Study on the risk signal mining related to lopinavir/ritonavir based on the US FDA Adverse Event Reporting System.

Objective: To explore the clinical safety of lopinavir/ritonavir (LPV/r) by mining the risk signals of adverse events (AEs) related to LPV/r for the safe application of the drug in the treatment of novel coronavirus pneumonia (COVID-19). Method(s): The risk signals related to LPV/r in AE reports of US FDA Adverse Event Reporting System (FAERS) from the first quarter of 2010 to the third quarter of 2019 were mined by reporting odds ratio (ROR). An AE with reports more than 3 and 95% confidence interval (CI) lower limit of ROR greater than 1 was defined as a positive signal. AEs were counted and classified using the preferred system organ class (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA). The PTs of top 50 adverse event reports and signal strength were selected and analyzed. Result(s): From the first quarter of 2010 to the third quarter of 2019, a total of 13 335 AE reports with LPV/r as the primary suspicious drug were reported in the FAERS database. Four hundred and fifty-five AE risk signals with reports more than 3 and the 95%CI lower limit of ROR greater than 1 were detected, involving 7 718 AE reports. The top 2 system organs involved in AE reports were "injury, poisoning and procedural complications" [13.6% (1 051/7 718)] and "pregnancy, puerperium and perinatal conditions" [11.7% (899/7 718)]. However, 998 (95.0%) of 1051 AE reports involved in "injury, poisoning and procedural complications" were related to drug exposure during pregnancy. The system organ with the highest signals was "congenital, familial and genetic disorders" [16.3% (74/455)]. In addition, 144 AEs caused by drug interactions were detected, which ranked the 7th in the AE reports. Conclusion(s): The risk signals of fetal, neonatal and infant abnormalities related to LPV/r during pregnancy were detected, suggesting that attention should be paid to the risk of using LPV/r in pregnant women and infants. The interaction between LPV/r and other drugs was also worthy of attention.Copyright © 2020 by the Chinese Medical Association.

Prevalence of adverse drug reactions associated with emergency department visits and risk factors for hospitalization

Objective: Adverse drug reactions increase morbidity and mortality, prolong hospital stay and increase healthcare costs. The primary objective of this study was to determine the prevalence of emergency department visits for adverse drug reactions and to describe their characteristics. The secondary objective was to determine the predictor variables of hospitalization for adverse drug reactions associated with emergency department visits. Method(s): Observational and retrospective study of adverse drug reactions registered in an emergency department, carried out from November 15th to December 15th, 2021. The demographic and clinical characteristics of the patients, the drugs involved and the adverse drug reactions were described. Logistic regression was performed to identify factors related to hospitalization for adverse drug reactions. Result(s): 10,799 patients visited the emergency department and 216 (2%) patients with adverse drug reactions were included. The mean age was 70 +/- 17.5 (18-98) years and 47.7% of the patients were male. A total of 54.6% of patients required hospitalization and 1.6% died from adverse drug reactions. The total number of drugs involved was 315 with 149 different drugs. The pharmacological group corresponding to the nervous system constituted the most representative group (n = 81). High-risk medications, such as antithrombotic agents (n = 53), were the subgroup of medications that caused the most emergency department visits and hospitalization. Acenocumarol (n = 20) was the main drug involved. Gastrointestinal (n = 62) disorders were the most common. Diarrhea (n = 16) was the most frequent adverse drug reaction, while gastrointestinal bleeding (n = 13) caused the highest number of hospitalizations. Charlson comorbidity index behaved as an independent risk factor for hospitalization (aOR 3.24, 95% CI: 1.47-7.13, p = 0.003, in Charlson comorbidity index 4-6;and aOR 20.07, 95% CI: 6.87-58.64, p = 0.000, in Charlson comorbidity index >= 10). Conclusion(s): The prevalence of emergency department visits for adverse drug reactions continues to be a non-negligible health problem. High-risk drugs such as antithrombotic agents were the main therapeutic subgroup involved. Charlson comorbidity index was an independent factor in hospitalization, while gastrointestinal bleeding was the adverse drug reaction with the highest number of hospital admissions.Copyright © 2022 Sociedad Espanola de Farmacia Hospitalaria (S.E.F.H)

Analysis of fatal cardiac adverse events caused by chloroquine: a study based on the related data from the WHO global database of individual case safety reports. TT -:Who.

Objective: To analyze the clinical characteristics of fatal cardiac adverse events associated with chloroquine, which was recommended for the antiviral treatment of novel coronavirus pneumonia, and provide reference for clinical safe drug use. Method(s): The fatal cardiac adverse events associated with chloroquine were searched from the World Health Organization global database of individual case safety reports (VigiBase). The clinical characteristics of the individual cases with well-documented reports (VigiGrade completeness score >=0.80 or with detailed original reports) were analyzed. The adverse events were coded using the systematic organ classification (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA) version 22.1 of International Conference on Harmonization (ICH). Result(s): Up to 23 February 2020, a total of 45 reports of fatal heart injuries related to chloroquine were reported in VigiBase, which were from 16 countries. Of them, 30 reports were fully informative. Among the 30 reports,20 cases developed fatal cardiac adverse events after a single large dose of chloroquine. Of them, 17 cases' fatal cardiac adverse events were caused by overdose of chloroquine (15 cases were suicide or suspected suicide, and 2 children took chloroquine by mistake);3 cases' fatal cardiac adverse events were caused in clinical treatment;18 cases showed arrhythmia and cardiac arrest;6 cases showed prolonged QRS wave or QT interval;6 cases were with hypokalemia, including 4 severe ones. Among the 30 reports, 10 cases developed fatal cardiac adverse events after multiple administration of chloroquine, of which 4 cases were treated with chloroquine for 23 days to 2 months and died of heart failure, cardiac arrest or myocardial infarction;6 cases were treated with chloroquine for 20 months to 29 years and all of them had cardiomyopathy, which were confirmed by endomyocardial biopsy to be caused by chloroquine in 3 cases. Conclusion(s): Cardiac toxicity was the primary cause of fatal adverse events caused by chloroquine;the main manifestation of single large dose of chloroquine was arrhythmia and the manifestation of multiple administration was cardiomyopathy.Copyright © 2020 by the Chinese Medical Association.

Hypersensitivity reactions to SARS-CoV- 2 vaccines reported in Latvia

Background: SARS-CoV- 2 infection remains a significant global concern. Since vaccination is one of the most effective methods of severe disease prevention, the question of its side effects is substantial. Therefore, collaboration between clinicians and the Pharmacovigilance department of the national competent authority is important and can provide essential information on this matter. Method(s): Spontaneous reports of adverse drug reactions received by the State Agency of Medicines of Latvia between 2021-01- 01 and 2022-01- 05 were reviewed to identify cases of hypersensitivity reactions. MedDRA Queries were used for data selection. In data analysis, descriptive statistics were used. Result(s): A total 90 possible hypersensitivity reactions were selected for analysis, of which 34 cases (37.8%) were reported by healthcare professionals and 56 cases (62.2%) by patients. 12 cases (13.3%) were anaphylaxis, 10 (11.1%) were immediate type reactions and 68 (75.6%) were potential delayed type reactions, among them 66 cases were possible type IV and 2 cases possible type III reactions. 70 patients (78.7%) were women and 19 (21.3%) were men. The mean age of patients was 43.13 +/- 15.9 (17-80) years old. 21 patients (23.3%) received Vaxzevria, 16 (17.8%) Janssen, 39 (43.3%) Comirnaty and 14 (15.6%) Spikevax. The most commonly reported symptoms in the anaphylaxis group was: impaired consciousness (33.3%), angioedema (33.3%), skin erythema (25%), urticaria (25%), hypotension (25%), tachycardia (25%), nausea and vomiting (25%), in the immediate type reaction group: dyspnoe (40%), skin erythema (30%), angioedema (30%), skin pruritus (20%), unspecified skin rash (20%), dizziness (20%), and in the delayed type reaction group: skin rash (92.6%), pruritus (25%), injection site reaction (23.5%). There were only eight patients with prior history of allergies. Conclusion(s): More than a half of the spontaneously reported cases of hypersensitivity reactions selected for the analysis were submitted by patients. Vast majority of all selected cases concerned women. Individuals who were affected by hypersensitivity reactions after COVID-19 vaccination were more likely to experience delayed-type than immediate-type reactions. Although, it should be considered that underreporting might be in place.

VOCLOSPORIN for LUPUS NEPHRITIS: RESULTS of the TWO-YEAR AURORA 2 CONTINUATION STUDY

Background: Voclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN signifcantly increased rates of complete renal response at 52 weeks. Objectives: Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 study Methods: Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, I V, or V ± III/IV), proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular fltration rate (eGFR) >45 mL/min/1.73 m2. Patients who completed AURORA 1 and who elected and were eligible to enter AURORA 2 continued on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed. Results: In total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm receiving treatment to the end of AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%];Table 1). Eight patients in each arm experienced serious adverse events of infection;serious coronavirus infections were observed in 2 patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2;four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m2 at 4 weeks following study drug discontinuation (Figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation. Conclusion: Voclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period, and the signifcant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a longterm treatment beneft of VCS in patients with LN. Includes adverse events starting on or after the frst dose of study drug in AURORA 2 up to 30 days after the last dose and all events of death reported during study follow-up. Adverse events were aggregated by System Organ Class and Preferred Term and coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0. AE, adverse event.

AEFI collected during COVID-19 vaccine campaign in Tunisia

Introduction/ Background: As part of the surveillance of Covid-19 vaccines, a specific and reinforced surveillance strategy for adverse events following immunization (AEFI) of Covid-19 vaccines was set up since the vaccination campaign has been started in Tunisia in order to monitor the safety profile of available vaccines in real time. Methods: We conducted a descriptive study on Covid-19 vaccines AEFI collected by the National Chalbi Belkahia Center for Pharmacovigilance (CNPV) from March 13th to November 3rd, 2021. The notifications were collected via the CNPV website / email, the eVAX platform, or at the CNPV external consultation. Activedata collection by phone was carried out during the 6 open days for vaccination. Data for the study were extracted from the national, WHO-dependent VigiBase database. Results: We collected 2773 AEFI on 9 264 263 administered doses (0.03%). Mean age=50.4 years. Sex ratio M/F = 0.62. Pfizer BioNTech® vaccine was used in 54.1% of cases, Vaxzevria® in 14%. AEFI SOCs: general and administration site disorders (48.6%), nervous disorders (29.3%), musculoskeletal disorders (18%), gastrointestinal disorders (13.7%). Main MedDRA terms were fever (23.2%), asthenia (19%), headache (15.8%), and injection site pain (10.4%). Serious adverse events were noted in 146 cases (5.3% of AEFI). SOCs: Nervous disorders (42.5%), General and administration site disorders (15.8%), Cardiac disorders (13.7%). In serious adverse events, Pfizer BioNTech® was used in 51.4%, and Vaxzevria® in 19.2%. Impact: Monitoring of any new medicinal product and the detection of adverse events is necessary, in particular, at the start of its use in order to ensure the safety of the population. Conclusion: This study confirms phase III clinical trials data in which the most frequent AEFIs were general and injection site disorders. Serious adverse event were rare. These results show that the benefit of vaccination outweighs the risk and encourage vaccination.

Liver related adverse events reported after the use of COVID-19 vaccines: A descriptive study

Objectives: The present study focus on the liver-related adverse events (AEs) reported with COVID-19 vaccines in VigiBase, a database maintained by WHO for reporting adverse events. Materials and Methods: The data of liver-related adverse events following COVID-19 vaccination was acquired on a subscription basis from VigiBase. This study included all the suspected liverrelated adverse events reported in VigiBase after administering any of the three COVID-19 vaccines: Moderna, BNT162b2 Pfizer and 1222 AstraZeneca between December 15, 2020, and January 24, 2021. The MedDRA (Medical Dictionary for Regulatory Activities) and WHOART terminology- SOC (System Organ Class) and PT (Preferred Terms) were used for analysis. We extracted three SOCs - hepatobiliary disorders, gastrointestinal disorders and investigations. All the SOC were further cleaned to remove all PTs other than those related to the liver. Disproportionality analysis was reported in the form of IC025, Reporting Odds Ratio and Prevalence Odds Ratio. Results: A total of 103,954 AEs were reported for COVID-19 vaccines from 32,044 individuals, out of which only 51 (0.049%) AE from 32 patients was related to the liver. Most common liver-related AE reported were in the SOC ''investigations''- increase in alanine amino transferase (0.009%) followed by increased aspartate aminotransferase and increased bilirubin (0.006%). Based on the disproportionality analysis (IC025 values) none of them was vaccinerelated AE. Conclusion: COVID-19 vaccines are safe for liver and there was no increase in the events were associated with the use of vaccines. As these were early data of vaccine use, analysis based on recent data need to be done to ascertain it fully.

Sudden hearing loss and COVID-19 vaccine: A potential signal?

Introduction: Vaccination against COVID-19 appears to be a promising approach to mitigate this pandemic. The French agency of medicinal products (ANSM) issued a signal concerning cases of sudden hearing loss (SHL) following vaccination with elasomeran (Spikevax® Moderna) [1] and AZD1222 (Vaxzevria® AstraZeneca) [2]. SHL is defined as a sensorineural hearing loss ≥30 dB within 72 hours [3]. We aimed to investigate the potential signal of SHL associated with COVID-19 vaccines. Material and methods: We queried VigiBase® (World Health Organization pharmacovigilance database), for all reports of "Sudden Hearing Loss" (MedDRA Preferred Term) related to "COVID-19 vaccine" (Active Ingredient), from 1967 to December 30, 2021 [4]. Disproportionality analysis was based on the Reporting Odds Ratio (ROR) with its 95% Confidence Interval (CI) and the Information Component (IC). A positive IC025 is statistically needed to confirm the detection of a signal [5]. Results: In VigiBase®, 1,602 cases of COVID-19 vaccine-associated SHL were collected. Tozinameran (Pfizer-BioNTech) was mostly notified with 1,053 (65.7%) reports, followed by elasomeran (Moderna, 281, 17.5%), AZD1222 (AstraZeneca, 217, 13.5%), and JNJ 78436735 (Janssen, 43, 2.7%). Most cases concerned women (885, 55.2%), with a median age of 51 years, and 827 (51.6%) were considered serious. The association of COVID-19 vaccines and SHL showed significant disproportionality, with a ROR of 7.4 (95% CI 6.9-7.9) and an IC025>0. Tozinameran reached the strongest ROR (8.2;95% CI 7.6-8.8), followed by elasomeran (4.6;95% CI 4.0-5.2), JNJ-78436735 (3.0;95% CI 2.2-4.0), and AZD1222 (2.7;95% CI 2.3-3.1), all with IC025>0. Discussion/Conclusion: Significant disproportionality was identified for COVID-19 vaccines and SHL. Even though this adverse drug event may rely on an inflammatory mechanism, causality cannot be established by this pharmacovigilance study. However, this finding may strengthen the signals issued by ANSM, concerning elasomeran and AZD1222. SHL following COVID-19 vaccination might be evoked and treated as soon as possible.

COVID-19 vaccine-associated trigeminal neuralgia: Analysis of the WHO safety database

Introduction: To contain the COVID-19 pandemic, vaccination is deemed as a promising approach. A French pharmacovigilance survey identified five cases of trigeminal neuralgia (TN) following vaccination with AZD1222 (Vaxzevria®, AstraZeneca) [1]. Furthermore, a case report mentioned such an adverse reaction with tozinameran (Comirnaty®, Pfizer-BioNTech) [2]. TN is characterized by recurrent, unilateral, and brief electric shock-like pain in one or more trigeminal divisions [3]. TN is triggered by innocuous stimuli. We aimed to investigate the potential signal of TN related to COVID-19 vaccines. Material and methods: We queried VigiBase® (World Health Organization pharmacovigilance database) for all reports of "Trigeminal Neuralgia" (MedDRA Preferred Term) associated with "COVID-19 vaccine" (Active Ingredient), from 1967 to December 29, 2021 [4]. Disproportionality analysis relied on the Reporting Odds Ratio (ROR) with its 95% Confidence Interval (CI), and the Information Component (IC). A positive IC025 is statistically needed to confirm the detection of a signal [5]. Results: In VigiBase®, we gathered 1,283 cases of COVID-19 vaccine-related TN. Most reports involved women (998, 77.8%), with a median age of 52 years, and 510 (39.8%) were deemed serious. Tozinameran was mostly reported with 782 (61.0%) cases, followed by AZD1222 (264, 20.6%), elasomeran (Spikevax® Moderna, 185, 14.4%), and JNJ-78436735 (Janssen® Johnson & Johnson, 37, 2.9%). The association of COVID-19 vaccines and TN revealed significant disproportionality, with an IC025>0 and a ROR of 3.1 (95% CI 2.9-3.3). Tozinameran showed the strongest ROR (3.6;95% CI 3.3-3.8), followed by AZD1222 (2.3;95% CI 2.0-2.6), elasomeran (2.0;95% CI 1.7-2.3), and JNJ-78436735 (1.8 95% CI 1.3-2.5), each with IC025>0. Discussion/Conclusion: COVID-19 vaccines and TN showed relevant disproportionality. Albeit this reaction may rely on an immune-mediated inflammation, causality can only remain hypothetical in this pharmacovigilance study. Nonetheless, this finding may suggest a signal, strengthening reports mentioned by literature and French pharmacovigilance. A TN occurring after COVID-19 vaccination should alert the clinician.

Anti-NMDA receptor encephalitis and COVID-19 vaccination?

Introduction: Anti-NMDAR encephalitis is an autoimmune neurological disease characterized by the presence in the cerebrospinal fluid (CSF) of antibodies targeting the GluN1 subunit of the N-methyl D-aspartate receptors (NMDAR) in the brain. This study assessed the putative link between anti-NMDAR encephalitis and COVID-19 vaccination. Material and methods: All Individual Case Safety Reports (ICSRs) of anti-NMDAR encephalitis with Tozinameran (Comirnaty®) vaccine and registered in the World Health Organization global database (VigiBase®) up to December 31, 2021, were analyzed. A description and a disproportionality analysis were conducted, using the MedDRA reaction term "Anti-NMDA receptor encephalitis". The reported odds ratio (ROR) and its 95% 2-sided confidence interval have been calculated to compare the proportion of anti-NMDAR encephalitis reports with the suspected vaccine and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. Results: Among the 662 168 ICSRs associated with the suspected vaccine, 3 were anti-NMDAR encephalitis. One of the patients was male (15 years old) and two were female (26 and 69 years old). All cases were serious and required hospitalization. One of those three patients died. The time to onset of anti-NMDAR encephalitis after vaccination was variable and differed between patients (from 2 to 98 days). ROR was significant [2, 95% CI (1.2;2.8)]. Discussion/Conclusion: Several cases of anti-NMDAR encephalitis have been described in the literature after vaccination. This study found a signal between the occurrence of anti-NMDAR encephalitis and Tozinameran. There are currently no available data regarding the potential implication of the vaccines against COVID-19 in the onset of autoimmune encephalitis. The exhaustive recording of anti-NMDAR encephalitis occurring after vaccines is necessary.

MRNA COVID-19 vaccine and IgA nephropathy: Analysis of French pharmacovigilance database and literature

Introduction: In December 2020, mRNA COVID-19 vaccines (mCV) obtained marketing authorization for immunisation in COVID-19. A case of IgA nephropathy (IgAN) after COVID-19 mRNA vaccine was reported recently to our pharmacovigilance center (PV). The aim is to analyse cases of IgAN following mCV. Material and methods: We requested the cases in French PV Database with the MedDRA term (HLGT) "nephropathy" with mCV and cases summary contains "iga" AND "Nephropa%". We performed a review of the literature, (equation used: "Glomerulonephritis, IGA" [Mesh]) AND "COVID-19 Vaccines" [Mesh]). Cases with non-evocative chronology, pharmaceutical industry declaration and other identified cause were excluded. Results: Twenty cases were included and concerned 55% of women. Median aged was 39 years [13-63 years] including 2 pediatric patients [13 and 17 years]. Mean time to onset was 3.18 days [1-31d]. Concerned mCV was COMIRNATY® for 60% and SPIKEVAX® for the others. IgAN is observed after the 2nd dose for 16 cases (80%), 1st dose for 2 cases (10%), and both for 2 cases (10%). Sudden onset of macroscopic haematuria was the symptom that revealed the kidney disease for these patients and seven patients was also having acute kidney injury (35%). Among all the patient, 67% had an history of IgAN. Almost all cases resolved spontaneously except in six cases which needed corticoids or cyclophosphamide in one case. Discussion/Conclusion: Two third of cases occurred in patient with pre-existing IgAN, vaccine could also unmask a previously undiagnosed disease [1-2], and we noted two cases of positive rechallenge. The mechanism by which mCV may be associated with IgAN flares is unclear, but suggests it is mediated by a delayed-type hypersensitivity reaction. Vaccine risk seems lower than COVID-19 kidney injury and benefit/risk ratio remains favourable for vaccination [2].

COVID-vaccines associated chilblains: Analysis of the reports in VigiBase®

Introduction: Cases of COVID-vaccine induced chilblains have recently been reported in the literature. The goal of this study was to assess the link between COVID vaccines and chilblains using VigiBase®, the WHO pharmacovigilance database. Material and methods: Chilblains reports were extracted from a deduplicated dataset of VigiBase® (dataset date 02/01/2022) using the following MedDRA preferred terms: chillblains and pernio-like erythema. Sex-ratio, seriousness and median age and time to onset were calculated for each vaccine (ATC class J07) as well as the Information Component (IC). Results: For tozinameran (Pfizer®) 293 reports of chilblains were found with an IC of 3.1 (2.9-3.2). The sex ratio was 0.43, patients had a median age of 45.5 years (IQR:37-61). Reports were considered serious in 18% and median time to onset was 4 days (IQR 1-8). For elasomeran (Moderna®) 66 reports of chilblains were found with an IC of 2.3 (1.9-2.6). The sex ratio was 0.29, patients had a median age of 45.5 years (IQR:35-55). Reports were considered serious in 18% and median time to onset was 4 days (IQR:1.5-8.5). For chAdOx1 (Astra-Zeneca®) 121 reports of chilblains were found with an IC of 2.8 (2.5-3.0). The sex ratio was 0.42, patients had a median age of 54.5 years (IQR 42-66). Reports were considered serious in 35% and median time to onset was 5 days (IQR 2-15). No significant signals were found with any other vaccine. Discussion/Conclusion: A significant signal between chilblains and tozinameran, elasomeran and chAdOx1 was found, but not with any other vaccine. Women over 35 years old might be more at risk of developing this symptom. As high type I interferon response to COVID infection has been associated with the onset of chilblains [1], it is plausible that the same mechanism is implied in COVID-vaccines associated chilblains. Physicians should be aware of this possible adverse effect.

COVID-19 vaccines associated vestibular disorders: A case series and disproportionality analysis in Vigibase®

Introduction: Reports of vestibular syndrome have been associated with COVID vaccination in the recent literature. In this study, we aimed to evaluate the association between COVID-19 vaccines and vestibular disorders using Vigibase®, the WHO pharmacovigilance database. Material and methods: On January 5th, 2022, we extracted in a deduplicated dataset of VigiBase® reports of vestibular disorders for tozinameran (Pfizer®), elasomeran (Moderna®), Ad26.COV2.S (Janssen®) and ChadOx1nCov-19 (Astra-Zeneca®), using MedDRA preferred terms neuronitis vestibular, acute vestibular syndrome, vestibular disorder and the low level term vestibular vertigo. Seriousness was analyzed and reported odds ratio (ROR) were calculated. We also reviewed the management of COVID-vaccine associated vestibular disorders reported in Caen Regional Pharmacovigilance Center. Results: In Vigibase®, 226 reports of vestibular disorders were found for ChadOx1nCov-19, 40 for Ad26.COV2.S, 254 for elasomeran and 1,050 for tozinameran. The ROR were respectively 2.5 (2.2-2.8), 2.5 (1.8-3.2), 3.6 (3.2-4.0) and 7.0 (6.6-7.4). Reports were considered serious in 74.3% for ChadOx1nCov-19, 70.0% for Ad26.COV2.S, 60.6% for elasomeran and 56.01% for tozinameran. Finally, we collected 13 reports of COVID-19 vaccines associated vestibular disorders in our pharmacovigilance center. Concerning the management of those vestibular disorders, 4 patients received antiemetics, 1 received betahistine, 7 received acetylleucine, 2 received corticoids and 6 had vestibular physiotherapy sessions. After 1 month of follow-up, only one patient had recovered. Discussion/Conclusion: The Vigibase® analysis showed a statistically significant association between the 4 COVID-19 vaccines under study and vestibular disorders. Short-term anticholinergics, antiemetics, antihistamines or benzodiazepines, and a corticosteroid burst with rapid taper as well as vestibular rehabilitation are usually recommended treatments. In our case series we noticed the long duration of the symptoms despite the treatments received and the heterogeneity of the adopted therapeutic strategy. Physicians should be aware and careful of the potential association of COVID-19 vaccines and vestibular disorders. Management guidelines are needed given the wide exposure to COVID-19 vaccines.

Is transient global amnesia an adverse event associated with COVID-19 vaccines?

Introduction: Vaccination against COVID-19 appears to be a promising approach to mitigate this pandemic. The French agency of medicinal products (ANSM) issued a signal concerning cases of transient global amnesia (TGA) following vaccination with elasomeran (Spikevax® Moderna) [1]. TGA is characterized by the sudden onset of anterograde amnesia with preservation of other cognitive functions and a spontaneous resolution within 24 h [2]. We aimed to investigate the potential link of TGA with COVID-19 vaccines. Material and methods: We queried the WHO VigiBase® for all reports of "Transient global amnesia" (MedDRA Preferred Term) related to "Covid-19 vaccine"(Active Ingredient), from 1967 to December 6, 2021 [3]. Disproportionality analysis was based on the Reporting Odds Ratio (ROR) with its 95% Confidence Interval [CI] and the Information Component (IC) [4]. A positive IC025 statistically detects a signal [5]. Results: The search yielded 289 COVID-19 vaccine-associated TGAs, 178 of which (61.6%) were deemed serious. Most cases concerned women (187, 64.7%), with a median age of 66 years. Tozinameran (T: Comirnarty® Pfizer-BioNTech) was the most represented with 147 reports (50.8%), followed by AZD1222 (A: Vaxzevria® AstraZeneca) with 69 reports (23,8%), elasomeran (E: Spikevax®, Moderna) with 60 reports (20.8%), and JNJ-78436735 (J: Janssen® Johnson & Johnson) with 12 reports (4.2%). With a IC025 > 0, COVID-19 vaccines proved a significant disproportionality (global ROR 5.1 [4.4-6.0]), with respective RORs at 4.6 [3.9-5.0] for T, E at 4.4 [3.4-6.0], A at 3.8 [3.0-5.0], and J at 3.7 [2.1-6.0]. Discussion/Conclusion: Our analysis of COVID-19 vaccines and TGA shows significant disproportionality. Various mechanisms, such as cerebrovascular, inflammatory, or migrainous, may underlie this association. Yet causality cannot be ascertained solely with this approach, although it strengthens the signal issued by the ANSM. Further studies may help to identify the causality of COVID-19 vaccines in triggering TGAs.

DRUG INDUCED RETINAL DISORDERS IDENTIFIED THROUGH SPONTANEOUS REPORTING SYSTEM

Introduction: The retina is a highly specialized sense organ subjected to constant exposure to systemic toxins and oxidative stress. The frequency and etiology of drug-induced retinopathy, as well as the number of new potential drugs involved, are largely unknown. Objective: Describe the most frequent drug-induced retinal disorders and the drugs implicated gathered through the spontaneous report registry of the Spanish System of Pharmacovigilance (SSP). Methods: All spontaneous reported cases describing Retinal structural change, deposit and degeneration, Retinopathies not elsewhere classified, and Retinal bleeding and vascular disorders (excluded retinopathy) (MedDRA-HLT) in the SSP database from 1983 to January 2022 were selected. Medical devices and marketing authorisation holder cases were excluded. The variables studied were age and sex of the patients, characteristics of adverse drug reactions (ADRs) (seriousness, outcome) and suspect drugs (active substance, anatomical therapeutic chemical code, previous knowledge of drug-reaction association, rechallenge and existence of alternative causes). Results: Out of 175 spontaneous reports (0.1% of the spontaneous reports in the SSP database) that describe 210 ocular ADRs and/or adverse events, the most frequent (MedDRA-HLT) were retinal bleeding and vascular disorders (111, 52.9%), ocular structural change, deposit and degeneration (59, 28.1%) and vision disorders (12, 5.7%). For MedDRA-PT;retinal vein thrombosis (38, 18.1%), retinal detachment (22, 10.5%) and retinal hemorrhage (20, 9.5%). In only 8 cases (3.8%) drug administration was ophthalmic. Patient's median age was 57.65 (IQR 48-67.5) years;68.6% (120) were adults and 56.6% (99) were women. 153 reports (87.4%) were serious. 10.9% (19) cases resolved after withdrawal of the suspect drug and 12.6% (22) resolved with sequelae. A total of 220 drugs were suspected, of which 55 (25%) were COVID-19 vaccines -vector vaccine ChAdOx1 nCoV-19/AZD1222, Oxford-AstraZeneca (27) and mRNA vaccine BNT162b2, Pfizer- BioNTech (23)-, followed by sex hormones (21), immunostimulants (16) and antiprotozoals (14). Of the 175 reports, 56% (98) were poorly or unknown ADR associations. Alternative causes were excluded in 46 (26.3%) cases of which 12 (26%) were poorly or unknown ADR associations and no cases had a positive rechallenge. Conclusion: Our study shows that drug-induced retinopathy is an infrequent but serious complication. In the SSP database more than half of ADRs were retinal bleeding and vascular disorders. A quarter of the suspected drugs were new COVID-19 vaccines, followed by other drugs for which retinal disorders are well known. Although striking, it is important to contextualize this data in the current situation, considering the particularities of pharmacovigilance in vaccines, the massive rollout campaign and the nascent and evolving data on COVID-19 vaccines. Thus, further studies are needed to confirm such associations. Moreover, clinicians should be aware of drug-induced retinal disorders, even when not listed in the product information leaflet.

Suspected adverse reactions to COVID-19 vaccines reported to the Agency for Medicinal Products and Medical Devices

The SARS-CoV-2 virus is the cause of COVID-19 disease. The SARS-CoV-2 virus binds to ACE-2 receptors in the human lung via spike protein and causes COVID-19 disease. SARS-CoV-2 virus infection most often leads to the development of severe respiratory conditions, sore throat, and dry cough. By administering the vaccine, the human immune system recognizes the viral antigen, thereby activating immune system cells that produce neutralizing antibodies to remove the viral antigen. To combat the COVID-19 disease pandemic vaccines have been developed. Most commonly used vaccines in Europe are mRNA (messenger ribonucleic acid) vaccines and adenoviral vaccines. In this paper, suspected adverse reactions to the COVID-19 vaccine were analyzed according to patient age, sex, the severity of reporting, severity criteria, type of notifier, reported reaction, and adverse reactions according to the MedDRA classification of organ systems. Analyzed reports of suspected adverse effects were evaluated in the period from 27.12.2020. to 1.7.2021. A total of 2932 reports of suspected adverse reactions to the COVID-19 vaccine were analyzed, of which 730 were considered serious (24.9%). Out of 730 seriously evaluated reports, the largest number of reports refers to the development of other medically significant conditions, 583 of them (70.3%). The largest number of reports relates to the vaccine Comirnaty, 1610 of them (54.9%). This is followed by reports of suspected adverse reactions to Vaxzevria with 1098 reports (27.4%) and Spikevax with 206 reports (7.0%). The lowest number of suspected adverse reactions relates to Vaccine Janssen's COVID-19 vaccine (15;0.5%), while for three suspected adverse reactions the vaccine is unknown (0.1%). 34 cases of suspected adverse reactions, which amounts to only 4.1% of the total number of serious reports, or 1.15% of the total number of all received reports. The most commonly reported reactions to COVID-19 vaccines were fever, headache, and chills.

Descriptive analysis of menstrual alterations reported to the Spanish pharmacovigilance system (SEFV as acronym of its name in Spanish) after vaccination against COVID-19

Objective: • To describe the most reported menstrual alterations to the SEFV in relation to vaccination against COVID-19. • To stratify cases by age, type of vaccine and reporter. • To collect the latencies of adverse events. Material and/or methods: Review of the notifications uploaded to the FEDRA database with the following search criteria: the suspected drug is a vaccine against COVID-19, the adverse drug reaction (ADR) is part of the Meddra HLGT “alterations of menstrual flow” and the upload date is between the date of authorisation of the first vaccine (22/12/20) and the cut-off date established by protocol (3/11/2021). Also, those cases corresponding to Canary Islands have been selected for a detailed analysis. Results: There are 2275 notifications in Spain that meet the search criteria. The SEFV is the source of 98% of the notifications, being the pharmaceutical industry the source of the 2% left. In Canary Islands, there have been 80 notifications that meet the criteria. Of these, 87.5% come from female users (patients). The average age is 36 years. The most reported menstrual disorders were “intermenstrual bleeding,” “menstrual disorder” and “irregular menstruation.” The latencies described have a mean of 12.5 days with a median of 6 days and a mode of 3 days, appearing after the first dose in most cases. Conclusions: Most of the reports are from female users. Coding is complex due to the difficulty of the terms, which complicates data analysis. Reported reactions are diverse, being the most frequent terms non-specific. Menstrual disturbances interfere with daily life, are underreported and under-diagnosed.

A Review of Anaphylaxis Reactions Following COVID-19 Vaccination, as Reported in the VAERS Database

Introduction: The development and approval of COVID-19 vaccines occurred relatively quickly, leading many members of the U.S. population to question their legitimacy and safety. This study aims to evaluate the likelihood of experiencing anaphylaxis after the administration of a COVID-19 in the U.S by considering spontaneous reports of adverse events from the Vaccine Adverse Event Reporting System (VAERS) database. Research Question or Hypothesis: How many patients who received the vaccine suffered anaphylaxis? Study Design: Observational descriptive study. Methods: Our study reviewed the VAERS database's reports of Pfizer/BioNTech, Moderna, and Janssen vaccinations from the date each vaccine was approved through May 2021. The VAERS database systemizes up to five symptoms for each report using the Medical Dictionary for Regulatory Activities (MedDRA). We extracted and analyzed symptoms of anaphylaxis. Results: Out of the of 248,271 reports, 827 individuals, or 0.39%, experienced anaphylaxis. 52.6% of anaphylaxis cases occurred after administration of the Pfizer/BioNTech vaccine, 39.3% occurred after administration of the Moderna vaccine, and 7.9% occurred after administration of the Janssen Vaccine. 66.6% of the reactions occurred after the first dose, while 17.53% occurred after the second dose. The majority of patients who suffered anaphylaxis were female (70.1%). 56.2% of anaphylaxis reactions occurred before or on the third day following administration;1.7% of reactions occurred between 4 and 14 days following administration;and 2.1% of reactions occurred after 14 days following administration. 60.2% of the patients who experienced anaphylaxis were hospitalized and six died. Conclusion: The COVID-19 vaccines were developed in less than a year. The U.S. medical community and population at large have expressed concerns with potential side-effects. The results of this observational study of vaccine-related adverse events, specifically anaphylaxis, resembles those reported in clinical trials.

WORLDWIDE POST-MARKETING SAFETY SURVEILLANCE EXPERIENCE WITH TOFACITINIB IN ULCERATIVE COLITIS

Background: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. First market authorization was received in the US in May 2018. Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs). Here, we report an analysis of PMS case safety reports for tofacitinib in patients with UC.Methods: We analyzed the worldwide tofacitinib PMS reports received in the Pfizer safety database from May 30, 2018 to August 25, 2020. The type and estimated reporting rate (RR) of serious AEs (SAEs) of interest, incl. infection, vascular, respiratory, neoplasm, and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate or extended-release formulations.Results: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8,916 PY. Overall, 4,226 case reports were received and included 12,103 AEs, of which 1,839 were SAEs. Among the cases reported, 1,141 (27.0%) included an SAE and 18 (0.4%) were fatal. Of cases with reported gender (88.1%) or age (81.6%), 46.5%occurred in men and the median age was 45 years (range 9–93). When analyzed by tofacitinib formulation, proportions of SAE cases were similar (Table 1). Table 2 presents a summary of AEs and SAEs by MedDRA system organ class. Among the 1,839 SAEs, RRs per 100 PY were 3.28 for infection events, 1.26 for vascular events, 0.74 for respiratory events, 0.55 for neoplasm events, and 0.50 for cardiac events. The most commonly reported serious infection events (MedDRA preferred term [PT] n≥8) were 2 PTs within the high level term (HLT) of Clostridia infections (C. difficile colitis/infection), pneumonia, COVID-19, cytomegalovirus, and herpes zoster. The most commonly reported serious vascular events (n≥10) included hemorrhage, thrombosis, and deep vein thrombosis. Most serious respiratory events were pulmonary embolism. The most commonly reported serious neoplasm events (n≥3) were 2 PTs within the HLT of breast and nipple neoplasms malignant (breast cancer female/breast cancer), colon cancer, lymphoma, malignant melanoma, neoplasm malignant, and prostate cancer. The most commonly reported serious cardiac events (n≥4) were 3 PTs within the HLT of ischemic coronary artery disorders (acute myocardial infarction/myocardial infarction, angina pectoris) and pericarditis.Conclusion: Based on this review of PMS data for tofacitinib in UC, the types of AEs and RRs were consistent with the known tofacitinib safety profile, with no new potential risks identified. Limitations of PMS reports, low numbers of case reports for extended-release formulation, and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.(Table Presented)(Table Presented)

Use of comprehensive solicited event reporting for safety monitoring in clinical trials with standard of care drugs

Safety reporting in traditional clinical trials is often accomplished through investigator's independent identification of events meeting Adverse Event reporting criteria. In some study settings, such as observational or standard of care-based research, the subjectivity in this reporting approach can result in gaps or inconsistencies in safety data, limiting the ability to confidently confirm both presence and absence of key events. The Emmes contract research organization has adopted a new approach for clinical research studies to improve upon the traditional, passive, non-specific collection of adverse events with a more targeted solicitation of study-specific Events of Special Interest. Events of Special Interests may be derived from the drug labels, package inserts, or known disease indications, and ensure consistency and uniformity in safety data collection across sites and similar studies. Events of Special Interest reporting aims to target specific events and avoids over or under reporting by sites. Events of Special Interests also reduce the burden of site reporting of irrelevant events, the need to determine if an event is or is not reportable, such as in a sick patient population, and finally supports efficient data and safety monitoring in alignment with the Food and Drug Administration Investigational New Drug Application Safety reporting guidance. The Emmes contract research organization has adopted this approach to ensure comprehensive data collection in support of improved labeling for marketed products in pediatric and adolescent populations. It has proven most effective in observational or standard of care studies, particularly those with sick and/or inpatient populations. Safety event data are bolstered with site required confirmation of occurrence in an unequivocal No or Yes manner, along with the addition of severity, causality, and association assessments by the clinician/ subject matter expert. Events of Special Interests are study-defined events, aiding study staff or programmatic searches of health records in the identification and ion of event data. Events of Special Interests also allow researchers to more accurately tabulate event frequency and rates, as well as assist sponsors in identifying site reporting imbalances. Clinical research is constantly evolving, driven by the need to optimize data collection and reduce time, effort, and cost, which is particularly important for trials being implemented during the COVID-19 pandemic. The traditional methods used to collect safety data require a high level of effort to collect, review by numerous subject matter experts, and can often result in the collection of large amounts of data that are irrelevant to research objectives. This utilization of safety reporting and analysis to include Events of Special Interests has been shown to significantly reduce the level of effort to collect, subject matter expert review, MedDRA code, and tabulate safety data. By improving data collection consistency and uniformity, utilization of Events of Special Interest reporting has improved the overall process of safety event reporting in our clinical research, increasing the efficacy of study data utilized to inform regulatory authorities.