Search

Enormous progress has been made globally in the use of evidence derived from patients’ clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.

Objective: To gain information on safety of drugs used in pediatrics through a 4-year post-marketing active pharmacovigilance program. The program sampled the Italian population and was termed 'Monitoring of the Adverse Effects in Pediatric population' (MEAP).Research design and methods: Adverse drug reactions (ADRs) were collected for individuals aged 0-17 years treated in hospitals and territorial health services in Lombardy, Tuscany, Apulia and Campania; located to gain an appropriate sampling of the population. ADRs were evaluated using the Adverse Drug Reaction Probability Scale (Naranjo) and analyzed with respect to time, age, sex, category of ADR, seriousness, suspected medicines, type of reporter and off-label use.Results: We collected and analyzed reports from 3539 ADRs. Vaccines, antineoplastic and psychotropic drugs were the most frequently pharmacotherapeutic subgroups involved. Seventeen percent of reported ADRs were serious; of them fever, vomiting and angioedema were the most frequently reported. Eight percent of ADRs were associated with off-label use, and 10% were unknown ADRs. Analysis of these revealed possible strategies of therapy optimization.Conclusions: The MEAP project demonstrated that active post-marketing pharmacovigilance programs are a valid strategy to increase awareness on pediatric pharmacology, reduce underreporting and provide information on drug actions in pediatrics. This information enhances drug therapy optimization in the pediatric patients. © Informa UK, Ltd.

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 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.

BackgroundGlyco-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.MethodsWe 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.ResultsWe 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.ConclusionsDrug 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.

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.

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. Electronic supplementary material The online version of this article (10.1007/s40259-020-00444-9) contains supplementary material, which is available to authorized users.

Purpose: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. Methods: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. Results: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9 %) but lower intra-patient (34.2 %) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1 %, while the intra-patient variability was much lower (29.3 %). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). Conclusion: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.