Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization's database.

BACKGROUND: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. METHODS: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. RESULTS: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively. CONCLUSION: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

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.

Six-year activity on approval of compassionate use of medicines by the Ethics Committee of the University Hospital of Bologna (Italy): time to update rules and recommendations.

PURPOSE: Compassionate use of forthcoming drugs has become an increasing pathway through which patients can take advantage of promising medicines. We aimed to analyse the main features of the requests of compassionate use submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2015. METHODS: The present analysis concerns the requests of compassionate use received by the IEC in the period 2010-2015. For each requested drug, we paired the date of the first request to our IEC with the date(s) of (a) submission to EMA, (b) CHMP positive opinion, and (c) European marketing authorization (if issued). RESULTS: In the period 2010-2015, our IEC received compassionate use requests for 610 patients. Most of the requests concerned patients suffering from solid or haematological cancers not responsive to first or second line of treatment. Sixty-five couples of medicine/clinical condition (corresponding to 56 individual medicines) were submitted to our IEC, and 62 of them regarded products following the centralised procedure at the EMA. Twenty-one out of the latter (34%) had already obtained CHMP positive opinion. CONCLUSIONS: Our results indicate that compassionate use of forthcoming medicines represents a not negligible portion of the therapies utilized in hospital care. The observed large resort to medicines still on trial may suggest that doctors are more aware with the potential benefits of the new drugs. However, this trend may also indicate an increasing marketing activity of the pharmaceutical industry, addressing to get the clinicians used to the upcoming medicines.

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.

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.

Off-label use of nicardipine as tocolytic and acute pulmonary oedema: a post-marketing analysis of adverse drug reaction reports in EudraVigilance.

PURPOSE: To evaluate a signal of acute pulmonary oedema (APO) due to nicardipine used off-label as tocolytic in pregnant women. METHODS: All the suspected cases of APO recorded in EudraVigilance database up to 31/01/2013 and associated with nicardipine containing medicinal products were retrieved. The Proportional Reporting Ratio was considered as measure of disproportionality. Individual cases evaluation was conducted. RESULTS: Thirty-four spontaneous cases regarding pregnancy women who experienced APO following nicardipine treatment as tocolytic were collected. The detected proportional reporting ratio was 50.96 (95% confidence interval lower bound equal to 36.75). The analysis focused on 10 serious cases. Most women, aged between 27 and 39 years, were treated with intravenous nicardipine. The most of the suspected adverse reactions occurred between 24 and 96 hours. CONCLUSIONS: A potentially causal association between APO and off-label use of nicardipine as tocolytic has been detected during a periodic signal detection activity. The Pharmacovigilance Risk Assessment Committee confirmed our findings, recommending an update of the summary of the product characteristics for medicines containing nicardipine for both intravenous and oral formulations. Then European Medicines Agency reaffirmed that nicardipine use in other indications is no longer recommended.

Ten years of pharmacovigilance in Italy: the experience of Emilia-Romagna region in the monitoring of drug's safety profile.

OBJECTIVE: To describe the evolution of adverse drug reactions (ADRs) spontaneously reporting in the Emilia-Romagna region (ERR) in the period 2001 - 2010 through qualitative and quantitative indicators following local educational and editorial initiatives. METHODS: Data of regional spontaneous reporting from 1 January 2001 to 31 December 2010 were obtained from the Pharmacovigilance National Network of the Italian Medicines Agency. Drugs were classified according to the Anatomical Therapeutic Chemical classification. ADRs were coded using the Medical Dictionary for Regulatory Activities Terminology. RESULTS: The overall contribution of the ERR was 9.7% of the total national number of reports (9631 out of 99,319) with a rate of 8 reports per 100 physicians and 230 per million inhabitants. Reports concerned more females and more patients aged 0 - 2 and 60 - 80 years. Differences between the individual local health authorities were identified in rate of ADR reporting. Hospital doctors were the main source of reports followed by general physicians. Out of 2555 serious reports, 124 cases were lethal (4.9% of serious ADRs and 1.3% of all regional reports). CONCLUSION: The results represent a useful trend analysis of the post-marketing surveillance and suggest that, although the pharmacovigilance system has succeeded in reaching a stable and lasting flow of information in ERR, there is considerable place for improvement.

Use of antibacterial agents in Italian hospitals: a 2004 to 2011 drug utilization survey in the Emilia-Romagna region.

To assess 8-year antibiotic consumption and expenditure in all of the hospitals of Emilia Romagna. The analysis was based on the pharmacy records of each hospital. Antibiotic drug consumption was expressed as DDDs per 100 bed-days used (BDU) and data were analyzed according to ATC classification and to single wards. Expenditure was expressed as Euros per 100 BDU. In the 8-years considered, overall consumption increased by 27% and expenditure by only 3%. Consumption was higher in surgical wards than in medical ones. Penicillins and ß-lactamase inhibitors ranked first, followed by fluoroquinolones and third generation cephalosporins. The results of the study strongly suggest that antibiotic use could be improved by educational interventions to improve clinical practice in hospitals, assessments of guidelines and monitoring of the outcomes of the interventions are needed.

Possible occurrence of paraesthesia in patients taking norethisterone: an analysis on the WHO Global Individual Case Reports database (VigiBase).

OBJECTIVE: Progestogens are widely used to treat a large number of common conditions. We aimed to investigate a potential signal concerning progestogens and paraesthesia. METHODS: Data were obtained from the VigiBase, the WHO Global Individual Case Safety Reports (ICSR) database, which is maintained by the Uppsala Monitoring Centre. We collected all suspected reports of paraesthesia associated with oral progestogens, reported between January 1972 and June 2012 and classified in VigiBase according to WHO-Adverse Reaction Terminology critical term 'paraesthesia'. A disproportionality analysis was conducted using the Information Component (IC) and the standard deviation (IC025) as a measure. RESULTS: Out of the total number of reports collected in the VigiBase (7,332,991), paraesthesia was associated with progestogen therapy in 920 reports, coming from 22 countries. Progestogens had the highest number of suspected reports (n = 864) than the other Anatomical Therapeutic Chemical (ATC) considered. Only norethisterone was associated with paraesthesia with positive IC (0.47) and IC025 (0.02). CONCLUSIONS: Norethisterone-associated paraesthesia appears to be a rare outcome. However, the widespread use of progestogens in medical practice suggests that it is a complaint that can affect a large number of women. Since paraesthesia can be caused by several drugs, clinicians should consider that it may be also caused by norethisterone.

Dronedarone-associated acute renal failure: evidence coming from the Italian spontaneous ADR reporting database.

AIM: To describe cases of acute renal failure (ARF) and of renal failure (RF) from dronedarone retrieved in the general population during post-marketing surveillance through the Italian spontaneous ADR reporting database. METHODS: A case by case analysis was performed. Reports codified with the System Organ Class (SOC) term 'urinary system disorders' of the ADR terminology of the World Health Organization associated with dronedarone treatment were selected. RESULTS: Out of 124,069 ADR reports, in 55 of them dronedarone was listed as the suspected drug. Among these reports, we identified four cases of ARF, two of RF and three cases of increase of blood creatinine submitted by physicians between October 2010 and December 2011. The patient age was from 61 to 84 years and most cases occurred within the first 13 days of initiation of dronedarone therapy (range 6 days-2 months). Only one patient received a co-suspected drug labelled for causing ARF. In all reports but one, positive dechallenge was reported. CONCLUSIONS: Clinicians should be made aware of the risk of ARF/RF associated with dronedarone and of the need to screen patients appropriately for ARF/RF risk factors before starting dronedarone therapy.