A real-world pharmacovigilance study of cardiac adverse events induced by sugammadex in the FDA adverse event reporting system.

BACKGROUND: Sugammadex is a novel agent that reverses neuromuscular blockade during general anesthesia. Recent case reports have raised concerns regarding potential cardiac adverse events (CAEs). However, no large-scale real-world studies have yet evaluated the potential link between sugammadex and CAEs. RESEARCH DESIGN AND METHODS: Data from the FDA Adverse Event Reporting System were obtained. The association between sugammadex and CAE was evaluated using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. Serious outcomes resulting from sugammadex-related CAEs were assessed, and complications associated with CAEs were evaluated. RESULTS: Nineteen CAEs were identified and classified into two categories: cardiac arrhythmias and coronary artery disorders. The most frequent CAEs were bradycardia (n=202), cardiac arrest (n=119), tachycardia (n=30), and Kounis syndrome (n=22). Subgroup analysis based on age, sex, and weight revealed parallel findings. The CAEs most likely to result in serious consequences were pulseless electrical activity and cardiac arrest. The most common concurrent adverse effects with CAEs were hypotension (n=51), anaphylactic reactions (n=46), and anaphylactic shock (n=23). CONCLUSION: This study suggests a potential link between sugammadex and CAEs, highlighting the need for careful monitoring and personalized risk assessment, especially in patients with cardiovascular risk factors.

Eye disorders associated with selective serotonin reuptake inhibitors: a real-world disproportionality analysis of FDA adverse event reporting system.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely used in depression and other psychiatric disorders. Despite their efficacy, there is a growing concern about the risk of eye disorders. This study aims to explore the potential correlation between eye disorders and SSRIs utilizing real-world data. RESEARCH DESIGN AND METHODS: The data were extracted from the US FDA Adverse Event Reporting System database from 2004Q1 to 2023Q3. The analysis focused on the clinical characteristics, the ranking of adverse reactions, the time-to-onset, and the severity proportion of SSRI-related eye disorders. RESULTS: Our analysis revealed that SSRIs were significantly associated with eye disorders, with a higher risk of vision blurred with escitalopram, angle closure glaucoma with citalopram, and photopsia with paroxetine. The most common eye disorders were vision blurred, visual impairment, mydriasis, etc. Most of these adverse events occurred within the first 30 days of treatment. The reported incidence of severe eye disorders was 38.6% for SSRIs, with fluoxetine exhibiting the highest rate at 45.9%. CONCLUSION: Our study demonstrates a significant association between SSRIs and the risk of eye disorders. These findings provide crucial insights for clinicians when prescribing SSRIs and underscore the need to monitor eye health in patients receiving these medications.

Central serous chorioretinopathy secondary to drugs: a real-world pharmacovigilance study of the FDA adverse event reporting system (FAERS).

BACKGROUND: The objective of this study was to evaluate the reporting associations between Central serous chorioretinopathy (CSCR) and many available drugs using FAERS. RESEARCH DESIGN AND METHODS: FAERS reports from 2004 to 2023 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CSCR cases. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the reporting associations between available drugs and CSCR were calculated. A reporting association was considered statistically significant when the lower limit of the 95% CI was > 1.0. RESULTS: There were 1002 reports of 110 drugs with suspected drug-associated CSCR based on the 'primary suspects' role code in the FAERS database found to have statistically significant signals. Among the top 20 ROR drugs, the most frequently reported drugs were dermatological drugs (ATC:D, 210 cases, 64.41%), followed by antitumor agents and immunological agents (ATC:L,77 cases, 23.62%), Systemic Hormonal Preparations, Excl. Sex hormones and Insulins (ATC:H, 19 cases, 5.80%) and sensory organ drugs (ATC:S, 9 cases, 2.76%). The top 3 drugs associated with CSCR were Prednisolone (144 cases, 44.17%), Fluticasone (29 cases, 8.90%), and Methylprednisolone (27 cases, 8.28%). CONCLUSIONS: This is the first real-world study using FAERS database to investigate drug-induced CSCR. Clinicians and pharmacist must keep in mind CSCR is a serious ocular complication associated with glucocorticoids, tyrosine kinase receptor inhibitor, and other drugs that can cause CSCR.

Hepatitis-related adverse events associated with immune checkpoint inhibitors in cancer patients: an observational, retrospective, pharmacovigilance study using the FAERS database.

Background: Immune checkpoint inhibitors (ICIs), including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, have become a standard treatment for multiple cancer types. However, ICIs can induce immune-related adverse events, with hepatitis-related adverse events (HRAEs) being of particular concern. Our objective is to identify and characterize HRAEs that exhibit a significant association with ICIs using real-world data. Methods: In this observational and retrospective pharmacovigilance study, we extracted real-world adverse events reports from the FDA Adverse Event Reporting System database spanning from the first quarter of 2004 to the first quarter of 2023. We conducted both Frequentist and Bayesian methodologies in the framework of disproportionality analysis, which included the reporting odds ratios (ROR) and information components (IC) to explore the intricate relationship between ICIs and HRAEs. Results: Through disproportionality analysis, we identified three categories of HRAEs as being significantly related with ICIs, including autoimmune hepatitis (634 cases, ROR 19.34 [95% CI 17.80-21.02]; IC025 2.43), immune-mediated hepatitis (546 cases, ROR 217.24 [189.95-248.45]; IC025 4.75), and hepatitis fulminant (80 cases, ROR 4.56 [3.65-5.70]; IC025 0.49). The median age of patients who report ICI-related HRAEs was 63 years (interquartile range [IQR] 53.8-72), with a fatal outcome observed in 24.9% (313/1,260) of these reports. Cases pertaining to skin cancer, lung cancer, and kidney cancer constituted the majority of these occurrences. Patients treated with anti-PD-1 or anti-PD-L1 antibodies exhibited a higher frequency of immune-mediated hepatitis in comparison to those undergoing anti-CTLA-4 monotherapy, with a ROR of 3.59 (95% CI 1.78-6.18). Moreover, the dual ICI therapy demonstrated higher reporting rates of ICI-related HRAEs compared to ICI monotherapy. Conclusion: Our findings confirm that ICI treatment carries a significant risk of severe HRAEs, in particular autoimmune hepatitis, immune-mediated hepatitis, and hepatitis fulminant. Healthcare providers should exercise heightened vigilance regarding these risks when managing patients receiving ICIs.

Long-term safety of lanthanum carbonate in the real word: a 19-year disproportionality analysis from the FDA Adverse Event Reporting System.

BACKGROUND: Lanthanum carbonate is widely used to manage serum phosphate and calcium levels in end-stage kidney disease (ESKD) patients, yet comprehensive long-term safety data are lacking. This study leverages the FDA Adverse Event Reporting System (FAERS) to assess the extended safety profile of lanthanum carbonate. RESEARCH DESIGN AND METHODS: We analyzed FAERS data (2004-2022) to study the association between lanthanum carbonate and adverse events (AEs). Using MedDRA v25.0, we identified risk signals through System Organ Classes (SOCs) and Preferred Terms (PTs). Disproportionality analyzes quantified lanthanum carbonate-associated AE signals. RESULTS: Among 3,284 reports, 2,466 were primary suspected AEs linked to lanthanum carbonate. Males reported AEs more frequently than females. Patients aged over 64 represented the majority. Median onset time for lanthanum carbonate-related AEs was 146 days. Gastrointestinal disorders were prevalent. We identified 16 new signals, including stress, abnormal hepatic function, cholelithiasis, bile duct stone, gastric cancer, and adenocarcinoma gastric. Stress was notable, particularly in male patients over 65 and those with lower weight. CONCLUSIONS: This study affirms lanthanum carbonate's long-term safety for reducing elevated blood phosphorus levels. While gastrointestinal disorders were common, attention must focus on emerging AEs, particularly stress, especially in elderly patients.

Investigating the safety profiles of exogenous melatonin and associated adverse events: A pharmacovigilance study using WHO-VigiBase.

Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders. However, there are limited studies on the safety of melatonin. Therefore, we aimed to present the overall patterns of adverse events (AEs) following melatonin administration and identify potential safety signals associated with melatonin. Using VigiBase, a global individual case safety report (ICSRs) database managed by the World Health Organization (WHO), we conducted a retrospective, observational, pharmacovigilance study of melatonin between January 1996 and September 2022. Disproportionality analysis was conducted using two comparator settings: all other drugs and other sleep medications. We used multivariable logistic regression to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs) to compare the frequencies of AEs reporting between melatonin and each comparator setting. Furthermore, we assessed adverse events of special interests (AESIs) that could potentially be associated with melatonin. Signals were identified when the following criteria were met: cases ≥3, x2 ≥ 4, IC025 ≥ 0, and the lower end of the 95% CI of ROR > 2. These signals were then compared with the AE information on the drug labels provided by regulatory bodies. A total of 35 479 AE reports associated with melatonin were identified, with a higher proportion of reports from females (57.1%) and individuals aged 45-64 years (20.8%). We identified 21 AEs that were commonly detected as safety signals in the disproportionality analyses, including tic, educational problems, disturbance in social behavior, body temperature fluctuation, and growth retardation. In AESI analyses, accidents and injuries (adjusted ROR 2.97; 95% CI, 2.80-3.16), fall (2.24; 2.12-2.37), nightmare (4.90; 4.37-5.49), and abnormal dreams (3.68; 3.19-4.25) were detected as a signal of melatonin when compared to all other drugs, whereas those signals were not detected when compared to other sleep medications. In this pharmacovigilance study, exogenous melatonin showed safety profiles comparable to other sleep medications. However, several unexpected potential safety signals were identified, underscoring the need for further investigation at the population level.

Comparison of agranulocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis caused by two antithyroid drugs: A pharmacovigilance study using the WHO international database.

BACKGROUND: Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database. METHODS: We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV. RESULTS: Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake. CONCLUSIONS: This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.

Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used due to their profound efficacy in glycemic control and weight management. Within real-world contexts, the manifestation of certain psychiatric adverse events (AEs) has been observed, which is potentially linked to the administration of GLP-1 RAs. The objective of this study was to undertake a comprehensive investigation and characterization of the psychiatric AEs associated with GLP-1 RAs. Methods: We retrieved reports of AEs associated with treatment with GLP-1 RAs during the period from the first quarter (Q1) of 2004 to Q1 2023 from the FDA Adverse Event Reporting System (FAERS) database. Descriptive analysis was performed to examine the clinical characteristics and time to onset of the psychiatric AEs caused by GLP-1 RAs. Moreover, disproportionality analyses were performed using the reporting odds ratio (ROR) to identify GLP-1 RA-related psychiatric AEs. Results: A total of 8,240 reports of psychiatric AEs were analyzed out of 181,238 AE reports with treatment with GLP-1 RAs. Among these cases, a higher percentage was represented by women compared to men (65.89% vs. 30.96%). The median age of these patients was 56 years, with an interquartile range (IQR) of 48-67 years, based on data available in 286 case reports. This study showed that the median time to onset of the overall GLP-1 RA-related AEs was 31 days (IQR = 7-145.4 days), which varied among GLP-1 RA regimens. Specifically, exenatide had a significantly longer onset time at 45 days (IQR = 11-213 days), with statistically significant differences from the onset times of the other five GLP-1 RAs (p< 0.0001). Moreover, eight categories of psychiatric AEs, namely, nervousness (ROR = 1.97, 95% CI = 1.85-2.11), stress (ROR = 1.28, 95% CI = 1.19-1.38), eating disorder (ROR = 1.57, 95% CI = 1.40-1.77), fear of injection (ROR = 1.96, 95% CI = 1.60-2.40), sleep disorder due to general medical condition-insomnia type (ROR = 2.01, 95% CI = 1.60-2.52), binge eating (ROR = 2.70, 95% CI = 1.75-4.16), fear of eating (ROR 3.35, 95% CI = 1.65-6.78), and self-induced vomiting (ROR = 3.77, 95% CI = 1.77-8.03), were defined as GLP-1 RA-related psychiatric AEs through disproportionality analysis. Conclusion: Our findings demonstrate a significant association between GLP-1 RAs and the development of specific psychiatric AEs. Despite the observational nature of this pharmacovigilance study and the inherent limitations of the FAERS database, our preliminary findings in this work could provide a better basis for understanding the potential psychiatric AEs that may occur with GLP-1 RA treatment, assisting clinicians to focus on these AEs and provide early intervention for optimal risk management.

Cardiac toxicity of brentuximab vedotin: a real-word disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database.

Brentuximab vedotin (BV) has obtained approval for the therapeutic management of classical Hodgkin lymphoma as well as systemic anaplastic large cell lymphoma. Given the inherent constraints of conventional clinical trials, the correlation between BV and cardiac adverse events (AEs) remains enigmatic. The objective of this investigation is to comprehensively assess cardiac AEs attributed to BV by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The indices for the assessment of disproportionality encompass the reporting odds ratio (ROR), the proportional reporting ratio, the information component, and the empirical Bayesian geometric mean. Employing these sophisticated metrics, we gauged the extent of disproportionate occurrences. The dataset was sourced from the FAERS from the first quarter of 2012 to first quarter of 2023, facilitating a comprehensive analysis of the potential correlation between BV and cardiac AEs. This scrutiny encompassed a comparative analysis of both cardiac and non-cardiac AEs. A total of 495 cases of BV's cardiac AEs were discerned, with the identification of 31 preferred terms (PTs). Among these, 8 PTs emerged as conspicuous signals of cardiac AEs, notably encompassing ventricular hypokinesia (ROR 7.59), tachyarrhythmia (ROR 7.06), sinus tachycardia (ROR 6.18), cardiopulmonary failure (ROR 4.44), pericardial effusion (ROR 4.32), acute coronary syndrome (ROR 4.02), cardiomyopathy (ROR 3.30), and tachycardia (ROR 2.76). The manifestation of severe outcomes demonstrates a discernible correlation with the cardiac AEs (P < 0.001). Our investigation furnishes invaluable insights for healthcare practitioners to proactively mitigate the incidence of BV-associated cardiac AEs.

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis.

AIM: Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also involved itself in the degradation of amyloid-ß, there is an ongoing concern about the effect of sacubitril/valsartan on cognition, especially in case of long-term administration. METHODS: The FDA Adverse Event Reporting System (FAERS) was mined between 2015Q3 and 2022Q4 to analyze the association between sacubitril/valsartan and adverse events (AEs) involving dementia. Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with "broad" and "narrow" preferred terms (PTs) relevant to dementia was applied to systematically search demented AE reports. The Empirical Bayes Geometric Mean (EBGM) from Multi-Item Gamma Poisson Shrinker (MGPS) and proportional reporting ratio with Chi-square (PRR, χ2 ) were used to calculate the disproportionality. RESULTS: We filtered the query for indication and identified 80,316 reports with heart failure indication in FAERS during the analytical period. Among all the reports, sacubitril/valsartan was listed as primary suspected or secondary suspected drug in 29,269 cases. No significantly elevated reporting rates of narrow dementia were evident with sacubitril/valsartan. The EBGM05 for narrow dementia-related AEs associated with sacubitril/valsartan was 0.88 and the PRR (χ2 ) was 1.22 (2.40). Similarly, broad demented complications were not over-reported in the heart failure patients administrated with sacubitril/valsartan (EBGM05 1.11; PRR 1.31, χ2 109.36). CONCLUSION: The number of dementia-related cases reported to FAERS generate no safety signal attributable to sacubitril/valsartan in patients with heart failure for now. Further follow-ups are still warranted to address this question.

Cardiovascular Toxicities of Ibrutinib: A Pharmacovigilance Study Based on the United States Food and Drug Administration Adverse Event Reporting System Database.

Background: Although ibrutinib has been widely used to treat haematological malignancies, many studies have reported associated cardiovascular events. These studies were primarily animal experiments and clinical trials. For more rational clinical drug use, a study based on post-marketing data is necessary. Aim: Based on post-marketing data, we investigated the clinical features, time to onset, and outcomes of potential cardiovascular toxicities of ibrutinib. Methods: This disproportionality study utilised data from the 2014−2021 United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. We used two disproportionality methods information component (IC) and reporting odds ratio (ROR)) to detect the potential cardiovascular toxicities of ibrutinib. Positive signals were defined as IC025 > 0 and ROR025 > 1. Results: A total of 10 cardiovascular events showed positive signals: supraventricular tachyarrhythmias, haemorrhagic central nervous system vascular conditions, ventricular tachyarrhythmias, cardiac failure, ischaemic central nervous system vascular conditions, cardiomyopathy, conduction defects, myocardial infarction, myocardial infarction disorders of sinus node function, and torsade de pointes/QT prolongation. Cardiomyopathy and supraventricular tachyarrhythmias were the two most common signals. Disorders of sinus node function were observed for the first time, which may be a new adverse effect of ibrutinib. Conclusions: This pharmacovigilance study systematically explored the adverse cardiovascular events of ibrutinib and provided new safety signals based on past safety information. Attention should be paid to some high-risk signals.

Toxicity signals associated with secukinumab: A pharmacovigilance study based on the United States Food and Drug Administration Adverse Event Reporting System database.

AIMS: Secukinumab, the first interleukin 17A inhibitor, is widely used to treat immune diseases, including plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. Recently, many studies have reported adverse events associated with secukinumab, including gastrointestinal disorders, infections and infestations, and hypersensitive and nervous system disorders. OBJECTIVE: Here, we aimed to explore the clinical characteristics, outcomes and time to onset of the four main toxicities of secukinumab using post-marketing data. METHODS: Our study utilized data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2015 to 2021, using disproportionality analysis. Toxicities were defined based on the standardized Medical Dictionary for Regulatory Activities queries. Two disproportionality methods were used to detect potential signals: information component (IC) and reporting odds ratio (ROR). The signals were defined as ROR025 > 1 and IC025 > 0. RESULTS: A total of 73 945 398 records were included in this study, of which 300 665 records were related to secukinumab. Diarrhoea (N = 3538), nasopharyngitis (N = 3458), pruritus (N = 4277) and rash (N = 3270) were the most common adverse events. Inflammatory bowel disease (IC025 /ROR025 = 3.25/9.69), genital candidiasis (IC025 /ROR025 = 3.46/11.54), dermatitis psoriasiform (IC025 /ROR025 = 1.94/4.04) and anosmia (IC025 /ROR025 = 1.62/3.17) had the highest IC025 values of all toxicities. The time to onset of the four toxicities was mainly concentrated in the first month. Some patients simultaneously presented with two or more toxicities. CONCLUSION: This pharmacovigilance study systematically explored the four main toxicities of secukinumab and provided new safety signals based on past safety information. Some high-risk signals need to be given attention.

Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a real-world pharmacovigilance study.

Objective: Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer's disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is essential for its safe and rational administration. This study aimed to evaluate the correlation between different ChEIs and TdP/QT prolongation. Methods: All ChEIs related TdP/QT prolongation cases were retrieved from the FAERS database using standard MedDRA query (SMQ) from the first quarter of 2004 to the third quarter of 2022. Disproportionality and sensitivity analysis were used to determine the signal of TdP/QT prolongation related to ChEIs. Results: 557 cases of TdP/QT prolongation related to 3 ChEIs were searched by SMQ. The patients were mostly elderly people, with markedly more female than male. The signals of TdP/QT prolongation for ChEIs were detected by disproportionality analysis, and the signal of Donepezil was the strongest. The sensitivity analysis results indicate a robust and stable correlation between these signals with ChEIs. TdP/QT prolongation usually occurs within 1 month after taking ChEIs. The drug with the highest frequency of combination with donepezil and galantamine is citalopram, and the drug with the highest frequency of combination with rivastigmine is atorvastatin. Conclusion: The signals of TdP/QT prolongation related to ChEIs were strong and stable. It is necessary to be vigilant about the TdP/QT prolongation of various ChEIs, especially in elderly women, the initial stage after taking ChEIs, and when ChEIs combining with drugs that could prolong the QT interval.

Type 1 diabetes with immune checkpoint inhibitors: A systematic analysis of clinical trials and a pharmacovigilance study of postmarketing data.

BACKGROUND: To estimate the risk of type 1 diabetes associated with immune checkpoint inhibitor (ICI-T1DM), and to describe its clinical features. METHODS: ICI-T1DM events in randomized clinical trials (RCTs) available in electronic databases were systematically reviewed. The primary outcome was the summary risk of T1DM related to ICIs, a meta-analysis was conducted to obtain Peto odds ratios (ORs) with 95 % CIs. In pharmacovigilance study, ICI-T1DM cases were extracted from FAERs. Disproportionality analyses were performed by calculating reporting odds ratio (ROR) and information components (IC). RESULTS: A total of 29 RCTs (20,234 patients) were included, treatment with ICIs significantly increased the risk of all-grade ICI-T1DM (OR: 4.54, 95 % CI: 2.66-7.72), and high-grade (grade 3 or above) ICI-T1DM (OR: 4.26, 95 % CI: 2.12-8.58). No significant differences among subgroup analyses were observed: ICIs treatment schedule, tumor type, case of events (T1DM vs F-T1DM), study design (double blind vs open label) or median PFS (PFS favours ICIs vs PFS favours Control). A total of 978 case reports form FAERS was extracted, treatment with ICIs significantly increased the reporting of ICI-T1DM (n = 978; ROR = 38.45, 95 %CI:35.70-41.41; IC = 4.77, 95 %CI:4.43-5.14). In cases with available data, the median latency period was 10.4 weeks, drug interruption was recorded in 82.3 % of cases, with a positive dechallenge in 76 % of cases, and death was recorded as outcome in 3.6 % of reports. CONCLUSIONS: Both data from clinical trials and postmarketing suggested that ICIs was associated with increased risk of ICI-T1DM. As ICIs gain greater clinical use, practitioners must be aware of ICI-T1DM events.

Thromboembolic events in Janus kinase inhibitors: A pharmacovigilance study from 2012 to 2021 based on the Food and Drug Administration's Adverse Event Reporting System.

AIMS: As a new type of drug developed rapidly in recent years, Janus kinase inhibitors (JAKinibs) have caused controversy due to possible adverse reactions of thromboembolism. The aim of this study was to analyse and evaluate the association between thromboembolic events and the use of JAKinibs, on the base of the latest data in the Food and Drug Administration's Adverse Event Reporting System. METHODS: A disproportionality analysis was conducted, utilizing data from 1 January 2012 to 30 September 2021 in the FAERS. For each drug-adverse event pair, reporting odds ratio (ROR) and information components (IC) were calculated. RESULTS: A total of 15 positive safety signals were detected within the FAERS: ruxolitinib was significantly associated with portal vein thrombosis (ROR025 = 3.49, IC025 = 1.50); tofacitinib immediate release with pulmonary embolism (ROR025 = 2.09, IC025 = 1.02) and thrombosis (ROR025 = 1.15, IC025 = 0.18); tofacitinib extended release with pulmonary embolism (ROR025 = 1.27, IC025 = 0.26) and thrombosis (ROR025 = 1.29, IC025 = 0.33); baricitinib with deep vein thrombosis (ROR025 = 8.27, IC025 = 3.00), portal vein thrombosis (ROR025 = 1.97, IC025 = 0.63), pulmonary embolism (ROR025 = 7.90, IC025 = 2.94), thrombosis (ROR025 = 2.04, IC025 = 0.93) and venous thrombosis (ROR025 = 2.15, IC025 = 0.81); upadacitinib with pulmonary embolism (ROR025 = 1.25, IC025 = 0.25), pulmonary thrombosis (ROR025 = 5.32, IC025 = 2.33) and thrombosis (ROR025 = 2.72, IC025 = 1.39); and filgotinib with pulmonary embolism (ROR025 = 4.83, IC025 = 2.10). In the analysis of the time to onset of thromboembolic events, no obviously recognizable pattern was found. Several safety signals with embolic and thrombotic events (Standardised MedDRA Query) were found in the study. CONCLUSION: This pharmacovigilance study covered 8 types of JAKinib that are already on the market, and provided new safety signals based on past safety information. Some of these signals still need more medical evidence.

Romosozumab and cardiovascular safety in Japan.

Romosozumab is a potent pharmacological tool to prevent fractures in osteoporosis patients, and its mechanism of action is distinct from any other drugs. The efficacy of romosozumab to prevent osteoporotic fractures is remarkable. However, there remains a concern of increased cardiovascular adverse events. Further relevant investigations are essential to understand whether romosozumab is actually involved in the development of cardiovascular events or not. We need more robust evidence to establish an appropriate and reasonable guide to prescribe romosozumab in our clinical practice.

Anaphylactic risk related to omalizumab, benralizumab, reslizumab, mepolizumab, and dupilumab.

BACKGROUND: Monoclonal antibodies (mAbs) are novel, effective therapeutics for the treatment of inadequately controlled severe asthma. Knowledge of the anaphylaxis risks related to different mAbs is essential for their appropriate and safe administration. This study aimed to evaluate the associations between different mAbs and anaphylactic reactions by applying statistical approaches to pharmacovigilance data. METHODS: This was a retrospective study using data from the US Food and Drug Administration Adverse Event Reporting System database from January 2004 to September 2020. A total of 2006 reports of anaphylaxis related to benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab were obtained through data mining. The clinical characteristics of the cases were analyzed, and the risk signals of anaphylactic reactions and corresponding outcomes were investigated in the five mAbs. RESULTS: The patients were mainly young and middle-aged adults, with markedly more women than men. Omalizumab, benralizumab, reslizumab, and mepolizumab showed positive signals for anaphylaxis, while only dupilumab showed a negative signal. The risk of initial or prolonged hospitalization due to anaphylaxis was significantly higher in the benralizumab group than in the omalizumab group (42.86% vs. 28.92%, p = 0.024). Further, when anaphylaxis to omalizumab occurred, patients with asthma were more likely to have life-threatening outcomes than those with chronic urticaria (18.0% vs. 12.9%, p = 0.022). CONCLUSION: In the current real-world study, the positive anaphylaxis signals related to omalizumab, benralizumab, reslizumab, and mepolizumab suggested the need for the close monitoring of patients after drug use, and dupilumab showed a negative signal for anaphylaxis.

Risk of pneumonitis in cancer patients treated with PARP inhibitors: A meta-analysis of randomized controlled trials and a pharmacovigilance study of the FAERS database.

OBJECTIVE/BACKGROUND: We aimed to evaluate the risk of PARP inhibitors (PARPis) causing pneumonitis in randomized controlled trials (RCTs) and in the real-world practice. METHODS: First, a systematic review based on meta-analysis was conducted. RCTs with available data reporting pneumonitis events for PARPis were eligible for analysis. Second, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the main features of PARPi-related pneumonitis. RESULTS: 16 trials with 5771 patients were included in our meta-analysis. Compared with control arms, PARPis showed a significant increase in the risk of pneumonitis events (Peto OR 2.68 [95% CI 1.31-5.47], p = 0.007) with no heterogeneity (I2 = 0%, χ2p = 0.70). The incidence of pneumonitis across treatment arms was 0.79% (28/3551). In the FAERS database, we identified 84 cases of PARPi-pneumonitis with a fatality rate of 16% (13/79). The median time to event onset was 81 (interquartile range [IQR] 27-131) days and 87% of the adverse events occurred within 6 months. CONCLUSION: PARPis increased the risk of pneumonitis that can result in serious outcomes and tend to occur early. Early recognition and management of PARPi-pneumonitis is of vital importance in clinical practice. The mechanisms and risk factors should be studied further to improve clinical understanding and innovative treatment strategies for these diseases.

Metabolic and Nutritional Disorders Following the Administration of Immune Checkpoint Inhibitors: A Pharmacovigilance Study.

Background: Although several metabolic and nutritional disorders (MNDs) have been reported in the recipients of immune checkpoint inhibitors (ICIs), these events have not been fully captured and comprehensively characterized in real-world population. Objectives: To provide complete metabolic and nutritional toxicity profiles after ICIs (single and combined) initiation through an integrated big database. Methods: Reporting odds ratios (ROR) and information component (IC) based on statistical shrinkage transformation were utilized to perform disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System. Both ROR and IC were used to calculate disproportionality when compared with the whole database, but only ROR was used when comparison was made for different ICI strategies. Only when both the lower limits of 95% confidence intervals (CIs) for ROR (ROR025) and IC (IC025) exceeded specified threshold values (1 and 0, respectively) was regarded as a signal. Results: A total of 29,294,335 records were involved and 8,662 records were for MNDs in patients exposed to ICIs. Statistically significant association was detected between ICIs use and total MNDs (IC025/ROR025 = 1.06/2.19). For monotherapy, three ICI monotherapies (anti-PD-1, anti-PDL-1, and anti-CTLA-4) were all disproportionately associated with MNDs. Statistically significant differences in reporting frequencies also emerged when comparing anti-PD-1 with anti-PD-L1/anti-CTLA-4 monotherapy, with RORs of 1.11 (95%CI 1.01-1.21), and 1.35 (95%CI 1.23-1.48), respectively. Notably, combination therapy was associated with a higher reporting frequency of theses toxicities compared to monotherapy with a ROR of 1.56 (95%CI 1.48-1.64). Additionally, disproportionality analysis at High-level Group Term level highlighted eight broad entities of MNDs. Further disproportionality analysis at Preferred Term level indicated a wide range and varied strength of signals. For ICI monotherapy, nivolumab and pembrolizumab showed the broadest spectrum of MNDs. For combination therapy, a variety of signals were detected for nivolumab + ipilimumab therapy even comparable to two PD-1 monotherapies. Conclusion: Metabolic and nutritional complications could be provoked by ICI monotherapy (especially anti-PD-1) and further reinforced by combination therapy. Clinicians and patients should be informed about these potential risks that might be encountered in real-world practice. Aforehand education and regular monitoring of related biochemical parameters (calcium, sodium, potassium, protein) are recommended to ensure better cancer survivorship.