Pharmacovigilance Risk Assessment Committee Research Articles

Pseudoephedrine-Induced Risks of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome

Abstract Background Pseudoephedrine is a sympathomimetic drug used as a nasal/sinus decongestant in common cold remedies. Objective The purpose of this review article is to discuss the pseudoephedrine-associated posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), which have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA) of United Kingdom and Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Medicinal Products for Human Use (CHMP) of European Medicines Agency (EMA). Methods The aim is to review the literature pertinent to PRES and RCVS linked to the use of pseudoephedrine; the literature was searched in databases such as Medline/PubMed/PMC, Google Scholar, Science Direct, Ebsco, Scopus, Web of Science, Embase, and reference lists. Results The review by MHRA of the United Kingdom and PRAC and CHMP of EMA, all available evidence, including postmarketing safety data, and a few case reports, have confirmed the rare risk of PRES and RCVS associated with the use of pseudoephedrine. Conclusion Health care professionals should be aware of pseudoephedrine-associated PRES and RCVS. Patients with severe or uncontrolled hypertension or those with severe acute or chronic renal disease should avoid using products containing pseudoephedrine.

Studying the Impact of European Union Regulatory Interventions for Minimising Risks From Medicines: Lessons Learnt and Recommendations.

The European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) launched a strategy to examine the public health impact of major regulatory interventions aimed at minimising risks of medicinal products. We conducted a lessons learnt analysis of impact studies completed between 2015 and 2023. We surveyed PRAC Sponsors and (Co-)Rapporteurs involved in the evaluation of 12 impact studies (10 commissioned by EMA and 2 conducted collaboratively by Member States) to explore how these support regulatory decision-making. Questions covered achievement of study objectives, risk minimisation effectiveness, added value for regulatory decision-making, and recommendations for future impact studies. Themes were generated using thematic content analysis. Survey responses from 15 PRAC Sponsors and (Co-)Rapporteurs from 10 European Union Member States were included in the analysis. Among four cross-sectional surveys and eight drug utilisation studies, 50% achieved all objectives, the other studies partially due to limitations. Two studies concluded that risk minimisation measures were overall effective, two were effective with variation across countries, two were partially effective and four studies showed limited effectiveness. Two studies were deemed inconclusive due to limitations. The reasons for the limited effectiveness of risk minimisation may be explored using mixed-method approaches. Assessment of study feasibility and a priori discussion of effectiveness measurements is important. Despite limitations, impact research adds value to regulatory decision-making by addressing knowledge gaps and providing additional information on unintended consequences of regulatory interventions. Our recommendations will help to improve planning, conducting and interpretating future impact studies.

Limitations Reported in Evaluating Effectiveness of Risk Minimization Measures in the EU during 2018-2021: A Qualitative Analysis of Industry-Sponsored Post-Authorization Safety Studies.

Marketing-authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post-authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry-sponsored PASS that did not render a conclusion. We conducted a thematic analysis of study limitations extracted from assessment reports and study reports finalized by the Pharmacovigilance Risk Assessment Committee between 2018 and 2021. In 39 (61.0%) of the PASS a conclusion on RMM effectiveness was drawn, where 25 (39.0%) PASS was inconclusive. Most PASS had a cross-sectional design with surveys as primary data sources (73.4% and 65.6% respectively). Four main themes emerged: (i) survey-specific limitations, (ii) limitations specifically related to secondary use of data, (iii) general limitations related to study design, and (iv) limitations not related to study design. In general, frequently reported limitations were survey-related, such as selection bias or information bias. Interestingly, well-known study limitations related to secondary use of data such as missing or misclassification of data were more often presented in inconclusive compared with conclusive PASS. Given that about 40% of PASS did not allow a conclusion on RMM effectiveness, our results suggest prioritization for strategies to mitigate limitations related to the secondary use of data at the protocol stage, for example, through feasibility assessments. Although many databases may have incomplete registration of some variables, feasibility testing prior to conducting a PASS could contribute to meeting study objectives and concluding on RMM effectiveness.

Physician Awareness of the Safe Use of Cyproterone Acetate in Europe: A Survey on the Effectiveness of Additional Risk Minimization Measures.

Cyproterone acetate (CPA) is a synthetic progesterone derivative introduced in the 1970s and prescribed as antiandrogenic therapy for inoperable prostate cancer, sexual deviations in men, and signs of androgenization in women. In 2020, the CPA summary of product characteristics (SmPC)was revised to include an updated special warning and precaution about (1) the risk of meningioma with increasing cumulative dose and (2) contraindication in patients with meningioma or history of meningioma. A Direct Healthcare Professional Communication(DHPC) was distributed. The European Medicine Agency's Pharmacovigilance Risk Assessment Committee requested that marketing authorization holders in Europe conduct a survey to assess physicians' knowledge of the updated key safety information. The primary objective of this study was to measure physicians' awareness (i.e., did they receive and review the revised SmPC and DHPC) and level of knowledge and understanding of the key safety information pertaining to the restricted use of CPA monotherapy because of the risk of meningioma. This cross-sectional web-based survey was administered to dermatologists, endocrinologists, gynecologists, urologists, oncologists, psychiatrists, and general practitioners in France, Germany, Poland, Spain, and the Netherlands who had prescribed CPA monotherapy in the previous 12 months to assess awareness of the risk of meningioma associated with CPA monotherapy. Of the 613 physicians who participated, 85% correctly indicated that CPA monotherapy should be prescribed with the lowest effective dose, 75% correctly indicated that the risk of meningioma increases with increasing cumulative CPA monotherapy doses, and 73% correctly indicated that treatment with CPA-containing products must be stopped permanently if a patient is diagnosed with meningioma. Overall, 40% of physicians reported having received the DHPC, and 42% reported having received the revised SmPC. Despite low recall of receipt of the updated SmPC and DHPC, most physicians surveyed are aware of the meningioma risk and actions to mitigate the risk.

Glucagon-like Peptide-1 Receptor Agonists and Suicidal Ideation: Analysis of Real-Word Data Collected in the European Pharmacovigilance Database.

A potential risk of suicide associated with liraglutide or semaglutide treatments has recently emerged. Therefore, we decided to investigate the reporting probability of suicidal events among glucagon-like peptide-1 receptor agonists (GLP-1 RAs). A retrospective pharmacovigilance study of the European Pharmacovigilance database was conducted for the period from 1 January 2018 to 10 July 2023. Disproportionality analyses (reporting odds ratio, ROR) were performed to assess the reporting probability of suicidal events among GLP-1 RAs. A total of 230 reports of suicidal events were identified. The most reported GLP-1 RA was liraglutide (38.3%), followed by semaglutide (36.5%) and dulaglutide (16.1%). The most reported events were suicidal ideation (65.3%) and suicide attempt (19.5%). Disproportionality analysis found a higher reporting probability of suicidal events for semaglutide than dulaglutide (ROR, 2.05; 95%CI, 1.40-3.01) and exenatide (ROR, 1.81; 95%CI, 1.08-3.05). In the same way, liraglutide was associated with a higher reporting probability of suicidal events than dulaglutide (ROR, 3.98; 95%CI, 2.73-5.82) and exenatide (ROR, 3.52; 95%CI, 2.10-5.92). On the contrary, a lower reporting probability was found for semaglutide than liraglutide (ROR, 0.51; 95%CI, 0.38-0.69). Suicidal events were mostly reported with semaglutide and liraglutide, which were also associated with significantly higher reporting probabilities compared to other GLP1 RAs. Although this study provides the reporting frequencies of suicide-related events with GLP-1 RAs, establishing causality requires further investigation, which will probably be addressed by the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency in the future.

Update on the efficiency and safety of orally administered nasal decongestants

Nasal congestion leading to obstruction is one of the main symptoms in acute rhinosinusitis (common cold), other upper respiratory infections and allergic rhinitis. The EPOS 2020 guidelines place oral decongestants as an efficient therapy for the relief of nasal obstruction. In Romania, there are more than 50 available nasal decongestants, so it is very important for practitioners from all medical domains to be aware of recent data regarding their effectiveness and safety profile. Recent concerns raised by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regarding the efficacy and safety of pseudoephedrine (PSE) and phenylephrine (PHE) emphasize the need for informed decision-making in prescribing. Notably, there were concerns raised about the association between PSE, reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES). EMA’s safety committee, Pharmacovigilance Risk Assessment Committee (PRAC), recently recommended measures to minimize risks of serious side effects when using medicines containing PSE. PRAC recommends that medicines containing PSE should not be used in patients with severe or uncontrolled hypertension and severe acute or chronic kidney disease or failure. Additionally, PRAC recommends healthcare professionals to counsel patients to discontinue the use of such medicines promptly and seek medical assistance if they experience symptoms suggesting PRES or RCVS, such as sudden onset of severe headache, confusion, vomiting, visual disturbances or seizures. While effectiveness of oral PSE is confirmed by clinical studies, expert consensus is unfavorable to PHE. Both in vitro and in vivo clinical pharmacology data indicate that neither the recommended doses nor higher doses of oral PHE demonstrate efficacy in alleviating symptoms of nasal congestion.

Menstrual Irregularities Following Covid-19 Vaccinations

Since 31 December 2019, when the WHO was informed of cases of pneumonia of unknown cause in Wuhan City, China; a novel coronavirus identified as the cause, has spread worldwide. With an urgent need to slow viral transmission, decrease disease severity, and reduce mortality, biopharmaceutical companies rapidly began investigating potential COVID-19 vaccinations. The American pharmaceutical company, Pfizer, in collaboration with the German company, BioNTech, developed a nucleoside-modified messenger RNA (modRNA) vaccine (BNT162b2), which was the first to receive an FDA permit for emergency use, with others following suit. Vaccine manufacturers provide a list of post-vaccination side effects with their preparations. Adverse vaccine reactions are evidence of the effectiveness of the vaccine and of increasing immunity against this disease. Interestingly, a growing number of women have reported menstrual irregularities after receiving COVID-19 vaccines. Those have been noted in post-authorization and post-licensure monitoring. This review provides evidence that women experience menstrual abnormalities, including menorrhagia, metrorrhagia, and polymenorrhea following COVID-19 vaccines. The importance of the issue has been recognized by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency which decided to list heavy menstrual bleeding as a side effect as a side effect of unknown frequency in the product information for the SARS-CoV-2 mRNA vaccines.

Enhancing Awareness of Diclofenac as an Over-the-Counter Analgesic in the Northern Border Region of Saudi Arabia

Introduction: Diclofenac was identified by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency as a high-risk NSAID in terms of its effects on the heart and circulation when administered systemically, i.e. capsules, tablets or injections.
 Objective: To evaluate the knowledge and awareness about over the counter analgesic medication (Diclofenac) among people living in northern border region – Saudi Arabia.
 Methodology: Self-administered cross-sectional study conducted during a period of two months (October and November 2023) on random sample of 430 Saudi people living in the Northern Border Region. The data was analyzed by Microsoft excel program by means of Descriptive statistics.
 Results: Toothache and headache were the most worried pain among participants (32%) and (31%) respectively, majority (72%) of participants buy OTC medication for pain from community pharmacy on the advice of pharmacist. Small percentage (20%) thought that medications containing diclofenac have very few side effects, 76% didn’t know any side effect of diclofenac, 47% didn’t know that diclofenac in high dose has adverse effects on kidney, 71% didn’t know that diclofenac cause gastrointestinal adverse effects. About one fifth of participants (21%) didn’t know the maximum dose of diclofenac when they use it, tablet is the preferred dosage form of diclofenac (27%) followed by granules (16%), dosage of 100 mg is the most frequently used (36%) followed by 50 mg (16%). 
 Conclusion: Saudi people’s knowledge about diclofenac as one member of non-steroidal anti-inflammatory drugs was insufficient. Knowledge about related adverse effects of diclofenac was lacked which exposes to misusage that may carry accidents and severe side effects especially among high-risk population.

Review of Studies Evaluating Effectiveness of Risk Minimization Measures Assessed by the European Medicines Agency Between 2016 and 2021.

The European Medicines Agency (EMA) supervises medicines' safe and effective use throughout the product's life cycle by, for example, monitoring the implementation of risk minimization measures (RMMs). Limited information is available on factors associated with effectiveness of RMMs. This study reviews post-authorization safety studies (PASS) evaluating the effectiveness of RMMs assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) between 2016 and 2021. PASS assessment reports finalized by PRAC between January 1, 2016, and December 31, 2021, were compiled from non-public EMA databases and PASS characteristics were extracted. Of the 93 PASS included, 62.4% aimed to measure healthcare professionals' awareness, knowledge, and behavior regarding RMMs. There were 67.7% of the 93 PASS that used primary data, 24.7% used secondary data sources, and 7.5% used both. A cross-sectional study design was most frequently applied (77.4%), followed by a cohort study design (29.0%). Nearly 40% of the included PASS did not render a conclusion on RMM effectiveness. Of the 60% that did render a conclusion, 82.1% were deemed effective. Only minor differences in characteristics were found when stratified by outcome (i.e., effective RMM, ineffective RMM, and no conclusion on RMM effectiveness). To conclude, 4 out of 10 PASS assessing impact of RMMs did not render a conclusion on RMM effectiveness. No clear differences in PASS characteristics were found in relation to their outcomes, indicating that additional research is needed to understand better the underlying reasons for PASS being inconclusive.

An Exploratory Study of the Impact of COVID-19 Vaccine Spontaneous Reporting on Masking Signal Detection in EudraVigilance.

During the signal detection process, statistical methods are used to identify drug-event combinations (DECs) which are disproportionately reported when compared with other drugs and events in the entire database. We hypothesise that the high volume of COVID-19 vaccine adverse drug reaction (ADR) reports transmitted to EudraVigilance may have affected the performance of disproportionality statistics used in routine signal detection, potentially resulting in signals either being masked, or false associations being flagged as potential signals. Our aim was to study the impact of COVID-19 vaccine spontaneous reporting on statistical signal detection in EudraVigilance. We recalculated the reporting odds ratio (ROR) for signals that were previously discussed at the level of the Pharmacovigilance Risk Assessment Committee, or signals that were retrieved from EudraVigilance, by omitting COVID-19 vaccine reports from the standard ROR calculation and then comparing the lower confidence interval (LCI) of the recalculated ROR to the LCI of the actual ROR in EudraVigilance. In total, 52 signals for 38 active substances were reviewed. For 35 signals, the LCI of the recalculated ROR value was lower than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had a positive effect on the strength of the signal) while for 15 signals the LCI of the recalculated ROR value was higher than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had an attenuating effect on the strength of the signal). For two signals, no change in the ROR was observed. In our analysis, six significant results were found. Five DECs were found to be masked: bleomycin and immune thrombocytopenia (actual ROR LCI = 0.94, recalculated ROR LCI = 1.02), vortioxetine and heavy menstrual bleeding (actual ROR LCI = 0.3, recalculated ROR LCI = 1.06), caplacizumab and heavy menstrual bleeding (actual ROR LCI = 0.98, recalculated ROR LCI = 3.47), ziprasidone and amenorrhoea (actual ROR LCI = 0.84, recalculated ROR LCI = 1.67), and azacitidine and pericarditis (actual ROR LCI = 0.81, recalculated ROR LCI = 2.01). For the DEC of adalimumab and immune reconstitution inflammatory syndrome, the LCI of the actual ROR value was 1.14 and removing COVID-19 vaccine reporting resulted in an LCI of the recalculated ROR value of 0.94 (below threshold). We demonstrated five cases of masking and one case of false-positive association due to the influence of COVID-19 vaccine spontaneous reporting on the ROR. This suggests that the high number of adverse drug reaction reports for COVID-19 vaccines in EudraVigilance has the potential to affect routine statistical signal detection activities. The impact of COVID-19 vaccine ADR reports on current signal detection practices requires further evaluation and solutions to tackle masking issues in EudraVigilance may need to be developed.

Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.

In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8-32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.

Thrombosis with thrombocytopenia syndrome: A database review of clinical trial and post-marketing experience with Ad26.COV2.S

BackgroundThrombosis with thrombocytopenia syndrome (TTS) is a very rare disorder described after vaccination with adenoviral vector-based COVID-19 vaccines. Co-occurring thrombosis with thrombocytopenia reported after vaccination can be a proxy for identification of TTS. MethodsDescriptive database review of all cases of co-occurring (within 42 days) thrombosis with thrombocytopenia in participants in Ad26.COV2.S clinical trials or recipients of Ad26.COV2.S in real-world clinical practice. Cases were retrieved from Janssens’ clinical trial and Global Medical Safety databases. ResultsThere were 34 cases of co-occurring thrombosis with thrombocytopenia in Ad26.COV2.S recipients (46 per 100,000 person-years) and 15 after placebo (75 per 100,000 person-years) in clinical trials. Among Ad26.COV2.S recipients, mean age at the time of the event was 63 years (range 25–85), 82 % were male, mean time-to-onset 112 days (range 8–339) post-last Ad26.COV2.S dose, 26 events occurred post-dose-1, and 7 within a 28-day risk window post-vaccination. Diagnostic certainty was evaluated using Brighton Collaboration, US Centers for Disease Control and Prevention, and European Medicines Agency Pharmacovigilance Risk Assessment Committee case definitions. One case met the highest level of diagnostic certainty for all 3 definitions. There were 355 spontaneous reports of co-occurring thrombosis with thrombocytopenia in the Global Medical Safety database, 47 % males, 85 % within 28-days after vaccination. Twenty-seven cases met the highest level of diagnostic certainty for all definitions, 21 female, 19 with cerebral venous sinus thrombosis, age-range 18–68 years. Time-to-onset was 7–14 days post-vaccination in 20 cases. There were 8 fatalities. ConclusionTTS induced by Ad26.COV2.S is very rare. Most co-occurring thrombosis with thrombocytopenia does not constitute TTS.

Hepatobiliary Adverse Reactions during Treatment with Cladribine: Analysis of Data from the European Spontaneous Reporting System.

Cladribine belongs to the group of disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS). According to the highlights of a meeting held by the Pharmacovigilance Risk Assessment Committee (PRAC) on 14 January 2022, cladribine may be associated with the occurrence of liver injury, and thus liver function monitoring is recommended. Using data from the European spontaneous reporting database (EudraVigilance-EV), we aimed to describe the main characteristics of Individual Case Safety Reports (ICSRs) reporting cases of hepatobiliary disorders related to cladribine. The reporting odds ratio (ROR) was calculated to provide the probability of reporting hepatobiliary ICSRs among DMTs used to treat MS. Overall, 118 ICSRs described the occurrence of cladribine-induced hepatobiliary ADRs. The majority of the ICSRs reported ADRs that were classified as serious (93%), and the outcome was mostly reported as "unknown" (50.8%). The most reported hepatobiliary disorders were drug-induced liver injury, abnormal hepatic function, ALT increases, liver disorders, hepatic failure, jaundice, lymphocyte count decreases, hepatotoxicity and hypertransaminasemia. The majority of cladribine-induced hepatic ADRs occurred in female patients belonging to the age group of 18-65 years. Considering the seriousness of cladribine-induced hepatic ADRs, a close monitoring of patients receiving this drug is highly recommended. In this context, further pharmacovigilance studies evaluating the hepatic safety profile of cladribine are strongly needed.

Signal management and risk minimization strategy: a case study on obinutuzumab and non-overt disseminated intravascular coagulation

Introduction: In December 2020, the Italian Medicines Agency (AIFA) in collaboration with the Italian Regional Centers of Pharmacovigilance evaluated four individual case safety reports (ICSRs) reporting obinutuzumab and non-overt disseminated intravascular coagulation (DIC) as a new possible signal. In this study, we described the process of signal management for obinutuzumab-associated non-overt DIC.Methods: In accordance with the Guideline on Good Pharmacovigilance Practices Module IX, we described the process of the Italian and European Union signal management process in five steps: signal detection, signal validation, signal confirmation, signal analysis, and prioritization and signal assessment.Results: In the signal detection phase, four cases of obinutuzumab-associated non-overt DIC met the criteria for signal definition (ROR 213.6 and IC025 77). In the signal validation phase, both the Italian and European databases of spontaneously reported adverse drug reactions were investigated with supporting evidence from medical literature. Four patients (two men and two women aged 67–77) were in treatment with obinutuzumab for chronic lymphocytic leukemia, and they developed a subclinical DIC within 24 h from the administration of the drug. The DIC spontaneously resolved in all cases. Three more ICSRs were reported in the EudraVigilance database. The medical literature provided poor evidence of the possible association between obinutuzumab and DIC. The signal was subsequently validated, first by AIFA and then by EMA. The signal was confirmed by the Pharmacovigilance Risk Assessment Committee (PRAC) Rapporteur in the “signal confirmation” phase, and it entered “signal analysis and prioritization” and “signal assessment”. In these phases, the PRAC assessed and confirmed DIC as a possible adverse reaction to obinutuzumab. Finally, the Summary of Product characteristics was updated with this new risk.Conclusion: Despite the intrinsic difficulties linked to the nature of the event itself, the process of signal detection and the issuing of the risk minimization measures by the Italian Medicines Agency as part of the EU procedures have proven to be efficient.

Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

A detailed look at the European Medicines Agency's recommendations for use of Janus kinase inhibitors in patients with atopic dermatitis.

Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit-risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long-term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. The benefit-risk profile of JAKi approved for AD remains favourable, including use as first-line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors.

Recommendations for risk minimization when using Janus kinase inhibitors for the treatment of chronic inflammatory skin diseases.

In accordance with article 20 of Regulation (EC) No 726/2004, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has re-evaluated the safety of Janus kinase inhibitors for the treatment of inflammatory diseases and formulated safety information deviating from the previous indications in the respective summary of product characteristics of the products concerned. These refer to the consideration of a possibly increased risk of venous thromboembolic or severe cardiovascular events, an increased infection rate and an increase in the prevalence of skin cancer across drugs and indications. Therefore, in patients with independent risk factors (age 65 years and older, smokers or former smokers, patients with oral contraception or hormone replacement therapy and other risk factors), it is recommended to use Janus kinase inhibitors therapeutically only if there are no suitable treatment alternatives. To facilitate a pragmatic and thorough detection of high-risk patients in everyday clinical practice, an interdisciplinary checklist was developed that is suitable as a working tool from the perspective of the dermatologist.

Identifying Safety Subgroups at Risk: Assessing the Agreement Between Statistical Alerting and Patient Subgroup Risk.

Identifying individual characteristics or underlying conditions linked to adverse drug reactions (ADRs) can help optimise the benefit-risk ratio for individuals. A systematic evaluation of statistical methods to identify subgroups potentially at risk using spontaneous ADR report datasets is lacking. In this study, we aimed to assess concordance between subgroup disproportionality scores and European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) discussions of potential subgroup risk. The subgroup disproportionality method described by Sandberg et al., and variants, were applied to statistically screen for subgroups at potential increased risk of ADRs, using data from the US FDA Adverse Event Reporting System (FAERS) cumulative from 2004 to quarter 2 2021. The reference set used to assess concordance was manually extracted from PRAC minutes from 2015 to 2019. Mentions of subgroups presenting potential differentiated risk and overlapping with the Sandberg method were included. Twenty-seven PRAC subgroup examples representing 1719 subgroup drug-event combinations (DECs) in FAERS were included. Using the Sandberg methodology, 2 of the 27 could be detected (one for age and one for sex). No subgroup examples for pregnancy and underlying condition were detected. With a methodological variant, 14 of 27 examples could be detected. We observed low concordance between subgroup disproportionality scores and PRAC discussions of potential subgroup risk. Subgroup analyses performed better for age and sex, while for covariates not well-captured in FAERS, such as underlying condition and pregnancy, additional data sources should be considered.

Can Twitter posts serve as early indicators for potential safety signals? A retrospective analysis.

As Twitter has gained significant popularity, tweets can serve as large pool of readily available data to estimate the adverse events (AEs) of medications. This study evaluated whether tweets were an early indicator for potential safety warnings. Additionally, the trend of AEs posted on Twitter was compared with AEs from the Yellow Card system in the United Kingdom. English Tweets for 35 drug-event pairs for the period 2017-2019, two years prior to the date of EMA Pharmacovigilance Risk Assessment Committee (PRAC) meeting, were collected. Both signal and non-signal AEs were manually identified and encoded using the MedDRA dictionary. AEs from Yellow Card were also gathered for the same period. Descriptive and inferential statistical analysis was conducted using Fisher's exact test to assess the distribution and proportion of AEs from the two data sources. Of the total 61,661 English tweets, 1,411 had negative or neutral sentiment and mention of at least one AE. Tweets for 15 out of the 35 drugs (42.9%) contained AEs associated with the signals. On pooling data from Twitter and Yellow Card, 24 out of 35 drug-event pairs (68.6%) were identified prior to the respective PRAC meetings. Both data sources showed similar distribution of AEs based on seriousness, however, the distribution based on labelling was divergent. Twitter cannot be used in isolation for signal detection in current pharmacovigilance (PV) systems. However, it can be used in combination with traditional PV systems for early signal detection, as it can provide a holistic drug safety profile.

Acute myocarditis in a young adult two days after Pfizer vaccination

We report the case of a 20-year-old healthy male who developed acute myopericarditis 2 days after receiving the second dose of the mRNA Pfizer-BioNTech COVID-19 vaccine. The course of the disease was mild and the patient was discharged after a few days of hospitalization.Recently, several case reports involving myopericarditis in patients who received an mRNA vaccine against SARS-CoV-2 have been published and the U.S. Centers for Disease Control and Prevention and the European Medicines Agency pharmacovigilance risk assessment committee are currently investigating an overall increased number of cases. They are also assessing whether there is a higher incidence than expected in vaccinated young adults and teenagers, especially males. Although a clear causal link has not been proven at this time, physicians should be aware of such potential adverse event, taking into account the increasing number of young people that will receive mRNA vaccination over the next few months.