Cardiac adverse events associated with lacosamide: a disproportionality analysis of the FAERS database.

Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide.

Comparing musculoskeletal and connective tissue disorder risks of teriparatide and abaloparatide in osteoporosis: an analysis based on FDA adverse event reporting system (FAERS).

BACKGROUND: Osteoporosis (OP), characterized by low bone mass and increased fracture risk, is a prevalent skeletal disorder. Teriparatide (TP) and abaloparatide (ABL) are anabolic agents that may reduce fracture incidence, but their impact on musculoskeletal and connective tissue disorders (MCTD) risk is uncertain. RESEARCH DESIGN AND METHODS: A retrospective, observational disproportionality analysis was conducted utilizing FAERS data from Q1 2004 to Q3 2023, where TP or ABL was identified as the primary suspect drug. Multiple data mining algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to detect MCTD safety signals. RESULTS: A total of 366,747 TP-related and 422,377 ABL-related cases were identified, predominantly among female patients aged ≥45 years. The top specific AEs involved musculoskeletal, connective tissue, and administration site disorders. Comparative analysis revealed a higher frequency of AEs related to the nervous, cardiovascular, and gastrointestinal systems for ABL compared to TP. Both drugs exhibited strong signals for arthralgia, limb pain, back pain, muscle spasms, bone pain, muscle pain, and muscle weakness. CONCLUSION: The analysis suggests a potential MCTD risk with TP and ABL treatment in OP patients, highlighting the need for AE monitoring and management in clinical practice. This contributes to a better understanding of the safety profiles of these anabolic medications.

Spectrum of psychiatric adverse reactions to cyclin-dependent kinases 4/6 inhibitors: A pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: The emergence of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) represented a major breakthrough in the treatment of breast cancer over the past decade. In both clinical trials and real-world settings, it was observed that patients using CDK4/6i might experience psychiatric adverse events (PAEs). Herein, we conducted a pharmacovigilance study to comprehensively assess the correlation between CDK4/6i and PAEs. METHOD: We obtained individual case safety reports submitted to the FDA Adverse Events Reporting System (FAERS) during the period from January 2015 to December 2023. In disproportionality analysis, the reporting odds ratio (ROR) and information component (IC) values were calculated for each adverse event-drug combination. Univariate logistic regression analysis was utilized to explore factors associated with PAEs following CDK4/6i treatment. RESULTS: A total of 95,591 reports related to CDK4/6i were identified, with 6.72% reporting PAEs, and this proportion exhibited an annual upward trend. Based on the ROR and IC values, 17 categories of PAEs were defined as CDK4/6i-related PAEs. Among these PAEs, insomnia, stress, eating disorder, depressed mood, and sleep disorder were very common, each accounting for over 10% of CDK4/6i reports. Ribociclib showed the highest risk signal of CDK4/6i-related PAEs (ROR = 1.89[1.75-2.04], IC025 = 0.79), followed by palbociclib (ROR = 1.47[1.41-1.53], IC025 = 0.49), while abemaciclib did not exhibit a significant signal (ROR = 0.52[0.44-0.62], IC025 = -1.13). Female sex, younger age and weight exceeding 80 kg were significant risk factors for the incidence of CDK4/6i-related PAEs. CONCLUSIONS: Using data from a real-world, large-scale spontaneous reporting system for adverse drug reactions, our study delineated the spectrum of PAEs to CDK4/6i. This potentially offered valuable insights for healthcare professionals to manage the risk of PAEs in patients receiving CDK4/6i treatment, particularly those with psychiatric disorders.

Characterization of second primary malignancies post CAR T-cell therapy: real-world insights from the two global pharmacovigilance databases of FAERS and VigiBase.

Background: The FDA's alerts regarding the T-cell lymphoma risk post CAR-T therapy has garnered global attention, yet a comprehensive profile of second primary malignancies (SPMs) following CAR-T treatment is lacking. Methods: We extracted adverse event reports of hematological malignancies (HMs) patients with clearly definable SPMs from the FAERS and VigiBase databases (2017-2023). Disproportionality analysis using reporting odds ratio (ROR) and adjusted ROR was performed to assess associations between SPMs and CAR-T therapy. Time-to-onset analysis explored factors affecting SPM manifestation. Findings: SPMs post CAR T-cell therapy include HMs and solid tumors. T-cell lymphoma and myelodysplastic syndromes were consistently identified as positive signals across the overall and subgroup analyses. Hematological SPMs showed earlier onset with increasing annual incidence post CAR-T therapy, whereas solid tumors exhibit delayed manifestation. SPMs in CAR-T recipients had significantly earlier onset than non-recipients. Furthermore, age-specific characteristics reveal earlier SPM manifestations in pediatric, adolescent, and young adult populations compared to older populations post CAR-T therapy. Interpretation: The current SPM profile highlights the necessity of long-term safety monitoring for all CAR-T recipients given the observed yearly increase of SPMs. Customizing long-term SPM screening across different age groups may enhance early detection and intervention strategies, ultimately improving patient outcomes in the follow-up of CAR-T recipients. Funding: This work was supported by grants from the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020), the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750, 82172811, and 82260546), the Guangdong Basic and Applied Basic Research Foundation (Guangdong-Guangzhou Joint Funds) (2022A1515111212), and the Science and Technology Program of Guangzhou (2023A04J1257).

Hypercalcemia in children induced by denosumab: a case report and an analysis of the FDA adverse event reporting system database.

BACKGROUND: The potential risks of denosumab on pediatric patients have raised concerns about its safety. This article aims to analyze the adverse effects of denosumab in minors, with a specific focus on hypercalcemia. RESEARCH DESIGN AND METHODS: A case study involving a child was analyzed. The OpenVigil 2.1 was utilized to extract adverse event data from the FAERS database, focusing on denosumab as the primary suspect drug in pediatric patients. The study also reviewed published cases of children developing hypercalcemia after discontinuing denosumab. RESULTS: The incidence of denosumab induced hypercalcemia in individuals under 18 years old is significantly higher than the overall incidence. The signal value for hypercalcemia was higher in the male group and was highest in the adolescent group. Hypercalcemia usually appeared approximately 4 months after denosumab discontinuation. Males had a higher peak blood calcium level. Patients aged 0-11 years had a higher average peak serum calcium compared to aged 12-17 years. CONCLUSIONS: This study highlights the risk of hypercalcemia after discontinuation of denosumab in minors, with young age and male gender identified as potential high-risk factors. These findings offer valuable safety warnings and preventative measures for the secure administration of this drug in pediatric populations.

Adverse drug events associated with fluorouracil use in patients with metastatic colorectal cancer: a real-world pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND: Fluorouracil (5-FU) is widely used to treat metastatic colorectal cancer (mCRC), but real-world safety data is limited. Our study aimed to evaluate 5-FU's safety profile in a large mCRC population using the FAERS database. RESEARCH DESIGN AND METHODS: We conducted disproportionality analyses to identify adverse drug events associated with 5-FU use in mCRC patients from 2004 to 2023. Subgroup analyses, gender difference analyses, and logistic regression were also performed. RESULTS: We identified 1,458 reports with 5-FU as the primary suspected drug, with males accounting for 48.8% of reports. Gastrointestinal disorders were the most common adverse event (864 cases), while pregnancy-related conditions showed the strongest signal intensity (ROR = 2.97). We found 19 preferred terms with positive signals, including ischemic hepatitis (ROR = 59.32), blood iron increased (ROR = 59.32), and stress cardiomyopathy (ROR = 51.94). Males were more susceptible to weight loss and skin toxicity. Most adverse events occurred within the first month of 5-FU administration. CONCLUSION: Our study provides a comprehensive analysis of 5-FU's safety profile in mCRC patients, helping healthcare professionals mitigate risks in clinical practice.

Hemorrhagic events associated with tacrolimus: a real-world pharmacovigilance study.

BACKGROUND: Tacrolimus is a potent macrolide immunosuppressant frequently used to prevent graft rejection in organ transplantation. Despite the known side effect of hemorrhage, there are no extensive descriptive series of patients who experience hemorrhage events associated with tacrolimus. We sought to review and describe tacrolimus-related hemorrhage events reported by healthcare professionals to the United States Food and Drug Association Adverse Event Reporting System (FAERS) database. METHODS: The FAERS database (2004q1-2022q4) was retrospectively analyzed to characterize reporting of hemorrhage adverse events (AEs) with tacrolimus. Subgroup analysis was completed on the hemorrhage. RESULTS: A total of 75,310 tacrolimus-associated AEs were identified, of which 1,511 cases met specific inclusion/exclusion criteria with most occurring in the gastrointestinal tract (422 cases, 27.93% of all included cases). Death was reported in 558 patients (36.93% of hemorrhage cases), the most of which occurred in cases of brain hemorrhage (219 cases, 39.25% of death cases). Among definitive organ transplants, renal transplant was the most common indication for tacrolimus (62 cases, 4.10%) followed by bone marrow transplant (44 cases, 2.91%) and liver transplant (30 cases, 1.99%). CONCLUSIONS: This study presents the largest collective description of tacrolimus-related hemorrhage events. We additionally described a number of previously unreported tacrolimus-related hemorrhage events.

Data mining study on adverse events of tirzepatide based on FAERS database.

BACKGROUND: Tirzepatide is a novel dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) for type 2 diabetes or obesity. To explore the safety profile of tirzepatide in real-world clinical applications. RESEARCH DESIGN AND METHODS: A retrospective analysis of adverse events (AEs) reports associated with tirzepatide was conducted from the second quarter of 2022 through the fourth quarter of 2023, utilizing the FDA Adverse Event Reporting System (FAERS) database. Signal mining utilized the reporting odds ratio (ROR) method, and onset time was analyzed utilizing the Weibull Shape Parameter (WSP). RESULTS: We identified 25,215 AE reports related to tirzepatide, predominantly in the 65 to 85 age group. Four positive signals were found at the system organ classes level. Additionally,109 AEs at the preferred terms level with positive signals were indicated. Included among these are novel signals, such as the presence of thyroid mass, medullary thyroid carcinoma, and conditions affecting the reproductive system and breast. Most AEs occurred within the first 30 days. The WSP was 0.66, indicating a propensity for early failure type. CONCLUSIONS: This study identified several novel AE signals for tirzepatide, highlighting the need for careful monitoring, especially in the early stages of treatment.

Gastroparesis treatment options metoclopramide and prucalopride: analysis of the FDA Adverse Event Reporting System (FAERS) database.

BACKGROUND: We aimed to examine the common adverse drug reactions (ADRs) of metoclopramide, FDA-approved for treating many gastrointestinal conditions including gastroparesis, and prucalopride, FDA-approved for treating chronic idiopathic constipation but used off-label for other gastrointestinal conditions including gastroparesis. RESEARCH DESIGN AND METHODS: The FDA Adverse Event Reporting System (FAERS) was analyzed from January 2013 to December 2023. ADR reports regarding use of only metoclopramide or prucalopride were analyzed following exclusion of reports indicating use for treatment of non-gastrointestinal conditions. RESULTS: Analysis of 1,085 reports on metoclopramide revealed tardive dyskinesia (n = 393, 36.2%) and dystonia (n = 170, 15.7%) among the most reported ADRs in addition to QTc prolongation (n = 16, 1.5%) with progression to Torsade de pointes (n = 5, 0.5%) and triggering of pheochromocytoma crisis (n = 24, 2.2%). Analysis of 865 reports on prucalopride revealed headache (n = 120, 13.9%), diarrhea (n = 116, 13.4%), and abdominal pain (n = 100, 11.6%) as the most common ADRs with 22 reports (2.5%) of dystonia with the use of prucalopride. CONCLUSIONS: This FAERS database analysis shows post-marketing reports of ADRs from metoclopramide most frequently include tardive dyskinesia, dystonia, and tremor in addition to potentially fatal arrhythmias such as Torsade de pointes. Consumers of prucalopride may also be at risk of dystonia and other ADRs.

A pharmacovigilance study of chronic kidney disease in diabetes mellitus patients with statin treatment by using the US Food and Drug Administration adverse event reporting system.

Background: Statins were regarded as a main medication for managing hypercholesterolemia. Administration of statin therapy could reduce the incidence of cardiovascular disease in individuals diagnosed with type 2 diabetes mellitus (DM), which was recognized by multipal clinical guidelines. But previous studies had conflicting results on whether the long-term use of statins could benefit the renal function in diabetic patients. Aim: To evaluate the association between statin treatment and Chronic Kidney Disease in DM patients. Methods: This is a retrospective disproportionality analysis and cohort study based on real-world data. All DM cases reported in US Food and Drug Administration adverse event reporting system (FAERS) between the first quarter of 2004 and the fourth quarter of 2022 were included. Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). We further compared the CKD odds ratio (OR) between the statins group and the other primary suspected drug group among the included diabetes mellitus cases. Results: We finally included 593647 DM cases from FAERS, 5113 (5.31%) CKD cases in the statins group and 8810 (1.77%) CKD cases in the control group. Data analysis showed that the statins group showed a significant CKD signal (ROR: 3.11, 95% CI: 3.00-3.22; IC: 1.18, 95% CI: 1.07-1.29). In case group with two or more statins treatment history, the CKD signal was even stronger (ROR: 19.56, 95% CI: 18.10-21.13; IC: 3.70, 95% CI:3.44-3.93) compared with cases with one statin treatment history. Conclusion: The impact of statin therapy on the progression of renal disease in individuals diagnosed with type 2 diabetes mellitus (DM) remains inconclusive. After data mining on the current FAERS dataset, we discovered significant signals between statin treatment and CKD in diabetic patients. Furthermore, the incidence rate of CKD was higher among DM patients who used statins compared to those who did not.

A real-world pharmacovigilance study of polatuzumab vedotin based on the FDA adverse event reporting system (FAERS).

Background: Polatuzumab vedotin, the first FDA-approved antibody-drug conjugate (ADC) targeting CD79b, is utilized in the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), as well as relapsed or refractory (R/R) DLBCL. Despite its approval, concerns persist regarding the long-term safety profile of polatuzumab vedotin. This study aims to evaluate the adverse events (AEs) associated with polatuzumab vedotin since its approval in 2019, utilizing data mining strategies applied to the FDA Adverse Event Reporting System (FAERS). Methods: Signal detection employed four methodologies, including reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS), to evaluate and quantify the signals of polatuzumab vedotin-associated AEs. Additionally, subgroup analyses based on patients age, gender, and fatal cases were conducted to investigate AEs occurrences in specific subpopulations. Results: A total of 1,521 reports listing polatuzumab vedotin as a "principal suspect (PS)" drug were collected from the FAERS database. Through concurrent compliance with four algorithms, 19 significant Standardized MedDRA Query (SMQ) AEs and 92 significant Preferred Term (PT) AEs were detected. Subgroup analyses revealed a higher incidence of PTs in male patients compared to female patients, increased likelihood of polatuzumab vedotin-associated AEs in elder patients (>65 years), and AEs with a high risk of fatal cases include: blood lactate dehydrogenase increased, cytopenia, and hydronephrosis. The median time to AEs occurrence following polatuzumab vedotin initiation was 18.5 (5∼57.75) days, with 95% of AEs occurred within 162 days. Conclusion: This study identified various AEs associated with polatuzumab vedotin, offering critical insights for clinical monitoring and risk identification in patients receiving polatuzumab vedotin therapy.

Pulmonary haemorrhage and haemoptysis associated with bevacizumab-related treatment regimens: a retrospective, pharmacovigilance study using the FAERS database.

Background: Bevacizumab (BV) is widely used in routine cancer treatment and clinical therapy in combination with many other agents. This study aims to describe and analyse post-market cases of pulmonary haemorrhage and haemoptysis reported with different BV treatment regimens by mining data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data were collected from the FAERS database between 2004 Q1 and 2023 Q1. Disproportionality analysis including the reporting odds ratio (ROR) was employed to quantify the signals of disproportionate reporting of pulmonary haemorrhage and haemoptysis adverse events (AEs) associated with BV-related treatment regimens. The demographic characteristics, time to onset and outcomes were further clarified. Results: A total of 55,184 BV-associated reports were extracted from the FAERS database, of which 497 reports related to pulmonary haemorrhage and haemoptysis. Overall, the median onset time of pulmonary haemorrhage and haemoptysis AEs was 43 days (interquartile range (IQR) 15-117 days). In the subgroup analysis, BV plus targeted therapy had the longest median onset time of 90.5 days (IQR 34-178.5 days), while BV plus chemotherapy had the shortest of 40.5 days (IQR 14-90.25). BV plus chemotherapy disproportionately reported the highest percentage of death (148 deaths out of 292 cases, 50.68%). Moreover, the BV-related treatments including four subgroups in our study demonstrated the positive signals with the association of disproportionate reporting of pulmonary haemorrhage and haemoptysis. Notably, BV plus chemotherapy showed a significant higher reporting risk in pulmonary haemorrhage and haemoptysis signals of disproportionate reporting in comparison to BV monotherapy (ROR 5.35 [95% CI, 4.78-6.02] vs. ROR 4.19 [95% CI, 3.56-4.91], p = 0.0147). Conclusion: This study characterized the reporting of pulmonary haemorrhage and haemoptysis, along with the time to onset and demographic characteristics among different BV-related treatment options. It could provide valuable evidence for further studies and clinical practice of BV.

Disproportionality Analysis of Nusinersen in the Food and Drug Administration Adverse Event Reporting System: A Real-World Postmarketing Pharmacovigilance Assessment.

BACKGROUND: Nusinersen is the first drug for precise targeted therapy of spinal muscular atrophy, a rare disease that occurs in one of 10,000 to 20,000 live births. Therefore, thorough and comprehensive reports on the safety of nusinersen in large, real-world populations are necessary. This study aimed to mine the adverse event (AE) signals related to nusinersen through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: We extracted reports of AEs with nusinersen as the primary suspect from FAERS between December 2016 and March 2023. Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) were used for AE signal detection. RESULTS: We extracted a total of 4807 suspected AE cases with nusinersen as the primary suspect from the FAERS database. Among them, 106 positive signals were obtained using the ROR and BCPNN. The highest frequency reported systemic organ class was general disorders and administration site conditions. Common clinical AEs of nusinersen were detected in the FAERS database, such as pneumonia, vomiting, back pain, headache, pyrexia, and post-lumbar puncture syndrome. In addition, we identified potential unexpected serious AEs through disproportionality analysis, including sepsis, seizure, epilepsy, brain injury, cardiorespiratory arrest, and cardiac arrest. CONCLUSIONS: Analyzing large amounts of real-world data from the FAERS database, we identified potential new AEs of nusinersen by disproportionate analysis. It is advantageous for health care professionals and pharmacists to concentrate on effectively managing high-risk AEs of nusinersen, improve medication levels in clinical settings, and uphold patient medication safety.

A disproportionality analysis of adverse events caused by GnRHas from the FAERS and JADER databases.

Background: Gonadotrophin-releasing hormone analogs (GnRHas) play a significant role in addressing gynecological diseases, central precocious puberty, and cancer. However, ensuring the safety of GnRHas in real-world applications requires continuous vigilance. In light of this, we undertook a disproportionality analysis focused on adverse events (AEs) associated with GnRHas using data from both the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). We evaluated GnRHas-associated AEs and characterized the clinical priority of unlisted AEs caused by each GnRHa from the different databases. Methods: In the disproportionality analysis, we applied two adjusted algorithms to identify signals related to GnRHas in the FAERS and JADER databases from 2004 to 2023. Additionally, we utilized the Statistical Analysis System (SAS, 9.4) to examine potential and high-aROR (adjusted reporting odds ratio) signals associated with GnRHas. We performed clinical priority assessment for suspicious PTs and an analysis of serious/non-serious outcomes. We also gathered information on the onset times of AEs linked with GnRHas from both databases. Results: From January 2004 to September 2023, FAERS and JADER recorded a total of 50,360,413 and 1,440,200 AEs, respectively. Employing two algorithms, the suspicious preferred terms (PTs) related to leuprolide (Leu) were 562 potential PTs (44 unlisted in specifications), followed by goserelin (Gos) with 189 PTs (28 unlisted), triptorelin (Tri) with 172 PTs (28 unlisted), and Leu-JADER with 85 PTs (10 unlisted). At the same PT level, the differences in GnRHas between the two databases were observed, such as cardiac failure, diabetes mellitus, liver disorder, dementia, suicidal ideation, interstitial lung disease, urinary disorders, and hypertensive crisis. In an analysis of serious vs. non-serious outcomes, a total of 43 AEs of Leu were more likely to be reported as serious AEs with p < 0.05 (such as asthenia, urinary retention, diabetes mellitus, interstitial lung disease, gait disturbance, and so on), following by Tri (6 AEs), and Gos (4 AEs). Based on the clinical priority score, 41 PTs of Leu, 26 PTs of Tri, 24 PTs of Gos, and 8 PTs of Leu-JADER were graded as weak. There were 3 PTs of Leu, 2 PTs of Tri, 4 PTs of Gos, and 2 PTs of Leu-JADER that were graded as moderate. Notably, in the assessment of the relevant evidence, 2 PTs (loss of libido and urinary tract toxicity caused by Leu), 1 PT (electrolyte imbalance caused by Tri), and 2 PTs (anorexia and suicidal ideation caused by Gos) showed a strong level of evidence with "++." The differences in the signal strength of the same PTs from two databases were also worth noting. Moreover, the median onset time for GnRHas (Leu, Tri, and Gos) was 23 days (0, 298), 22 days (0, 181), and 217 days (29, 706), respectively, as median (Q1, Q3). Conclusion: An examination of two databases revealed suspicious AEs associated with GnRHas. Our study found potential new AE signals of GnRHas and supported continuous clinical monitoring, pharmacovigilance, regional differences, and further studies of GnRHas.

Adverse events associated with eteplirsen: A disproportionality analysis using the 2016-2023 FAERS data.

Background: Eteplirsen (Exondys 51) is an orphan drug approved for the treatment of Duchenne muscular dystrophy (DMD), having received accelerated approval from the U.S. Food and Drug Administration (FDA) in 2016. The primary aim of this study is to closely monitor adverse events (AEs) associated with eteplirsen and to identify emerging signals to better characterize their safety profile. Methods: AEs due to eteplirsen usage reported from the third quarter (Q3) of 2016 to the fourth quarter (Q4) of 2023 were collected from the FDA Adverse Event Reporting System (FAERS). The role_code of AEs mainly includes primary suspect (PS), secondary suspect (SS), concomitant (C), and interaction (I). This study targeted reports with a role_cod of 'PS.' According to the FDA deduplication rule, the latest FDA_DT is selected when the CASEID is the same, and the higher PRIMARYID is selected when the CASEID and FDA_DT are the same. Disproportionality analyses, encompassing four algorithms for reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian configuration promotion neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were utilized to quantify the signals of AEs associated with eteplirsen. Results: From the FAERS database, a total of 13,205,369 reports were amassed throughout the study duration. Following the eradication of duplicates, the number of reports with eteplirsen designated as the PS amounted to 1480 encompassed 25 organ systems. Among these, "general disorders and administration site conditions," "injury, poisoning, and procedural complications," "respiratory, thoracic, and mediastinal disorders," "infections and infestations," "vascular disorders," and "product issues" met at least one of the four computational criteria. Additionally, 55 Preferred Terms (PTs) aligned with the prescribed algorithms. The median time to AEs in these patients was 903 days with an interquartile range (IQR) of 269-1575 days. Moreover, 70.04 % of AEs manifested one year or more after the initiation of treatment. Conclusion: As an orphan drug granted accelerated approval, our study has confirmed well-known adverse drug reactions and identified potential safety issues associated with eteplirsen treatment. This has contributed to a deeper understanding of the complex interrelations between adverse reactions and the use of eteplirsen. The findings underscore the critical importance of ongoing monitoring and sustained observation to promptly detect and effectively manage AEs, thereby enhancing the overall safety and well-being of patients treated with eteplirsen for DMD.

Identification of novel signal of proton pump inhibitor-associated drug reaction with eosinophilia and systemic symptoms: a disproportionality analysis.

BACKGROUND: Proton pump inhibitors (PPIs) are commonly prescribed for treating upper gastrointestinal hemorrhage, eradicating Helicobacter pylori, and stress ulcer prophylaxis, among other digestive system diseases. Recent case reports provided limited evidence of a correlation between PPIs and drug reactions with eosinophilia and systemic symptoms (DRESS). However, there is currently no established association between PPIs and DRESS. AIM: This research aimed to identify the associations between PPIs and DRESS using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database. METHOD: A retrospective investigation of DRESS associated with six PPIs used FAERS data from Q1 2004 to Q3 2023. Data mining algorithms were used to identify adverse events in the FAERS database that met the following criteria: (1) proportional reporting ratio (PRR) ≥ 2; (2) reporting odds ratio (ROR) > 1; (3) 95% confidence interval (CI) of ROR > 1; (4) Chi-square (χ2) ≥ 4 and case count ≥ 3. RESULTS: There were 495 reports of PPI-related DRESS, including pantoprazole (174, 35.2%), omeprazole (103, 20.8%), lansoprazole (103, 20.8%), esomeprazole (101, 20.4%), rabeprazole (8, 1.6%), and dexlansoprazole (6, 1.2%). The results indicated a significant association of three PPIs (pantoprazole, omeprazole, and lansoprazole) with DRESS. The sensitivity analysis demonstrated that only pantoprazole remained significantly associated with DRESS after 10 concomitant drugs had been removed (ROR: 3.00, PRR: 2.99, and information component [IC]: 1.57). CONCLUSION: This study identified the signals suggesting a potential association between DRESS and six PPIs. However, more investigation of epidemiological data is required to validate of these conclusions.

Safety assessment of sildenafil use in neonates: a real-world data analysis based on the FDA adverse event reporting system (FAERS).

BACKGROUND: The safety of neonatal sildenafil use remains uncertain. This study aimed to investigate adverse events (AEs) associated with sildenafil use in neonates. RESEARCH DESIGN AND METHODS: We collected data on AEs associated with sildenafil use in neonates from the US Food and Drug Administration Adverse Event Reporting System database, spanning from its inception of the database in 2004 to 2023. Disproportionality measures were employed to analyze the correlation between AEs and sildenafil. RESULTS: Sildenafil was identified as the primary suspect drug in 75 AE reports, involving 214 AEs. Three system organ classes, namely, eye disorders, hepatobiliary disorders, and vascular disorders were associated with sildenafil use. Six preferred terms, namely, flushing, retinopathy of prematurity, hyperbilirubinemia, pulmonary hemorrhage, hypotension, and diarrhea were associated with sildenafil use. Notably, hyperbilirubinemia and pulmonary hemorrhage were previously unreported AEs associated with sildenafil use. CONCLUSION: The results highlight the ongoing uncertainty surrounding the safety of neonatal sildenafil use and provide vital support for risk monitoring and identification in neonates receiving sildenafil. Additionally, the study underscores the need for continuous safety surveillance in neonates treated with sildenafil and suggests further exploration of the precise causal relationships between AEs and sildenafil.

Pharmacovigilance study of GLP-1 receptor agonists for metabolic and nutritional adverse events.

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are employed extensively in the management of type 2 diabetes and obesity. However, there is a paucity of real-world data on their safety and tolerability for metabolic and nutritional adverse events in large sample populations. This study aimed to analyse the metabolic and nutritional safety signatures of different GLP-1 RAs by exploring the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: AEs data were extracted from the FDA Adverse Event Reporting System database for each GLP-1 RA from the time of its launch until the second quarter of 2023. The reported odds ratio (ROR), proportional reporting ratio (PRR), Empirical Bayesian Geometric Mean and Bayesian Confidence Propagation Neural Network were employed to identify AE signals. Results: A system organ class of metabolism and nutrition disorders was employed to filter AE reports, resulting in the identification of 10,450 reports for exenatide, 2,860 reports for liraglutide, 240 reports for albiglutide, 4,847 reports for dulaglutide, 2,905 reports for semaglutide, 1,089 reports for tirzepatide, and 13 reports for lixisenatide. Semaglutide (ROR, 3.34; 95%CI, 3.22), liraglutide (ROR, 2.78; 95%CI, 2.69), and exenatide (ROR, 2.15; 95%CI, 2.11) were associated with metabolism and nutrition disorders. The number of AE signals detected were as follows: albiglutide (n = 1), lixisenatide (n = 2), tirzepatide (n = 11), exenatide (n = 12), liraglutide (n = 16), semaglutide (n = 20), dulaglutide (n = 22). Dehydration was the most frequent AE contributing to serious outcomes for liraglutide (n = 318, 23.93%), dulaglutide (n = 434, 20.90%), semaglutide (n = 370, 25.10%) and tirzepatide (n = 70, 32.86%). The time to onset (TTO) of AE was statistically different between exenatide and the other GLP-1 RAs (p < 0.001), and the Weibull parameters for dehydration for liraglutide, dulaglutide, and semaglutide analyses all showed an early failure-type profile. Conclusion: Our study suggests that exenatide, liraglutide, and semaglutide are more susceptible to metabolic and nutritional AEs than other GLP-1 RAs. Liraglutide, dulaglutide, semaglutide, and tirzepaptide's potential to induce dehydration, necessitates special attention. Despite certain deficiencies, GLP-1 RAs have considerable potential for the treatment of eating disorders.

Association of thrombocytopenia with immune checkpoint inhibitors: a large-scale pharmacovigilance analysis based on the data from FDA adverse event reporting system database.

Introduction: An increasing number of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been reported during clinical treatment. We aimed to explore the clinical characteristics of patients with ICIs-induced ITP under different therapeutic strategies based on the FAERS database and explore the potential biological mechanisms in combination with TCGA pan-cancer data. Methods: Data from FAERS were collected for ICIs adverse reactions between January 2012 and December 2022. Disproportionality analysis identified ICIs-induced ITP in the FAERS database using the reporting odds ratio (ROR), proportional reporting ratio (PRP), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker algorithms (MGPS). The potential biological mechanisms underlying ITP induced by ICIs were examined using TCGA transcriptome data on cancers. Results: In the FAERS, 345 ICIs-induced ITP reports were retrieved, wherein 290 (84.06%) and 55 (15.94%) were reported as monotherapy and combination therapy, respectively. The median age of the reported patients with ICIs-induced ITP was 69 years (IQR 60-76), of which 62 (18%) died and 47 (13.6%) had a life-threatening outcome. The majority of reported indications were lung, skin, and bladder cancers, and the median time to ITP after dosing was 42 days (IQR 17-135), with 64 patients (43.5%) experiencing ITP within 30 days of dosing and 88 patients experiencing ITP in less than 2 months (59.9%). The occurrence of ICIs-induced ITP may be associated with ICIs-induced dysregulation of the mTORC1 signaling pathway and megakaryocyte dysfunction. Conclusion: There were significant reporting signals for ITP with nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab/ipilimumab, and pembrolizumab/ipilimumab. Patients treated with anti-PD-1 in combination with anti-CTLA-4 are more likely to have an increased risk of ICIs-induced ITP. Patients with melanoma are at a higher risk of developing ITP when treated with ICI and should be closely monitored for this risk within 60 days of treatment. The potential biological mechanism of ICIs-induced ITP may be related to the dysfunction of megakaryocyte autophagy through the overactivation of the mTOR-related signaling pathway. This study provides a comprehensive understanding of ICIs-induced ITP. Clinicians should pay attention to this potentially fatal adverse reaction.

Hepatic injury and hepatic failure adverse events in 3,4-methylenedioxymethamphetamine users reported to the FDA Adverse Event Reporting System.

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.