Two Years of Active Pharmacovigilance Surveillance and Therapeutic Reconciliation in Frail Populations: The MEAP 3.0 Study.

Awareness related to the risk/benefit profile of therapies used in paediatric and elderly patients is limited. We carried out a study, called the MEAP 3.0 study, to collect and analyse evidence of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) that occurred in frail populations under polypharmacy in a real-world setting. Data were retrieved from reports of ADRs and pharmacological counselling from patients treated in hospitals and territorial health services. We collected 2977 ADRs reports and identified 'anti-infectives for systemic use' and 'cardiovascular system' as the most frequently implicated pharmacological classes in under-18 and over-65 patients, respectively. We detected 2179 DDIs, of which 10.7% were related to at least one ADR: 22 were classified as 'contraindicated' (7 in the paediatric group and 15 in the elderly one), and 61 as 'major' (6 in the paediatric patients and 55 in the geriatric ones), while 151 DDIs were classified as 'moderate' (10 referred to paediatric population, and 109 to elderly patient) and as 'minor' (1 in paediatric patients, and 31 in the elderly ones). The MEAP 3.0 project demonstrates that pharmacovigilance surveillance and therapeutic reconciliation are valid strategies to avoid potential DDIs and the occurrence of ADRs, allowing for personalised medicine.

The potential effect of metformin on cognitive and other symptom dimensions in patients with schizophrenia and antipsychotic-induced weight gain: a systematic review, meta-analysis, and meta-regression.

Introduction: Metformin has shown good efficacy in the management of antipsychotic-induced metabolic syndrome (MetS) in patients with schizophrenia or schizoaffective disorders. Its ability to induce antidepressant behavioural effects and improve cognitive functions has also been investigated: yet information has not been systematized. The aim of this study was therefore to investigate the effects of metformin on cognitive and other symptom dimension in schizophrenic patients treated with antipsychotics through a systematic review and meta-analysis. Methods: We searched PubMed, ClinicalTrials.Gov, Embase, PsycINFO, and WHO ICTRP database up to February 2022, Randomised Controlled Trials (RCT) evaluating patients diagnosed with schizophrenia and related disorders, who were treated with metformin as add-on therapy to antipsychotics for the treatment of weight gain and in which changes in psychiatric symptoms and cognitive functions were evaluated. Results: A total of 19 RCTs met the inclusion criteria. Meta-analysis was performed on 12 eligible studies. We found a positive trend after 24 weeks of treatment in schizophrenic patients with stable conditions [SMD (95%CI) = -0.40 (-0.82;0.01), OR (95%CI) = 0.5 (-2.4;3.4)]. Better performance was detected in the Brief Assessment of Cognition in Schizophrenia and Positive and Negative Syndrome Scale (PANSS) with low heterogeneity among studies. One study reported changes in BACS-verbal memory subdomain in favour of placebo [MD (95%CI) = -16.03 (-23.65;8.42)]. Gastrointestinal disorders, xerostomia, and extrapyramidal syndrome were the most reported adverse effects. Psychiatric adverse events were also described: in particular, symptoms attributable to a relapse of schizophrenia. Conclusion: Some degree of efficacy was found for Metformin in improving cognitive and other symptom dimensions in patients with Schizophrenia. Given the clinical relevance of this potential pharmacological effect, longer specific studies using adequate psychometric scales are strongly recommended. Likewise, how metformin acts in this context needs to be evaluated in order to enhance its efficacy or find more efficacious drugs.

On the potential of drug repurposing in dysphagia treatment: New insights from a real-world pharmacovigilance study and a systematic review.

Background: Polypharmacy is common in patients with dysphagia. Routinely used drugs may influence swallowing function either improving or worsening it. We aimed to explore the potential effects of three commonly used drug classes on dysphagia and aspiration pneumonia through a systematic review and a real-world data analysis to probe the possibility of drug repurposing for dysphagia treatment. Material and Methods: Five electronic databases were searched. Studies on adults at risk for dysphagia, treated with Dipeptidyl-Peptidase IV Inhibitors (DPP-4i), Adrenergic Beta-Antagonists (beta-blockers), or Angiotensin-Converting Enzyme Inhibitors (ACEi), and reporting outcomes on dysphagia or aspiration pneumonia were included. A nested case/non-case study was performed on adverse events recorded in the FDA Adverse Event Reporting System (FAERS) on patients >64 years. Cases (dysphagia or aspiration pneumonia) were compared between patients only treated with Levodopa and patients who were concomitantly treated with the drugs of interest. Results: Twenty studies were included in the review (17 on ACEi, 2 on beta-blockers, and 1 on DPP-4i). Contrasting findings on the effects of ACEi were found, with a protective effect mainly reported in Asian studies on neurological patients. Beta-blockers were associated with a reduced dysphagia rate. The study on DPP-4i suggested no effect on dysphagia and an increased risk of aspiration pneumonia. The FAERS analysis showed a reduction of the risk for dysphagia/aspiration pneumonia with ACEi, beta-blockers, and DPP-4i. Conclusion: Our study explores the potential drug repurposing of ACEi, beta-blockers and DPP-4i in neurological patients with dysphagia to improve swallowing function and reduce aspiration pneumonia risk. Future randomized controlled studies should confirm these results and clarify the underlying mechanisms of action.

The potential antidepressant effect of antidiabetic agents: New insights from a pharmacovigilance study based on data from the reporting system databases FAERS and VigiBase.

Background: Growing evidence supports a bidirectional association between diabetes and depression; promising but limited and conflicting data from human studies support the intriguing possibility that antidiabetic agents may be used to relieve effectively depressive symptoms in diabetic patients. We investigated the potential antidepressant effects of antidiabetic drugs in a high-scale population data from the two most important pharmacovigilance databases, i.e., the FDA Adverse Event Reporting System (FAERS) and the VigiBase. Material and methods: From the two primary cohorts of patients treated with antidepressants retrieved from FDA Adverse Event Reporting System and VigiBase we identified cases (depressed patients experiencing therapy failure) and non-cases (depressed patients experiencing any other adverse event). We then calculated the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Empirical Bayes Regression-Adjusted Mean (ERAM) for cases versus non-cases in relation with the concurrent exposure to at least one of the following antidiabetic agent: A10BA Biguanides; A10BB Sulfonylureas; A10BG Thiazolidinediones; A10BH DPP4-inhibitors; A10BJ GLP-1 analogues; A10BK SGLT2 inhibitors (i.e., those agents for which preliminary evidence from literature supports our pharmacological hypothesis). Results: For GLP-1 analogues, all the disproportionality scores showed values <1, i.e., statistically significant, in both analyses [from the FAERS: ROR confidence interval of 0.546 (0.450-0.662); PRR (p-value) of 0.596 (0.000); EBGM (CI) of 0.488 (0.407-0.582); ERAM (CI) of 0.480 (0.398-0.569) and VigiBase: ROR (CI) of 0.717 (0.559-0.921); PRR (p-value) of 0.745 (0.033); EBGM (CI) of 0.586 (0.464-0.733); ERAM of (CI): 0.515 (0.403-0.639)]. Alongside GLP-1 analogues, DPP-4 Inhibitors and Sulfonylureas showed the greatest potential protective effect. With regard to specific antidiabetic agents, liraglutide and gliclazide were associated with a statistically significant decrease in all disproportionality scores, in both analyses. Conclusion: The findings of this study provide encouraging results, albeit preliminary, supporting the need for further clinical research for investigating repurposing of antidiabetic drugs for neuropsychiatric disorders.

Exploring the underlying mechanisms of drug-induced impulse control disorders: a pharmacovigilance-pharmacodynamic study.

INTRODUCTION: Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed. AIM: We aimed to identify targets potentially contributing to pathologic impulsivity. METHOD: We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results. RESULTS: Among 19 887 reports of impulsivity, 5898 recorded an antipsychotic, and 3100 a dopamine agonist. The more robust signals concerned aripiprazole (N = 3091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta = 1.52; P-value = 0.047) and 5-HT1a within antipsychotics (1.92, 0.029). CONCLUSION: Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity.

Antibiotic-Induced Neutropenia in Pediatric Patients: New Insights From Pharmacoepidemiological Analyses and a Systematic Review.

Aim: to characterize pediatric cases of antibiotic-associated neutropenia through a multidisciplinary approach, focusing on the temporal association between the wide spectrum of treatment options and the occurrence of this relatively uncommon but potentially clinically relevant adverse event. Methods: we carried out a pharmacoepidemiological analysis based on the FDA Adverse Event Reporting System (FAERS) database, a retrospective chart review and a systematic review of the literature, focusing on the time to onset (TTO) of this side effect, in the pediatric clinical setting. Results: A total of 281 antibiotic-related neutropenia events, involving 11 categories of antibiotics, were included in the time to onset analysis. The median TTO ranged from 4 to 60 days after the start of the therapy. A shorter median TTO was found from the retrospective chart review [16 patients: median days (25th-75th percentiles) = 4 (3-5)], compared to 15 (9-18) vs. 10 (6-18) for literature (224 patients) and FAERS (41 cases), respectively. The Anatomical Therapeutic Chemical classes, J01X, J01F, J01E and J04A, and the median TTOs retrieved from more than one source revealed high accordance (p > 0.05), with J01X causing neutropenia in less than a week and J01F/J01E/J04A in more than 10 days. Antibiotics were discontinued in nearly 34% of cases. In FDA Adverse Event Reporting System reports, half of the patients experiencing neutropenia were hospitalized. Conclusion: Whereas antibiotic associated neutropenia is benign in the majority of cases, yet it should not be neglected as, even if rarely, it may put children at higher risk of clinical consequences. Clinicians' awareness of antibiotic-associated neutropenia and its mode of presentation contributes to the continuous process of monitoring safety of antibiotics.

Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis.

BACKGROUND: A few cases of Herpes Zoster and Simplex reactivation following COVID-19 immunization have been recently described, but the real extent of this suspected adverse event has not been elucidated yet. METHODS: We performed a nested case/control study by using the U.S. Vaccine Adverse Event Reporting System database. We carried out a case-level clinical review of all Herpes reactivation cases following the administration of COVID-19 vaccines. For cases and controls, significance was set at P = 0.05, differential risk of reporting was assessed for each vaccine as reporting odds ratio and incidence was estimated based on the total number of vaccine doses administered. RESULTS: Of 6,195 cases included in the analysis (5,934 and 273 reporting Herpes Zoster and Herpes Simplex, respectively) over 90% were non-serious. We found a slightly higher risk of reporting both for Zoster (ROR = 1.49) and Simplex (ROR = 1.51) infections following the Pfizer-BioNTech vaccine. The estimated incidence was approximately 0.7/100,000 and 0.03/100,000 for Zoster and Simplex, respectively. CONCLUSIONS: The paucity of cases (almost all of non-serious nature) makes the potential occurrence of this adverse effect negligible from clinical standpoints, thus supporting the good safety profile of the COVID-19 vaccination, which remains strongly recommended.

Managing folate deficiency implies filling the gap between laboratory and clinical assessment.

The characterization of folate status in subjects at risk of deficiency and with altered vitamin homeostasis is crucial to endorse preventive intervention health policies, especially in developed countries. Several physiological changes (i.e. pregnancy), clinical situations and diseases have been associated to increased requirement, impaired intake and absorption of folate. However clinical practice guidelines (CPG) endorse folic acid supplementation generally discarding the use of its determination in serum to assess the risk of deficiency and/or its concentration at baseline. Poor confidence on the diagnostic accuracy of serum folate assays still persists in the current CPGs although recent standardization efforts have greatly improved inter-method variability and precision. In this review we critically appraise the methodological issues concerning laboratory folate determination and the evidence on the potential adverse effects of folic acid exposure. The final aim is to build a sound background to promote serum folate-based cost-effective health care policies by optimizing folic acid supplementation in subjects at risk of deficiency and with altered folate homeostasis. Our first result was to adjust in relation to current serum folate assays the thresholds reported by CPGs as index of folate status, defined on the association with metabolic and hematologic indicators. We identify a statistically significant difference between the estimated thresholds and accordingly show that the assessment of folate status actually changes in relation to the assay employed. The use of the method-dependent thresholds here reported may pragmatically endorse the stewardship of folic acid supplementation in clinical practice and increase the cost-effectiveness of health care policies.

Weight and body mass index increase in children and adolescents exposed to antipsychotic drugs in non-interventional settings: a meta-analysis and meta-regression.

Antipsychotics increase weight, BMI and waist size, particularly in pediatric patients. Switching antipsychotics is common practice, thus defining the risk for each antipsychotic in real-life settings can be important for clinical guidance. We conducted a meta-analysis on antipsychotic-related changes in body measures in pediatric observational studies. Of 934 publications found on PubMed, we analyzed 38, including nine treatment arms: no treatment, mixed antipsychotic treatment, first-generation antipsychotics, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. Changes in weight, BMI, BMI-Z and waist size were meta-analyzed according to the duration of clinical observations: 6, 12, > 12 months. Meta-regressions probed influencing factors. Weight in Kg was increased at 6, 12, > 12 months by olanzapine [+ 10.91, + 10.7, data not available (n/a)], mixed antipsychotic treatment (n/a, + 9.42, + 12.59), quetiapine (+ 5.84, n/a, n/a) and risperidone (+ 4.47, + 6.01, + 9.51) and without treatment (n/a, + 2.3, n/a). BMI was increased at 6, 12, > 12 months by olanzapine (+ 3.47, + 3.42, n/a), clozapine (n/a, + 3, n/a) mixed antipsychotic treatment (+ 3.37, + 2.95, + 3.32), risperidone (+ 2, + 2.13, + 2.16), quetiapine (+ 1.5, + 1.82, n/a), aripiprazole (n/a, + 1.7, + 2.1) and without treatment (n/a, + 0.75, n/a). BMI-Z was increased at 6, 12, > 12 months by olanzapine (+ 0.94, + 0.98, + 0.89), clozapine (n/a, + 0.8, n/a), risperidone (+ 0.62, + 0.61, + 0.48), quetiapine (+ 0.57, + 0.54, n/a), mixed antipsychotic treatment (+ 0.51, + 0.94, + 0.44), without treatment (n/a, + 0.37, n/a) and aripiprazole (no gain, + 0.31, n/a). Waist size in cm was increased at 6, 12 months by risperidone (+ 8.8, + 11.5), mixed antipsychotics treatment (+ 9.1, + 10.2) and quetiapine (+ 6.9, + 9.1). Overall, olanzapine and clozapine displayed maximum risk, followed by risperidone, quetiapine and aripiprazole (more risky at longer terms); ziprasidone was associated with no gains. No time-based trends emerged, suggesting a drug-specific risk magnitude. Meta-regressions evidenced variable roles for persistence in therapy and follow-up length, increased risk for drug-naïve patients, and a ceiling effect determined by higher baseline BMI/BMI-Z values.

The impact of anti-TNFα agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database.

INTRODUCTION: Studies in patients with immune-mediated inflammatory diseases (IMIDs) have inconsistently suggested that anti-TNFα therapy may be associated with excessive weight gain. AREAS COVERED: We performed a nested case/non-case analysis to investigate the anti-TNF-α inhibitor-associated body-changes in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The risk was expressed as a measure of disproportionality using the reporting odds ratio (ROR) while adjusting for sex, drugs known to cause weight gain and reporter type. We also performed a time-to-onset (TTO) analysis of body weight-related events. RESULTS: Infliximab was the most commonly involved TNF-α inhibitor in body weight-related changes, reaching an aROR of 1.42 (95%CI:1. 26; 1.59). An increased risk was especially found in patients affected by rheumatic disorders, both in the adult and pediatric population. The median TTO after the start of anti- TNFα therapy was about 6-7 months for both children and adults. CONCLUSIONS: Given the potential effect of these agents on the excess weight gain in IMIDs patients, continuous attention for this side effect with appropriate counseling regarding lifestyle modifications are warranted, especially in those at high risk for obesity.

Preliminary evidence on the safety profile of BNT162b2 (Comirnaty): new insights from data analysis in EudraVigilance and adverse reaction reports from an Italian health facility.

The first vaccine against SARS-CoV-2 made available in Italy has been BNT162b2, the two-dose mRNA-based vaccine developed by Pfizer-BioNTech. The ASST Fatebenefratelli-Sacco hospital is located in one of the areas most affected by the pandemic, and to date over 2000 healthcare professionals have been injected with both vaccine doses. We have collected all spontaneous safety reports in which BNT162b2 was designated as the possible cause. We also have carried out a descriptive analysis of reports submitted in EudraVigilance in the same time-frame and compared our findings with those observed in clinical trials. We have identified several new and unexpected adverse reactions that will be helpful for reviewing the safety profile defined in the Summary of Product Characteristics for this vaccine.

Association between the glyco-metabolic adverse effects of antipsychotic drugs and their chemical and pharmacological profile: a network meta-analysis and regression.

BACKGROUND: Glyco-metabolic deteriorations are the most limiting adverse reactions to antipsychotics in the long term. They have been incompletely investigated and the properties of antipsychotics that determine their magnitude are not clarified.To rank antipsychotics by the magnitude of glyco-metabolic alterations and to associate it to their pharmacological and chemical properties, we conducted a network meta-analysis. METHODS: We searched PubMed, Embase, and Psycinfo on 10 September 2020. We selected studies containing the endpoint-baseline difference or the distinct values of at least one outcome among glucose, HbA1c, insulin, HOMA-IR, triglycerides, total/HDL/LDL cholesterols. Of 2094 articles, 46 were included in network meta-analysis. Study quality was assessed by the RoB 2 and ROBINS-I tools. Mean differences (MD) were obtained by random-effects network meta-analysis; relations between MD and antipsychotic properties were analyzed by linear regressions. Antipsychotic properties investigated were acidic and basic pKa, polar surface area, polarizability, and occupancies of D2, H1, M1, M3, α1A, α2A, 5-HT1A, 5-HT2A, 5-HT2C receptors. RESULTS: We meta-analyzed 46 studies (11 464 patients); on average, studies lasted 15.47 weeks, patients had between 17.68 and 61.06 years of mean age and 61.64% were males. Olanzapine and clozapine associated with greater deteriorations, aripiprazole and ziprasidone with smaller deteriorations. Higher polarizability and 5-HT1A receptor occupancy were associated with smaller deteriorations, H1, M1, and M3 receptor occupancies with larger deteriorations. CONCLUSIONS: Drug rankings may guide antipsychotic switching toward metabolically safer drugs. Mechanistic insights may suggest improvements for combination therapies and drug development. More data are required regarding newer antipsychotics.

Hyponatremia Following Antipsychotic Treatment: In Silico Pharmacodynamics Analysis of Spontaneous Reports From the US Food and Drug Administration Adverse Event Reporting System Database and an Updated Systematic Review.

BACKGROUND: Hyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet been explained. METHODS: We investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatremia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatremia. We also performed a systematic review of clinical studies on this association. RESULTS: Of 139 816 reports involving at least 1 antipsychotic, 1.1% reported hyponatremia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D3, D4, and hyponatremia, while adrenergic α 1, serotonin 5-HT1A, and 5-HT2A receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D3 (adj. odds ratio = 1.21; 95% CI = 1.09-1.34; P < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT2A occupancy (Adj. odds ratio = 0.78; 95% CI = 0.68-0.90; P < .01) exhibited a protective effect against hyponatremia. Among the 11 studies included in the systematic review, incidence rates of hyponatremia diverged between 0.003% and 86%, whereas the odds of developing hyponatremia from effect studies ranged between 0.83 and 3.47. CONCLUSIONS: Antipsychotic drugs having a combined modest occupancy for D3 and 5-HT2A receptors and higher levels of D3 receptor occupancy correspond to different degrees of risk for hyponatremia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatremia.

Beta-blocker-associated hypoglycaemia: New insights from a real-world pharmacovigilance study.

AIMS: To investigate the statistical association between hypoglycaemia and ß-blocker use and to define what patient and drug characteristics could potentially increase the risk for its occurrence. METHODS: We investigated the relationship between pharmacological parameters of ß-blockers and the occurrence of hypoglycaemia by conducting a case/non case analysis using the Food and Drug Administration Adverse Event Reporting System database. Pharmacological properties that could represent a predictive factor for hypoglycaemia were analysed through a multilinear binary logistic regression (null hypothesis rejected for values of P < .05). We also performed a systematic review of clinical studies on this association. RESULTS: Of 83 954 selected reports, 1465 cases (1.75%) of hypoglycaemia were identified. The association was found statistically significant for nadolol (reporting odds ratio [95% confidence interval]: 6.98 [5.40-9.03]), celiprolol (2.35 [1.35-4.10]), propranolol (2.14 [1.87-2.46]) and bisoprolol (1.42 [1.25-1.61]). Paediatric cases (n = 310) showed a positive association with hypoglycaemia for long half-life drugs (odds ratio [95% confidence interval]: 2.232 [1.398-3.563]) and a negative association for ß1-selectivity (0.644 [0.414-0.999]). Seven papers were included in the systematic review. Because of great heterogeneity in study design and demographics, hypoglycaemia incidence rates varied greatly among studies, occurring in 1.73% of the cases for propranolol treatment (n total participants = 575), 6.6% for atenolol (n = 30) and 10% for carvedilol (n = 20). CONCLUSION: Nadolol appears to be the ß-blocker significantly most associated with hypoglycaemia and children represent the most susceptible sample. Furthermore, long half-life and nonselective ß-blockers seem to increase the risk for its occurrence.

Severe hypoglycemia in children treated with nadolol: A case report and FDA adverse event reporting system (FAERS) database analysis.

OBJECTIVE: We describe a case of severe hypoglycemia in a 14-month-old child as a suspected adverse drug reaction (ADR) to nadolol, and we performed an analysis of the FDA Adverse Event Reporting System (FAERS) database. Although previous reports have identified the risk of severe hypoglycemia in children during treatment with ß-blockers, little is known about hypoglycemia as an ADR in infants treated with nadolol. Moreover, the pharmacodynamic and pharmacokinetic profiles of nadolol in children aged less than 1 year old are still not fully known. MATERIALS AND METHODS: We extracted all ADR reports involving nadolol from the FAERS database; in order to reduce the risk of bias, we only considered cases that exclusively reported nadolol as the suspect drug. We then selected cases of hypoglycemia in the pediatric population and conducted a manual deduplication. RESULTS: Upon FAERS database analysis, a total of 2,674 suspected ADR reports to nadolol were found. Of these, 1,950 (73%) were solely attributed to nadolol, and 63 of them were hypoglycemic events. A total of 47 reports included the relevant pediatric age (74.6%). After deduplication, we identified 25 cases (mean age: 3.65 years old); all of these reports were categorized as serious, and hospitalization was required in 15 cases. CONCLUSION: Hypoglycemia is a reported life-threatening ADR associated with nadolol, especially in infants, in whom this drug should be used with caution.

Drug Use in Pediatric Patients Admitted to Rehabilitation For Severe Acquired Brain Injury: Analysis of the Associations With Rehabilitation Outcomes.

INTRODUCTION: Patients with severe acquired brain injuries require drug therapies in intensive care for life support and injury treatment. Patients who then access rehabilitation usually maintain their drug treatments long term, with a potential influence on the rehabilitation course. Whereas drug effects have been reported for specific drugs and clinical issues in adults, comprehensive data on pediatric patients with traumatic and non-traumatic injuries are scant. OBJECTIVES: The aims of this study were to describe the therapeutic classes and groups of drugs prescribed to pediatric inpatients recovering from severe acquired brain injury when they enter rehabilitation; to assess whether clinical variables may determine the use of drug classes; and to assess whether the use of drug classes may be associated with differences in rehabilitation outcomes. METHODS: We carried out a retrospective chart review, following a previous study on the clinical-epidemiological characteristics of our patients. We collected information on drug therapies present at admittance to rehabilitation and analyzed their distribution according to therapeutic classes and groups. We verified the associations of drug groups with clinical variables (putatively antecedents to drug use) and with rehabilitation outcomes (putatively resultant of drug use and of clinical variables) in regression models. The clinical variables considered were injury etiology, Glasgow Outcome Score (GOS) at admittance to rehabilitation, sex, age at injury, plus two aggregate factors resulting from the previous work, 'neurological dysfunction' regarding the use of devices and 'injury severity' regarding the neurological status. The rehabilitation outcomes used were death after rehabilitation, persistence of a vegetative/minimally conscious state, coma duration, duration of the rehabilitation stay, rehabilitation efficiency (GOS at discharge minus GOS at admittance, divided by the length of rehabilitation stay). RESULTS: We described the distribution of drug classes and groups among pediatric patients with severe acquired brain injuries. Regarding the associations between drug classes and clinical variables, we found greater use of cardiovascular agents with higher patient age, 'neurological dysfunction' score, and with an etiology of hypoxic brain injury. The use of antithrombotic agents was greater with higher patient age and 'neurological dysfunction' score. Glucocorticoid use was greater with higher GOS at admittance and with several etiologies: brain tumor, infective encephalitis, and autoimmune encephalitis. Regarding drug classes and rehabilitation outcomes, we found that the use of cardiovascular drugs was associated with increased occurrence of death after rehabilitation. The use of antispastic drugs was associated with a more frequent permanence in vegetative/minimally conscious states. The use of antispastic drugs and melatonin was associated with longer coma duration. The use of glucocorticoid drugs was associated with decreased rehabilitation efficiency. CONCLUSIONS: We provided a description of drug use in pediatric rehabilitation after severe acquired brain injuries, which was lacking in the literature. Prospective studies should verify our associative observations regarding clinical variables, drugs use, and outcomes, to assess causality.

We Really Need Clear Guidelines and Recommendations for Safer and Proper Use of Aripiprazole and Risperidone in a Pediatric Population: Real-World Analysis of EudraVigilance Database.

Background: Although aripiprazole and risperidone are used widespread in pediatrics, there are still limited pieces of evidence on their actual safety profile. By using the EudraVigilance database, we carried out an analysis to perform a comprehensive overview of reported adverse events among children and adolescents treated with aripiprazole and risperidone. Methods: Descriptive analysis was performed of all individual case safety reports (ISCRs) submitted to EudraVigilance associated with aripiprazole and risperidone and related to the pediatric population from 2016 to 2018. Results: A total of 855 and 2,242 ISCRs for aripiprazole and risperidone, respectively, were recorded for a total of 11,042 suspected adverse drug reactions (2,993 for aripiprazole and 8,049 for risperidone). Most ISCRs were related to male patients (65.0 and 86.3% for aripiprazole and risperidone, respectively) and were serious (81.0 and 94.1% for aripiprazole and risperidone, respectively). Schizophrenia spectrum and other psychotic disorders, such as disruptive, impulse-control, and conduct disorders, and autism spectrum disorder were the top three clinical indications for aripiprazole (19.0, 16.1, and 11.6%, respectively). For risperidone, attention-deficit/hyperactivity disorder (25.4%), disruptive, impulse-control, and conduct disorders (17.1%), and bipolar and related disorders (14.2%) were more commonly reported as clinical indications. Data also showed a high proportion of use for clinical conditions not authorized in children. Psychiatric disorders were the main related adverse events for aripiprazole (20.2%), and among these, suicidal behavior was one of the most reported (14.9%). Reproductive system and breast disorders were the main related adverse events for risperidone (19.8%), and gynecomastia was the most reported event; metabolism and nutrition disorders, mainly reported as weight gain disorders, were more reported in children (3-11 years) than in adolescents (12-17 years). Conclusions: Our results demonstrate that spontaneously reported adverse events associated with aripiprazole and risperidone reflect what is already known in terms of safety profile, although with about 90% of them being serious. This analysis stresses the need for further studies and effective training and information activities to better define the actual benefit/risk ratio of these drugs in pediatric patients.

Changes in Anthropometric Parameters After Anti-TNFα Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Tumour necrosis factor (TNF)-α inhibitors have been widely used for the treatment of moderate-to-severe inflammatory bowel disease (IBD). TNFα also plays an important role in the regulation of weight homeostasis and metabolism and has been linked to variations in anthropometric responses. This relationship in patients with IBD has yet to be determined. OBJECTIVES: Our objective was to evaluate the effects of TNFα inhibitors on changes in anthropometric measures in both adults and children with IBD through a systematic review and meta-analysis. METHODS: Multiple database searches identified studies involving children and adults with IBD and treated with TNFα inhibitors and reporting at least one primary outcome measure. Where possible, data were combined for meta-analysis. The primary outcomes included weight, body mass index (BMI), waist circumference, height, height/velocity, and fat and lean mass. Secondary outcomes included surrogate markers of disease activity. A random-effects model was used to estimate the standardised mean difference (SMD). RESULTS: In total, 23 cohort studies (total 1167 participants) met the inclusion criteria. Meta-analysis was performed on 13 of these studies. In children, 6-29.3 months of anti-TNFα therapy had a small but statistically significant effect on weight (SMD 0.31; 95% confidence interval [CI] 0.12-0.49; P = 0.001) with a mean gain in z score of 0.30 (standard error [SE] 0.12). In adults, 2-22.4 months of treatment had a moderate effect on BMI (SMD 0.72; 95% CI 0.17-1.26; P = 0.010; mean gain 1.23 kg/m2; SE 0.21). A small but statistically significant increase in BMI z score was found in children (SMD 0.28; 95% CI 0.03-0.53; P = 0.026; mean change 0.31 ± standard deviation [SD] 0.14) after 12-29.3 months of therapy. A meta-analysis of four studies found a negligible but statistically significant increase in height (SMD 0.16; 95% CI 0.06-0.26; P = 0.002; mean change 0.17 z score [SE 0.05]). A negligible effect on fat mass (SMD 0.24; 95% CI -0.19-0.66; P = 0.272) was found in a meta-analysis of five studies. Of note, despite the high heterogeneity among the studies that addressed the issue, these results were also consistently supported by findings from studies not included in the meta-analysis and reviewed in the systematic review. Unfortunately, a lack of data meant we were unable to perform moderator analysis on observed heterogeneity. CONCLUSION: Anti-TNFα treatment appears to be associated with an increase in body weight, BMI, and other anthropometric parameters. Given the differing courses of IBD between children and adults, this association should be considered before initiating biologics for undernourished, overweight, and obese patients. Registration: PROSPERO registration number CRD42020163079.