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Introdcution: The FARO project is an Italian multiregional project of active surveillance of drug safety in emergency department (ED). [1] Aim: We analyzed all the individual case safety reports (ICSRs) collected in the FARO database in the first three years of the project for the Tuscany region. We also analyzed the contribution of the project to the Tuscany reports. Methods: A total of 9 hospitals contributed to the FARO project in Tuscany. Dedicated monitors screened everyday ED visits using key words related to possible adverse drug reactions (ADR) (e.g., drug-induced, reaction to drug). Then, all the selected ED visits were manually revised and only those caused by an ADR were reported as ICSRs first in the FARO database, and finally in the national pharmacovigilance network. Results: In the three-year period 2020-2022, in Tuscany we reported the following number of ICSRs: 5043, 9267 and 7133. In the same period, the ICSRs of the FARO which contributed to the total of yearly Tuscan reports were 1100 (22%), 474 (5%) and 1574 (22%) for 2020, 2021 and 2022, respectively. Most of the patients of the FARO project ICSRs were in the 18-65 years group. The seriousness of ICSRs were equally distributed between \"not serious\" (52%) and \"serious\" (48%). Among the \"serious\" ICSRs, 555 were classified as \"other condition medically significant\", 401 \"hospitalization\", 18 \"life-threating\", 6 \"death\" and 1 \"permanent disability\". The most reported outcome was \"recovering\" (58%). Acetylsalicylic acid was the most reported suspected active substance (50.3% \"serious\" and 49.7% \"not serious\"), followed by warfarin (63.4% \"serious\" and 36.6% \"not serious\"), and amoxicillin-clavulanate (43.9% \"serious\" and 56.2% \"not serious\"). The three most reported System Organ Classes were \"gastrointestinal disorders\" (20%), \"skin and subcutaneous tissue disorders\" (14%), and \"nervous system disorders\" (10%). The three most reported Preferred Term were \"anemia\" (160), \"epistaxis\" (147), and \"urticaria\" (116). Conclusion: The ED is a privilege observatory for pharmacovigilance, offering the possibility to intercept ADRs in an outpatient setting that may result in hospitalization. The FARO project contributed for more than 20% of the regional ICSRs, with a noticeable reduction during 2021 due to the massive reporting storm of COVID-19 vaccine ICSRs.

Introduction: Tardive dyskinesia (TD), a chronic and disabling syndrome, usually develops after at least 3 months of anti-dopaminergic treatment, but it can also appear after shorter periods or even after discontinuation of the medication1. Aim: To evaluate whether there is significant risk of reporting for early-onset TD (<60 days) for some specific drugs. Methods: We used data from the FDA's Adverse Event Reporting System (FAERS) database from 2004 to 2022. We quantified for all drugs in the database, the number of drug-event pairs with the preferred term \"Tardive Dyskinesia\" (TD). Then, we counted those with Time to onset (TTO) < 60 days (cases). All other adverse events where classified as \"non-cases\". Finally, we calculate Reporting Odds Ratio (ROR) as a measure of disproportionality, for drugs with at least 3 cases of TD with a TTO < 60 days (index), using the entire database as reference. Results: Our dataset includes 66.461.955 drug-event pairs. We found that the overall number of TD-drug pairs reported in FAERS database was 10,352. The overall TD-drug pairs with available TTO information available was 1,871 (18.1%). The overall TD cases with TTO < 60 days was 1,269 (68.8% of TD cases with TTO defined). Sixtyseven drugs with at least 3 reports with TD with TTO < 60 days were listed. Valbenazine has the highest number of case (n = 445), but it was excluded from the analysis due to its primary use in treating TD (indication bias). Among the remaining drugs, the overall number of pairs was 824. Risperidone has the highest count with 317 pairs (38.5%), Aripiprazole follows with 226 pairs (27.4%), Olanzapine with 109 pairs (13.2%), Paliperidone with 77 pairs (9.3%), and Haloperidol with 62 pairs (7.5% ). The RORs for these drugs are as follows: Risperidone - 510.9 (95% CI 443.9 - 588.0), Aripiprazole - 331.1 (95% CI 284.1 - 385.9), Olanzapine - 192.1 (95% CI 157.0 - 235.3), Paliperidone - 203 (95% CI 160.8 - 257.3), Haloperidol - 44.7 (95% CI 34.5 - 57.9). Conclusions: For many drugs, especially antipsychotics, there is a reporting risk of early onset tardive dyskinesia. It is important to underline that the TTO can be calculated for a proportion of drugevent pairs of less than 20%. It is possible that cases for which information is not known are predominantly with later onset because it is more difficult to report therapy initiation dates for events occurring after years of treatment.

Introduction: A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. These types of errors can occur for many reasons when a medicine is prescribed, dispensed, stored, prepared or administered and are the leading cause of preventable harm to patients, accounting for up to 56% of adverse drug reactions. (1) Aim: Describes the life-threatening consequences of overdose of ILE as an antidote for bupivacaine intoxication. Methods: Here, we present a clinical case, received at the Tuscan Pharmacovigilance Center, of a possible fatal overdose of intravenous lipid emulsion (ILE) used as an antidote for suspected anesthetic intoxication. Results: A 28-year-old woman, operated on the hip under loco-regional anesthesia with bupivacaine, experienced a cardiac arrest about half an hour after administration of the anesthetic. She was revived and admitted to intensive care with a picture of respiratory failure, deep coma and severe metabolic acidosis (with an excess of bases equal to - 7 and lactate equal to 4 mmol/l). Computed tomography (CT) of the brain showed no acute blood extravasations, nor focal lesions of the cerebral parenchyma, while CT of the chest showed probable cardiogenic alveolar interstitial edema with consolidations of parenchymal stasis, in the absence of signs of pulmonary embolism. Despite pharmacological and mechanical cardiorespiratory support, the patient's condition worsened, and the doctors decided to administer high doses of ILE in bolus and continuous infusion for suspected bupivacaine intoxication. The patient's condition remained serious and she died. The autopsy showed the ubiquitous presence of dense, oily, white-yellowish material within the vascular system, with optically empty halos in all examined organs that intervened or replaced the blood column of veins and capillaries. These findings are likely compatible with an intravenous administration of fatty substance. Conclusions: The high dose of ILE reported in the patient's medical record reveals a clear prescribing error by the physician, which led the patient to a potentially fatal fat overload syndrome. This type of error could be the result of misinterpretation of the guidelines or miscalculation of the patient's weight-based dose by the doctor. (2),(3),(4) Healthcare professionals must be aware of the potential risks associated with the use of ILE as an antidote, implementing effective management and monitoring strategies (e.g. warning labels over the product package with instructions about dose calculation) to minimize the incidence and impact of medication errors.

Introduction: Despite adverse drug reactions (ADRs) being responsible for 10% of outpatient visits and 3.5-10% of hospital admissions the widespread phenomenon of underreporting by health care professionals persists (1). Clinicians could encounter barriers to report ADRs such as time constraints, competing priorities, causal uncertainty, reporting form accessibility, form length, limited awareness, misconceptions about reporting requirements and attribution challenges in ADR reporting (1,2). Aim: to introduce a pilot project that supports healthcare professionals in spontaneous reporting activities at the University Hospital of Pisa. Additionally, we will assess its impact during the initial three months of implementation. Methods: The Adverse Drug Reaction Monitoring Unit (ADRMU) at the University Hospital of Pisa is undertaking a pilot project to enhance the number and quality of reports on spontaneous suspected adverse reactions. The project includes two main components. Firstly, the ADRMU staff provides direct support in the outpatient clinics. Secondly, medical records management system has been implemented to enable the inpatient wards to directly seek assistance from the ADRMU. The outpatient clinics currently participating in the project are the Unit of Immuno-allergology and the Unit of Neurology. As for the inpatient wards, the Unit of Emergency Medicine and the Unit of Metabolic Diseases and Diabetology are presently involved. Results: Between March 1st, 2023, and May 31st, 2023, the staff at the University Hospital of Pisa generated a total of 129 Individual Case Safety Reports (ICSRs), 39 (30.2%) originated from a noninterventional study. Among the remaining 90 spontaneous reports, 45 (50%) were directly attributed to the support activity provided by the ADRMU, effectively doubling the overall number of spontaneous reports for the entire hospital. Of the 45 reports resulting from the ADRMU's support activity, 22 (48.9%) were from the Unit of Immuno-allergology, 19 (42.2%) were from the Unit of Neurology. Four reports (8.9%) were from the inpatient wards, 2 from the Unit of Metabolic Diseases and Diabetology and 2 from the Unit of Emergency Medicine. Between March, 1st, 2022 and May 31st, 2022, the University Hospital of Pisa had generated a total of 63 spontaneous ICSRs. Therefore, the number of spontaneous reports in 2023 showed a 42.9% increase when compared to the corresponding period of the previous year. Conclusions: Despite the project's limited duration and the involvement of only four departments, the results clearly indicate that the support provided by dedicated pharmacovigilance units in hospitals can effectively address the barriers to underreporting by healthcare professionals.

Introduction: Raynaud's phenomenon (RP) is a vasospastic disorder characterized by a digital vascular alteration [1]. In literature there are few case reports suggesting the onset or the exacerbation of RP in patients with migraine, caused by calcitonin gene-related peptide (CGRP) antagonists, the newest class of anti-migraine drug [2]. Aim: To identify a risk of reporting for RP for anti-CGRP drugs using VigiBase® Methods: We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase®) by calculating the Reporting Odds Ratio (ROR) and Information Component (IC) for all anti-CGRPs, for the single class of mAbs and gepants and for single anti-CGRPs. The ROR and IC were calculated as follow: Cases: all reports with RP events; Non-cases: all reports without RP events; Index: a) all anti-CGRPs (class); b) mAbs (sub-class); c) gepants (sub-class); d) single anti-CGRP; reference: all drugs other than anti-CGRP. The information contained in this abstract does not represent the opinion of Uppsala Monitoring Center or the WHO. Results: We identified 166 drug-event pairs of suspected RP associated with anti-CGRPs in VigiBase®. The ICSRs in which a mAb was suspected were 81 erenumab, 52 galcanzeumab, and 28 fremanezumab. Ubrogepant and rimegepant, included in the gepant subclass, are reported with 4 and 5 ICSRs, respectively. Most of the patients were women (146, 88%). Of 166 ICSRs, 76.5% (127 ICSRs) were \"not serious\" while 23.5% (39) were \"serious\". The most quently events were constipation (11), arthralgia (9) and alopecia and weight increased (8 each one). Triptans are the most reported drugs as suspected/interacting/concomitant. The disproportionality analysis for all anti-CGRP revealed a significant ROR (12.3; ROR025 10.6) and IC (3.5; IC025 3.3). The disproportionality analysis for mAbs sub-class showed a significant ROR (13.3; ROR025 11.4) and IC (3.6; IC025 3.4). Also, the disproportionality analysis for gepants sub-class revealed a significant ROR (n = 8; 4.9; ROR025 2.5) and IC (2.0; IC025 0.8). Each single anti-CGRP had a significant ROR and IC. Conclusion: The disproportionality analysis showed a significant risk of reporting for RP associated with anti-CGRP. Notably, RP is described in patient with migraine. The exact mechanism of how RP and migraine are related is not fully understood, but it may involve CGRP. CGRP could have a protective role in maintaining peripheral blood flow. In this way, some authors suggest that anti-CGRP could activate or exacerbate RP. Further investigations, including observational studies and clinical assessments, are warranted to clarify the role of these drugs.

Introduction: Acquired haemophilia A (AHA) is a rare, haematological disorder characterized by the development of autoantibodies to Anti-Factor VIII (FVIII), which can cause spontaneous hemorrhage 1. During 2021, some authors reported an unusual and unexpected number of AHA diagnoses that were temporally related to COVID-19 vaccination2,3 Objective: To explore a possible signal of risk of AHA associated with COVID-19 immunization. Methods: We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase) to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. We calculated the information component (IC) for all the COVID-19 vaccines and for single COVID-19 vaccine product using the entire database as reference. Reports of AHA have been systematically reviewed all the selected cases to check for clinical plausibility Results: In Vigibase, we identified 150 cases of suspected AHA associated with COVID-19 vaccines (146 included the PT \"acquired haemophilia\"). Only three vaccine products have been reported as suspected causative agents for AHA. The disproportionality analysis showed a significant IC for the Preferred term \"Acquired haemophilia\" associated with all COVID-19 vaccines (IC: 1.3; IC025: 1.1) and with the vaccine product BNT162b2 (IC: 1.9; IC025: 1.6). After the integration with data available on VAERS and on the medical literature, and after the elimination of duplicates, 96 unique cases of AHA following COVID-19 vaccines (mostly mRNA vaccines) have been reviewed. Overall, about 22% of cases occurred in patients B 65 and no case associated with pregnancy was reported. Patients with at least one pre-existing condition that can be considered a risk factor for AHA (history of AHA, cancer, autoimmune disorder) were 20 (21%). A pre-existing condition predisposing to AHA was excluded in 57 (59%) of cases and not reported in 19 (20%) cases. The outcome was death in 10 (11%) patients and complete resolution or recovering in 39 (41%) patients with a single resolution without specific AHA treatment. Median time from last vaccine dose to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Conclusion: Our disproportionality analysis confirmed a reporting risk for AHA associated with COVID-19 vaccines. The case review analysis identified several good-quality reports of AHA for which no alternative causes other than COVID-19 immunization can be considered. Although detection bias should be considered to explain the unexpected frequency of AHA in the population, the signal identified is robust and deserves further investigation.

Introduction: Hypertension is a serious disease that occurs when blood pressure is persistently elevated over time1. During the COVID19 vaccination campaign, several reports of hypertension occurred in plausible temporal relationship with immunization have been reported. Objective: To explore a possible signal of risk of hypertension associated with COVID-19 immunization using VigiBase® the World Health Organization (WHO) pharmacovigilance database and to review the evidence available from real world. Methods: We performed a disproportionality analysis using data on spontaneous reports recorded in VigiBase®. Data have been extract on May 8th, 2022. We calculated reporting odds ratio (ROR) as a measure of disproportionality for hypertension defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) narrow. ROR was estimated for all reports including the MedDRA preferred term (PT) \"hypertension\", \"blood pressure increased\" and \"hypertensive crisis\" (cases). All other reports have been defined as non-cases. All reports in which the suspected causative agent was a COVID-19 vaccine were used as index reports and all other reports as reference. A signal was defined by at least three reports of the PT of interest and ROR025 > 1. We reviewed the medical literature using MEDLINE from January 2021 to May 2022 using \"COVID-19 vaccines\" AND \"hypertension\" as a search terms to check for evidence from observational studies. Results: As of May 8th, 2022, VigiBase® included 3,746,090 reports of adverse events following immunization for COVID-19 vaccines and 87,653 de-duplicated reports of hypertension define by the SMQ. We identified 34,955 reports of \"hypertension\" (ROR:1.3; ROR025:1.2), 47,733 reports of \"blood pressure increased\" (ROR:2.6; ROR025:2.6) and 3,741 reports of \"hypertensive crisis\" (ROR:4.0; ROR025:3.8) in which a COVID-19 vaccine was indicated as suspected causative agent. Most frequently co-reported symptoms (> 9%) included headache (n = 16.817; 19.2%), dizziness (n = 12,892; 14.7%), fatigue (n = 8,406; 9.6%). Overall, 75% of cases (n = 65,761) have been classified as not serious. A meta-analysis of observational studies that includes 357,387 individuals reported 13,444 events of blood pressure abnormal or increased2. These events have been often described as short periods of hypertensive response and often observed in patients with risk factors. Conclusion: Our results confirmed a signal of risk of events of elevated blood pressure following immunization with COVID-19 vaccines. However, there is no evidence that these episodes could result in serious complication typically associated with hypertension, such as stroke, aneurysms, heart failure, myocardial infarction and chronic kidney disease.

Background/Introduction: Unresolved outcomes are frequently reported for gustatory, olfactory and auditory (GOA) ADRs in spontaneous reporting databases [1, 2]. However, such high volume of unresolved GOA ADRs could reflect an under-investigated clinical issue or an intrinsic difficulty in the outcome assessment [3]. Objective/Aim: The primary aim was to demonstrate that unresolved outcomes are reported more frequently for GOA ADRs than for other ADRs to systemic antibiotics. The secondary aim was to identify potential signals of unresolved GOA ADRs for specific classes of antibiotic drugs and for specific antibiotics. Methods: We extracted the number of ADRs to systemic antibiotics of the Anatomical Therapeutic Chemical (ATC) class J01 from Eudravigilance up to February 2019. We classified ADRs in \"non-GOA ADRs\" and \"GOA ADRs\". ADRs were categorised in three groups according to the outcome: defined, persistent/permanent (unresolved) and undetermined ADRs. We performed disproportionality analyses with the case/non-case methodology, by calculating the crude reporting odds ratio (ROR) and 95% confidence interval (CI). Cases were all persistent/permanent ADRs, and non-cases were defined and undetermined ADRs. For the primary aim, index groups were gustatory or olfactory or auditory ADRs, while reference group included all non-GOA ADRs. For the secondary aim, we performed a disproportionality analysis by using the sub-set of GOA ADRs. Index and reference groups varied with subgroups of ATC class, so that each class was compared with the others. We conducted two sensitivity analyses for each analysis by varying case definition. Results: We extracted 748,798 ADRs, including 10,770 GOA ADRs. The primary analysis showed that ROR for unresolved gustatory, olfactory and auditory ADRs was 2.68 (95% CI 2.51-2.85), 5.20 (95% CI 4.66-5.81) and 2.64 (95% CI 2.51-2.79), respectively. The secondary analyses detected signals of unresolved gustatory ADRs to doxycycline (ROR 1.69, 95% CI 1.18-2.41, p < 0.05), azithromycin (ROR 2.07, 95% CI 1.58-2.72, p < 0.001) and levofloxacin (ROR 1.59, 95% CI 1.22-2.07, p< 0.05). Signals of auditory unresolved ADRs were found for doxycycline (ROR 1.52, 95% CI 1.09-2.12, p< 0.05), clarithromycin (ROR 1.31, 95% CI 1.09-1.59, p < 0.05) and several aminoglycosides (e.g. ROR 3.49, 95% CI 2.23-5.45, p < 0.001 for amikacin). Signals of olfactory unresolved ADRs were detected for doxycycline (ROR 2.4, 95% CI 1.26-4.58, p < 0.05) and levofloxacin (ROR 1.92, 95% CI 1.28-2.86, p < 0.05). Sensitivity analyses mostly confirmed the results of the main analysis. Conclusion: In this study, we tested and used an appropriate expected frequency standard to identify signals of unresolved GOA ADRs. This approach allowed the identification of several signals of potential persistent/permanent GOA reactions for antibiotic drugs in the Eudravigilance database.

Introduction: Riluzole is a drug indicated to improve survival and time free from invasive mechanical ventilation (or tracheostomy) in individuals with amyotrophic lateral sclerosis (ASL). Riluzole is contraindicated in the presence of renal and/or hepatic impairment, after tracheostomy, or in patients with an ALS history of more than 5 years, and during pregnancy and breastfeeding [1-2]. Objective: This brief analysis aims to describe the use of riluzole in ALS individuals with contraindications and the off-label use for subjects with other motor neuron diseases (o-MND) in three Italian regions. Methods: A cohort of adults diagnosed with ALS and incident users of riluzole during the years 2016-2019 was enrolled from administrative databases of Latium, Tuscany and Umbria, excluding subjects with o-MND in the preceding 5 years. Being affected by ALS for more than 5 years, presence of tracheostomy, renal or hepatic failure were considered as contraindications to riluzole use. A cohort of adults affected by o-MND was enrolled in 2016-2019, for whom offlabel use of riluzole was retrieved, analysing over the time differences related to sex and Italian region. Results: Among 206 ALS individuals prescribed with riluzole in Latium, 336 in Tuscany and 60 in Umbria, less than 1% were diagnosed with ALS for more than 5 years. Less than 2% had undergone tracheostomy or were affected by hepatic failure. Renal failure was documented for 1.9%, 2.7%, and 5.0% of ALS individuals in Latium, Tuscany and Umbria. The o-MND cohort comprised 264 subjects in Latium, 222 in Tuscany, and 66 in Umbria. Non-negligible off-label riluzole use was observed: 8.5%, 33.0%, and 4.2% in females, and 19.9%, 26.5% and 2.4% in males in Latium, Tuscany and Umbria. Conclusion: These preliminary findings highlight that riluzole use in ALS in the presence of contraindications was rare, and its off-label use in o-MND was found to be non-negligible.

Introduction: Disseminated intravascular coagulation (DIC) is a rare disorder of coagulation with different etiologies, including treatments with drug [1]. On December 2020, during a scheduled periodic assessment meeting, the Agenzia Italiana del Farmaco (AIFA) evaluated four individual case safety reports (ICSRs) reporting obinutuzumab and non-overt DIC [2] as new possible signal. Objective: We reported the process of signal detection for obinutuzumab-associated non-overt DIC. Methods: Periodic assessments of signal detection for drugs are conducted by AIFA in collaboration with the Italian Regional Centers of Pharmacovigilance. Reporting odds ratio (ROR) is calculated for each drug-event pair as measure of disproportionality. A signal is generated when the number of ICSRs is ≥ 3 and the lower limit of the 95% confidence interval of ROR is ≥ 1. Priority is given to unexpected and important medical events. Possible signals are presented and discussed in the light of information reported in medical literature. Eudravigilance is also checked for similar ICSRs. When a signal is considered enough robust, an assessment report is submitted to the rapporteur country for a possible evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicine Agency. Results: During routine signal evaluation meetings in December 2020, 4 cases of obinutuzumab-associated non-overt DIC meet the criteria for signal definition (ROR 213.6 and IC025 77). At that time, the Italian database of ICSRs, contained about 150.000 ICSRs. The patients (2 men and 2 women, age 67-77) received obinutuzumab for chronic lymphocytic leukemia. Patients received drug for the treatment of age-related diseases. A subclinical DIC was detected within 48 hours from obinutuzumab administration. After the exclusion of alternative causes, the hematologists decided to report all the 4 cases as suspected adverse drug reactions to obinutuzumab. The DIC spontaneously resolved in all cases. Three more ICRSs were reported in Eudravigilance database. Medical literature reported only one case-report on a woman who developed a DIC following obinutuzumab administration was published [3]. Other authors showed that the administration of the drug induced a pro-inflammatory response with the increase of interleukins and tumor necrosis factor [4, 5]. The DIC is a rare adverse reaction also for rituximab, another anti-CD20 and a rare class effect cannot be excluded [3]. The evidence was robust enough to present the signal to the PRAC. Conclusion: The PRAC identified non-overt DIC as an uncommon adverse reaction to obinutuzumab, and recommended to update the summary of product characteristics (SPC) of obinutuzumab.