Novel insights into post-marketing AEs associated with leuprorelin: A comprehensive analysis utilizing the FAERS database

Huawei Han: Writing – original draft, Software, Formal analysis, Data curation, Conceptualization. Xinping Bu: Methodology, Formal analysis, Conceptualization. Xinzhe Wang: Resources, Methodology, Formal analysis, Conceptualization. Shuai Chen: Software, Data curation. Ningsheng Tian: Software, Investigation, Data curation. Jie Jin: Supervision, Resources, Project administration. Qian Feng: Software, Data curation. Bo Ma: Software, Data curation. Jiasong Teng: Writing – original draft, Visualization, Validation, Supervision. Zhiwei Li: Writing – review & editing, Writing – original draft, Validation, Supervision.

Not applicable.

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This work was supported by the Foundation of Jiangsu Provincial Science and Technology Plan Special Fund Key R&D Plan Social Development Project ( BE2023787 ), the Elderly Health Research Project of 10.13039/100017962 Jiangsu Commission of Health ( LKZ2022008 ), and the Foundation of The Second Affiliated Hospital of 10.13039/501100007956 Nanjing University of Chinese Medicine ( SEZYB2023004 ).

Over the course of the study, we collected a total of 16,800,135 unique AERs from the FAERS database, among which 60,709 were specifically associated with leuprorelin ( Fig. 1 ). The demographic characteristics of leuprorelin-associated AEs are described in Table 2 . In the dataset of leuprorelin-linked AEs that we analyzed, there was a noticeable gender disparity: 65.82 % of the reports involved males, while females accounted for only 24.82 %. Additionally, the highest incidence of AEs was observed in patients over 65, who made up 31.45 % of the reports. From 2004 to 2023, there was a noticeable increase in AERs related to Leuprorelin. Consumers were the predominant reporters, contributing 34,116 cases (56.20 %), followed by pharmacists with 11,665 cases (19.21 %), and physicians with 8,945 cases (14.73 %). There were 15,716 cases reported in the United States (28.83 %). The most common serious medical events reported, aside for unspecified ones, included deaths, which accounted for 30.12 % (10,856 cases), hospitalizations at 24.57 % (8,855 cases), and disability conditions at 2.21 % (795 cases). AEs were most frequently reported within 7 days or after more than 60 days following treatment, making up 21.37 % and 20.87 % of cases, respectively. The leading indications for leuprorelin usage included prostate cancer (37,236 cases, 61.84 %), unspecified reasons (8,968 cases, 14.9 %), endometriosis (6,589 cases, 10.94 %), uterine leiomyoma (1,987 cases, 3.3 %), and precocious puberty (1,468 cases, 2.44 %). These findings are in line with FDA-approved indications and provide crucial insights into leuprorelin AE reporting patterns, helping to assess the drug's safety profile and clinical effectiveness. Table 2 Clinical characteristics of reports with leuprorelin from the FAERS database (2004 Q1–2023 Q4). Table 2 Factors Available case number, n Case proportion, % Gender female 14,966 24.65 male 39,956 65.82 unkown 5,787 9.53 Age <18 1,592 2.62 18∼65 10,215 16.83 ≥65 19,095 31.45 unknow 29,807 49.10 Reporter ( Top five ) Consumer 34,116 56.20 Pharmacist 11,665 19.21 Physician 8,945 14.73 Other health-professional 4,395 7.24 unkown 1,561 2.57 Reported countries ( Top five ) United States 15,716 28.83 Canada 13,348 24.48 other 9,260 16.99 Netherlands 5,350 9.81 Australia 4,109 7.54 Route ( Top five ) other 24,448 40.29 subcutaneous 24,279 40.02 intramuscular 11,626 19.16 transplacental 98 0.16 parenteral 78 0.13 Outcomes other serious 14,688 40.76 death 10,856 30.12 hospitalization 8,855 24.57 disability 795 2.21 life threatening 643 1.78 required intervention to Prevent Permanent Impairment/Damage 162 0.45 Year 2004 171 0.28 2005 110 0.18 2006 133 0.22 2007 162 0.27 2008 527 0.87 2009 1,115 1.84 2010 1,518 2.50 2011 1,694 2.79 2012 1,166 1.92 2013 2,360 3.89 2014 3,589 5.91 2015 4,124 6.79 2016 4,203 6.92 2017 3,205 5.28 2018 3,073 5.06 2019 3,924 6.46 2020 5,737 9.45 2021 6,395 10.53 2022 7,494 12.34 2023 10,009 16.49 Adverse event occurrence time - medication date (days) <7 9,741 21.37 7∼28 1,259 2.76 28∼60 1,074 2.36 ≥60 9,515 20.87 unknow 24,001 52.65 Indications prostate cancer 37,236 61.84 product used for unknown indication 8,968 14.9 endometriosis 6,589 10.94 uterine leiomyoma 1,987 3.3 precocious puberty 1,468 2.44 bulbospinal muscular atrophy congenital 526 0.87 breast cancer 722 1.21 drug use for unknown indication 215 0.36 gender dysphoria 177 0.29 menorrhagia 131 0.22 Clinical characteristics of reports with leuprorelin from the FAERS database (2004 Q1–2023 Q4). When leuprorelin was identified as the main suspect in AE signals, screening using methods like ROR, PRR, BCPNN, and EBGM ultimately highlighted AE signals across 24 SOCs. The outcomes of the study suggested that AEs most closely associated with the use of leuprorelin predominantly occur within the realms of general disorders, general disorders and administration site conditions (n = 34,532, ROR 1.28, PRR 1.22 IC 0.28, EBGM 1.22), injury, poisoning and procedural complications (n = 21,435, ROR 1.53, PRR 1.46, IC 0.54, EBGM 1.46), and nervous system disorders (n = 11,060, ROR 0.78, PRR 0.79, IC -0.34, EBGM 0.79). Utilizing the ROR method to gauge signal intensity, the top three categories identified were reproductive system and breast disorders with 7,036 cases (ROR 5.41, PRR 5.21, IC 2.36, EBGM 5.14), followed by vascular disorders with 10,772 cases (ROR 3.19, PRR 3.04, IC 1.59, EBGM 3.02), and neoplasms benign, malignant and unspecified (incl cysts and polyps) with 7,493 cases (ROR 1.73, PRR 1.70, IC 0.76, EBGM 1.69), in that order. The first two systems satisfied all four algorithmic requirements. Additionally, this study identified several other frequently occurring AEs, such as Infections and infestations, and Ear and labyrinth disorders, besides those explicitly mentioned in the drug insert. These AEs need clinical attention. There are no warnings or precautions given in leuprorelin's instructions regarding pregnancy, puerperium, and perinatal conditions. See Table 3 for details. Table 3 The signal strength of ADEs of leuprorelin at the SOC level. Table 3 System organ class Case Reports ROR (95 % CI) PRR (95 % CI) χ 2 IC(IC025) EBGM (EBGM05) general disorders and administration site conditions 34532 1.28(1.26, 1.29) 1.22(1.22, 1.22) 1626.59 0.28(0.27) 1.22(1.2) injury, poisoning and procedural complications 21435 1.53(1.51, 1.56) 1.46(1.43, 1.49) 3425.22 0.54(0.52) 1.46(1.44) nervous system disorders 11060 0.78(0.76, 0.79) 0.79(0.77, 0.81) 669.34 −0.34(-0.37) 0.79(0.78) vascular disorders 10772 3.19(3.13, 3.25) 3.04(2.98, 3.1) 14927.77 1.59(1.57) 3.02(2.97) musculoskeletal and connective tissue disorders 10437 1.22(1.2, 1.24) 1.21(1.19, 1.23) 386.02 0.27(0.24) 1.2(1.18) investigations 9657 0.95(0.93, 0.96) 0.95(0.93, 0.97) 28.75 −0.08(-0.11) 0.95(0.93) psychiatric disorders 8535 0.9(0.88, 0.92) 0.9(0.88, 0.92) 95.76 −0.15(-0.18) 0.9(0.89) gastrointestinal disorders 8133 0.56(0.55, 0.57) 0.58(0.57, 0.59) 2695.58 −0.78(-0.81) 0.58(0.57) neoplasms benign, malignant and unspecified (incl cysts and polyps) 7493 1.73(1.69, 1.77) 1.7(1.67, 1.73) 2193.64 0.76(0.73) 1.69(1.66) reproductive system and breast disorders 7036 5.41(5.28, 5.54) 5.21(5.11, 5.31) 23746.91 2.36(2.33) 5.14(5.04) skin and subcutaneous tissue disorders 5257 0.59(0.57, 0.6) 0.6(0.59, 0.61) 1469.22 −0.73(-0.77) 0.6(0.59) infections and infestations 4784 0.55(0.53, 0.56) 0.56(0.55, 0.57) 1744.4 −0.83(-0.88) 0.56(0.55) renal and urinary disorders 3590 1.19(1.15, 1.23) 1.18(1.13, 1.23) 102.14 0.24(0.19) 1.18(1.15) respiratory, thoracic and mediastinal disorders 3587 0.45(0.43, 0.46) 0.46(0.44, 0.48) 2401.5 −1.12(-1.17) 0.46(0.45) cardiac disorders 2602 0.58(0.56, 0.6) 0.59(0.57, 0.61) 777.65 −0.77(-0.82) 0.59(0.57) metabolism and nutrition disorders 2429 0.68(0.66, 0.71) 0.69(0.66, 0.72) 346.7 −0.53(-0.59) 0.69(0.67) eye disorders 1408 0.43(0.4, 0.45) 0.43(0.41, 0.46) 1074.9 −1.21(-1.29) 0.43(0.41) blood and lymphatic system disorders 1179 0.42(0.4, 0.45) 0.42(0.4, 0.45) 933.21 −1.23(-1.31) 0.43(0.41) hepatobiliary disorders 662 0.44(0.41, 0.48) 0.44(0.41, 0.48) 466.36 −1.17(-1.28) 0.44(0.42) immune system disorders 436 0.24(0.22, 0.26) 0.24(0.22, 0.26) 1049.41 −2.05(-2.18) 0.24(0.22) ear and labyrinth disorders 424 0.6(0.54, 0.66) 0.6(0.54, 0.66) 113.78 −0.74(-0.87) 0.6(0.55) endocrine disorders 410 1(0.91, 1.1) 1(0.91, 1.1) 0 0(-0.14) 1(0.92) pregnancy, puerperium and perinatal conditions 409 0.57(0.52, 0.63) 0.57(0.52, 0.63) 132.21 −0.81(-0.95) 0.57(0.53) congenital, familial and genetic disorders 142 0.28(0.23, 0.33) 0.28(0.24, 0.33) 267.8 −1.85(-2.08) 0.28(0.24) The signal strength of ADEs of leuprorelin at the SOC level. To further elucidate the adverse effects of leuprorelin in different medical conditions, we conducted specific analyses according to different diseases, and focused on the AEs of leuprorelin in the treatment of prostate cancer. Signal strengths of reports of leuprorelin in treatment of prostate cancer at the SOC level are described in Table 4 . The top three SOCs ranked by case numbers were general disorders and administration site conditions (n = 22,569, ROR 1.6, PRR 1.44 IC 0.53, EBGM 1.44), injury, poisoning and procedural complications (n = 13,649, ROR 1.81, PRR 1.68, IC 0.75, EBGM 1.68), and vascular disorders (n = 6,134, ROR 3.29, PRR 3.12, IC 1.64, EBGM 3.11). Utilizing the ROR method to gauge signal intensity, the top three categories identified were vascular disorders with 6,134 cases (ROR 3.29, PRR 3.12, IC 1.64, EBGM 3.11), followed by neoplasms benign, malignant and unspecified (incl cysts and polyps) with 5,886 cases (ROR 2.52, PRR 2.41, IC 1.27, EBGM 2.41), and injury, poisoning and procedural complications with 13,649 cases (ROR 1.81, PRR 1.68, IC 0.75, EBGM 1.68), in that order. The first systems satisfied all four algorithmic requirements. Moreover, signal strengths of reports of leuprorelin in treatment of endometriosis, uterine fibroids and precocious puberty at the SOC level are described detailedly in Supplementary Tables S2 , 3, 4. Table 4 The signal strength of ADEs of leuprorelin in treatment of prostate cancer at the SOC level. Table 4 System organ class Case Reports ROR (95 % CI) PRR (95 % CI) χ 2 IC(IC025) EBGM (EBGM05) general disorders and administration site conditions 22569 1.6(1.57, 1.62) 1.44(1.41, 1.47) 3709.02 0.53(0.5) 1.44(1.42) injury, poisoning and procedural complications 13649 1.81(1.78, 1.85) 1.68(1.65, 1.71) 4178.01 0.75(0.72) 1.68(1.66) vascular disorders 6134 3.29(3.2, 3.37) 3.12(3.06, 3.18) 9020.41 1.64(1.6) 3.11(3.05) investigations 5897 1.05(1.03, 1.08) 1.05(1.03, 1.07) 14.61 0.07(0.03) 1.05(1.03) neoplasms benign, malignant and unspecified (incl cysts and polyps) 5886 2.52(2.45, 2.59) 2.41(2.36, 2.46) 4998.38 1.27(1.23) 2.41(2.36) nervous system disorders 4836 0.6(0.59, 0.62) 0.63(0.62, 0.64) 1181.97 −0.67(-0.72) 0.63(0.61) musculoskeletal and connective tissue disorders 4813 1.01(0.98, 1.04) 1.01(0.99, 1.03) 0.2 0.01(-0.03) 1.01(0.98) gastrointestinal disorders 3243 0.4(0.38, 0.41) 0.42(0.4, 0.44) 2855.95 −1.25(-1.3) 0.42(0.41) infections and infestations 2992 0.62(0.6, 0.65) 0.64(0.62, 0.67) 663.13 −0.65(-0.71) 0.64(0.62) psychiatric disorders 2846 0.53(0.51, 0.55) 0.54(0.52, 0.56) 1151.75 −0.88(-0.93) 0.55(0.53) renal and urinary disorders 2723 1.64(1.58, 1.71) 1.62(1.56, 1.68) 664.91 0.7(0.64) 1.62(1.57) skin and subcutaneous tissue disorders 2186 0.44(0.42, 0.46) 0.45(0.43, 0.47) 1528.01 −1.14(-1.2) 0.45(0.44) respiratory, thoracic and mediastinal disorders 2186 0.49(0.47, 0.52) 0.51(0.49, 0.53) 1100.26 −0.98(-1.04) 0.51(0.49) cardiac disorders 1871 0.76(0.73, 0.8) 0.76(0.73, 0.79) 138.91 −0.39(-0.45) 0.77(0.74) metabolism and nutrition disorders 1358 0.69(0.66, 0.73) 0.7(0.66, 0.74) 180.56 −0.52(-0.59) 0.7(0.67) reproductive system and breast disorders 1003 1.33(1.25, 1.42) 1.33(1.25, 1.41) 81.76 0.41(0.32) 1.33(1.26) blood and lymphatic system disorders 668 0.43(0.4, 0.47) 0.44(0.41, 0.48) 494.72 −1.19(-1.3) 0.44(0.41) eye disorders 583 0.32(0.29, 0.35) 0.32(0.3, 0.35) 839.87 −1.62(-1.74) 0.32(0.3) hepatobiliary disorders 404 0.49(0.44, 0.54) 0.49(0.44, 0.54) 215.65 −1.03(-1.17) 0.49(0.45) ear and labyrinth disorders 189 0.48(0.42, 0.56) 0.48(0.42, 0.55) 104.26 −1.05(-1.25) 0.48(0.43) endocrine disorders 144 0.63(0.54, 0.75) 0.64(0.55, 0.75) 30.13 −0.65(-0.89) 0.64(0.55) immune system disorders 136 0.14(0.11, 0.16) 0.14(0.12, 0.17) 750.6 −2.87(-3.11) 0.14(0.12) congenital, familial and genetic disorders 39 0.14(0.1, 0.19) 0.14(0.1, 0.19) 210.35 −2.85(-3.3) 0.14(0.11) The signal strength of ADEs of leuprorelin in treatment of prostate cancer at the SOC level. After a comprehensive analysis, 102 essential PTs that met the criteria of all four algorithms were identified and ranked using the ROR technique, highlighting the top 30 terms. The findings revealed that PTs exhibiting the strongest signals included bulbospinal muscular atrophy congenital (n = 26, ROR 1346.97, PRR 1346.75, IC 7.98, EBGM 253.33), intercepted product preparation error (n = 5202, ROR 814.15, PRR 787.11, IC 7.8, EBGM 223.53) and blood testosterone normal (n = 5, ROR 777, PRR 776.97, IC 7.8, EBGM 222.71). The study results were compared with the instructions for use of leuprorelin to identify potential new adverse reactions. These included artificial menopause, ovarian adhesion, follicular cystitis, intercepted product preparation errors, metastases to the penis, and bulbospinal muscular atrophy congenital. Refer to Table 5 for more details. Leuprorelin users should be especially vigilant for potential adverse reactions such as abscess sterile, injection site granuloma, and intercepted medication errors. Table 5 The top 30 signal strength of AEs of leuprorelin ranked by ROR at the PTs level. Table 5 SOC PTs Case reports ROR (95 % CI) PRR (95 % CI) χ2 IC (IC025) EBGM (EBGM05) investigations blood testosterone normal 5 777(150.74, 4004.99) 776.97(149.76, 4031.13) 1107.1 7.8(6.27) 222.71(56.47) investigations prostatic specific antigen abnormal 343 225.86(196.54, 259.57) 225.37(196.48, 258.51) 44412.77 7.03(6.85) 131.06(116.66) investigations blood testosterone abnormal 332 172.05(150.45, 196.74) 171.68(149.67, 196.93) 36290.58 6.79(6.61) 110.95(99.17) investigations blood luteinising hormone abnormal 13 144.31(74.75, 278.6) 144.29(74.1, 280.96) 1263.36 6.63(5.75) 98.86(57.01) investigations laparoscopy 47 95.5(68.87, 132.43) 95.47(68.42, 133.22) 3361.14 6.2(5.74) 73.27(55.74) investigations prostatic specific antigen decreased 66 85.86(65.37, 112.77) 85.82(65.23, 112.92) 4335.87 6.08(5.69) 67.47(53.71) investigations blood testosterone increased 373 80.19(71.56, 89.87) 80(71.12, 89.98) 23143.3 6(5.84) 63.83(58.03) investigations blood follicle stimulating hormone abnormal 12 79.36(42.1, 149.59) 79.35(42.38, 148.57) 739.54 5.99(5.12) 63.41(37.31) investigations prostatic specific antigen 8 73.13(33.85, 157.98) 73.13(34.05, 157.06) 460.72 5.89(4.86) 59.39(31.18) investigations prostatic specific antigen increased 1898 60.02(57.13, 63.05) 59.3(57.02, 61.67) 91381.06 5.64(5.57) 49.96(47.94) reproductive system and breast disorders artificial menopause 22 106.85(65.82, 173.44) 106.83(65.45, 174.38) 1716.5 6.32(5.65) 79.76(53.18) reproductive system and breast disorders endometriosis 853 82.6(76.58, 89.08) 82.15(75.96, 88.85) 54088.07 6.03(5.92) 65.19(61.19) reproductive system and breast disorders ovarian adhesion 12 69.07(36.95, 129.11) 69.06(36.88, 129.31) 658.59 5.82(4.97) 56.69(33.59) reproductive system and breast disorders menopause delayed 3 62.16(17.99, 214.72) 62.16(18.08, 213.69) 150.43 5.7(4.14) 51.96(18.42) reproductive system and breast disorders bilateral breast buds 4 59.2(20.32, 172.46) 59.2(20.14, 173.98) 192.24 5.64(4.26) 49.89(20.39) general disorders and administration site conditions injection site abscess sterile 45 333.08(218.73, 507.22) 332.99(220.64, 502.56) 7190.5 7.33(6.82) 161.27(113.43) general disorders and administration site conditions abscess sterile 59 291.17(204.13, 415.31) 291.06(204.53, 414.19) 8806.86 7.24(6.79) 150.78(112.02) general disorders and administration site conditions administration site ulcer 4 77.7(25.98, 232.42) 77.7(25.93, 232.86) 242.27 5.96(4.56) 62.36(24.93) general disorders and administration site conditions injection site granuloma 30 64.76(43.7, 95.97) 64.75(43.75, 95.83) 1558.26 5.75(5.2) 53.76(38.68) renal and urinary disorders follicular cystitis 3 133.2(34.44, 515.11) 133.2(34.45, 515.04) 275.53 6.55(4.9) 93.54(30.16) renal and urinary disorders urinary tract toxicity 7 114.51(48.14, 272.39) 114.5(48.34, 271.23) 575.53 6.39(5.25) 83.94(40.65) renal and urinary disorders urethral intrinsic sphincter deficiency 5 62.16(23.8, 162.38) 62.16(23.79, 162.41) 250.72 5.7(4.44) 51.96(23.27) neoplasms benign, malignant and unspecified (incl cysts and polyps) metastases to penis 3 116.55(30.92, 439.32) 116.55(30.74, 441.92) 249.94 6.41(4.78) 85.03(28.02) neoplasms benign, malignant and unspecified (incl cysts and polyps) prostate cancer metastatic 716 102.73(94.4, 111.8) 102.26(94.55, 110.6) 54023.56 6.27(6.15) 77.19(71.92) neoplasms benign, malignant and unspecified (incl cysts and polyps) metastatic salivary gland cancer 6 88.8(35.84, 220.02) 88.8(36.05, 218.76) 405.1 6.11(4.92) 69.29(32.43) injury, poisoning and procedural complications intercepted product preparation error 5202 814.15(773.42, 857.03) 787.11(742.16, 834.78) 1156295.78 7.8(7.75) 223.53(214.13) injury, poisoning and procedural complications radiation induced fatigue 3 186.48(44.56, 780.31) 186.47(44.59, 779.83) 345.9 6.87(5.17) 116.92(35.3) injury, poisoning and procedural complications intercepted medication error 1111 107.76(100.64, 115.38) 107(100.89, 113.48) 86793.35 6.32(6.22) 79.85(75.41) infections and infestations tracheobronchitis bacterial 3 62.16(17.99, 214.72) 62.16(18.08, 213.69) 150.43 5.7(4.14) 51.96(18.42) endocrine disorders pituitary apoplexy 24 81.98(52.28, 128.54) 81.97(52.22, 128.66) 1518.9 6.02(5.4) 65.07(44.66) congenital, familial and genetic disorders bulbospinal muscular atrophy congenital 26 1346.97(554.41, 3272.58) 1346.75(557.49, 3253.38) 6555.67 7.98(7.25) 253.33(120.53) investigations blood testosterone normal 5 777(150.74, 4004.99) 776.97(149.76, 4031.13) 1107.1 7.8(6.27) 222.71(56.47) The top 30 signal strength of AEs of leuprorelin ranked by ROR at the PTs level. In order to analyze the AEs associated with leuprorelin in the treatment of prostate cancer, a total of 100 significant PTs that met the criteria of all four algorithms were identified and ranked using the ROR technique, highlighting the top 30 PTs. The results revealed that PTs exhibiting the strongest signals included intercepted medication error (n = 3721, ROR 620.05, PRR 593.98, IC 8.18, EBGM 289.6), prostatic specific antigen abnormal (n = 294, ROR 318.58, PRR 317.49, IC 7.67, EBGM 203.46) and follicular cystitis (n = 3, ROR 241.6, PRR 241.59, IC 7.4, EBGM 169.41). The top three PTs ranked by case numbers were hot flush (n = 4,937, ROR 54.2, PRR 51.16 IC 5.55, EBGM 46.98), intercepted product preparation error (n = 3,721, ROR 620.05, PRR 593.38, IC 8.18, EBGM 289.6), and prostatic specific antigen increased (n = 1,605, ROR 90.01, PRR 88.36, IC 6.26, EBGM 76.52). Further details can be found in Table 6 . Additionally, the signal strengths of reports on the use of leuprorelin in the treatment of endometriosis, uterine fibroids, and precocious puberty at the PTs level are elaborated in Supplementary Tables S5, S6, and S7 . Table 6 The top 30 signal strength of AEs of leuprorelin in treatment of prostate cancer ranked by ROR at the PTs level. Table 6 SOC PTs Case reports ROR (95 % CI) PRR (95 % CI) χ2 IC (IC025) EBGM (EBGM05) injury, poisoning and procedural complications intercepted product preparation error 3721 620.05(591.86, 649.59) 593.38(570.57, 617.1) 1072213.82 8.18(8.12) 289.6(278.54) injury, poisoning and procedural complications intercepted medication error 904 149.96(139.32, 161.41) 148.4(137.21, 160.5) 104778.65 6.88(6.77) 117.68(110.66) injury, poisoning and procedural complications radiation associated haemorrhage 6 96.64(40.65, 229.77) 96.64(40.8, 228.92) 484.78 6.37(5.21) 82.64(40.04) injury, poisoning and procedural complications cystitis radiation 17 69.96(42.26, 115.82) 69.95(42.02, 116.44) 1027.85 5.96(5.26) 62.34(40.89) injury, poisoning and procedural complications radiation proctitis 16 69.93(41.59, 117.57) 69.92(41.19, 118.69) 966.99 5.96(5.24) 62.31(40.34) investigations prostatic specific antigen abnormal 294 318.58(276.11, 367.58) 317.49(276.79, 364.18) 59337.8 7.67(7.48) 203.46(180.51) investigations blood testosterone abnormal 223 177.51(152.69, 206.36) 177.05(151.36, 207.11) 29708.21 7.08(6.87) 134.97(118.99) investigations blood testosterone increased 279 102.26(90, 116.18) 101.93(90.62, 114.65) 23614.16 6.43(6.25) 86.47(77.71) investigations prostatic specific antigen decreased 46 100.17(73.2, 137.08) 100.12(73.17, 137) 3833.18 6.41(5.97) 85.17(65.51) investigations prostatic specific antigen increased 1605 90.01(85.36, 94.91) 88.36(83.31, 93.71) 119865.34 6.26(6.18) 76.52(73.2) renal and urinary disorders follicular cystitis 3 241.6(62.47, 934.33) 241.59(62.48, 934.15) 503.15 7.4(5.75) 169.41(54.63) renal and urinary disorders urinary tract toxicity 7 207.7(87.31, 494.09) 207.68(87.67, 491.96) 1052.18 7.25(6.11) 152.04(73.63) renal and urinary disorders bladder stenosis 6 52.85(22.89, 122.04) 52.85(22.75, 122.76) 279.04 5.6(4.48) 48.4(24.03) reproductive system and breast disorders reproductive toxicity 5 100.67(38.87, 260.72) 100.66(38.53, 263) 418.61 6.42(5.17) 85.56(38.59) reproductive system and breast disorders testicular atrophy 60 50.82(39.02, 66.19) 50.79(39.37, 65.53) 2686.32 5.54(5.17) 46.67(37.41) neoplasms benign, malignant and unspecified (incl cysts and polyps) metastases to penis 3 211.4(56.08, 796.87) 211.39(55.75, 801.52) 456.87 7.27(5.63) 154.01(50.74) neoplasms benign, malignant and unspecified (incl cysts and polyps) prostate cancer metastatic 667 170.3(156.14, 185.73) 168.99(156.25, 182.77) 85700.56 7.03(6.9) 130.24(121.12) neoplasms benign, malignant and unspecified (incl cysts and polyps) hormone-refractory prostate cancer 116 85.26(70.13, 103.65) 85.14(69.99, 103.58) 8380.49 6.21(5.93) 74.1(62.93) neoplasms benign, malignant and unspecified (incl cysts and polyps) anaplastic meningioma 3 84.56(25.13, 284.57) 84.56(25.08, 285.05) 215.4 6.2(4.68) 73.66(26.68) neoplasms benign, malignant and unspecified (incl cysts and polyps) neuroendocrine carcinoma of prostate 4 64.43(22.9, 181.28) 64.42(22.8, 182.04) 224.14 5.86(4.51) 57.92(24.37) neoplasms benign, malignant and unspecified (incl cysts and polyps) prostate cancer recurrent 45 57.29(42.16, 77.86) 57.26(41.85, 78.35) 2258.22 5.7(5.27) 52.07(40.29) infections and infestations tracheobronchitis bacterial 3 112.75(32.64, 389.47) 112.74(32.8, 387.57) 276.88 6.56(5) 94.12(33.36) general disorders and administration site conditions administration site ulcer 3 99.48(29.15, 339.47) 99.48(28.94, 341.98) 248.6 6.4(4.86) 84.71(30.33) general disorders and administration site conditions injection site abscess sterile 12 90.21(49.04, 165.92) 90.19(49.12, 165.59) 912.47 6.28(5.44) 77.89(46.78) general disorders and administration site conditions injection site granuloma 23 85.89(55.38, 133.19) 85.86(55.79, 132.15) 1674.14 6.22(5.61) 74.65(51.71) general disorders and administration site conditions terminal state 572 62.21(57.05, 67.84) 61.81(57.15, 66.85) 30841.22 5.8(5.68) 55.8(51.9) gastrointestinal disorders abdominal fat apron 10 90.93(46.63, 177.34) 90.92(46.69, 177.04) 765.81 6.29(5.38) 78.43(44.85) endocrine disorders pituitary apoplexy 15 84.57(49.15, 145.52) 84.56(48.85, 146.39) 1076.99 6.2(5.45) 73.66(46.77) endocrine disorders pituitary haemorrhage 24 48.68(32.08, 73.87) 48.67(32.25, 73.45) 1031.44 5.49(4.9) 44.88(31.66) vascular disorders hot flush 4937 54.2(52.6, 55.85) 51.16(50.17, 52.17) 222857.7 5.55(5.51) 46.98(45.82) The top 30 signal strength of AEs of leuprorelin in treatment of prostate cancer ranked by ROR at the PTs level.

Considering the date leuprorelin was introduced to the market, this research extracted American Standard Code for Information Interchange (ASCII) report files from the FAERS database, covering the period from Q1 2004 to Q4 2023. The analysis was conducted using R software version 4.3.2. ( Fig. 1 ). Fig. 1 The flow diagram of selecting leuprorelin -related AEs from FAERS database. ( DEMO, demographic and administrative information; DRUG, drug Information; REAC, preferred terminology for adverse drug reactions; PS, primary suspect drug) . Fig. 1 The flow diagram of selecting leuprorelin -related AEs from FAERS database. ( DEMO, demographic and administrative information; DRUG, drug Information; REAC, preferred terminology for adverse drug reactions; PS, primary suspect drug) . To ensure data integrity, redundant reports were eliminated and only the most recent report per case date was retained. Drug name standardization was carried out using the Medex_UIMA_1.8.3 system. Reports pinpointing leuprorelin as the main substance associated with adverse drug event (ADE) signals were extracted. Additionally, this study employed the 'Medical Dictionary for Regulatory Activities' (MedDRA) to standardize and localize AE terminology in the Preferred Terms (PTs) format. Adverse drug reaction reports sharing the same PTs were consolidated, with PTs categorized by their respective System Organ Classes (SOCs) [ 13 ]. In this study, four disproportionality analysis methods were utilized for data mining purposes: ROR [ 14 ], PRR [ 15 ], BCPNN [ 16 ], and EBGM [ 17 ]. ROR is effective in reducing biases associated with events that have a limited number of reports, while PRR is known for its higher specificity compared to ROR. BCPNN excels in synthesizing and cross-verifying data from multiple sources. By integrating ROR, PRR, BCPNN, and EBGM, this research capitalizes on the unique strengths of each method, expanding the detection and validation capabilities. This comprehensive approach aids in identifying safety signals more accurately, reducing false positives through mutual verification, and improving the detection of rare adverse reactions by adjusting thresholds and variability. These methods all utilize a disproportionality measure based on a 2 x 2 table, as illustrated in Table 1 . The specific formulas for the four methods used in this study can be found in Supplementary Table S1 . Table 1 Four grid table. Table 1 Target ADEs Non-target ADEs Total Leuprorelin a b a + b Non- leuprorelin c d c + d Total a + c b + d N = a + b + c + d Notes: a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions. Four grid table. Notes: a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions.

Leuprorelin is a widely used drug known for its effectiveness in various therapeutic applications. However, its side effects require careful consideration. This study conducted a comprehensive analysis of the adverse events (AEs) associated with leuprorelin, revealing a wide range of AEs connected to its usage. Our detailed investigation uncovered several unexpected and uncommon adverse drug reactions (ADRs), including injection site granuloma and induced menopause. These findings emphasize the crucial role of leuprorelin's information leaflet in offering clinical guidance and underscore the necessity for further exploration of its biological mechanisms and clinical impacts. It is essential for healthcare providers and patients to consistently assess the risks linked to its usage and adjust treatment plans as needed.

Leuprorelin post-marketing AEs were thoroughly analyzed using the FAERS database for the first time in pharmacovigilance. The main objective of the study was to comprehensively characterize, describe, and analyze the AEs associated with leuprorelin reported to date. This research would yield valuable and accurate insights into the safety profile of leuprorelin in clinical practice. The proportion of adverse reactions of leuprolide in patients aged 65 and older (31.45 %) was higher compared to those under 65 years old. This could be attributed to the drug's common use in treating prostate cancer, which is more prevalent in elderly patients. The other reasons also caused more adverse reactions occurred in male patients. Due to a larger user base, American and Canadian AEs were significantly higher than those seen in other countries. This trend might be explained by a variety of factors such as an increase in population size, more willingness to report incidents, early market entry, and the quick expansion of approved uses. In our research, the most frequently observed and notable AEs at the SOC level—including general disorders and administration site conditions, disorders of the nervous system, vascular disorders, and musculoskeletal and connective tissue disorders—aligned with safety data reported in drug labeling and from clinical trials. Within the PTs related to general disorders and administration site conditions, the three most frequently reported PTs were abscess sterile [ 18 , 19 ], injection site granuloma [ 20 ] and administration site ulcer [ 21 ]. Local AEs associated with leuprorelin acetate were found in 5 %–15 % of patients [ 22 , 23 ]. Johnson, Stephanie R et al. identified a sterile abscess in the long-acting treatment of Central Precocious Puberty (CPP) with leuprorelin, but the underlying mechanism remains unclear [ 24 ]. Sterile abscess formation has also been reported in 1.5 %–3 % of all patients receiving this treatment [ 25 , 26 ]. Shiota et al. reported a 4.2 % incidence rate of leuprorelin acetate granuloma [ 27 ]. Additionally, Ian Janes, W C et al. noted that leuprorelin acetate could result in injection site ulceration and skin necrosis [ 28 ]. The unique formulation and method of administration(subcutaneous, intramuscular, etc.) of the drug may contribute to such adverse effects, highlighting the importance of recognizing this rare adverse event for clinicians. Another SOC identified was "injury, poisoning and procedural complications," which included issues such as medication administration errors and medication use problems. This highlights the essential requirement for standardized drug administration protocols when utilizing leuprorelin in clinical settings. Additionally, there were frequent reports of reproductive system and breast disorders, aligning with the drug's known adverse effects, emphasizing the importance of recognizing established risks. The AEs signals identified in this study covered the majority of events outlined in the leuprorelin instructions, including severe conditions like pituitary apoplexy and ulcers at the administration site. The occurrence of these relevant AEs require attention and necessitate prompt intervention. Furthermore, our analysis revealed several critical AE signals previously undocumented. These novel AE signals included injection site granuloma, follicular cystitis, bulbospinal muscular atrophy congenital, artificial menopause, progression of cancer (metastases to penis, prostate cancer metastatic, metastatic salivary gland cancer) etc. The development of sterile abscesses and granulomas was likely a response to the polymers used in delivering long-acting gonadotropin-releasing hormone agonists, akin to a foreign body reaction as seen with absorbable sutures. It is also plausible that these reactions were triggered by gonadotropin-releasing hormone agonist peptides [ 25 , 29 , 30 ]. Prolonged use of leuprorelin could result in significant hypoestrogenic side effects, leading to artificial amenorrhea and other adverse reactions [ 31 ]. Moreover, a prospective, non-interventional study declared that there were serious AEs such as metastatic prostate cancer and tumor progression (i.e., metastasis) after treatment with leuprorelin, which warranted our vigilance [ 32 ]. Merseburger, A.S. and Roesch, M.C. also observed the same phenomenon [ 33 ]. Additional adverse reactions, such as follicular cystitis, ovarian adhesion, bacterial tracheobronchitis, and congenital bulbospinal muscular atrophy, which have not yet been reported, could also result from direct drug toxicity or allergic responses. Further research is necessary to fully understand the specific mechanisms involved. Therefore, close monitoring of patients receiving leuprorelin is essential, including regular tumor marker assessments, blood routine examinations, skin tests, and pathological examinations. Timely symptomatic interventions should be implemented if necessary. What's more, similar to the findings regarding leuprorelin related AER, the most frequently observed and notable AEs for SOC levels in leuprorelin treatment for prostate cancer included: general disorders and administration site conditions, injury, poisoning and procedural complications and vascular disorders. To be specific, these AEs include intercepted product preparation error, hot flush, prostatic specific antigen increased, which were found with high frequency and high signal intensity. We realize that high frequency of PTs may be caused by objective factors such as underlying diseases or medication usage methods. However, the signal intensity calculated by ROR shows a statistical correlation between the drug and adverse reactions. Therefore, signal strength can reduce bias and should be more worthy of attention as a more objective indicator for AEs research. Although clinical trials and guidelines have documented AEs such as dizziness, sweats, nausea, gastroenteritis, decreased libido, tremor, weight gain, flatulence, and cardiovascular diseases, our extensive data analysis from the FAERS database did not show significant signals for these specific AEs. Unlike clinical trials, reporting in FAERS is voluntary and often sporadic, potentially leading to adverse reactions being inadequately documented. Minor adverse reactions may be easily missed during the reporting process, resulting in an underrepresentation of these events. However, we should still pay attention to the supplementary significance of new adverse reactions identified by the FAERS database to clinical practice. Safety studies of leuprorelin have predominantly consisted of meta-analyses or short-term clinical trials with limitations such as small sample sizes and short follow-up periods, hindering a comprehensive analysis of adverse effects [ [34] , [35] , [36] , [37] , [38] ]. Our study represents a significant advancement by compiling the largest dataset of leuprorelin-related cases to date, encompassing 60,709 reported cases and 156,409 adverse events. Our study included detailed assessments of the timing and severity of adverse events, providing a valuable perspective on leuprorelin's safety profile. Furthermore, this comprehensive analysis not only confirmed previously recognized adverse reactions but also uncovered several significant, previously unreported adverse events, which complemented the management of ADRs during clinical use of leuprorelin. And we should add these positive signals to the management of adverse drug reactions during clinical use of leuprorelin. It's important to recognize a few limitations that need careful consideration: 1) The FAERS database operates as a voluntary reporting system, potentially leading to incomplete or inaccurate data from various countries and healthcare providers. For instance, healthcare professionals might over-report rare AEs, whereas those with minimal patient impact could be underreported.2) In disproportionality analyses, rare AEs associated with leuprorelin may not reach statistical significance due to their infrequency, leaving unidentified some safety signals. 3)Determining whether AEs are specifically due to leuprorelin is challenging, particularly with the potential confounding effects of other concurrent medications. 4)Given that FAERS is solely maintained by the U.S Food and Drug Administration, which may lead to some of the data has certain deviation, such as the United States found that may arise more AERs. Besides, when adverse events occur, a comprehensive evaluation of the patient's primary disease and its progression, drug/food interactions, timing of symptom onset, and dose correlation is necessary.5) It is crucial to emphasize that disproportionality analysis solely enables the identification of statistical significance based on signal strength and does not offer conclusive evidence of causality. These points underscore the complexity of interpreting real-world data and the need for meticulous analysis to ensure accurate safety assessments.

Leuprorelin acetate, a synthetic nonapeptide, is a potent gonadotropin releasing hormone (GnRH) agonist commonly used in various clinical settings. It is utilized for the treatment of conditions such as prostate cancer, endometriosis, uterine fibroids, central precocious puberty, and in vitro fertilization techniques [ 1 ]. Initially introduced in 1985 as an alternative to surgical castration and estrogen therapy for prostate cancer [ 2 , 3 ], leuprorelin acetate has since become a well-established treatment option for endometriosis, uterine fibroids, and central precocious puberty (CPP) [ [4] , [5] , [6] , [7] ]. These conditions pose significant global burdens, with prostate cancer affecting approximately 10 million men worldwide [ 8 ]. Prostate cancer is the second most common cancer and the fifth leading cause of cancer death in the world [ 9 ]. Endometriosis impacting 10 % of women of reproductive age (approximately 190 million women globally), and uterine fibroids accounting for over 75 % of women worldwide [ 10 , 11 ]. And the incidence of CPP may be as high as 1 in 5000, whereas a more modest definition estimates an incidence of 1 in 10,000 [ 12 ]. Leuprorelin acetate initially induces a notable increase in the secretion and serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary, accompanied by elevated sexual steroid levels within three days of treatment initiation. However, upon continued administration, this GnRH agonist suppresses the pituitary-gonadal axis by downregulating gonadotropin receptors, desensitizing gonadotropin-producing cells, and reducing circulating levels of LH, FSH, and sex hormones within two to four weeks. These downregulation mechanisms are essential for the drug's clinical applications in gynecology and other fields [ 1 ]. Despite its extensive usage, there are sporadic reports of rare adverse reactions when leuprorelin is used alone or in combination with other medications, highlighting gaps in our knowledge of its safety profile. Further research and analysis of leuprorelin's safety in practical, real-world scenarios are warranted. Our study focused on conducting a detailed analysis of adverse effects associated with leuprorelin using real-world data from the FDA Adverse Event Reporting System (FAERS). We employed four different algorithms for adverse reaction signal strength analysis: Reported Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Our study can effectively detect and manage adverse reactions of leuprolide, so as to improve patient medication safety.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data included in article/supp. material/referenced in article. The survey data are publicly available on the Internet for data users and researchers throughout the world https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers .