Search

Rationale and background In March 2018, the European risk minimisation measures (RMMs) with a Pregnancy Prevention Program (PPP) for valproate-containing medicines was updated. A pharmacoepidemiological study was conducted using longitudinal data collected in five electronic health care databases from four EU countries and the UK to investigate the use of valproates authorised in the EU before and after implementation of the 2018 revised measures for pregnancy prevention in clinical practice, and effectiveness of the 2018 intervention. Objectives Objective 1: To determine drug utilisation and prescription patterns of valproate-containing medicinal products in females of childbearing potential, and to investigate whether significant changes in prescribing patterns occurred (pre-/post-intervention). Objective 2: To determine prescribers’ compliance with the recommendations in the Summary of Products Characteristics (SmPC) for valproate-containing medicinal products, by indication, age group, duration of use, and database. Objective 3: To determine patients’ use of effective contraception in compliance with recommendations in the SmPC for valproate-containing medicinal products, by indication, age group, method of contraception, and database. Objective 4: To determine drug utilisation and prescription patterns over time for alternative medicines prescribed in women who became pregnant, where valproate-containing medicinal products had previously been prescribed or discontinued, by indication, by age group and by database. Objective 5: Based on the results of the above, to estimate the effectiveness of the 2018 RMMs for valproates. Methods We performed an observational times series study including all female subjects of childbearing age (aged 12 to 55 years) from the corresponding databases in Denmark (Danish National Registers, DNR), Italy (ARS Tuscany), the Netherlands (PHARMO Database Network), Spain (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria, BIFAP), and UK (Clinical Practice Research Datalink, CPRD) between 01 January 2010 to 31 December 2020. In Objective 1, the incident use, prevalent use and rate of discontinuation thereof was estimated per month in each data source, in addition to the change in level and trend in use after the implementation of the 2018 EU RMMs, using an interrupted time series (ITS) analysis design. In Objective 2, first, we separately estimated the proportion of valproate users with a record of a pregnancy test within the 90 days i) before and ii) after the date of valproate prescribing or dispensing per month. We estimated the change in level and trend in these proportions after the implementation of the 2018 EU RMMs. Second, we estimated the proportion of valproate users with a record of contraceptive (prescribed or dispensed with a prescription, or identified through medical events or procedures records) in 90-days before the prescription, or prescribed/dispensed during a contraceptive episode. We then estimated the change in level and trend in this proportion after the implementation of the 2018 EU intervention, using an ITS analysis design. In Objective 3, we estimated the incidence of new pregnancies during a period of valproate use per month and the change in level and trend in this rate after the implementation of the 2018 EU intervention, using an ITS analysis design. In Objective 4, we estimated the rates of alternative medication prescriptions/dispensings for the indications epilepsy, bipolar disorder, and migraine among valproate users and the rate of switching from valproate to an alternative medicine per month. Then, the change in trend of switches from valproate to alternative medications before and after the implementation of the 2018 EU intervention was estimated, using an ITS analysis design. In Objective 5, evidence generated from Objectives 1-4, weighed by the strengths and limitations of the analyses, was used to draw conclusions on the effectiveness of the RMMs, per country and across European countries included in the study. Results Objective 1: There were 69,533 valproate users out of a total of 9,699,371 female subjects of childbearing age from the five participating centres during the study period. The median follow-up time of the study population ranged between 3.5-10.0 years and the mean age at the start of follow-up was always ≥30 years in different centres. The monthly incidence rate of valproate use ranged between 0.01-0.47 per 1000 persons months across databases and the prevalence rate ranged between 1.2-7.7 per 1000 female subjects. While the observed rates were similar for DNR, PHARMO, BIFAP and CPRD, the rates of prevalent use were much higher in ARS Tuscany. We observed a statistically significant declining trend in prevalent use of valproates in all countries/regions, for which an ITS analysis could be performed, but no significant decreasing trend in incidence rates after the 2018 RMMs compared to the period before. The monthly rate of valproate discontinuers ranged between 1-8% across all databases, and in no database we observed a significant increase in trend or level of valproate discontinuation after the 2018 intervention compared to time prior. Objective 2: We included 69,533 female valproate users from the five participating centres during the study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. Due to the limited data on pregnancy tests from all databases, modelling of any trend change in proportion of valproate prescriptions or dispensings with an adherent pregnancy test before versus after 2018 RMMs was not possible. The rate of recorded contraceptive coverage at the start of valproate treatment was low across all centres, as only 0.5-23% of valproate prescriptions/dispensings each month were accompanied by a contraceptive prescription in 90-days before, and only between 0.5-25% of new valproate treatment episode had started during contraceptive use. There was no increasing trend in compliant valproate prescriptions/ dispensings with a contraceptive coverage after the 2018 RMMs across the studied databases, and the only increase in level was observed in PHARMO. Objective 3: We included 69,533 female valproate users from the five participating centres during study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. In general, we observed a substantial number of concurrent new valproate prescriptions/dispensings during a pregnancy time window in ARS Tuscany (386 pre- and 40 post 2018 intervention), BIFAP (330 pre and 20 post) and CPRD (204 pre and 56 post), while there were fewer concurrent events in PHARMO (27 pre and 0 post). However, the rates of concurrent events declined for most databases after the 2018 intervention. There was no data on pregnancy counts available from DNR. Objective 4: We included 69,533 female valproate users from the five participating centres during study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. We found an increasing trend in rates of alternative medicine use for epilepsy and bipolar diseases indications of valproates across the study period in most databases (i.e., DNR, ARS Tuscany, PHARMO and CPRD), while the rates for migraine were mostly steady. The monthly rate of switch from a valproate to an alternative medication was similar across all DAPs and ranged between 1-8%. Running an ITS analysis was not possible for most of the included databases due to the low frequency of switching, but there was a significant increase in trend in switching rates from valproates to alternative medicine after the 2018 RMMs in ARS Tuscany. Objective 5: We found a generally declining trend in prevalence rate of valproate use after the 2018 RMMs in almost all databases (Objective 1), but also no increasing trend in compliant valproate prescriptions/dispensings with a contraceptive coverage (Objective 2). There was a substantial number of occurrences of pregnancy events (as the final endpoint) concurrently with valproate exposure across most included databases, but the rates declined after 2018 (Objective 3). Furthermore, we observed a significant increase in switching rates from valproates to alternative medications only in few regions (such as ARS Tuscany) (Objective 4). Noteworthy, these findings should be interpreted in context of the limitations that we faced, such as an inability to investigate some objectives due to limited data availability on pregnancy test or over-the-counter use of some contraceptives, and the occurrence of COVID-19 pandemic, which has shortened and impacted our post-intervention period and limited our ability to run ITS analyses for some objectives and some databases. Conclusions Objective 1: We observed declining trends in prevalent use of valproates after the 2018 RMMs across all databases. However, there were no declining trends in incidence rate of valproates in none of databases. The rate of discontinuation of valproates was not affected by the 2018 RMMs. Objective 2: We found in general low rates of recorded adherent contraceptive coverage with valproate use across all studied regions/countries, and there was no increased trend in compliant valproate prescriptions/dispensings with a contraceptive coverage after the 2018 RMMs compared to time prior. Due to limited data availability, rates of adherent pregnancy tests and the trend change after the intervention could not be studied. Objective 3: Despite the declining rates after the 2018 intervention, high counts and rates of concurrent pregnancy events with a valproate prescription/dispensing were observed across most studied countries/regions. Objective 4: Although the trend in alternative medication use for most indications of valproates (epilepsy and bipolar disorder) was increasing during the study period, the only significant increase in trend in switching rates from valproates to alternative medications after the 2018 RMMs was observed in ARS Tuscany. Objective 5: Based on the findings on various objectives in this study, we can conclude that there was a small impact of the 2018 RMMs on valproate use and prescribing in the studied European countries/regions. Considering the limitations of this study (such as not studying all PPP elements, the included databases had important limitations, and the study period after 2018 intervention was rather short), the results of other currently ongoing studies are needed to have a clearer picture of the appropriate implementation of 2018 RMMs on valproate use in Europe., The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the Utrecht University, the Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE. The content of this paper expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

To evaluate the impact of pharmacological treatment in osteoporosis patients with recent fracture and to assess the incidence of subsequent fracture and all-cause mortality. This observational retrospective study was based on data from administrative databases of five Italian Local Health Units. Osteoporosis patients aged ≥ 50 years with hospitalization for vertebral or hip fracture occurring between 01/01/2011 and 31/12/2015 were included. Treatment adherence was calculated using the medication possession ratio. Multivariable proportional hazard Cox model was used to identify factors associated with time to re-fracture and all-cause mortality. A cohort of 3475 patients were included and 41.5% of them did not receive any specific anti-fracture treatment. Among treated patients (N = 2032), the majority (83.6%) received calcium/vitamin D supplementation. Over a mean follow-up of 3 years, the risk of subsequent fractures was 44.4% lower in treated patients compared to untreated ones (HR = 0.556, 95% CI = 0.420–0.735, p

Le informazioni disponibili sul profilo rischio-beneficio dei farmaci nel periodo prenatale e neonatale sono molto limitate, principalmente per la difficoltà nel condurre sperimentazioni cliniche. La ricerca farmaco-epidemiologica può svolgere un importante ruolo nell’aumento delle conoscenze sulla sicurezza d’uso dei farmaci in questa popolazione. Le tematiche di ricerca del presente progetto di Dottorato sono state: (i) impatto dell’esposizione pre-natale a psicofarmaci sullo sviluppo neuro-comportamentale nel bambino, (ii) pattern di utilizzo dei farmaci in neonati prematuri, e (iii) valutazione della funzionalità renale in neonati prematuri e ruolo dei farmaci nell’insorgenza di danno renale. Con il primo studio si è analizzato il database della Société Marcé Francophone presso l’Unità INSERM 1219 (Università di Bordeaux), che include dati collezionati in 10 anni presso le Unità Madre-Figlio del Network Francofono. Le analisi hanno mostrato come, indipendentemente dalla patologia psichiatrica materna, l’esposizione prenatale ad alcune classi di psicofarmaci è stata associata ad alterazioni dello sviluppo neuro-comportamentale nei bambini. Con lo studio di farmaco-utilizzazione in neonati prematuri si è voluto descrivere il reale impiego dei farmaci in questa popolazione, in particolare le associazioni di farmaci nefrotossici. I risultati di questo studio retrospettivo indicano che i neonati prematuri con inferiore peso alla nascita sono stati più frequentemente esposti a combinazioni di farmaci nefrotossici rispetto ad altri neonati; inoltre, sono state identificate le associazioni di principi attivi nefrotossici più utilizzate. Il terzo studio, di natura prospettica, ha coinvolto una coorte di neonati prematuri ricoverati presso la Terapia Intensiva Neonatale, con l’obiettivo di identificare i fattori di rischio correlati ad alterazione della funzione renale. I risultati delle analisi preliminari hanno mostrato come i neonati con alterata funzione renale hanno inferiori peso alla nascita ed età gestazionale e superiore incidenza di sepsi; questi risultati mettono in luce la necessità di nuovi biomarcatori per la diagnosi di danno renale in questa popolazione., The benefit-risk profile of drugs in the prenatal and neonatal period is still largely unexplored, because of the difficulties in performing clinical trials. The pharmaco-epidemiological approach could play and important role in increasing knowledge on the benefit-risk profile of drugs used in this special population. The present thesis addressed three specific aspects: (i) impact of prenatal exposure to psychotropic drugs on developmental skills in babies up to 6 months, (ii) pattern of drug use in neonates born prematurely, and (iii) identification of risk factors, including drugs, for renal damage in preterm neonates. In the first study, the analysis of the database of the Société Marcé Francophone at INSERM Unit 1219 (University of Bordeaux), which included data collected over 10 years in the Mother-Baby Units of the Francophone Network, showed that the prenatal exposure to some classes of psychotropic drugs were associated to alterations of developmental skills in babies, independently from maternal psychiatric diagnosis. With the second study, we aimed at assessing the actual use of drugs in preterm neonates, especially the combination of those drugs with known nephrotoxicity in adults. Results of this retrospective study showed that preterm neonates with lower birth weight were more likely to receive combinations of nephrotoxic agents compared to other neonates; moreover, we identified most commonly reported combination of drugs with known nephrotoxicity. The third study was conducted prospectively in a cohort of preterm neonates admitted to a tertiary-level Neonatal Intensive Care Unit (NICU), aiming at identifying risk factors, especially drugs, for renal function alteration. Preliminary data show that neonates with altered renal function had lower gestational age and lower weight at birth as well as higher frequency of diagnosis of sepsis; these results highlight the need for novel biomarkers to diagnose renal damage in neonates.

Background and Aims:In this study we used a connectomic approach by means of Diffusion Tensor Imaging (DTI) tractography data to describe the rules that govern the interregional brain interactions in Anorexia Nervosa (AN).Methods:38 patients with acute AN and 38 healthy controls (HC) were included in this study. Freesurfer was used for the parcellation of the cortex, according to Destrieux atlas. FSL Probtrackx was used for the DTI tractograpy analysis. The Graph Analysis Toolbox was used for the networks extraction.Results:From a global perspective, patients with AN showed a reduced network clusterization and reduced small-world properties. From a regional analysis, patients with AN showed a higher clustering coefficient in right anterior cingulate gyrus and a higher betweenness in right fusiform gyrus. An analysis of the most central and influential nodes in the network showed an identical hub distribution in AN patients and HC, except for superior parietal lobule and the right superior occipital gyrus. These two nodes showed a high centrality and influence only in HC. Subcortical hubs were equally represented in both groups.Conclusions:From a global perspective, altered clusterization and small worldness indicate an unbalanced connectome wiring in AN. Regional analysis evidenced local alterations in two areas with high integrative properties and with a role in AN pathophysiology, being involved in decision making processing and error detection and in the recognition of face and body. Differences in hub distribution and the absence of two important cortical hubs, allow to hypothesize a weakness of the connective backbone architecture in AN.

Introduction: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events. Methods: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs. Results: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for “general disorders and administration site conditions,” whereas CAERS received also a high number of reports for “investigations” and “musculoskeletal and connective tissue disorders”. Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44–34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44–13.10). Conclusions: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.

Only a small fraction of drugs widely used in neonatal intensive care units (NICU) are specifically authorized for this population. Even if unlicensed or off-label use is necessary, it is associated with increased adverse drug reactions, which must be carefully weighed against expected benefits. In particular, renal damage is frequent among preterm babies, and is considered a predisposing factor for the development of chronic kidney disease in adulthood. Apart from specific conditions affecting premature neonates (e.g. respiratory distress syndrome, perinatal asphyxia), drugs play an important role in impairing renal function because of well-known nephrotoxicity and/or interaction with renal developmental factors. From a review of the available studies on drug use in NICU patients, we identified and described the most commonly administered drugs that are correlated to renal damage. Early detection of kidney injury is becoming an essential aspects for clinicians because of the limited number of biomarkers applicable in the neonatal population. Postnatal changes of biochemical processes that influence pharmacokinetic and pharmacodynamic aspects need to be further investigated in order to better understand the mechanisms of drug toxicity in this population. The most promising strategies for dose adjustment and therapeutic schemes are discussed. The purpose of this review was to describe current knowledge on drug use among premature babies and their implication in kidney injury development, as well as to highlight available strategies for early detection of renal damage. ispartof: Drug Safety vol:38 issue:6 pages:535-551 ispartof: location:New Zealand status: published

Acute kidney injury (AKI) is frequently diagnosed in the neonatal population, especially in those admitted to intensive care units, and poses several challenges for clinicians mainly because of difficulties in timely identification of renal impairment and the need to administer drugs with potential nephrotoxicity. In this context, research on biomarkers is growing for their implication in the early detection of renal damage and their higher sensitivity in monitoring renal activity, but also as an important tool for drug development. Areas covered: We described the tools currently used to detect renal damage in neonatal settings, their limits and applicability, as well as the role of drugs on renal toxicity occurrence. Subsequently, we discuss current knowledge on new biomarkers for the detection of kidney injury and drug-induced kidney injury in neonates, and the qualification programs developed by regulatory agencies for biomarkers intended as tools in drug development. Expert opinion: Some molecules are emerging as potential biomarkers for early detection of AKI: promising data has demonstrated higher sensitivity and accuracy compared with tools currently used in the clinical setting. In addition, novel techniques (e.g. high power magnetic resonance imaging) to assess long-term consequences of AKI in neonates are in early steps of development.

Background Use of food supplements-containing phytoestrogens among postmenopausal women is rapidly increasing. Although phytoestrogens are often perceived as safe, evidence for overall positive risk-benefit profile is still inconclusive. The chance to buy them by user’s initiative does not facilitate surveys on their prevalence and pattern of use. The aim of this study was to describe the pattern of use and self-reported positive and negative perceptions of phytoestrogens in post-menopausa. Methods A questionnaire was administered to women who were buying food supplements containing phytoestrogens in 22 pharmacies located in the Bologna area (400,000 inhabitants). Questionnaire was structured into 3 sections: (a) socio-demographic information, (b) pattern of use, (c) positive and negative perceptions. Results Data on 190 peri- and post-menopausal women (aged 38–77) were collected. Women stated to use phytoestrogens to reduce hot flushes (79%), insomnia (15%), mood disturbances (14%) and prevent osteoporosis (15%). The majority (59%) took phytoestrogens routinely, whereas 28% in 3-month cycles. Among positive perceptions between short- and long-term users, a not negligible difference was reported for relief of hot-flushes (68% in short-term vs. 81% in long-term users; p = 0.04). Negative perceptions were reported more frequently in the long-term group, and this difference was statistically significant for edema (6% in short-term vs. 17% in long-term users; p = 0.04), but not for other effects: e.g., swelling sensation (10% vs. 21%; p = 0.09), somnolence (7% vs. 10% p = 0.62), fatigue (4% vs.11% p = 0.15). Conclusions In the Bologna area, the pattern of use of phytoestrogens for menopausal symptoms is heterogeneous, and women overall find these substances to be beneficial, especially for relief of hot-flushes. Other positive perceptions decreased with long-term use. Negative perceptions, especially estrogen-like effects, seem to be infrequent and increase with long-term therapy. Physicians should pay attention to effects perceived by post-menopausal women and routinely monitor the use of phytoestrogens, in order to recognize possible adverse effects and actual benefits. Electronic supplementary material The online version of this article (doi:10.1186/1472-6882-14-262) contains supplementary material, which is available to authorized users.