID-19 vaccine suspected were retrieved, with a total of 4275 impaired glucose metabolism events. Overall, the most reported events were related to "high glucose levels" (2012; 47.06%). The mRNA vaccines were associated with an increased reporting frequency of "type 1 diabetes mellitus" (ROR 1.86; 95% CI 1.33-2.60), "type 2 diabetes mellitus" (ROR 1.58; 95% CI 1.03-2.42), "high glucose levels" (ROR 1.16; 95% CI 1.06-1.27), "diabetes mellitus inadequate control" (ROR 1.63; 95% CI 1.25-2.11), and "hypoglycemia" (ROR 1.62; 95% CI 1.41-1.86) compared to viral vector-based vaccines. mRNA COVID-19 vaccines were associated with an increased reporting frequency of alterations of glucose homeostasis compared to viral-vector COVID-19 vaccines. Clinicians should be aware of these events to better manage glycemic perturbations. Larger nationwide studies are warranted to verify these findings.

Hypernatremia During Intravenous Treatment With Fosfomycin: A Retrospective Medical Record Review Study and an Analysis of Spontaneous Reports in the EudraVigilance Database.

Background: Hypernatremia is a serious event that can occur during intravenous (IV) treatment with fosfomycin, and it can also be caused by a wrong drug preparation. Considering the clinical significance of hypernatremia, we decided to carry out two studies by using two different data sources with the aim to evaluate cases of IV fosfomycin-induced hypernatremia. Methods: A retrospective medical record review was performed from June 2017 to June 2019 using data from two hospitals in Southern Italy. The information collected was related to the patients, the antibiotic treatment regimen, type of adverse drug reaction (ADR), hypernatremia severity classification, and drug withdrawal due to ADRs. Moreover, a pharmacovigilance study was performed from the date of the European marketing authorization of fosfomycin to October 11, 2021, using data reported on the European website of suspected ADRs. Information related to the patient characteristics, treatment, hypernatremia, and type of reporter was retrieved. Results: From the retrospective medical record review, a total of 62 patients (48 men and 14 women) in treatment with fosfomycin were identified, of which 17 experienced ADRs. Specifically, 11 patients experienced hypernatremia. During the period from June 2017 to June 2018, a total of 63.7% of hypernatremia events were related to the wrong reconstitution of the drug. According to these results, a surveillance and training campaign about the correct drug reconstitution was managed. However, from June 2018 to June 2019, we still had four new hypernatremia cases. Drug withdrawal occurred in only one patient with hypernatremia. From the pharmacovigilance study, a total of 25 cases of IV fosfomycin-induced hypernatremia were retrieved. No substantial difference was found for patients' distribution by sex. Most cases were classified as serious (68%) and reported "Recovered/resolved" as the outcome (44%). In the majority of cases, fosfomycin was the only suspected drug reported (72%). Conclusion: Our results show that training campaigns on the correct drug preparation need to be strengthened to allow a reduction of hypernatremia cases. Moreover, when close monitoring and management is performed by the infectious disease (ID) specialist and hospital pharmacist, there also is a reduction in antibiotic withdrawal due to hypernatremia.

The Reporting Frequency of Ketoacidosis Events with Dapagliflozin from the European Spontaneous Reporting System: The DAPA-KETO Study.

Dapagliflozin was associated with an increased risk of diabetic ketoacidosis that has led to the European withdrawal of the authorization for the type 1 diabetes. However, it is still used for the treatment of type 2 diabetes. Therefore, we aim to evaluate the occurrence of dapagliflozin-induced ketoacidosis events by using the European spontaneous reporting system. The reporting odds ratios (ROR) were computed to assess the reporting frequency of ketoacidosis events for dapagliflozin compared to Dipeptidyl peptidase-4 (DPP-4) inhibitors, insulins, or all other Sodium-glucose cotransporter-2 (SGLT-2) inhibitors. A total of 2406 cases with dapagliflozin reported at least one event of ketoacidosis. The three most reported events were: diabetic ketoacidosis (1412; 55.39%), ketoacidosis (476; 18.67%), and euglycaemic diabetic ketoacidosis (296; 11.61%). Dapagliflozin was associated with the higher reporting frequency of ketoacidosis events compared to DPP-4 inhibitors (ROR 12.07, 95%CI 11.67-13.81) or insulins (ROR 7.59, 95%CI 7.13-7.89). A lower reporting frequency was instead observed compared to other SGLT2 inhibitors (ROR 0.91, 95%CI 0.87-0.96). Considering the higher reporting frequency of ketoacidosis observed with dapagliflozin then DPP-4 inhibitors or insulins, attention should be given to patients treated with this drug.