A real-world drug safety surveillance study from the FAERS database of breast cancer patients receiving abemaciclib alone and plus letrozole

A real-world drug safety surveillance study from the FAERS database of breast cancer patients receiving abemaciclib alone and plus letrozole | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A real-world drug safety surveillance study from the FAERS database of breast cancer patients receiving abemaciclib alone and plus letrozole Lu Hu, Yuye Ran, Chunqiao Zhou, Peng Gu, Hailin Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6217610/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Abemaciclib in combination with letrozole is considered a crucial treatment regimen for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. This study aims to monitor and identify adverse events (AEs) associated with this combination therapy to enhance patient safety and provide evidence-based recommendations for the appropriate use of these drugs. We collected data on adverse drug reactions (ADRs) related to breast cancer patients receiving either abemaciclib monotherapy or its combination with letrozole from the FDA Adverse Event Reporting System (FAERS) database between the first quarter of 2014 and the fourth quarter of 2024. ADR signal detection was conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) methods. A total of 6,649 and 750 AE cases were collected for patients receiving abemaciclib monotherapy and its combination with letrozole, respectively. Using four signal detection techniques, we identified 42 and 28 distinct AEs, involving 15 and 11 different system organ class (SOC) categories, respectively. The most common AEs associated with abemaciclib were diarrhea, dehydration, and myelosuppression. In the combination therapy group, the most frequently reported AEs were diarrhea, interstitial lung disease, and acute kidney injury (AKI). Additionally, we observed a higher incidence of abnormal liver function in the combination therapy group, with a detected signal for hepatocellular necrosis. The United States reported the highest number of AEs, followed by Japan, China, France, and Italy. The median onset time of AEs associated with abemaciclib monotherapy and its combination with letrozole was 30 days (interquartile range [IQR]: 11–115 days) and 35 days (IQR: 14–109 days), respectively. This study provides novel insights into the monitoring and management of ADRs in breast cancer patients receiving abemaciclib monotherapy or in combination with letrozole. Health sciences/Diseases/Cancer/Breast cancer Health sciences/Medical research/Drug development Abemaciclib Letrozole Breast Cancer Adverse Drug Reactions FAERS Medication Safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Breast cancer remains a significant global health challenge. Among women, it is the most frequently diagnosed cancer and the leading cause of cancer-related mortality 1 . Since the mid-2000s, the incidence of breast cancer has been increasing by approximately 1% annually, primarily due to a rise in cases of localized-stage and hormone receptor-positive (HR+) breast cancer 2 , 3 . The development and approval of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for the treatment of HR+/HER2 − metastatic breast cancer represent a major milestone in breast cancer therapy 4 . CDK4/6i Currently, CDK4/6i in combination with endocrine therapy (ET) plays a crucial role in the adjuvant intensification treatment of high-risk early-stage HR+/HER2 − breast cancer, as well as in the management of locally advanced or metastatic disease. The approved CDK4/6i agents include abemaciclib, palbociclib, and ribociclib. Studies have demonstrated that abemaciclib is the first CDK4/6i to show a significant improvement in invasive disease-free survival (IDFS) when combined with ET in HR+/HER2 − lymph node-positive breast cancer patients at high risk of early recurrence 5 . It is also the only CDK4/6i recommended for adjuvant therapy in HR + breast cancer patients by the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Diagnosis and Treatment Guidelines 6 . Among ET agents, letrozole is a novel, highly selective aromatase inhibitor (AI). Due to its cost-effectiveness, the combination of abemaciclib and letrozole is a frequently chosen treatment strategy. Although the combination of abemaciclib and letrozole has demonstrated statistically and clinically significant improvements in progression-free survival (PFS) 7 , the occurrence of adverse drug reactions (ADRs) remains a critical concern. Abemaciclib is an orally administered CDK4/6i that, in estrogen receptor-positive (ER+) breast cancer cell lines, promotes the phosphorylation of retinoblastoma protein (Rb) through cyclin D1 and CDK4/6, thereby facilitating cell cycle progression and proliferation. Abemaciclib inhibits Rb phosphorylation, preventing the transition from the G1 to the S phase of the cell cycle, ultimately leading to cellular senescence and apoptosis 8 . Letrozole, on the other hand, inhibits the synthesis of aromatase 9 , thereby reducing estrogen levels in the body and decreasing estrogen-driven tumor growth. The combination of these two agents may lead to the amplification of certain adverse effects or the emergence of novel ones. Understanding the safety profile of this combination therapy is crucial for optimizing treatment outcomes and improving patients' quality of life. Preliminary studies have shown that elderly patients receiving abemaciclib in combination with ET experience a higher incidence of clinically significant diarrhea (Grade 2/3) compared to those receiving placebo plus ET. Additionally, elderly patients exhibit moderate increases in nausea, decreased appetite, and venous thromboembolic events, with slightly higher rates of dose adjustments and treatment discontinuation. Moreover, they are more likely to have potential confounding comorbidities, including hypertension, gastrointestinal disorders, and metabolic/nutritional disturbances 10 – 14 . Furthermore, known adverse effects of abemaciclib, such as thrombosis, pulmonary toxicity, and hematologic toxicity, may further complicate the clinical scenario 15 – 17 . The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, maintained by the U.S. Food and Drug Administration (FDA), is designed to collect and analyze reports of drug-related adverse events (AEs). This database contains various information on adverse reactions, drug interactions, and therapeutic outcomes reported by patients during the use of marketed drugs. In this study, real-world data from the FAERS database were utilized to investigate the safety profile of abemaciclib monotherapy and its combination with letrozole in the treatment of breast cancer. The goal is to develop effective management strategies and ultimately improve the therapeutic index for patients battling this challenging malignancy. Materials and Methods Data Collection and Processing The data for this study were sourced from the FDA Adverse Event Reporting System (FAERS) database. We extracted AE reports related to drug reactions from the first quarter of 2014 to the fourth quarter of 2024 and analyzed them using R (version 4.3.3). The FAERS database consists of seven sections: demographic and administrative information (DEMO), adverse drug reactions (REAC), patient outcome information (OUTC), drug information (DRUG), drug therapy start and end dates (THER), report source information (RPSR), and indications/diagnoses (INDI). To remove duplicate reports, we followed the FDA-recommended deduplication method by selecting the PRIMARYID, CASEID, and FDA_DT fields from the DEMO table. Reports were sorted by CASEID, FDA_DT, and PRIMARYID in that order, retaining the report with the latest FDA_DT for cases with duplicate CASEID. If multiple reports had the same CASEID and FDA_DT, the report with the highest PRIMARYID was retained. After deduplication, we focused on AE reports associated with either abemaciclib monotherapy or the combination of abemaciclib and letrozole. A fuzzy search was performed on the DRUGNAME field in the DRUG table using both brand and generic names of the drugs (Table 1 ). Additionally, the following search terms were used to identify breast cancer cases: Table 1 Search Terms for Abemaciclib and Letrozole Drug Search Term Abemaciclib 'Abemaciclib', 'Verzenio', 'Verzenios', 'Abemaciclib 150mg', 'Verzenios 150mg', 'Blinded Abemaciclib', 'Abemaciclib 200mg', 'Abemaciclib Code Not Broken', 'Ramiven', 'Abemaciclib 100mg', 'Abemaciclib 50mg', 'Abemaciclib Mesylate', 'Verzenios 50mg', 'Verzenios 100mg', 'Verzenios 200mg'" Letrozole 'Letrozole', 'Femara', 'Letrozole Ribociclib', 'Kisqali Femara Co Pack', 'Letrozole Unknown', 'Comparator Letrozole', 'Letrozole 1a Pharma', 'Letrozole Table 2 5 mg', 'Apo Letrozole', 'Letrozole 25 mg', 'Letrozole Accord', 'Letrozole Manufacturer Unknown', 'Letrozole Letrozole', 'Letrozole Sandoz', 'Letrozole Mylan', 'Letrozole Tablets Usp 25 Mg', 'Letrozole 25 Mg', 'Letrozole Teva', 'Letrozole Tablets Usp 25 Mg', 'Femara Letrozole', 'Letrozole Film Coated Tablet', 'Generic Letrozole', 'Letrozole Tables 25 mg', 'Letrozole 25 Mg Filmcoated Tablets', 'Letrozole Tablets Usp 25 Mg', 'Letrozole 25 mg Tab Teva', 'Letrozole 25 mg Teva Pharmaceuticals Usa Inc', 'Letrozole Sun', 'Letrozole Winthrop', 'Letrozole Mylan 25 Mg Comprim Pellicul', 'Letrozole Manufacturer Unknown Letrozole Letrozole', 'Letrozole Tablets 25 mg', 'Letrozole 25 Mg Tablet', 'Letrazole Femara 25 Mg Generic Femara', 'Letrozole Atllc', 'Letrozole 25 mg Tab', 'Letrozole Stada', 'Letrozole Tablet', 'Letrozole 25 Mg Film Coated Tablets', 'Letrozole 25 mg Tablets', 'Letrozole Accord Healthcare', 'Letrozole Tab', 'Accord Letrozole', 'Avomit Letrozole', 'Famos Letrozole', 'Letrozole 25 Mg Teva', 'Letrozole Table 2 5mg', 'Letrozole Tablets', 'Teva Letrozole', 'Letrozole 25 Mg Tab', 'Letrozole 25 mg Breckenridge', 'Letrozole Arrow Film Coated Tablet 25 mg', 'Letrozole Tablets Usp 25 mg Mfr Labler Sun Pharm', 'Teva Uk Letrozole', 'Accord Healthcare Letrozole', 'Letrozole 25 Mg', 'Letrozole 25', 'Letrozole 25 Mg Breckenridge', 'Letrozole Actavis', 'Letrozole Gonadotropins', 'Letrozole Temsirolimus Letrozole Temsirolimus Tablet', 'Rad001 And Letrozole', 'Blinded Letrozole', 'Femara 25 Mg Compresse Rivestite Con Film', 'Jamp Letrozole', 'Letrozole Arrow Generics Ltd', 'Letrozole 25 Mg Oral', 'Letrozole 25 Mg Sun Pharmaceuticals', 'Letrozole 25 mg Oral', 'Letrozole 25 mg Sun Pharmaceuticals', 'Letrozole Apotex', 'Letrozole Arrow', 'Letrozole Sun 25 Mg Filmcoated Tablets', 'Letrozole Temsirolimus Letrozole Temsirolimus', 'Mar Letrozole', 'Nexazole Letrozole', 'Trezor Letrozole' "Breast Cancer Metastatic", "Breast Cancer", "Breast Cancer Female", "Oestrogen Receptor Positive Breast Cancer", "Her-2 Positive Breast Cancer", "Breast Cancer Stage IV", "Breast Cancer Stage", "Breast Cancer Recurrent", "Breast Cancer Male", "Hormone Receptor Positive HER2 Negative Breast Cancer", "Hormone Receptor Positive Breast Cancer", "HER2 Negative Breast Cancer", "HER2 Positive Breast Cancer", "Breast Cancer Stage II", "Hormone Receptor Negative HER2 Positive Breast Cancer", "Breast Cancer Stage I". This approach enabled us to classify the drugs as primary suspect (PS), secondary suspect (SS), or concomitant (C) drugs, while also capturing potential drug interactions (I) to ensure data completeness. Through this process, we successfully filtered a total of 55,249,058 reports related to abemaciclib. After restricting the indications to breast cancer and selecting cases where abemaciclib was identified as the primary suspect drug, we obtained 6,649 reports related to abemaciclib monotherapy and 750 reports related to the combination of abemaciclib and letrozole (Fig. 1 ). All AE reports associated with abemaciclib and letrozole were categorized according to system organ class (SOC) and preferred term (PT) levels. Statistical Analysis This study employed disproportionality analysis based on the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM) to explore the relationship between abemaciclib, letrozole, and adverse events (AEs). PRR is useful for estimating relative risk; however, it is highly sensitive and prone to false-positive signals, especially when the number of reported cases is low 18 . In contrast, ROR helps mitigate bias in cases with fewer reported events 19 . BCPNN is particularly effective in integrating and cross-validating data from multiple sources, efficiently managing uncertainty and missing data to enhance predictive accuracy 20 . MGPS is especially effective in detecting signals from rare events 21 , 22 . By integrating these four methods—ROR, PRR, BCPNN, and MGPS—this study leveraged their respective advantages to broaden the scope of signal detection and validation from multiple perspectives, ensuring the identification of significantly associated signals. In this process, an AE was considered a positive signal if it met the threshold in at least one of the four algorithms. Conversely, when all four algorithms met the threshold, a strong association between the AE and the drug was indicated, effectively reducing the risk of potential false-positive signals. These methods were based on a 2 × 2 contingency table, as shown in Supplementary Table 1. The formulas and signal detection criteria for each method are detailed in Supplementary Table 2. Data processing and statistical analyses were performed using Microsoft Excel 2016 and R (version 4.3.3). Results Descriptive Analysis After excluding duplicate data, adverse event (AE) reports related to abemaciclib treatment in breast cancer patients were extracted from the FAERS database, covering records from the first quarter of 2014 to the fourth quarter of 2024. A total of 6,649 AEs were identified for abemaciclib monotherapy, where abemaciclib was the primary suspect drug and letrozole was not included in the concomitant medication. Additionally, 750 AEs were identified for the combination of abemaciclib and letrozole, where abemaciclib was the primary suspect drug and letrozole was included as a concomitant medication. Over 90% of these events occurred in female patients. Age stratification analysis showed that the incidence of AEs was similar in patients aged 18 to 65 years and 65 to 85 years. For those on abemaciclib monotherapy, AEs were more common in the 18 to 65 years age group, while for patients on the combination therapy, the incidence of AEs was similar between the 65 to 85 years and 18 to 65 years age groups. The top five countries reporting AEs were the United States, Japan, China, France, and Italy. Furthermore, the number of reported cases showed an increasing trend over the years. Notably, abemaciclib monotherapy and the combination with letrozole resulted in 1,672 and 286 cases of serious outcomes, respectively, including death, disability, and life-threatening consequences. Among these, 471 deaths were related to abemaciclib monotherapy, while 61 deaths were related to the combination therapy with letrozole (Table 2 ). Table 2 Demographic and Clinical Characteristics of AE Reports Related to Abemaciclib Monotherapy and Abemaciclib Plus Letrozole from the FAERS Database Parameters Abemaciclib Counts (%) Abemaciclib + Letrozole Counts (%) Sex F 6229 (93.7%) 718 (95.7%) M 74 (1.1%) 7 (0.9%) Missing 346 (5.2%) 25 (3.3%) Weight 100 kg 83 (1.2%) 18 (2.4%) 50ཞ100 kg 764 (11.5%) 233 (31.1%) Missing 5666 (85.2%) 459 (61.2%) Age 85 90 (1.4%) 8 (1.1%) Missing 3176 (47.8%) 161 (21.5%) Occupation reporter s Consumer 3758 (56.5%) 438 (58.4%) Health Professional 1015 (15.3%) 58 (7.7%) Physician 817 (12.3%) 141 (18.8%) Pharmacist 367 (5.5%) 52 (6.9%) Other healthcare professionals 386 (5.8%) 6 (0.8%) Missing 306 (4.6%) 55 (7.3%) Reporting countries (top 5) United States 5150 (77.5%) 341 (45.5%) Japan 387 (5.8%) 130 (17.3%) China 329 (4.9%) 31 (4.1%) France 107 (1.6%) 54 (7.2%) Italy 66 (1.0%) 25 (3.3%) Reporting time 2017 9 (0.14%) 0(0.00%) 2018 557(8.38%) 28(3.73%) 2019 777(11.69%) 59(7.87%) 2020 738(11.10%) 99(13.20%) 2021 745(11.20%) 117(15.60%) 2022 1090(16.39%) 137(18.27%) 2023 1403(21.10%) 155(20.67%) 2024 1330(20.00%) 155(20.67%) Patient outcomes Congenital anomaly ( CA) 0(0.00%) 1 (0.1%) Death (DE) 471 (7.1%) 61 (8.1%) Disability (DS) 24 (0.4%) 2 (0.3%) Hospitalization (HO) 1262 (19.0%) 229 (30.5%) Life-threatening (LT) 62 (0.9%) 22 (2.9%) Required intervention (RI) 8 (0.1%) 0(0.00%) Other serious outcomes (OT) 1115 (16.8%) 201 (26.8%) Unknown 3707 (55.8%) 234 (31.2%) Signal Detection We performed statistical analysis using four algorithms: ROR, PRR, BCPNN, and MGPS. For patients receiving only abemaciclib as the primary suspect drug, with no concomitant use of letrozole, each algorithm identified positive signals for 126, 105, 359, and 120 preferred terms (PTs), with 42 PTs being positive in all four algorithms. In patients receiving abemaciclib as the primary suspect drug with concomitant use of letrozole, the algorithms identified positive signals for 55, 49, 277, and 146 PTs, with 28 PTs being positive in all four algorithms (Table 3 ). Table 3 Positive Signals for Drug-Related AEs Identified Using Four Algorithms Parameters ROR PRR BCPNN MGPS ALL Abemaciclib 126 105 359 120 42 Abemaciclib + Letrozole 55 49 277 146 28 Additionally, we analyzed the grouped onset times for each PT, as shown in Fig. 2 . We observed that the majority of PTs for both abemaciclib monotherapy and combination therapy occurred in the first month of treatment, with the incidence of PTs within the first 60 days being 59.17% and 59.31%, respectively (Fig. 2 ). The median time to the occurrence of PTs was 30 days (interquartile range: 11–115 days) for patients on abemaciclib monotherapy, while it was 35 days (interquartile range: 14–109 days) for patients receiving combination therapy with letrozole. Signals of System Organ Classes The positive signals of PTs were classified according to the SOC in MedDRA version 26.1. The results showed that 42 PTs associated with abemaciclib monotherapy and 28 PTs associated with the combination of abemaciclib and letrozole involved 15 and 11 different organ systems, respectively. Tables 4 and 5 list the PTs with positive signals across all four algorithms in the FAERS database for both abemaciclib monotherapy and combination therapy with letrozole, along with their corresponding SOCs. The most commonly reported PTs for abemaciclib monotherapy were diarrhea, dehydration, and bone marrow suppression. Interestingly, diarrhea remained the most frequently reported PT in the combination therapy with abemaciclib and letrozole. Notably, interstitial lung disease and acute kidney injury ranked among the top three adverse events in the combination therapy, with higher incidences of liver dysfunction, drug-induced liver injury, and hepatocellular necrosis observed. Hepatocellular necrosis was not reported in the abemaciclib monotherapy group. Table 4 Signal Strength of PTs and Corresponding SOCs for Abemaciclib Monotherapy in the FAERS Database for Breast Cancer Treatment PT SOC Case reports ROR(95%Cl) PRR χ2 IC(IC025) EBGM(EBGM05) Diarrhoea Gastrointestinal disorders 2080 6.97 ( 6.64–7.32 ) 6.21(6.17,6.26) 8390.51 2.51 ( 2.44 ) 5.7 ( 5.48 ) Drug ineffective General disorders and administration site conditions 320 3.8 ( 3.39–4.26 ) 3.74(3.63,3.63) 606.94 1.84 ( 1.67 ) 3.57 ( 3.25 ) Dehydration Metabolism and nutrition disorders 221 3.71 ( 3.23–4.25 ) 3.67(3.53,3.8) 404.79 1.81 ( 1.61 ) 3.51 ( 3.13 ) Myelosuppression Blood and lymphatic system disorders 179 3.31 ( 2.84–3.85 ) 3.28(3.13,3.43) 269.36 1.66 ( 1.44 ) 3.16 ( 2.78 ) Abdominal pain upper Gastrointestinal disorders 177 3.76 ( 3.23–4.39 ) 3.74(3.58,3.89) 333.69 1.83 ( 1.61 ) 3.57 ( 3.14 ) Therapy interrupted Surgical and medical procedures 148 15.21 ( 12.68–18.24 ) 15.08(14.9,15.26) 1539.41 3.6 ( 3.34 ) 12.13 ( 10.42 ) Therapy cessation Surgical and medical procedures 145 11.89 ( 9.94–14.23 ) 11.8(11.62,11.98) 1188.12 3.31 ( 3.05 ) 9.94 ( 8.56 ) Product dose omission issue Injury, poisoning and procedural complications 127 3.67 ( 3.07–4.4 ) 3.65(3.47,3.83) 230.28 1.8 ( 1.54 ) 3.49 ( 3 ) Blood creatinine increased Investigations 110 3.95 ( 3.25–4.79 ) 3.93(3.73,4.12) 224.76 1.9 ( 1.62 ) 3.74 ( 3.18 ) Interstitial lung disease Respiratory, thoracic and mediastinal disorders 108 2.52 ( 2.08–3.06 ) 2.51(2.32,2.7) 94.19 1.29 ( 1.01 ) 2.45 ( 2.08 ) Abdominal discomfort Gastrointestinal disorders 98 2.59 ( 2.11–3.17 ) 2.58(2.38,2.78) 90.69 1.33 ( 1.03 ) 2.51 ( 2.12 ) Covid-19 Infections and infestations 89 2.6 ( 2.1–3.22 ) 2.59(2.38,2.8) 83.29 1.33 ( 1.02 ) 2.52 ( 2.11 ) Hospitalisation Surgical and medical procedures 76 4.9 ( 3.88–6.2 ) 4.89(4.65,5.12) 216.52 2.19 ( 1.85 ) 4.58 ( 3.76 ) Hepatic function abnormal Hepatobiliary disorders 72 3.17 ( 2.5–4.03 ) 3.16(2.93,3.4) 101.11 1.61 ( 1.26 ) 3.05 ( 2.5 ) Acute kidney injury Renal and urinary disorders 70 2.86 ( 2.25–3.64 ) 2.85(2.61,3.09) 80.28 1.47 ( 1.12 ) 2.76 ( 2.26 ) Thrombosis Vascular disorders 69 2.91 ( 2.29–3.71 ) 2.9(2.66,3.15) 82.11 1.49 ( 1.14 ) 2.81 ( 2.3 ) Renal impairment Renal and urinary disorders 58 2.8 ( 2.15–3.64 ) 2.79(2.53,3.05) 63.58 1.44 ( 1.05 ) 2.71 ( 2.17 ) Taste disorder Nervous system disorders 52 4.54 ( 3.42–6.02 ) 4.53(4.25,4.81) 132.53 2.09 ( 1.68 ) 4.27 ( 3.37 ) Therapy change Surgical and medical procedures 46 10.99 ( 8.01–15.07 ) 10.96(10.65,11.28) 349.33 3.23 ( 2.77 ) 9.35 ( 7.18 ) Drug-induced liver injury Hepatobiliary disorders 36 3.66 ( 2.61–5.13 ) 3.65(3.32,3.99) 65.28 1.81 ( 1.32 ) 3.49 ( 2.64 ) Hospice care Surgical and medical procedures 28 4.71 ( 3.2–6.93 ) 4.7(4.32,5.09) 75.47 2.14 ( 1.59 ) 4.42 ( 3.2 ) Therapy non-responder General disorders and administration site conditions 26 5.77 ( 3.85–8.64 ) 5.76(5.36,6.16) 92.95 2.41 ( 1.83 ) 5.32 ( 3.8 ) Surgery Surgical and medical procedures 26 3.6 ( 2.42–5.35 ) 3.59(3.2,3.99) 45.81 1.78 ( 1.21 ) 3.44 ( 2.47 ) Embolism venous Vascular disorders 22 26.69 ( 16.09–44.3 ) 26.66(26.15,27.17) 370.12 4.21 ( 3.51 ) 18.48 ( 12.09 ) Glomerular filtration rate decreased Investigations 18 3.77 ( 2.34–6.08 ) 3.77(3.29,4.25) 34.36 1.85 ( 1.16 ) 3.6 ( 2.41 ) Blood glucose decreased Investigations 14 3.84 ( 2.23–6.59 ) 3.83(3.29,4.37) 27.48 1.87 ( 1.1 ) 3.65 ( 2.32 ) Renal injury Renal and urinary disorders 10 11.17 ( 5.67–22.01 ) 11.17(10.49,11.85) 77.4 3.25 ( 2.3 ) 9.5 ( 5.39 ) Brain fog Nervous system disorders 10 3.96 ( 2.08–7.51 ) 3.96(3.31,4.6) 20.65 1.91 ( 1.01 ) 3.76 ( 2.2 ) Transfusion Surgical and medical procedures 9 8.69 ( 4.31–17.53 ) 8.69(7.99,9.39) 53.13 2.94 ( 1.96 ) 7.67 ( 4.26 ) Lung opacity Respiratory, thoracic and mediastinal disorders 9 4.75 ( 2.41–9.37 ) 4.75(4.07,5.43) 24.57 2.16 ( 1.21 ) 4.46 ( 2.52 ) Blood creatine increased Investigations 9 4.98 ( 2.52–9.84 ) 4.98(4.3,5.66) 26.3 2.22 ( 1.27 ) 4.66 ( 2.63 ) Sleep disorder due to general medical condition, insomnia type Psychiatric disorders 9 19.73 ( 9.24–42.1 ) 19.71(18.96,20.47) 118.78 3.9 ( 2.87 ) 14.9 ( 7.9 ) Covid-19 pneumonia Infections and infestations 8 5.18 ( 2.51–10.68 ) 5.18(4.45,5.9) 24.72 2.27 ( 1.27 ) 4.83 ( 2.64 ) Therapeutic product effect decreased General disorders and administration site conditions 7 6.88 ( 3.14–15.07 ) 6.87(6.09,7.66) 31.35 2.64 ( 1.56 ) 6.24 ( 3.24 ) Emergency care Surgical and medical procedures 6 9.77 ( 4.11–23.22 ) 9.76(8.9,10.63) 40.29 3.08 ( 1.91 ) 8.48 ( 4.11 ) Loss of therapeutic response General disorders and administration site conditions 6 48.84 ( 16.41–145.33 ) 48.82(47.73,49.91) 151.33 4.74 ( 3.41 ) 26.75 ( 10.74 ) Sleep disorder due to a general medical condition Psychiatric disorders 5 20.35 ( 7.33–56.5 ) 20.34(19.32,21.36) 67.75 3.93 ( 2.59 ) 15.25 ( 6.49 ) Creatinine renal clearance increased Investigations 4 8.76 ( 3.06–25.12 ) 8.76(7.71,9.81) 23.84 2.95 ( 1.56 ) 7.73 ( 3.2 ) Cerebral venous sinus thrombosis Nervous system disorders 3 10.68 ( 3.11–36.66 ) 10.68(9.45,11.91) 22.16 3.19 ( 1.61 ) 9.15 ( 3.26 ) Pneumomediastinum Respiratory, thoracic and mediastinal disorders 3 7.43 ( 2.23–24.75 ) 7.43(6.23,8.63) 14.76 2.74 ( 1.2 ) 6.69 ( 2.44 ) Spinal cord disorder Nervous system disorders 3 8.14 ( 2.43–27.29 ) 8.14(6.93,9.35) 16.43 2.86 ( 1.3 ) 7.24 ( 2.63 ) Superficial vein thrombosis Vascular disorders 3 9.49 ( 2.8–32.23 ) 9.49(8.27,10.71) 19.54 3.05 ( 1.48 ) 8.28 ( 2.98 ) Table 5 Signal Strength of PTs and Corresponding SOCs for Abemaciclib in Combination with Letrozole in the FAERS Database PT SOC Case reports ROR(95%Cl) PRR (95% CI) χ2 IC(IC025) EBGM(EBGM05) Diarrhoea Gastrointestinal disorders 232 4.37 ( 3.82–5 ) 4.07(3.94,4.19) 542.66 2.01 ( 1.81 ) 4.03 ( 3.6 ) Interstitial lung disease Respiratory, thoracic and mediastinal disorders 46 6.81 ( 5.08–9.14 ) 6.71(6.42,7) 220.09 2.72 ( 2.3 ) 6.61 ( 5.17 ) Acute kidney injury Renal and urinary disorders 31 7.99 ( 5.59–11.43 ) 7.91(7.55,8.26) 183.4 2.96 ( 2.44 ) 7.76 ( 5.75 ) Abdominal pain Gastrointestinal disorders 28 2.8 ( 1.92–4.06 ) 2.78(2.41,3.15) 31.71 1.47 ( 0.93 ) 2.76 ( 2.02 ) Blood creatinine increased Investigations 22 4.82 ( 3.16–7.36 ) 4.79(4.37,5.21) 65.22 2.24 ( 1.64 ) 4.74 ( 3.33 ) Hepatic function abnormal Hepatobiliary disorders 21 5.75 ( 3.73–8.87 ) 5.71(5.29,6.14) 80.55 2.5 ( 1.87 ) 5.64 ( 3.93 ) Covid-19 Infections and infestations 19 3.45 ( 2.19–5.44 ) 3.44(2.99,3.89) 32.58 1.77 ( 1.12 ) 3.41 ( 2.34 ) Drug-induced liver injury Hepatobiliary disorders 16 10.15 ( 6.17–16.71 ) 10.1(9.6,10.59) 127.67 3.3 ( 2.59 ) 9.85 ( 6.49 ) Therapy interrupted Surgical and medical procedures 16 8.53 ( 5.19–14.03 ) 8.49(7.99,8.98) 103.38 3.06 ( 2.35 ) 8.32 ( 5.49 ) Gamma-glutamyltransferase increased Investigations 13 5.01 ( 2.89–8.67 ) 4.99(4.44,5.54) 40.96 2.3 ( 1.52 ) 4.94 ( 3.12 ) Therapy cessation Surgical and medical procedures 10 4.4 ( 2.36–8.22 ) 4.39(3.77,5.01) 25.89 2.12 ( 1.24 ) 4.35 ( 2.58 ) Hepatic cytolysis Hepatobiliary disorders 10 8.46 ( 4.51–15.85 ) 8.43(7.8,9.05) 64.02 3.05 ( 2.16 ) 8.26 ( 4.88 ) Hepatotoxicity Hepatobiliary disorders 9 3.55 ( 1.84–6.86 ) 3.54(2.89,4.2) 16.29 1.82 ( 0.9 ) 3.52 ( 2.03 ) Pneumothorax Respiratory, thoracic and mediastinal disorders 7 6.11 ( 2.89–12.91 ) 6.1(5.35,6.84) 29.34 2.59 ( 1.56 ) 6.01 ( 3.22 ) Liver function test increased Investigations 7 3.96 ( 1.88–8.34 ) 3.95(3.2,4.69) 15.25 1.97 ( 0.94 ) 3.92 ( 2.1 ) Hospice care Surgical and medical procedures 5 5.07 ( 2.1–12.27 ) 5.06(4.18,5.94) 16.09 2.32 ( 1.14 ) 5.01 ( 2.39 ) Lung opacity Respiratory, thoracic and mediastinal disorders 5 16.39 ( 6.69–40.19 ) 16.36(15.47,17.26) 69.06 3.97 ( 2.76 ) 15.71 ( 7.42 ) Hepatitis acute Hepatobiliary disorders 4 12.99 ( 4.79–35.25 ) 12.98(11.98,13.97) 42.71 3.65 ( 2.33 ) 12.57 ( 5.45 ) Pulmonary toxicity Respiratory, thoracic and mediastinal disorders 4 5.92 ( 2.2–15.91 ) 5.91(4.93,6.9) 16.07 2.54 ( 1.24 ) 5.83 ( 2.55 ) Pancreatitis acute Gastrointestinal disorders 4 5.8 ( 2.16–15.59 ) 5.8(4.81,6.78) 15.63 2.52 ( 1.21 ) 5.72 ( 2.5 ) Lymphangiosis carcinomatosa Neoplasms benign, malignant and unspecified (incl cysts and polyps) 4 7.81 ( 2.9–21.04 ) 7.8(6.81,8.79) 23.22 2.94 ( 1.63 ) 7.66 ( 3.34 ) Renal function test abnormal Investigations 4 15.79 ( 5.8–42.99 ) 15.77(14.77,16.77) 53.04 3.92 ( 2.6 ) 15.16 ( 6.56 ) Metabolic acidosis Metabolism and nutrition disorders 3 6.75 ( 2.15–21.17 ) 6.75(5.61,7.89) 14.42 2.73 ( 1.27 ) 6.64 ( 2.55 ) Fibrosis General disorders and administration site conditions 3 14.11 ( 4.45–44.75 ) 14.1(12.95,15.25) 35.16 3.77 ( 2.29 ) 13.61 ( 5.18 ) Renal tubular necrosis Renal and urinary disorders 3 10.01 ( 3.18–31.53 ) 10(8.85,11.14) 23.65 3.29 ( 1.82 ) 9.76 ( 3.74 ) Appendicitis Infections and infestations 3 9.83 ( 3.12–30.96 ) 9.82(8.67,10.96) 23.15 3.26 ( 1.79 ) 9.59 ( 3.67 ) Subcutaneous emphysema Skin and subcutaneous tissue disorders 3 91.75 ( 25.88–325.32 ) 91.64(90.38,92.91) 215.17 6.2 ( 4.59 ) 73.52 ( 25.49 ) Coronavirus infection Infections and infestations 3 10.59 ( 3.36–33.38 ) 10.57(9.43,11.72) 25.28 3.37 ( 1.9 ) 10.31 ( 3.94 ) We selected the top three risk signals for each system based on the ROR for abemaciclib monotherapy and its combination with letrozole, and presented them in the forest plots (Fig. 3 , Fig. 4 ). As shown in the figure, sleep disorders and thrombotic diseases were the higher-risk signals for abemaciclib monotherapy, while subcutaneous emphysema, abnormal renal function tests, and acute hepatitis had higher-risk signals in the combination therapy of abemaciclib and letrozole. Discussion Abemaciclib is a CDK4/6 inhibitor that suppresses the activity of the CDK4/6-Cyclin D1 complex, preventing tumor cells from entering the cell cycle, thereby inhibiting tumor cell proliferation or inducing apoptosis 23 . Letrozole is an aromatase inhibitor (AI) that blocks the conversion of androgens to estrogens, thereby reducing estrogen levels in the body, and is used for endocrine therapy in breast cancer patients. Existing studies indicate that the combination of abemaciclib with endocrine therapy significantly benefits patients in early high-risk breast cancer as adjuvant intensification therapy, as well as in the treatment of locally advanced or metastatic breast cancer. However, this combination therapy is also associated with a higher incidence of more severe adverse reactions. The Monarch E study is an open-label phase III trial 24 , 25 , which suggests that in patients with high recurrence risk HR+, HER2- lymph node-positive early breast cancer, the combination of abemaciclib and endocrine therapy showed superior invasive disease-free survival (IDFS) compared to endocrine therapy alone (P = 0.01; hazard ratio, 0.75; 95% CI, 0.60–0.93). The 2-year IDFS rates were 92.2% and 88.7%, respectively. However, the addition of abemaciclib to endocrine therapy resulted in a higher incidence of ≥ 3 grade adverse events (49.7% vs 16.3% for endocrine therapy alone), primarily laboratory findings such as neutropenia. 18.5% of patients discontinued abemaciclib and/or endocrine therapy due to adverse events, mainly due to grade 1/2 adverse events (66.8%). Grade 2/3 events peaked during the first month (20.5%) but were mostly transient (≤ 7 days) and did not recur. Venous thromboembolic events (VTE) occurred in 2.5% of the abemaciclib plus endocrine therapy group compared to 0.6% in the endocrine therapy alone group. The MONARCH 3 study is a double-blind, randomized phase III trial 7 , 26 , which involved 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received abemaciclib vs placebo combined with anastrozole or letrozole. The results showed that the median progression-free survival (PFS) in the abemaciclib group was significantly longer than that in the placebo group (28.18 months vs 14.76 months; hazard ratio [95% CI], 0.540 [0.418–0.698]; p = 0.000002), and the median duration of response was longer in the abemaciclib group (27.39 months vs 17.46 months). The most common grade 3 or 4 adverse events in the abemaciclib group compared to the placebo group were neutropenia (21.1% vs 1.2%), diarrhea (9.5% vs 1.2%), and leukopenia (7.6% vs 0.6%). Thus, although the combination of abemaciclib and endocrine therapy demonstrates superior clinical efficacy compared to endocrine therapy alone, its adverse event (AE) incidence is relatively higher, particularly the increased occurrence of grade 2–3 AEs, which has raised concerns regarding its safety. Therefore, this study focuses on the analysis of AEs associated with the combination of abemaciclib and endocrine therapy, aiming to further explore the differences in the AE profile of combination therapy and provide more comprehensive safety evidence for rational clinical use. In the Monarch E and MONARCH 3 studies, common AEs associated with combination therapy included diarrhea, neutropenia, leukopenia, and fatigue. Compared to monotherapy, the incidence of these AEs was higher. In our study, the most common AEs for the combination therapy were diarrhea, interstitial lung disease, acute kidney injury, and liver dysfunction, which were not widely reported or emphasized in Monarch E and MONARCH 3. Many previous studies have reported associations between abemaciclib and certain adverse events (AEs), such as drug-induced liver injury, skin toxicity, drug-related osteonecrosis of the jaw, venous thromboembolism, and infections 27 – 30 . However, there has been a lack of comprehensive summaries and studies focusing on the safety of abemaciclib in combination with letrozole. In this study, we provide an in-depth understanding of the safety of combination therapy, offering important data on the safety of abemaciclib and letrozole in the treatment of breast cancer. This information helps clinicians better assess treatment risks in real-world practice and develop personalized management plans. Using the largest available real-world data from the FAERS database, we explored the AEs associated with the combination of abemaciclib and letrozole in the treatment of breast cancer. We identified and analyzed important new adverse drug reactions (ADRs) to inform product labeling and support evidence-based clinical decision-making. Our study, based on the FAERS database, includes data from multiple countries worldwide (such as the United States, China, Japan, France, Italy, etc.), highlighting the global diversity of drug-related adverse events (AEs). Understanding the frequency of AEs in different regions and their management strategies may provide valuable data to support international treatment standards and clinical guidelines. The results of the study show that the incidence of AEs for abemaciclib monotherapy and its combination with letrozole was higher in female patients (93.7% and 95.7%, respectively) compared to male patients (1.1% and 0.9%, respectively). This could be attributed to the larger number of female breast cancer patients. The age distribution indicates that AEs were most common in patients aged 18-64.9 years, which may reflect the higher incidence rate of breast cancer in this age group and the larger number of users of these two drugs. Notably, these AEs led to severe outcomes in patients. Among those receiving abemaciclib monotherapy and its combination with letrozole, 7.1% and 8.1% of patients experienced fatal outcomes, 18.1% and 30% experienced disabling, life-threatening AEs or other severe outcomes, and 19.0% and 30.5% required hospitalization. This suggests that as the clinical use of CDK4/6 inhibitors in combination with endocrine therapy expands, clinicians should pay particular attention to potential AEs in patients to prevent life-threatening complications. Our study shows that among the most common PTs observed in abemaciclib monotherapy, thrombus formation and venous thromboembolism were noted. A retrospective cohort study of patients with hormone receptor-positive metastatic breast cancer (mBC) treated with the three FDA-approved CDK inhibitors (palbociclib, ribociclib, and abemaciclib) found that the incidence of venous thromboembolism (VTE) in patients treated with CDK inhibitors for mBC was 2 to 5 times higher than reported in the registration trials, and it may be associated with poorer outcomes 31 . Combined with the findings of this study, the high report rate of thrombus formation in abemaciclib monotherapy suggests that clinicians should be highly attentive to the blood hypercoagulability-related toxicities of CDK inhibitors in the real-world setting. This risk-benefit balance is crucial for treatment decisions, particularly in high-risk populations such as the elderly, obese individuals, or those with a history of VTE. Based on these findings, we recommend baseline VTE risk assessment (e.g., Caprini score) for all patients with mBC who are scheduled to receive CDK inhibitor therapy, with a focus on patient subgroups with high VTE risk, such as those who are elderly, have a BMI ≥ 30, have a history of VTE, or carry prothrombotic gene mutations (e.g., Factor V Leiden). In analyzing the adverse events (AEs) associated with the combination of abemaciclib and letrozole, we found that acute kidney injury (AKI) ranked among the top three AEs in the combination treatment. Additionally, we identified several hepatobiliary-related PTs, such as “drug-induced liver injury,” “liver function abnormal,” and severe AEs like “hepatocellular necrosis,” as well as “interstitial lung disease,” which ranked in the top three for incidence. Case reports have suggested that abemaciclib may induce reversible grade 4 nephrotoxicity, potentially related to the use of metformin 32 . Two interesting phenomena were also observed: One case involved abemaciclib-induced pseudorenal AKI. The report indicated that pseudorenal AKI could be distinguished from true AKI by measuring the estimated glomerular filtration rate (eGFR) based on serum cystatin C, serum creatinine-based eGFR, and using other clearance estimation methods such as iohexol clearance. After differentiating pseudorenal AKI, the patient continued abemaciclib treatment, and kidney function remained stable, with consistent eGFR values based on cystatin C and routine metabolic indicators even after more than a year of therapy 33 . Another case report 34 described a 79-year-old female patient with stage 4 A2 chronic kidney disease secondary to type 2 diabetes and long-term hypertension. After being diagnosed with invasive breast cancer, she started treatment with letrozole, followed by palbociclib, and developed pseudorenal AKI. The mechanism of pseudorenal AKI could involve the interference of targeted therapies with renal tubular secretion of creatinine. Our study, for the first time, highlights through FAERS data mining that the combination of abemaciclib and letrozole significantly increases the risk of acute kidney injury (AKI). However, case reports suggest the need to differentiate between true AKI and pseudorenal AKI. Relying solely on traditional creatinine measurements may lead to misdiagnosis of true AKI and premature discontinuation of effective cancer treatment or neglect of true kidney damage, which could worsen renal function. Therefore, we recommend including cystatin C as part of routine kidney function monitoring for patients on CDK4/6 inhibitors and being vigilant in differentiating true AKI from pseudorenal AKI to avoid unnecessary treatment interruptions. Our study showed a higher incidence of hepatobiliary-related PTs in patients receiving the combination of abemaciclib and letrozole. Previous research has revealed differences in hepatobiliary toxicity between various CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appears relatively safe 35 . A case report described a patient who experienced grade 4 liver injury during abemaciclib treatment, but after switching to palbociclib, liver dysfunction did not recur. This case suggests that switching to palbociclib may be a viable option for continuing treatment after severe liver injury from abemaciclib 36 . Taniguchi A et al. found through multivariable analysis that the concurrent use of aromatase inhibitors (AI) was an independent risk factor for abemaciclib-induced liver injury (odds ratio [OR] = 10.23, 95% confidence interval [CI] = 2.02–51.91, p = 0.005). However, the mechanism by which AI combined with abemaciclib leads to liver injury requires further investigation 37 , which is consistent with our study. Our study also reveals for the first time that the combination of abemaciclib and letrozole can lead to hepatocellular necrosis. These findings suggest that if patients have impaired liver function, special caution should be exercised when using this combination therapy, or palbociclib could be considered as an alternative to abemaciclib. Interstitial lung disease (ILD) was found to have a high incidence in both abemaciclib monotherapy and the combination with letrozole. Chen Y et al. 38 reported 82 cases of ILD (46 severe, 13 fatal) among 4,700 patients treated with abemaciclib. Most patients (91%) had at least one symptom at the time of diagnosis, typically including dyspnea (59%), cough (44%), and/or fever (37%). Fatal cases were characterized by advanced age (≥ 70 years), pre-existing interstitial changes, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2. Takeda T et al. 39 analyzed the VigiBase and FAERS databases to compare the AE profiles of palbociclib and abemaciclib. They found that patients on palbociclib often reported cytopenia, while those on abemaciclib frequently reported interstitial lung disease and diarrhea. Lin W et al. 40 also found that pneumonia was a common signal for abemaciclib. Zhang Y et al. 41 , in their investigation of AE profiles for aromatase inhibitors (AIs) using FAERS, found that letrozole was associated with severe AEs such as ILD (n = 159, ROR = 2.91). These findings are consistent with our study, and for the first time, we report a high incidence of ILD in patients receiving the combination of abemaciclib and letrozole. The two drugs may exhibit a synergistic risk, potentially exceeding the threshold for lung tissue damage, particularly in elderly patients, those with baseline lung dysfunction, or those with an ECOG PS ≥ 2, who may be at a fatal risk. Undoubtedly, this study has certain limitations. First, although the disproportionality analysis in the FAERS database provides statistically significant signal strength, adverse event reports can only suggest a potential association between the drug and the event, but cannot directly prove causality. Second, FAERS data is based on spontaneous reporting, which leads to a higher likelihood of severe or newly emerging events being reported, while mild or common events may be underreported. This introduces significant underreporting and selective reporting issues, which may not accurately reflect the real-world incidence of adverse events. Moreover, there may be duplicate reports, and critical information such as patient age, gender, or dosage may be missing or incomplete, affecting the accuracy of the analysis and potentially introducing bias into the results. In this study, we analyzed the adverse events associated with abemaciclib monotherapy and its combination with letrozole in breast cancer, but we cannot exclude the influence of concomitant drugs, comorbidities, or other patient-specific factors. Notably, our results show that the number of adverse events in the abemaciclib and letrozole combination group was relatively low. This finding is independent of the period during which the adverse event report data was collected, and therefore, may not accurately reflect the drug's safety in the real world and may be affected by reporting bias. This is a limitation of our study. Therefore, further prospective studies and clinical trials are needed to confirm the causal relationship between abemaciclib, its combination with letrozole, and these adverse events. Despite these limitations, the FAERS database remains crucial in identifying drug-related adverse events in oncology, helping to identify risk patterns and duration, and supporting clinical treatment decisions and drug label updates. Conclusion We conducted a pharmacovigilance analysis using the FAERS database to systematically identify patient characteristics and adverse event signals associated with abemaciclib monotherapy and its combination with letrozole in breast cancer. Diarrhea, dehydration, and bone marrow suppression were the most common adverse events (AEs) observed with abemaciclib monotherapy, while thromboembolism had a higher incidence. When the two drugs were used in combination, the incidence of AEs such as diarrhea, interstitial lung disease (ILD), acute kidney injury (AKI), and liver dysfunction was higher, with the potential occurrence of hepatic cellular necrosis. These AEs require close monitoring. Moreover, we recommend careful differentiation between true AKI and pseudo-AKI when AKI occurs during combination therapy to avoid unnecessary treatment interruption. We suggest enhanced monitoring and risk assessment of these AEs, especially in high-risk populations, to better evaluate the risk-benefit profile of combining abemaciclib with letrozole. Declarations Author Contribution LH: Data curation, Formal Analysis, Writing–original draft, Writing—review and editing. YR: Data curation, Formal Analysis, Methodology, Software, Supervision, Visualization, Writing—review and editing. CZ: Data curation, Supervision, Validation, Writing—review and editing. PG: Data curation, Supervision, Validation, Writing—review and editing. HL: Data curation, Formal Analysis, Supervision, Resources, Writing–review and editing. Data Availability Publicly available datasets were analyzed in this study. 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Area","correspondingAuthor":false,"prefix":"","firstName":"Yuye","middleName":"","lastName":"Ran","suffix":""},{"id":442030847,"identity":"f37859f9-748d-471d-b4e1-d398ccde6306","order_by":2,"name":"Chunqiao Zhou","email":"","orcid":"","institution":"People’s Hospital of Chongqing Liangjiang New Area","correspondingAuthor":false,"prefix":"","firstName":"Chunqiao","middleName":"","lastName":"Zhou","suffix":""},{"id":442030848,"identity":"aeaaf9db-50d4-48d7-8461-bedaa694fa58","order_by":3,"name":"Peng Gu","email":"","orcid":"","institution":"Second Affiliated Hospital of Army Medical University","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Gu","suffix":""},{"id":442030850,"identity":"39ec081a-9cbb-41d4-9e3c-9ca5b6e62f3b","order_by":4,"name":"Hailin Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACPmYGNgYGAwseIJvxQUKFDWEtbBAtEiAtzAYPzqQRoQWMGCTAbMmHbYeI0MLOY/bgR4GEjDn74WcVCWwHGPjbuxMIOIzH3LAH6DDLnjSzGwk8dxgkzpzdQEiLmQQPUIvBgQSgFolnQH/lEtYi+Qek5fzzbwUJBoeJ0yINtuVGjhlDQgJRWtjKpGXAWt4USyQcSOMh6Bd+/sPbJN/8sbE3OJ++8ePPfzZy/O29+LVgAB7SlI+CUTAKRsEowAoAJus8ZokJJRgAAAAASUVORK5CYII=","orcid":"","institution":"People’s Hospital of Chongqing Liangjiang New Area","correspondingAuthor":true,"prefix":"","firstName":"Hailin","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-03-13 07:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6217610/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6217610/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80710477,"identity":"085109b4-1c6f-4d32-8927-09710fa4f4ac","added_by":"auto","created_at":"2025-04-16 09:00:23","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":241025,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of This Study\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6217610/v1/a09b00b30c06ec3604cc1989.jpeg"},{"id":80708355,"identity":"2d5ad037-3f0f-459f-b245-2f0dabd9cb65","added_by":"auto","created_at":"2025-04-16 08:52:23","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":283213,"visible":true,"origin":"","legend":"\u003cp\u003eTiming of drug-related AEs.\u003cbr\u003e\n(A) Timing of AEs associated with abemaciclib alone.\u003cbr\u003e\n(B) Timing of AEs associated with the combination of abemaciclib and letrozole.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6217610/v1/3d195f6507a0b359af32a9d9.jpeg"},{"id":80708358,"identity":"bb17c3c6-4ebe-4e68-a0c3-e02fedb62cb0","added_by":"auto","created_at":"2025-04-16 08:52:23","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":527356,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot displaying the top three risk signals for each system associated with abemaciclib monotherapy (based on the ROR algorithm).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6217610/v1/c272ca3093d0aaae538a21da.jpeg"},{"id":80711543,"identity":"dbe142d8-24a0-4478-8466-d0992fddd1d8","added_by":"auto","created_at":"2025-04-16 09:08:23","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":411604,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot displaying the top three risk signals for each system associated with the combination therapy of abemaciclib and letrozole (based on the ROR algorithm).\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6217610/v1/67cea1371bb70fb6eb76cdff.jpeg"},{"id":108804266,"identity":"8fa404b0-c8d6-4b65-a963-8e9e12aa53cf","added_by":"auto","created_at":"2026-05-08 15:18:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2199198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6217610/v1/71f38472-2a25-4ab4-8673-ad74286f049c.pdf"},{"id":80710479,"identity":"bd96648d-5be1-48ac-b459-1cc9ef588feb","added_by":"auto","created_at":"2025-04-16 09:00:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19908,"visible":true,"origin":"","legend":"","description":"","filename":"SM.docx","url":"https://assets-eu.researchsquare.com/files/rs-6217610/v1/76d00376d670127b6a2518ce.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A real-world drug safety surveillance study from the FAERS database of breast cancer patients receiving abemaciclib alone and plus letrozole","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer remains a significant global health challenge. Among women, it is the most frequently diagnosed cancer and the leading cause of cancer-related mortality\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Since the mid-2000s, the incidence of breast cancer has been increasing by approximately 1% annually, primarily due to a rise in cases of localized-stage and hormone receptor-positive (HR+) breast cancer\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The development and approval of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for the treatment of HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;metastatic breast cancer represent a major milestone in breast cancer therapy\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. CDK4/6i Currently, CDK4/6i in combination with endocrine therapy (ET) plays a crucial role in the adjuvant intensification treatment of high-risk early-stage HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;breast cancer, as well as in the management of locally advanced or metastatic disease. The approved CDK4/6i agents include abemaciclib, palbociclib, and ribociclib. Studies have demonstrated that abemaciclib is the first CDK4/6i to show a significant improvement in invasive disease-free survival (IDFS) when combined with ET in HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;lymph node-positive breast cancer patients at high risk of early recurrence\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. It is also the only CDK4/6i recommended for adjuvant therapy in HR\u0026thinsp;+\u0026thinsp;breast cancer patients by the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Diagnosis and Treatment Guidelines\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Among ET agents, letrozole is a novel, highly selective aromatase inhibitor (AI). Due to its cost-effectiveness, the combination of abemaciclib and letrozole is a frequently chosen treatment strategy.\u003c/p\u003e \u003cp\u003eAlthough the combination of abemaciclib and letrozole has demonstrated statistically and clinically significant improvements in progression-free survival (PFS)\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, the occurrence of adverse drug reactions (ADRs) remains a critical concern.\u003c/p\u003e \u003cp\u003eAbemaciclib is an orally administered CDK4/6i that, in estrogen receptor-positive (ER+) breast cancer cell lines, promotes the phosphorylation of retinoblastoma protein (Rb) through cyclin D1 and CDK4/6, thereby facilitating cell cycle progression and proliferation. Abemaciclib inhibits Rb phosphorylation, preventing the transition from the G1 to the S phase of the cell cycle, ultimately leading to cellular senescence and apoptosis\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Letrozole, on the other hand, inhibits the synthesis of aromatase\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, thereby reducing estrogen levels in the body and decreasing estrogen-driven tumor growth. The combination of these two agents may lead to the amplification of certain adverse effects or the emergence of novel ones. Understanding the safety profile of this combination therapy is crucial for optimizing treatment outcomes and improving patients' quality of life.\u003c/p\u003e \u003cp\u003ePreliminary studies have shown that elderly patients receiving abemaciclib in combination with ET experience a higher incidence of clinically significant diarrhea (Grade 2/3) compared to those receiving placebo plus ET. Additionally, elderly patients exhibit moderate increases in nausea, decreased appetite, and venous thromboembolic events, with slightly higher rates of dose adjustments and treatment discontinuation. Moreover, they are more likely to have potential confounding comorbidities, including hypertension, gastrointestinal disorders, and metabolic/nutritional disturbances \u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFurthermore, known adverse effects of abemaciclib, such as thrombosis, pulmonary toxicity, and hematologic toxicity, may further complicate the clinical scenario\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, maintained by the U.S. Food and Drug Administration (FDA), is designed to collect and analyze reports of drug-related adverse events (AEs). This database contains various information on adverse reactions, drug interactions, and therapeutic outcomes reported by patients during the use of marketed drugs.\u003c/p\u003e \u003cp\u003eIn this study, real-world data from the FAERS database were utilized to investigate the safety profile of abemaciclib monotherapy and its combination with letrozole in the treatment of breast cancer. The goal is to develop effective management strategies and ultimately improve the therapeutic index for patients battling this challenging malignancy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eData Collection and Processing\u003c/p\u003e \u003cp\u003eThe data for this study were sourced from the FDA Adverse Event Reporting System (FAERS) database. We extracted AE reports related to drug reactions from the first quarter of 2014 to the fourth quarter of 2024 and analyzed them using R (version 4.3.3).\u003c/p\u003e \u003cp\u003eThe FAERS database consists of seven sections: demographic and administrative information (DEMO), adverse drug reactions (REAC), patient outcome information (OUTC), drug information (DRUG), drug therapy start and end dates (THER), report source information (RPSR), and indications/diagnoses (INDI). To remove duplicate reports, we followed the FDA-recommended deduplication method by selecting the PRIMARYID, CASEID, and FDA_DT fields from the DEMO table. Reports were sorted by CASEID, FDA_DT, and PRIMARYID in that order, retaining the report with the latest FDA_DT for cases with duplicate CASEID. If multiple reports had the same CASEID and FDA_DT, the report with the highest PRIMARYID was retained.\u003c/p\u003e \u003cp\u003eAfter deduplication, we focused on AE reports associated with either abemaciclib monotherapy or the combination of abemaciclib and letrozole. A fuzzy search was performed on the DRUGNAME field in the DRUG table using both brand and generic names of the drugs (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, the following search terms were used to identify breast cancer cases:\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSearch Terms for Abemaciclib and Letrozole\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSearch Term\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbemaciclib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e'Abemaciclib', 'Verzenio', 'Verzenios', 'Abemaciclib 150mg', 'Verzenios 150mg', 'Blinded Abemaciclib', 'Abemaciclib 200mg', 'Abemaciclib Code Not Broken', 'Ramiven', 'Abemaciclib 100mg', 'Abemaciclib 50mg', 'Abemaciclib Mesylate', 'Verzenios 50mg', 'Verzenios 100mg', 'Verzenios 200mg'\"\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLetrozole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e'Letrozole', 'Femara', 'Letrozole Ribociclib', 'Kisqali Femara Co Pack', 'Letrozole Unknown', 'Comparator Letrozole', 'Letrozole 1a Pharma', 'Letrozole Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e5 mg', 'Apo Letrozole', 'Letrozole 25 mg', 'Letrozole Accord', 'Letrozole Manufacturer Unknown', 'Letrozole Letrozole', 'Letrozole Sandoz', 'Letrozole Mylan', 'Letrozole Tablets Usp 25 Mg', 'Letrozole 25 Mg', 'Letrozole Teva', 'Letrozole Tablets Usp 25 Mg', 'Femara Letrozole', 'Letrozole Film Coated Tablet', 'Generic Letrozole', 'Letrozole Tables\u0026nbsp;25 mg', 'Letrozole 25 Mg Filmcoated Tablets', 'Letrozole Tablets Usp 25 Mg', 'Letrozole 25 mg Tab Teva', 'Letrozole 25 mg Teva Pharmaceuticals Usa Inc', 'Letrozole Sun', 'Letrozole Winthrop', 'Letrozole Mylan 25 Mg Comprim Pellicul', 'Letrozole Manufacturer Unknown Letrozole Letrozole', 'Letrozole Tablets 25 mg', 'Letrozole 25 Mg Tablet', 'Letrazole Femara 25 Mg Generic Femara', 'Letrozole Atllc', 'Letrozole 25 mg Tab', 'Letrozole Stada', 'Letrozole Tablet', 'Letrozole 25 Mg Film Coated Tablets', 'Letrozole 25 mg Tablets', 'Letrozole Accord Healthcare', 'Letrozole Tab', 'Accord Letrozole', 'Avomit Letrozole', 'Famos Letrozole', 'Letrozole 25 Mg Teva', 'Letrozole Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e 5mg', 'Letrozole Tablets', 'Teva Letrozole', 'Letrozole 25 Mg Tab', 'Letrozole 25 mg Breckenridge', 'Letrozole Arrow Film Coated Tablet 25 mg', 'Letrozole Tablets Usp 25 mg Mfr Labler Sun Pharm', 'Teva Uk Letrozole', 'Accord Healthcare Letrozole', 'Letrozole 25 Mg', 'Letrozole 25', 'Letrozole 25 Mg Breckenridge', 'Letrozole Actavis', 'Letrozole Gonadotropins', 'Letrozole Temsirolimus Letrozole Temsirolimus Tablet', 'Rad001 And Letrozole', 'Blinded Letrozole', 'Femara 25 Mg Compresse Rivestite Con Film', 'Jamp Letrozole', 'Letrozole Arrow Generics Ltd', 'Letrozole 25 Mg Oral', 'Letrozole 25 Mg Sun Pharmaceuticals', 'Letrozole 25 mg Oral', 'Letrozole 25 mg Sun Pharmaceuticals', 'Letrozole Apotex', 'Letrozole Arrow', 'Letrozole Sun 25 Mg Filmcoated Tablets', 'Letrozole Temsirolimus Letrozole Temsirolimus', 'Mar Letrozole', 'Nexazole Letrozole', 'Trezor Letrozole'\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\"Breast Cancer Metastatic\", \"Breast Cancer\", \"Breast Cancer Female\", \"Oestrogen Receptor Positive Breast Cancer\", \"Her-2 Positive Breast Cancer\", \"Breast Cancer Stage IV\", \"Breast Cancer Stage\", \"Breast Cancer Recurrent\", \"Breast Cancer Male\", \"Hormone Receptor Positive HER2 Negative Breast Cancer\", \"Hormone Receptor Positive Breast Cancer\", \"HER2 Negative Breast Cancer\", \"HER2 Positive Breast Cancer\", \"Breast Cancer Stage II\", \"Hormone Receptor Negative HER2 Positive Breast Cancer\", \"Breast Cancer Stage I\".\u003c/p\u003e \u003cp\u003eThis approach enabled us to classify the drugs as primary suspect (PS), secondary suspect (SS), or concomitant (C) drugs, while also capturing potential drug interactions (I) to ensure data completeness.\u003c/p\u003e \u003cp\u003eThrough this process, we successfully filtered a total of 55,249,058 reports related to abemaciclib. After restricting the indications to breast cancer and selecting cases where abemaciclib was identified as the primary suspect drug, we obtained 6,649 reports related to abemaciclib monotherapy and 750 reports related to the combination of abemaciclib and letrozole (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All AE reports associated with abemaciclib and letrozole were categorized according to system organ class (SOC) and preferred term (PT) levels.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThis study employed disproportionality analysis based on the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM) to explore the relationship between abemaciclib, letrozole, and adverse events (AEs).\u003c/p\u003e \u003cp\u003ePRR is useful for estimating relative risk; however, it is highly sensitive and prone to false-positive signals, especially when the number of reported cases is low \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In contrast, ROR helps mitigate bias in cases with fewer reported events\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. BCPNN is particularly effective in integrating and cross-validating data from multiple sources, efficiently managing uncertainty and missing data to enhance predictive accuracy\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. MGPS is especially effective in detecting signals from rare events\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBy integrating these four methods\u0026mdash;ROR, PRR, BCPNN, and MGPS\u0026mdash;this study leveraged their respective advantages to broaden the scope of signal detection and validation from multiple perspectives, ensuring the identification of significantly associated signals. In this process, an AE was considered a positive signal if it met the threshold in at least one of the four algorithms. Conversely, when all four algorithms met the threshold, a strong association between the AE and the drug was indicated, effectively reducing the risk of potential false-positive signals.\u003c/p\u003e \u003cp\u003eThese methods were based on a 2 \u0026times; 2 contingency table, as shown in Supplementary Table\u0026nbsp;1. The formulas and signal detection criteria for each method are detailed in Supplementary Table\u0026nbsp;2. Data processing and statistical analyses were performed using Microsoft Excel 2016 and R (version 4.3.3).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDescriptive Analysis\u003c/p\u003e \u003cp\u003eAfter excluding duplicate data, adverse event (AE) reports related to abemaciclib treatment in breast cancer patients were extracted from the FAERS database, covering records from the first quarter of 2014 to the fourth quarter of 2024. A total of 6,649 AEs were identified for abemaciclib monotherapy, where abemaciclib was the primary suspect drug and letrozole was not included in the concomitant medication. Additionally, 750 AEs were identified for the combination of abemaciclib and letrozole, where abemaciclib was the primary suspect drug and letrozole was included as a concomitant medication.\u003c/p\u003e \u003cp\u003eOver 90% of these events occurred in female patients. Age stratification analysis showed that the incidence of AEs was similar in patients aged 18 to 65 years and 65 to 85 years. For those on abemaciclib monotherapy, AEs were more common in the 18 to 65 years age group, while for patients on the combination therapy, the incidence of AEs was similar between the 65 to 85 years and 18 to 65 years age groups.\u003c/p\u003e \u003cp\u003eThe top five countries reporting AEs were the United States, Japan, China, France, and Italy. Furthermore, the number of reported cases showed an increasing trend over the years. Notably, abemaciclib monotherapy and the combination with letrozole resulted in 1,672 and 286 cases of serious outcomes, respectively, including death, disability, and life-threatening consequences. Among these, 471 deaths were related to abemaciclib monotherapy, while 61 deaths were related to the combination therapy with letrozole (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and Clinical Characteristics of AE Reports Related to Abemaciclib Monotherapy and Abemaciclib Plus Letrozole from the FAERS Database\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbemaciclib Counts (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbemaciclib\u0026thinsp;+\u0026thinsp;Letrozole Counts (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6229 (93.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e718 (95.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e346 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;50 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e136 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;100 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50ཞ100 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e764 (11.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e233 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5666 (85.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e459 (61.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18ཞ64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1983 (29.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e290 (38.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65ཞ85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1399 (21.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e291 (38.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 (1.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3176 (47.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e161 (21.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccupation reporter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003es\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsumer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3758 (56.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e438 (58.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealth Professional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1015 (15.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e58 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysician\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e817 (12.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e141 (18.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePharmacist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e367 (5.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52 (6.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther healthcare professionals\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e386 (5.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e306 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55 (7.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReporting countries (top 5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5150 (77.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e341 (45.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e387 (5.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e130 (17.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e329 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54 (7.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (1.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReporting time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (0.14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.00%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e557(8.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28(3.73%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e777(11.69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59(7.87%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e738(11.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e99(13.20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e745(11.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e117(15.60%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1090(16.39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e137(18.27%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1403(21.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e155(20.67%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1330(20.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e155(20.67%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital anomaly ( CA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0(0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (0.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath (DE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e471 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisability (DS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization (HO)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1262 (19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e229 (30.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-threatening (LT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22 (2.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRequired intervention (RI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.00%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther serious outcomes (OT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1115 (16.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e201 (26.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3707 (55.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e234 (31.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSignal Detection\u003c/p\u003e \u003cp\u003eWe performed statistical analysis using four algorithms: ROR, PRR, BCPNN, and MGPS. For patients receiving only abemaciclib as the primary suspect drug, with no concomitant use of letrozole, each algorithm identified positive signals for 126, 105, 359, and 120 preferred terms (PTs), with 42 PTs being positive in all four algorithms. In patients receiving abemaciclib as the primary suspect drug with concomitant use of letrozole, the algorithms identified positive signals for 55, 49, 277, and 146 PTs, with 28 PTs being positive in all four algorithms (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePositive Signals for Drug-Related AEs Identified Using Four Algorithms\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eROR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBCPNN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMGPS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eALL\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbemaciclib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbemaciclib\u0026thinsp;+\u0026thinsp;Letrozole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e277\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdditionally, we analyzed the grouped onset times for each PT, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. We observed that the majority of PTs for both abemaciclib monotherapy and combination therapy occurred in the first month of treatment, with the incidence of PTs within the first 60 days being 59.17% and 59.31%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median time to the occurrence of PTs was 30 days (interquartile range: 11\u0026ndash;115 days) for patients on abemaciclib monotherapy, while it was 35 days (interquartile range: 14\u0026ndash;109 days) for patients receiving combination therapy with letrozole.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSignals of System Organ Classes\u003c/p\u003e \u003cp\u003eThe positive signals of PTs were classified according to the SOC in MedDRA version 26.1. The results showed that 42 PTs associated with abemaciclib monotherapy and 28 PTs associated with the combination of abemaciclib and letrozole involved 15 and 11 different organ systems, respectively. Tables\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e list the PTs with positive signals across all four algorithms in the FAERS database for both abemaciclib monotherapy and combination therapy with letrozole, along with their corresponding SOCs. The most commonly reported PTs for abemaciclib monotherapy were diarrhea, dehydration, and bone marrow suppression. Interestingly, diarrhea remained the most frequently reported PT in the combination therapy with abemaciclib and letrozole. Notably, interstitial lung disease and acute kidney injury ranked among the top three adverse events in the combination therapy, with higher incidences of liver dysfunction, drug-induced liver injury, and hepatocellular necrosis observed. Hepatocellular necrosis was not reported in the abemaciclib monotherapy group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSignal Strength of PTs and Corresponding SOCs for Abemaciclib Monotherapy in the FAERS Database for Breast Cancer Treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSOC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase reports\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR(95%Cl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eχ2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIC(IC025)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEBGM(EBGM05)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.97 ( 6.64\u0026ndash;7.32 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.21(6.17,6.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8390.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.51 ( 2.44 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.7 ( 5.48 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug ineffective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e320\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.8 ( 3.39\u0026ndash;4.26 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.74(3.63,3.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e606.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.84 ( 1.67 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.57 ( 3.25 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDehydration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.71 ( 3.23\u0026ndash;4.25 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.67(3.53,3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e404.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.81 ( 1.61 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.51 ( 3.13 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyelosuppression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.31 ( 2.84\u0026ndash;3.85 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.28(3.13,3.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e269.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.66 ( 1.44 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.16 ( 2.78 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal pain upper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.76 ( 3.23\u0026ndash;4.39 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.74(3.58,3.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e333.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.83 ( 1.61 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.57 ( 3.14 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy interrupted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.21 ( 12.68\u0026ndash;18.24 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.08(14.9,15.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1539.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.6 ( 3.34 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12.13 ( 10.42 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy cessation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.89 ( 9.94\u0026ndash;14.23 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.8(11.62,11.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1188.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.31 ( 3.05 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.94 ( 8.56 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProduct dose omission issue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.67 ( 3.07\u0026ndash;4.4 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.65(3.47,3.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e230.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.8 ( 1.54 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.49 ( 3 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood creatinine increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.95 ( 3.25\u0026ndash;4.79 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.93(3.73,4.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e224.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.9 ( 1.62 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.74 ( 3.18 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterstitial lung disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.52 ( 2.08\u0026ndash;3.06 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.51(2.32,2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e94.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.29 ( 1.01 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.45 ( 2.08 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal discomfort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.59 ( 2.11\u0026ndash;3.17 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.58(2.38,2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e90.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.33 ( 1.03 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.51 ( 2.12 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovid-19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.6 ( 2.1\u0026ndash;3.22 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.59(2.38,2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e83.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.33 ( 1.02 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.52 ( 2.11 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalisation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.9 ( 3.88\u0026ndash;6.2 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.89(4.65,5.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e216.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.19 ( 1.85 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.58 ( 3.76 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic function abnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.17 ( 2.5\u0026ndash;4.03 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.16(2.93,3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e101.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.61 ( 1.26 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.05 ( 2.5 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute kidney injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.86 ( 2.25\u0026ndash;3.64 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.85(2.61,3.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e80.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.47 ( 1.12 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.76 ( 2.26 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVascular disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.91 ( 2.29\u0026ndash;3.71 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.9(2.66,3.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e82.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.49 ( 1.14 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.81 ( 2.3 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.8 ( 2.15\u0026ndash;3.64 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.79(2.53,3.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e63.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.44 ( 1.05 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.71 ( 2.17 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTaste disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.54 ( 3.42\u0026ndash;6.02 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.53(4.25,4.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e132.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.09 ( 1.68 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.27 ( 3.37 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.99 ( 8.01\u0026ndash;15.07 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.96(10.65,11.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e349.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.23 ( 2.77 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.35 ( 7.18 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug-induced liver injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.66 ( 2.61\u0026ndash;5.13 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.65(3.32,3.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e65.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.81 ( 1.32 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.49 ( 2.64 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospice care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.71 ( 3.2\u0026ndash;6.93 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.7(4.32,5.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e75.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.14 ( 1.59 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.42 ( 3.2 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy non-responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.77 ( 3.85\u0026ndash;8.64 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.76(5.36,6.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e92.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.41 ( 1.83 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.32 ( 3.8 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.6 ( 2.42\u0026ndash;5.35 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.59(3.2,3.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e45.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.78 ( 1.21 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.44 ( 2.47 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbolism venous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVascular disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26.69 ( 16.09\u0026ndash;44.3 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e26.66(26.15,27.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e370.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.21 ( 3.51 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e18.48 ( 12.09 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlomerular filtration rate decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.77 ( 2.34\u0026ndash;6.08 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.77(3.29,4.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e34.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.85 ( 1.16 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.6 ( 2.41 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood glucose decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.84 ( 2.23\u0026ndash;6.59 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.83(3.29,4.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e27.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.87 ( 1.1 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.65 ( 2.32 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.17 ( 5.67\u0026ndash;22.01 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.17(10.49,11.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e77.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.25 ( 2.3 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.5 ( 5.39 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain fog\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.96 ( 2.08\u0026ndash;7.51 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.96(3.31,4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.91 ( 1.01 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.76 ( 2.2 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransfusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.69 ( 4.31\u0026ndash;17.53 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.69(7.99,9.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e53.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.94 ( 1.96 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.67 ( 4.26 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung opacity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.75 ( 2.41\u0026ndash;9.37 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.75(4.07,5.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e24.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.16 ( 1.21 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.46 ( 2.52 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood creatine increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.98 ( 2.52\u0026ndash;9.84 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.98(4.3,5.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e26.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.22 ( 1.27 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.66 ( 2.63 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep disorder due to general medical condition, insomnia type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePsychiatric disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.73 ( 9.24\u0026ndash;42.1 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.71(18.96,20.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e118.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.9 ( 2.87 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e14.9 ( 7.9 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovid-19 pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.18 ( 2.51\u0026ndash;10.68 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.18(4.45,5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e24.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.27 ( 1.27 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.83 ( 2.64 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapeutic product effect decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.88 ( 3.14\u0026ndash;15.07 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.87(6.09,7.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e31.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.64 ( 1.56 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.24 ( 3.24 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.77 ( 4.11\u0026ndash;23.22 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.76(8.9,10.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.08 ( 1.91 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.48 ( 4.11 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLoss of therapeutic response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48.84 ( 16.41\u0026ndash;145.33 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e48.82(47.73,49.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e151.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.74 ( 3.41 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e26.75 ( 10.74 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep disorder due to a general medical condition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePsychiatric disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.35 ( 7.33\u0026ndash;56.5 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20.34(19.32,21.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e67.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.93 ( 2.59 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.25 ( 6.49 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine renal clearance increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.76 ( 3.06\u0026ndash;25.12 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.76(7.71,9.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e23.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.95 ( 1.56 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.73 ( 3.2 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebral venous sinus thrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.68 ( 3.11\u0026ndash;36.66 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.68(9.45,11.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e22.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.19 ( 1.61 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.15 ( 3.26 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumomediastinum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.43 ( 2.23\u0026ndash;24.75 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.43(6.23,8.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.74 ( 1.2 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.69 ( 2.44 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpinal cord disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.14 ( 2.43\u0026ndash;27.29 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.14(6.93,9.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.86 ( 1.3 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.24 ( 2.63 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuperficial vein thrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVascular disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.49 ( 2.8\u0026ndash;32.23 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.49(8.27,10.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e19.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.05 ( 1.48 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.28 ( 2.98 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSignal Strength of PTs and Corresponding SOCs for Abemaciclib in Combination with Letrozole in the FAERS Database\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSOC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase reports\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR(95%Cl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eχ2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIC(IC025)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEBGM(EBGM05)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.37 ( 3.82\u0026ndash;5 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.07(3.94,4.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e542.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.01 ( 1.81 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.03 ( 3.6 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterstitial lung disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.81 ( 5.08\u0026ndash;9.14 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.71(6.42,7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e220.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.72 ( 2.3 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.61 ( 5.17 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute kidney injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.99 ( 5.59\u0026ndash;11.43 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.91(7.55,8.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e183.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.96 ( 2.44 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.76 ( 5.75 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.8 ( 1.92\u0026ndash;4.06 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.78(2.41,3.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e31.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.47 ( 0.93 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.76 ( 2.02 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood creatinine increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.82 ( 3.16\u0026ndash;7.36 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.79(4.37,5.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e65.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.24 ( 1.64 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.74 ( 3.33 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic function abnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.75 ( 3.73\u0026ndash;8.87 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.71(5.29,6.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e80.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.5 ( 1.87 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.64 ( 3.93 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovid-19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.45 ( 2.19\u0026ndash;5.44 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.44(2.99,3.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e32.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.77 ( 1.12 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.41 ( 2.34 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug-induced liver injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.15 ( 6.17\u0026ndash;16.71 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.1(9.6,10.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e127.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.3 ( 2.59 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.85 ( 6.49 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy interrupted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.53 ( 5.19\u0026ndash;14.03 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.49(7.99,8.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e103.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.06 ( 2.35 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.32 ( 5.49 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGamma-glutamyltransferase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.01 ( 2.89\u0026ndash;8.67 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.99(4.44,5.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.3 ( 1.52 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.94 ( 3.12 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy cessation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.4 ( 2.36\u0026ndash;8.22 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.39(3.77,5.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e25.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.12 ( 1.24 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.35 ( 2.58 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic cytolysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.46 ( 4.51\u0026ndash;15.85 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.43(7.8,9.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e64.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.05 ( 2.16 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.26 ( 4.88 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatotoxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.55 ( 1.84\u0026ndash;6.86 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.54(2.89,4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.82 ( 0.9 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.52 ( 2.03 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.11 ( 2.89\u0026ndash;12.91 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.1(5.35,6.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e29.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.59 ( 1.56 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.01 ( 3.22 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver function test increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.96 ( 1.88\u0026ndash;8.34 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.95(3.2,4.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.97 ( 0.94 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.92 ( 2.1 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospice care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.07 ( 2.1\u0026ndash;12.27 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.06(4.18,5.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.32 ( 1.14 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.01 ( 2.39 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung opacity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.39 ( 6.69\u0026ndash;40.19 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.36(15.47,17.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e69.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.97 ( 2.76 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.71 ( 7.42 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis acute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.99 ( 4.79\u0026ndash;35.25 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.98(11.98,13.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e42.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.65 ( 2.33 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12.57 ( 5.45 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.92 ( 2.2\u0026ndash;15.91 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.91(4.93,6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.54 ( 1.24 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.83 ( 2.55 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreatitis acute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.8 ( 2.16\u0026ndash;15.59 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.8(4.81,6.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.52 ( 1.21 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.72 ( 2.5 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphangiosis carcinomatosa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.81 ( 2.9\u0026ndash;21.04 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.8(6.81,8.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e23.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.94 ( 1.63 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.66 ( 3.34 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal function test abnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.79 ( 5.8\u0026ndash;42.99 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.77(14.77,16.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e53.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.92 ( 2.6 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.16 ( 6.56 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolic acidosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.75 ( 2.15\u0026ndash;21.17 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.75(5.61,7.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.73 ( 1.27 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.64 ( 2.55 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.11 ( 4.45\u0026ndash;44.75 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14.1(12.95,15.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e35.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.77 ( 2.29 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e13.61 ( 5.18 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal tubular necrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.01 ( 3.18\u0026ndash;31.53 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10(8.85,11.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e23.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.29 ( 1.82 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.76 ( 3.74 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAppendicitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.83 ( 3.12\u0026ndash;30.96 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.82(8.67,10.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e23.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.26 ( 1.79 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.59 ( 3.67 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubcutaneous emphysema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e91.75 ( 25.88\u0026ndash;325.32 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e91.64(90.38,92.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e215.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e6.2 ( 4.59 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e73.52 ( 25.49 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoronavirus infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.59 ( 3.36\u0026ndash;33.38 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.57(9.43,11.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e25.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.37 ( 1.9 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e10.31 ( 3.94 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe selected the top three risk signals for each system based on the ROR for abemaciclib monotherapy and its combination with letrozole, and presented them in the forest plots (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). As shown in the figure, sleep disorders and thrombotic diseases were the higher-risk signals for abemaciclib monotherapy, while subcutaneous emphysema, abnormal renal function tests, and acute hepatitis had higher-risk signals in the combination therapy of abemaciclib and letrozole.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAbemaciclib is a CDK4/6 inhibitor that suppresses the activity of the CDK4/6-Cyclin D1 complex, preventing tumor cells from entering the cell cycle, thereby inhibiting tumor cell proliferation or inducing apoptosis\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Letrozole is an aromatase inhibitor (AI) that blocks the conversion of androgens to estrogens, thereby reducing estrogen levels in the body, and is used for endocrine therapy in breast cancer patients. Existing studies indicate that the combination of abemaciclib with endocrine therapy significantly benefits patients in early high-risk breast cancer as adjuvant intensification therapy, as well as in the treatment of locally advanced or metastatic breast cancer. However, this combination therapy is also associated with a higher incidence of more severe adverse reactions. The Monarch E study is an open-label phase III trial\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, which suggests that in patients with high recurrence risk HR+, HER2- lymph node-positive early breast cancer, the combination of abemaciclib and endocrine therapy showed superior invasive disease-free survival (IDFS) compared to endocrine therapy alone (P\u0026thinsp;=\u0026thinsp;0.01; hazard ratio, 0.75; 95% CI, 0.60\u0026ndash;0.93). The 2-year IDFS rates were 92.2% and 88.7%, respectively. However, the addition of abemaciclib to endocrine therapy resulted in a higher incidence of \u0026ge;\u0026thinsp;3 grade adverse events (49.7% vs 16.3% for endocrine therapy alone), primarily laboratory findings such as neutropenia. 18.5% of patients discontinued abemaciclib and/or endocrine therapy due to adverse events, mainly due to grade 1/2 adverse events (66.8%). Grade 2/3 events peaked during the first month (20.5%) but were mostly transient (\u0026le;\u0026thinsp;7 days) and did not recur. Venous thromboembolic events (VTE) occurred in 2.5% of the abemaciclib plus endocrine therapy group compared to 0.6% in the endocrine therapy alone group. The MONARCH 3 study is a double-blind, randomized phase III trial\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, which involved 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received abemaciclib vs placebo combined with anastrozole or letrozole. The results showed that the median progression-free survival (PFS) in the abemaciclib group was significantly longer than that in the placebo group (28.18 months vs 14.76 months; hazard ratio [95% CI], 0.540 [0.418\u0026ndash;0.698]; p\u0026thinsp;=\u0026thinsp;0.000002), and the median duration of response was longer in the abemaciclib group (27.39 months vs 17.46 months). The most common grade 3 or 4 adverse events in the abemaciclib group compared to the placebo group were neutropenia (21.1% vs 1.2%), diarrhea (9.5% vs 1.2%), and leukopenia (7.6% vs 0.6%).\u003c/p\u003e \u003cp\u003eThus, although the combination of abemaciclib and endocrine therapy demonstrates superior clinical efficacy compared to endocrine therapy alone, its adverse event (AE) incidence is relatively higher, particularly the increased occurrence of grade 2\u0026ndash;3 AEs, which has raised concerns regarding its safety. Therefore, this study focuses on the analysis of AEs associated with the combination of abemaciclib and endocrine therapy, aiming to further explore the differences in the AE profile of combination therapy and provide more comprehensive safety evidence for rational clinical use. In the Monarch E and MONARCH 3 studies, common AEs associated with combination therapy included diarrhea, neutropenia, leukopenia, and fatigue. Compared to monotherapy, the incidence of these AEs was higher. In our study, the most common AEs for the combination therapy were diarrhea, interstitial lung disease, acute kidney injury, and liver dysfunction, which were not widely reported or emphasized in Monarch E and MONARCH 3.\u003c/p\u003e \u003cp\u003eMany previous studies have reported associations between abemaciclib and certain adverse events (AEs), such as drug-induced liver injury, skin toxicity, drug-related osteonecrosis of the jaw, venous thromboembolism, and infections\u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, there has been a lack of comprehensive summaries and studies focusing on the safety of abemaciclib in combination with letrozole. In this study, we provide an in-depth understanding of the safety of combination therapy, offering important data on the safety of abemaciclib and letrozole in the treatment of breast cancer. This information helps clinicians better assess treatment risks in real-world practice and develop personalized management plans. Using the largest available real-world data from the FAERS database, we explored the AEs associated with the combination of abemaciclib and letrozole in the treatment of breast cancer. We identified and analyzed important new adverse drug reactions (ADRs) to inform product labeling and support evidence-based clinical decision-making.\u003c/p\u003e \u003cp\u003eOur study, based on the FAERS database, includes data from multiple countries worldwide (such as the United States, China, Japan, France, Italy, etc.), highlighting the global diversity of drug-related adverse events (AEs). Understanding the frequency of AEs in different regions and their management strategies may provide valuable data to support international treatment standards and clinical guidelines. The results of the study show that the incidence of AEs for abemaciclib monotherapy and its combination with letrozole was higher in female patients (93.7% and 95.7%, respectively) compared to male patients (1.1% and 0.9%, respectively). This could be attributed to the larger number of female breast cancer patients. The age distribution indicates that AEs were most common in patients aged 18-64.9 years, which may reflect the higher incidence rate of breast cancer in this age group and the larger number of users of these two drugs. Notably, these AEs led to severe outcomes in patients. Among those receiving abemaciclib monotherapy and its combination with letrozole, 7.1% and 8.1% of patients experienced fatal outcomes, 18.1% and 30% experienced disabling, life-threatening AEs or other severe outcomes, and 19.0% and 30.5% required hospitalization. This suggests that as the clinical use of CDK4/6 inhibitors in combination with endocrine therapy expands, clinicians should pay particular attention to potential AEs in patients to prevent life-threatening complications.\u003c/p\u003e \u003cp\u003eOur study shows that among the most common PTs observed in abemaciclib monotherapy, thrombus formation and venous thromboembolism were noted. A retrospective cohort study of patients with hormone receptor-positive metastatic breast cancer (mBC) treated with the three FDA-approved CDK inhibitors (palbociclib, ribociclib, and abemaciclib) found that the incidence of venous thromboembolism (VTE) in patients treated with CDK inhibitors for mBC was 2 to 5 times higher than reported in the registration trials, and it may be associated with poorer outcomes\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Combined with the findings of this study, the high report rate of thrombus formation in abemaciclib monotherapy suggests that clinicians should be highly attentive to the blood hypercoagulability-related toxicities of CDK inhibitors in the real-world setting. This risk-benefit balance is crucial for treatment decisions, particularly in high-risk populations such as the elderly, obese individuals, or those with a history of VTE. Based on these findings, we recommend baseline VTE risk assessment (e.g., Caprini score) for all patients with mBC who are scheduled to receive CDK inhibitor therapy, with a focus on patient subgroups with high VTE risk, such as those who are elderly, have a BMI\u0026thinsp;\u0026ge;\u0026thinsp;30, have a history of VTE, or carry prothrombotic gene mutations (e.g., Factor V Leiden).\u003c/p\u003e \u003cp\u003eIn analyzing the adverse events (AEs) associated with the combination of abemaciclib and letrozole, we found that acute kidney injury (AKI) ranked among the top three AEs in the combination treatment. Additionally, we identified several hepatobiliary-related PTs, such as \u0026ldquo;drug-induced liver injury,\u0026rdquo; \u0026ldquo;liver function abnormal,\u0026rdquo; and severe AEs like \u0026ldquo;hepatocellular necrosis,\u0026rdquo; as well as \u0026ldquo;interstitial lung disease,\u0026rdquo; which ranked in the top three for incidence. Case reports have suggested that abemaciclib may induce reversible grade 4 nephrotoxicity, potentially related to the use of metformin\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Two interesting phenomena were also observed: One case involved abemaciclib-induced pseudorenal AKI. The report indicated that pseudorenal AKI could be distinguished from true AKI by measuring the estimated glomerular filtration rate (eGFR) based on serum cystatin C, serum creatinine-based eGFR, and using other clearance estimation methods such as iohexol clearance. After differentiating pseudorenal AKI, the patient continued abemaciclib treatment, and kidney function remained stable, with consistent eGFR values based on cystatin C and routine metabolic indicators even after more than a year of therapy\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Another case report\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e described a 79-year-old female patient with stage 4 A2 chronic kidney disease secondary to type 2 diabetes and long-term hypertension. After being diagnosed with invasive breast cancer, she started treatment with letrozole, followed by palbociclib, and developed pseudorenal AKI. The mechanism of pseudorenal AKI could involve the interference of targeted therapies with renal tubular secretion of creatinine. Our study, for the first time, highlights through FAERS data mining that the combination of abemaciclib and letrozole significantly increases the risk of acute kidney injury (AKI). However, case reports suggest the need to differentiate between true AKI and pseudorenal AKI. Relying solely on traditional creatinine measurements may lead to misdiagnosis of true AKI and premature discontinuation of effective cancer treatment or neglect of true kidney damage, which could worsen renal function. Therefore, we recommend including cystatin C as part of routine kidney function monitoring for patients on CDK4/6 inhibitors and being vigilant in differentiating true AKI from pseudorenal AKI to avoid unnecessary treatment interruptions.\u003c/p\u003e \u003cp\u003eOur study showed a higher incidence of hepatobiliary-related PTs in patients receiving the combination of abemaciclib and letrozole. Previous research has revealed differences in hepatobiliary toxicity between various CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appears relatively safe\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. A case report described a patient who experienced grade 4 liver injury during abemaciclib treatment, but after switching to palbociclib, liver dysfunction did not recur. This case suggests that switching to palbociclib may be a viable option for continuing treatment after severe liver injury from abemaciclib\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Taniguchi A et al. found through multivariable analysis that the concurrent use of aromatase inhibitors (AI) was an independent risk factor for abemaciclib-induced liver injury (odds ratio [OR]\u0026thinsp;=\u0026thinsp;10.23, 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;2.02\u0026ndash;51.91, p\u0026thinsp;=\u0026thinsp;0.005). However, the mechanism by which AI combined with abemaciclib leads to liver injury requires further investigation\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, which is consistent with our study. Our study also reveals for the first time that the combination of abemaciclib and letrozole can lead to hepatocellular necrosis. These findings suggest that if patients have impaired liver function, special caution should be exercised when using this combination therapy, or palbociclib could be considered as an alternative to abemaciclib.\u003c/p\u003e \u003cp\u003eInterstitial lung disease (ILD) was found to have a high incidence in both abemaciclib monotherapy and the combination with letrozole. Chen Y et al.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e reported 82 cases of ILD (46 severe, 13 fatal) among 4,700 patients treated with abemaciclib. Most patients (91%) had at least one symptom at the time of diagnosis, typically including dyspnea (59%), cough (44%), and/or fever (37%). Fatal cases were characterized by advanced age (\u0026ge;\u0026thinsp;70 years), pre-existing interstitial changes, and an Eastern Cooperative Oncology Group performance status (ECOG PS)\u0026thinsp;\u0026ge;\u0026thinsp;2. Takeda T et al.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e analyzed the VigiBase and FAERS databases to compare the AE profiles of palbociclib and abemaciclib. They found that patients on palbociclib often reported cytopenia, while those on abemaciclib frequently reported interstitial lung disease and diarrhea. Lin W et al.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e also found that pneumonia was a common signal for abemaciclib. Zhang Y et al.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, in their investigation of AE profiles for aromatase inhibitors (AIs) using FAERS, found that letrozole was associated with severe AEs such as ILD (n\u0026thinsp;=\u0026thinsp;159, ROR\u0026thinsp;=\u0026thinsp;2.91). These findings are consistent with our study, and for the first time, we report a high incidence of ILD in patients receiving the combination of abemaciclib and letrozole. The two drugs may exhibit a synergistic risk, potentially exceeding the threshold for lung tissue damage, particularly in elderly patients, those with baseline lung dysfunction, or those with an ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;2, who may be at a fatal risk.\u003c/p\u003e \u003cp\u003eUndoubtedly, this study has certain limitations. First, although the disproportionality analysis in the FAERS database provides statistically significant signal strength, adverse event reports can only suggest a potential association between the drug and the event, but cannot directly prove causality. Second, FAERS data is based on spontaneous reporting, which leads to a higher likelihood of severe or newly emerging events being reported, while mild or common events may be underreported. This introduces significant underreporting and selective reporting issues, which may not accurately reflect the real-world incidence of adverse events. Moreover, there may be duplicate reports, and critical information such as patient age, gender, or dosage may be missing or incomplete, affecting the accuracy of the analysis and potentially introducing bias into the results. In this study, we analyzed the adverse events associated with abemaciclib monotherapy and its combination with letrozole in breast cancer, but we cannot exclude the influence of concomitant drugs, comorbidities, or other patient-specific factors. Notably, our results show that the number of adverse events in the abemaciclib and letrozole combination group was relatively low. This finding is independent of the period during which the adverse event report data was collected, and therefore, may not accurately reflect the drug's safety in the real world and may be affected by reporting bias. This is a limitation of our study. Therefore, further prospective studies and clinical trials are needed to confirm the causal relationship between abemaciclib, its combination with letrozole, and these adverse events. Despite these limitations, the FAERS database remains crucial in identifying drug-related adverse events in oncology, helping to identify risk patterns and duration, and supporting clinical treatment decisions and drug label updates.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe conducted a pharmacovigilance analysis using the FAERS database to systematically identify patient characteristics and adverse event signals associated with abemaciclib monotherapy and its combination with letrozole in breast cancer. Diarrhea, dehydration, and bone marrow suppression were the most common adverse events (AEs) observed with abemaciclib monotherapy, while thromboembolism had a higher incidence. When the two drugs were used in combination, the incidence of AEs such as diarrhea, interstitial lung disease (ILD), acute kidney injury (AKI), and liver dysfunction was higher, with the potential occurrence of hepatic cellular necrosis. These AEs require close monitoring. Moreover, we recommend careful differentiation between true AKI and pseudo-AKI when AKI occurs during combination therapy to avoid unnecessary treatment interruption. We suggest enhanced monitoring and risk assessment of these AEs, especially in high-risk populations, to better evaluate the risk-benefit profile of combining abemaciclib with letrozole.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLH: Data curation, Formal Analysis, Writing\u0026ndash;original draft, Writing\u0026mdash;review and editing. YR: Data curation, Formal Analysis, Methodology, Software, Supervision, Visualization, Writing\u0026mdash;review and editing. CZ: Data curation, Supervision, Validation, Writing\u0026mdash;review and editing. PG: Data curation, Supervision, Validation, Writing\u0026mdash;review and editing. HL: Data curation, Formal Analysis, Supervision, Resources, Writing\u0026ndash;review and editing.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003ePublicly available datasets were analyzed in this study. This data can be found here: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray, F. \u003cem\u003eet al.\u003c/em\u003e Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA. Cancer J. Clin.\u003c/em\u003e \u003cstrong\u003e74\u003c/strong\u003e, 229\u0026ndash;263 (2024).\u003c/li\u003e\n\u003cli\u003eSiegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. \u0026amp; Jemal, A. Cancer statistics, 2025. \u003cem\u003eCA. Cancer J. Clin.\u003c/em\u003e \u003cstrong\u003e75\u003c/strong\u003e, 10\u0026ndash;45 (2025).\u003c/li\u003e\n\u003cli\u003eGiaquinto, A. 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This study aims to monitor and identify adverse events (AEs) associated with this combination therapy to enhance patient safety and provide evidence-based recommendations for the appropriate use of these drugs. We collected data on adverse drug reactions (ADRs) related to breast cancer patients receiving either abemaciclib monotherapy or its combination with letrozole from the FDA Adverse Event Reporting System (FAERS) database between the first quarter of 2014 and the fourth quarter of 2024. ADR signal detection was conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) methods. A total of 6,649 and 750 AE cases were collected for patients receiving abemaciclib monotherapy and its combination with letrozole, respectively. Using four signal detection techniques, we identified 42 and 28 distinct AEs, involving 15 and 11 different system organ class (SOC) categories, respectively. The most common AEs associated with abemaciclib were diarrhea, dehydration, and myelosuppression. In the combination therapy group, the most frequently reported AEs were diarrhea, interstitial lung disease, and acute kidney injury (AKI). Additionally, we observed a higher incidence of abnormal liver function in the combination therapy group, with a detected signal for hepatocellular necrosis.\u003c/p\u003e \u003cp\u003eThe United States reported the highest number of AEs, followed by Japan, China, France, and Italy. The median onset time of AEs associated with abemaciclib monotherapy and its combination with letrozole was 30 days (interquartile range [IQR]: 11\u0026ndash;115 days) and 35 days (IQR: 14\u0026ndash;109 days), respectively. This study provides novel insights into the monitoring and management of ADRs in breast cancer patients receiving abemaciclib monotherapy or in combination with letrozole.\u003c/p\u003e","manuscriptTitle":"A real-world drug safety surveillance study from the FAERS database of breast cancer patients receiving abemaciclib alone and plus letrozole","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-16 08:52:18","doi":"10.21203/rs.3.rs-6217610/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"06bdd0ee-bb94-499c-b059-e15e434d735e","owner":[],"postedDate":"April 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47067450,"name":"Health sciences/Diseases/Cancer/Breast cancer"},{"id":47067451,"name":"Health sciences/Medical research/Drug development"}],"tags":[],"updatedAt":"2026-05-05T11:42:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-16 08:52:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6217610","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6217610","identity":"rs-6217610","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}