Comparing the Prevalence of Polypharmacy and Potential Drug-Drug Interactions in Nursing Homes and in the Community Dwelling Elderly of Emilia Romagna Region.

Backround: We aimed at assessing the prevalence of polypharmacy and potential drug-drug interactions (DDIs) with clinical relevance in elderly patient on Emilia Romagna area. Both outpatients and residents in nursing homes were assessed, with only partially overlapping strategies. Methods: We defined a list of 190 pairs of potentially interacting drugs, based on literature appraisal and availability of therapeutic alternatives. January-June 2018 data on drug use in patients over 65 years-old were collected from nine Local Health Authorities of Emilia Romagna: data on community-dwelling subjects were extracted from archives of reimbursed prescriptions, while drug use in a sample of nursing homes was recorded from clinical charts in one index day within the same semester. The frequency of polypharmacy (at least five or at least 10 concurrent drugs) and of each DDI was calculated. Results: In line with different rates of polypharmacy (80% vs 16%), the risk of exposure to at least one interaction was 53.7% in nursing homes and 26.4% in outpatients. Among DDIs, in nursing homes antidepressants-anxiolytics (11.9%) ranked first, followed by antidepressants-aspirin (7.4%). In outpatients, ACE-inhibitors-non-steroidal anti-inflammatory drugs (NSAIDs) reached 7.2% followed by the calcium channel blockers-α-blockers (2.4%). Discussion: Polypharmacy and risk of DDIs appeared very different in the two settings, due to both technical and clinical reasons. In order to reduce use of benzodiazepines, NSAIDs, antidepressants and relevant DDIs, 1) defining alternative options for pain relief in elderly outpatients, and 2) implementing non-pharmacological management of insomnia and anxiety in nursing homes should be prioritized.

Antibacterial prescription in Italian preschool children: analysis of 7 years of data from the Emilia-Romagna region reimbursement database.

OBJECTIVES: To describe antibacterial prescribing patterns in outpatients aged 0-5 years from 2007 to 2013 in the Emilia-Romagna region, assessing sex- and age-specific consumption over time. METHODS: All children aged 0-5 years resident in the Emilia-Romagna region who received at least one prescription of a systemic antibacterial in the period 2007-13 were enrolled. The prescriptions of systemic antibacterials to children were collected from the regional prescription database. Data were stratified by year, sex and age, and analysed in terms of periodic prevalence and of annual prescription rate per 1000 person-years. RESULTS: The prevalence of children receiving at least one prescription per year varied from 68.0% in 2007 to 59.0% in 2013, while the average prevalence of children receiving five or more prescriptions per year was 6.96%. The annual prescription rate varied from 1621.26 in 2007 to 1372.27 in 2013. Penicillins + ß-lactamase inhibitors accounted for 35.3% of total prescriptions, followed by extended-spectrum penicillins (28.6%), macrolides (17.0%) and third-generation cephalosporins (13.9%). CONCLUSIONS: Despite recommendations, a significant overprescription of antibacterials to children still exists, showing no satisfactory improvements over the years. In contrast to Northern European countries, adherence to evidence-based guidelines was poor, with frequent prescribing of broad-spectrum agents for the treatment of mostly viral childhood infectious disease.

Comparative risk/benefit profile of biosimilar and originator erythropoiesis-stimulating agents (ESAs): data from an Italian observational study in nephrology.

PURPOSE: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD). METHODS: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results. RESULTS: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001). CONCLUSIONS: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators.

Antidepressant-Induced Acute Liver Injury: A Case-Control Study in an Italian Inpatient Population.

INTRODUCTION: Pre-marketing clinical trials show that antidepressant-induced liver injury seems to be a rare adverse event. Because of short follow-up trial duration, the incidence of liver injury due to antidepressant use could be underestimated. OBJECTIVES: We aimed to quantify the risk of acute liver injury associated with antidepressant use through a case-control analysis among an inpatient population. METHODS: A multicenter study was carried out in nine Italian hospitals from October 2010 to January 2014, within the DILI-IT (Drug-Induced Liver Injury in Italy) study project. After exclusion of all patients with a clear competing cause of liver injury, cases were defined as adults admitted to the hospital with a diagnosis of acute liver injury, while controls had any other acute clinical condition not related to the liver. Antidepressant exposure was evaluated within 90 days prior to the date of the first sign/symptom of liver injury. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated as a measure of risk estimates for liver injury. RESULTS: We included 17 cases exposed to antidepressants matched to 99 controls. According to the features of liver injury, all cases showed symptomatic liver function test abnormalities at hospital admission, with the main signs/symptoms represented by fatigue, nausea, asthenia, or dark urine. Citalopram was the antidepressant mostly involved in the increase of liver enzymes, mainly alanine aminotransferase. Compared with non-use, current use of antidepressants was associated with a significantly increased risk of liver injury (adjusted OR, ORADJ, 1.84; 95% CI 1.02-3.32). Specifically, an increased, but not significant, risk of developing liver injury was observed for citalopram, a selective serotonin-reuptake inhibitor (ORADJ 1.82; 95% CI 0.60-5.53). CONCLUSION: The use of antidepressants is not as safe in terms of liver injury as expected; instead, the risk of antidepressant-induced liver injury is likely underestimated. The lack of significance does not reflect the absence of risk, but rather suggests the need to evaluate it in a wider setting of antidepressant users.

Safety profile of H1-antihistamines in pediatrics: an analysis based on data from VigiBase.

PURPOSE: H1-antihistamines are commonly used in infants and children for the relief of histamine-mediated symptoms in a variety of conditions. Little is known about their safety profile in these patients. We performed a comparative analysis of the safety profiles of H1-antihistamines using data from the WHO database (VigiBase). METHODS: We selected adverse drug reaction (ADR) reports on H1-antihistamines in children (0-16 years) up to June 2014 from VigiBase. ADRs were codified according to MedDRA terminology. The reporting odds ratios (RORs) with 95% confidence for drug-reaction pairs were calculated. RESULTS: The analysis was performed on 8918 reports related to antihistamines, corresponding to 19503 drug reaction pairs for 68 different drugs. Most of reports involved children aged 2 to 6 years (32%) and 6 to 12 years (34%). Most reported drugs were cetirizine (1608 reports, corresponding to 18%), loratadine (16%), and diphenhydramine (10%). ADRs were classified as serious in 23% of cases, and 400 cases had a fatal outcome. We found a significant associations for several drug-reaction pairs such as levocetirizine and epilepsy (ROR, 6.57; 95% confidence interval [CI], 1.51-28.53) and chlorphenamine and toxic epidermal necrolysis (ROR, 7.29; 95% CI, 2.39-22.2). CONCLUSIONS: H1-antihistamines are among the most used drugs in pediatrics, also in an off-label manner. Our data highlights associations with serious and unexpected ADRs. Educative intervention to clinicians and parents are needed to help doctors to make proper choices on the drug treatment and for the early detection of ADRs to maximize the benefits and reduce the risk of ADRs in these patients.

Signal detection activity on EudraVigilance data: analysis of the procedure and findings from an Italian Regional Centre for Pharmacovigilance.

BACKGROUND: In July 2012 a new European legislation (Directive 2010/84/EU and Regulation No. 1235/2010) regarding pharmacovigilance has become effective. It has boosted the activity of Signal Detection through a monthly analysis of potential safety signals on EudraVigilance (EV). Our aim is to describe the procedure of signal detection on EV data and to present results obtained by the our pharmacovigilance centre. METHOD: Data are extracted from EV database, which collects suspected Adverse Drug Reactions (ADRs) of medicinal products in Europe. We are appointed to supervise digoxin, nicardipine, delapril, manidipine and hydrochlorothiazide/ramipril. ADRs are coded through MedDRA Preferred Terms and collected in the electronic Reaction Monitoring Report (eRMR). Statistical analysis is based on the Proportional Reporting Ratio (PRR) as a measure of disproportionality. RESULTS: Up to April 2016 we have analyzed 45 eRMR for each drug. Two signals for nicardipine were submitted to the Pharmacovigilance Risk Assessment Committee of European Medicines Agency (EMA): acute pulmonary oedema (off-label use as tocolytic) and thrombocytopenia. CONCLUSIONS: Our experience shows the scientific and regulatory value of signal detection activity on EV data in order to continuously evaluate the benefit/risk profile of recent and older drugs.

Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.

AIM: Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. METHODS: Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. RESULTS: We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. CONCLUSIONS: As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.

Ibuprofen-associated hypothermia in children: analysis of the Italian spontaneous reporting database.

PURPOSE: An analysis of Italian spontaneous adverse drug reactions (ADR) reporting database highlighted a potential association between hypothermia and ibuprofen in children. Hypothermia is defined as a core body temperature of 35 °C (95 °F). Ibuprofen is the most prescribed NSAID for the treatment of fever and moderate pain in children. We aimed to analyze the cases of ibuprofen-associated hypothermia retrieved in the Italian database in order to contribute to the discussion on this potential association. METHODS: We extracted all suspected cases of ibuprofen-associated hypothermia from the Italian spontaneous reporting database and from VigiBase up to December 2015. We considered the proportional reporting ratio (PRR) as a measure of disproportionality for the Italian cases and the information component (IC) for the reports from VigiBase. We performed a case-by-case analysis to exclude duplicates. RESULTS: Nineteen cases of hypothermia associated with ibuprofen use were retrieved from the Italian spontaneous reporting database (PRR 19.8, CI 95 %, 12.0-32.9). The reports concerned ten females and nine males with an average age of 2.5 years. Up to 31 December 2015, 168 cases of hypothermia associated with ibuprofen were reported to VigiBase, with an IC of 2.05 (IC025, 1.82). Among these, 126 cases involved children (49 % males) with an average age of 4.4 years. CONCLUSIONS: Although the risk of this ADR is unknown so far, the widespread use of this drug recommends the need for further studies to better characterize this possible association. Clinicians and pharmacists but also parents should be aware that this risk is theoretical as not yet been confirmed.

Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.

AIM: Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. METHODS: This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. RESULTS: We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00). CONCLUSION: Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.

Drug-Induced Progressive Multifocal Leukoencephalopathy: A Comprehensive Analysis of the WHO Adverse Drug Reaction Database.

OBJECTIVE: To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML). METHODS: All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved. We identified safety signals by analysing the drug-reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio >2 and a lower 95 % confidence limit >1. RESULTS: We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18-64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with 'progressive multifocal leukoencephalopathy' or 'leukoencephalopathy' as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only 'progressive multifocal leukoencephalopathy' as the Preferred Term). CONCLUSION: We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies.

Use of Antibiotics in Pediatrics: 8-Years Survey in Italian Hospitals.

OBJECTIVES: To evaluate antibiotic consumption in the pediatric wards of Emilia-Romagna Region, from 2004 to 2011, with a focus on the antibiotics reserved to the most serious infections, and to analyse the ADRs reported for antibiotics by the pediatric wards of Emilia-Romagna hospitals. METHODS: Reference population was represented by all the patients (0-14 years old) admitted to the pediatric wards of all the hospitals of Emilia-Romagna Region. Drug consumption was expressed as number of DDDs per 100 Bed-Days (BD) and data were analysed by active substance, by therapeutic subgroups or by ward type. The time trends of antibiotic consumption were statistically analysed by linear regression. All the suspected ADR reports associated with antibiotics, reported between January 2004 and December 2011 were drawn by the Italian Spontaneous Reporting Database. RESULTS: Overall antibiotic consumption showed only a slight increase (p = 0.224). Among the pediatric wards, pediatric surgery showed the highest increase from 2004 to 2011 (p = 0.011). Penicillins and ß-lactamase inhibitors was the first therapeutic group with a statistically significant increase over years (p = 0.038), whereas penicillins with extended spectrum presented a statistically significant reduction (p = 0.008). Moreover, only 5 drugs out of the 8 antibiotics reserved to the most serious infections were used. Pharmacovigilance data showed 27 spontaneous ADR reports associated to ATC J01 drugs. Amoxicillin/clavulanic acid had the highest number of ADR reports (n = 7). CONCLUSIONS: The steadily increasing consumption in penicillins and ß-lactamase inhibitors, in association with a considerable decrease of plain penicillins, raises a serious concern. Pharmacovigilance reports seem to suggest a safe use of antibiotics in the hospital setting of Emilia-Romagna. Further studies to investigate the reason for prescribing antibiotics in children inpatients are needed.

Acute renal failure in patients treated with dronedarone or amiodarone: a large population-based cohort study in Italy.

PURPOSE: Causes of ARF are numerous including drugs. In 2012, spontaneous reporting showed a possible association between dronedarone and ARF. To further investigate such association, a retrospective cohort study on health-service claim databases was performed taking amiodarone as comparison. METHODS: All patients receiving new prescription of amiodarone or dronedarone between September 2010 and December 2012 were selected. Cox regression models to estimate the hazard ratios (HRs), with 95 % confidence intervals (CIs), for dronedarone versus amiodarone were performed. HRs were calculated: (i) for the entire cohort; (ii) for matched cohorts using propensity score; (iii) and high-dimensional propensity score. RESULTS: New users without previous episodes of ARF were 56,739 and 1761 on dronedarone and 54,978 on amiodarone. After 1:1 matching for propensity score, new users with dronedarone and amiodarone were 1467 and 1467, respectively. The cumulative incidence rate of ARF was 1.6 % (95 % CI 0.7-3.6 %) among dronedarone group and 2.3 % (1.0-5.1 %) among amiodarone group (p from log rank test = 0.4884). The unadjusted HR of ARF was 0.34 (0.18-0.64) in dronedarone new users compared to amiodarone; in propensity score matched cohort, it was 0.75 (0.26-2.16), and in high-dimensional propensity score, it was 0.83 (0.25-2.73). CONCLUSIONS: This large community-based study did not confirm the signal of an increased nephrotoxicity from dronedarone compared to amiodarone. Nevertheless, given the increasing number of reports collected from pharmacovigilance databases worldwide on this association, it is advisable for clinicians and patients to be aware of the possible kidney damage due to dronedarone in order to improve clinical outcomes with early intervention.

No differences between men and women in adverse drug reactions related to psychotropic drugs: a survey from France, Italy and Spain.

A large number of studies have suggested that being a woman represents a potential risk factor for the development of adverse drug reactions (ADRs). The aim of this study is to further explore the differences between men and women with regard to reported ADRs, particularly those associated with psychotropic drugs. We used spontaneous reports of suspected ADRs collected by Midi-Pyrénées (France), Veneto (Italy) and Castilla y León (Spain) Regional Pharmacovigilance Centres (January 2007-December 2009). All the reports including a psychotropic medication were selected in a first step; age distribution, seriousness and type of ADRs were compared between men and women. Reports of nonpsychotropic drugs were similarly identified and treated. The absolute number of reports and the proportion, considering population, were higher in women than in men. This was observed for all reports, but was particularly higher for psychotropic drugs (592 vs. 375; P < 0.001) than for nonpsychotropics drugs (5193 vs. 4035; P < 0.001). Antidepressants were the most reported (women, 303; men, 141; P < 0.001); the reporting rates (number of reports divided by exposed patients in the same period, estimated through sales data) for these drugs, however, were not significantly different between women (0.87 cases per 10 000 treated persons per year) and men (0.81 cases per 10 000 treated persons per year). Although there was a higher number of reports of ADRs in women, ADR reporting rates might be similar as highlighted by the case of antidepressants. Antidepressant ADRs in fact were similarly reported in men and in women. Gender differences are sometimes subtle and difficult to explore. International networks, as the one established for this study, do contribute to better analyse problems associated with medications.

Lormetazepam addiction: data analysis from an Italian medical unit for addiction.

BACKGROUND: The purpose of this study was to determine, in the context of a hospital addiction unit, which benzodiazepines were abused and to look for correlations with the characteristics of detoxified patients. METHODS: A retrospective study was carried out using the database of hospital admissions to the addiction unit for detoxification from 2003 to 2010. RESULTS: Of 879 admissions to the addiction unit during the seven-year period, 281 were for benzodiazepines. The percentage of patients addicted only to benzodiazepines was higher among females than males. Benzodiazepine consumption had started as a drug addiction behavior in only 10% of cases. The main sources of prescription identified were general practitioners (52% of cases) or compliant pharmacists (25%). Overall, 15 different benzodiazepines were abused, with lormetazepam being the most commonly used (by 123 patients, 43.8% of the total). CONCLUSION: Our data show that, outside the population of multidrug addicts, there is an underestimated group of chronic benzodiazepine consumers who are often not referred to medical institutions for treatment. Even in the group of patients addicted to one substance only, we observed an abnormal number of requests for detoxification from lormetazepam, which appears to be more "popular" than other benzodiazepines. This drug should be prescribed according to stricter criteria and submitted to closer control.