Methimazole-Induced Agranulocytosis in Patients with Graves' Disease Is More Frequent with an Initial Dose of 30 mg Daily than with 15 mg Daily
Abstract
BACKGROUND: Antithyroid drugs (ATDs) are prescribed as the initial therapy for the majority of patients with Graves' disease in many areas of the world. Although, it is well known that agranulocytosis is one of the most serious side effects of ATDs, there has not yet been any conclusive evidence that the prevalence of agranulocytosis induced by ATDs is dose related. This study was performed to determine if the prevalence of agranulocytosis is different depending on the starting dosage of ATDs in patients with Graves' disease. METHODS: Until 1996, we had typically prescribed 30 mg/d of methimazole (MMI) as the initial dosage for the treatment of Graves' disease at our institution. We changed the initial MMI dosage to 15 mg/d as a general rule in 1997. As a consequence, we acquired two groups of patients with Graves' disease who received different dosages of MMI. We retrospectively compared the prevalence of MMI-induced agranulocytosis in patients who received 15 mg/d of MMI to those who received 30 mg/d of MMI. RESULTS: There were 2087 subjects treated with 30 mg/d of MMI and 2739 treated with 15 mg/d of MMI. The prevalence of agranulocytosis in the 30 mg/d group was significantly higher than in the 15 mg/d group (0.814% vs. 0.219%, respectively, p < 0.01). The prevalence of agranulocytosis plus neutropenia in the 30 mg/d group was also significantly higher than in the 15 mg/d group (1.581% vs. 0.474%, respectively, p < 0.001). CONCLUSIONS: It is very likely that MMI-induced agranulocytosis occurs with a larger dosage of MMI and is dose related. Considering both the effectiveness and the risk of serious side effects, we recommend 15 mg/d of MMI as the starting dosage for the treatment of Graves' disease.
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PTU at any dose appears to be more likely to cause agranulocytosis compared with low doses of MMI.
“PTU at any dose appears to be more likely to cause agranulocytosis compared with low doses of MMI (124-126).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [126]
Cites
Nakamura, H., Noh, J. Y., Itoh, K., Fukata, S., Miyauchi, A., Hamada, N., & Working Group of the Japan Thyroid Association for the Guideline of the Treatment of Graves’ Disease (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2135 · Cited by 277 · see citing works
Self-citationAgranulocytosis Associated with Antithyroid Drugs: Effects of Patient Age and Drug Dose
COOPER, D. S., GOLDMINZ, D., LEVIN, A. A., LADENSON, P. W., DANIELS, G. H., MOLITCH, M. E., & RIDGWAY, E. C. (1983) · Annals of Internal Medicine · doi:10.7326/0003-4819-98-1-26 · Cited by 245 · see citing works
Tajiri, J. (1990) · Archives of Internal Medicine · doi:10.1001/archinte.1990.00390150107020 · Cited by 156 · see citing works
Tajiri, J., & Noguchi, S. (2004) · Thyroid · doi:10.1089/105072504323150787 · Cited by 116 · see citing works
The Side Effects of Antithyroid Drugs
Cooper, D. S. (1999) · The Endocrinologist · doi:10.1097/00019616-199911000-00008 · Cited by 102 · see citing works
Clinical Pharmacokinetics of Antithyroid Drugs
Kampmann, J. P., & Hansen, J. (1981) · Clinical Pharmacokinetics · doi:10.2165/00003088-198106060-00001 · Cited by 91 · see citing works
Meyer-Geßner, M., Benker, G., Lederbogen, S., Olbricht, T., & Reinwein, D. (1994) · Journal of Endocrinological Investigation · doi:10.1007/bf03344959 · Cited by 88 · see citing works
OKAMURA, K., IKENOUE, H., Shiroozu, A., Sato, K., Yoshinari, M., & Fujishima, M. (1987) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-65-4-719 · Cited by 78 · see citing works
Treatment of Hyperthyroidism with a Small Single Daily Dose of Methimazole
Shiroozu, A., Okamura, K., IKENOUE, H., et al. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-1-125 · Cited by 73 · see citing works
Tajiri, J., & Noguchi, S. (2005) · Thyroid · doi:10.1089/thy.2005.15.292 · Cited by 68 · see citing works
NICHOLAS, W. C., FISCHER, R. G., STEVENSON, R. A., & BASS, J. D. (1995) · Southern Medical Journal · doi:10.1097/00007611-199509000-00018 · Cited by 64 · see citing works
Mashio, Y., Beniko, M., Matsuda, A., et al. (1997) · Endocrine Journal · doi:10.1507/endocrj.44.553 · Cited by 40 · see citing works
KALLNER, G., Vitols, S., & Ljunggren, J. ‐. (1996) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.1996.489827000.x · Cited by 38 · see citing works
Treatment of hyperthyroidism with a small single daily dose of methimazole
Mashio, Y., Beniko, M., Ikota, A., Mizumoto, H., & KUNITA, H. (1988) · European Journal of Endocrinology · doi:10.1530/acta.0.1190139 · Cited by 33 · see citing works
Messina, M., Milani, P., Gentile, L., monaco, A. G. D., Brossa, C., Porta, M., & Camanni, F. (1987) · Journal of Endocrinological Investigation · doi:10.1007/bf03348132 · Cited by 16 · see citing works
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Ross, D. S., Burch, H. B., Cooper, D. S., Greenlee, M. C., Laurberg, P., Maia, A. L., Rivkees, S. A., Samuels, M., Sosa, J. A., Stan, M. N., et al. (2016) · Thyroid® · doi:10.1089/thy.2016.0229 · Cited by 2,938 · see citing works
Thyroid disease in pregnancy: new insights in diagnosis and clinical management
Korevaar, T. I. M., Medici, M., Visser, T. J., & Peeters, R. P. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.93 · Cited by 441 · see citing works
Cooper, D. S., & Laurberg, P. (2013) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(13)70086-x · Cited by 310 · see citing works
Franklyn, J. A., & Boelaert, K. (2012) · The Lancet · doi:10.1016/s0140-6736(11)60782-4 · Cited by 262 · see citing works
Analysis of 754 Cases of Antithyroid Drug-Induced Agranulocytosis Over 30 Years in Japan
Nakamura, H., Miyauchi, A., Miyawaki, N., & Imagawa, J. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2569 · Cited by 180 · see citing works
Self-citationAntithyroid Drug Side Effects in the Population and in Pregnancy
Andersen, S. L., Olsen, J., & Laurberg, P. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-4274 · Cited by 107 · see citing works
Boelaert, K., Maisonneuve, P., Torlinska, B., & Franklyn, J. A. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3459 · Cited by 82 · see citing works
Sato, S., Noh, J. Y., Sato, S., Suzuki, M., Yasuda, S., Matsumoto, M., Kunii, Y., Mukasa, K., Sugino, K., Ito, K., et al. (2015) · Thyroid · doi:10.1089/thy.2014.0084 · Cited by 67 · see citing works
Preventing Postoperative Hypocalcemia in Patients with Graves Disease: A Prospective Study
Oltmann, S. C., Brekke, A. V., Schneider, D. F., Schaefer, S. C., Chen, H., & Sippel, R. S. (2015) · Annals of Surgical Oncology · doi:10.1245/s10434-014-4077-8 · Cited by 65 · see citing works
Kim, H. K., Yoon, J. H., Jeon, M. J., Kim, T. Y., Shong, Y. K., Lee, M. J., Kim, B. H., Kim, I. J., Joung, J. Y., Kim, S. W., et al. (2015) · Endocrinology and Metabolism · doi:10.3803/enm.2015.30.4.475 · Cited by 23 · see citing works
- Authors
- Takata, K., Kubota, S., Fukata, S., Kudo, T., Nishihara, E., Ito, M., Amino, N., & Miyauchi, A.
- Affiliations
- Kuma Hospital (JP)
- Department of Internal Medicine, Kuma Hospital, Kobe, Japan.
- Corresponding author
- Takata, Kazuna
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2009-06
- Volume
- 19
- Issue
- 6
- Pages
- 559-563
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W2012861708
- Cited by
- 128
- References
- 15
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 3 · 2018: 5 · 2017: 14 · 2016: 9 · 2015: 7 · 2014: 10 · 2013: 12 · 2012: 6
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- methimazole, agranulocytosis, Graves' disease, antithyroid drugs, drug-induced neutropenia, dose dependence, initial dose, adverse drug reactions, hyperthyroidism treatment
- MeSH terms
- Adolescent, Adult, Agranulocytosis, Dose-Response Relationship, Drug, Female, Graves Disease, Humans, Leukocyte Count, Male, Methimazole, Middle Aged, Neutropenia, Neutrophils, Retrospective Studies, Antithyroid Agents, Young Adult
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