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AIMS: To assess the extent of off-label drug use and the occurrence of suspected adverse drug reactions (ADRs) among paediatric patients in Italian hospitals. METHODS: We conducted a 2-year prospective cohort study across 22 Italian hospital wards from September 2020 to September 2022. As part of the surveillance project, we performed a 6-month retrieval of all reported ADRs and evaluated all drug prescriptions for their possible off-label use. Following an educational project on pharmacovigilance addressed to healthcare professionals in participating wards, the same data collection was performed. RESULTS: Among the 892 patients included in the study, 64% were admitted to paediatric wards and 36% to neonatal wards. Fifty per cent of all drugs prescribed were used off-label and mainly concerned the administration of a different dose from the one authorized. In neonatal wards, off-label prescriptions occurred slightly more often, with antibacterials being the most frequently used off-label drugs. A total of 35 reports of suspected ADRs were collected, five before the educational project and 30 afterwards. Based on product licence, 10 of the total 35 reports concerned at least one off-label drug use. CONCLUSIONS: The off-label use of drugs in treating paediatric patients was extensive in Italian hospitals. Regulatory interventions are needed to promote the use of drugs based on the latest available literature and improve ADR reporting on children. Paediatric indications and dosages of the drugs most commonly used in children should be supported by appropriate ad hoc studies.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transtornos Relacionados ao Uso de Substâncias , Recém-Nascido , Criança , Humanos , Uso Off-Label , Estudos Prospectivos , Preparações Farmacêuticas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hospitais , Sistemas de Notificação de Reações Adversas a Medicamentos , Itália/epidemiologiaRESUMO
PURPOSE: Since vaccination against COVID-19 is recommended in pregnant people, we aimed to provide further evidence on the safety profile of COVID-19 vaccines in pregnancy. METHODS: Data on COVID-19 vaccines adverse events following immunizations (AEFIs) in pregnant people were retrieved from the open-access Vaccine Adverse Event Reporting System (VAERS) from December 2020 to April 2022. RESULTS: From December 2020 to April 1, 2022, a total of 4,869 reports involving pregnant women at COVID-19 vaccination were reported to VAERS. Among vaccines recipients, most belonged to the age group between 30 and 39 years old (3,029; 62.21%) and nearly half experienced an adverse event within 48 h of immunization (2,344; 48.14%). Overall, 21,816 suspected adverse reactions associated with COVID-19 vaccines were reported, and for as many as 80.43% of patients, they were described as non-serious. Most reactions occurred after administration of the mRNA-1273 (53.34%) and the BNT162b2 (40.68%) vaccines, while only a small proportion were related to the Johnson & Johnson's vaccine (5.69%). The most common non-pregnancy specific adverse events were headache (482; 2.21%), fatigue (472; 2.16%), and pyrexia (436; 2.00%), while adverse pregnancy outcomes with the highest reporting rate were abortions spontaneous (762; 3.49%), and vaginal haemorrhage (229; 1.05%). CONCLUSION: This post-marketing survey on VAERS data have provided updated evidence on the safety of COVID-19 vaccines during pregnancy, thus supporting clinicians in recommending maternal immunization.
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Vacinas contra COVID-19 , COVID-19 , Vacinas , Adulto , Feminino , Humanos , Gravidez , Sistemas de Notificação de Reações Adversas a Medicamentos , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Estados UnidosRESUMO
AIM: To provide further evidence on the safety profile of COVID-19 vaccines in paediatrics by analysing the spontaneous reports of adverse effects related to these vaccines. METHODS: Reports related to US paediatric population (from 0 to 17 years) vaccinated with authorised COVID-19 vaccines were extracted from Vaccine Adverse Event Reporting System from December 2020 to 17 November 2022. We conducted a descriptive analysis of Adverse Events Following Immunization (AEFI), calculating reporting rate of serious AEFIs and focusing on myocarditis and Guillain-Barré Syndrome after mRNA COVID-19 vaccines. RESULTS: Overall, 52 720 reports were retrieved: 77% (40541)-Pfizer-BioNTech, 19% (10083)-Moderna, a small proportion for other vaccines 4% (2096). Most of AEFIs were non-serious and listed in corresponding SPCs. Of serious AEFIs, 96% were related to the Pfizer-BioNTech vaccine. Roughly 91% (47874) were related to people from 6 to 17 years, a small percentage of 9% (4773) to the younger group (0-5 years). In both groups, most of the reports were related to mRNA vaccines and the percentage of AEFIs experienced by females were similar to males. CONCLUSIONS: Data showed that events most frequently reported were non-serious and listed in the corresponding SPCs, extending the evidence of safety of COVID-19 vaccines authorised in the United States in children.
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WHAT IS KNOWN AND OBJECTIVE: Migraine is one of the most prevalent and disabling medical illnesses. Preventive drugs are used to reduce the frequency, severity, and duration of attacks. Most patients were no longer on their medication due to contraindications or poor clinical response. Therefore, there is need for novel prophylactic agents for migraine. New preventive treatments are those of the class of calcitonin gene related peptide (CGRP)-targeting therapies. We aimed to assess the real level of therapeutic innovation of these new drugs. METHODS: The information on the new drugs was collected from several documents, including the European public assessment reports. The level of therapeutic innovation was assessed with the algorithm published by some of us in 2006. RESULTS: All new approved drugs (eptinezumab, galcanezumab, fremanezumab, erenumab) are indicated for the prophylaxis of migraine in adults who have at least four migraine days for month. All these drugs have been tested only in comparison to placebo. Their level of therapeutic innovation was only modest, that is, the lowest value of our algorithm. DISCUSSION: The new monoclonal antibodies of the class of CGRP targeting therapies have been authorized with efficacy data only against placebo. They do not offer additional clinical benefits compared to available therapies for the prevention of migraine attacks, with the exception of a lower frequency of administration and a more rapid effect. All this assigns to these drugs only a modest role in therapy according to our algorithm for therapeutic innovation with a significantly higher cost than similar therapies.
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Peptídeo Relacionado com Gene de Calcitonina , Transtornos de Enxaqueca , Adulto , Humanos , Peptídeo Relacionado com Gene de Calcitonina/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , AlgoritmosRESUMO
AIMS: Human papilloma virus (HPV) is 1 of the most common sexually transmitted infection responsible for different types of cancer: cervical, penile, vulvar, anal and oropharyngeal. It can affect both males and females. Our aim was to enrich the knowledge on the safety profiles of HPV vaccines in the male population. METHODS: We reviewed all the reports of adverse events following immunization (AEFI) present in the US Vaccine Adverse Event Reporting System from 1 January 2006 to 30 September 2018. Statistical data mining was performed using the reporting odds ratio with 95% confidence interval in order to detect disproportionality in reporting. RESULTS: A total of 5493 reports of AEFI were retrieved. The events most reported and that proportionally occurred more frequently with HPV vaccines than with others in males were: syncope (n = 701, reporting odds ratio = 2.85, 95% confidence interval [1.41-5.76p), loss of consciousness (n = 425, 2.79 [1.36-5.72]) and fall (n = 272, 3.54 [2.00-6.26]). CONCLUSION: Most of the AEFIs were already reported in premarketing clinical trials and acknowledged for the corresponding vaccines. A disproportionate reporting was found for some of these events including syncope. The HPV vaccines are generally well tolerated in males, although limitations own of spontaneous reporting should be considered.
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Vacinas contra Papillomavirus , Farmacovigilância , Sistemas de Notificação de Reações Adversas a Medicamentos , Feminino , Humanos , Imunização , Masculino , Papillomaviridae , Vacinas contra Papillomavirus/efeitos adversos , Vacinação/efeitos adversosRESUMO
PURPOSE: Various incentives are provided by the European Medicines Agency (EMA) to facilitate the development and marketing of orphan drugs. A 10-year period of market exclusivity is reserved to an orphan medicinal product. Sometimes, the sponsor renounces the designation before the expiration of that standard period. Our aim was to focus on these premature withdrawals. METHODS: We retrieved all the molecules included in the Community Register of Orphan Medicinal Products for Human Use from 2000 to November 2020. We considered the active substance, therapeutic indication, sponsor, year of designation, year of approval of the corresponding medicinal product, and that of the withdrawal of the orphan designation, if occurred. RESULTS: Overall, 2350 orphan designations were approved from 2000 to November 2020. Of these, 141 have been marketed. Premature withdrawal of orphan designation concerned 23 drugs (20 being antineoplastic agents), corresponding to 16 medicinal products. These withdrawals occurred after almost 2 years (range <1-7 years). CONCLUSIONS: A not negligible fraction of marketed orphan medicinal products underwent premature removal of their orphan designation. No motivation is requested by the EMA for this renouncement, although the peculiarity of the orphan medicinal products would need a greater transparency. We can only speculate about possible compensations in support of this decision, for instance in terms of commercial agreements between pharmaceutical companies, giving way to alternative products, as a couple of examples suggest. An open debate on this topic among members of academia, regulatory bodies, price and reimbursements committees, and pharmaceutical industry representatives will be welcome.
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Indústria Farmacêutica/estatística & dados numéricos , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Produção de Droga sem Interesse Comercial/estatística & dados numéricos , União Europeia , HumanosRESUMO
PURPOSE: Two chimeric antigen receptor T-cell (CAR-T) therapies have been approved in the United States (USA) in 2017 and Europe (EU) in 2018: axicabtagene ciloleucel and tisagenlecleucel. They contain the patient's own T cells, which are extracted, genetically modified, and reinfused. Alongside the good efficacy results, the assessment of safety profile of these new therapies represents a great challenge. Our aim was to analyze the reports of the adverse drug reactions (ADR) after CAR-T administration as occurred in the real clinical setting. METHODS: We performed a retrospective observational study, collecting all the reports in EU (EudraVigilance, EV) and US (FAERS) databases of ADRs regarding axicabtagene ciloleucel and tisagenlecleucel. Both descriptive and statistical analyses were performed, the latter by using Reporting Odds Ratio (ROR). RESULTS: A total number of 1426 reports of suspected ADRs were retrieved in EudraVigilance and FAERS. Patients' reported age reflected the age range for which the drugs are approved (18-64 years for axicabtagene ciloleucel and patients aged under 25 years for tisagenlecleucel). The most reported event was cytokine release syndrome (CRS), 185 events for tisagenlecleucel and 462 for axicabtagene ciloleucel in FAERS and 137 and 498, respectively, in EudraVigilance. A disproportionality was found comparing axicabtagene ciloleucel with tisagenlecleucel for the above-mentioned event: EV ROR 2.47, 95% CI 2.22-2.74, FAERS 1.89, 1.70-2.10. CONCLUSION: CRS represents the major problem with the administration of CAR-T therapies. Our analysis has not revealed new ADRs; however, it supports the safety profile of CAR-T with new data from real clinical setting.
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Antineoplásicos Imunológicos/efeitos adversos , Produtos Biológicos/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Adolescente , Adulto , Fatores Etários , Antineoplásicos Imunológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Adulto JovemRESUMO
Little is known about the administration of direct-acting oral anticoagulants (DOACs) and the occurrence of alopecia. Our aim was to analyse the reports of alopecia following DOAC administration received until 2 May 2018 from VigiBase, the World Health Organization database. A descriptive analysis of age, sex, seriousness and dechallenge/rechallenge outcome was carried out. For each report, the time-to-onset was evaluated and the causality was assessed by using Naranjo algorithm. Overall, 1316 reports were retrieved, most concerning rivaroxaban (58.8%); 80% of the reports were related to females, in particular to those aged ≥65 years (23.1%). The median value of the time-to-onset was 28 days, with an interquartile range of 63 days. In 54.3% of the reports the causality was assessed as possible. In conclusion, a possible association could exist between DOACs administration and alopecia, but further observational studies are needed to confirm these findings.
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Alopecia/induzido quimicamente , Anticoagulantes , Inibidores do Fator Xa , Administração Oral , Adolescente , Adulto , Idoso , Alopecia/tratamento farmacológico , Alopecia/epidemiologia , Anticoagulantes/efeitos adversos , Criança , Bases de Dados Factuais , Feminino , Humanos , Recém-Nascido , Masculino , Rivaroxabana/efeitos adversosRESUMO
BACKGROUND: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. METHODS: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. RESULTS: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively. CONCLUSION: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.
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Antibacterianos/efeitos adversos , Antineoplásicos/efeitos adversos , Coagulação Intravascular Disseminada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fibrinolíticos/efeitos adversos , Antibacterianos/classificação , Antineoplásicos/classificação , Bases de Dados Factuais/estatística & dados numéricos , Coagulação Intravascular Disseminada/induzido quimicamente , Coagulação Intravascular Disseminada/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Fibrinolíticos/classificação , Humanos , Conduta do Tratamento Medicamentoso , Farmacovigilância , Projetos de Pesquisa/estatística & dados numéricos , Organização Mundial da SaúdeRESUMO
OBJECTIVES: To describe antibacterial prescribing patterns in outpatients aged 0-5 years from 2007 to 2013 in the Emilia-Romagna region, assessing sex- and age-specific consumption over time. METHODS: All children aged 0-5 years resident in the Emilia-Romagna region who received at least one prescription of a systemic antibacterial in the period 2007-13 were enrolled. The prescriptions of systemic antibacterials to children were collected from the regional prescription database. Data were stratified by year, sex and age, and analysed in terms of periodic prevalence and of annual prescription rate per 1000 person-years. RESULTS: The prevalence of children receiving at least one prescription per year varied from 68.0% in 2007 to 59.0% in 2013, while the average prevalence of children receiving five or more prescriptions per year was 6.96%. The annual prescription rate varied from 1621.26 in 2007 to 1372.27 in 2013. Penicillins + ß-lactamase inhibitors accounted for 35.3% of total prescriptions, followed by extended-spectrum penicillins (28.6%), macrolides (17.0%) and third-generation cephalosporins (13.9%). CONCLUSIONS: Despite recommendations, a significant overprescription of antibacterials to children still exists, showing no satisfactory improvements over the years. In contrast to Northern European countries, adherence to evidence-based guidelines was poor, with frequent prescribing of broad-spectrum agents for the treatment of mostly viral childhood infectious disease.
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Antibacterianos/economia , Antibacterianos/uso terapêutico , Custos e Análise de Custo/estatística & dados numéricos , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Fatores Etários , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Fatores SexuaisRESUMO
AIMS: Human papilloma virus (HPV) is the cause of different types of carcinoma. Despite the remarkable effectiveness of the HPV vaccines, there have been many complaints about their risk-benefit profile due to adverse events following immunization (AEFI). The purpose of this study is to analyse the safety profile of the HPV vaccine basing on real-life data derived from reports of suspected AEFIs collected in the US Vaccine Adverse Events Reporting System (VAERS) and assess if the searches on Google overlap with spontaneous reporting. METHODS: We collected all the reports in VAERS between January 2007 to December 2017 related to the HPV vaccines. A disproportionality analysis using reporting odds ratio (ROR) with 95% confidence interval was performed. RESULTS: Over the 10-year period, 55 356 reports of AEFI related to HPV vaccines were retrieved in VAERS, corresponding to 224 863 vaccine-event pairs. The highest number of reports was related to Gardasil (n = 42 244). The two events more frequently reported and statistically significant for HPV vaccines were dizziness (n = 6259; ROR = 2.60; 95% confidence interval 2.53-2.66) and syncope (n = 6004; ROR = 6.28; 95% confidence interval 6.12-6.44). The trends of spontaneous reporting and Google searches overlap. CONCLUSION: The AEFI analysis showed that the events most frequently reported were non-serious and listed in the corresponding summary of product characteristics. Potential safety signals arose regarding less frequent AEFIs that would deserve further investigation. It is extremely important to disseminate correct and evidence-based scientific information.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Tontura/epidemiologia , Vacinas contra Papillomavirus/efeitos adversos , Síncope/epidemiologia , Vacinação/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Mineração de Dados , Tontura/induzido quimicamente , Feminino , Humanos , Lactente , Internet/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Autorrelato/estatística & dados numéricos , Síncope/induzido quimicamente , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinação/estatística & dados numéricos , Adulto JovemRESUMO
PURPOSE: In Italy, the non-commercial trials on medicines are regulated by the Ministry Decree 17 December, 2004. Its intent is of encouraging the independent research for the improvement of clinical practice. We aimed to analyze the main features of the proposals of non-commercial clinical trials on medicines submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2017. METHODS: Data were extracted from IEC registry and were organized with an ad hoc database. The relationships between the variables were examined using contingency tables. When appropriate, we applied the chi-square statistical test for the comparison of the categorical variables. RESULTS: Over the 8-year period, the IEC evaluated 2931 studies, of which 1156 (39.4%) related to clinical trials on medicines; 245 (21.2%) out of the latter were non-commercial ones. A percentage of 49.8 of the trials were of phase II; 137 trials (55.9%) were promoted by hospitals, medical schools or institutes for research, hospitalization and health care. Non-profit organizations and scientific societies were promoters of 88 trials (35.9%). Most phase I and phase II trials received additional support from pharmaceutical companies. CONCLUSIONS: Our results show a not negligible industrial influence on non-commercial trials through additional support, mostly to those of phase II. An update of the present legislation on this matter is desirable, adopting clearer rules on the relations sponsor-industry.
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Ensaios Clínicos como Assunto/estatística & dados numéricos , Comissão de Ética/estatística & dados numéricos , Academias e Institutos , Ensaios Clínicos como Assunto/economia , Indústria Farmacêutica , Apoio Financeiro , Hospitais , Hospitais Universitários , Humanos , Itália , Organizações sem Fins Lucrativos , Sistema de Registros , Faculdades de MedicinaRESUMO
INTRODUCTION: The cardiovascular safety profile of macrolides and fluoroquinolones has been widely discussed. The aim of the present study is to provide the contribution of real-world data onto the ongoing discussion about cardiovascular toxicity of both macrolides and fluoroquinolones. METHODS: Reports of adverse drug reactions (ADRs) were retrieved from VigiBase. Macrolides and fluoroquinolones were compared with amoxicillin by using the reporting odds ratio (ROR) as a measure of disproportionality. Macrolides were then compared with fluoroquinolones. RESULTS: Overall, 6810 reports of ADRs were retrieved: 62% of them were serious and 35% concerned female. Macrolides were more frequently associated with "atrial fibrillation" (ROR = 1.26, CI 1.02-1.57) and "ventricular fibrillation" ROR = 2.60, CI 1.92-3.54) than fluoroquinolones. Antimicrobials more frequently reported for "cardiac disorder" were azithromycin (375 reports) and clarithromycin (302) for macrolides and levofloxacin (470) and moxifloxacin (391) for fluoroquinolones. CONCLUSION: Our data highlighted that macrolides and fluoroquinolones may influence cardiac rhythm and suggest caution in the prescribing of these drugs to patients with hidden cardiovascular risk factors. Although these ADRs seem to be not common, they have a notable impact in clinical practice because of the huge number of the exposed subjects.
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Antibacterianos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Fluoroquinolonas/efeitos adversos , Macrolídeos/efeitos adversos , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Antibacterianos/administração & dosagem , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Fluoroquinolonas/administração & dosagem , Humanos , Lactente , Recém-Nascido , Macrolídeos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
PURPOSE: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD). METHODS: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results. RESULTS: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001). CONCLUSIONS: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators.
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Anemia/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Hematínicos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Darbepoetina alfa/uso terapêutico , Epoetina alfa/uso terapêutico , Eritropoetina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Insuficiência Renal Crônica/complicações , Medição de Risco , Resultado do TratamentoRESUMO
AIM: Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. METHODS: Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. RESULTS: We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. CONCLUSIONS: As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Hemorragia Cerebral/epidemiologia , Hemorragia Gastrointestinal/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Adolescente , Adulto , Idoso , Hemorragia Cerebral/induzido quimicamente , Criança , Pré-Escolar , Dabigatrana/efeitos adversos , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Fatores de Risco , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/etiologia , Varfarina/efeitos adversos , Organização Mundial da Saúde , Adulto JovemRESUMO
PURPOSE: Compassionate use of forthcoming drugs has become an increasing pathway through which patients can take advantage of promising medicines. We aimed to analyse the main features of the requests of compassionate use submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2015. METHODS: The present analysis concerns the requests of compassionate use received by the IEC in the period 2010-2015. For each requested drug, we paired the date of the first request to our IEC with the date(s) of (a) submission to EMA, (b) CHMP positive opinion, and (c) European marketing authorization (if issued). RESULTS: In the period 2010-2015, our IEC received compassionate use requests for 610 patients. Most of the requests concerned patients suffering from solid or haematological cancers not responsive to first or second line of treatment. Sixty-five couples of medicine/clinical condition (corresponding to 56 individual medicines) were submitted to our IEC, and 62 of them regarded products following the centralised procedure at the EMA. Twenty-one out of the latter (34%) had already obtained CHMP positive opinion. CONCLUSIONS: Our results indicate that compassionate use of forthcoming medicines represents a not negligible portion of the therapies utilized in hospital care. The observed large resort to medicines still on trial may suggest that doctors are more aware with the potential benefits of the new drugs. However, this trend may also indicate an increasing marketing activity of the pharmaceutical industry, addressing to get the clinicians used to the upcoming medicines.
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Ensaios de Uso Compassivo , Indústria Farmacêutica , Comissão de Ética , Humanos , ItáliaRESUMO
PURPOSE: H1-antihistamines are commonly used in infants and children for the relief of histamine-mediated symptoms in a variety of conditions. Little is known about their safety profile in these patients. We performed a comparative analysis of the safety profiles of H1-antihistamines using data from the WHO database (VigiBase). METHODS: We selected adverse drug reaction (ADR) reports on H1-antihistamines in children (0-16 years) up to June 2014 from VigiBase. ADRs were codified according to MedDRA terminology. The reporting odds ratios (RORs) with 95% confidence for drug-reaction pairs were calculated. RESULTS: The analysis was performed on 8918 reports related to antihistamines, corresponding to 19503 drug reaction pairs for 68 different drugs. Most of reports involved children aged 2 to 6 years (32%) and 6 to 12 years (34%). Most reported drugs were cetirizine (1608 reports, corresponding to 18%), loratadine (16%), and diphenhydramine (10%). ADRs were classified as serious in 23% of cases, and 400 cases had a fatal outcome. We found a significant associations for several drug-reaction pairs such as levocetirizine and epilepsy (ROR, 6.57; 95% confidence interval [CI], 1.51-28.53) and chlorphenamine and toxic epidermal necrolysis (ROR, 7.29; 95% CI, 2.39-22.2). CONCLUSIONS: H1-antihistamines are among the most used drugs in pediatrics, also in an off-label manner. Our data highlights associations with serious and unexpected ADRs. Educative intervention to clinicians and parents are needed to help doctors to make proper choices on the drug treatment and for the early detection of ADRs to maximize the benefits and reduce the risk of ADRs in these patients.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Epilepsia/epidemiologia , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Síndrome de Stevens-Johnson/epidemiologia , Adolescente , Cetirizina/efeitos adversos , Criança , Mortalidade da Criança , Pré-Escolar , Clorfeniramina/efeitos adversos , Bases de Dados Factuais/estatística & dados numéricos , Difenidramina/efeitos adversos , Epilepsia/induzido quimicamente , Feminino , Humanos , Lactente , Recém-Nascido , Loratadina/efeitos adversos , Masculino , Farmacovigilância , Síndrome de Stevens-Johnson/etiologia , Organização Mundial da SaúdeRESUMO
AIM: Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. METHODS: This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. RESULTS: We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00). CONCLUSION: Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Sulfonamidas/efeitos adversos , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Ibuprofeno/administração & dosagem , Ibuprofeno/efeitos adversos , Itália/epidemiologia , Cetoprofeno/administração & dosagem , Cetoprofeno/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Risco , Sulfonamidas/administração & dosagemRESUMO
PURPOSE: An analysis of Italian spontaneous adverse drug reactions (ADR) reporting database highlighted a potential association between hypothermia and ibuprofen in children. Hypothermia is defined as a core body temperature of 35 °C (95 °F). Ibuprofen is the most prescribed NSAID for the treatment of fever and moderate pain in children. We aimed to analyze the cases of ibuprofen-associated hypothermia retrieved in the Italian database in order to contribute to the discussion on this potential association. METHODS: We extracted all suspected cases of ibuprofen-associated hypothermia from the Italian spontaneous reporting database and from VigiBase up to December 2015. We considered the proportional reporting ratio (PRR) as a measure of disproportionality for the Italian cases and the information component (IC) for the reports from VigiBase. We performed a case-by-case analysis to exclude duplicates. RESULTS: Nineteen cases of hypothermia associated with ibuprofen use were retrieved from the Italian spontaneous reporting database (PRR 19.8, CI 95 %, 12.0-32.9). The reports concerned ten females and nine males with an average age of 2.5 years. Up to 31 December 2015, 168 cases of hypothermia associated with ibuprofen were reported to VigiBase, with an IC of 2.05 (IC025, 1.82). Among these, 126 cases involved children (49 % males) with an average age of 4.4 years. CONCLUSIONS: Although the risk of this ADR is unknown so far, the widespread use of this drug recommends the need for further studies to better characterize this possible association. Clinicians and pharmacists but also parents should be aware that this risk is theoretical as not yet been confirmed.