Appropriateness of Proton Pump Inhibitor (PPI) prescription in patients admitted to hospital: Attitudes of general practitioners and hospital physicians in Italy.

INTRODUCTION: Proton pump inhibitor (PPI) prescriptions have raised concern for both huge increase of health expenditure and possible long-term adverse effects. OBJECTIVE: To evaluate appropriateness of PPI prescription in ambulatory and hospital care. DESIGN: Observational cohort study. PATIENTS: Patients admitted to the Internal Medicine Unit of Bologna S. Orsola Hospital between 15/09/2013 and 15/12/2013. Data on clinical condition and drug therapy were collected at three time points: admission (reflecting GP's prescription), hospital stay and discharge. MAIN MEASURES: Appropriateness of PPI use was evaluated as follows: (1) agreement between PPI use/non-use and appropriate clinical condition; (2) in PPI users, assessment of Medication Appropriateness Index (MAI). Differences in appropriateness among time points were analyzed by chi-square test. Logistic regression model was used to identify possible determinants of PPI appropriateness. KEY RESULTS: Among 280 patients, 56% received PPI at least once in the three time points. Appropriateness, according to indication of use, was similar between admission and hospital stay (61% vs. 62%; p=0.82) and between hospital stay and discharge (62% vs. 59%; p=0.94). MAI score showed important, although statistically non-significant, change in appropriateness between admission and hospital stay (20% vs. 28%; p=0.16). Age≥65 was always associated with appropriate PPI use (up to OR=4.37; p<0.01), whereas cardiovascular comorbidity and conditions requiring analgesic treatment influenced appropriateness only at admission (OR=3.84; p<0.01 and OR=0.34; p<0.01, respectively). CONCLUSIONS: Hospital clinicians only rarely reconsidered GP's choice to prescribe PPI. Room for improvement in PPI appropriateness is represented by (1) assessing gastrointestinal risk in each patient under analgesics and anti-inflammatory drugs, and (2) short-term re-evaluation of PPI prescription after discharge.

The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project.

INTRODUCTION: Spontaneous reporting systems (SRSs) are pivotal for signal detection, especially for rare events with a high drug-attributable component, such as torsade de pointes (TdP). Use of different national SRSs is rarely attempted because of inherent difficulties, but should be considered on the assumption that rare events are diluted in international databases. OBJECTIVE: The aim was to describe TdP-related events associated with antipsychotics, H1-antihistamines and anti-infectives in three national SRSs (in Italy, Germany and France) and highlight potential signals of torsadogenicity through a combined literature evaluation. METHODS: A common search strategy was applied to extract TdP-related events: (1) TdP, (2) QT interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. Signals of disproportionate reporting (SDRs) were calculated for TdP + QT interval abnormalities and defined by a lower limit of the 95 % confidence interval of the reporting odds ratio (ROR) >1. Among SDRs with at least three cases without concomitant pro-arrhythmic drugs, we defined potential new signal of torsadogenicity as drugs with no published evidence from (a) the crediblemeds(®) website ( http://www.crediblemeds.com , as of November 1st, 2014); (b) studies on the FDA Adverse Event Reporting System (FAERS); and (c) safety trials or pharmaco-epidemiological studies (as of December 16th, 2014). RESULTS: Overall, 3505 cases were retrieved (1372, 1468, and 801 for France, Germany and Italy, respectively). Antipsychotics were mainly recorded in Germany (792 cases), whereas antibiotics peaked at 515 and 491 (France and Italy, respectively). Forty-one drugs met criteria for SDRs in at least one single source, of which 31 were detected only from one single SRS: 18, ten and three (French, German and Italian SRS, respectively). By contrast, only five SDRs were detected in all national data sources (amisulpride, aripiprazole, haloperidol, olanzapine, risperidone). Overall, five potential new signals of torsadogenicity were identified: flupentixol, ganciclovir, levocetirizine, oxatomide and tiapride. CONCLUSIONS: We found differences across and within national SRSs in the reporting of drug-induced TdP, which finally resulted in five potential new signals of torsadogenicity. These findings warrant targeted pharmacovigilance studies to formally assess the existence of actual drug-event associations.

Switching among Equivalents in Chronic Cardiovascular Therapies: 'Real World' Data from Italy.

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.

Social and clinical descriptors of antipsychotic prescription.

OBJECTIVE: To identify descriptors of Antipsychotic (AP) prescription, focusing on second generation antipsychotics (SGAs), polypharmacy, and long-acting injections (LAIs). METHODS: Outpatients of the Bologna-Community-Mental-Health-Centres with at least one AP prescription were selected. Patients' characteristics, service utilization, and AP prescriptions were collected from administrative databases. Prescriptions were grouped by class (SGA vs. First Generation Antipsychotics), drug combination (polypharmacy vs. monotherapy), and preparation (LAIs vs. regular administration). Multi-variate analyses were performed to identify prescription descriptors among socio-demographic and clinical variables. RESULTS: Among 6,074 patients and 41,121 AP prescriptions, SGAs were used in 70.7% of subjects, AP polypharmacy in 25.3%, and LAIs in 17.5%. SGAs were prescribed more often for young, Italian patients, with higher education, voluntary hospitalization, and high number of visits. Descriptors of AP polypharmacy were: high number of visits and hospitalization, length of treatment, non-urban residency, male gender, unemployment. Characteristics associated to LAI prescription were: long duration of treatment, high number of visits, compulsory admissions, non-Italian nationality, male gender, age > 34, low education, unmarried status. CONCLUSIONS: Besides illness severity, this study identified different socio-demographic descriptors of AP choices, raising concerns on the equity of treatments. Efforts should be directed to investigate appropriateness of AP treatments especially in social disadvantaged populations.

Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe.

BACKGROUND: There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. AIM: To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. METHODS: We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance. RESULTS: Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible. CONCLUSIONS: Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.

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 (<1 week) was detected in 46% of patients (47% and 44%, respectively). CONCLUSIONS: The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database.

AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI). METHODS: The publicly available international FAERS database (2004-2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate. RESULTS: From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk. CONCLUSION: Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment.

Use of phytoestrogens and effects perceived by postmenopausal women: result of a questionnaire-based survey.

BACKGROUND: Use of food supplements-containing phytoestrogens among postmenopausal women is rapidly increasing. Although phytoestrogens are often perceived as safe, evidence for overall positive risk-benefit profile is still inconclusive. The chance to buy them by user's initiative does not facilitate surveys on their prevalence and pattern of use. The aim of this study was to describe the pattern of use and self-reported positive and negative perceptions of phytoestrogens in post-menopausa. METHODS: A questionnaire was administered to women who were buying food supplements containing phytoestrogens in 22 pharmacies located in the Bologna area (400,000 inhabitants). Questionnaire was structured into 3 sections: (a) socio-demographic information, (b) pattern of use, (c) positive and negative perceptions. RESULTS: Data on 190 peri- and post-menopausal women (aged 38-77) were collected. Women stated to use phytoestrogens to reduce hot flushes (79%), insomnia (15%), mood disturbances (14%) and prevent osteoporosis (15%). The majority (59%) took phytoestrogens routinely, whereas 28% in 3-month cycles. Among positive perceptions between short- and long-term users, a not negligible difference was reported for relief of hot-flushes (68% in short-term vs. 81% in long-term users; p = 0.04). Negative perceptions were reported more frequently in the long-term group, and this difference was statistically significant for edema (6% in short-term vs. 17% in long-term users; p = 0.04), but not for other effects: e.g., swelling sensation (10% vs. 21%; p = 0.09), somnolence (7% vs. 10% p = 0.62), fatigue (4% vs.11% p = 0.15). CONCLUSIONS: In the Bologna area, the pattern of use of phytoestrogens for menopausal symptoms is heterogeneous, and women overall find these substances to be beneficial, especially for relief of hot-flushes. Other positive perceptions decreased with long-term use. Negative perceptions, especially estrogen-like effects, seem to be infrequent and increase with long-term therapy. Physicians should pay attention to effects perceived by post-menopausal women and routinely monitor the use of phytoestrogens, in order to recognize possible adverse effects and actual benefits.

Torsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe.

BACKGROUND: Antipsychotics (APs) have been associated with risk of torsade de Pointes (TdP). This has important public health implications. Therefore, (a) we exploited the public FDA Adverse Event Reporting System (FAERS) to characterize their torsadogenic profile; (b) we collected drug utilization data from 12 European Countries to assess the population exposure over the 2005-2010 period. METHODS: FAERS data (2004-2010) were analyzed based on the following criteria: (1) ≥ 4 cases of TdP/QT abnormalities; (2) Significant Reporting Odds Ratio, ROR [Lower Limit of the 95% confidence interval>1], for TdP/QT abnormalities, adjusted and stratified (Arizona CERT drugs as effect modifiers); (3) ≥ 4 cases of ventricular arrhythmia/sudden cardiac death (VA/SCD); (4) Significant ROR for VA/SCD; (5) Significant ROR, combined by aggregating TdP/QT abnormalities with VA and SCD. Torsadogenic signals were characterized in terms of signal strength: from Group A (very strong torsadogenic signal: all criteria fulfilled) to group E (unclear/uncertain signal: only 2/5 criteria). Consumption data were retrieved from 12 European Countries and expressed as defined daily doses per 1,000 inhabitants per day (DID). RESULTS: Thirty-five antipsychotics met at least one criterium: 9 agents were classified in Group A (amisulpride, chlorpromazine, clozapine, cyamemazine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). In 2010, the overall exposure to antipsychotics varied from 5.94 DID (Estonia) to 13.99 (France, 2009). Considerable increment of Group A agents was found in several Countries (+3.47 in France): the exposure to olanzapine increased across all Countries (+1.84 in France) and peaked 2.96 in Norway; cyamemazine was typically used only in France (2.81 in 2009). Among Group B drugs, levomepromazine peaked 3.78 (Serbia); fluphenazine 1.61 (Slovenia). CONCLUSIONS: This parallel approach through spontaneous reporting and drug utilization analyses highlighted drug- and Country-specific scenarios requiring potential regulatory consideration: levomepromazine (Serbia), fluphenazine (Slovenia), olanzapine (across Europe), cyamemazine (France). This synergy should be encouraged to support future pharmacovigilance activities.

Antipsychotics and torsadogenic risk: signals emerging from the US FDA Adverse Event Reporting System database.

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.

Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature.

PURPOSE: The aim of this study was to add to the body of evidence on statin-induced gynecomastia based on data retrieved from the Italian spontaneous adverse drug reaction (ADR) reporting database. METHODS: Spontaneous ADR reports collected in the Italian database up to 31 December 2010 were assessed on a case-by-case basis in a search for evidence of a possible causal association between statins and gynecomastia. Cases of gynecomastia or possible gynecomastia, according to the Medical Dictionary of Regulatory Activities (MedDRA) classification, associated with statin use were retrieved from the database. The findings were compared with the available literature in PubMed. RESULTS: The database contained 90,448 ADR reports on 21 December 2010. At least one statin was listed as the suspected drug in 2,862 reports, of which 1,334 concerned a male patient. Among these reports, we identified eight cases with the preferred term "gynecomastia" with a statin as suspected drug: four reports of rosuvastatin and four of atorvastatin. One additional report of an unspecified "breast disorder" in a male patient attributed to fluvastatin was identified and included as a possible case. Four case-reports of statin-induced gynecomastia published between 2006 and 2010 were retrieved from PubMed. CONCLUSIONS: Our findings suggest an association between gynecomastia and statins as a drug class, and the occurrence of this ADR would appear to be more likely with active substances that show an higher potency in inhibiting HMG-CoA reductase enzyme. To date, the safety information provided on the labels of different statin-containing medicines is not standardized. Harmonization of this information would be helpful for both healthcare practitioners and patients.