Risk Signal Mining of Adverse Events Related to Levothyroxine Sodium Tablets Based on FAERS

doi:10.19803/j.1672-8629.20240036

Abstract

Abstract: Objective To analyze the adverse drug events (ADE) caused by levothyroxine sodium tablets to provide a reference for rational and safe clinical use. Methods The U. S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) was searched to retrieve the ADE data on the primarily suspected drug collected from the first quarter of 2015 to the second quarter of 2023. The reporting odds ratio (ROR)、proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCNPP) and multi-item gamma poisson shrinker (MGPS) methods were used to screen for effective signals of ADEs of drugs. Results A total of 271 356 ADEs related to levothyroxine tablets as the primary suspect were reported. Most of the people involved were women (198 219, 73.05%) and the patients ranged from 18 to 85 in age (62.46%). A total of 5 991 adverse events of levothyroxine sodium tablets were mined, 3 371 signals were obtained after excluding non-drug adverse event signals, and 20 organ systems were found to be involved. Fatigue (22 511 items), nausea (17 591 items), diarrhea (16 400 items), headache (15 043 items) and dyspnea (12 866 items)were the top five ADEs reported.Analysis showed that neonatal gangrene (ROR=267.57, IC₀₂₅=4.66), bronchiolithiasis (ROR=187.30, IC₀₂₅=267.57), homophonic association (ROR=107.03, IC₀₂₅=267.57), increased trans-triiodothyronine (ROR=89.19, IC₀₂₅=4.42), and decreased free thyroxine indexes (ROR=80.27, IC₀₂₅=4.38）were the top five ADEs in terms of intensities of signals. Based on secondary screening, the top three PTs related to the neonatal risk signal intensity were neonatal gangrene, neonatal intestinal dilation, and neonatal thyrotoxicosis. The top three PTs regarding the stone risk signal intensity were bronchial stones, cerebral stones, and staghorn stones. A total of 146 signals that were not recorded in the instructions were found, which were mostly manifested in various examinations, gastrointestinal system diseases, infections and invasive diseases, nervous system diseases, benign and malignant tumors of unknown nature. Conclusion Levothyroxine sodium tablets can potentially cause such ADRs as calculuses, infections and secondary tumors in patients with hypothyroidism. Clinical multidisciplinary follow-up is recommended for patients taking levothyroxine sodium tablets.

Key words: Levothyroxine Sodium Tablets, FAERS, Reporting Odds Ratio (ROR), Proportional Reporting ratio (PRR), Bayesian Conﬁdence Interval Neural Propagation Network Method (BCPNN), Multi-item Gamma Poisson Shrinker, (MGPS), Spontaneous Reporting, Uncommensurate Analysis, Data Mining

CLC Number:

CHEN Chongze, ZHOU Tianyu, SUN Siman, GUO Shushu, JIN Hongtao. Risk Signal Mining of Adverse Events Related to Levothyroxine Sodium Tablets Based on FAERS[J]. Chinese Journal of Pharmacovigilance, 2024, 21(12): 1425-1431.

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https://zgywjj.magtechjournal.com/EN/Y2024/V21/I12/1425

References

[1] HUANG QY, LI TT.Efficacy of Levothyroxine Sodium Tablet in Treatment of Pregnancy Complicated with Subclinical Hypothyroidism and its Influence on Thyroid Hormone Level,pregnancy Outcomes and Growth and Development of Offspring[J]. J Reprod Med(生殖医学杂志), 2024, 33(7): 900-906.
[2] ICHIRO Y, TAKURO H, TAKU S, et al.Prediction-Based Prompt Levothyroxine Replacement to Prevent a Hypothyroid State After Immune-Related Adverse Events Involving the Thyroid Gland[J]. Endocrine J, 2023, 70(10): 987-998.
[3] LAYAL C, SALMAN R, ISABELA MB, et al.Hypothyroidism[J]. Nat Rev Dis Primers, 2022, 8(1): 30.
[4] NEGRO, R, ŽARKOVIĆ, M, ATTANASIO R, et al.Use of Levothyroxine for Euthyroid, Thyroid Antibody Positive Women with Infertility: Analyses of Aggregate Data from a Survey of European Thyroid Specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey)[J]. Clin Endocrinol, 2024, 101(2): 180-190.
[5] MCANINCH EA.Safety of Levothyroxine Plus Liothyronine in Postsurgical Hypothyroidism[J]. Clin Thyroidol, 2024, 36(1): 99-119.
[6] JYOTIRMOY S, EMIR C, KAROLINA P, et al.Antiviral Influenza Treatments and Hemorrhage-Related Adverse Events in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database[J]. Pharmacotherapy, 2024, 44(5): 383-393.
[7] SHI GH, WANG Q, SUN H, et al.Safety Signal Analysis of Antidepressants Use in Fetus and Neonate Based on US FAERS Database[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2024, 21(6): 687-692.
[8] KONTSIOTI E, MASKELL S, DUTTA B, et al.A Reference set of Clinically Relevant Adverse Drug-Drug Interactions[J]. Scientific Data, 2022, 9(1): 72.
[9] PERA V, BRUSSELLE GG, RIEMANN S, et al.Parasitic Infections Related to Anti-Type 2 Immunity Monoclonal Antibodies: a Disproportionality Analysis in the Food and Drug Administration's Adverse event Reporting System (FAERS)[J]. Front Pharmacol, 2023, 14:1276340.
[10] HOU Y, YE X, WU G, et al.A Comparison of Disproportionality Analysis Methods in National Adverse Drug Reaction Databases of China[J]. Expert Opin Drug Saf, 2014, 13(7): 853-857.
[11] ANG PS, CHEN Z, CHAN CL, et al.Data Mining Spontaneous Adverse Drug Event Reports for Safety Signals in Singapore-a Comparison of Three Different Disproportionality Measures[J]. Expert Opin Drug Safe, 2016, 15(5): 583-90.
[12] CHEN X, GUO XJ, XU JF, et al.Machine Learning Method in the Detection of Adverse Drug Reaction Signals of Brigatinib Based on FAERS Database[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2023, 20(6): 639-645.
[13] JIANG Y, ZHOU L, SHEN Y, et al.Safety Assessment of Brexpiprazole: Real-world Adverse Event Analysis From the FAERS database[J]. J Affect Disord, 2024, 346: 223-229.
[14] FDA. Instructions for Levothyroxine Sodium [EB/OL].(2020-08-3)[2023-08-31]. https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/d6ce9798-7204-41df-9aeb-067000cb0895/spl-doc?hl=levothyroxine%20sodium#section-6.
[15] KUIPER JG, FENNEMAN AC.Levothyroxine Use and the Risk of Colorectal Cancer: A Large Population-Based Case-Control Study[J]. Endocrine Connection, 2022, 11(1): e210463.
[16] GE GM, MAN KKC, CHEUNG ECL, et al.Levothyroxine Treatment Among Pregnant Women and Risk of Seizure in Children: A Population-Based Cohort Study[J]. Drug Safety, 2023, 46(11): 1149-1159.
[17] YANG WJ, SUN Z, YANG CY, et al.Hypokalemia Caused by Levothyroxine Sodium[J]. ADRJ, 2023, 25(4): 253-254.
[18] ANTONITIS JJ, KISH GB, BARON A.Levothyroxine-Sodium/Tamsulosin: Drug Induced Liver Injury: 2 Case Reports[J]. Reactions Weekly, 2023, 1958(1): 305.
[19] GEORGE S, MAITI R, MISHRA A.Efficacy and Safety of Supraphysiologic Doses of Levothyroxine for Patients With Bipolar Depression in Adults: A Systematic Review[J]. Journal of Psychopharmacology, 2022, 36(5): 521-530.
[20] RAZV S.Cardiac Safety and Efficacy of Combination Levothyroxine and L-Triiodothyronine in Patients with Athyreotic Hypothyroidism: Reassuring Initial Data But More is Needed[J]. Thyroid, 2023, 33(12): 1393-1394.
[21] ASTA U, ANTTI T, PIETA L, et al.Heart rate in Newborns is Associated with Age, Sex and Maternal Levothyroxine Therapy[J]. Acta Paediatrica, 2024, 113(5): 973-979.
[22] CHEN JJ, LI ZY, YIN FL, et al.Effects of Initiation Time of Levothyroxine Therapy in Women with Gestational Subclinical Hypothyroidism and Negative Thyroid Peroxidase Antibodies on the Neurological Development of Offspring[J]. Journal of Evidence-Based Medicine, 2024, 17(2): 239-241.
[23] MOHANTY K, PATTNAIK S, MISHRA G.et al.Regulatory Effect of Thyroxine on Calcium and Phosphorus Metabolism in Tissues of Common Indian Toad[J]. Asian Journal of Water, Environment and Pollution, 2022, 19(5): 73-82.
[24] MARAKA S, DOSIOU C.Subclinical Hypothyroidism and Thyroid Autoimmunity in Pregnancy: to Treat or not to Treat[J]. Endocrinology and Metabolism Clinics of North America, 2024, 53(3): 363-376.
[25] INTRA J, SARTO C, BRAMBILLA P.A Rare Case of Cutaneous Papiliotrema (Cryptococcus) Laurentii Infection in a 23-year-Old Caucasian Woman Affected by an Autoimmune Thyroid Disorder with Hypothyroidism[J]. European Journal of Clinical Microbiology & Infectious Diseases: Official Publication of the European Society of Clinical Microbiology, 2021, 40(3): 647-650.
[26] TULI G, MUNARIN J, MIGNONE F, et al.Cytomegalovirus Infection and Congenital Hypothyroidism: Possible Association[J]. Acta Endocrinol (Buchar), 2022, 8(1): 93-96.
[27] NANJAPPA H, RODRIGUES AJ.Atrial Fibrillation Secondary to Levothyroxine Overdose with Underlying Secondary Infection[J]. The Journal of the Association of Physicians of India, 2024, 72(8): 96-98.
[28] MS K, JW L, MK H, et al.Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors According to the Dose of Levothyroxine: ANationwide Cohort Study[J]. Endocrinology and Metabolism (Seoul, Korea), 2024, 39(2): 288-299.