Ariola Koci

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.

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.

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.

Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Introduction: Concern exists on the pro-arrhythmic potential of macrolides, namely Torsade de Pointes (TdP). Recent evidence has challenged the common opinion of considering azithromycin a safer therapeutic option, causing emerging regulatory and clinical interest. Materials and Methods: We analyzed cases of drug-induced TdP (2004-2011) submitted to the publicly available FDA Adverse Event Reporting System (FAERS). Four groups of mutually exclusive events were identified in decreasing order of drug-attributable risk: 1) TdP; 2) QT interval abnormalities; 3) ventricular arrhythmia (VA); 4) Sudden Cardiac Death (SCD). They were combined into case definition A (TdP/QT abnormalities) and case definition B (VA/SCD). Both case-by-case analysis (information on concomitant drugs, especially QT-prolonging agents listed by Arizona CERT, and disproportionality approach (Reporting Odds Ratio, ROR, with 95%CI) were carried out. Results: Over the 8-year period, macrolides were associated with 183 and 419 cases of interest (case definition A and B, respectively). Clarithromycin was the most frequently reported (84 and 162 cases), followed by azithromycin (63 and 140). Only 27% of cases of TdP/QT abnormalities with azithromycin occurred in patients >65 years of age (63, 47 and 44% for clari-, ery- and telithromycin, respectively). In cases of TdP/QT abnormalities, concomitant QT-prolonging drugs (Arizona CERT lists 1 or 2) were recorded with a proportion very different among macrolides (11 to 89%). The highest percentage of fatal outcome was recorded for azithromycin (17%). Disproportionality was found for azithromycin, clarithromycin and telithromycin for both events of interest, whereas erithromycin showed disproportion only for TdP/QT abnormalities. Conclusions: Despite inherent limitations of spontaneous reporting analyses, the remarkable proportion of fatal cases and the occurrence of TdP-related events in middle-aged patients strengthen the view that caution is needed before considering azithromycin as a safer therapeutic option among macrolides.

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

PurposeThe 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.MethodsSpontaneous 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.ResultsThe 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.ConclusionsOur 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.

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 GPs 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 GPs 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.

QT interval shortening in spontaneous reports submitted to the FDA: the need for consensus.

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

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

BackgroundUse 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.MethodsA 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.ResultsData 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).ConclusionsIn 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.

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.