Data mining study on adverse events of cinacalcet based on JADER database

Data mining study on adverse events of cinacalcet based on JADER database | 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 Research Article Data mining study on adverse events of cinacalcet based on JADER database Feilong Tan, Hongying Xia, Wenjie Yin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5302434/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 Background Cinacalcet is the first calcium-sensing receptor agonist (calcimimetic) primarily indicated for the management of secondary hyperparathyroidism in patients with chronic kidney disease. This study aims to evaluate the safety profile of cinacalcet in real-world clinical settings. Methods Data on adverse events (AEs) associated with cinacalcet, reported from the second quarter of 2004 to the fourth quarter of 2023, were extracted from the Japanese Adverse Drug Event Report (JADER) database. Data mining was performed using the reporting odds ratio (ROR) method, and the time to onset was analyzed using the Weibull Shape Parameter (WSP). Results A total of 663 AE reports related to cinacalcet were identified, involving 284 Preferred Terms (PTs) and 24 System Organ Classes (SOCs). Six noteworthy SOCs qualified based on criteria. Additionally, 67 AEs were identified with positive signals, comprising 41 significant AEs and 36 unexpected AEs. Notable signals that warrant particular attention include parathyroid haemorrhage, electrocardiogram QT shortened, sphincter of Oddi dysfunction, nephrolithiasis, intestinal obstruction, pancreatitis, ascites, gastrointestinal necrosis. The majority of AEs occurred within the first month of treatment. The WSP was calculated to be 0.66, indicating an early failure type. Conclusion This study has identified several significant and unexpected AEs associated with cinacalcet use, highlighting the need for careful monitoring, especially during the early stages of therapy. cinacalcet adverse events data mining JADER database reporting odds ratio Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Chronic Kidney Disease (CKD) has a global prevalence of approximately 10–15% across different regions. In 2017, CKD was responsible for 1.2 million deaths worldwide, and the all-age mortality rate associated with CKD increased by 41.5% from 1990 to 2017, underscoring its impact as a major public health concern [ 1 , 2 ]. Secondary hyperparathyroidism (SHPT) is a common yet serious complication of CKD, characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Persistent elevation of PTH levels, along with abnormalities in serum calcium and phosphorus, not only adversely affect the skeletal, nervous, and cardiovascular systems but also increase the risk of hospitalization and mortality, thereby imposing significant economic and psychological burdens on patients undergoing dialysis [ 3 , 4 ]. Current treatments for SHPT include both pharmacological and surgical approaches. For patients with refractory SHPT who do not have contraindications to surgery, parathyroidectomy is considered the preferred treatment option. In contrast, for patients who are either unable or unwilling to undergo surgical resection, calcimimetic therapy is recommended as the initial treatment strategy. Calcimimetics modulate parathyroid function by mimicking the action of calcium ions on calcium-sensing receptors (CaSRs) in the parathyroid glands, thereby activating cellular signaling pathways mediated by CaSRs [ 5 ]. Currently, three calcimimetics have been globally approved for clinical use: cinacalcet, etelcalcetide, and evocalcet [ 6 ]. Cinacalcet, the first oral calcimimetic, was approved in the United States in March 2004, followed by approval in Europe in December of the same year. It was subsequently approved in Japan in October 2007 and entered the Chinese market in February 2015. Cinacalcet has been shown to effectively control serum PTH levels in patients with SHPT, reducing the risk of bone disease and cardiovascular events [ 7 ]. Despite its efficacy in managing PTH levels, cinacalcet's clinical application has been limited by its adverse effects, including hypocalcemia, nausea, vomiting, arrhythmia, and severe dehydration [ 8 – 11 ]. However, there is a lack of comprehensive analysis of cinacalcet-associated adverse events (AEs). While previous studies have utilized the US FDA Adverse Event Reporting System (FAERS) database for safety analysis of AEs [ 12 , 13 ], the use of the Japanese Adverse Drug Event Reporting (JADER) database has not been documented in the literature. The JADER database, managed by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, is a spontaneous reporting system (SRS) that collects AE data primarily from healthcare professionals, as well as serious AEs reported in post-marketing clinical trials, drug use outcome surveys, and specific drug use surveys [ 14 ]. Thus, this study aims to explore the incidence, onset time, and post-hoc outcomes of cinacalcet-associated AEs with high risk using the JADER database. 2. Methods 2.1. Data source The study data is sourced from the JADER database ( https://www.pmda.go.jp ), encompassing AE reports from the second quarter of 2004 (2004Q2) through to the fourth quarter of 2023 (2023Q4). The JADER database is stored in the form of Comma-Separated Values (CSV) files and comprises four tables: a demographic information table (DEMO), a medication record table (DRUG), an adverse event information table (REAC), and a past medical history table (HIST). 2.2. Data Acquisition The DEMO, DRUG, REAC, and HIST tables were imported into SAS 9.4 software for analysis. To enhance the accuracy of the study, cinacalcet was identified using its generic name “シナカルセト” or its trade name “レグパラ” as search terms. The screening for relevant drug-AE combinations was conducted by focusing on reports where cinacalcet was a suspected drug. AEs recorded in the REAC table and primary diseases listed in the HIST table were coded according to the Preferred Term (PT) and the System Organ Class (SOC) from the Medical Dictionary for Regulatory Activities (MedDRA) version 26.1. 2.3. Data mining Signal detection was carried out using the reporting odds ratio (ROR) method, a disproportionality analysis technique. The key metrics for the ROR method include the ROR value and its 95% two-sided confidence interval (95% CI), calculated based on a contingency table (as shown in Table 1 ). The formulas and criteria for this method are provided in Table 2 . Significant AEs are signals documented in the Important Medical Event (IME) list 27.0, released by the European Union; Unexpected AEs are signals not listed in any of the labels. Table 1 Four-grid table for analysis. Drugs Target AEs Non-target AEs Total cinacalcet a b a + b Non-cinacalcet c d c + d Total a + c b + d N = a + b + c + d a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions. 2.4. The analysis of onset time The time-to-onset (TTO) of cinacalcet-related AEs was defined as the time interval between the date of the AE recorded in the REAC table and the date of initiation of cinacalcet dosing recorded in the DEMO table. Reports with input errors or incomplete dates were excluded from the analysis. TTO was assessed using the median, interquartile range (IQR), and the Weibull distribution shape parameter (β). If β < 1 and its 95% CI < 1, the incidence of AEs is considered to decrease over time (early failure type). If β is equal to or near 1 and its 95% CI includes 1, the incidence of AEs is considered to occur randomly over time (random failure type). If β > 1 and its 95% CI excludes 1, the incidence of AEs is considered to increase over time (wear-out failure type). Data processing and analysis were conducted using Microsoft Excel 2019, Prism 8.0, and R version 4.4.0. 3. Results 3.1. Basic information on AE reports From 2004Q2 to 2023Q4, the JADER database recorded a total of 663 AE reports related to cinacalcet, involving 1,222 cases and 284 PTs. Table 3 provides a summary of the clinical characteristics of these AEs. Among the reported cases, 52.94% occurred in males and 45.10% in females, with the majority of AEs observed in patients aged 45–65 years (58.87%) and those over 65 years (40.12%). The reports were predominantly from research studies (64.25%), with physicians being the primary reporters (93.82%). The annual number of reports initially increased, peaking in 2016 (25.34%), and subsequently declined. Table 3 Characteristics of AE reports related to cinacalcet from JADER databases. Characteristics Number (%) Gender Male 351 (52.94) Female 299 (45.10) Unknown 13 (1.96) Age < 18 1 (0.15) 18≥, < 45 68 10.26) 45≥, < 65 324 (48.87) 65≥ 266 (40.12) Missing 4 (0.60) Report type Spontaneous reports 219 (33.03) Research reports 426 (64.25) Other 18 (2.71) Reporter a Physician 622 (93.82) Pharmacist 36 (5.43) Other health-professional 74 (11.16) Consumer 3 (0.45) Unknown 10 (1.51) Report year 2007 11 (1.66) 2008 64 (9.65) 2009 37 (5.58) 2010 24 (3.62) 2011 21 (3.17) 2012 14 (2.11) 2013 10 (1.51) 2014 15 (2.26) 2015 48 (7.24) 2016 168 (25.34) 2017 115 (17.35) 2018 89 (13.42) 2019 24 (3.62) 2020 12 (1.81) 2021 2 (0.30) 2022 7 (1.06) 2023 2 (0.30) 3.2. Signals of cinacalcet-related AEs at the SOC Level As shown in Table 4 , cinacalcet-related AEs were distributed across 24 SOCs. Six SOCs met the criteria for significant association: gastrointestinal disorders (SOC: 10017947, 203 reports), cardiac disorders (SOC: 10007541, 160 reports), injury, poisoning, and procedural complications (SOC: 10022117, 141 reports), metabolism and nutrition disorders (SOC: 10027433, 89 reports), surgical and medical procedures (SOC: 10042613, 72 reports), and product issues (SOC: 10077536, 4 reports). The top three categories, based on intensity, were surgical and medical procedures, product issues, and injury, poisoning, and procedural complications. Table 4 Signal values of reports related to cinacalcet at the SOC level. SOC N ROR (95% CI) Endocrine disorders 4439 17.20 (16.62–17.81)* Respiratory, thoracic and mediastinal disorders 3896 2.13 (2.06–2.21)* Neoplasms benign, malignant and unspecified (incl cysts and polyps) 2653 2.84 (2.73–2.96)* Gastrointestinal disorders 2503 1.31 (1.25–1.36)* Hepatobiliary disorders 1680 1.45 (1.38–1.53)* Infections and infestations 1500 0.61 (0.58–0.64) Metabolism and nutrition disorders 1231 1.12 (1.05–1.18)* Skin and subcutaneous tissue disorders 1196 0.70 (0.66–0.74) Nervous system disorders 1092 0.44 (0.42–0.47) Renal and urinary disorders 1067 1.09 (1.03–1.16)* Blood and lymphatic system disorders 1036 0.45 (0.42–0.48) General disorders and administration site conditions 1001 0.70 (0.66–0.75) Cardiac disorders 737 0.71 (0.66–0.77) Musculoskeletal and connective tissue disorders 694 1.09 (1.01–1.18)* Investigations 635 0.21 (0.2–0.23) Immune system disorders 267 0.32 (0.29–0.36) Vascular disorders 260 0.41 (0.36–0.46) Eye disorders 221 0.61 (0.53–0.69) Injury, poisoning and procedural complications 170 0.24 (0.21–0.28) Psychiatric disorders 90 0.16 (0.13–0.19) Reproductive system and breast disorders 23 0.22 (0.15–0.34) Ear and labyrinth disorders 18 0.33 (0.21–0.53) Surgical and medical procedures 16 0.20 (0.12–0.33) Congenital, familial and genetic disorders 5 0.09 (0.04–0.21) Pregnancy, puerperium and perinatal conditions 3 0.03 (0.01–0.09) N, the number of adverse event reports; ROR, the reporting odds ratio; CI, confidence interval. * Indicates a statistically significant signal in the algorithm. 3.3. Signals of cinacalcet-related AEs at the PT level Based on the established thresholds and excluding signals related to cinacalcet’s indications, a total of 67 positive risk signals involving 19 SOCs were identified (Fig. 1 ). Among these, 41 were significant AEs (61.19%), and 36 were unexpected AEs (53.73%). Notably, the top three AEs were parathyroid hemorrhage (ROR = 1114.49, 95% CI: 266.05–4668.68), electrocardiogram QT shortening (ROR = 928.74, 95% CI: 232.01–3717.82), and sphincter of Oddi dysfunction (ROR = 619.16, 95% CI: 167.42–2289.83), all of which were significant and unexpected. 3.4. Timing of cinacalcet-associated AE onset A total of 455 records with documented AE onset times were analyzed. Figure 2 illustrates the distribution of AE onset times, categorized into eight intervals. The findings indicate that the majority of AEs occurred within the first month of cinacalcet use and after more than one year of use. Additionally, Fig. 3 presents the histogram and Weibull distribution of AE onset times related to cinacalcet, with a Weibull Shape Parameter (WSP) of 0.66, suggesting an early failure type. 3.5. Outcomes of cinacalcet-related AEs Figure 4 presents a bar chart illustrating the outcomes of AEs associated with cinacalcet, as reported in the JADER database. The results demonstrated that the majority of outcomes were classified as remission and recovery. Conversely, death, unrecovery, and after-effects constituted a smaller proportion of the overall data. 4. Discussion This study utilized data from the JADER database to conduct a comprehensive, large-scale real-world analysis of cinacalcet, thereby enhancing the evidence base for its clinical use beyond clinical trials, case reports, and other study types. The AEs were predominantly reported among males (52.94%), aligning with findings that indicate males as a high-risk group for developing secondary hyperparathyroidism (SHPT) [ 15 ]. Reports were mainly from individuals aged over 45 years, which is consistent with the age distribution observed in the FAERS database [ 12 ]. The number of annual reports showed a trend of initially increasing and then decreasing, suggesting that healthcare professionals have been vigilant about the safe use of cinacalcet and have implemented effective measures to mitigate risks. At the SOC level, our analysis identified six noteworthy SOCs qualified based on criteria, with notable signals in surgical and medical procedures, product issues, injury, poisoning and procedural complications exhibiting being more pronounced signals. It is noteworthy that our comprehensive evaluation indicates that these AEs are predominantly attributable to procedural related injuries and complications, bone and joint injuries, device issues and therapeutic procedures. These findings imply that such AEs associated with cinacalcet are largely preventable, rather than an inherent property of the drug. This underscores the necessity for differentiating between pharmacological side effects and complications resulting from procedural errors. The signal for cardiac disorders was notably strong. CaSRs are widely distributed in β-cells, enteroendocrine cells, adipocytes, and myocytes, providing a basis for calcium ions' involvement in regulating cardiac function and metabolism [ 16 ]. Calcimimetics can induce cardiac-related AEs by mimicking calcium ions' actions on CaSRs, warranting clinical attention. The prescribing information indicates that cardiotoxicity associated with cinacalcet is primarily manifested by myocardial infarction, myocardial ischemia, atrial fibrillation, palpitations, tachycardia, and cardiac failure. The use of calcimimetics can affect blood calcium levels, potentially impacting the cardiac system. One study showed that cinacalcet-induced transient hypocalcemia was associated with an increased risk of cardiovascular mortality [ 17 ]. Another study suggested that cinacalcet dosing regimens exceeding eight weeks may heighten the risk of cardiac-related AEs, which should be considered in clinical practice [ 13 ]. Therefore, it is recommended that clinicians closely monitor patients' blood calcium levels to adjust medication regimens as needed and enhance surveillance for cardiac AE signals. Signals from the gastrointestinal system were also pronounced. A meta-analysis indicated that gastrointestinal AEs are among the most frequent AEs linked to cinacalcet treatment, significantly contributing to poor medication compliance and discontinuation among patients with SHPT [ 18 ]. In this study, positive signals for gastrointestinal hemorrhage, gastritis, nausea, vomiting, and abdominal pain were detected, consistent with the drug's specifications. Additionally, this study identified unexpected significant AEs such as intestinal obstruction, pancreatitis, ascites, and gastrointestinal necrosis. Studies have shown that deoxynivalenol (vomitoxin) can cause food refusal and vomiting, with its secretion being associated with CaSR activation, which might be a potential mechanism for gastrointestinal toxicity induced by calcimimetics [ 19 ]. Ceglia et al. [ 20 ] found that cinacalcet might increase basal gastric acid production in healthy adults, leading to gastric ulcers, gastritis, and other disorders, suggesting a potential risk of inducing gastrointestinal AEs such as gastric ulcers and bleeding. Metabolic and nutritional disorders also showed strong signals, with hypocalcaemia being the most frequent. A machine learning-based systematic evaluation indicated that cinacalcet is associated with an increased risk of hypocalcemia (RR = 4.05, 95% CI = 2.33 to 7.04, p = 0.001) [ 21 ]. Additionally, new positive signals for hypercalcaemia and hyperphosphataemia caused by cinacalcet were detected in this study. These signals may relate to disease progression and indirectly suggest that the patient's condition is not being effectively controlled, potentially providing evidence to support drug efficacy evaluation. It is recommended that clinicians regularly monitor serum calcium, phosphorus, and PTH levels when administering calcimimetics to timely assess treatment efficacy and prevent serious AEs. Notably, this study identified several significant and unexpected signals, with parathyroid haemorrhage being the most prominent. Nagasawa et al. [ 22 ] reported a case of parathyroid hemorrhage in a rare SHPT patient on cinacalcet. The authors suggested a potential mechanism where partial loss of thyroid hyperplastic cells responsive to cinacalcet might reduce intracapsular pressure, leading to an oversupply of blood, potentially resulting in vessel rupture and haemorrhage. We identified three cases of electrocardiogram QT prolongation; however, literature reviews revealed more reports of cinacalcet causing QT prolongation [ 23 – 25 ]. Interestingly, cinacalcet has been shown to reverse short QT intervals in familial hypocalciuric hypercalcemia type 1 [ 26 ]. Further clinical studies are necessary to fully understand cinacalcet's effect on the QT interval. Additionally, Bernardor et al. [ 27 ] reported a case of a child wiath SHPT treated with cinacalcet who developed nephrolithiasis secondary to hypercalciuria. While other signals, such as cataract, bile duct stone, gangrene, diverticulitis, osteonecrosis, malignant neoplasm, facial paralysis, and renal haemorrhage, have not been reported in clinical studies or case reports, caution should be exercised when interpreting these findings due to the limited number of cases included. It is imperative for clinicians to recognize and manage potential AEs early to prevent serious outcomes. The onset time analysis in our study indicated that AEs could occur at any time during the one-year treatment period, with a notable proportion (21.89%) occurring within the first month. Long-term AEs were also a concern, with 40.56% of patients reporting AEs more than one year after initiating cinacalcet treatment. The Weibull Shape Parameter (WSP) was 0.66, indicating an early failure type, meaning the incidence of AEs declines over time. This analysis provides insight into cinacalcet's risk profile over time, which can inform the development of monitoring strategies for patients on this medication. As shown in Fig. 4 , while cinacalcet is generally regarded as having a favorable safety profile, there have been instances of serious AEs. Notably, deaths constituted 7.53% of the reported cases. The diversity within this category may provide insights into various health challenges facing the population. However, it is crucial to consider the high proportion of missing data when interpreting these results, as it could significantly impact the understanding of the drug's safety profile. This study has several limitations. First, the JADER database is a self-reporting system prone to omissions, duplicate reporting, and incomplete case information, which may introduce bias. Second, the database does not record the total number of medicine users, preventing calculations of AE incidence rates. Third, the data analysis did not account for unmeasured confounders such as drug-drug interactions, comorbidities, and concurrent medications. Furthermore, the ROR method reflects statistical correlations rather than cause-and-effect relationships, which require validation through large-scale clinical studies. Despite these limitations, this study provides critical insights into cinacalcet's safety profile, which can guide clinical practice and inform risk management strategies. 5. Conclusion This study represents the most comprehensive analysis of cinacalcet-related AEs using data from the JADER database. We identified several serious and novel AE signals related to cinacalcet, such as parathyroid haemorrhage, electrocardiogram QT shortened, sphincter of Oddi dysfunction, nephrolithiasis, intestinal obstruction, pancreatitis, ascites, gastrointestinal necrosis. etc. These findings highlight the need for increased vigilance for potential adverse reactions across various systems, particularly during the early stages of treatment. Ongoing pharmacovigilance and regularly updated safety information are essential for optimizing the clinical use of cinacalcet. Declarations Funding This research was funded by the Kunming Health Science and Technology Talent Cultivation "Thousand Project" Programme (2023-SW (back-up)-84), Kunming Health Care Commission's Health Research Project (2023-13-01-017), The Scientific Research Fund Project of the Yunnan Provincial Department of Education (2024J0371), and Yunnan Provincial Association of Pharmacists in Healthcare Facilities Scientific Research Special Fund Project (2024YSXH06). Declaration of interests The authors thank the JADER database for providing the data and the FastSignal team for technical support. Reviewer disclosures Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments The authors acknowledge the data provided by JADER database. Author contributions Feilong Tan: conception and design the study. Feilong Tan, Hongying Xia: acquisition, analysis and interpretation of the data. Feilong Tan, Wenjie Yin: draft and revision of the paper. 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Nefrologia 33(2):272–273. 10.3265/Nefrologia.pre2012.Oct.11679 Cuny T, Romanet P, Goldsworthy M et al (2024) Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1. J Clin Endocrinol Metab 109(2):549–556. 10.1210/clinem/dgad494 Bernardor J, Flammier S, Salles JP et al (2022) Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience. Front Pediatr 10:926986 Published 2022 Aug 24. 10.3389/fped.2022.926986 Tables Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5302434","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":369918813,"identity":"a7f92989-132c-4a4d-bf5d-f4c9b3040027","order_by":0,"name":"Feilong Tan","email":"","orcid":"","institution":"Yan'an Hospital Affiliated to Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Feilong","middleName":"","lastName":"Tan","suffix":""},{"id":369918814,"identity":"65b53a57-5ff7-480d-b07e-02b8970325b9","order_by":1,"name":"Hongying Xia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBACefbmg4//VNjU87M3EKnFsOdYsgHPmbQEyZ4DxFpzI8dMgrftcILBjAQidTDOSEs2kGA7nGcg+XjjDYYam2iCWth5Hh98YMCTXmwunVZswXAsLbeBoC3tQFsSJKwZd84GupCx4TBhLQwHgCoPGDAzbrh5hlgtJ3LMJBsSnBM33OAhUgsokI0ZDqQZS/YA/ZJAjF/AUcn4z0aOn/3wxhsfamyIcBgSMJBIIEU5RAupOkbBKBgFo2BkAADtZkJsXpQESAAAAABJRU5ErkJggg==","orcid":"","institution":"Yan'an Hospital Affiliated to Kunming Medical University","correspondingAuthor":true,"prefix":"","firstName":"Hongying","middleName":"","lastName":"Xia","suffix":""},{"id":369918815,"identity":"0e6dd74d-5783-41ce-aed1-01d72e252288","order_by":2,"name":"Wenjie Yin","email":"","orcid":"","institution":"Yan'an Hospital Affiliated to Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenjie","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2024-10-21 08:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5302434/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5302434/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67614473,"identity":"90468921-6abe-4974-a247-96a98c62202f","added_by":"auto","created_at":"2024-10-28 06:22:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":205163,"visible":true,"origin":"","legend":"\u003cp\u003eThe positive AE signals related to cinacalcet of the ROR.\u003c/p\u003e\n\u003cp\u003e★Indicates significant AEs; ▲Indicates unexpected AEs.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5302434/v1/31aa6879a98bf825bf530212.png"},{"id":67614475,"identity":"cd522084-a860-4bd4-9dd7-d120c5a793a8","added_by":"auto","created_at":"2024-10-28 06:22:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":28447,"visible":true,"origin":"","legend":"\u003cp\u003eThe onset time of cinacalcet-related to AE from the FAERS database.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5302434/v1/f44552113c92d74567fc2198.png"},{"id":67616406,"identity":"8b8c68f9-4f3e-4554-8f0d-b2405c0fb9bf","added_by":"auto","created_at":"2024-10-28 06:30:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32950,"visible":true,"origin":"","legend":"\u003cp\u003eThe histogram and Weibull distribution of AEs onset time related to cinacalcet.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5302434/v1/702f8fd0918200be63b16ea8.png"},{"id":67614472,"identity":"28476247-b77b-43e9-8d65-067605173466","added_by":"auto","created_at":"2024-10-28 06:22:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":63809,"visible":true,"origin":"","legend":"\u003cp\u003eThe outcome of cinacalcet -associated with AEs from the JADER database.\u003c/p\u003e\n\u003cp\u003eMultiple outcomes may be recorded for a single case.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5302434/v1/09c4adb9a336bae003962317.png"},{"id":80742003,"identity":"21553317-5bf7-471f-9213-f2058058683c","added_by":"auto","created_at":"2025-04-16 14:38:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1027875,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5302434/v1/a89ab2ad-1ed1-4621-ae10-c65b9f0d6173.pdf"},{"id":67616405,"identity":"ae0cc4ac-bf7d-481c-9428-d3fffa7acfc4","added_by":"auto","created_at":"2024-10-28 06:30:14","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13735,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5302434/v1/199778452ef036a2654f496f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Data mining study on adverse events of cinacalcet based on JADER database","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eChronic Kidney Disease (CKD) has a global prevalence of approximately 10\u0026ndash;15% across different regions. In 2017, CKD was responsible for 1.2\u0026nbsp;million deaths worldwide, and the all-age mortality rate associated with CKD increased by 41.5% from 1990 to 2017, underscoring its impact as a major public health concern [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Secondary hyperparathyroidism (SHPT) is a common yet serious complication of CKD, characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Persistent elevation of PTH levels, along with abnormalities in serum calcium and phosphorus, not only adversely affect the skeletal, nervous, and cardiovascular systems but also increase the risk of hospitalization and mortality, thereby imposing significant economic and psychological burdens on patients undergoing dialysis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent treatments for SHPT include both pharmacological and surgical approaches. For patients with refractory SHPT who do not have contraindications to surgery, parathyroidectomy is considered the preferred treatment option. In contrast, for patients who are either unable or unwilling to undergo surgical resection, calcimimetic therapy is recommended as the initial treatment strategy. Calcimimetics modulate parathyroid function by mimicking the action of calcium ions on calcium-sensing receptors (CaSRs) in the parathyroid glands, thereby activating cellular signaling pathways mediated by CaSRs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Currently, three calcimimetics have been globally approved for clinical use: cinacalcet, etelcalcetide, and evocalcet [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Cinacalcet, the first oral calcimimetic, was approved in the United States in March 2004, followed by approval in Europe in December of the same year. It was subsequently approved in Japan in October 2007 and entered the Chinese market in February 2015. Cinacalcet has been shown to effectively control serum PTH levels in patients with SHPT, reducing the risk of bone disease and cardiovascular events [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite its efficacy in managing PTH levels, cinacalcet's clinical application has been limited by its adverse effects, including hypocalcemia, nausea, vomiting, arrhythmia, and severe dehydration [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, there is a lack of comprehensive analysis of cinacalcet-associated adverse events (AEs). While previous studies have utilized the US FDA Adverse Event Reporting System (FAERS) database for safety analysis of AEs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], the use of the Japanese Adverse Drug Event Reporting (JADER) database has not been documented in the literature. The JADER database, managed by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, is a spontaneous reporting system (SRS) that collects AE data primarily from healthcare professionals, as well as serious AEs reported in post-marketing clinical trials, drug use outcome surveys, and specific drug use surveys [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, this study aims to explore the incidence, onset time, and post-hoc outcomes of cinacalcet-associated AEs with high risk using the JADER database.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Data source\u003c/h2\u003e \u003cp\u003eThe study data is sourced from the JADER database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pmda.go.jp\u003c/span\u003e\u003cspan address=\"https://www.pmda.go.jp\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), encompassing AE reports from the second quarter of 2004 (2004Q2) through to the fourth quarter of 2023 (2023Q4). The JADER database is stored in the form of Comma-Separated Values (CSV) files and comprises four tables: a demographic information table (DEMO), a medication record table (DRUG), an adverse event information table (REAC), and a past medical history table (HIST).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Data Acquisition\u003c/h2\u003e \u003cp\u003eThe DEMO, DRUG, REAC, and HIST tables were imported into SAS 9.4 software for analysis. To enhance the accuracy of the study, cinacalcet was identified using its generic name \u0026ldquo;シナカルセト\u0026rdquo; or its trade name \u0026ldquo;レグパラ\u0026rdquo; as search terms. The screening for relevant drug-AE combinations was conducted by focusing on reports where cinacalcet was a suspected drug. AEs recorded in the REAC table and primary diseases listed in the HIST table were coded according to the Preferred Term (PT) and the System Organ Class (SOC) from the Medical Dictionary for Regulatory Activities (MedDRA) version 26.1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Data mining\u003c/h2\u003e \u003cp\u003eSignal detection was carried out using the reporting odds ratio (ROR) method, a disproportionality analysis technique. The key metrics for the ROR method include the ROR value and its 95% two-sided confidence interval (95% CI), calculated based on a contingency table (as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The formulas and criteria for this method are provided in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Significant AEs are signals documented in the Important Medical Event (IME) list 27.0, released by the European Union; Unexpected AEs are signals not listed in any of the labels.\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\u003eFour-grid table for analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrugs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTarget AEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-target AEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecinacalcet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ea\u0026thinsp;+\u0026thinsp;b\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-cinacalcet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ea\u0026thinsp;+\u0026thinsp;c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eb\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;a\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ea, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. The analysis of onset time\u003c/h2\u003e \u003cp\u003eThe time-to-onset (TTO) of cinacalcet-related AEs was defined as the time interval between the date of the AE recorded in the REAC table and the date of initiation of cinacalcet dosing recorded in the DEMO table. Reports with input errors or incomplete dates were excluded from the analysis. TTO was assessed using the median, interquartile range (IQR), and the Weibull distribution shape parameter (β). If β\u0026thinsp;\u0026lt;\u0026thinsp;1 and its 95% CI\u0026thinsp;\u0026lt;\u0026thinsp;1, the incidence of AEs is considered to decrease over time (early failure type). If β is equal to or near 1 and its 95% CI includes 1, the incidence of AEs is considered to occur randomly over time (random failure type). If β\u0026thinsp;\u0026gt;\u0026thinsp;1 and its 95% CI excludes 1, the incidence of AEs is considered to increase over time (wear-out failure type). Data processing and analysis were conducted using Microsoft Excel 2019, Prism 8.0, and R version 4.4.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Basic information on AE reports\u003c/h2\u003e \u003cp\u003eFrom 2004Q2 to 2023Q4, the JADER database recorded a total of 663 AE reports related to cinacalcet, involving 1,222 cases and 284 PTs. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e provides a summary of the clinical characteristics of these AEs. Among the reported cases, 52.94% occurred in males and 45.10% in females, with the majority of AEs observed in patients aged 45\u0026ndash;65 years (58.87%) and those over 65 years (40.12%). The reports were predominantly from research studies (64.25%), with physicians being the primary reporters (93.82%). The annual number of reports initially increased, peaking in 2016 (25.34%), and subsequently declined.\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\u003eCharacteristics of AE reports related to cinacalcet from JADER databases.\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=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e351 (52.94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e299 (45.10)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (1.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ge;, \u0026lt;\u0026thinsp;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68 10.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e45\u0026ge;, \u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e324 (48.87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ge;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e266 (40.12)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (0.60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReport type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous reports\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e219 (33.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResearch reports\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e426 (64.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18 (2.71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReporter\u003c/b\u003e \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysician\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e622 (93.82)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36 (5.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther health-professional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74 (11.16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsumer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (0.45)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (1.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReport year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 (1.66)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64 (9.65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (5.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24 (3.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21 (3.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (2.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (1.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (2.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48 (7.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e168 (25.34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e115 (17.35)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e89 (13.42)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24 (3.62)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (1.81)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (0.30)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (1.06)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (0.30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Signals of cinacalcet-related AEs at the SOC Level\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, cinacalcet-related AEs were distributed across 24 SOCs. Six SOCs met the criteria for significant association: gastrointestinal disorders (SOC: 10017947, 203 reports), cardiac disorders (SOC: 10007541, 160 reports), injury, poisoning, and procedural complications (SOC: 10022117, 141 reports), metabolism and nutrition disorders (SOC: 10027433, 89 reports), surgical and medical procedures (SOC: 10042613, 72 reports), and product issues (SOC: 10077536, 4 reports). The top three categories, based on intensity, were surgical and medical procedures, product issues, and injury, poisoning, and procedural complications.\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 values of reports related to cinacalcet at the SOC level.\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=\"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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eROR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.20 (16.62\u0026ndash;17.81)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3896\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.13 (2.06\u0026ndash;2.21)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2653\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.84 (2.73\u0026ndash;2.96)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2503\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.31 (1.25\u0026ndash;1.36)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1680\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.45 (1.38\u0026ndash;1.53)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.61 (0.58\u0026ndash;0.64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.12 (1.05\u0026ndash;1.18)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.70 (0.66\u0026ndash;0.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.44 (0.42\u0026ndash;0.47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.09 (1.03\u0026ndash;1.16)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.45 (0.42\u0026ndash;0.48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.70 (0.66\u0026ndash;0.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e737\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.71 (0.66\u0026ndash;0.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.09 (1.01\u0026ndash;1.18)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.21 (0.2\u0026ndash;0.23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.32 (0.29\u0026ndash;0.36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.41 (0.36\u0026ndash;0.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEye disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.61 (0.53\u0026ndash;0.69)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.24 (0.21\u0026ndash;0.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsychiatric disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16 (0.13\u0026ndash;0.19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReproductive system and breast disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.22 (0.15\u0026ndash;0.34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEar and labyrinth disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.33 (0.21\u0026ndash;0.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical and medical procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.20 (0.12\u0026ndash;0.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital, familial and genetic disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.09 (0.04\u0026ndash;0.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePregnancy, puerperium and perinatal conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.03 (0.01\u0026ndash;0.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eN, the number of adverse event reports; ROR, the reporting odds ratio; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e* Indicates a statistically significant signal in the algorithm.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Signals of cinacalcet-related AEs at the PT level\u003c/h2\u003e \u003cp\u003eBased on the established thresholds and excluding signals related to cinacalcet\u0026rsquo;s indications, a total of 67 positive risk signals involving 19 SOCs were identified (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among these, 41 were significant AEs (61.19%), and 36 were unexpected AEs (53.73%). Notably, the top three AEs were parathyroid hemorrhage (ROR\u0026thinsp;=\u0026thinsp;1114.49, 95% CI: 266.05\u0026ndash;4668.68), electrocardiogram QT shortening (ROR\u0026thinsp;=\u0026thinsp;928.74, 95% CI: 232.01\u0026ndash;3717.82), and sphincter of Oddi dysfunction (ROR\u0026thinsp;=\u0026thinsp;619.16, 95% CI: 167.42\u0026ndash;2289.83), all of which were significant and unexpected.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Timing of cinacalcet-associated AE onset\u003c/h2\u003e \u003cp\u003eA total of 455 records with documented AE onset times were analyzed. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the distribution of AE onset times, categorized into eight intervals. The findings indicate that the majority of AEs occurred within the first month of cinacalcet use and after more than one year of use. Additionally, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the histogram and Weibull distribution of AE onset times related to cinacalcet, with a Weibull Shape Parameter (WSP) of 0.66, suggesting an early failure type.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Outcomes of cinacalcet-related AEs\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents a bar chart illustrating the outcomes of AEs associated with cinacalcet, as reported in the JADER database. The results demonstrated that the majority of outcomes were classified as remission and recovery. Conversely, death, unrecovery, and after-effects constituted a smaller proportion of the overall data.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study utilized data from the JADER database to conduct a comprehensive, large-scale real-world analysis of cinacalcet, thereby enhancing the evidence base for its clinical use beyond clinical trials, case reports, and other study types. The AEs were predominantly reported among males (52.94%), aligning with findings that indicate males as a high-risk group for developing secondary hyperparathyroidism (SHPT) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Reports were mainly from individuals aged over 45 years, which is consistent with the age distribution observed in the FAERS database [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The number of annual reports showed a trend of initially increasing and then decreasing, suggesting that healthcare professionals have been vigilant about the safe use of cinacalcet and have implemented effective measures to mitigate risks.\u003c/p\u003e \u003cp\u003eAt the SOC level, our analysis identified six noteworthy SOCs qualified based on criteria, with notable signals in surgical and medical procedures, product issues, injury, poisoning and procedural complications exhibiting being more pronounced signals. It is noteworthy that our comprehensive evaluation indicates that these AEs are predominantly attributable to procedural related injuries and complications, bone and joint injuries, device issues and therapeutic procedures. These findings imply that such AEs associated with cinacalcet are largely preventable, rather than an inherent property of the drug. This underscores the necessity for differentiating between pharmacological side effects and complications resulting from procedural errors.\u003c/p\u003e \u003cp\u003eThe signal for cardiac disorders was notably strong. CaSRs are widely distributed in β-cells, enteroendocrine cells, adipocytes, and myocytes, providing a basis for calcium ions' involvement in regulating cardiac function and metabolism [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Calcimimetics can induce cardiac-related AEs by mimicking calcium ions' actions on CaSRs, warranting clinical attention. The prescribing information indicates that cardiotoxicity associated with cinacalcet is primarily manifested by myocardial infarction, myocardial ischemia, atrial fibrillation, palpitations, tachycardia, and cardiac failure. The use of calcimimetics can affect blood calcium levels, potentially impacting the cardiac system. One study showed that cinacalcet-induced transient hypocalcemia was associated with an increased risk of cardiovascular mortality [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Another study suggested that cinacalcet dosing regimens exceeding eight weeks may heighten the risk of cardiac-related AEs, which should be considered in clinical practice [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, it is recommended that clinicians closely monitor patients' blood calcium levels to adjust medication regimens as needed and enhance surveillance for cardiac AE signals.\u003c/p\u003e \u003cp\u003eSignals from the gastrointestinal system were also pronounced. A meta-analysis indicated that gastrointestinal AEs are among the most frequent AEs linked to cinacalcet treatment, significantly contributing to poor medication compliance and discontinuation among patients with SHPT [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In this study, positive signals for gastrointestinal hemorrhage, gastritis, nausea, vomiting, and abdominal pain were detected, consistent with the drug's specifications. Additionally, this study identified unexpected significant AEs such as intestinal obstruction, pancreatitis, ascites, and gastrointestinal necrosis. Studies have shown that deoxynivalenol (vomitoxin) can cause food refusal and vomiting, with its secretion being associated with CaSR activation, which might be a potential mechanism for gastrointestinal toxicity induced by calcimimetics [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Ceglia et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] found that cinacalcet might increase basal gastric acid production in healthy adults, leading to gastric ulcers, gastritis, and other disorders, suggesting a potential risk of inducing gastrointestinal AEs such as gastric ulcers and bleeding.\u003c/p\u003e \u003cp\u003eMetabolic and nutritional disorders also showed strong signals, with hypocalcaemia being the most frequent. A machine learning-based systematic evaluation indicated that cinacalcet is associated with an increased risk of hypocalcemia (RR\u0026thinsp;=\u0026thinsp;4.05, 95% CI\u0026thinsp;=\u0026thinsp;2.33 to 7.04, p\u0026thinsp;=\u0026thinsp;0.001) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Additionally, new positive signals for hypercalcaemia and hyperphosphataemia caused by cinacalcet were detected in this study. These signals may relate to disease progression and indirectly suggest that the patient's condition is not being effectively controlled, potentially providing evidence to support drug efficacy evaluation. It is recommended that clinicians regularly monitor serum calcium, phosphorus, and PTH levels when administering calcimimetics to timely assess treatment efficacy and prevent serious AEs.\u003c/p\u003e \u003cp\u003eNotably, this study identified several significant and unexpected signals, with parathyroid haemorrhage being the most prominent. Nagasawa et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] reported a case of parathyroid hemorrhage in a rare SHPT patient on cinacalcet. The authors suggested a potential mechanism where partial loss of thyroid hyperplastic cells responsive to cinacalcet might reduce intracapsular pressure, leading to an oversupply of blood, potentially resulting in vessel rupture and haemorrhage. We identified three cases of electrocardiogram QT prolongation; however, literature reviews revealed more reports of cinacalcet causing QT prolongation [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Interestingly, cinacalcet has been shown to reverse short QT intervals in familial hypocalciuric hypercalcemia type 1 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Further clinical studies are necessary to fully understand cinacalcet's effect on the QT interval. Additionally, Bernardor et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] reported a case of a child wiath SHPT treated with cinacalcet who developed nephrolithiasis secondary to hypercalciuria. While other signals, such as cataract, bile duct stone, gangrene, diverticulitis, osteonecrosis, malignant neoplasm, facial paralysis, and renal haemorrhage, have not been reported in clinical studies or case reports, caution should be exercised when interpreting these findings due to the limited number of cases included. It is imperative for clinicians to recognize and manage potential AEs early to prevent serious outcomes.\u003c/p\u003e \u003cp\u003eThe onset time analysis in our study indicated that AEs could occur at any time during the one-year treatment period, with a notable proportion (21.89%) occurring within the first month. Long-term AEs were also a concern, with 40.56% of patients reporting AEs more than one year after initiating cinacalcet treatment. The Weibull Shape Parameter (WSP) was 0.66, indicating an early failure type, meaning the incidence of AEs declines over time. This analysis provides insight into cinacalcet's risk profile over time, which can inform the development of monitoring strategies for patients on this medication. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, while cinacalcet is generally regarded as having a favorable safety profile, there have been instances of serious AEs. Notably, deaths constituted 7.53% of the reported cases. The diversity within this category may provide insights into various health challenges facing the population. However, it is crucial to consider the high proportion of missing data when interpreting these results, as it could significantly impact the understanding of the drug's safety profile.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the JADER database is a self-reporting system prone to omissions, duplicate reporting, and incomplete case information, which may introduce bias. Second, the database does not record the total number of medicine users, preventing calculations of AE incidence rates. Third, the data analysis did not account for unmeasured confounders such as drug-drug interactions, comorbidities, and concurrent medications. Furthermore, the ROR method reflects statistical correlations rather than cause-and-effect relationships, which require validation through large-scale clinical studies. Despite these limitations, this study provides critical insights into cinacalcet's safety profile, which can guide clinical practice and inform risk management strategies.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study represents the most comprehensive analysis of cinacalcet-related AEs using data from the JADER database. We identified several serious and novel AE signals related to cinacalcet, such as parathyroid haemorrhage, electrocardiogram QT shortened, sphincter of Oddi dysfunction, nephrolithiasis, intestinal obstruction, pancreatitis, ascites, gastrointestinal necrosis. etc. These findings highlight the need for increased vigilance for potential adverse reactions across various systems, particularly during the early stages of treatment. Ongoing pharmacovigilance and regularly updated safety information are essential for optimizing the clinical use of cinacalcet.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Kunming Health Science and Technology Talent Cultivation \"Thousand Project\" Programme (2023-SW (back-up)-84), Kunming Health Care Commission's Health Research Project (2023-13-01-017), The Scientific Research Fund Project of the Yunnan Provincial Department of Education (2024J0371), and Yunnan Provincial Association of Pharmacists in Healthcare Facilities Scientific Research Special Fund Project (2024YSXH06).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the JADER database for providing the data and the FastSignal team for technical support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReviewer disclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePeer reviewers on this manuscript have no relevant financial or other relationships to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the data provided by JADER database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFeilong Tan: conception and design the study. Feilong Tan, Hongying Xia: acquisition, analysis and interpretation of the data. Feilong Tan, Wenjie Yin: draft and revision of the paper. All authors agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD Chronic Kidney Disease Collaboration (2020) Global, regional, and national burden of chronic kidney disease, 1990\u0026ndash;2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 395(10225):709\u0026ndash;733. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(20)30045-3\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(20)30045-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevin A, Tonelli M, Bonventre J et al (2017) Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. 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Osteoporos Int 20(1):71\u0026ndash;78. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00198-008-0637-8\u003c/span\u003e\u003cspan address=\"10.1007/s00198-008-0637-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Ding W, Zhang H (2023) Cinacalcet use in secondary hyperparathyroidism: a machine learning-based systematic review. Front Endocrinol (Lausanne) 14:1146955 Published 2023 Jul 19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fendo.2023.1146955\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2023.1146955\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagasawa M, Ubara Y, Suwabe T et al (2012) Parathyroid hemorrhage occurring after administration of cinacalcet in a patient with secondary hyperparathyroidism. Intern Med 51(24):3401\u0026ndash;3404. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2169/internalmedicine. 51.8055\u003c/span\u003e\u003cspan address=\"10.2169/internalmedicine. 51.8055\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan N, Oesterle A, Botting P et al (2023) High-Throughput Assessment of Real-World Medication Effects on QT Interval Prolongation: Observational Study. JMIR Cardio 7:e41055 Published 2023 Jan 20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2196/41055\u003c/span\u003e\u003cspan address=\"10.2196/41055\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTemiz G, Yal\u0026ccedil;ın AU, Mutluay R et al (2016) Effects of cinacalcet treatment on QT interval in hemodialysis patients. Anatol J Cardiol 16(7):520\u0026ndash;523. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5152/AnatolJCardiol.2015.6284\u003c/span\u003e\u003cspan address=\"10.5152/AnatolJCardiol.2015.6284\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorrego-Utiel FJ, P\u0026eacute;rez-del Barrio Mdel P, Biechy-Baldan Mdel M et al (2013) Cinacalcet may prolong the QT interval in patients on haemodialysis with secondary hyperparathyroidism. Nefrologia 33(2):272\u0026ndash;273. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3265/Nefrologia.pre2012.Oct.11679\u003c/span\u003e\u003cspan address=\"10.3265/Nefrologia.pre2012.Oct.11679\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCuny T, Romanet P, Goldsworthy M et al (2024) Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1. J Clin Endocrinol Metab 109(2):549\u0026ndash;556. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1210/clinem/dgad494\u003c/span\u003e\u003cspan address=\"10.1210/clinem/dgad494\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernardor J, Flammier S, Salles JP et al (2022) Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience. Front Pediatr 10:926986 Published 2022 Aug 24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fped.2022.926986\u003c/span\u003e\u003cspan address=\"10.3389/fped.2022.926986\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"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},"keywords":"cinacalcet, adverse events, data mining, JADER database, reporting odds ratio","lastPublishedDoi":"10.21203/rs.3.rs-5302434/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5302434/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCinacalcet is the first calcium-sensing receptor agonist (calcimimetic) primarily indicated for the management of secondary hyperparathyroidism in patients with chronic kidney disease. This study aims to evaluate the safety profile of cinacalcet in real-world clinical settings.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData on adverse events (AEs) associated with cinacalcet, reported from the second quarter of 2004 to the fourth quarter of 2023, were extracted from the Japanese Adverse Drug Event Report (JADER) database. Data mining was performed using the reporting odds ratio (ROR) method, and the time to onset was analyzed using the Weibull Shape Parameter (WSP).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 663 AE reports related to cinacalcet were identified, involving 284 Preferred Terms (PTs) and 24 System Organ Classes (SOCs). Six noteworthy SOCs qualified based on criteria. Additionally, 67 AEs were identified with positive signals, comprising 41 significant AEs and 36 unexpected AEs. Notable signals that warrant particular attention include parathyroid haemorrhage, electrocardiogram QT shortened, sphincter of Oddi dysfunction, nephrolithiasis, intestinal obstruction, pancreatitis, ascites, gastrointestinal necrosis. The majority of AEs occurred within the first month of treatment. The WSP was calculated to be 0.66, indicating an early failure type.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study has identified several significant and unexpected AEs associated with cinacalcet use, highlighting the need for careful monitoring, especially during the early stages of therapy.\u003c/p\u003e","manuscriptTitle":"Data mining study on adverse events of cinacalcet based on JADER database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-28 06:22:09","doi":"10.21203/rs.3.rs-5302434/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":"887453c6-f78b-4dd0-ada7-e1342f2c188f","owner":[],"postedDate":"October 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-16T14:38:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-28 06:22:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5302434","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5302434","identity":"rs-5302434","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}