Alberto Vaccheri

Underreporting in pharmacovigilance: an intervention for Italian GPs (Emilia–Romagna region)

PurposeUnderreporting is a major limitation of spontaneous reporting systems for suspected adverse drug reactions (ADRs). Several interventions to increase the ADR reporting rate have been proposed, but their efficacy remains poorly investigated.MethodsThis was a questionnaire study aimed at assessing the knowledge, attitudes, and behavior of general practitioners (GPs) regarding ADR reporting and at evaluating whether a monthly e-mail-based newsletter on drug safety could affect the rate and the quality of the ADR reports submitted by these GPs. Three local health authorities (LHAs) of the Emilia–Romagna region were chosen on the basis of their ADR reporting rate during the period preceding the study: Rimini (high), Ferrara (average), and Piacenza (low reporting rate). All GPs (nu2009=u2009737) associated with these three LHAs were recruited. The pooled number of ADR reports sent by GPs in the remaining seven LHAs of the region was used as controls. The study covered a period of 3xa0years and was divided into: (1) identification of the reasons leading to underreporting through a questionnaire (Phase I); (2) the intervention, i.e., sending a newsletter for a 10-month period (Phase II); (3) evaluation of the intervention outcomes during the 10xa0months following the period in which the newsletter had been received (Phase III).ResultsAmong GPs involved, 22.8xa0% returned the questionnaire. Over 94xa0% of the respondents considered the spontaneous reporting of suspected ADRs to be part of their professional obligations, but only 6.5xa0% had submitted at least one report in the previous 6xa0months. Following the completion of Phase II, the overall number of reports coming from the LHAs subjected to the intervention rose by 49.2xa0% compared to 2009, while the number of reports coming from the control LHAs increased by 8.8xa0%. Rimini and Piacenza showed a 200xa0% increase in the number of ADR reports submitted by GPs, while the number of ADR reported submitted by the control group decreased by 25.5xa0%. In 2011, the number of overall ADRs reports from the LHAs subjected to the intervention decreased by 6.8xa0%; this decrease reached 50.0xa0% of the GPs. Control HLAs showed an overall decline of 4.3xa0%, while the total number of ADRs from GPs increased by 63.3xa0%. Ferrara was excluded from the analysis due to confounding factors.ConclusionsThe periodic e-mail update on the safety of drugs represents an effective and inexpensive way to raise the awareness of GPs on the importance of spontaneous ADR reporting. Since the outcome of the intervention seemed to disappear after the intervention was stopped, there appears to be a need to adopt a policy of regular updates and educational strategies for health professionals.

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures

SummaryThere is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized.IntroductionThe purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ.MethodsAn Italian record linkage claims database with a target population of around 18xa0million individuals (6xa0million over 55xa0years of age) constituted the data source. We conducted a nested case–control study within a cohort of individuals aged 55+u2009years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95xa0% confidence intervals (95xa0% CI) for the likely association between use of BPs and the risk of ONJ.ResultsAny one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95xa0% CI) for current users was 2.8 (1.3–5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed.ConclusionsAlthough the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.

User-only design to assess drug effectiveness in clinical practice: application to bisphosphonates and secondary prevention of fractures

Different strategies applicable to control for confounding by indication in observational studies were compared in a large population‐based study regarding the effect of bisphosphonates (BPs) for secondary prevention of fractures.

Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO database of adverse drug reactions

PurposeThe purpose of this study is to conduct a comparative analysis of the suspected adverse drug reactions (ADRs) associated with intravitreal bevacizumab, ranibizumab and pegaptanib in the WHO database in order to have a real-life information on these drugs, which now is only based on data coming from clinical trials.MethodsADR reports for intravitreal use of bevacizumab, ranibizumab and pegaptanib from January 2002 to December 2012 were selected from the WHO-VigiBase. Reporting odds ratio (ROR) with confidence interval of 95xa0% and p value was calculated. The analysis was performed for drug-reaction pairs. The Medical Dictionary for Regulatory Activities (MedDRA) terminology for ADRs was used.ResultsThe analysis was performed on 3180 reports corresponding to 7753 drug-reaction pairs. Significant RORs for endophthalmitis and uveitis (1.90, 95xa0% confidence interval (CI) 1.48–2.43, and 10.62, 6.62–17.05, respectively) were retrieved for bevacizumab, and cerebrovascular accident and myocardial infarction produced significant ROR (1.54, 1.14–2.10 and 1.73, 1.18–2.53, respectively) for ranibizumab. Pegaptanib was significantly associated with visual impairment (1.98, 1.12–3.5, pu2009=u20090.02), nausea (3.29, 1.57–6.86, pu2009<u20090.001), vomiting (2.91, 1.2–7.07, pu2009=u20090.01) and drug hypersensitivity (8.75, 3.1–24.66, pu2009<u20090.001).ConclusionsOur data showed an elevated disproportionality for cardiovascular ADRs in patients treated with ranibizumab and for infective ocular reactions in those treated with bevacizumab. No relevant safety issues were identified for pegaptanib. These findings suggest bevacizumab as a suitable choice for AMD therapy due to its effectiveness similar to that of ranibizumab, its favourable safety profile and for its lower cost.

Effectiveness of oral bisphosphonates for primary prevention of osteoporotic fractures: evidence from the AIFA-BEST observational study

PurposeOsteoporosis is a chronic disease of the bone, whose incidence increases progressively with aging. The main consequences of osteoporosis are fragility fractures, which have considerable medical, social, and economic implications. Adequate treatment of osteoporosis must be considered as a compelling public health intervention. Bisphosphonates (BPs) represent the most significant advance in this field in the past decade, and they are widely used in the treatment of osteoporosis. However, evidence for their effectiveness is limited to secondary prevention, whereas their effect in primary prevention is uncertain and needs further investigation.MethodsUsing administrative data collected in the “Biphosphonates Efficacy-Safety Tradeoff” (BEST) study, a nested case-control study was conducted by including 56,058 participants, aged 55xa0years who were started on oral BPs from 2003 to 2005. Cases were the 1,710 participants who were hospitalized for osteoporotic fractures until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio of fracture associated with categories of treatment duration.ResultsCompared with participants assuming BPs for less than 1xa0year, those who remained on therapy for at least 2xa0years had a 21xa0% (95xa0% confidence interval (CI) 7 to 33xa0%) fracture risk reduction.ConclusionThis study provides evidence that BPs, dispensed for primary prevention of osteoporotic fractures, are associated with a reduced risk of osteoporotic fractures after at least 2xa0years of treatment.

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

ObjectiveTo identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML).MethodsAll 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 1xa0September 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 ratioxa0>2 and a lower 95xa0%xa0confidence limit >1.ResultsWe retrieved 2452 reports associated with PML (Nxa0=xa01612), leukoencephalopathy (Nxa0=xa0835) or both (Nxa0=xa05), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18–64xa0years), and almost 30xa0% of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5xa0%), antivirals for systemic use (10.1xa0%) or immunostimulants (4.6xa0%). 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 antithymocytexa0Ig), 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).ConclusionWe 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 β-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 β-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.

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 β-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.

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.

Ticlopidine Safety Profile: A Case/Non-Case Study on the Basis of the Spontaneous ADRs Reporting in Italy

UNLABELLEDnINTRODUCTON: Ticlopidine is an antiplatelet agent available from several decades. Its most important adverse drug reactions (ADRs) involve haematological system. Our aim was to evaluate the safety profile of ticlopidine in the real life, on the basis of spontaneous ADR reporting.nnnMATERIALS AND METHODSnSpontaneous reports from 8 Italian Regions collected from 1990 to March 2007 were analysed. According to WHO Adverse Reaction Terminology for causality assessment only certain, probable or possible ADRs were included. Association between drugs and any ADR was assessed by using the case/non-case methodoloy. Reporting odds ratio (ROR) was computed as a measure of disproportionality.nnnRESULTSnOverall, 478 reports concerning ticlopidine were analysed. The system organ classes with significant disproportionality for ticlopidine included White Cell Disorders (ROR=22.43, 95% CI 18.54-27.12), Red Cell Disorders (8.22; 6.03-11.18), Liver And Biliary System (6.67; 5.35-8.32), Platelet, Bleeding & Clotting (6.59; 5.16-8.40). Fifteen percent of the ADRs occurred beyond the first three months of ticlopidine therapy. In 386 reports (80.7%), ticlopidine was the only suspected drug.nnnCONCLUSIONnSafety profile of ticlopidine can be considered well-established in terms of ADRs type but their frequency and severity continue to be higher in its current use. Since this drug is still widely used in Italy, both healthcare providers and patients should be aware of its ADRs. More specifically, patients should be regularly monitored during the whole period of use and not only in the first months of treatment.