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Objective: The adalimumab originator Humira® introduced a new citrate-free formulation in 2016, before the patent expiry that occurred in the European Union in October 2018. Some of the adalimumab biosimilars that were subsequently marketed are citrate-free, while others are not. Since citrate as an excipient is associated with pain at the injection site, recent anecdotical reporting in Italy raised the issue of possible prescription biases related to the differences in formulation existing among the various adalimumab products. In this study, we analyzed the data obtained from the 'Rete Nazionale di Farmacovigilanza' (Pharmacovigilance National Network) to investigate whether, and to what extent, the differences in the formulation of the various adalimumab versions had an impact on the rate of injection site reactions reported in Italy in the period 2016-2019., Materials and Methods: A search was conducted based on 3 search criteria: (1) time frame; (2) suspected drugs, and (3) adverse reaction type. Reports classified in the System Organ Class "Administration site conditions" were analyzed by year, product, and type of adverse event (whether including or not 'pain'). Data were reported both as absolute numbers, as well as signaling rates, considering the consumption data expressed as defined daily doses (DDD)., Results: We found that: (1) The change in Humira® formulation introduced in august 2016 was followed by a decrease in the reports of injection site reactions (from 45 in 2016 to 12, 12 and 8 in 2017, 2018, and 2019, respectively); (2) after the introduction of biosimilars during 2018, in 2019 a marked shift in reporting toward biosimilars was observed (52 out of 60; 87%)., Conclusions: While the decrease in Humira® reports is consistent with the improved tolerability of the new formulation, the huge increase in biosimilar reporting may be only in part explained by the differences in formulation and cannot be accounted for by a parallel increase in exposure, since 58.3% of total DDDs provided in 2019 were still attributed to Humira®.

Reporting and analysis of Adverse Events Following Immunization (AEFIs) are the cornerstones of vaccine safety surveillance prompting causality assessment and signal detection. This paper describes the impact of the Italian Pharmacovigilance System of vaccines over a 10-year period (2008-2017). The reporting rate (RR) per all distributed dose was calculated. Serious AEFIs and causality assessments for fatal cases were described. The main results from signal detection were reported. During the study period, 46,430 AEFIs were reported with an overall RR of 17.2 per 100,000 distributed doses. Italy showed the highest number of reports among European countries. Only 4.4% of the reports came from citizens. Of the total, 12.7% were classified as serious with a RR over the study period of 2.20 per 100,000 distributed doses. They were mainly related to hyperpyrexia and usually had a positive outcome. Fatal outcomes were reported in 0.3% of the cases and were primarily associated with the influenza vaccine in elderly patients. None of these outcomes had a consistent causal association with the vaccination. Febrile convulsions by the measles, mumps, rubella and varicella vaccines and intussusception by the rotavirus vaccine were among the highlighted signals. The reporting rate and the analysis of serious events from 10 years support the good risk/benefit profiles of vaccines.

Background: Several types of vasculitis have been observed and reported in temporal association with the administration of various vaccines. A systematic review of current evidence is lacking., Objective: This systematic literature review aimed to assess available evidence and current reporting practice of vasculitides as adverse events following immunization (AEFI)., Methods: We reviewed the literature from 1st January 1994 to 30th June 2014. This review comprises randomized controlled trials, observational studies, case series, case reports, reviews and comments regardless of vaccine and target population., Results: The initial search resulted in the identification of 6656 articles. Of these, 157 articles were assessed for eligibility and 75 studies were considered for analysis, including 6 retrospective/observational studies, 2 randomized controlled trials, 7 reviews, 11 case series, 46 case reports and 3 comments. Most of the larger, higher quality studies found no causal association between vaccination and subsequent development of vasculitis, including several studies on Kawasaki disease and Henoch-Schönlein purpura (IgA vasculitis). Smaller case series reported a few cases of vasculitis following BCG and vaccines against influenza and hepatitis. Only 24% of the articles reported using a case definition of vasculitis., Conclusions: Existing literature does not allow establishing a causative link between vaccination and vasculitides. Further investigations were strengthened by the use of standardized case definitions and methods for data collection, analysis and presentation to improve data comparability and interpretation of vasculitis cases following immunization., (Published by Elsevier Ltd.)

Background: Vasculitides have been reported as adverse events following immunization (AEFI) following various vaccines. We describe reports of vasculitis to three international spontaneous reporting systems., Methods: All spontaneous reports of vasculitis following immunization between January 2003 and June 2014 were retrieved from Eudravigilance (EV), the Vaccine Adverse Event Reporting System (VAERS), and VigiBase ® . A Standard MedDRA Query (SMQ) for vasculitis was used and vaccine types were categorized using the Anatomical Therapeutic Chemical classification system. We performed a descriptive analysis by source, sex, age, country, time to onset, vaccine, and type of vasculitis., Results: We retrieved 1797 reports of vasculitis in EV, 1171 in VAERS, and 2606 in VigiBase ® . Vasculitis was predominantly reported in children aged 1-17 years, and less frequently in the elderly (>65 years). The generic term "vasculitis" was the most frequently reported AEFI in this category across the three databases (range 21.9% to 27.5% of all reported vasculitis for vaccines). For the more specific terms, Henoch-Schoenlein Purpura (HSP) was most frequently reported, (19.1% on average), followed by Kawasaki disease (KD) (16.1% on average) and polymyalgia rheumatica (PMR) (9.2% on average). Less frequently reported subtypes were cutaneous vasculitis (CuV), vasculitis of the central nervous system (CNS-V), and Behcet's syndrome (BS). HSP, PMR and CuV were more frequently reported with influenza vaccines: on average in 29.3% for HSP reports, 61.5% for PMR reports and in 39.2% for CuV reports. KD was reported with pneumococcal vaccines in 32.0% of KD reports and with rotavirus vaccines in more than 20% of KD reports. BS was most frequently reported after hepatitis and HPV vaccines and CNS-V after HPV vaccines., Conclusion: Similar reporting patterns of vasculitides were observed in different databases. Implementation of standardized case definitions for specific vasculitides could improve overall data quality and comparability of reports., (Published by Elsevier Ltd.)

Background: Study to investigate the intussusception incidence background in the pediatric population and its temporal trend in Italy., Methods: A cross-sectional study was conducted on the pediatric population aged 0 to 15 years, in the period 1 January 2002 to 31 December 2012. Intussusception cases were identified using the national hospital discharge database. The annual intussusception incidence, the incidence rate ratios (IRRs) and the related 95 % confidence Intervals (CI) were calculated., Results: The overall intussusception incidence rate was 21 per 100,000 children aged ≤15 years, and was higher among boys than girls. The highest intussusception incidence rate occurred in infants <1 year of age (39 per 100,000 infants). Among infants, incidence varied with the geographical area, with higher rates in the central Italy (50 per 100,000 infants). The annual incidence rates in infants were stable since 2004 and up to 2012, ranging from 40.1 and 33.0 per 100,000 infants. Similar stable patterns were observed when conducting the analysis on children over 1 year of age., Conclusions: This study provided the intussusception incidence background in Italy in different pediatric ages, including infants, over an 11-year period. This information is essential in post-marketing safety surveillance, to continuously monitor the benefit/risk profile of rotavirus vaccinations.

Vaccines have peculiar characteristics as well as their surveillance. Specific requirements, needs and challenges for the vaccine vigilance are discussed in the perspective to improve the whole system in order to guarantee a safer vaccine use and the keeping of the public confidence in vaccinations. Key elements for the routine safety monitoring, new regulations and some available tools are taken into account. Finally, the Italian experience is shortly described., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: To assess Guillain-Barré syndrome (GBS) incidence we relied on the Italian Network for the study of GBS (ITANG) established in 2010 in 7 Italian regions to analyse the association between influenza vaccination and GBS., Methods: All individuals aged ≥18 years, presenting with clinical manifestations that suggested GBS according to the universally accepted Asbury's diagnostic criteria (1990) were prospectively notified to a centralised database by ITANG neurologists over the period October 1, 2010-September 30, 2011. Through a telephone survey, 9 trained interviewers followed up the cases to diagnosis and then for 1 year since hospital discharge. Validation of case reporting was performed with the support of administrative data in 5 regions., Results: We found 365 cases fulfilling the definition for GBS or one of its variants over 19,846,068 population ≥18 years of age, yielding an annual incidence rate of 1.84 per 100,000 (95% CI 1.65-2.03), 2.30 (95% CI 1.99-2.60) in men and 1.41 (95% CI 1.18-1.64) in women. A highly significant peak of incidence was observed in February 2011 as compared to reference month (September 2011, rate ratio 3.3:1, p < 0.01)., Conclusions: In Italy, GBS incidence was among the highest reported in Europe and higher than previously observed in Italian studies.

Objective: To describe the characteristics of pediatric adverse drug reactions (ADRs) reported in Italian spontaneous reporting database., Methods: Reports of suspected ADRs related to children and adolescents were extracted from 2001 - 2012. After exclusion of duplicates, vaccines and reports containing missing age data, the report characteristics were investigated in terms of implicated drug and adverse drug event across different age-categories., Results: Among 123,129 selected reports, 8338 (6.8%) concerned pediatrics. Of these, 52.2% involved male patients compared to 47.5% female up to the age of 11. After the age of 11 this statistic reversed. 39.4% of pediatric reports were serious and of these, 75.2% required hospitalization mainly in very young children. Most of reports were issued by hospital physicians (61.9%), followed by pharmacists (10.1%), while reports from family pediatricians accounted for 8.1%. The most frequently implicated drug categories were anti-infectives for systemic use (44.9%), drugs for the nervous system (15.6%), and anti-inflammatory drugs (10.2%). The most frequently suspected compounds differed between children and adults and reports for the same drug were likely to be more serious in adults than in children., Conclusions: This ADR reporting system reflects real safety concerns for drugs used in children and emphasizes the need for stratifying analyses by age-subgroup to increase the sensitivity of signal detection procedure.

Objective: To evaluate the effectiveness of seasonal influenza vaccine in preventing Emergency Department (ED) visits and hospitalisations for influenza like illness (ILI) in children., Methods: We conducted a test negative case-control study during the 2011-2012 and 2012-2013 influenza seasons. Eleven paediatric hospital/wards in seven Italian regions participated in the study. Consecutive children visiting the ED with an ILI, as diagnosed by the doctor according to the European Centre for Disease Control case definition, were eligible for the study. Data were collected from trained pharmacists/physicians by interviewing parents during the ED visit (or hospital admission) of their children. An influenza microbiological test (RT-PCR) was carried out in all children., Results: Seven-hundred and four children, from 6 months to 16 years of age, were enrolled: 262 children tested positive for one of the influenza viruses (cases) and 442 tested negative (controls). Cases were older than controls (median age 46 vs. 29 months), though with a similar prevalence of chronic conditions. Only 25 children (4%) were vaccinated in the study period. The overall age-adjusted vaccine effectiveness (VE) was 38% (95% confidence interval -52% to 75%). A higher VE was estimated for hospitalised children (53%; 95% confidence interval -45% to 85%)., Discussion: This study supports the effectiveness of the seasonal influenza vaccine in preventing visits to the EDs and hospitalisations for ILI in children, although the estimates were not statistically significant and with wide confidence intervals. Future systematic reviews of available data will provide more robust evidence for recommending influenza vaccination in children., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Influenza vaccination has been implicated in Guillain Barré Syndrome (GBS) although the evidence for this link is controversial. A case-control study was conducted between October 2010 and May 2011 in seven Italian Regions to explore the relation between influenza vaccination and GBS. The study included 176 GBS incident cases aged ≥18 years from 86 neurological centers. Controls were selected among patients admitted for acute conditions to the Emergency Department of the same hospital as cases. Each control was matched to a case by sex, age, Region and admission date. Two different analyses were conducted: a matched case-control analysis and a self-controlled case series analysis (SCCS). Case-control analysis included 140 cases matched to 308 controls. The adjusted matched odds ratio (OR) for GBS occurrence within 6 weeks after influenza vaccination was 3.8 (95 % CI: 1.3, 10.5). A much stronger association with gastrointestinal infections (OR = 23.8; 95 % CI 7.3, 77.6) and influenza-like illness or upper respiratory tract infections (OR = 11.5; 95 % CI 5.6, 23.5) was highlighted. The SCCS analysis included all 176 GBS cases. Influenza vaccination was associated with GBS, with a relative risk of 2.1 (95 % CI 1.1, 3.9). According to these results the attributable risk in adults ranges from two to five GBS cases per 1,000,000 vaccinations.

Background: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification., Methods: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom., Results: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time., Conclusions: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We report the case of a 4-years-old boy who was admitted with hypovolemic shock due to a severe gastrointestinal bleeding. The esophagogastroduodenoscopy (EGDS) showed hiatus hernia, erosions and ulcerations of the lower esophagus, possibly due to a gastroesophageal reflux, and a small duodenal erosion. The child was previously healthy and he had never shown any symptoms related to this condition. The only product taken by the child in the previous days was a syrup containing several herbs, among which Filipendula ulmaria (L.) Maxim. and Salix spp. (known to contain salicylates), marketed as food and prescribed by his paediatrician to treat a mild cold accompanied by fever. Quali-quantitative analysis confirmed the presence of salicylates in the syrup. Naranjo algorithm showed a probable correlation between the onset of symptoms and the consumption of the herbal remedy. The child recovered after receiving intensive care. The product was withdrawn from Italian market.

Ethnopharmacological Relevance: Folk medicine is a rich source of useful therapeutic tools. Nevertheless, use of medicinal plants can have unwanted, negative effects. By means of the description of an adverse reaction to a herbal remedy, we highlight the need for better efficacy-toxicity studies on these products., Aim of the Study: To report a case of possible Chelidonium majus L. (Greater celandine)-induced hepatitis and evaluate the past published cases., Materials and Methods: We outlined the main features of hepatitis associated with use of Chelidonium majus by providing a review of cases reported and analysing in detail a new one., Results: Several cases of acute hepatitis related to Greater celandine consumption were found in the literature. The assessment for causality using Naranjo probability scale showed a probable relationship between the liver injury and the consumption of Chelidonium majus in the case we described., Conclusions: Our case, along with the other ones reported in the literature, increases the concern about the safety of oral use of Chelidonium majus. Plants used in traditional medicine are not necessarily harmless. Customers and prescribers should be aware of this, especially when a herbal drug is used with therapeutic purposes in absence of reliable studies of clinical efficacy and benefit-risk assessment.

Purpose: To review the current literature on suspected green tea-related hepatic reactions and to describe two new cases reported within the framework of the Italian surveillance system of natural health products., Results: A literature search of publication between 1999 and October 2008 retrieved 34 cases of hepatitis. Histological examination of the liver revealed inflammatory reactions, cholestasis, occasional steatosis, and necrosis. A positive dechallenge was reported in 29 cases. There was one reported death. A positive rechallenge occurred in seven cases (20%). In the two new cases, the causality assessment was judged as "possible" according to the RUCAM score., Conclusions: Our analysis of the published case reports suggests a causal association between green tea and liver damage. The hepatotoxicity is probably due to (-)-epigallocatechin gallate or its metabolites which, under particular conditions related to the patient's metabolism, can induce oxidative stress in the liver. In a few cases, toxicity related to concomitant medications could also be involved.

Purpose: Natural health products are promoted to the public as equally or more effective and less toxic than conventional drugs. However, some 'natural' medicines, and in particular some herbal medicines, are known to have adverse effects. The Italian Pharmacovigilance System, in charge of the Italian Medicines Agency, collects spontaneous reports only for registered drugs. The awareness of the need of surveillance of the safety of natural health products has stimulated the implementation of a suspected adverse reaction reporting system in Italy. The system has been set up by the Italian National Institute of Health., Methods: An ad hoc reporting form can be downloaded from different institutional web sites. Voluntary reports of suspected adverse reactions are sent to the National Institute of Health and are evaluated by a multidisciplinary group of experts., Results: From April 2002 to March 2007, 233 spontaneous reports of suspected adverse reactions to natural health products were collected. A large proportion of suspected adverse reactions were serious: hospitalization was reported in 35% of forms; 6% reported life threatening clinical events and two fatal events were notified. About 50% of suspected adverse reactions were related to gastrointestinal, skin, psychiatric and nervous system disorders. Mainly herbal products (66%) were involved. Twenty-one cases of hepatitis of various seriousness were reported. Twenty-one reports were associated with 27 homeopathic preparations, mostly preparations containing mixtures of substances. Fourteen reports regarded suspected reactions to products containing propolis., Conclusion: Safety and efficacy of 'natural' medicines have not been thoroughly investigated. It is important to improve communication with the public on safety issues. Encouraging spontaneous reporting can contribute to improve awareness among health personnel and patients about the benefit-harm profile of these remedies.

Background: Adverse drug reactions (ADRs) represent a major public health concern, with death as the ultimate adverse drug outcome. Despite the relevance of this, the frequency of fatal ADRs (FADRs) is to a large extent unknown. Although spontaneous reporting data cannot give an exact estimate of the magnitude of drug-related mortality, it may highlight the importance and large dimensions of this public health problem., Objective: To describe the types and pattern of reported FADRs by analysing data from the national spontaneous reporting system in Italy., Methods: The Italian Medicines Agency (AIFA) runs a pharmacovigilance database where all the individual case safety reports (since January 2001) are stored. We selected and then analysed in detail all the case reports (to the end of December 2006) in which death was reported as the outcome. We included in the study only FADR case reports with a probable or possible causality assessment, according to the criteria established by the WHO. In line with the Italian reporting form, we divided FADR reports into two groups: (i) suspected ADRs that caused death; and (ii) suspected ADRs that contributed to death., Results: In the AIFA database 38 507 suspected ADR case reports were collected, of which 641 (1.66%) had a fatal outcome. We analysed 450 case reports (1.17% of total reports), 159 (35.33%) of them causing the patient's death and 291 (64.67%) contributing to death. The annual percentage of FADR reports followed a constant trend during the 6-year period. The majority of fatal reports (79%) were sent by hospital doctors. In total, 222 different drugs were suspected as causes of FADRs. 'Systemic anti-infective drugs' was the drug category associated with the highest percentage of FADRs (21.9%), followed by antineoplastic and immunomodulating agents (18.8%), and then by nervous system drugs (14.8%). Other drug categories involved in the fatal case reports were antithrombotic agents, NSAIDs and contrast media., Conclusions: The drugs most frequently involved in FADRs were drugs of wide usage with a narrow therapeutic range or those that caused serious skin or systemic allergic reactions. Ceftriaxone, ticlopidine and nimesulide were associated with the highest number of fatal case reports; the related FADRs were already known and recognized for each of these drugs. We highlight some cases reflecting probable inappropriate drug use by Italian physicians. This suggests a need for continued clinical pharmacology training and that many FADRs might be preventable through better medical and prescribing practice.

Natural health products are promoted to the public as equally or more effective and less toxic than conventional drugs. However, some 'natural' medicines are known to have adverse effects. From April 2002 to August 2007, 18 suspected adverse reactions associated with propolis-containing products were reported to the national surveillance system of natural health products, coordinated by the Italian National Health Institute. Sixteen reports concerned allergic reactions (with dermatological or respiratory symptoms), while two concerned the digestive tract. Some of the reactions were serious: six patients were admitted to hospital or visited an emergency department and in two of these a life-threatening event was reported. In seven patients (four of whom were children), an allergic predisposition was indicated. Propolis, a resinous substance collected by honeybees from the buds of living plants, has been used for several purposes (dermatitis, laryngitis, oral ulcers) because of its wide range of suggested activities (antibacterial, antiviral, antifungal, anti-inflammatory, antioxidant and chemopreventive actions). However, propolis is also a potent sensitizer and should not be used in patients with an allergic predisposition, in particular an allergy to pollen. In Italy, products containing bee derivatives (bee pollen, royal jelly or propolis) are available to the public as food supplements. No label warning of possible adverse reactions is found on the packaging, although it is well known that atopic and asthmatic individuals may be at an increased risk of allergic reactions after using these products. The public and healthcare practitioners should be aware of the risk of allergic reactions to products derived from bees and a warning should be added to the packaging of these products.