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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.We aimed to identify targets potentially contributing to pathologic impulsivity.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.Among 19,887 reports of impulsivity, 5,898 recorded an antipsychotic, and 3,100 a dopamine agonist. The more robust signals concerned aripiprazole (N=3,091; 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).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. This article is protected by copyright. All rights reserved.

Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.

Aims The aim was to assess the impact of a campaign for general practitioners (GPs) to reduce clinically-important drug–drug interactions (DDIs) in poly-treated elderly patients. Methods We compiled a list of 53 DDIs and analyzed reimbursed prescriptions dispensed to poly-treated (≥four drugs) elderly (>65 years) patients in the Emilia Romagna region during January 2011–June 2011 (first pre-intervention period), January 2012–June 2012 (second pre-intervention period) and January 2013–June 2013 (post-intervention period). Educational initiatives to GPs were completed in July 2012–December 2012. Pre-test/post-test analysis (2013 vs. 2012) was performed, also using predicted 2013 data (P

Since August 2012, Italian general practitioners are required to prescribe the generic name of medicines, except for refill of chronic therapy. We evaluated the extent of switching among equivalents in chronic cardiovascular therapies, the influence of the 2012 regulatory intervention and of patient-related or drug-related factors. Prescriptions of off-patent anti-arrhythmics, oral antidiabetics and ACE inhibitors dispensed from August 2011 to August 2013 within the Bologna Local Health Authority (870,000 inhabitants) was collected. The rate of actual switching among equivalents was evaluated monthly. The effect of the regulatory intervention was estimated by interrupted-time-series analysis. Adjusted odds ratios (aORs) of switching were calculated for the following: age, gender, number of different equivalents available for each drug and change in dispensing pharmacy between subsequent refills. The average monthly rates of switches were 9.6%, 16.3% and 16.3% for anti-arrhythmics, antidiabetics and ACE inhibitors, respectively. Values significantly increased soon after the regulatory intervention for ACE inhibitors (+1.81%, p < 0.01), anti-arrhythmics (+1.46%, p = 0.01) and antidiabetics (+1.09%, p = 0.01), and no significant decreasing trends were observed in the following 12 months. For all drug classes, odd of switching was higher in case of change in dispensing pharmacy (up to aOR = 4.31, 95 CI = 4.26-4.35 for ACE inhibitors) and availability of ≥5 different equivalents (up to aOR = 7.82, 95 CI = 7.39-8.28 for antidiabetics). Switching was lower for age ≥65 for antidiabetics and ACE inhibitors (aOR = 0.92, 95 CI = 0.90-0.93; 0.87, 0.86-0.88, respectively). The Italian regulatory intervention generated an immediate increase, not sustained in time, in switching among equivalents of cardiovascular therapies. Young age, high number of available equivalents and changes in dispensing pharmacy between subsequent refills were associated with switching.

Aim We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). Methods We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. Results DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (

Aims To investigate spontaneous reports of TdP present in the public version of the FDA Adverse Event Reporting System (AERS) in the light of what is already known on their TdP-liability. Methods Reports of TdP from January 2004 through December 2007 were retrieved from the public version of the AERS database. All reports were selected from REACTION files and the relevant suspected and/or interacting drugs were identified from DRUG files. Qualitative analysis was performed by the case/non-case method. Cases were represented by TdP reports, whereas non-cases were all reports of adverse drug reactions other than TdP. Quantitative analysis was assessed by calculating the crude and adjusted reporting odds ratio (ROR), as a measure of disproportionality, with the 95% confidence interval. Results Reports of TdP were 1665 over a 4-year period, involving 376 active substances. Thirty-five drugs with at least 10 reports were identified: amiodarone and methadone were associated with the highest number of cases (113 and 83 respectively) and most of the other reports were ascribable to antibacterials, antidepressants and antipsychotics; remarkable differences in number of cases and ROR were present among agents within each therapeutic class. A disproportionate reporting was also observed for other compounds such as donepezil, famotidine and mitoxantrone. Conclusions Large spontaneous reporting databases represent an important source for signal detection of rare adverse drug reactions (ADR), such as TdP. The number of reports associated to donepezil, famotidine and mitoxantrone could be considered unexpected on the basis of current evidence and needs further investigations on their true TdP-liability.

Drug-induced QT prolongation is recognized as a surrogate marker of cardiotoxicity with significant regulatory and clinical impact [1]. Recently, concern is emerging about the pro-arrhythmic risk associated with QT interval shortening, which is also recognized as a congenital clinical entity that may trigger potentially fatal tachyarrhythmias (i.e. ventricular fibrillation and sudden cardiac death) [2][w1, w2]. From a regulatory standpoint, whether or not QT shortening (and especially the magnitude of shortening) should be taken as a safety surrogate is a matter of debate [w3, w4], although a recent industry survey estimated that 13% of compounds with QT shortening potential were discontinued in the pre-clinical phase [3]. As compared with drug-induced QT prolongation/torsade de pointes (TdP) [4], the magnitude of the problem in the clinical setting is currently unknown and, to the best of our knowledge, no post-marketing investigations have been carried out. Therefore, we investigated spontaneous reports of QT interval shortening submitted to the FDA Adverse Event Reporting System (FDA_AERS) database. To this end, publicly accessible quarterly data files (2004–2010) were used (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm083765.htm, last accessed 19/04/2011). Methodological issues are detailed in the ‘online supporting information’ material [w5, w6]. After duplicate removal, 2 131 688 cases were retrieved: QT shortening was reported in 42 cases (as compared with 5323 reports of QT prolongation). Paracetamol was reported in five cases as suspect. Digoxin and ziprasidone received three reports (Table 1). Details on demographic data, concomitant drugs, severity of reports and relevant co-reported adverse drug reactions (ADRs) are provided in the ‘online supporting information’. Table 1 Synopsis of implicated drugs associated with spontaneous reports of QT shortening Notably, in 35 cases (83%), QT shortening was reported in association with arrhythmia-related events, especially with atrial fibrillation (nine reports), some of which were potentially fatal (seven cases with ventricular fibrillation, five with cardiac arrest and three with TdP). QT prolongation and shortening were co-reported in 10 cases. Most cases occurred in females (62%, three missing data), were serious (i.e. in 68% of cases death, hospitalization or life-threatening events were reported) and submitted by the USA (11 reports, with 14 missing data). Although the FDA_AERS represents a great opportunity to detect emerging safety issues and increase transparency, several caveats should be addressed before interpreting the results [w7]. In this specific case, the causality assessment remains challenging due to the high number of reported drugs in each case and lack of additional clinical information (e.g. the actual QT interval value). As compared with QT prolongation, QT shortening remains elusive. The reasons for this are unclear, but rarity of the event, under-recognition/lack of awareness among physicians and novelty of the topic may play a role. An active monitoring in the next 5 years could provide a more realistic clinical picture, especially if clinicians consider QT shortening among differential diagnoses when suspecting an ADR or a drug-induced arrhythmia. The reporting pattern with serious arrhythmic events is remarkable, consistent with the hypothesis that QT shortening can predict arrhythmia [2] and warrants further investigation (also in terms of risk factors). For rufinamide and digoxin, reports were expected. Rufinamide is probably the first example of a QT shortening drug approved in the post ICH E14 period, showing a concentration-dependent decrease of the QT interval (7.5 ms at therapeutic plasma concentration, with a maximum effect of 27.8 ms). However, no signals of sudden death or ventricular arrhythmia were detected [5]. The single QT shortening report (out of total 78 ADRs, data not shown) is easily explained by the recent marketing authorization and its restricted therapeutic indication (the Lennox-Gastaut syndrome). Digoxin (three reports) is touted as having QT shortening properties [w8], whereas lamotrigine had no cases retrieved in our analysis, despite a recently documented QT shortening effect [w9]. In several cases, QT shortening was reported with drugs known for QT prolonging effect (e.g. moxifloxacin). While this may be interpreted as an electrocardiographic artifact or even a coding error, one could argue that long and short QT syndrome share similar electrophysiological mechanisms subtending arrhythmogenesis (i.e. increase in transmural dispersion of repolarization with early after depolarizations) [w10, w11]. Because several variables may affect the QT interval, cardiologists should interpret the clinical significance of this electrocardiographic paradox case-by-case. For instance, the imprecision of Bazett's correction may lead to erroneous QT shortening in the case of bradycardia (see reports associated with aripiprazole, atomoxetine and atenolol) [w12]. This exploratory study calls for consensus among regulators and clinicians on event definition (i.e. thresholds of concern in drug-induced QT shortening). On clinical grounds, formal diagnostic criteria have been recently developed [w13]. On regulatory grounds, Shah proposed the following values: 320 ms (absolute value) or an 80 ms decrease vs. baseline (with a mean decrease in central tendency of −15 ms with a 95% lower limit of 30 ms) [5]. Cardiologists should also define ‘minimum requirements’ to report QT interval abnormalities (e.g. by providing the QT interval value). In conclusion, drug-induced QT shortening remains elusive and requires further studies on its role as a surrogate marker of pro-arrhythmia. The current interest of the European Union in improving pharmacovigilance calls for multidisciplinary efforts by regulators and clinicians to reach consensus on the definition and reporting of QT interval abnormalities. This will enable pharmacovigilance data to become a more reliable indicator of risk.