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美國食物及藥物管理局(USFDA)通知衛生專業人士, 若孕婦於懷孕首三個月長期服用高劑量(400-800mg/天)的fluconazole治療真菌感染, 誕下的小孩可能會出現罕見且異常的先天性缺陷。根據現有少量關於孕婦於懷孕首三個月長期服用高劑量fluconazole的醫學文獻, 這些個案中的胎兒皆與常染色體隱性遺傳病症-Antley-Bixler綜合症具有部分共同特徵, 包括扁頭畸形﹑面形奇異﹑顱骨發育異常﹑腭裂﹑股骨彎曲﹑肋骨瘦長﹑關節彎曲以及先天性心臟病, 上述畸型個案於一般人群中很少會發生。胎兒長期及高劑量暴露於fluconazole可能會導致畸型, 然而, 並不清楚上述潛在風險的程度。目前文獻資料並未指出單獨用於治療陰道酵母菌感染(念珠菌病)的低劑量fluconazole(150mg)會引起先天性缺陷, 因此胎兒長期及高劑量暴露於fluconazole出現的先天性缺陷顯示fluconazole的胚胎毒性存在藥物閾值效應。
基於上述原因, USFDA仍維持單獨用於治療陰道念珠菌病的低劑量fluconazole(150mg)的懷孕分級為C, 但已將fluconazole用於下列慢性感染疾病時的懷孕分級,由C改為D*：
- 治療由特定真菌引起的內部器官感染﹑腦膜炎或念珠菌血病。
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預防免疫缺陷病人於骨髓移植前接受化療或放射治療時的酵母菌感染。
同時, 提醒醫生﹑藥劑師及其他衛生專業人士：
- 了解上述fluconazole對胎兒的風險, 以及注意懷孕首三個月長期服用高劑量fluconazole時懷孕分級的相應改變。
- 如於懷孕期間處方fluconazole或病人於服用該藥期間懷孕, 需向病人說明上述風險。
- 建議服用fluconazole的病人如計劃或即將懷孕, 需告知醫生。
*懷孕分級D – 臨床數據顯示藥物對人類胎兒存在風險, 然而對處於嚴重或具有危及生命狀況的孕婦, 使用該藥的潛在效益可能高於其風險。
United Food and Drug Administration (USFDA) notified healthcare professionals about a possible association in the occurrence of a rare and distinct set of congenital anomalies in infants whose mothers were treated with chronic high-dose (400-800 mg/day) fluconazole for fungal infections during the first trimester of pregnancy. According to the few documented medical reports describing cases linked with the chronic uses of high-dose fluconazole and the mother during their first trimester of pregnancy, all shared some characteristics with the autosomal recessive genetic disorder known as Antley-Bixler syndrome. Though occurs rarely in the general population, congenital abnormalities seen in these infants are characterized with brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. Chronic high-dose utero fluconazole exposure may be teratogenic in human; however, the magnitude of this potential risk is unknown. Current available data in the literature does not suggest an association between congenital anomalies and a single, low dose of 150mg fluconazole’s use in vaginal yeast infection (candidiasis). Therefore, development of congenital anomalies following chronic, high-dose in utero exposure to fluconazole suggest a possible drug threshold effect for a fluconazole embryopathy.
In light of the above, the USFDA left the pregnancy category of low-dose fluconazole (150 mg) use singly for vaginal candidiasis to remain at C, while the pregnancy categories of fluconazole intended for the following chronic indications have been revised from C to D*:
- treatment of certain types of yeast infections on the internal organs, meningitis and candidemia.
- prevention of yeast infection for patients who are immunocompromised with chemotherapy or radiation therapy before their bone marrow transplants.
Meanwhile, physicians, pharmacists and other healthcare professionals are reminded that:
- recognize the above fetal risk and be aware of the respective changes on pregnancy category when high doses of fluconazole are used chronically as indicated during the first trimester of pregnancy.
- counsel patients about the above risk when fluconazole is being used during pregnancy or if a patient becomes pregnant while taking the drug.
- advise patients to notify their physicians if they are planning or become pregnant while taking fluconazole.
*Category D - positive evidence of human fetal risk based on human data but the potential benefits from use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks.
參考資料/References and websites： https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm266468.htm