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Aims: To investigate the occurrence of myopathy with oral glucose-lowering drugs (OGLDs) and statins, with a focus on dipeptidyl peptidase-4 inhibitors (DPP4-is). Methods: The FDA adverse event reporting system (FAERS) was queried (2004–2016) to compare the proportion of adverse events with OGLDs, alone and in combination with statins, using the reporting odds ratio (ROR) with relevant 95% confidence interval (95%Cl), adjusted for sex, age and concomitant presence of other OGLDs/lipid-lowering drugs. Drug–drug interaction is claimed whenever the frequency of an event is enhanced by combination treatment. Consistency/robustness of findings was tested by applying additive/multiplicative models and accounting for competition bias (i.e., adverse events previously known to be associated with OGLDs were removed). Results: Over a 13-year period, we retrieved 142,888 cases of myopathy. The use of DPP4-is alone was not associated with higher reporting of myopathy (no. of cases = 4898; adjusted ROR = 1.00; 95%CI = 0.96–1.04), with the notable exclusion of vildagliptin (262; 1.64; 1.42–1.88). No increased occurrence emerged when used in combination with statins, with consistent findings from additive/multiplicative models for all DPP4-is. Likewise, no increased reporting was found for other OGLDs (28,964; 0.64; 0.62–0.67); data on the interaction with statins were consistent/robust across analyses only for sulfonylureas (the interaction is likely and biologically plausible) and sodium glucose cotransporter-2 inhibitors. Conclusions: Real-world FAERS data do not raise concern for muscular toxicity with DPP4-is in combination with statins, making a drug interaction very unlikely.

Background: Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 or its ligand (PD1/PDL1), elicit different immune-related adverse events (irAEs), but their global safety is incompletely characterized. Objective: The aim of this study was to characterize the spectrum, frequency, and clinical features of ICI-related adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS). Patients and methods: AEs from FAERS (up to June 2018) recording ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab) as suspect were extracted. Comprehensive disproportionality analyses were performed through the reporting odds ratio (ROR) with 95% confidence interval (95% CI), using other oncological drugs as comparison. An overview of systematic reviews (OoSRs) was also undertaken to identify irAEs with consistent positive associations. Results: ICIs were recorded in 47,266 reports, submitted mainly by consumers receiving monotherapy with anti-PD1/PDL1 drugs. Three areas of toxicity emerged from both disproportionality analysis and the OoSRs (32 studies): endocrine (N = 2863; ROR = 6.91; 95% CI 6.60–7.23), hepatobiliary (2632; 1.33; 1.28–1.39), and respiratory disorders (7240; 1.04; 1.01–1.06). Different reporting patterns emerged for anti-CTLA4 drugs (e.g., hypophysitis, adrenal insufficiency, hypopituitarism, and prescribed overdose) and anti-PD1/PDL1 agents(e.g., pneumonitis, cholangitis, vanishing bile duct syndrome, tumor pseudoprogression, and inappropriate schedule of drug administration). No increased reporting emerged when comparing combination with monotherapy regimens, but multiple hepatobiliary/endocrine/respiratory irAEs were recorded. Conclusions: This parallel approach through contemporary post-marketing analysis and OoSRs confirmed that ICIs are associated with a multitude of irAEs, with different reporting patterns between anti-CTLA4 and anti-PD1/PDL1 medications. Close clinical monitoring is warranted to early diagnose and timely manage irAEs, especially respiratory, endocrine, and hepatic toxicities, which warrant further characterization; patient- and drug-related risk factors should be assessed through analytical pharmaco-epidemiological studies and prospective multicenter registries.

Background: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. Objective: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. Methods: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. Results: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12–2.52; and 2.53; 2.40–2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09–1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). Conclusion: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.

Background: Possible relationship between drug exposure and multiple sclerosis (MS) development is insufficiently investigated, and further challenged by the incomplete understanding of MS etiopathogenesis. The study aims to investigate whether drug exposure could contribute to MS, by analyzing worldwide spontaneous reporting archives of adverse drug reaction (ADRs). Research design and methods: We retrieved information from the US Food and Drug Administration Adverse Event Reporting System (FAERS) over a 13-year period. Reporting odds ratio (ROR) for MS was calculated for each single substance. Disproportionality signals were considered when at least 10 cases were retrieved with a lower limit of the 95% confidence interval (CI) >1. Results: After a customized data-mining process, 3,226 reports of MS were retrieved. ‘Antineoplastic and immunomodulating drugs’ (33% of total reports) were the most frequently reported, with 10 disproportionality signals, including etanercept (445 cases; ROR: 2.48; 95% Cl: 2.24–2.74), adalimumab (329; 2.05; 1.83–2.30), and infliximab (119; 2.25; 1.87–2.70). We also observed signals for drugs acting on hormone balance, bone density, and central nervous system. Conclusion: Our findings suggest that immunomodulatory drugs increase the risk of MS and point out that some other drug classes should be further investigated for this risk.

This observational study was aimed to identify patients who experienced non-deferrable surgery and/or uncontrolled severe bleeding following dabigatran administration and then are potentially eligible to the use of the specific antidote idarucizumab in a real-world setting. From the big Italian real-world database ARCO, a cohort of adult patients treated with dabigatran and hospitalized due to diagnoses attributable to urgent interventions and/or major bleeding was selected in 2014. Baseline characteristics and all-cause hospitalizations, specialist/diagnostic outpatient services, and healthcare costs over the 1-year follow-up were described. Out of 16,756,843 Italian citizens, 271,540 (1.9%) were prescribed with oral anticoagulants, and specifically, 17,450 with dabigatran. Patients identified to be hospitalized for non-deferrable surgery (n = 106) and/or uncontrolled severe bleeding (n = 190) following dabigatran use were 289 (1.7%) [mean age (± SD) 79 ± 7, 50% of female sex]. On average, patients stayed in hospital 13.7 and 17.0 days, respectively. The per patient and per year cost to the Italian National Health System was on average 19,708€ (specifically 1487€ for drugs, of which 311€ for dabigatran, 17,353€ for all-cause hospitalizations, and 869€ for outpatient care), about four times more than the mean healthcare integrated cost of a single patient treated with dabigatran (4775€). This analysis of the ARCO database reliably describes the population potentially eligible to the dabigatran reversal agent, idarucizumab. These data may be useful for Healthcare Decision Makers to organize, define, and improve present and future emergency healthcare, mainly as starting point for cost-effectiveness analyses of new reversal agents.

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.

Epidemiological data on primary progressive multiple sclerosis (PPMS) are scarce. This study was aimed to evaluate the burden of PPMS in Italy with healthcare resources utilisation and costs for Italian National Health System (INHS). A 2-year cross-sectional analysis of real-world data collected in the ARCO database, covering > 10 million Italian inhabitants, was performed. From a cohort of patients affected by MS in 2014, those supposedly affected by PPMS were defined by the concurrent matching of absence of disease-modifying treatments and use of rehabilitation services. Any other drug prescriptions, outpatient services and hospitalisations were analysed in 2015 for each subject. The average annual cost per patient was provided both for each expenditure item and by integrating these. Of 13,253,591 inhabitants, 18,453 resulted affected by MS (prevalence 139 × 100,000). Of these, 1849 agreed with additional criteria to identify PPMS (10% of MS population). The 26.8% of these experienced at least one admission in 1 year, 97.3% used at least one outpatient service and 94.3% received at least one reimbursed drug. In the perspective of INHS, PPMS generated an average annual cost of € 3783 per person: 49% for hospitalisations, 28% for outpatient services and 23% for drugs. This study provides a reliable estimation of the PPMS burden in Italy, in terms of healthcare utilisation and direct costs. These findings could be useful to estimate the changes in health expenditure following the incoming of new drugs to treat PPMS with increase of pharmaceutical cost and potential decrease of rehabilitation and hospitalisation costs.

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.

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.