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The recent position paper of the European Society of Cardiology (ESC) on cardiovascular toxicity of cancer treatments has attracted considerable interest by healthcare professionals, since it is the first concrete help in the difficult task of monitoring and approaching cardiovascular side effects of anticancer treatments. The ESC expert opinion was not intended as a clinical practice guideline; however, it reports major cardiovascular complications grouped into nine categories, addressing current clinical strategies for prevention and mitigation. In this point of view, we discuss key challenges emerging from critical appraisal of the ESC position paper: (1) the wide spectrum of cardiovascular toxicities associated with oncological drugs, focusing on targeted agents, (2) managing strategies in patients with cardiac implantable devices, (3) the underappreciated (but emerging) immune-related cardiovascular toxicities of checkpoint inhibitors, which may also result in severe heart failure and fulminant myocarditis, (4) the evolving role of anticoagulation in oncology, and the evidence supporting (or not) the use of direct-acting oral anticoagulants in cancer-associated thrombosis.

Arnaud and colleagues used WHO’s VigiBase, an international spontaneous reporting system, to compile an updated list (19 March 2018) of drugs suspected to be implicated in drug-induced systemic lupus erythematosus (SLE), an evolving clinical entity.1 They analysed 12 166 reports of drug-induced SLE and identified 118 suspected drugs with pharmacovigilance signal, which were reported in 8163 cases, mainly occurring in women (81%, 49 years as median age), defined as serious (55%), with a median onset of 172 days. Of note, 76 drugs (64.4%) were already known to cause SLE in the literature, including anti-TNF agents (infliximab received the highest number of reports), procainamide and hydralazine (receiving the highest disproportional reporting). Our attention was drawn to the lack of pharmacovigilance signal for immune checkpoint inhibitors (ICIs), emerging oncological drugs recently associated with a unique and distinct spectrum of …

This chapter aims to describe current and emerging roles of spontaneous reporting systems (SRSs) for assessing and monitoring drug safety. Moreover, it offers a perspective on the near future, which entails the so-called era of Big Data, keeping in mind both regulator and researcher viewpoints. After a panorama on key data sources and analyses of post-marketing data of adverse drug reactions, a critical appraisal of methodological issues and debated future applications of SRSs will be presented, including the exploitation and challenges in evidence integration (i.e., merging and combining heterogeneous sources of data into a unique indicator of risk) and patient’s reporting via social media. Finally, a call for a responsible use of these studies is offered, with a proposal on a set of minimum requirements to assess the quality of disproportionality analysis in terms of study conception, performing and reporting.

Background The management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections. Methods Three spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999–2008 vs. 2009–2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009–2017) was investigated for both Italy and UK. Results A total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p p p = 0.005) and UK (p = 0.032; p = 0.013) was found. Conclusion KPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues.

Introduction: Individuals with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk with regulatory agencies requiring cardiovascular outcome trials (CVOTs) for the approval of new antidiabetic drugs. Areas covered: In this paper, the authors critically discuss the background, trial design, results and implications of a recent CVOT [NCT01730534; DECLARE-TIMI 58 study], which demonstrated that dapagliflozin was non-inferior to placebo in terms of major adverse cardiovascular events, and superior for the occurrence of hospitalization for heart failure (HF) and composite renal endpoints, thus confirming the cardiovascular benefit of sodium-glucose co-transporter-2 (SGLT2) inhibitors. No statistically-significant effects were found for amputations, fractures, and stroke (debated safety issues having emerged in previous CVOTs). Expert opinion: DECLARE-TIMI 58 is the longest (4.2 years of follow up), largest (>17,000 participants) and most inclusive (only 41% of individuals with established atherosclerotic cardiovascular disease) CVOT raising the debate towards SGLT2 inhibitor therapy in primary prevention and the potential use of these drugs also in patients with HF without T2DM and other subpopulations.

PurposeThis study aims to describe factors associated to treatment continuity and psychiatric relapses in patients treated with Long Acting Injectable antipsychotics (LAIs) in Bologna Community Mental Health Centers (CMHCs).MethodsNew LAI treatments administered between July 1, 2010 and June 30, 2015 in CMHCs were selected. The cohort was followed-up for 6 months; predictors of continuity and psychiatric admissions were investigated by using logistic regression- and Cox- analysis respectively.ResultsAmong the cohort of 1 070 patients, only 222 (21%) continued LAI treatment during the follow-up. LAI continuity was higher with first generation agents (OR: 1.71, 95%CI 1.18-2.49) and in case of previous psychiatric hospitalizations (OR 2.00, 95%CI 1.47-2.74). Incidence of psychiatric hospital admissions showed a sharp reduction in the follow-up compared with 6-month period before initiation (from 458 to 212), and was associated with previous psychiatric hospitalizations (HR 3.20, 95%CI 2.22-4.59), immigration (HR 3.13, 95%CI 1.28-7.69) and LAI discontinuation (HR 1.14, 95%Cl 1.01-1.97).ConclusionsPsychiatric hospital admission before LAI initiation was the main predictor both of LAI continuity and hospitalization during the follow-up.

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.

BACKGROUND: An increasing number of reports indicates that vaccines against influenza may interact with specific drugs via drug metabolism. To date, actual impact of vaccine-drug interactions observed in the real world clinical practice has not been investigated. METHODS: From VAERS and VigiBase, we collected Adverse Event Following Immunization (AEFI) reports for individuals receiving vaccines against influenza recorded as suspect and selected cases where predictable toxicity was recorded with oral anticoagulants, antiepileptics and statins (i.e. hemorrhages, overdosage and rhabdomyolysis, respectively). We applied AEFI and Drug Interaction Probability Scale (DIPS) Algorithms to assess causality of drug-vaccine interactions. RESULTS: 116 AEFI reports submitted to VAERS and 83 from Vigibase were included in our analysis; antiepileptics and statins were related to the highest number of indeterminate/consistent (93.7%; 65.3%) and possible/probable (50%; 57.7%) cases according to the AEFI and DIPS, respectively. The majority of cases occurred within the first week after vaccine administration (5-7 days). CONCLUSION: The relative paucity of detected interactions does not impact on the benefit of the vaccination against influenza, which remains strongly recommended; this does not exclude that closer monitoring for selected patients exposed to concomitant chronic pharmacological therapies and affected by predisposing factors may be useful.

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches. Areas covered: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA. Expert opinion: The new 5-HT3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.

BACKGROUND: Approved in 2006, human papillomavirus (HPV) vaccines were initially targeted for girls aged 9-14 years. Although the safety of these vaccines has been monitored through post-licensure surveillance programmes, cases of neurological events have been reported worldwide. PURPOSE: The present study aimed to assess the risk of developing demyelination after HPV immunization by meta-analysing risk estimates from pharmacoepidemiologic studies. DATA SOURCES: A systematic review was conducted in Medline, Embase, ISI Web of Science and the Cochrane Library from inception to 10 May 2017, without language restriction. STUDY SELECTION: Only observational studies including a control group were retained. Study selection was performed by two independent reviewers with disagreements solved through discussion. DATA EXTRACTION: This meta-analysis was performed using a generic inverse variance random-effect model. Outcomes of interest included a broad category of central demyelination, multiple sclerosis (MS), optic neuritis (ON), and Guillain-Barre syndrome (GBS), each being considered independently. Heterogeneity was investigated; sensitivity and subgroup analyses were performed when necessary. In parallel, post-licensure safety studies were considered for a qualitative review. This study followed the PRISMA statement and the MOOSE reporting guideline. DATA SYNTHESIS: Of the 2863 references identified, 11 articles were selected for meta-analysis. No significant association emerged between HPV vaccination and central demyelination, the pooled odds ratio being 0.96 [95%CI 0.77-1.20], with a moderate but non-significant heterogeneity (I(2)=29%). Similar results were found for MS and ON. Sensitivity analyses did not alter our conclusions. Findings from qualitative review of 14 safety studies concluded in an absence of a relevant signal. LIMITATIONS: Owing to limited data on GBS, no meta-analysis was performed for this outcome. CONCLUSION: This study strongly supports the absence of association between HPV vaccines and central demyelination.

Introduction Pharmacotherapy used to treat type 2 diabetes mellitus (T2DM) is facing a paradigm shift in clinical practice with recent cardiovascular (CV) outcome trials having a substantial impact on drug prescription with treatment having a more tailored approach. In patients with T2DM, the issue of chronic liver disease is multifaceted. However, a clinical evidence is emerging on the beneficial effect of antidiabetic medications on nonalcoholic fatty liver disease (NAFLD). Areas covered The authors provide a synopsis on the current and upcoming pharmacotherapy for NAFLD, including the challenges with their development, focusing on drugs for T2DM. Clinical data on the potential benefits and safety issues are assessed with the aim of proposing an individualized algorithm for patient management. Both MEDLINE and ClinicalTrials.Gov are used to derive the relevant information. Expert opinion Considering the pivotal role of insulin resistance in NAFLD, insulin sensitizers should be the treatment of choice. Accordingly, pioglitazone is the only drug with a significant effect on liver fibrosis, the driver of disease progression and long-term outcome. Among new glucose-lowering drugs, glucagon-like-peptide 1 receptor agonists or sodium-glucose cotransporter type 2 inhibitors have shown positive effects in phase II studies and are qualifying as potential candidates for NAFLD treatment in diabetes.

Sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) have consistently demonstrated a clinically significant reduction of cardiovascular mortality. However, their safety in clinical practice is still incompletely characterized, and post-marketing monitoring is required considering the expected increase in clinical use. Different analyses of international spontaneous reporting systems, known as disproportionality analyses (DAs), have highlighted the occurrence of ketoacidosis, amputations, acute renal failure and skin toxicity. In this viewpoint, we critically appraise these pharmacovigilance data on SGLT2-Is, with the aim of supporting clinicians in proper interpretation of these studies, and discussing their risk-benefit profile. To this aim, we offer a broad perspective on basic technical aspects subtending DAs of spontaneous reporting databases (describing peculiarities of the Food and Drug Administration Adverse Event Reporting System), their common and evolving uses, key pitfalls in presenting study results (in terms of "risk" or "association") and relevant strategies to account for major confounders. This will also facilitate reviewers and editors in proper evaluation of DAs, and prompt pharmacovigilance experts in converging towards a set of minimum requirements in standardization of design, performance and reporting of DAs. A consensus on quality assessment of DAs will finally establish their transferability to clinical practice. It is anticipated that DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient.

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 (

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

Aim: To characterize cases of myocarditis (MC) and pericarditis (PC) recorded in the Vaccine Adverse Event Reporting System (VAERS). Methods: Cases were extracted from VAERS (2011–2015) and assessed for causality using standardized WHO algorithm. Disproportionality analysis was performed through reporting odds ratio (ROR) with 95%CI. MEDLINE was also searched. Results: In VAERS, 199 cases of MC or PC were collected, among which 149 reported smallpox vaccine. The remaining were: 15 cases in ‘YOUNGER GROUP’ (YG; 18 years old). Main reported vaccines were against Human Papilloma Virus (n = 6) in YG and influenza (n = 16) in OG. Causality always resulted “undeterminate” for YG, whereas either “undetermined” (30 cases) and “correlated” (3 cases) for OG. Statistically significant ROR was found in YG for meningococcal vaccine (ROR = 3.55; 95%CI = 1.23–10.24) and in OG for thyphoid vaccine (11.13; 7.73–16.03), Japanese encephalitis vaccine (8.54; 2.7–27.01), anthrax (25.5; 18.8–34.5), and, as expected, smallpox (71.88; 49.25–104.89). In MEDLINE, 91 articles were found: positive/possible causality was frequently reported. Conclusions: MC and PC after immunization appear extremely rare; only in very few cases can a role of vaccine be actually identified. Signals for vaccines against typhus, Japanese encephalitis, anthrax and meningococcus warrant monitoring.

Direct-acting oral anticoagulants (DOACs), by virtue of pharmacological properties perceived as innovative, are changing the therapeutic scenario of patients requiring short- and long-term anticoagulation. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirms that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy, effectiveness and unequivocally documents a clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (AF) and venous thromboembolism. The following issues are attracting considerable clinical interest: (a) identifying specific subpopulations of patients with AF most likely to benefit from one of these agents (the so-called tailored therapy), and (b) expanding therapeutic indications in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk–benefit profile of DOACs, as compared to VKAs or heparins, is still incompletely characterized. In cardiology, the challenging task of selecting a suitable or even the most appropriate DOAC for patients with AF and a particular phenotype prompted experts to provide suggestions based on careful review of subgroups of patients from pivotal RCTs. However, in the past few months, variegated multicenter trials have been published (RE-CIRCUIT, PIONEER-AF-PCI, GEMINI-ACS-1), with potential influence on clinical practice. Therefore, this review aims to update the latest evidence on the evolving therapeutic uses of DOACs in the cardiovascular area, addressing potential impact for clinicians.

Introduction: The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated. Objective: The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association. Methods: A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies. Results: After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results. Conclusion: A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes.

Background: Drug use in preterm neonates admitted to Neonatal Intensive Care Unit (NICU) has been investigated, so far, in terms of unauthorized or off-label use; very little is known on the use of combinations of different active substances, which is frequently required in this population (prophylaxis of infections, treatment of concomitant diseases). The aim of this study was to describe the most common patterns of drug use in an Italian NICU, focusing on those with nephrotoxic potential. Methods: Medical records of preterm neonates (

Aims Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). Methods Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO-Vigibase was also queried. Results From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase. Conclusions The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.

A systematic review was performed to categorize the hERG (human ether-a-go-go-related gene) liability of antihistamines, antipsychotics, and anti-infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half-minimal inhibitory concentrations (IC50). A "hERG safety margin" was calculated from the IC50 divided by the peak human plasma concentration (free Cmax ). A margin below 30 defined hERG liability. Each drug was assigned an "uncertainty score" based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty-one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti-infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/Cmax data, or other patient/drug-specific factors that contribute to real-life TdP risk.

Direct-acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short- and long-term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories.

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Background and aims We assessed post-marketing safety of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) by analyzing adverse events (AEs) reported in international pharmacovigilance databases. Methods and results Eudravigilance, WHO-Vigibase (as of Feb 25, 2017) and the FDA Adverse Event Reporting System (FAERS, from 2004 to 2016 second quarter) were queried to extract AEs recording SGLT2-Is as suspect. Disproportionality analyses (case/non-case method) were performed in FAERS by calculating the reporting odds ratios (RORs) from System Organ Classes (SOCs) to Preferred Terms (PTs) (precise clinical entities). Potential signals were defined by statistically-significant ROR (lower limit of the 95% confidence interval – LL95%CI – >1) undetected by literature analysis (as of December 2016). SGLT2-Is were recorded in 7972, 19,775, 11,137 reports (Eudravigilance, WHO-Vigibase and FAERS, respectively); in FAERS, statistically significant ROR emerged for the following SOCs: “infections and infestations” (N = 2162; LL95%CI = 3.25), “metabolism and nutrition disorders” (2278; 1.36), “renal and urinary disorders” (1665; 2.31), “reproductive system and breast disorders” (471; 4.85), “skin and subcutaneous tissue disorders” (1136; 1.52). Skin toxicity emerged as potential signal (e.g., rash, photosensitivity, urticaria as PTs), both for SGLT2-Is as a class and as individual drugs. Severe adverse skin events (81 reports, 7% of the skin cases) mainly occurred in females aged 18–65 using SGLT2-Is as single antidiabetic regimen. Conclusion Among antidiabetics, SGLT2-Is are associated with higher reporting of infections, metabolism, renal and reproductive AEs, corroborating clinical trial evidence. Their large reporting patterns and the unexpected signal of skin toxicity justify active vigilance by clinicians and “real-time” monitoring by pharmacovigilance experts.

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 Apart from the underlying cardiovascular (CV) risk associated with migraine, both triptans and ergotamines can induce vasoconstriction and potentially increase the risk of serious ischemic events. Because of the low frequency of such events in eligible patients, randomized controlled trials are not exhaustive to assess the drug-related CV risk. Observational studies are, therefore, an essential source of information to clarify this matter of concern. Aim The aim of this study was to systematically review the available published observational studies investigating the risk of serious CV events in triptan or ergotamine users, as compared to unexposed migraineur controls. Methods We systematically searched MEDLINE and EMBASE electronic databases for cohort or case-control studies up to December 1, 2013. Studies retrieved from CDSR, DARE and HTA databases of the Cochrane Library were used for snowballing. Studies investigating the risk of any CV outcome in patients with a migraine diagnosis and exposed to triptans or ergotamines were considered for inclusion. Selection of studies, data extraction, and risk of bias assessment were conducted independently by two reviewers. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were computed using a random-effects model for studies and outcomes judged eligible for quantitative data synthesis. Results From a total of 3370 citations retrieved, after duplicate removal and screening, only four studies met the inclusion criteria (three nested case-control analyses and one retrospective cohort study). These studies investigated the risk of different CV outcomes associated with either the recency or the intensity of exposure to the studied drugs. As for the intensity of use, the pooled OR of serious ischemic events was 2.28 (95% CI 1.18–4.41; I2 = 0%) for ergotamine use (two studies), whereas for triptans (three studies) it was 0.86 (95% CI 0.52–1.43; I2 = 24.5%). Recent use of ergotamines was not significantly associated with any CV outcome (only one available study). Two studies investigated the risk of stroke related to recent triptan use: the first study reported an OR of 0.90 (0.64–1.26), and the second one suggested an increased risk of 2.51 (1.10–5.71). In this case, because of the high degree of heterogeneity, results were not pooled. Conclusions To date, few comparative observational studies have investigated the CV safety of migraine-specific drugs in clinical practice. Evidence gathered here suggests that intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues, although no firm conclusions can be drawn. In particular, evidence on stroke risk is conflicting. However, if an increase of the absolute stroke risk in recently exposed patients does actually exist, it must be small. Overall, residual uncontrolled confounding factors reduce the confidence in the risk estimates collected from the included studies. Further investigations are needed to better define the risk for rare but serious CV events related to triptan and ergotamine use for treatment of migraine.

PURPOSE: Data mining in spontaneous reporting databases generates large numbers of signals of disproportionate reporting (SDRs) that need to be prioritised for assessment. The pharmacological relevance of drug-event associations is not considered in SDR prioritisation algorithms. This aimed to propose and test a pharmacological score for SDR prioritisation. METHODS: The Pharmacological Score for SDRs Prioritisation (PS-SP) was developed using a Delphi approach. An expert group agreed that PS-SP should include general criteria concerning SDRs and criteria concerning pharmacological relevance, and that criteria should be weighted for their risk representation. Once defined, the PS-SP was tested for prioritisation of SDRs for extrapyramidal syndrome in the French Pharmacovigilance database; the SDR classification was compared to that obtained using a traditional disproportionality approach. RESULTS: For a given drug, the general criteria retained were the reporting rate of the adverse drug reaction (ADR) and value of the 95% confidence interval (CI) lower boundary of the Reporting Odds Ratio (ROR). Pharmacological criteria consisted of the ADR reporting rate without concomitant at-risk drugs or those indicated for ADR treatment, and the value of the ROR 95% CI lower boundary as estimated in the subset of reports concerning drugs from the same therapeutic and then pharmacological class. Compared with traditional disproportionality, PS-SP prioritised specific drugs within congeners: metoclopramide, indoramin, and trimetazidine appeared as outliers within their classes; conventional antipsychotics had higher prioritisation than atypical antipsychotics. CONCLUSION: The pilot evaluation of PS-SP performed in extrapyramidal syndrome advocates for the use of pharmacological criteria in SDR prioritisation algorithms.

INTRODUCTION: Lubiprostone acts locally (apical membrane of human intestinal epithelial cells) as a highly selective type-2 chloride channel activator. It was approved in the USA for chronic idiopathic constipation (January 2006) and in women aged ≥ 18 years suffering from irritable bowel syndrome with constipation (IBS-C) (April 2008). So far, the only other pro-secretory medication approved in IBS-C and currently available in USA and Europe (since August and November 2012, respectively) is linaclotide. AREAS COVERED: This review outlines the regulatory history, pharmacokinetic, pharmacodynamic and safety data in the treatment of IBS-C with a European perspective. It is based on publicly available data, namely, published literature, drug labels and the FDA's spontaneous reporting system. EXPERT OPINION: Although interesting pharmacodynamic data suggest that lubiprostone may have additional mechanisms of action, its beneficial effects in IBS-C must be confirmed in the actual clinical scenario taking into account the new version of European Medicines Agency's guideline. This is especially important with regard to duration of studies (recommended to be at least 6 months) to adequately assess long-term sustained efficacy, withdrawal, rebound and safety. Further research is warranted in uncertain areas (i.e., males, pediatric and elderly patients). On the basis of current data, it is still too early to draw definite conclusions on the overall risk-benefit balance for IBS-C.

Introduction: Multiple reforms in Sweden appreciably enhanced prescribing efficiency for proton pump inhibitors, statins and renin-angiotensin inhibitor drugs. Potential exists to extend this to atypical antipsychotic drugs (AAPs), given their expenditure and oral generic risperidone available in Sweden from January 2009. However schizophrenia and bipolar disease are complex to treat and there is a need to tailor treatments, given the considerable inter-patient variability in responses and side-effects to different AAPs. Objectives: Assess changes in risperidone utilisation before and after oral generic risperidone reimbursed in January 2009 alongside any specific demand-side measures. In addition, to: (a) assess price reductions for risperidone over time and overall AAP expenditure; (b) suggest additional measures that could potentially be introduced; and (c) provide guidance to other European countries on the implications of any findings. Method: Principally a retrospective observational study and interrupted time series design. Key findings: No specific measures to encourage the prescribing of risperidone, and no appreciable change in its utilisation, after generics reimbursed. Oral risperidone was 96% generic, and its price 80% below pre-patent loss prices, by August 2011. This limited the increase in AAP expenditure compared with utilisation after generics. Conclusion: No apparent effectiveness or safety problems with generic risperidone. Authorities cannot rely on a spill-over from other disease areas to effect changes in physician prescribing habits. Specific measures are needed to encourage the prescribing of generic AAPs first line, where appropriate, exacerbated by the complexity of the disease areas. Their influence will be probably limited by the need to tailor treatment. © 2013 Royal Pharmaceutical Society.

Background Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82–84.60), cyamemazine (11; 15.48, 6.87–34.91), and olanzapine (189; 7.74, 6.45–9.30). Conclusions This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk. Electronic supplementary material The online version of this article (doi:10.1007/s40264-013-0032-z) contains supplementary material, which is available to authorized users.

In response to Tufan and colleagues, it is true that older frail patients are under-represented in our meta-analysis, but such patients are under-represented in clinical trials in general, not just those investigating type 2 diabetes.1 2 Even when there is no formal age limit, the common exclusion of patients with organ dysfunction and comorbidities means that most older people are excluded.3 We can but hope that further trials will provide more information on benefits and risks of drugs in older people and will update …

Since 2008, the direct-acting oral anticoagulants (DOACs) have expanded the therapeutic options of cardiovascular diseases with recognized clinical and epidemiological impact, such as non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and also in the preventive setting of orthopedic surgical patients. The large body of evidence, not only from pivotal clinical trials but also from ‘real-world’ postmarketing observational findings (e.g. analytical epidemiological studies and registry data) gathered to date allow for a first attempt at verifying a posteriori whether or not the pharmacological advantages of the DOACs actually translate into therapeutic innovation, with relevant implications for clinicians, regulators and patients. This review aims to synthesize the risk–benefit profile of DOACs in the aforementioned consolidated indications through an ‘evidence summary’ approach gathering the existent evidence-based data, particularly systematic reviews with meta-analyses of randomized controlled trials, as well as observational studies, comparing DOACs with vitamin K antagonists. Clinical evidence will be discussed and compared with major international guidelines to identify whether an update is needed. Controversial clinically relevant safety issues will be also examined in order to highlight current challenges and unsettled questions (e.g. actual bleeding risk in susceptible populations). It is anticipated that the large number of publications on NVAF or VTE (44 systematic reviews with meta-analyses and 12 observational studies retained in our analysis) suggests the potential existence of overlapping studies and calls for common criteria to qualitatively and quantitatively assess discordances, thus guiding future research. Electronic supplementary material The online version of this article (doi:10.1007/s40264-016-0464-3) contains supplementary material, which is available to authorized users.

We are facing a paradigm shift in the era of antidiabetics, because agents marketed after 2008 (i.e., after the rosiglitazone saga) are not only required to reduce levels of HbA1, but also to demonstrate beneficial or at least neutral effect with regard to cardiovascular (CV) outcomes (Figure 1). This is of paramount relevance, considering that the risk of developing CV disease is two-fold higher in patients with diabetes compared with individuals without diabetes [1]. Thus, pharmacovigilance is gaining a crucial role in guiding research and supporting clinical practice.

Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), have entered the market in 2008 with the expected breakthrough potential of circumventing limitations related to treatment with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although data derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit of DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safety in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy, in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluate the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need for pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) the importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section, emerging and debated safety issues potentially associated with the use of DOACs in the postmarketing setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period); 2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports or series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepatic and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.

PURPOSE: Our aim was to evaluate whether dronedarone authorization impacts antiarrhythmic drug prescribing in Sweden and Emilia Romagna (Italy). METHODS: Prescriptions of classes I and III antiarrhythmics, expressed as defined daily doses per thousand inhabitants per day (DDD/TID) were monthly using information collected from pharmacy-reimbursed databases. Interrupted time series analysis was applied to compare prescription data over the 2009-2011 period. RESULTS: In Emilia Romagna, the overall consumption of antiarrhythmics was six times as high as in Sweden (7.6 vs. 1.2 DDD/TID). In the first year on the market, dronedarone represented 1.0 % in Italy and 10.7 % in Sweden of the overall antiarrhythmic prescriptions. In Sweden, dronedarone authorization generated an increase in the prescription trend of antiarrhythmics (trend change +0.02; p < 0.001) without variation in amiodarone use In Emilia Romagna, dronedarone marketing did not influence the prescription pattern of either overall antiarrhythmics or amiodarone. CONCLUSIONS: Emilia Romagna and Sweden substantially differ in terms of overall antiarrhythmic use. Although clinical guidelines place dronedarone among first-choice treatments for atrial fibrillation, amiodarone prescribing was not affected in either country by the entry of dronedarone, probably due to a cautious approach by clinicians in line with regulatory recommendations and safety warnings.

BACKGROUND: The risk of myocardial infarction, macular oedema and bone fractures associated with thiazolidinediones (TZDs) has been extensively investigated. OBJECTIVE: The aim of the study was to verify if the analysis of a large spontaneous reporting database could generate early signals on these adverse drug reactions (ADRs) associated with TZDs. METHODS: A case/non-case study, restricted to antidiabetic drugs, was performed on spontaneous reports of ADRs (2005-2008) in the US FDA Adverse Event Reporting System (AERS). The method was applied to TZDs, both as a drug class and as single agents. The reporting odds ratio (ROR) with 95% CI was calculated as a measure of disproportionality in the whole dataset and in a quarter-by-quarter analysis. RESULTS: TZD use was registered in 49 589 out of 301 950 drug-reaction pairs (16%), with significant disproportionality for myocardial infarction (ROR 4.71; 95% CI 4.40, 5.05), macular oedema (3.88; 2.79, 5.39) and bone fractures (1.73; 1.53, 1.96). Separate analysis of the two TZDs showed that only rosiglitazone was associated with myocardial infarction (7.86; 7.34, 8.34) and macular oedema (5.55; 3.94, 7.79), whereas pioglitazone was associated with multiple site fractures (2.00; 1.70, 2.35), in particular upper and lower limb and pelvic fractures. The quarter-by-quarter analysis identified disproportionality for myocardial infarction (3.13; 2.38, 4.10) and bone fractures since January-March 2005 (2.70; 1.04, 2.78). CONCLUSIONS: The frequency of reporting of myocardial infarction, macular oedema and fractures was significantly higher for TZDs in comparison with other antidiabetic drugs, with large intraclass differences. Both myocardial infarction and bone fracture signals appeared before major publications on these safety issues.

Over the last decade, the advent of molecular targeted therapy radically changed the treatment of several forms of cancer. However, these innovative anticancer drugs, namely monoclonal antibodies and small molecule tyrosine kinase inhibitors were found to adversely affect cardiovascular function. These "on-target" and "off-target" drug side effects encompass a wide range of cardio toxicities, including left ventricular dysfunction leading to heart failure, electrocardiographic abnormalities with dysrhythmias, hypertension, myocardial ischemia and thromboembolic events. The unclear incidence of drug-induced cardiovascular events together with uncertainty on their reversibility and long-term safety call for a multidisciplinary effort embracing cardio-oncological expertise supported by primary care physicians, pharmacologists and toxicologists. Here we address emerging cardiovascular events associated with targeted anticancer drugs by offering a concise review on: (1) mechanistic basis subtending cardiotoxicity and (2) clinical advice for effective patient management (i.e., detection, treatment, monitoring and reporting of cardiovascular side effects). In this scenario, onco-vigilance (i.e., pharmacovigilance oriented to oncologic drugs) is emerging as a key to support cardio-oncologists in appropriateness [corrected].