Portuguese Pharmacovigilance System Research Articles

Medication and the Risk of Falls: An Analysis of Adverse Drug Reactions Reported to the Portuguese Pharmacovigilance System

Medication and the Risk of Falls: An Analysis of Adverse Drug Reactions Reported to the Portuguese Pharmacovigilance System

Analysis of Reports Sent to the Portuguese Pharmacovigilance System and Published Literature Regarding the Safety of Metformin in the Elderly.

The first line medication for the treatment of type 2 diabetes is metformin. This study aims to investigate the safety profile of metformin and metformin combination medications in older adults using pharmacovigilance data. A literature search was used to identify published clinical studies reporting safety of metformin in older patients (age ≥ 65 years old), which were then thoroughly evaluated. Additionally, a deep analysis was performed, taking into account suspected adverse drug reaction (ADR) reports submitted to the Portuguese Pharmacovigilance System involving patients with 65 years old or older, with metformin or metformin combination as the suspected drug. The results suggest that metformin is safer when used in combination with other antidiabetics than when used in monotherapy. Metformin prolonged-release tablets have a lower incidence of adverse effects compared to treatment with immediate-release metformin tablets. The analysis of the reports showed that "gastrointestinal disorders" was one of the most common classes reported, and metformin alone was the drug most commonly associated with serious gastrointestinal reactions that resulted in hospitalization. In addition, it was the drug most commonly associated with the lactic acidosis ADR. Even though most ADRs in the reports were serious, the majority progressed to cure. According to the analysis performed, the results suggest that the patient's renal function should be considered in order to prevent ADRs associated with metformin, such as lactic acidosis. Therefore, monitoring the safety profile of metformin remains essential to prevent serious ADRs.

Assessment of risk perception of patients concerning adverse drug reactions

Abstract Introduction. The use of medicines involves trade-offs between their therapeutic benefits and inherent risks. Several studies show that numerous adverse drug reactions (ADRs) could be avoided by increasing patients’ awareness of medicine’s risks. Even though drug labels enclose relevant information about risks and benefits, this information often requires patient education and overall health literacy to improve medication adherence, thereby preventing ADR frequency. Aim. To describe patient awareness of ADR risks and the Portuguese Pharmacovigilance System. Methods. A questionnaire comprising 27 questions was conducted at a health centre in Coimbra, Portugal. This study included ninety-one patients. Risk perception was scored as positive (≥2.5 points) or negative (<2.5 points). Results were analysed by SPSS v 27.0. Results. This work highlights poor patient perceptions of risk with a rate of negative responses of 85,7%. Although some responders were aware of the possibility of reporting ADRs, only some participants were familiar with the Portuguese Pharmacovigilance System. Additionally, only five patients – out of the vast majority of those who had previously encountered ADRs – reported the event to INFARMED. Conclusion. Patient low literacy regarding ADRs and the national reporting systems need to be urgently improved. Patient-centred communication strategies for recognising regulatory requirements and standards of product safety are important measures to achieve effective awareness through routine reporting within the Pharmacovigilance systems.

Delayed Extensive Local Reaction to the mRNA-1273 Vaccine against SARS-CoV-2: A Case Report

In response to the COVID-19 pandemic, two mRNA vaccines (Comirnaty and Spikevax) received emergency use authorization from the European Medicines Agency. This case report aimed to report a delayed adverse reaction to the mRNA-1273 vaccine against COVID-19 from a Portuguese vaccination center. A case report was performed with medical observation and reported to the Portuguese Pharmacovigilance System, then investigated based on the WHO-UMC Causality Categories. A 66-year-old female patient with a clinical history of dyslipidemia, essential arterial hypertension, obesity, multinodular goitre and cholecystectomy, who presented delayed large cutaneous hypersensitivity reaction following Spikevax COVID-19 mRNA (mRNA-1273) vaccine administration. Our clinical findings (time and clinical appearance), along with evidence of previously reported histological findings, are strongly suggestive of T-cell-mediated hypersensitivity. There is no contraindication to the inoculation of subsequent doses in patients developing these clinical conditions, and vaccination should continue to be strongly encouraged.

Motivation and Knowledge of Portuguese Community Pharmacists Towards the Reporting of Suspected Adverse Reactions to Medicines: A Cross-Sectional Survey.

The close contact between patients and community pharmacists, along with the extensive geographical distribution of pharmacies in Portugal, offer exceptional conditions to detect and report adverse drug reactions (ADR). This study aimed to evaluate the motivation and knowledge of spontaneous reporting of ADR by community pharmacists of Porto, Portugal. Secondly, we aimed to generate real-world evidence on the main factors determining ADR report and at raising potential alternatives to the current reporting procedure in community pharmacy. We performed a descriptive, cross-sectional, observational, anonymous web survey-based study. Between April and July 2021, a web survey was implemented, targeting community pharmacists in the Porto district, Portugal. We validated 217 surveys from pharmacists. Regular notifiers seem to be more familiarised than non-regular notifiers with the Portuguese Pharmacovigilance System (PPS), with the Portal RAM for reporting suspected ADR, and with the update of the concept of ADR. Moreover, regular notifiers seem to be more proactive with their care in questioning patients about ADR and have more self-knowledge to identify suspected ADR. Conversely, non-regular notifiers, seem to be more reluctant to be judged by their ADR reporting activities. Respondents suggested to simplify and optimise the reporting process (31% of the suggestions), or to integrate a reporting platform into the pharmacy's software (27%). This study identified opportunities to promote the ADR reporting process by community pharmacists, namely receiving feedback from the PPS on the reported case and its regulatory implications, implementing training programs in pharmacovigilance, and creating solutions to simplify the reporting process.

Adverse Drug Reactions and Potentially Inappropriate Medication in Older Patients: Analysis of the Portuguese Pharmacovigilance Database.

Criteria have been developed to identify potentially inappropriate medications that can enhance adverse reactions, highly prevalent in older patient’s therapy. This study aimed to identify potentially inappropriate medications within the adverse drug reactions reported in the Portuguese pharmacovigilance system, characterizing the reports where inappropriate medications were identified. INFARMED, I.P. provided all adverse drug reactions reported from January to December 2019 in 65-year-old and older patients. Adverse drug reactions were characterized according to the System Organs Classes, seriousness, and medications with the Anatomical Therapeutical Classification. Potentially inappropriate medications were identified by applying the EU-(7)-PIM and the Beers criteria. A p value < 0.05 was considered statistically significant. From the 2337 reports considered for the analysis, PIMs were found in 12.8% of these, and 64.7% of all adverse reaction reports were classified as serious. Within the group of reports including at least one PIM, 71.4% were classified as serious, with hospitalization the most common criteria (35.1%). From the 3170 suspected medicines identified, 10.6% were classified as PIMs. Amiodarone was the most frequent PIM identified in the study (10.1%). Reports including at least one PIM were more associated with a higher number of ADRs (p = 0.025) reported in the same record, higher number of suspected medicines identified (p < 0.001), seriousness (p = 0.005), and hospitalization (p < 0.001). Potentially inappropriate medications are important enhancers of serious adverse drug reactions, increasing the likelihood of hospitalizations. This reinforces the importance of improving medication appropriateness in the older population.

Safety of Non-Steroidal Anti-Inflammatory Drugs in the Elderly: An Analysis of Published Literature and Reports Sent to the Portuguese Pharmacovigilance System.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used agents to treat musculoskeletal disorders (principally by the elderly), thus raising the risk of adverse drug reactions (ADRs). This work aims to monitor NSAIDs safety profile in older people by using literature and pharmacovigilance data. Published clinical studies reporting the NSAIDs safety in elderly patients (age ≥ 65) were identified by a literature search and were then deeply analyzed. In addition, suspected ADRs reports submitted to the Portuguese Pharmacovigilance System (PPS) involving patients aged ≥65 with at least one NSAID as suspected drug were explored in detail. Most studies concluded that the risk of gastrointestinal, cardiovascular, and renal ADRs was significantly lower with cyclooxygenase-2 (COX-2)-selective NSAIDs use than with nonselective NSAIDs. The PPS data analysis showed that serious gastrointestinal ADRs occurred mostly in patients taking more than one NSAID and/or another concomitant drug that increases the incidence of these events, in the absence of gastroprotection. The results suggest that while NSAID toxicity is well understood, their safe use needs to be monitored in clinical practice. Furthermore, the pharmacovigilance data analyzed also showed that monitoring NSAIDs use in elderly remains essential to mitigate the associated risks, especially in those with comorbidities and under polytherapy.

Inhaled Drug Therapy-Associated Adverse Reactions in Obstructive Respiratory Diseases: A Review of a Decade of Reporting to the Portuguese Pharmacovigilance System.

Inhaled medication used for treatment of chronic obstructive lung diseases (asthma, chronic obstructive pulmonary disease-COPD, and Asthma-COPD overlap) may be associated with adverse drug reactions (ADRs). The aim of this study was to characterise spontaneous reports (SRs) of suspected ADRs received by the Portuguese Pharmacovigilance System (PPS), from 2007 to 2017. Methods: Retrospective observational study of SRs associated with single substance and combination inhalers, analysed in terms of pharmacological class of the involved drugs, sex and age range of the involved patients, and seriousness and type of ADRs. Results: 230 SRs were analysed, accounting for a total of 599 suspected ADRs. Inhaled corticosteroid/long-acting beta-2 agonist combination had the highest frequency in SRs (32.2%) and in ADRs (32.7%). There was a slight predominance in men (51.3%) and non-elderly adults were the most affected age group (39.1%). Most SRs were serious (70.4%). In total, “respiratory, thoracic and mediastinal diseases” ADRs were the most reported (19.5%), with “dyspnea” being the most frequent (4.8%). Conclusions: Most SRs were associated with controller medications and were expected. Most ADRs involved non-elderly adults, were serious and of respiratory nature and many were due to overuse of reliever medication.

Drug Induced Liver Injury: Perspective of the Adverse Drug Reaction Reports to the Portuguese Pharmacovigilance System from 2010 to 2019.

Background: Drug induced liver injury (DILI) is an adverse drug reaction that causes liver damage in a predictable (dose-dependent) or an unpredictable (idiosyncratic) fashion. We performed an assessment of DILI in Portugal, by analyzing the reports, sent to the Portuguese Pharmacovigilance System (PPS). Methods: A search was performed on the PPS database, in a 10-year time frame, from 1 January 2010 to 31 December 2019. Results: There was not a prevalence of either sex in any age group. Most reports (n = 1120, 55.0%) belonged to patients in the age group 19–64 years old. Hepatitis (n = 626, 26.7%) was the most common adverse drug reaction in our study. Hepatotoxicity (n = 362, 15.5%) and hepatitis (n = 333, 14.2%) were more frequent in age group 19–64 years old. Cholestasis was more prevalent in adults independently of age. Hepatic fibrosis and encephalopathy were more common in the elderly. Most patients consumed between one and four suspected drugs (n = 1867, 92%). Most patients in our study evolved to “cure” (n = 796; 39%). Hepatotoxicity (n = 23; 13.8%) and hepatitis (n = 610; 25.9%) had a female predominancy while choluria (n = 8; 4.8%) and splenomegaly (n = 8; 4.8%) were of male predominance. Conclusions: DILI is rare but can be fatal. As such, an active search of DILI is necessary.

Assessment of suspected adverse drug reactions in elderly patients with diabetes mellitus based on a Portuguese spontaneous reporting database: analysis of reporting from 2008 to 2018

ABSTRACT Background Age is one of the most important risk factors in the development of diabetes mellitus and certain drug classes indicated for this condition may be associated with clinically important adverse drug reactions (ADRs). The aim of this study was to analyze the suspected ADRs in older patients with diabetes mellitus, reported to the Portuguese Pharmacovigilance System from 2008 to 2018. Research design and methods A retrospective analysis of suspected ADRs reports was performed, involving patients aged ≥65 years. Results Of a total of 751 reports collected, 439 were considered serious, 199 led to hospitalization and in 19 of them occurred a fatal outcome. Most of them were observed in females (n = 393) and involved patients belonging mainly to the age group 65–74 years (n = 405). Taking into account a total of 2134 suspected ADRs, the most frequent were hypoglycemia (2.67%) and lactic acidosis (2.62%). The drugs specifically indicated for glycemic control were the most frequently involved in ADRs. Conclusions Most of the ADRs were reported as serious and were mainly associated to drugs in diabetes mellitus. In addition, the majority of them, such as hypoglycemia, are preventable, highlighting the importance to identify possible factors that determine this occurrence, especially in the elderly.

PDG17 Adverse Drug Reactions Associated to Hydroxychloroquine and Remdesivir in COVID-19 Patients: Analysis of Reported ADR to the Portuguese Pharmacovigilance System

To analyse the adverse reactions that occurred with the two main drugs used in the context of the COVID-19 disease - Hydroxychloroquine (1st pandemic wave) and Remdesivir (2nd pandemic wave) - based on notifications of adverse reactions from Portugal.

PNS22 Real-World DATA of ADR Reports in Signal Detection - DME Perspective

The Designated Medical Event (DME) is a serious medical event that is often causally associated with medicines. This way, EMA has developed a list of DME, through Medical Dictionary for Regulatory Activities (MedDRA). The list is used by the EMA and Member States to focus on suspected adverse drug reaction(ADR) reports that deserve special attention, irrespective of statistical criteria used to prioritise safety reviews. DME search in ADR reports is one of the methods used to detect safety signals. The objective of our study is to identify and characterize the reports of ADR that contain the DME, in Portugal. A retrospective study was conducted to identify and characterize the spontaneous ADR reports with DME, occurred in Portugal, between 2014 to 2019. A descriptive analysis was performed for the following data: type of notifier (consumer or healthcare professional), medicines classified by the Anatomical Therapeutic Chemical Code, ADR coded with MedDRA and description of ADR in the summary of product characteristics (SmPC). During this 5-year period, the Portuguese Pharmacovigilance System received 15344 reports, of these 1335 correspond to reports with DME (1305 by healthcare professionals; 30 by consumers). The annual percentage of reports with DME has been increasing, with the exception of the last year. The most frequent ATC group with or without DME is “Antiinfectives For Systemic Use”. The most frequent System Organ Classes of the reports with the DME is “Skin and subcutaneous tissue disorders”. Of the 1335 reports with DME terms, 130 of these reports are not described in the SmPC. It is important to obtain real-word data, especially in the area of drug safety, because it is a way to prevent ADR. In this way, notifiers should be made aware of the importance of sharing data related to ADR, thus increasing knowledge about the safety profile of medicines.

Headache as an Adverse Reaction to the Use of Medication in the Elderly: A Pharmacovigilance Study.

There is a consensus that elderly individuals are quite vulnerable to adverse drug reactions (ADRs), and headaches are one of the most frequent clinical presentations of central nervous system problems in the general population, which can be an ADR. The purpose of our work was to analyze reports of “headache” associated ADRs in the elderly sent to the Portuguese Pharmacovigilance System (PPS), and also which drugs were more frequently associated with this adverse reaction. A retrospective analysis of suspected ADR reports involving patients aged 65 years or older received by the PPS in the last 10 years was conducted. A search of all the terms associated with the High Level Term “headache” was performed. All duplicate reports were excluded from the analysis. A total of 155 ADRs reports were included, in which 15 reported isolated “headache” as suspected ADR, while the remaining 140 ADRs reports reported “headache” together with several other adverse reactions. Most reports of “headache” ADR occurred in women (74.8%; n = 116). About half (46.5%; n = 72) of the ADR reports were considered serious. Anti-viral medication, anti-depressants, anti-dyslipidemic agents and central nervous system-acting analgesics were the most frequent drugs associated with “headache” ADR reports in this population. In elderly patients, most ADR reports involving headaches occurred in women and a high percentage (46.5%) were considered serious. Thus, it is important that healthcare professionals pay more attention to headaches reported as ADRs in the elderly and drugs suspected to cause them, in order to increase knowledge about this type of reaction and contribute towards safely using drugs in this age group.

A prospective, observational study to evaluate adverse drug reactions in patients with COVID-19 treated with remdesivir or hydroxychloroquine: a preliminary report

ObjectivesSince the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pressure to minimise its impact on public health has led to the implementation of different therapeutic strategies, the efficacy...

Adverse drug reactions in elderly: a five-year review of spontaneous reports to the Portuguese pharmacovigilance system

ABSTRACT Background: Adverse drug reactions (ADRs) are responsible for considerable morbidity and mortality in elderly. This study aimed to characterize the ADRs profile in Portuguese elderly patients, thus enhancing ADRs knowledge in this vulnerable population. Methods: All spontaneous ADRs reported to the Portuguese Pharmacovigilance System from 2013 to 2017 were examined. However, considering the aim of this study, ADRs referring to patients aged 65 and over were analyzed in higher detail and compared with those reported in non-elderly adults. Results: Considering the age of 65 years and above, 3692 spontaneous reports of suspected ADRs were analyzed. The suspected ADRs most frequently reported fall within the categories of general disorders and administration site conditions, and skin and subcutaneous tissue complaints. Regarding therapeutic agents, the antineoplastic drugs were the most common involved. Among the 2458 cases of serious ADRs reported, 34.0% led to hospitalization and in 5.8% of them occurred a fatal outcome. The antineoplastic and antithrombotic drugs were the most represented pharmacotherapeutic groups of suspected drugs involved in patient’s death (25.0% and 13.6%, respectively). Conclusions: Most of the suspected ADRs were classified as serious. The majority of them were expected, so preventable, highlighting the importance of improving medication use in elderly.

Adverse drug reactions in adolescents: a review of reporting to a national pharmacovigilance system

ABSTRACT Objective Adverse drug reactions (ADR) cause significant morbidity, mortality and health costs and have an important prevalence in all ages. Few studies focus on ADR in adolescents. The goal of this study was to characterize a case series of ADR reported to the Portuguese Pharmacovigilance System (PPS) of the National Authority of Medicines and Health Products (INFARMED, I.P.) during an eleven-year period (from 2006 to 2016) concerning this specific population. Methods Retrospective analysis of reports concerning patients from 10 to 18 years received by the PPS between 2006 and 2016. The authors evaluated patients’ demographics (age and sex). The characteristics and seriousness of the reactions, the type of reaction reported, and the drugs involved were assessed. Results The authors found 782 reports (59% females). Most reports came from physicians (61%). Overall 80% of the reports described serious ADR. A greater proportion of serious events was found among males. Most reactions referred to general disorders and administration site conditions (38%), followed by skin and subcutaneous tissue reactions (33%). In 3rd and 4th were gastrointestinal disorders (24%) and the nervous system disorders (23%), the former more frequent among females. Vaccines were the most represented group (42%) followed by antibacterials for systemic use (19%). Conclusion Major findings considering drugs involved and the reported reactions varied according to age and sex.

Suspected Adverse Drug Reactions From Corticosteroids: Analysis of Reported Notifications to the Portuguese Pharmacovigilance System

We performed a retrospective, observational, and descriptive study on the reports of adverse reactions resulting from the use of corticosteroids, based on data from the Portuguese Pharmacovigilance System recorded between January 2009 and December 2018. A total of 569 reports with at least 1 suspected corticosteroid were included in the study, of which 59.1% belonged to individuals aged between 19 and 64 years. There was no significant predominance of sex, with 55% female patients. The notification trend has increased over the years, with the highest number of cases in 2018, 29.5%. Among the 3 groups of health professionals (nurses, pharmacists, and physicians), physicians were the ones who notified the majority. Regarding seriousness, 89.1% were classified as serious, and the most commonly reported corticosteroid as suspected drug was prednisolone, 65.6%. The system organ class group was reported in 37.8% of adverse reactions was infections and infestations. Despite the seriousness of most reports, 42.7% evolved to cure, even though 9.3% of the reports led to the death of patients. The assessment of causality by the regulatory authority was not performed in 84.4% of the reported cases. Although there were enhanced reporting rates of adverse reactions to corticosteroids, active search of their occurrence must be done. In light of the results obtained, educational programs about the importance of pharmacovigilance are essential.

Biological therapy-associated adverse reactions in asthma: analysis of reporting to the Portuguese pharmacovigilance system

ABSTRACT Objectives: Biological drugs have been successfully tested in asthma, especially in the most severe forms of the disease. The goal of this study was to characterize the safety profile of biologicals used in asthma. Methods: Retrospective and descriptive analysis of spontaneous reports (SRs) involving omalizumab and mepolizumab, sent to the Portuguese Pharmacovigilance System, since market launch until October 2018. Results: A total of 127 SRs for omalizumab and 10 SRs mepolizumab were found. Most patients were female (75.6% omalizumab and 90.0% mepolizumab), and aged 18–64 years (61.4% and 50.0%, respectively). 71.7% of the reports for omalizumab were serious, with 2 cases of anaphylaxis, 12 malignant neoplasms and 2 abortions. Only 20.0% of the reports for mepolizumab were considered serious. A total of 391 adverse drug reactions (ADRs) for omalizumab and 20 ADRs for mepolizumab were found. Most reported ADRs belonged to System organ class (SOC) groups: ‘respiratory, thoracic and mediastinal disorders’ and ‘investigations’, for omalizumab; ‘musculoskeletal and connective tissue disorders’ and ‘general disorders and administration site conditions’ for mepolizumab. Conclusion: Over the years, there was an increasing trend of SRs with these biological drugs. However, it is necessary to continue to develop educational programs in order to get a better reporting system.

Adverse drug reactions in children: a ten-year review of reporting to the Portuguese Pharmacovigilance System

Objective: Adverse drug reactions (ADR) are a public health problem. They cause significant morbidity, mortality and health costs. Less is known about pediatric ADR. Our goal was to characterize a pediatric case series of ADR reported to the Portuguese Pharmacovigilance System (PPS) during the past 10 years.Research design and methods: Retrospective analysis of ADR reports concerning patients till 17 years old received by the PPS between 2003 and 2012. We evaluated patients’ demographic data and involved drugs, as well as characteristics and seriousness of reactions, stratified by age groups.Results: We found 1742 reports (50% females) corresponding to 9.7% of the total received. The age of the patients varied from 0 to 17 years (median: 5 years, interquartile range: 10.6), with 566 cases (32%) occurring in patients younger than 2y. Among the 1195 serious cases, 31% (370) episodes led to hospitalization. In 32 cases (2%) there was a fatal outcome. Most of the ADR reported referred to general disorders and administration site conditions, followed by skin and subcutaneous tissue reactions. Vaccines were the most represented group (42%) followed by antibacterials for systemic use (17%).Conclusions: Pediatric ADR represents about 10% of the reports received by the PPS. Most ADR were considered serious. Major findings varied according to age groups.

Hepatotoxicity Related to Agomelatine and Other New Antidepressants

Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4-9.7)], France (ROR, 2.4 [95% CI, 1.5-3.7]), and Italy (ROR, 5.1 [95% CI, 1.7-14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.