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BackgroundEvidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitor (SSRIs).MethodsIn our case/non-case pharmacovigilance study, based on VigiBase®, the WHO database of suspected adverse drug reactions, we estimated reporting odds ratio (ROR) and the Bayesian information component (IC) with 95% confidence/credibility intervals (CI) as measures of disproportionate reporting of antidepressant-related neonatal withdrawal syndrome. Antidepressants were first compared to all other medications, then to methadone, and finally within each class of antidepressants: SSRIs, tricyclics (TCA) and other antidepressants. Antidepressants were ranked in terms of clinical priority, based on semiquantitative score ratings. Serious v. non-serious reports were compared.ResultsA total of 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants were included. Disproportionate reporting was detected for antidepressants as a group as compared to all other drugs (ROR: 6.18, 95% CI 5.45–7.01, IC: 2.07, 95% CI 1.92–2.21). Signals were found for TCAs (10.55, 95% CI 8.02–13.88), followed by other antidepressants (ROR: 5.90, 95% CI 4.74–7.36) and SSRIs (ROR: 4.68, 95% CI 4.04–5.42). Significant disproportionality emerged for all individual antidepressants except for bupropion, whereas no disproportionality for any antidepressant was detected v. methadone. Eleven antidepressants had a moderate clinical priority score and four had a weak one. Most frequent symptoms included respiratory symptoms (n = 106), irritability/agitation (n = 75), tremor (n = 52) and feeding problems (n = 40).ConclusionsMost antidepressants are associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome, which should be considered when prescribing an antidepressant during pregnancy, irrespective of class.

IntroductionEvidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitors (SSRIs).ObjectivesTo ascertain whether maternal antidepressant treatment may be associated with withdrawal syndrome in neonates, investigating the comparative reporting between individual antidepressants and classes.MethodsWe performed a case/non-case pharmacovigilance study, searching reports of withdrawal syndrome in newborns in the VigiBase, the WHO database of suspected adverse drug reactions. Disproportionality analysis was performed, estimating reporting odds ratio (ROR) and the Bayesian information component (IC). Antidepressants were compared to all other medications, to methadone, and within each class of antidepressants (SSRIs, tricyclics (TCA) and other antidepressants). Antidepressants were ranked in terms of clinical priority, based on a semiquantitative score.ResultsWe retrieved 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants. Compared to all other drugs, disproportionate reporting was detected for antidepressants altogether (ROR: 6.18, 95%CI:5.45-7.01), for TCAs (10.55, 95%CI:8.02-13.88), other antidepressants (ROR: 5.90, 95%CI:4.74-7.36) and SSRIs (ROR: 4.68, 95%CI:4.04-5.42). All antidepressants showed a significant disproportionality, apart from bupropion (figure 1). We did not find any disproportionate reporting for any antidepressant compared to methadone. The clinical priority ranking showed moderate clinical priority for all antidepressants, with the exception four, that had a weak one (figure 1). Most frequently reported symptoms were respiratory symptoms (n=106), irritability/agitation (n=75), tremor (n=52) and feeding problems (n=40).Image:ConclusionsExposure to antidepressants in utero is associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome for most antidepressants. Clinicians should pay extra attention to neonates with antidepressant-treated mothers.Disclosure of InterestC. Gastaldon: None Declared, E. Arzenton : None Declared, E. Raschi: None Declared, O. Spigset: None Declared, D. Papola: None Declared, G. Ostuzzi: None Declared, U. Moretti: None Declared, G. Trifirò Grant / Research support from: he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until Oct 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also scientific coordinator of the academic spin-off “INSPIRE srl” which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.)., Consultant of: has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen, Speakers bureau of: has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen, C. Barbui: None Declared, G. Schoretsanitis Consultant of: Dr. Schoretsanitis has served as a consultant for HLS Therapeutics and Thermo Fisher Scientific.

IntroductionAntidepressant discontinuation may cause withdrawal syndrome in some cases. However, evidence on this syndrome related to individual antidepressants is limited, as well as about individual risk factors for severe reactions.ObjectivesTo ascertain whether each individual antidepressant is associated with an increased reporting of withdrawal syndrome as compared with other medications, and to examine clinical risk factors for severe reactions.MethodsWe conducted a pharmacovigilance study, with a case/non-case design. We included reports of antidepressant-related withdrawal syndrome from the VigiBase, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis (calculating reporting odds ratio (ROR) and the Bayesian information component (IC)) of reports of antidepressant-related withdrawal syndrome, comparing antidepressants to all other drugs and to buprenorphine (as a positive control). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. We compared serious versus non-serious reactions to determine clinical risk factors for severe reactions.ResultsBased on 31,688 reports of antidepressant-related withdrawal syndrome, we detected a disproportionate reporting for 23 antidepressants. The ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95%CI:14.08-14.45), 17.01 for other antidepressants (95%CI:16.73-17.29), 13.65 for SSRIs (95%CI:13.41-13.90) and 2.8 for tricyclics (95%CI:2.59-3.02). Based on clinical priority ranking, the strongest signals were found for paroxetine, duloxetine, venlafaxine and desvenlafaxine (figure 1), being comparable to buprenorphine. Severe reactions were more frequently reported in males, adolescents, persons with multiple medications, and with longer treatment duration.Image:ConclusionsAntidepressants are associated with increased reporting of withdrawal syndrome compared with other medications, with differences between individual antidepressants. Clinicians should be aware of such differences, when prescribing and discontinuing these drugs, as well as of the risk to experience more severe withdrawal symptoms in specific cases.Disclosure of InterestC. Gastaldon: None Declared, G. Schoretsanitis Consultant of: Dr. Schoretsanitis has served as a consultant for HLS Therapeutics, E. Arzenton : None Declared, E. Raschi : None Declared, D. Papola: None Declared, G. Ostuzzi: None Declared, U. Moretti: None Declared, E. Seifritz Grant / Research support from: Dr. Seifritz has received educational grants, consulting fees and lecture honoraria from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Ricordati, Vifor, Sunovion, Schwabe and Mepha, Consultant of: Dr. Seifritz has received educational grants, consulting fees and lecture honoraria from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Ricordati, Vifor, Sunovion, Schwabe and Mepha, J. Kane Shareolder of: LB Pharmaceuticals and Vanguard Research Group, Consultant of: Dr. Kane has been a consultant and/or advisor for or has received honoraria from Alkermes, Allergan, LB Pharmaceuticals, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson and Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva and UpToDate, G. Trifirò Grant / Research support from: he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until Oct 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also scientific coordinator of the academic spin-off “INSPIRE srl” which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.)., Consultant of: Dr. Trifirò has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen;, Speakers bureau of: Dr. Trifirò has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen;, C. Barbui: None Declared

Reporting and analysis of Adverse Events Following Immunization (AEFIs) are the cornerstones of vaccine safety surveillance prompting causality assessment and signal detection. This paper describes the impact of the Italian Pharmacovigilance System of vaccines over a 10-year period (2008–2017). The reporting rate (RR) per all distributed dose was calculated. Serious AEFIs and causality assessments for fatal cases were described. The main results from signal detection were reported. During the study period, 46,430 AEFIs were reported with an overall RR of 17.2 per 100,000 distributed doses. Italy showed the highest number of reports among European countries. Only 4.4% of the reports came from citizens. Of the total, 12.7% were classified as serious with a RR over the study period of 2.20 per 100,000 distributed doses. They were mainly related to hyperpyrexia and usually had a positive outcome. Fatal outcomes were reported in 0.3% of the cases and were primarily associated with the influenza vaccine in elderly patients. None of these outcomes had a consistent causal association with the vaccination. Febrile convulsions by the measles, mumps, rubella and varicella vaccines and intussusception by the rotavirus vaccine were among the highlighted signals. The reporting rate and the analysis of serious events from 10 years support the good risk/benefit profiles of vaccines.

Aims: To determine in a case-control study possible associations between the development of acute renal failure in preterm newborns and therapeutic interventions, particularly drug treatments. Methods: The study population was 172 preterm infants of <38 weeks gestation; 71 had acute renal failure and 101 were controls closely matched for gestational age and birth weight. Maternal and neonatal information was collected for both groups through questionnaires and interviews. Routine data on renal variables were also collected. Univariate and multivariate logistic regression analyses were performed. Results: Very low birthweight infants were at high risk of acute renal failure (79% of cases were <1500 g). However, the acute renal failure was transient. Mothers of infants with acute renal failure received more drugs during pregnancy and delivery (mainly antibiotics and non-steroidal anti-inflammatory drugs). Of the possible therapeutic interventions, intubation, catheterisation, and phototherapy were mainly applied to case subjects. A low Apgar score and patent ductus arteriosus were diagnosed in a greater percentage of neonates with acute renal failure. Moreover, in the first few days of life and before diagnosis of acute renal failure, case subjects received more drugs (antibiotics, non-steroidal anti-inflammatory drugs, and diuretics) and for a longer time. In the multivariate logistic analysis, medullary hyperechogenicity (odds ratio (OR) 4.491; 95% confidence interval (CI) 1.879 to 10.731) and ceftazidime administration (OR 5.082; 95% CI 1.493 to 17.297) were associated with a greater risk of acute renal failure. Conclusions: The results suggest the need for careful monitoring of very low birthweight infants and attention to drug treatments, as it is difficult to differentiate between normality and renal failure in the first few days of life.

Spearman correlation coefficient was used to calculate correlations between the total AD use and the Hoftede's country scores for the six cultural dimensions (power distance, masculinity, indulgence, uncertainty avoidance, individualism) adjusted by pharmaceutical expenditure and general practitioners by 1000 inhabitants.

Introduction: The dispersion of chemicals in water ecosystems nowadays is a serious threat to wildlife animals, plants and can cause damage also to humans. Studies confirmed the presence of pharmaceuticals, namely NSAIDs and hormones, per- and polyfluoroalkyl substances (PFAS), and pesticides in small amounts in a wide variety of ecosystems, including rivers, lakes, and seas. As regards the pharmaceuticals class, NSAIDs and hormones have been detected in concentrations ranging from ng/L to lg/L [1]. Exposure to these compounds could damage the central nervous system, altering behavior and cognitive capacities. Among NSAIDs, ibuprofen and diclofenac were proven to be the most harmful for freshwater fish, also acting in a concerted fashion [2]. As for the hormones, 17-alpha-ethinylestradiol and 17-beta-estradiol are the ones most present in the environment and contributed > 97% to the total potential estro-genicity of the waters of Venice lagoon [3]. Many studies investigated the occurrence of human pharmaceuticals in the environment [4], although very limited knowledge is available on the effects of those drugs on non-target organisms (polychaetes, crustaceans, mollusks, fish, and others) in the aquatic environment [5]. Objective: Evaluate the neurodegenerative effects that the chronic exposure of adult zebrafish to diclofenac, ibuprofen, 17-alpha-ethinylestradiol, and 17-beta-estradiol at levels encountered in the environment. Methods: Animals are exposed for four weeks to 4 ascending concentrations of each pharmaceutical. Behavioral trials are carried out before and after the treatment. Novel tank test is performed to evaluate anxiety-like, stress and locomotion parameters, T-maze for assessing damages in spatial memory and olfactory preference test for the recognition of the insurgence of anosmia-i.e. the impairment of the sense of smell. Immediately after these trials, fishes are euthanized and included in paraffin. Immunohistochemistry studies are focused on the detection of tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT), markers of dopaminergic and cholinergic neurons. TH+ and ChAT? neurons are expected to be reduced by the treatment. Results: Ongoing studies prove that chronic exposure to diclofenac, ibuprofen, 17-alpha-ethinylestradiol, and 17-beta-estradiol alter cognitive and motor performance in line with neuroanatomical rearrangement. Conclusion: Our study provides a useful model for understanding the effects of pharmaceuticals in concentrations found in environmental waters [6], on behavioral and neuroanatomical substrates in the central and peripheral nervous systems.

Introduction: Raynaud's phenomenon (RP) is a vasospastic disorder characterized by a digital vascular alteration [1]. In literature there are few case reports suggesting the onset or the exacerbation of RP in patients with migraine, caused by calcitonin gene-related peptide (CGRP) antagonists, the newest class of anti-migraine drug [2]. Aim: To identify a risk of reporting for RP for anti-CGRP drugs using VigiBase® Methods: We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase®) by calculating the Reporting Odds Ratio (ROR) and Information Component (IC) for all anti-CGRPs, for the single class of mAbs and gepants and for single anti-CGRPs. The ROR and IC were calculated as follow: Cases: all reports with RP events; Non-cases: all reports without RP events; Index: a) all anti-CGRPs (class); b) mAbs (sub-class); c) gepants (sub-class); d) single anti-CGRP; reference: all drugs other than anti-CGRP. The information contained in this abstract does not represent the opinion of Uppsala Monitoring Center or the WHO. Results: We identified 166 drug-event pairs of suspected RP associated with anti-CGRPs in VigiBase®. The ICSRs in which a mAb was suspected were 81 erenumab, 52 galcanzeumab, and 28 fremanezumab. Ubrogepant and rimegepant, included in the gepant subclass, are reported with 4 and 5 ICSRs, respectively. Most of the patients were women (146, 88%). Of 166 ICSRs, 76.5% (127 ICSRs) were \"not serious\" while 23.5% (39) were \"serious\". The most quently events were constipation (11), arthralgia (9) and alopecia and weight increased (8 each one). Triptans are the most reported drugs as suspected/interacting/concomitant. The disproportionality analysis for all anti-CGRP revealed a significant ROR (12.3; ROR025 10.6) and IC (3.5; IC025 3.3). The disproportionality analysis for mAbs sub-class showed a significant ROR (13.3; ROR025 11.4) and IC (3.6; IC025 3.4). Also, the disproportionality analysis for gepants sub-class revealed a significant ROR (n = 8; 4.9; ROR025 2.5) and IC (2.0; IC025 0.8). Each single anti-CGRP had a significant ROR and IC. Conclusion: The disproportionality analysis showed a significant risk of reporting for RP associated with anti-CGRP. Notably, RP is described in patient with migraine. The exact mechanism of how RP and migraine are related is not fully understood, but it may involve CGRP. CGRP could have a protective role in maintaining peripheral blood flow. In this way, some authors suggest that anti-CGRP could activate or exacerbate RP. Further investigations, including observational studies and clinical assessments, are warranted to clarify the role of these drugs.

Objective To analyze prescriptions in a general-practitioner database over 1 year to determine the frequency, the characteristics, and the monitoring of the severe potential drug-drug interactions (DDIs). Methods We retrospectively analyzed the clinical records from 16 general practitioners in the Veneto region, an area in northern Italy. The study covered the period from January 1 to December 31, 2004. We selected all severe and well-documented interactions according to the book Drug Interaction Facts by David S. Tatro (Facts and Comparisons, St. Louis, MO, 2006). We grouped severe potential DDIs according to their specific potential risk, and for the most frequently interacting drug pairs, we investigated whether some specific tests had been prescribed by physicians for safety monitoring. Results During the study period, 16,037 patients (55% female) with at least one drug prescription were recorded, and a total of 185,704 prescriptions relating to 1,020 different drugs were analyzed. Ramipril was the most frequently prescribed drug followed by acetylsalicylic acid and atorvastatin. The final number of different types of severe potential DDIs was 119, which occurred 1,037 times in 758 patients (4.7% of the total number of patients). More than 80% of drugs involved in severe potential DDIs were cardiovascular drugs. Digoxin was the most frequently involved drug. Electrolyte disturbances, increase in serum digoxin levels, risk of hemorrhage, severe myopathy or rhabdomyolysis, and cardiac arrhythmias were the most commonly implicated potential risks. When considering patients using digoxin with loop or thiazide diuretics for more than 5 months, 72% had at least one test to monitor potential digoxin toxicity, whereas 28% had no tests. Sixty-four percent of patients using digoxin with amiodarone, verapamil, or propafenone had an ECG and/or digoxin monitoring, and 36% of them did not have any tests. Conclusions The present study revealed that, in a group of Italian general practitioners, the risks of severe potential drug interactions are relatively low and the drugs concerned are few. Analyses of specific tests showed that physicians are generally aware of the potential risks caused by digoxin drug associations. However not all patients were closely monitored and this should be improved.