Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily.
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.
Takata
Kazuna
K
Department of Internal Medicine, Kuma Hospital, Chuo-ku, Kobe, Japan. takata@kuma-h.or.jp
Kubota
Sumihisa
S
Fukata
Shuji
S
Kudo
Takumi
T
Nishihara
Eijun
E
Ito
Mitsuru
M
Amino
Nobuyuki
N
Miyauchi
Akira
A
D000293:Adolescent; D000328:Adult; D000380:Agranulocytosis / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006111:Graves Disease / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008713:Methimazole / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced; D009504:Neutrophils; D012189:Retrospective Studies; D055815:Young Adult
D013956:Antithyroid Agents; D008713:Methimazole