Carlo Piccinni

Assessing the Association of Pioglitazone Use and Bladder Cancer Through Drug Adverse Event Reporting

OBJECTIVE To analyze the association between pioglitazone use and bladder cancer through a spontaneous adverse event reporting system for medications. RESEARCH DESIGN AND METHODS Case/noncase bladder cancer reports associated with antidiabetic drug use were retrieved from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) between 2004 and 2009 and analyzed by the reporting odds ratio (ROR). RESULTS Ninety-three reports of bladder cancer were retrieved, corresponding to 138 drug-reaction pairs (pioglitazone, 31; insulin, 29; metformin, 25; glimepiride, 13; exenatide, 8; others, 22). ROR was indicative of a definite risk for pioglitazone (4.30 [95% CI 2.82–6.52]), and a much weaker risk for gliclazide and acarbose, with very few cases being treated with these two drugs (6 and 4, respectively). CONCLUSIONS In agreement with preclinical and clinical studies, AERS analysis is consistent with an association between pioglitazone and bladder cancer. This issue needs constant epidemiologic surveillance and urgent definition by more specific studies.

Phytoestrogens in Postmenopause: The State of the Art from a Chemical, Pharmacological and Regulatory Perspective

Phytoestrogens represent a diverse group of non-steroidal natural products, which seem to have some oestrogenic effects and are often marketed as food supplements. Population exposed to phytoestrogens is potentially increasing, in part because an unfavourable risk-benefit profile of Hormone Replacement Therapy (HRT) for prolonged treatments (e.g., osteoporosis prevention) highlighted by the publication of the Women Health Initiative (WHI) trial in 2002, but also because many post-menopausal women often perceived phytoestrogens in food supplements as a safer alternative than HRT. Despite of increasing preclinical and clinical studies in the past decade, appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens. Their status as food supplements seems to discourage studies to obtain new evidence, and the chance to buy them by user’s initiative make it difficult to survey their prevalence and pattern of use. The aim of the present review is to: (a) outline the clinical scenario underlying the increased interest on phytoestrogens, by overviewing the evolution of the evidence on HRT and its main therapeutic goals (e.g., menopausal symptoms relief, chemoprevention, osteoporosis prevention); (b) address the chemical and pharmacological features (e.g. chemical structure, botanical sources, mechanism of action) of the main compounds (e.g., isoflavones, lignans, coumestans); (c) describe the clinical evidence on potential therapeutic applications; (d) put available evidence on their riskbenefit profile in a regulatory perspective, in light of the recent regulation on health claims of food supplements.

Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS)

© 2012 Poluzzi et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS)

Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: Systematic review of observational studies

Background Apart from the underlying cardiovascular (CV) risk associated with migraine, both triptans and ergotamines can induce vasoconstriction and potentially increase the risk of serious ischemic events. Because of the low frequency of such events in eligible patients, randomized controlled trials are not exhaustive to assess the drug-related CV risk. Observational studies are, therefore, an essential source of information to clarify this matter of concern. Aim The aim of this study was to systematically review the available published observational studies investigating the risk of serious CV events in triptan or ergotamine users, as compared to unexposed migraineur controls. Methods We systematically searched MEDLINE and EMBASE electronic databases for cohort or case-control studies up to December 1, 2013. Studies retrieved from CDSR, DARE and HTA databases of the Cochrane Library were used for snowballing. Studies investigating the risk of any CV outcome in patients with a migraine diagnosis and exposed to triptans or ergotamines were considered for inclusion. Selection of studies, data extraction, and risk of bias assessment were conducted independently by two reviewers. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were computed using a random-effects model for studies and outcomes judged eligible for quantitative data synthesis. Results From a total of 3370 citations retrieved, after duplicate removal and screening, only four studies met the inclusion criteria (three nested case-control analyses and one retrospective cohort study). These studies investigated the risk of different CV outcomes associated with either the recency or the intensity of exposure to the studied drugs. As for the intensity of use, the pooled OR of serious ischemic events was 2.28 (95% CI 1.18–4.41; I2 = 0%) for ergotamine use (two studies), whereas for triptans (three studies) it was 0.86 (95% CI 0.52–1.43; I2 = 24.5%). Recent use of ergotamines was not significantly associated with any CV outcome (only one available study). Two studies investigated the risk of stroke related to recent triptan use: the first study reported an OR of 0.90 (0.64–1.26), and the second one suggested an increased risk of 2.51 (1.10–5.71). In this case, because of the high degree of heterogeneity, results were not pooled. Conclusions To date, few comparative observational studies have investigated the CV safety of migraine-specific drugs in clinical practice. Evidence gathered here suggests that intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues, although no firm conclusions can be drawn. In particular, evidence on stroke risk is conflicting. However, if an increase of the absolute stroke risk in recently exposed patients does actually exist, it must be small. Overall, residual uncontrolled confounding factors reduce the confidence in the risk estimates collected from the included studies. Further investigations are needed to better define the risk for rare but serious CV events related to triptan and ergotamine use for treatment of migraine.

Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

AimThe aim of the present study was to collect and compare cases of drug-induced PML in order to contribute to the debate about the role of the underlying diseases and/or drug immunosuppression in PML occurrence.MethodsWe searched for drug-induced PML cases in two international spontaneous adverse drug reaction (ADR) report databases, FDA-AERS and WHO-VigiBase. From MEDLINE, we retrieved case reports and case series containing the MESH term “leukoencephalopathy, progressive multifocal/chemically induced”. In order to assess the PML-drug relationship, we analysed drug-reaction pairs in terms of the patients’ underlying diseases and co-suspected drugs.ResultsOverall, 214 cases in FDA-AERS, 118 in WHO-VigiBase and 140 in MEDLINE were collected. Therapeutic groups more frequently involved in PML cases were monoclonal antibodies (MAbs), conventional immunosuppressive drugs and anti-HIV drugs. The most frequent underlying diseases were lymphoproliferative diseases (28%), autoimmune disorders (20%) and transplants (10%). MAbs were more often reported in cases where they were the only suspected drugs, whereas for the other therapeutic groups, concomitant drugs were reported.ConclusionsWe found a strong relationship between PML and MAbs, especially when used in autoimmune diseases. PML is becoming a crucial issue of MAbs, since they can cause severe ADRs through the imbalance of the immune system. Based on these results, patients treated with MAbs should be carefully monitored for early signs and symptoms of PML.

Cardiovascular, Ocular and Bone Adverse Reactions Associated with Thiazolidinediones

AbstractBackground: The risk of myocardial infarction, macular oedema and bone fractures associated with thiazolidinediones (TZDs) has been extensively investigated. Objective: The aim of the study was to verify if the analysis of a large spontaneous reporting database could generate early signals on these adverse drug reactions (ADRs) associated with TZDs. Methods: A case/non-case study, restricted to antidiabetic drugs, was performed on spontaneous reports of ADRs (2005–2008) in the US FDA Adverse Event Reporting System (AERS). The method was applied to TZDs, both as a drug class and as single agents. The reporting odds ratio (ROR) with 95% CI was calculated as a measure of disproportionality in the whole dataset and in a quarter-by-quarter analysis. Results: TZD use was registered in 49 589 out of 301 950 drug-reaction pairs (16%), with significant disproportionality for myocardial infarction (ROR 4.71; 95%CI 4.40, 5.05), macular oedema (3.88; 2.79, 5.39) and bone fractures (1.73; 1.53, 1.96). Separate analysis of the two TZDs showed that only rosiglitazone was associated with myocardial infarction (7.86; 7.34, 8.34) and macular oedema (5.55; 3.94, 7.79), whereas pioglitazone was associated with multiple site fractures (2.00; 1.70, 2.35), in particular upper and lower limb and pelvic fractures. The quarter-by-quarter analysis identified disproportionality for myocardial infarction (3.13; 2.38, 4.10) and bone fractures since January-March 2005 (2.70; 1.04, 2.78). Conclusions: The frequency of reporting of myocardial infarction, macular oedema and fractures was significantly higher for TZDs in comparison with other antidiabetic drugs, with large intraclass differences. Both myocardial infarction and bone fracture signals appeared before major publications on these safety issues.

Burden of community-acquired pneumonia in Italian general practice

To the Editor: Community-acquired pneumonia (CAP) is a major respiratory health disease with high prevalence in the general population, clinical heterogeneity and different degrees of severity. In both the USA and Europe, CAP is the most frequent cause of infection-related death. Its incidence varies from country to country and from study to study, and it is higher in very young children and elderly persons [1]. A recent UK study documented an increase of 34% in hospital admissions due to CAP over the past decade [2]. Despite the importance of its social impact, actual incidence of CAP in different settings is still under scrutiny. Thus, we aimed to explore the epidemiology of CAP in Italian general practice. We collected data from the Health Search - CSD Patient Database (HSD), an electronic general practice database, representative of the Italian general population, which was set up in 1998 by the Italian College of General Practitioners (Florence, Italy). The HSD contains data from approximately 1.2 million inhabitants under the care of 800 general practitioners (GPs), homogenously distributed across Italy. All clinical diagnoses are coded according to the International Classification of Diseases 9th Revision (ICD-9). Drugs are coded according to the Anatomical Therapeutic and Chemical classification system. The HSD has been extensively used for pharmaco-epidemiologic research [3]. Patients recruited between January 1, 2005 and December 31, 2009 were eligible if aged ≥15 years with clinical records in the database spanning a minimum duration of 2 years and an ICD-9-based incident diagnosis of CAP. The first date of CAP diagnosis was defined as …

Triptans and serious adverse vascular events: Data mining of the FDA Adverse Event Reporting System database:

Aim The aim of this article is to investigate the vascular safety profile of triptans through an analysis of the United States Food and Drug Administration Adverse Event Reporting System (FDA_AERS) database with a special focus on serious and unexpected adverse events. Methods A case/non-case analysis was performed on the reports entered in the FDA_AERS from 2004 to 2010: Cases were reports with at least one event included in the MedDRA system organ classes ‘Cardiac disorder’ or ‘Vascular disorders’, whereas non-cases were all the remaining reports. Co-reported cardiovascular drugs were used as a proxy of cardiovascular risk and the adjusted reporting odds ratio (adj.ROR) with 95% confidence intervals (95% CI) was calculated. Disproportionality signals were defined as adj.ROR value >1. Adverse events were considered unexpected if not mentioned on the relevant label. Results Among 2,131,688 reports, 7808 concerned triptans. Cases were 2593 among triptans and 665,940 for all other drugs. Unexpected disproportionality signals were found in the following high-level terms of the MedDRA hierarchy: ‘Cerebrovascular and spinal necrosis and vascular insufficiency’ (103 triptan cases), ‘Aneurysms and dissections non-site specific’ (15), ‘Pregnancy-associated hypertension’ (10), ‘Reproductive system necrosis and vascular insufficiency’ (3). Discussion Our analysis revealed three main groups of unexpected associations between triptans and serious vascular events: ischaemic cerebrovascular events, aneurysms and artery dissections, and pregnancy-related vascular events. A case-by-case assessment is needed to confirm or disprove their plausibility and large-scale analytical studies should be planned for risk rate estimation. In the meantime, clinicians should pay special attention to migraine diagnosis and vascular risk assessment before prescribing a triptan, also promptly reporting any unexpected event to pharmacovigilance systems.

Natalizumab : a country-based surveillance program

Natalizumab is a humanized monoclonal antibody with a selective adhesion-molecule inhibitor effect, and a demonstrated efficacy in decreasing the frequency of relapses and progression of disability in relapsing-remitting multiple sclerosis (RR MS). After the approval of FDA and EMEA in MS cases unresponsive to immunomodulating therapy or in severe MS patients also not previously treated with interferons, and considering the concern on the possible side effects, an accurate program of surveillance was organized in our country by a combined effort of AIFA, Cineca, Department of Pharmacology of University of Bologna, and a group of neurologists appointed by the National Society of Neurology (SIN). After 15 months from the authorization of natalizumab therapy in MS, as of 31 March 2008, 908 cases have been treated with natalizumab and enrolled in this pharmaco-vigilance study. The mean age is 35 years, while the duration of disease is longer and disability is higher than that reported in the registrative study. Side effects are at the moment mild and similar to those previously described. At follow-up, the majority of treated cases are stable or ameliorated. The treatment was discontinued in 6% of patients.

Clinically important drug–drug interactions in poly-treated elderly outpatients: a campaign to improve appropriateness in general practice

AIMS The aim was to assess the impact of a campaign for general practitioners (GPs) to reduce clinically-important drug-drug interactions (DDIs) in poly-treated elderly patients. METHODS We compiled a list of 53 DDIs and analyzed reimbursed prescriptions dispensed to poly-treated (≥four drugs) elderly (>65 years) patients in the Emilia Romagna region during January 2011-June 2011 (first pre-intervention period), January 2012-June 2012 (second pre-intervention period) and January 2013-June 2013 (post-intervention period). Educational initiatives to GPs were completed in July 2012-December 2012. Pre-test/post-test analysis (2013 vs. 2012) was performed, also using predicted 2013 data (P < 0.01 for statistical significance). RESULTS Despite the slight increase in poly-therapy rate (16% in 2013, +1.5% from 2011), we found a stable or slightly declining number of potential DDIs for each elderly poly-treated patient (~1.5). In 2013, 11 DDIs exceeded 5% of prevalence rate: antidiabetics-β-adrenoceptor blockers ranked first (20.3%), followed by ACE Inhibitors (ACEIs)/sartans-non steroidal anti-inflammatory drugs (NSAIDs) (16.4%), diuretics-NSAIDs (13.6%), selective serotonin re-uptake inhibitors (SSRIs)-NSAIDs/acetyl salicylic acid (ASA) (12.7%) and corticosteroids-NSAIDs/ASA (9.7%). A remarkable reduction emerged for NSAID-related DDIs (diuretics-NSAIDs peaked -14.5%; P < 0.01), whereas prevalence of antidiabetics-β-adrenoceptor blockers increased (+7.9%; P < 0.01). When using predicted values, the statistical significance disappeared for antidiabetics-β-adrenoceptor blockers (+1.3%; P = 0.04), whereas it persisted for almost all NSAIDs-related DDIs: ACEIs/sartans-NSAIDs (-3.0%), diuretics-NSAIDs (-6.0%), SSRIs-NSAIDs/ASA (-5.9%). CONCLUSIONS This campaign contained the burden of DDIs in poly-treated elderly patients by 1) reducing most prevalent DDIs, especially NSAIDs-related DDIs and 2) balancing the observed rise in poly-therapy rate with stable rate in overall prescriptions of potentially interacting drugs per patient.