Pharmacovigilance analysis of drug-induced hypofibrinogenemia using the FDA Adverse Event Reporting System

Pharmacovigilance analysis of drug-induced hypofibrinogenemia using the FDA Adverse Event Reporting System | 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 Pharmacovigilance analysis of drug-induced hypofibrinogenemia using the FDA Adverse Event Reporting System Xiao Wen, Le Cai, Ao Gao, An Fu, Daihong Guo, Man Zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5326354/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jan, 2025 Read the published version in International Journal of Clinical Pharmacy → Version 1 posted 6 You are reading this latest preprint version Abstract Background Drug-induced hypofibrinogenemia (DIHF) has received increasing scrutiny; however, the specific drugs involved remain poorly characterized. Hypofibrinogenemia can have significant clinical implications, including increased bleeding risks. Aim This study aimed to utilize the FDA Adverse Event Reporting System (FAERS) to identify and analyze drugs frequently implicated in drug-induced hypofibrinogenemia. Method A disproportionality analysis was conducted using FAERS data from January 2004 to March 2024. Various statistical tools were used, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio, Medicines and Healthcare Products Regulatory Agency metrics, and Bayesian confidence propagation neural network. Results The analysis included 17,627,340 cases involving 52,373,206 adverse events, with 1,661 cases identified as hypofibrinogenemia, representing just 0.0032% of the total FAERS reports. The top five drugs associated with DIHF by case number were methotrexate (124 cases), tigecycline (119 cases), tocilizumab (100 cases), pegaspargase (83 cases), and alteplase (57 cases). The drugs ranked by signal strength included eravacycline (ROR 2173.84, 95% CI 1208.80-3909.30), tigecycline (ROR 747.34, 95% CI 619.03-902.24), crotalidae polyvalent immune Fab (ROR 407.67, 95% CI 291.07-570.99), pegaspargase (ROR 216.06, 95% CI 173.15-269.61), and asparaginase (ROR 184.93, 95% CI 132.18-258.72). Conclusion This analysis of FAERS data identified 52 drugs associated with hypofibrinogenemia, many of which do not mention this risk in their prescribing information. These findings demonstrate the need for improved pharmacovigilance and may serve as a reference for the prevention and early intervention of DIHF. Hypofibrinogenemia FAERS database Adverse drug event Signal mining Disproportionality Figures Figure 1 Impacts On Practice This study suggests the need for improved surveillance and routine monitoring of coagulation parameters in patients treated with drugs identified as high-risk for drug-induced hypofibrinogenemia (DIHF). The findings support the inclusion of hypofibrinogenemia risks in the prescribing information for implicated drugs, which could help clinicians make safer drug management decisions. Early detection and intervention for DIHF, informed by these practices, could significantly improve patient outcomes. Introduction Fibrinogen, a plasma glycoprotein synthesized exclusively by the liver, plays a central role in the hemostatic process, particularly in the formation and stabilization of clots [ 1 ]. Fibrinogen facilitates platelet aggregation in primary hemostasis by binding to platelets and supports tissue repair by adhering to endothelial cells [ 2 ]. Typically, healthy individuals exhibit plasma fibrinogen levels ranging from 2.0 to 4.0 g/L. Hypofibrinogenemia is diagnosed when levels drop below 2 g/L, with severe cases (fibrinogen < 0.5 mg/L) often associated with bleeding in the nose and gastrointestinal tract, sometimes escalating to life-threatening hemorrhages [ 3 ]. These conditions are commonly managed with fresh frozen plasma or cryoprecipitate [ 4 ]. Medications represent a primary cause of hypofibrinogenemia, with increasing reports and small-scale retrospective clinical studies identifying drug-induced hypofibrinogenemia (DIHF), particularly associated with agents such as tigecycline, tocilizumab, and valproic acid [ 5 – 7 ]. However, the distribution characteristics of DIHF and the incidences related to these drugs remain poorly defined in real-world settings. The discrepancies in risk factors reported by retrospective studies may arise from variations in sample sizes, data accuracy, degree of missing data, and selection biases. These risks are typically not highlighted in the prescribing information provided by drug manufacturers, potentially leading to oversight of this serious adverse reaction by clinicians. The US Food and Drug Administration Adverse Event Reporting System (FAERS), the largest global database for post-marketing adverse event reports [ 8 ], can be utilized to identify drugs frequently implicated in DIHF. Aim This study aimed to use FAERS to identify and analyze drugs frequently implicated in drug-induced hypofibrinogenemia. Ethics approval Ethical approval was not required, as only anonymous data was used. Method Data source and data cleaning procedures Data spanning from the first quarter of 2004 to the first quarter of 2024 were retrieved from the FAERS database and imported into MySQL 5.7 for analysis. Duplicates were removed according to FDA guidelines; cases with identical ID and FDA_date were resolved by retaining the most recent entry based on the FDA_date. The analysis focused on the "primary suspect" drugs associated with hypofibrinogenemia. Brand names were converted to their approved generic counterparts. The search terms "hypofibrinogenemia" and "blood fibrinogen decreased" were used to isolate relevant adverse drug event (ADE) data. Reports that were undecipherable, unrelated to drugs, or related to nonrelevant indications were excluded. To ensure accuracy, the primary suspect drug names were cross-referenced on the FDA website and standardized with their generic names. Capitalization, spacing, and other extraneous characters in drug names were ignored, and misspelled drug names were corrected. Comprehensive ADE data, including patient demographics, report sources, drugs, reactions, indications, and outcomes, were extracted for further analysis. Statistical analysis The relationship between hypofibrinogenemia and suspected drugs was evaluated using disproportionality analysis. To mitigate bias from any single algorithm, four standard disproportionality methods were used: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Medicines and Healthcare Products Regulatory Agency (MHRA) criteria, and Bayesian Confidence Propagation Neural Network (BCPNN) [ 9 ]. The thresholds for these methods were set as follows: (1) ROR and PRR: a value ≥ 3 with a lower bound of the 95% confidence interval (95%CI) > 1; (2) MHRA: a value ≥ 3, PRR ≥ 2, and χ 2 ≥ 4; (3) BCPNN: information component (IC) > 0. A drug-event pair was considered to have a strong signal of disproportionality if all four methods yielded significant results. Results Primary characteristics of hypofibrinogenemia cases Between the first quarter of 2004 and the first quarter of 2024, 52,373,206 ADEs were reported in the FAERS database, including 17,627,340 distinct cases. Among these, 1,661 cases of hypofibrinogenemia associated with primary suspect drugs were identified, representing 0.0032% of all reported ADE cases. The annual distribution of these reports is shown in Fig. 1 . [insert Fig. 1 here] The average age of the patients in the reported cases was 42.60 ± 26.39 years. Detailed characteristics such as sex, outcome, reporter's profession, and reporter's country are summarized in Table 1 . Male patients constituted 48.59% of the cases (807 individuals), slightly outnumbering female patients, who represented 36.97% (614 individuals). Most cases, 86.69% (1,440), were reported by health professionals. The countries with the highest number of reports were France (326 cases, 19.63%), the United States (279 cases, 16.80%), and China (210 cases, 12.64%). Among the reported cases, there were 276 deaths (16.62%) and 200 life-threatening cases (12.04%). Table 1 Primary characteristics of hypofibrinogenemia cases in the US FDA adverse event reporting system (FAERS), 2004 to 2024 Characteristics DIHF(n) DIHF (%) Sex Male 807 48.59 Female 614 36.97 Unknown 240 14.45 Age(years) <18 333 20.05 18–44 271 16.32 45–64 262 15.77 65–74 187 11.26 ≥ 75 143 8.61 Unknown 465 28.00 Reporter occupation Health professional 1440 86.69 Non-health professional 120 7.22 Unknown 101 6.08 Reporting country France 326 19.63 United States 279 16.80 China 210 12.64 Japan 95 5.72 Spain 84 5.06 Unknown 327 19.69 Outcome Death 276 16.62 Life-Threatening 200 12.04 Hospitalization 725 43.65 Disability 20 1.20 Congenital Anomaly 3 0.18 Required Intervention 8 0.48 Other Serious 1151 69.30 Unknown 46 2.77 DIHF: drug-induced hypofibrinogenemia [insert Table 1 here] Hypofibrinogenemia signal detection A total of 276 primary suspect drugs were identified, with the top 100 drugs reporting more than three cases each for hypofibrinogenemia signals. Of these, 53 drugs showed a positive signal and were categorized using the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system. The five most notable drug categories included glucocorticoids (ATC code H02A, 5 drugs), the heparin group (ATC code B01A, 3 drugs), antineoplastic cell and gene therapy (ATC code L01X, 3 drugs), other antineoplastic agents (ATC code L01X, 3 drugs), and interleukin inhibitors (ATC code L04A, 3 drugs), detailed in Table 2 . Table 2 Classification of positive drugs according to the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) system WHO ATC category Number of drugs Drugs Blood substitutes and perfusion solutions 1 Albumin Human Antihemorrhagics 1 Factor VIII Inhibitor Bypassing Fraction Antithrombotic agents 8 Fondaparinux, Dabigatran, Argatroban, Tenecteplase, Alteplase, Enoxaparin, Dalteparin Heparin Corticosteroids for systemic use 5 Hydrocortisone, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone Antimycotics for systemic use 1 Caspofungin Antibacterials for systemic use 7 Linezolid, Azithromycin, Cilastatin;Imipenem, Meropenem, Piperacillin;Tazobactam, Eravacycline, Tigecycline Immunosuppressants 4 Canakinumab, Tocilizumab, Anakinra, Antithymocyte Immunoglobulin Immunostimulants 1 Aldesleukin Antineoplastic agents 19 Arsenic Trioxide, Pegaspargase, Asparaginase Brexucabtagene Autoleucel, Tisagenlecleucel, Axicabtagene Ciloleucel, Bortezomib, Oxaliplatin, Polatuzumab Vedotin, Blinatumomab, Imatinib, Daunorubicin, Doxorubicin, Vincristine, Cytarabine, Fludarabine, Mercaptopurine, Methotrexate, Cyclophosphamide Antigout preparations 1 Allopurinol Antiepileptics 2 Lamotrigine, Valproic Acid Antiprotozoals 1 Hydroxychloroquine Unknown 1 Crotalidae polyvalent immune Fab [insert Table 2 here] The drugs were further analyzed and ranked by the number of cases (Table 3 ) and signal strength (Table 4 ), according to WHO ATC classifications. The five drugs with the highest number of cases were methotrexate (124 cases), tigecycline (119 cases), tocilizumab (100 cases), pegaspargase (83 cases), and alteplase (3,478 cases). The drugs with the strongest signals based on ROR were eravacycline (ROR 2173.84, 95% CI 1208.80-3909.30), tigecycline (ROR 747.34, 95% CI 619.03-902.24), crotalidae polyvalent immune Fab (ROR 407.67, 95% CI 291.07-570.99), pegaspargase (ROR 216.06, 95% CI 173.15-269.61), and asparaginase (ROR 184.93, 95% CI 132.18-258.72). A drug was confirmed to have a positive signal when all ROR, PRR, Chi-Square, and IC signals were generated. Six drugs were excluded from the positive signal list based on these criteria. Table 3 Signal detection of drug-induced hypofibrinogenemia (top 30 drugs, ranked by number of cases) WHO ATC category Drug DIHF (n) ROR ROR (95%CI) PRR PRR (95%CI) MHRA PRR (χ 2 ) BCPNN IC (IC ± 2SD) Folic Acid Analogues Methotrexate 124 8.78 (7.31,10.55) 8.78 (7.31,10.54) 8.78 (791.35) 2.95 (2.69,3.22) Tigecyclines Tigecycline 119 747.34 (619.03,902.24) 731.24 (607.98,879.47) 731.24 (80575.85) 6.67 (1.80,2.74) Interleukin inhibitors Tocilizumab 100 14.92 (12.19,18.26) 14.91 (12.18,18.25) 14.91 (1219.83) 3.64 (3.34,3.93) Other Antineoplastic Agents Pegaspargase 83 216.06 (173.15,269.61) 214.67 (172.27,267.50) 214.67 (16771.98) 5.90 (5.58,6.22) Enzymes Alteplase 57 68.97 (52.94,89.84) 68.82 (52.86,89.61) 68.82 (3679.36) 4.96 (4.58,5.35) Vinca alkaloids and analogues Vincristine 44 69.39 (51.42,93.65) 69.25 (51.34,93.40) 69.25 (2881.35) 4.77 (4.33,5.20) Valproic acid Valproic acid 43 9.64 (7.12,13.05) 9.64 (7.12,13.05) 9.64 (324.36) 2.98 (2.54,3.42) Glucocorticoids Prednisolone 43 13.79 (10.19,18.67) 13.78 (10.18,18.66) 13.78 (496.67) 3.39 (2.95,3.83) Glucocorticoids Dexamethasone 39 10.43 (7.59,14.33) 10.43 (7.59,14.33) 10.43 (324.75) 3.05 (2.59,3.51) Antineoplastic cell and gene therapy Tisagenlecleucel 38 84.50 (61.23,116.60) 84.28 (61.12,116.21) 84.28 (3055.71) 4.74 (4.27,5.21) Pyrimidine analogues Cytarabine 36 24.96 (17.94,34.74) 24.94 (17.93,34.70) 24.94 (809.55) 3.90 (3.42,4.38) Antineoplastic cell and gene therapy Axicabtagene ciloleucel 35 56.09 (40.12,78.43) 56.00 (40.08,78.25) 56.00 (1850.86) 4.46 (3.97,4.94) Other antineoplastic agents Asparaginase 35 184.93 (132.18,258.72) 183.88 (131.68,256.77) 183.88 (6232.15) 4.91 (4.43,5.40) Unknown Crotalidae polyvalent immune Fab 35 407.67 (291.07,570.99) 402.58 (288.62,561.53) 402.58 (13725.89) 5.05 (4.56,5.54) BCR-ABL tyrosine kinase inhibitors Imatinib 30 5.77 (4.02,8.28) 5.77 (4.02,8.28) 5.77 (116.11) 2.30 (1.78,2.83) Glucocorticoids Prednisone 29 8.66 (6.00,12.50) 8.66 (6.00,12.49) 8.66 (192.93) 2.77 (2.24,3.30) Anthracyclines and related substances Doxorubicin 19 6.34 (4.03,9.96) 6.34 (4.03,9.96) 6.34 (84.42) 2.31 (1.66,2.96) Other antiepileptics Lamotrigine 19 3.22 (2.05,5.07) 3.22 (2.05,5.07) 3.22 (28.80) 1.53 (0.88, 2.17) Nitrogen mustard analogues Cyclophosphamide 17 6.55 (4.06,10.56) 6.55 (4.06,10.56) 6.55 (79.07) 2.31 (1.63,3.00) Direct thrombin inhibitors Dabigatran 16 3.20 (1.96,5.24) 3.20 (1.96,5.24) 3.20 (24.02) 1.50 (0.79,2.20) Antineoplastic cell and gene therapy Brexucabtagene autoleucel 15 144.53 (86.83,240.56) 143.88 (86.64,238.93) 143.88 (2109.15) 3.86 (3.13,4.58) Anthracyclines and related substances Daunorubicin 14 73.36 (43.32,124.21) 73.19 (43.28,123.78) 73.19 (988.47) 3.65 (2.90,4.40) Macrolides Azithromycin 13 5.68 (3.29,9.81) 5.68 (3.29,9.81) 5.68 (49.78) 2.08 (1.31,2.86) Platinum Compounds Oxaliplatin 13 3.95 (2.29,6.81) 9.89 (3.19,30.62) 9.89 (36.62) 1.62 (0.17,3.06) Other antibacterials Linezolid 13 12.06 (6.99,20.82) 12.06 (6.99,20.81) 12.06 (130.83) 2.75 (1.97,3.52) Direct thrombin inhibitors Argatroban 12 173.46 (98.16,306.55) 172.53 (97.93,303.95) 172.53 (2031.68) 3.60 (2.80,4.41) Heparin group Heparin 12 6.70 (3.80,11.83) 6.70 (3.80,11.82) 6.70 (57.78) 2.21 (1.41,3.02) Glucocorticoids Methylprednisolone 12 4.69 (2.66,8.28) 4.69 (2.66,8.28) 4.69 (34.64) 1.86 (1.06,2.67) Interleukin inhibitors Canakinumab 12 13.83 (7.84,24.41) 13.83 (7.84,24.39) 13.83 (141.76) 2.79 (1.99,3.60) Tetracyclines Eravacycline 12 2173.84 (1208.80,3909.30) 2034.40 (1174.37,3524.26) 2034.40 (24213.74) 3.69 (2.86,4.52) DIHF: drug-induced hypofibrinogenemia Table 4 Signal detection of drug-induced hypofibrinogenemia (top 30 drugs, ranked by signal strength/ROR) WHO ATC category Drug DIHF (n) ROR ROR (95%CI) PRR PRR (95%CI) MHRA PRR (χ 2 ) BCPNN IC (IC ± 2SD) Tetracyclines Eravacycline 12 2173.84 (1208.80,3909.30) 2034.40 (1174.37,3524.26) 2034.40 (24213.74) 3.69 (2.86,4.52) Tigecyclines Tigecycline 119 747.34 (619.03,902.24) 731.24 (607.98,879.47) 731.24 (80575.85) 6.67 (1.80,2.74) Unknown Crotalidae polyvalent immune Fab 35 407.67 (291.07,570.99) 402.58 (288.62,561.53) 402.58 (13725.89) 5.05 (4.56,5.54) Other Antineoplastic Agents Pegaspargase 83 216.06 (173.15,269.61) 214.67 (172.27,267.50) 214.67 (16771.98) 5.90 (5.58,6.22) Other antineoplastic agents Asparaginase 35 184.93 (132.18,258.72) 183.88 (131.68,256.77) 183.88 (6232.15) 4.91 (4.43,5.40) Direct thrombin inhibitors Argatroban 12 173.46 (98.16,306.55) 172.53 (97.93,303.95) 172.53 (2031.68) 3.60 (2.80,4.41) Antineoplastic cell and gene therapy Brexucabtagene autoleucel 15 144.53 (86.83,240.56) 143.88 (86.64,238.93) 143.88 (2109.15) 3.86 (3.13,4.58) Antineoplastic cell and gene therapy Tisagenlecleucel 38 84.50 (61.23,116.60) 84.28 (61.12,116.21) 84.28 (3055.71) 4.74 (4.27,5.21) Blood coagulation factors Factor VIII inhibitor bypassing fraction 8 80.57 (40.19,161.52) 80.37 (40.16,160.83) 80.37 (624.04) 3.03 (2.07,4.00) Anthracyclines and related substances Daunorubicin 14 73.36 (43.32,124.21) 73.19 (43.28,123.78) 73.19 (988.47) 3.65 (2.90,4.40) Vinca alkaloids and analogues Vincristine 44 69.39 (51.42,93.65) 69.25 (51.34,93.40) 69.25 (2881.35) 4.77 (4.33,5.20) Enzymes Alteplase 57 68.97 (52.94,89.84) 68.82 (52.86,89.61) 68.82 (3679.36) 4.96 (4.58,5.35) Antineoplastic cell and gene therapy Axicabtagene ciloleucel 35 56.09 (40.12,78.43) 56.00 (40.08,78.25) 56.00 (1850.86) 4.46 (3.97,4.94) Enzymes Tenecteplase 4 45.92 (17.20,122.59) 45.86 (17.20,122.24) 45.86 (175.09) 2.20 (0.91,3.49) Blood substitutes and plasma protein fractions Albumin human 8 38.83 (19.38,77.82) 38.79 (19.37,77.66) 38.79 (293.11) 2.90 (1.93,3.86) Interleukins Aldesleukin 3 29.71 (9.57,92.25) 29.68 (9.57,92.07) 29.68 (82.99) 1.86 (0.42,3.31) Other antineoplastic agents Arsenic trioxide 4 26.57 (9.95,70.89) 26.54 (9.95,70.78) 26.54 (98.09) 2.12 (0.83,3.41) Pyrimidine analogues Cytarabine 36 24.96 (17.94,34.74) 24.94 (17.93,34.70) 24.94 (809.55) 3.90 (3.42,4.38) Other antimycotics for systemic use Caspofungin 4 21.83 (8.18,58.25) 21.81 (8.18,58.17) 21.81 (79.25) 2.08 (0.79,3.37) Other monoclonal antibodies and antibody drug conjugates Polatuzumab vedotin 3 19.83 (6.39,61.57) 19.82 (6.39,61.49) 19.82 (53.51) 1.80 (0.35,3.24) Heparin group Dalteparin 5 18.96 (7.88,45.62) 18.95 (7.88,45.57) 18.95 (84.75) 2.25 (1.07,3.43) Purine analogues Mercaptopurine 5 17.54 (7.29,42.21) 17.53 (7.29,42.17) 17.53 (77.72) 2.22 (1.04,3.40) Carbapenems Meropenem 6 16.41 (7.36,36.59) 16.40 (7.36,36.55) 16.40 (86.47) 2.36 (1.26,3.45) Interleukin inhibitors Tocilizumab 100 14.92 (12.19,18.26) 14.91 (12.18,18.25) 14.91 (1219.83) 3.64 (3.34,3.93) Interleukin inhibitors Canakinumab 12 13.83 (7.84,24.41) 13.83 (7.84,24.39) 13.83 (141.76) 2.79 (1.99,3.60) Glucocorticoids Prednisolone 43 13.79 (10.19,18.67) 13.78 (10.18,18.66) 13.78 (496.67) 3.39 (2.95,3.83) Other antibacterials Linezolid 13 12.06 (6.99,20.82) 12.06 (6.99,20.81) 12.06 (130.83) 2.75 (1.97,3.52) Purine analogues Fludarabine 10 11.34 (6.09,21.12) 11.34 (6.09,21.11) 11.34 (93.71) 2.54 (1.67,3.42) Glucocorticoids Dexamethasone 39 10.43 (7.59,14.33) 10.43 (7.59,14.33) 10.43 (324.75) 3.05 (2.59,3.51) Preparations inhibiting uric acid production Allopurinol 10 10.32 (5.54,19.22) 10.32 (5.54,19.21) 10.32 (83.67) 2.48 (1.60,3.35) DIHF: drug-induced hypofibrinogenemia. [insert Table 3 here] [insert Table 4 here] Discussion We identified 1,661 cases of DIHF in the past two decades. Of these, 43.65% resulted in hospitalization, 12.04% were life-threatening, and 16.62% resulted in death. On average, hypofibrinogenemia occurred ten days after drug administration, with 52 drugs potentially associated with this ADE. We identified 112 cases of hypofibrinogenemia attributed to tigecycline, demonstrating a high signal intensity. Tigecycline, a synthetic glycylcycline antibiotic, is noted for its broad-spectrum activity, especially against multidrug-resistant bacteria. Retrospective studies report varying incidence rates of hypofibrinogenemia among patients receiving tigecycline: 50.5%-95.0% in Chinese studies [ 10 – 14 ], compared to lower rates of 5% and 19.4% in other studies [ 15 , 16 ], potentially indicating racial disparities. Most patients treated with tigecycline developed hypofibrinogenemia within 3–9 days [ 10 , 14 , 17 ], with fibrinogen levels dropping to 1.0–2.0 g/L, and a smaller proportion (13.3%-19.5%) experiencing levels below 1.0 g/L [ 10 , 13 ]. Following the cessation of tigecycline, fibrinogen levels typically normalized within 3–10 days [ 14 , 17 , 18 ]. In critically ill patients, fibrinogen reductions greater than 30% occurred within 6–7 days of treatment [ 11 , 19 ], with levels returning to normal roughly three days after stopping the drug [ 19 ]. Bleeding events, primarily gastrointestinal (57.6%) and mucocutaneous hemorrhages (21.2%), were observed in 6.4%-10.1% of patients [ 12 , 16 ]. In patients who received fibrinogen concentrate during tigecycline treatment, only 22.7% returned to normal fibrinogen levels [ 10 ]. For other synthetic tetracyclines, eravacycline showed a high signal strength. Rausch et al. reported six cases of eravacycline-associated hypofibrinogenemia, with fibrinogen levels decreasing by 58.9%-68.4% and normalizing 3–9 days post-discontinuation [ 20 ]. However, in longer-term case series, neither fibrinogen declines nor bleeding complications were observed in omadacycline therapy beyond 30 days [ 20 , 21 ]. This suggests that drug formulation or structure differences might contribute to the distinct impacts on fibrinogen levels. The risk factors associated with tigecycline-induced hypofibrinogenemia remain a subject of debate. Recently, Guo et al. developed a nomogram to predict this condition, incorporating variables such as age, total dose, baseline fibrinogen levels, prothrombin time (PT), comorbidities, and concomitant use of voriconazole for the general population. Predictions for patients with malignant hematologic diseases include total dose, baseline fibrinogen, PT, activated partial thromboplastin time, white blood cell count, and concurrent voriconazole use [ 5 ]. Multiple retrospective studies have commonly reported age, dosage, treatment duration, and baseline fibrinogen levels as significant risk factors. Specifically, an age ≥ 80 years [ 13 , 22 ] and a baseline fibrinogen level ≤ 3.5-4 g/L [ 10 , 13 ] have been independently linked to hypofibrinogenemia. Regarding treatment specifics, a long duration (≥ 6 days for high-dose tigecycline; ≥ 11 days for low-dose tigecycline) and a high daily dose (200 mg/d) have been identified as risk factors in multicenter retrospective studies [ 16 , 22 ]. Additionally, a treatment duration > 4 weeks [ 16 ] and a cumulative dose ≥ 1,000 mg [ 10 ] have also been associated with hypofibrinogenemia. Multivariate regression analysis further suggests a possible link between tigecycline-induced hypofibrinogenemia and a baseline PT > 14 s, total bilirubin > 21 µmol/L [ 10 ], a protein C level > 25 mg/dL [ 16 ], and intra-abdominal infections [ 11 ]. Conversely, skin and soft tissue infections may be protective factors [ 10 ]. Yang et al. [ 23 ] investigated the relationship between serum tigecycline concentration and hypofibrinogenemia, finding that a serum concentration ≥ 0.645 mg/L at 6 hours post-dosing (C 1/2 ) might serve as the optimal threshold for toxicity prediction. The role of renal function in hypofibrinogenemia is contentious. Zhang et al. [ 12 ] reported that renal failure could exacerbate the condition, whereas Campany-Herrero et al. [ 16 ] observed no such correlation. Continuous renal replacement therapy, due to potential fibrinogen adsorption by the therapy membrane [ 24 ], constitutes a risk factor, in contrast to chronic kidney disease or elevated serum creatinine [ 10 ]. A common mechanism by which antibiotics influence coagulation is inhibiting vitamin K synthesis due to reduced intestinal flora. However, vitamin K is not essential for fibrinogen synthesis [ 22 ], and coagulopathies are generally not reversed by vitamin K supplementation [ 18 ]. Although interleukin-6 (IL-6) improves fibrinogen levels by promoting its gene expression, tigecycline may lower fibrinogen levels by suppressing IL-6 synthesis [ 22 , 25 ]. Fibrinogen production occurs exclusively in the liver [ 26 ], where tigecycline, at supratherapeutic levels, has been shown to cause a rapid loss of mitochondrial activity in liver cells [ 27 ]. Tigecycline undergoes significant metabolism in the liver, with drug clearance rates reduced by 25% and 55% in patients with Child-Pugh B and C liver impairment, respectively [ 28 ]. This reduced clearance rate in patients with severe hepatic impairment may lead to a higher tigecycline pharmacokinetic/pharmacodynamic (PK/PD) target attainment [ 29 ], which has been associated with the development of hypofibrinogenemia [ 23 ]. However, multiple case reports and retrospective studies have not observed significant increases in liver enzymes such as alanine aminotransferase, aspartate aminotransferase, total bilirubin, or creatinine levels during tigecycline therapy, even in cases of tigecycline-induced hypofibrinogenemia [ 19 , 30 – 33 ]. Tocilizumab, a recombinant humanized monoclonal antibody targeting IL-6 receptors [ 34 ], is used in the treatment of various inflammatory diseases, including rheumatic conditions, cytokine release syndrome, and severe COVID-19, all of which may exhibit significantly elevated IL-6 levels [ 35 , 36 ]. Fibrinogen biosynthesis, particularly during acute phase reactions, is positively regulated by IL-6 through the transcription of fibrinogen mRNA [ 25 ]. As an IL-6 receptor inhibitor, tocilizumab could suppress fibrinogen expression by blocking the IL-6 signaling pathway, potentially leading to prolonged hypofibrinogenemia. Current knowledge, derived primarily from case reports and small-scale studies [ 37 – 41 ], suggests that tocilizumab-induced hypofibrinogenemia occurs with a probability ranging from 29–76.47% [ 7 , 39 , 41 , 42 ]. Our retrospective analysis of 221 tocilizumab-treated patients from 2015 to 2023 revealed that 54.75% developed hypofibrinogenemia in a median of six days. In particular, the incidence was significantly higher in patients treated with COVID-19 and CAR-T therapy (74/103) compared to those with rheumatic diseases (25/67) (χ2 = 12.90, p < 0.001). Our findings also highlighted that infection, COVID-19, CAR-T therapy, and concurrent glucocorticoid use were independent risk factors for tocilizumab-induced hypofibrinogenemia. In contrast, high baseline fibrinogen levels and concurrent antirheumatic drug use had a protective effect (unpublished data). Although cumulative tocilizumab dose might influence hypofibrinogenemia occurrence [ 40 ], our data did not show a significant difference in cumulative doses between cases and controls. Baseline fibrinogen levels have been consistently a strong predictor of hypofibrinogenemia in multiple studies [ 5 , 13 , 43 ]. Clinical reports indicate that patients with systemic-onset juvenile idiopathic arthritis, COVID-19, and post-CAR-T therapy generally exhibit baseline fibrinogen levels above 4.0 g/L without tocilizumab treatment [ 7 , 44 , 45 ]. Following tocilizumab treatment for severe COVID-19 pneumonia, fibrinogen levels decreased to a median of 2.17 g/L within 10 days [ 44 ]. Similar trends were observed [ 46 ], although the incidence rate was not reported. In rheumatoid arthritis patients, while tocilizumab treatment typically reduces fibrinogen levels [ 37 , 42 , 47 ], not all patients show bleeding symptoms [ 37 , 47 ]. In our cohort, 52.9% of patients with severe and life-threatening hypofibrinogenemia experienced bleeding, compared to 20.2% with mild to moderate levels. Furthermore, patients with baseline fibrinogen levels between 2 and 4.4 g/L had a significantly higher risk of bleeding compared to those with levels above 4.4 g/L (95%CI: 1.037–3.026, p = 0.036) (unpublished data). These findings demonstrate the need to closely monitor serum fibrinogen levels in patients treated with tocilizumab, even when within the normal range, due to the increased risk of bleeding. Methotrexate, a folate antagonist with anti-proliferative, anti-metabolic, and anti-inflammatory effects, is widely used in treating acute leukemia, malignancy, and rheumatic disorders. Although a pharmacovigilance investigation based on the FAERS database from 2016 to 2022 indicated a strong correlation between methotrexate and hypofibrinogenemia [ 48 ], we did not find case reports or direct evidence supporting this association. Asparaginase, a critical component in the chemotherapy regimen for lymphoma, can impair the hepatic synthesis of fibrinogen and other coagulation proteins through asparagine depletion, potentially leading to hemorrhagic outcomes [ 49 ]. However, the association between asparaginase-induced hypofibrinogenemia and bleeding in acute lymphoblastic leukemia (ALL) patients presents conflicting evidence. Studies report that fibrinogen levels were reduced to below 1 g/L in 47.9%-73.0% of ALL patients [ 50 , 51 ] and below 0.5 g/L in 9%-13% of T-lymphoblastic lymphoma patients following L-asparaginase treatment [ 52 , 53 ]. Yet, Hunault-Berger et al. [ 51 ] and Orvain et al. [ 52 ] found no correlation between hemorrhage and fibrinogen levels < 0.5 g/L in ALL patients treated with L-asparaginase. The coagulation disorders induced by asparaginase are multifaceted. Contrary to the common understanding that hypofibrinogenemia increases bleeding risk, severe hypofibrinogenemia (fibrinogen < 0.5 g/L) might indicate a hypercoagulable state in ALL patients receiving L-asparaginase [ 53 ]. Additionally, blood coagulation activation coincides with the hemostatic derangement caused by L-asparaginase, evidenced by a threefold molar increase in the ratio of fibrinopeptide A to fibrinogen [ 54 ]. Comparisons of toxicities between two asparaginase formulations revealed that more patients treated with native L-asparaginase faced a higher risk of hypofibrinogenemia compared to those treated with pegylated asparaginase (86.4% vs 36.8%) [ 55 ]. Over the past two decades, the FAERS database recorded 83 spontaneously reported cases of hypofibrinogenemia associated with pegylated asparaginase and 35 cases with L-asparaginase. In lymphoma treatment, as asparaginase is typically combined with a chemotherapy regimen known to cause coagulation disorders, pinpointing the primary suspect drug for hypofibrinogenemia is challenging. Additionally, the potential impact of hematological malignancy complications, such as disseminated intravascular coagulation and sepsis, cannot be disregarded. Among the top 20 drugs associated with adverse events, three were glucocorticoids: prednisolone, dexamethasone, and prednisone. Glucocorticoid-associated hypofibrinogenemia is frequently reported in patients with lymphocytic leukemia. Specifically, at the diagnosis of B-cell ALL, grade 1 hypofibrinogenemia was observed in 5% of patients before the commencement of treatment [ 56 , 57 ]. A notable decrease in plasma fibrinogen levels was observed in 64% of patients within a median of 7 days (range 3 to 28 days) following the initiation of glucocorticoid therapy [ 56 ]. A small cohort study indicated a possible trend towards glucocorticoid-associated hypofibrinogenemia in older B-cell ALL patients, identifying this condition in 3 out of 4 patients aged over 65 years [ 58 ]; however, these findings have not been corroborated by larger case studies [ 56 ]. Furthermore, Buzzatti et al. [ 56 ] discovered a significant association between the BCR-ABL1 rearrangement and glucocorticoid-related hypofibrinogenemia in B-cell ALL patients, even in the absence of significant liver function abnormalities (p = 0.00158). Alteplase, a commonly used recombinant tissue plasminogen activator (rt-PA), is indicated for treating acute ischemic stroke within a 4.5-hour window. Significant and persistent hypofibrinogenemia, with fibrinogen levels dropping below 1 g/L, was observed in 14% of patients 24 hours post-administration [ 59 ]. In a large-scale study, approximately 20% of patients with consecutive strokes treated with alteplase experienced significant hypofibrinogenemia, a decrease of 2 g/L or 50% from baseline. The nadir of fibrinogen levels occurred 6 hours post-administration and did not return to baseline by 24 hours [ 60 ]. Overall, 13% of acute ischemic stroke patients develop hypofibrinogenemia following rt-PA treatment, with severe cases noted in nearly 5% of patients [ 61 ]. Fibrinogen levels were reported to decrease by 25% within 2 hours of rt-PA administration [ 62 ], eventually dropping to 1.33 g/L (60%), and remained below normal even after fibrinogen concentrate infusion [ 63 ]. In case studies, fibrinogen levels decreased from normal to < 0.25 g/L within 4.5 hours following rt-PA administration in stroke patients, normalizing 35 hours later [ 64 ]. This rt-PA-related hypofibrinogenemia significantly increases the risk of major bleeding events, such as symptomatic intracranial hemorrhage [ 65 ]. The persistence of subnormal fibrinogen levels complicates the use of antiplatelet or anticoagulant therapy, heightening the risk of bleeding. Consequently, the implementation of antiplatelet therapy in these patients requires careful consideration. This study has several limitations. First, the number of DIHF reports within the FAERS database is limited, and the inclusion of reports by non-medical professionals may affect the completeness and accuracy of the findings. Additionally, since the ADE reports are predominantly from Europe and North America, ethnic differences could introduce biases into the results. Conclusion This pharmacovigilance analysis identified 52 drugs potentially associated with hypofibrinogenemia, many of which are not included in their prescribing information. It is crucial to closely monitor the coagulation indicators during treatment with these high-risk drugs. The underlying mechanisms of hypofibrinogenemia associated with many of these drugs remain unclear, highlighting the need for further investigative research to better understand and mitigate this risk. Declarations Conflicts of interest The authors declare no conflicting interests. Funding This manuscript was funded by the Capital Funds for Health Improvement and Research (No. 2024-2-5012); The Special research project on monitoring and evaluation of the use of key clinical drugs by the Committee for Drug evaluation of Chinese Research Hospital Association (No. Y2023FH-YWPJ03-101). Acknowledgment None References Lissitchkov T, Madan B, Djambas Khayat C, et al. Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients. J Thromb Haemost. 2020;18(4):815–24. 10.1111/jth.14727 . Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thromb Haemost. 2023;21(11):3005–15. 10.1016/j.jtha.2023.08.014 . Peyvandi F, Haertel S, Knaub S, et al. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost. 2006;4(7):1634–7. 10.1111/j.1538-7836.2006.02014.x . Franchini M, Lippi G. 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13:38:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5326354/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5326354/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11096-025-01867-6","type":"published","date":"2025-01-31T15:58:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69084610,"identity":"b311335b-0fc3-43ce-876c-331fc676f040","added_by":"auto","created_at":"2024-11-15 12:30:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":216009,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual reported hypofibrinogenemia cases in the US FDA adverse event reporting system (FAERS) from 2004 to 2024.\u003c/p\u003e","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5326354/v1/a31597039a355b90b5bc7d36.png"},{"id":75351355,"identity":"43a9d50b-4dd6-4c71-8bcd-7ab659843d56","added_by":"auto","created_at":"2025-02-03 16:10:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1340941,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5326354/v1/9de2c632-db95-4d80-b9c6-202a7db236ca.pdf"},{"id":69084611,"identity":"986fa8b8-b7f0-4a45-87fa-c271feb288dd","added_by":"auto","created_at":"2024-11-15 12:30:59","extension":"doc","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":147968,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementmaterial.doc","url":"https://assets-eu.researchsquare.com/files/rs-5326354/v1/c698d289613722046a98c42d.doc"}],"financialInterests":"","formattedTitle":"Pharmacovigilance analysis of drug-induced hypofibrinogenemia using the FDA Adverse Event Reporting System","fulltext":[{"header":"Impacts On Practice","content":"\u003cul\u003e\n \u003cli\u003eThis study suggests the need for improved surveillance and routine monitoring of coagulation parameters in patients treated with drugs identified as high-risk for drug-induced hypofibrinogenemia (DIHF).\u003c/li\u003e\n \u003cli\u003eThe findings support the inclusion of hypofibrinogenemia risks in the prescribing information for implicated drugs, which could help clinicians make safer drug management decisions.\u003c/li\u003e\n \u003cli\u003eEarly detection and intervention for DIHF, informed by these practices, could significantly improve patient outcomes.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eFibrinogen, a plasma glycoprotein synthesized exclusively by the liver, plays a central role in the hemostatic process, particularly in the formation and stabilization of clots [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Fibrinogen facilitates platelet aggregation in primary hemostasis by binding to platelets and supports tissue repair by adhering to endothelial cells [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Typically, healthy individuals exhibit plasma fibrinogen levels ranging from 2.0 to 4.0 g/L. Hypofibrinogenemia is diagnosed when levels drop below 2 g/L, with severe cases (fibrinogen\u0026thinsp;\u0026lt;\u0026thinsp;0.5 mg/L) often associated with bleeding in the nose and gastrointestinal tract, sometimes escalating to life-threatening hemorrhages [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These conditions are commonly managed with fresh frozen plasma or cryoprecipitate [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMedications represent a primary cause of hypofibrinogenemia, with increasing reports and small-scale retrospective clinical studies identifying drug-induced hypofibrinogenemia (DIHF), particularly associated with agents such as tigecycline, tocilizumab, and valproic acid [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, the distribution characteristics of DIHF and the incidences related to these drugs remain poorly defined in real-world settings. The discrepancies in risk factors reported by retrospective studies may arise from variations in sample sizes, data accuracy, degree of missing data, and selection biases. These risks are typically not highlighted in the prescribing information provided by drug manufacturers, potentially leading to oversight of this serious adverse reaction by clinicians. The US Food and Drug Administration Adverse Event Reporting System (FAERS), the largest global database for post-marketing adverse event reports [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], can be utilized to identify drugs frequently implicated in DIHF.\u003c/p\u003e\n\u003ch3\u003eAim\u003c/h3\u003e\n\u003cp\u003eThis study aimed to use FAERS to identify and analyze drugs frequently implicated in drug-induced hypofibrinogenemia.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eEthical approval\u003c/strong\u003e \u003cp\u003ewas not required, as only anonymous data was used.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData source and data cleaning procedures\u003c/h2\u003e \u003cp\u003eData spanning from the first quarter of 2004 to the first quarter of 2024 were retrieved from the FAERS database and imported into MySQL 5.7 for analysis. Duplicates were removed according to FDA guidelines; cases with identical ID and FDA_date were resolved by retaining the most recent entry based on the FDA_date. The analysis focused on the \"primary suspect\" drugs associated with hypofibrinogenemia. Brand names were converted to their approved generic counterparts. The search terms \"hypofibrinogenemia\" and \"blood fibrinogen decreased\" were used to isolate relevant adverse drug event (ADE) data. Reports that were undecipherable, unrelated to drugs, or related to nonrelevant indications were excluded. To ensure accuracy, the primary suspect drug names were cross-referenced on the FDA website and standardized with their generic names. Capitalization, spacing, and other extraneous characters in drug names were ignored, and misspelled drug names were corrected. Comprehensive ADE data, including patient demographics, report sources, drugs, reactions, indications, and outcomes, were extracted for further analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe relationship between hypofibrinogenemia and suspected drugs was evaluated using disproportionality analysis. To mitigate bias from any single algorithm, four standard disproportionality methods were used: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Medicines and Healthcare Products Regulatory Agency (MHRA) criteria, and Bayesian Confidence Propagation Neural Network (BCPNN) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The thresholds for these methods were set as follows: (1) ROR and PRR: a value\u0026thinsp;\u0026ge;\u0026thinsp;3 with a lower bound of the 95% confidence interval (95%CI)\u0026thinsp;\u0026gt;\u0026thinsp;1; (2) MHRA: a value\u0026thinsp;\u0026ge;\u0026thinsp;3, PRR\u0026thinsp;\u0026ge;\u0026thinsp;2, and χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;4; (3) BCPNN: information component (IC)\u0026thinsp;\u0026gt;\u0026thinsp;0. A drug-event pair was considered to have a strong signal of disproportionality if all four methods yielded significant results.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePrimary characteristics of hypofibrinogenemia cases\u003c/h2\u003e \u003cp\u003eBetween the first quarter of 2004 and the first quarter of 2024, 52,373,206 ADEs were reported in the FAERS database, including 17,627,340 distinct cases. Among these, 1,661 cases of hypofibrinogenemia associated with primary suspect drugs were identified, representing 0.0032% of all reported ADE cases. The annual distribution of these reports is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e[insert\u003c/em\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003ehere]\u003c/em\u003e\u003c/p\u003e \u003cp\u003eThe average age of the patients in the reported cases was 42.60\u0026thinsp;\u0026plusmn;\u0026thinsp;26.39 years. Detailed characteristics such as sex, outcome, reporter's profession, and reporter's country are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Male patients constituted 48.59% of the cases (807 individuals), slightly outnumbering female patients, who represented 36.97% (614 individuals). Most cases, 86.69% (1,440), were reported by health professionals. The countries with the highest number of reports were France (326 cases, 19.63%), the United States (279 cases, 16.80%), and China (210 cases, 12.64%). Among the reported cases, there were 276 deaths (16.62%) and 200 life-threatening cases (12.04%).\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\u003ePrimary characteristics of hypofibrinogenemia cases in the US FDA adverse event reporting system (FAERS), 2004 to 2024\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\u003eCharacteristics\u003c/p\u003e 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colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReporting country\u003c/b\u003e\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\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e326\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19.63\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e279\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.80\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.64\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.06\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\u003e327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome\u003c/b\u003e\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\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-Threatening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e725\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital Anomaly\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\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRequired Intervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Serious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69.30\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\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eDIHF: drug-induced hypofibrinogenemia\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e[insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003ehere]\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHypofibrinogenemia signal detection\u003c/h3\u003e\n\u003cp\u003eA total of 276 primary suspect drugs were identified, with the top 100 drugs reporting more than three cases each for hypofibrinogenemia signals. Of these, 53 drugs showed a positive signal and were categorized using the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system. The five most notable drug categories included glucocorticoids (ATC code H02A, 5 drugs), the heparin group (ATC code B01A, 3 drugs), antineoplastic cell and gene therapy (ATC code L01X, 3 drugs), other antineoplastic agents (ATC code L01X, 3 drugs), and interleukin inhibitors (ATC code L04A, 3 drugs), detailed in 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\u003eClassification of positive drugs according to the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) system\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO ATC category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of drugs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDrugs\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood substitutes and perfusion solutions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlbumin Human\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntihemorrhagics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFactor VIII Inhibitor Bypassing Fraction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntithrombotic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFondaparinux, Dabigatran, Argatroban, Tenecteplase, Alteplase, Enoxaparin, Dalteparin Heparin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticosteroids for systemic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHydrocortisone, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntimycotics for systemic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCaspofungin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibacterials for systemic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLinezolid, Azithromycin, Cilastatin;Imipenem, Meropenem, Piperacillin;Tazobactam, Eravacycline, Tigecycline\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppressants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanakinumab, Tocilizumab, Anakinra, Antithymocyte Immunoglobulin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunostimulants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAldesleukin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eArsenic Trioxide, Pegaspargase, Asparaginase\u003c/p\u003e \u003cp\u003eBrexucabtagene Autoleucel, Tisagenlecleucel, Axicabtagene Ciloleucel, Bortezomib, Oxaliplatin, Polatuzumab Vedotin, Blinatumomab, Imatinib, Daunorubicin, Doxorubicin, Vincristine, Cytarabine, Fludarabine, Mercaptopurine, Methotrexate, Cyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntigout preparations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAllopurinol\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntiepileptics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLamotrigine, Valproic Acid\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntiprotozoals\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHydroxychloroquine\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\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCrotalidae polyvalent immune Fab\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 \u003cem\u003e[insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cem\u003ehere]\u003c/em\u003e\u003c/p\u003e \u003cp\u003eThe drugs were further analyzed and ranked by the number of cases (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and signal strength (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), according to WHO ATC classifications. The five drugs with the highest number of cases were methotrexate (124 cases), tigecycline (119 cases), tocilizumab (100 cases), pegaspargase (83 cases), and alteplase (3,478 cases). The drugs with the strongest signals based on ROR were eravacycline (ROR 2173.84, 95% CI 1208.80-3909.30), tigecycline (ROR 747.34, 95% CI 619.03-902.24), crotalidae polyvalent immune Fab (ROR 407.67, 95% CI 291.07-570.99), pegaspargase (ROR 216.06, 95% CI 173.15-269.61), and asparaginase (ROR 184.93, 95% CI 132.18-258.72). A drug was confirmed to have a positive signal when all ROR, PRR, Chi-Square, and IC signals were generated. Six drugs were excluded from the positive signal list based on these criteria.\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\u003eSignal detection of drug-induced hypofibrinogenemia (top 30 drugs, ranked by number of cases)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO ATC category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDIHF\u003c/p\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR\u003c/p\u003e \u003cp\u003eROR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003cp\u003ePRR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMHRA\u003c/p\u003e \u003cp\u003ePRR (χ\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBCPNN\u003c/p\u003e \u003cp\u003eIC (IC\u0026thinsp;\u0026plusmn;\u0026thinsp;2SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolic Acid Analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethotrexate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.78\u003c/p\u003e \u003cp\u003e(7.31,10.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.78\u003c/p\u003e \u003cp\u003e(7.31,10.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.78\u003c/p\u003e \u003cp\u003e(791.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.95\u003c/p\u003e \u003cp\u003e(2.69,3.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecyclines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e747.34\u003c/p\u003e \u003cp\u003e(619.03,902.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e731.24\u003c/p\u003e \u003cp\u003e(607.98,879.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e731.24\u003c/p\u003e \u003cp\u003e(80575.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.67\u003c/p\u003e \u003cp\u003e(1.80,2.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterleukin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTocilizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.92\u003c/p\u003e \u003cp\u003e(12.19,18.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.91\u003c/p\u003e \u003cp\u003e(12.18,18.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.91\u003c/p\u003e \u003cp\u003e(1219.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.64\u003c/p\u003e \u003cp\u003e(3.34,3.93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Antineoplastic Agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePegaspargase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e216.06\u003c/p\u003e \u003cp\u003e(173.15,269.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e214.67\u003c/p\u003e \u003cp\u003e(172.27,267.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e214.67\u003c/p\u003e \u003cp\u003e(16771.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.90\u003c/p\u003e \u003cp\u003e(5.58,6.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnzymes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlteplase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.97\u003c/p\u003e \u003cp\u003e(52.94,89.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.82\u003c/p\u003e \u003cp\u003e(52.86,89.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68.82\u003c/p\u003e \u003cp\u003e(3679.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.96\u003c/p\u003e \u003cp\u003e(4.58,5.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVinca alkaloids and analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVincristine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69.39\u003c/p\u003e \u003cp\u003e(51.42,93.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69.25\u003c/p\u003e \u003cp\u003e(51.34,93.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e69.25\u003c/p\u003e \u003cp\u003e(2881.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.77\u003c/p\u003e \u003cp\u003e(4.33,5.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValproic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValproic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.64\u003c/p\u003e \u003cp\u003e(7.12,13.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.64\u003c/p\u003e \u003cp\u003e(7.12,13.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.64\u003c/p\u003e \u003cp\u003e(324.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.98\u003c/p\u003e \u003cp\u003e(2.54,3.42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.79\u003c/p\u003e \u003cp\u003e(10.19,18.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.78\u003c/p\u003e \u003cp\u003e(10.18,18.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.78\u003c/p\u003e \u003cp\u003e(496.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.39\u003c/p\u003e \u003cp\u003e(2.95,3.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.43\u003c/p\u003e \u003cp\u003e(7.59,14.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.43\u003c/p\u003e \u003cp\u003e(7.59,14.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.43\u003c/p\u003e \u003cp\u003e(324.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003cp\u003e(2.59,3.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic cell and gene therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTisagenlecleucel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.50\u003c/p\u003e \u003cp\u003e(61.23,116.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84.28\u003c/p\u003e \u003cp\u003e(61.12,116.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84.28\u003c/p\u003e \u003cp\u003e(3055.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.74\u003c/p\u003e \u003cp\u003e(4.27,5.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePyrimidine analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytarabine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.96\u003c/p\u003e \u003cp\u003e(17.94,34.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.94\u003c/p\u003e \u003cp\u003e(17.93,34.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.94\u003c/p\u003e \u003cp\u003e(809.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.90\u003c/p\u003e \u003cp\u003e(3.42,4.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic cell and gene therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAxicabtagene ciloleucel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.09\u003c/p\u003e \u003cp\u003e(40.12,78.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56.00\u003c/p\u003e \u003cp\u003e(40.08,78.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.00\u003c/p\u003e \u003cp\u003e(1850.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.46\u003c/p\u003e \u003cp\u003e(3.97,4.94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antineoplastic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsparaginase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e184.93\u003c/p\u003e \u003cp\u003e(132.18,258.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e183.88\u003c/p\u003e \u003cp\u003e(131.68,256.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e183.88\u003c/p\u003e \u003cp\u003e(6232.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.91\u003c/p\u003e \u003cp\u003e(4.43,5.40)\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\u003eCrotalidae polyvalent immune Fab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e407.67\u003c/p\u003e \u003cp\u003e(291.07,570.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e402.58\u003c/p\u003e \u003cp\u003e(288.62,561.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e402.58\u003c/p\u003e \u003cp\u003e(13725.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.05\u003c/p\u003e \u003cp\u003e(4.56,5.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCR-ABL tyrosine kinase inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003cp\u003e(4.02,8.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003cp\u003e(4.02,8.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003cp\u003e(116.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.30\u003c/p\u003e \u003cp\u003e(1.78,2.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrednisone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.66\u003c/p\u003e \u003cp\u003e(6.00,12.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.66\u003c/p\u003e \u003cp\u003e(6.00,12.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.66\u003c/p\u003e \u003cp\u003e(192.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.77\u003c/p\u003e \u003cp\u003e(2.24,3.30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnthracyclines and related substances\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDoxorubicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.34\u003c/p\u003e \u003cp\u003e(4.03,9.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.34\u003c/p\u003e \u003cp\u003e(4.03,9.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.34\u003c/p\u003e \u003cp\u003e(84.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.31\u003c/p\u003e \u003cp\u003e(1.66,2.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antiepileptics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLamotrigine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.22\u003c/p\u003e \u003cp\u003e(2.05,5.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.22\u003c/p\u003e \u003cp\u003e(2.05,5.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.22\u003c/p\u003e \u003cp\u003e(28.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.53\u003c/p\u003e \u003cp\u003e(0.88, 2.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNitrogen mustard analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.55\u003c/p\u003e \u003cp\u003e(4.06,10.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.55\u003c/p\u003e \u003cp\u003e(4.06,10.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.55\u003c/p\u003e \u003cp\u003e(79.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.31\u003c/p\u003e \u003cp\u003e(1.63,3.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDirect thrombin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDabigatran\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.20\u003c/p\u003e \u003cp\u003e(1.96,5.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.20\u003c/p\u003e \u003cp\u003e(1.96,5.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.20\u003c/p\u003e \u003cp\u003e(24.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003cp\u003e(0.79,2.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic cell and gene therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrexucabtagene autoleucel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e144.53\u003c/p\u003e \u003cp\u003e(86.83,240.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e143.88\u003c/p\u003e \u003cp\u003e(86.64,238.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e143.88\u003c/p\u003e \u003cp\u003e(2109.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003cp\u003e(3.13,4.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnthracyclines and related substances\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDaunorubicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.36\u003c/p\u003e \u003cp\u003e(43.32,124.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73.19\u003c/p\u003e \u003cp\u003e(43.28,123.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e73.19\u003c/p\u003e \u003cp\u003e(988.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.65\u003c/p\u003e \u003cp\u003e(2.90,4.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacrolides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAzithromycin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.68\u003c/p\u003e \u003cp\u003e(3.29,9.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.68\u003c/p\u003e \u003cp\u003e(3.29,9.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.68\u003c/p\u003e \u003cp\u003e(49.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003cp\u003e(1.31,2.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatinum Compounds\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOxaliplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.95\u003c/p\u003e \u003cp\u003e(2.29,6.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.89\u003c/p\u003e \u003cp\u003e(3.19,30.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.89\u003c/p\u003e \u003cp\u003e(36.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003cp\u003e(0.17,3.06)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antibacterials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLinezolid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003cp\u003e(6.99,20.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003cp\u003e(6.99,20.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003cp\u003e(130.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.75\u003c/p\u003e \u003cp\u003e(1.97,3.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDirect thrombin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArgatroban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e173.46\u003c/p\u003e \u003cp\u003e(98.16,306.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e172.53\u003c/p\u003e \u003cp\u003e(97.93,303.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e172.53\u003c/p\u003e \u003cp\u003e(2031.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.60\u003c/p\u003e \u003cp\u003e(2.80,4.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeparin group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.70\u003c/p\u003e \u003cp\u003e(3.80,11.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.70\u003c/p\u003e \u003cp\u003e(3.80,11.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.70\u003c/p\u003e \u003cp\u003e(57.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.21\u003c/p\u003e \u003cp\u003e(1.41,3.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethylprednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.69\u003c/p\u003e \u003cp\u003e(2.66,8.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.69\u003c/p\u003e \u003cp\u003e(2.66,8.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.69\u003c/p\u003e \u003cp\u003e(34.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.86\u003c/p\u003e \u003cp\u003e(1.06,2.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterleukin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanakinumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.83\u003c/p\u003e \u003cp\u003e(7.84,24.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.83\u003c/p\u003e \u003cp\u003e(7.84,24.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.83\u003c/p\u003e \u003cp\u003e(141.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.79\u003c/p\u003e \u003cp\u003e(1.99,3.60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTetracyclines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEravacycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2173.84\u003c/p\u003e \u003cp\u003e(1208.80,3909.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2034.40\u003c/p\u003e \u003cp\u003e(1174.37,3524.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2034.40\u003c/p\u003e \u003cp\u003e(24213.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.69\u003c/p\u003e \u003cp\u003e(2.86,4.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eDIHF: drug-induced hypofibrinogenemia\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \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 detection of drug-induced hypofibrinogenemia (top 30 drugs, ranked by signal strength/ROR)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO ATC category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDIHF\u003c/p\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR\u003c/p\u003e \u003cp\u003eROR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003cp\u003ePRR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMHRA\u003c/p\u003e \u003cp\u003ePRR (χ\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBCPNN\u003c/p\u003e \u003cp\u003eIC (IC\u0026thinsp;\u0026plusmn;\u0026thinsp;2SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTetracyclines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEravacycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2173.84\u003c/p\u003e \u003cp\u003e(1208.80,3909.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2034.40\u003c/p\u003e \u003cp\u003e(1174.37,3524.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2034.40\u003c/p\u003e \u003cp\u003e(24213.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.69\u003c/p\u003e \u003cp\u003e(2.86,4.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecyclines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e747.34\u003c/p\u003e \u003cp\u003e(619.03,902.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e731.24\u003c/p\u003e \u003cp\u003e(607.98,879.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e731.24\u003c/p\u003e \u003cp\u003e(80575.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.67\u003c/p\u003e \u003cp\u003e(1.80,2.74)\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\u003eCrotalidae polyvalent immune Fab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e407.67\u003c/p\u003e \u003cp\u003e(291.07,570.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e402.58\u003c/p\u003e \u003cp\u003e(288.62,561.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e402.58\u003c/p\u003e \u003cp\u003e(13725.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.05\u003c/p\u003e \u003cp\u003e(4.56,5.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Antineoplastic Agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePegaspargase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e216.06\u003c/p\u003e \u003cp\u003e(173.15,269.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e214.67\u003c/p\u003e \u003cp\u003e(172.27,267.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e214.67\u003c/p\u003e \u003cp\u003e(16771.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.90\u003c/p\u003e \u003cp\u003e(5.58,6.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antineoplastic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsparaginase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e184.93\u003c/p\u003e \u003cp\u003e(132.18,258.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e183.88\u003c/p\u003e \u003cp\u003e(131.68,256.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e183.88\u003c/p\u003e \u003cp\u003e(6232.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.91\u003c/p\u003e \u003cp\u003e(4.43,5.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDirect thrombin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArgatroban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e173.46\u003c/p\u003e \u003cp\u003e(98.16,306.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e172.53\u003c/p\u003e \u003cp\u003e(97.93,303.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e172.53\u003c/p\u003e \u003cp\u003e(2031.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.60\u003c/p\u003e \u003cp\u003e(2.80,4.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic cell and gene therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrexucabtagene autoleucel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e144.53\u003c/p\u003e \u003cp\u003e(86.83,240.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e143.88\u003c/p\u003e \u003cp\u003e(86.64,238.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e143.88\u003c/p\u003e \u003cp\u003e(2109.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003cp\u003e(3.13,4.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic cell and gene therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTisagenlecleucel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.50\u003c/p\u003e \u003cp\u003e(61.23,116.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84.28\u003c/p\u003e \u003cp\u003e(61.12,116.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84.28\u003c/p\u003e \u003cp\u003e(3055.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.74\u003c/p\u003e \u003cp\u003e(4.27,5.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood coagulation factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFactor VIII inhibitor bypassing fraction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80.57\u003c/p\u003e \u003cp\u003e(40.19,161.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80.37\u003c/p\u003e \u003cp\u003e(40.16,160.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80.37\u003c/p\u003e \u003cp\u003e(624.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.03\u003c/p\u003e \u003cp\u003e(2.07,4.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnthracyclines and related substances\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDaunorubicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.36\u003c/p\u003e \u003cp\u003e(43.32,124.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73.19\u003c/p\u003e \u003cp\u003e(43.28,123.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e73.19\u003c/p\u003e \u003cp\u003e(988.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.65\u003c/p\u003e \u003cp\u003e(2.90,4.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVinca alkaloids and analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVincristine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69.39\u003c/p\u003e \u003cp\u003e(51.42,93.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69.25\u003c/p\u003e \u003cp\u003e(51.34,93.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e69.25\u003c/p\u003e \u003cp\u003e(2881.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.77\u003c/p\u003e \u003cp\u003e(4.33,5.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnzymes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlteplase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.97\u003c/p\u003e \u003cp\u003e(52.94,89.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.82\u003c/p\u003e \u003cp\u003e(52.86,89.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68.82\u003c/p\u003e \u003cp\u003e(3679.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.96\u003c/p\u003e \u003cp\u003e(4.58,5.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntineoplastic cell and gene therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAxicabtagene ciloleucel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.09\u003c/p\u003e \u003cp\u003e(40.12,78.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56.00\u003c/p\u003e \u003cp\u003e(40.08,78.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.00\u003c/p\u003e \u003cp\u003e(1850.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.46\u003c/p\u003e \u003cp\u003e(3.97,4.94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnzymes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTenecteplase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.92\u003c/p\u003e \u003cp\u003e(17.20,122.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45.86\u003c/p\u003e \u003cp\u003e(17.20,122.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45.86\u003c/p\u003e \u003cp\u003e(175.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.20\u003c/p\u003e \u003cp\u003e(0.91,3.49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood substitutes and plasma protein fractions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlbumin human\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.83\u003c/p\u003e \u003cp\u003e(19.38,77.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.79\u003c/p\u003e \u003cp\u003e(19.37,77.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.79\u003c/p\u003e \u003cp\u003e(293.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.90\u003c/p\u003e \u003cp\u003e(1.93,3.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterleukins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAldesleukin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.71\u003c/p\u003e \u003cp\u003e(9.57,92.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29.68\u003c/p\u003e \u003cp\u003e(9.57,92.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29.68\u003c/p\u003e \u003cp\u003e(82.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.86\u003c/p\u003e \u003cp\u003e(0.42,3.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antineoplastic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArsenic trioxide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.57\u003c/p\u003e \u003cp\u003e(9.95,70.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.54\u003c/p\u003e \u003cp\u003e(9.95,70.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26.54\u003c/p\u003e \u003cp\u003e(98.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.12\u003c/p\u003e \u003cp\u003e(0.83,3.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePyrimidine analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytarabine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.96\u003c/p\u003e \u003cp\u003e(17.94,34.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.94\u003c/p\u003e \u003cp\u003e(17.93,34.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.94\u003c/p\u003e \u003cp\u003e(809.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.90\u003c/p\u003e \u003cp\u003e(3.42,4.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antimycotics for systemic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCaspofungin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.83\u003c/p\u003e \u003cp\u003e(8.18,58.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.81\u003c/p\u003e \u003cp\u003e(8.18,58.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.81\u003c/p\u003e \u003cp\u003e(79.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003cp\u003e(0.79,3.37)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther monoclonal antibodies and antibody drug conjugates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePolatuzumab vedotin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.83\u003c/p\u003e \u003cp\u003e(6.39,61.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.82\u003c/p\u003e \u003cp\u003e(6.39,61.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19.82\u003c/p\u003e \u003cp\u003e(53.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.80\u003c/p\u003e \u003cp\u003e(0.35,3.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeparin group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDalteparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.96\u003c/p\u003e \u003cp\u003e(7.88,45.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.95\u003c/p\u003e \u003cp\u003e(7.88,45.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18.95\u003c/p\u003e \u003cp\u003e(84.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003cp\u003e(1.07,3.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePurine analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMercaptopurine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.54\u003c/p\u003e \u003cp\u003e(7.29,42.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.53\u003c/p\u003e \u003cp\u003e(7.29,42.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17.53\u003c/p\u003e \u003cp\u003e(77.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.22\u003c/p\u003e \u003cp\u003e(1.04,3.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbapenems\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.41\u003c/p\u003e \u003cp\u003e(7.36,36.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.40\u003c/p\u003e \u003cp\u003e(7.36,36.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16.40\u003c/p\u003e \u003cp\u003e(86.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.36\u003c/p\u003e \u003cp\u003e(1.26,3.45)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterleukin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTocilizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.92\u003c/p\u003e \u003cp\u003e(12.19,18.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.91\u003c/p\u003e \u003cp\u003e(12.18,18.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.91\u003c/p\u003e \u003cp\u003e(1219.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.64\u003c/p\u003e \u003cp\u003e(3.34,3.93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterleukin inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanakinumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.83\u003c/p\u003e \u003cp\u003e(7.84,24.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.83\u003c/p\u003e \u003cp\u003e(7.84,24.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.83\u003c/p\u003e \u003cp\u003e(141.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.79\u003c/p\u003e \u003cp\u003e(1.99,3.60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.79\u003c/p\u003e \u003cp\u003e(10.19,18.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.78\u003c/p\u003e \u003cp\u003e(10.18,18.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.78\u003c/p\u003e \u003cp\u003e(496.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.39\u003c/p\u003e \u003cp\u003e(2.95,3.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antibacterials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLinezolid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003cp\u003e(6.99,20.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003cp\u003e(6.99,20.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003cp\u003e(130.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.75\u003c/p\u003e \u003cp\u003e(1.97,3.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePurine analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFludarabine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.34\u003c/p\u003e \u003cp\u003e(6.09,21.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.34\u003c/p\u003e \u003cp\u003e(6.09,21.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.34\u003c/p\u003e \u003cp\u003e(93.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.54\u003c/p\u003e \u003cp\u003e(1.67,3.42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.43\u003c/p\u003e \u003cp\u003e(7.59,14.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.43\u003c/p\u003e \u003cp\u003e(7.59,14.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.43\u003c/p\u003e \u003cp\u003e(324.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003cp\u003e(2.59,3.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreparations inhibiting uric acid production\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAllopurinol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.32\u003c/p\u003e \u003cp\u003e(5.54,19.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.32\u003c/p\u003e \u003cp\u003e(5.54,19.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.32\u003c/p\u003e \u003cp\u003e(83.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.48\u003c/p\u003e \u003cp\u003e(1.60,3.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eDIHF: drug-induced hypofibrinogenemia.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e[insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cem\u003ehere]\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003e[insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e \u003cem\u003ehere]\u003c/em\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe identified 1,661 cases of DIHF in the past two decades. Of these, 43.65% resulted in hospitalization, 12.04% were life-threatening, and 16.62% resulted in death. On average, hypofibrinogenemia occurred ten days after drug administration, with 52 drugs potentially associated with this ADE.\u003c/p\u003e \u003cp\u003eWe identified 112 cases of hypofibrinogenemia attributed to tigecycline, demonstrating a high signal intensity. Tigecycline, a synthetic glycylcycline antibiotic, is noted for its broad-spectrum activity, especially against multidrug-resistant bacteria. Retrospective studies report varying incidence rates of hypofibrinogenemia among patients receiving tigecycline: 50.5%-95.0% in Chinese studies [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], compared to lower rates of 5% and 19.4% in other studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], potentially indicating racial disparities. Most patients treated with tigecycline developed hypofibrinogenemia within 3\u0026ndash;9 days [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], with fibrinogen levels dropping to 1.0\u0026ndash;2.0 g/L, and a smaller proportion (13.3%-19.5%) experiencing levels below 1.0 g/L [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Following the cessation of tigecycline, fibrinogen levels typically normalized within 3\u0026ndash;10 days [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In critically ill patients, fibrinogen reductions greater than 30% occurred within 6\u0026ndash;7 days of treatment [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], with levels returning to normal roughly three days after stopping the drug [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Bleeding events, primarily gastrointestinal (57.6%) and mucocutaneous hemorrhages (21.2%), were observed in 6.4%-10.1% of patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn patients who received fibrinogen concentrate during tigecycline treatment, only 22.7% returned to normal fibrinogen levels [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. For other synthetic tetracyclines, eravacycline showed a high signal strength. Rausch et al. reported six cases of eravacycline-associated hypofibrinogenemia, with fibrinogen levels decreasing by 58.9%-68.4% and normalizing 3\u0026ndash;9 days post-discontinuation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, in longer-term case series, neither fibrinogen declines nor bleeding complications were observed in omadacycline therapy beyond 30 days [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This suggests that drug formulation or structure differences might contribute to the distinct impacts on fibrinogen levels.\u003c/p\u003e \u003cp\u003eThe risk factors associated with tigecycline-induced hypofibrinogenemia remain a subject of debate. Recently, Guo et al. developed a nomogram to predict this condition, incorporating variables such as age, total dose, baseline fibrinogen levels, prothrombin time (PT), comorbidities, and concomitant use of voriconazole for the general population. Predictions for patients with malignant hematologic diseases include total dose, baseline fibrinogen, PT, activated partial thromboplastin time, white blood cell count, and concurrent voriconazole use [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Multiple retrospective studies have commonly reported age, dosage, treatment duration, and baseline fibrinogen levels as significant risk factors. Specifically, an age\u0026thinsp;\u0026ge;\u0026thinsp;80 years [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and a baseline fibrinogen level\u0026thinsp;\u0026le;\u0026thinsp;3.5-4 g/L [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] have been independently linked to hypofibrinogenemia. Regarding treatment specifics, a long duration (\u0026ge;\u0026thinsp;6 days for high-dose tigecycline; \u0026ge; 11 days for low-dose tigecycline) and a high daily dose (200 mg/d) have been identified as risk factors in multicenter retrospective studies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Additionally, a treatment duration\u0026thinsp;\u0026gt;\u0026thinsp;4 weeks [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and a cumulative dose\u0026thinsp;\u0026ge;\u0026thinsp;1,000 mg [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] have also been associated with hypofibrinogenemia. Multivariate regression analysis further suggests a possible link between tigecycline-induced hypofibrinogenemia and a baseline PT\u0026thinsp;\u0026gt;\u0026thinsp;14 s, total bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;21 \u0026micro;mol/L [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], a protein C level\u0026thinsp;\u0026gt;\u0026thinsp;25 mg/dL [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and intra-abdominal infections [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Conversely, skin and soft tissue infections may be protective factors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Yang et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] investigated the relationship between serum tigecycline concentration and hypofibrinogenemia, finding that a serum concentration\u0026thinsp;\u0026ge;\u0026thinsp;0.645 mg/L at 6 hours post-dosing (C\u003csub\u003e1/2\u003c/sub\u003e) might serve as the optimal threshold for toxicity prediction. The role of renal function in hypofibrinogenemia is contentious. Zhang et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] reported that renal failure could exacerbate the condition, whereas Campany-Herrero et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] observed no such correlation. Continuous renal replacement therapy, due to potential fibrinogen adsorption by the therapy membrane [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], constitutes a risk factor, in contrast to chronic kidney disease or elevated serum creatinine [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA common mechanism by which antibiotics influence coagulation is inhibiting vitamin K synthesis due to reduced intestinal flora. However, vitamin K is not essential for fibrinogen synthesis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and coagulopathies are generally not reversed by vitamin K supplementation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although interleukin-6 (IL-6) improves fibrinogen levels by promoting its gene expression, tigecycline may lower fibrinogen levels by suppressing IL-6 synthesis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Fibrinogen production occurs exclusively in the liver [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], where tigecycline, at supratherapeutic levels, has been shown to cause a rapid loss of mitochondrial activity in liver cells [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Tigecycline undergoes significant metabolism in the liver, with drug clearance rates reduced by 25% and 55% in patients with Child-Pugh B and C liver impairment, respectively [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This reduced clearance rate in patients with severe hepatic impairment may lead to a higher tigecycline pharmacokinetic/pharmacodynamic (PK/PD) target attainment [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], which has been associated with the development of hypofibrinogenemia [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, multiple case reports and retrospective studies have not observed significant increases in liver enzymes such as alanine aminotransferase, aspartate aminotransferase, total bilirubin, or creatinine levels during tigecycline therapy, even in cases of tigecycline-induced hypofibrinogenemia [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTocilizumab, a recombinant humanized monoclonal antibody targeting IL-6 receptors [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], is used in the treatment of various inflammatory diseases, including rheumatic conditions, cytokine release syndrome, and severe COVID-19, all of which may exhibit significantly elevated IL-6 levels [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Fibrinogen biosynthesis, particularly during acute phase reactions, is positively regulated by IL-6 through the transcription of fibrinogen mRNA [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. As an IL-6 receptor inhibitor, tocilizumab could suppress fibrinogen expression by blocking the IL-6 signaling pathway, potentially leading to prolonged hypofibrinogenemia. Current knowledge, derived primarily from case reports and small-scale studies [\u003cspan additionalcitationids=\"CR38 CR39 CR40\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], suggests that tocilizumab-induced hypofibrinogenemia occurs with a probability ranging from 29\u0026ndash;76.47% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur retrospective analysis of 221 tocilizumab-treated patients from 2015 to 2023 revealed that 54.75% developed hypofibrinogenemia in a median of six days. In particular, the incidence was significantly higher in patients treated with COVID-19 and CAR-T therapy (74/103) compared to those with rheumatic diseases (25/67) (χ2\u0026thinsp;=\u0026thinsp;12.90, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Our findings also highlighted that infection, COVID-19, CAR-T therapy, and concurrent glucocorticoid use were independent risk factors for tocilizumab-induced hypofibrinogenemia. In contrast, high baseline fibrinogen levels and concurrent antirheumatic drug use had a protective effect (unpublished data). Although cumulative tocilizumab dose might influence hypofibrinogenemia occurrence [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], our data did not show a significant difference in cumulative doses between cases and controls.\u003c/p\u003e \u003cp\u003eBaseline fibrinogen levels have been consistently a strong predictor of hypofibrinogenemia in multiple studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Clinical reports indicate that patients with systemic-onset juvenile idiopathic arthritis, COVID-19, and post-CAR-T therapy generally exhibit baseline fibrinogen levels above 4.0 g/L without tocilizumab treatment [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Following tocilizumab treatment for severe COVID-19 pneumonia, fibrinogen levels decreased to a median of 2.17 g/L within 10 days [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Similar trends were observed [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], although the incidence rate was not reported. In rheumatoid arthritis patients, while tocilizumab treatment typically reduces fibrinogen levels [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], not all patients show bleeding symptoms [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In our cohort, 52.9% of patients with severe and life-threatening hypofibrinogenemia experienced bleeding, compared to 20.2% with mild to moderate levels. Furthermore, patients with baseline fibrinogen levels between 2 and 4.4 g/L had a significantly higher risk of bleeding compared to those with levels above 4.4 g/L (95%CI: 1.037\u0026ndash;3.026, p\u0026thinsp;=\u0026thinsp;0.036) (unpublished data). These findings demonstrate the need to closely monitor serum fibrinogen levels in patients treated with tocilizumab, even when within the normal range, due to the increased risk of bleeding.\u003c/p\u003e \u003cp\u003eMethotrexate, a folate antagonist with anti-proliferative, anti-metabolic, and anti-inflammatory effects, is widely used in treating acute leukemia, malignancy, and rheumatic disorders. Although a pharmacovigilance investigation based on the FAERS database from 2016 to 2022 indicated a strong correlation between methotrexate and hypofibrinogenemia [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], we did not find case reports or direct evidence supporting this association.\u003c/p\u003e \u003cp\u003eAsparaginase, a critical component in the chemotherapy regimen for lymphoma, can impair the hepatic synthesis of fibrinogen and other coagulation proteins through asparagine depletion, potentially leading to hemorrhagic outcomes [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. However, the association between asparaginase-induced hypofibrinogenemia and bleeding in acute lymphoblastic leukemia (ALL) patients presents conflicting evidence. Studies report that fibrinogen levels were reduced to below 1 g/L in 47.9%-73.0% of ALL patients [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] and below 0.5 g/L in 9%-13% of T-lymphoblastic lymphoma patients following L-asparaginase treatment [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Yet, Hunault-Berger et al. [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] and Orvain et al. [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] found no correlation between hemorrhage and fibrinogen levels\u0026thinsp;\u0026lt;\u0026thinsp;0.5 g/L in ALL patients treated with L-asparaginase. The coagulation disorders induced by asparaginase are multifaceted.\u003c/p\u003e \u003cp\u003eContrary to the common understanding that hypofibrinogenemia increases bleeding risk, severe hypofibrinogenemia (fibrinogen\u0026thinsp;\u0026lt;\u0026thinsp;0.5 g/L) might indicate a hypercoagulable state in ALL patients receiving L-asparaginase [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Additionally, blood coagulation activation coincides with the hemostatic derangement caused by L-asparaginase, evidenced by a threefold molar increase in the ratio of fibrinopeptide A to fibrinogen [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Comparisons of toxicities between two asparaginase formulations revealed that more patients treated with native L-asparaginase faced a higher risk of hypofibrinogenemia compared to those treated with pegylated asparaginase (86.4% vs 36.8%) [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Over the past two decades, the FAERS database recorded 83 spontaneously reported cases of hypofibrinogenemia associated with pegylated asparaginase and 35 cases with L-asparaginase. In lymphoma treatment, as asparaginase is typically combined with a chemotherapy regimen known to cause coagulation disorders, pinpointing the primary suspect drug for hypofibrinogenemia is challenging. Additionally, the potential impact of hematological malignancy complications, such as disseminated intravascular coagulation and sepsis, cannot be disregarded.\u003c/p\u003e \u003cp\u003eAmong the top 20 drugs associated with adverse events, three were glucocorticoids: prednisolone, dexamethasone, and prednisone. Glucocorticoid-associated hypofibrinogenemia is frequently reported in patients with lymphocytic leukemia. Specifically, at the diagnosis of B-cell ALL, grade 1 hypofibrinogenemia was observed in 5% of patients before the commencement of treatment [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. A notable decrease in plasma fibrinogen levels was observed in 64% of patients within a median of 7 days (range 3 to 28 days) following the initiation of glucocorticoid therapy [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. A small cohort study indicated a possible trend towards glucocorticoid-associated hypofibrinogenemia in older B-cell ALL patients, identifying this condition in 3 out of 4 patients aged over 65 years [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]; however, these findings have not been corroborated by larger case studies [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Furthermore, Buzzatti et al. [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e] discovered a significant association between the BCR-ABL1 rearrangement and glucocorticoid-related hypofibrinogenemia in B-cell ALL patients, even in the absence of significant liver function abnormalities (p\u0026thinsp;=\u0026thinsp;0.00158).\u003c/p\u003e \u003cp\u003eAlteplase, a commonly used recombinant tissue plasminogen activator (rt-PA), is indicated for treating acute ischemic stroke within a 4.5-hour window. Significant and persistent hypofibrinogenemia, with fibrinogen levels dropping below 1 g/L, was observed in 14% of patients 24 hours post-administration [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. In a large-scale study, approximately 20% of patients with consecutive strokes treated with alteplase experienced significant hypofibrinogenemia, a decrease of 2 g/L or 50% from baseline. The nadir of fibrinogen levels occurred 6 hours post-administration and did not return to baseline by 24 hours [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Overall, 13% of acute ischemic stroke patients develop hypofibrinogenemia following rt-PA treatment, with severe cases noted in nearly 5% of patients [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Fibrinogen levels were reported to decrease by 25% within 2 hours of rt-PA administration [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e], eventually dropping to 1.33 g/L (60%), and remained below normal even after fibrinogen concentrate infusion [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. In case studies, fibrinogen levels decreased from normal to \u0026lt;\u0026thinsp;0.25 g/L within 4.5 hours following rt-PA administration in stroke patients, normalizing 35 hours later [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. This rt-PA-related hypofibrinogenemia significantly increases the risk of major bleeding events, such as symptomatic intracranial hemorrhage [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. The persistence of subnormal fibrinogen levels complicates the use of antiplatelet or anticoagulant therapy, heightening the risk of bleeding. Consequently, the implementation of antiplatelet therapy in these patients requires careful consideration.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the number of DIHF reports within the FAERS database is limited, and the inclusion of reports by non-medical professionals may affect the completeness and accuracy of the findings. Additionally, since the ADE reports are predominantly from Europe and North America, ethnic differences could introduce biases into the results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis pharmacovigilance analysis identified 52 drugs potentially associated with hypofibrinogenemia, many of which are not included in their prescribing information. It is crucial to closely monitor the coagulation indicators during treatment with these high-risk drugs. The underlying mechanisms of hypofibrinogenemia associated with many of these drugs remain unclear, highlighting the need for further investigative research to better understand and mitigate this risk.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicting interests.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis manuscript was funded by the Capital Funds for Health Improvement and Research (No. 2024-2-5012); The Special research project on monitoring and evaluation of the use of key clinical drugs by the Committee for Drug evaluation of Chinese Research Hospital Association (No. Y2023FH-YWPJ03-101).\u003c/p\u003e\u003ch2\u003eAcknowledgment\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLissitchkov T, Madan B, Djambas Khayat C, et al. 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Vasc Endovascular Surg. 2013;47(7):519\u0026ndash;23. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1538574413497107\u003c/span\u003e\u003cspan address=\"10.1177/1538574413497107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-pharmacy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcp","sideBox":"Learn more about [International Journal of Clinical Pharmacy](https://www.springer.com/journal/11096)","snPcode":"11096","submissionUrl":"https://submission.nature.com/new-submission/11096/3","title":"International Journal of Clinical Pharmacy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Hypofibrinogenemia, FAERS database, Adverse drug event, Signal mining, Disproportionality","lastPublishedDoi":"10.21203/rs.3.rs-5326354/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5326354/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDrug-induced hypofibrinogenemia (DIHF) has received increasing scrutiny; however, the specific drugs involved remain poorly characterized. Hypofibrinogenemia can have significant clinical implications, including increased bleeding risks.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eThis study aimed to utilize the FDA Adverse Event Reporting System (FAERS) to identify and analyze drugs frequently implicated in drug-induced hypofibrinogenemia.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eA disproportionality analysis was conducted using FAERS data from January 2004 to March 2024. Various statistical tools were used, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio, Medicines and Healthcare Products Regulatory Agency metrics, and Bayesian confidence propagation neural network.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe analysis included 17,627,340 cases involving 52,373,206 adverse events, with 1,661 cases identified as hypofibrinogenemia, representing just 0.0032% of the total FAERS reports. The top five drugs associated with DIHF by case number were methotrexate (124 cases), tigecycline (119 cases), tocilizumab (100 cases), pegaspargase (83 cases), and alteplase (57 cases). The drugs ranked by signal strength included eravacycline (ROR 2173.84, 95% CI 1208.80-3909.30), tigecycline (ROR 747.34, 95% CI 619.03-902.24), crotalidae polyvalent immune Fab (ROR 407.67, 95% CI 291.07-570.99), pegaspargase (ROR 216.06, 95% CI 173.15-269.61), and asparaginase (ROR 184.93, 95% CI 132.18-258.72).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis analysis of FAERS data identified 52 drugs associated with hypofibrinogenemia, many of which do not mention this risk in their prescribing information. These findings demonstrate the need for improved pharmacovigilance and may serve as a reference for the prevention and early intervention of DIHF.\u003c/p\u003e","manuscriptTitle":"Pharmacovigilance analysis of drug-induced hypofibrinogenemia using the FDA Adverse Event Reporting System","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-15 12:30:54","doi":"10.21203/rs.3.rs-5326354/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-11-26T07:24:38+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-11-04T07:10:50+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-28T00:46:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"International Journal of Clinical Pharmacy","date":"2024-10-25T15:58:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-25T12:49:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Pharmacy","date":"2024-10-24T09:37:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-pharmacy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcp","sideBox":"Learn more about [International Journal of Clinical Pharmacy](https://www.springer.com/journal/11096)","snPcode":"11096","submissionUrl":"https://submission.nature.com/new-submission/11096/3","title":"International Journal of Clinical Pharmacy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dc7d7344-a6b6-45d0-aedb-2ccb3a274b88","owner":[],"postedDate":"November 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-03T16:04:12+00:00","versionOfRecord":{"articleIdentity":"rs-5326354","link":"https://doi.org/10.1007/s11096-025-01867-6","journal":{"identity":"international-journal-of-clinical-pharmacy","isVorOnly":false,"title":"International Journal of Clinical Pharmacy"},"publishedOn":"2025-01-31 15:58:07","publishedOnDateReadable":"January 31st, 2025"},"versionCreatedAt":"2024-11-15 12:30:54","video":"","vorDoi":"10.1007/s11096-025-01867-6","vorDoiUrl":"https://doi.org/10.1007/s11096-025-01867-6","workflowStages":[]},"version":"v1","identity":"rs-5326354","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5326354","identity":"rs-5326354","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}