110 research outputs found
Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System
No full textBackground and aims: We tested the possible association between dipeptidyl peptidase-4 inhibitors (DPP-4-I) use and heart failure (HF) occurrence by assessing the publicly available US-FDA Adverse Event Reporting System (FAERS). Methods: FAERS data reporting HF and DPP-4-Is use in the period from the fourth quarter of 2006 through 2013 were extracted, using the Standardized MedDRA Query "Cardiac failure". Disproportionality (case/non-case method) was implemented by calculating Reporting Odds Ratios (RORs) with 95% Confidence Interval (CI): (1) exploratory analysis on the entire FAERS (using rosiglitazone as positive control); (2) consolidated analyses by therapeutic area (within antidiabetics), correcting for event- and drug-related competition bias and adjusting for co-reported drugs as confounders. Results: HF during DPP4-I use was recorded in 390 reports (4.4% of total reports). In exploratory analysis, statistically significant ROR emerged for DPP-4-I as a class (ROR = 1.17; 95% CI = 1.05-1.29), saxagliptin (1.68; 1.29-2.17), vildagliptin (2.39; 1.38-4.14), and rosiglitazone (13.98; 13.30-14.70). In consolidated analyses, the ROR for saxagliptin (2.60; 1.92-3.50) and vildagliptin (4.07; 2.28-7.27) increased, and became also significant for sitagliptin (1.61; 1.40-1.86). Concomitant drugs were reported in more than 50% of cases; the adjusted RORs of saxagliptin (2.30; 1.70-3.10), vildagliptin (3.15; 1.76-5.63), and sitagliptin (1.48; 1.28-1.71) were nonetheless significant. Conclusion: FAERS data are consistent with clinical studies on a possible association between saxagliptin and HF. The disproportionate reporting of HF with sitagliptin, conflicting with a recent phase IV trial, suggests that cardiovascular safety requires close post-marketing vigilance by clinicians of individual DPP-4-I in the community until the issue of class effect is solved
Adverse events with sacubitril/valsartan in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system
No full textAims: The aim of this study was to characterise clinical priority of adverse events with sacubitril/valsartan for targeting preventive measures. Methods: We used the US Food and Drug Administration adverse event reporting system (worldwide pharmacovigilance database) to compare adverse events recording sacubitril/valsartan as suspect with other cardiovascular drugs. Disproportionality analyses were performed by calculating the reporting odds ratios, deemed significant when the lower limit of the 95% confidence interval was greater than 1. Clinical priority was assigned to adverse events with significant disproportionality by scoring (range 0–10 points) five features (number of events, magnitude of the lower limit of the 95% confidence interval, mortality frequency, important/designated medical event, biological plausibility). Results: Sacubitril/valsartan was recorded in 20,021 reports, with 178 adverse events associated with significant disproportionality: 71.9%, 25.9% and 2.2% were classified as weak, moderate and strong clinical priorities, respectively. Increased reporting emerged for several cardiovascular adverse events, including ‘renal failure’ (N = 388; lower limit of the 95% confidence interval 2.26), ‘hyperkalaemia’ (314; 2.42) and ‘angioedema’ (309; 1.56). Sudden cardiac death (priority score 9 points) was the only designated medical event with strong clinical priority. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration (average onset 124 days), with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, loop diuretics) in 26.2% of records. Conclusion: The increased cardiovascular reporting of sacubitril/valsartan in the real world was largely predictable from pre-approval evidence, underlying disease and likely patients’ comorbidities. The unexpected reporting of sudden cardiac death occurred well before the complete development of positive electrical remodelling induced by sacubitril/valsartan, and calls for stringent clinical monitoring (to reduce the pro-arrhythmic burden related to co-medications), and further investigation on appropriate combination with other preventive measures
Assessing intravitreal anti-VEGF drug safety using real-world data: methodological challenges in observational research
No full textIt is generally acknowledged that the ocular safety profile of intravitreal anti-VEGF drugs is acceptable, while the burden of systemic safety of these intravitreal agents is still being debated. The evaluation of the systemic safety of these drugs using real-world data (RWD), such as spontaneous reporting systems (SRS), electronic medical records (EMRs) and claims databases has several advantages, including the capture of outcomes among real-world populations over long observational periods. Nevertheless, there is a relatively small body of research exploring the post-marketing safety of these drugs
Evolving Roles of Spontaneous Reporting Systems to Assess and Monitor Drug Safety
No full textThis chapter aims to describe current and emerging roles of spontaneous reporting systems (SRSs) for assessing and monitoring drug safety. Moreover, it offers a perspective on the near future, which entails the so-called era of Big Data, keeping in mind both regulator and researcher viewpoints. After a panorama on key data sources and analyses of post-marketing data of adverse drug reactions, a critical appraisal of methodological issues and debated future applications of SRSs will be presented, including the exploitation and challenges in evidence integration (i.e., merging and combining heterogeneous sources of data into a unique indicator of risk) and patient’s reporting via social media. Finally, a call for a responsible use of these studies is offered, with a proposal on a set of minimum requirements to assess the quality of disproportionality analysis in terms of study conception, performing and reporting
Real-world evidence and pharmacovigilance: workshop of the Italian Epidemiological Association and of the Italian Society of Pharmacology
No full textNot applicabl
Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping
No full textIntroduction: The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated. Objective: The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association. Methods: A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies. Results: After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results. Conclusion: A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes
Budget Impact Analysis of Lebrikizumab for Treating Severe Atopic Dermatitis
No full textLebrikizumab is a novel mono-
clonal antibody that targets interleukin-13, a
pivotal factor in atopic dermatitis (AD). Previous
studies revealed a positive benefit–risk profile
of lebrikizumab as treatment for patients with
moderate-to-severe AD. In Italy, lebrikizumab
has been approved and reimbursed as treat-
ment for patients with severe AD (aged 12 years
or older and with an Eczema Area and Severity Index (EASI) ≥ 24). However, data on economic
impact of lebrikizumab in these subjects are still
scarce. This study aimed to assess the budget
impact of lebrikizumab in Italian patients with
severe AD, according to Italian Medicine Agency
(AIFA) reimbursement criteria, from the Italian
National Healthcare System (NHS) perspective.
Methods: The budget impact analysis model was
used to estimate the economic impact of lebriki-
zumab as treatment of patients with severe AD by
comparing the total budget expenditure under two
scenarios: scenario A, which includes the current
standard of care with biologic agents (dupilumab
and tralokinumab), and scenario B, which includes
dupilumab and tralokinumab along with the
introduction of lebrikizumab. The analysis was
conducted by adopting the Italian NHS perspec-
tive and a 3-year time horizon. The clinical data
input was based on published evidence, pivotal
clinical trial, and expert opinion. Cost data was
retrieved from the Italian tariff and literature. One-
way sensitivity analysis was conducted to assess
the robustness of the model.
Results: The base case analysis, conducted over
a 3-year period, estimated that the number of
patients treated with lebrikizumab increased
from 1198 in the first year to 5849 in the final
year of the simulation. The adoption of leb-
rikizumab for patient treatment resulted in a
cumulative cost-saving of €3.3 million in 3 years
(€786 thousand in the first year, − €1.7 million
in the second year, and −€2.4 in the last year). The number of patients potentially eligible to
the treatment, the injection site reaction cost,
and the injection site reaction rate were the
main drivers of the findings.
Conclusion: The availability of lebrikizumab as
treatment for patients with severe AD would result
in cost savings for Italy. Given the paucity of eco-
nomic data on lebrikizumab, new economic stud-
ies should be conducted to confirm these findings
Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System
No full textBACKGROUND: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. OBJECTIVE: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. METHODS: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. RESULTS: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12-2.52; and 2.53; 2.40-2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09-1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). CONCLUSION: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI
Toxicities with Immune Checkpoint Inhibitors: Emerging Priorities From Disproportionality Analysis of the FDA Adverse Event Reporting System
No full textImmune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 or its ligand (PD1/PDL1), elicit different immune-related adverse events (irAEs), but their global safety is incompletely characterized
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