FDA对口服酮康唑片提出严重警告

美国食品药品管理局（FDA）宣布，酮康唑片不应作为真菌感染的一线治疗药，因为该治疗与肾上腺功能不全、潜在致死性肝毒性以及药物间相互作用有关。

据7月26日发布的MedWatch安全性警示，商品名为“Nizoral”的口服酮康唑片不再适用于治疗念珠菌及皮肤真菌感染，“应该仅在其潜在收益大于风险并且没有或不能耐受替代疗法时用于治疗某种危及生命的真菌病”。此外，口服酮康唑也不得用于治疗皮肤及指甲的真菌感染，仅适用于治疗其他疗法无效或对其他疗法不耐受的芽生菌病、球孢子菌病、组织胞浆菌病、广色霉菌病以及副球孢子菌病患者。该产品的说明书已经被修改，加入了反映这些风险和建议的内容。风险部分提示，在患者每次按处方取药时都要向他们提供用药指导。

由于口服酮康唑与能导致肝移植或死亡的肝毒性有关，因此目前该药禁用于有急慢性肝病的患者。说明书现在也建议评估患者及监测其肝毒性；对服用该药的口服制剂且存在肾上腺问题或是“长时间处于应激状态下”（比如近期进行了大手术或现处于医院的重症监护下等）的患者，推荐进行肾上腺功能监测。

另外，酮康唑是细胞色素P450 3A4同工酶（CYP3A4）的一种潜在抑制剂，与其他药物联用会增加联用药物的血药浓度及发生QT延长和其他严重反应的风险。禁止联用的药物包括多菲莱德、奎尼丁、匹莫齐特以及西沙必利。

FDA是根据对上报至FDA不良事件报告系统的资料进行的风险收益分析做出相应改动的。据FDA称，乳膏、香波及其他常用的酮康唑制剂与上述问题无关。

欧洲药品管理局人用药品管理委员会（CHMP）在7月26日宣布，已认定口服酮康唑药品的肝毒性风险大于其治疗真菌感染的收益，并且建议这些产品不再在欧盟范围内销售。

点击此处可获取最新的说明书。与酮康唑相关的严重不良事件应该上报至FDA，致电  800-332-1088或报告至MedWatch均可。

爱思唯尔版权所有  未经授权请勿转载

By: ELIZABETH MECHCATIE, Clinical Endocrinology News Digital Network

Ketoconazole tablets should not be used as a first-line treatment for fungal infections because treatment has been associated with an increased risk of adrenal insufficiency, potentially fatal hepatotoxicity, and drug interactions, the Food and Drug Administration has announced.

Marketed as Nizoral, oral ketoconazole is no longer indicated for the treatment of Candida and dermatophyte infections and "should be used only for the treatment of certain life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or tolerated," according to the MedWatch safety alert issued on July 26.

In addition, oral ketoconazole should not be used to treat fungal infections of the skin and nails, and is only indicated for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis "in patients in whom other treatments have failed or who are intolerant to other therapies," according to the label, which has been modified to reflect these risks and recommendations.

There is now a Medication Guide that will be provided to patients with each filled prescription of oral ketoconazole, explaining the risks.

Because oral ketoconazole has been associated with hepatoxicity that can result in liver transplantation or death, it is now contraindicated in patients with acute or chronic liver disease. The label also now recommends that patients be assessed and monitored for liver toxicity. Monitoring of adrenal function also is now recommended in patients who take the oral formulation of the drug and have adrenal problems or "are under prolonged periods of stress such as those who have had a recent major surgery or who are under intensive care in the hospital."

In addition, coadministration of ketoconazole – a potent inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4) – with certain drugs is either restricted or contraindicated because of the increase in drug concentrations and increased risk of QT prolongation and other serious reactions. Contraindicated drugs include dofetilide, quinidine, pimozide, and cisapride.

The FDA changes are based on risk-benefit analyses of data that include reports made to the FDA’s Adverse Events Reporting System.

On July 26, the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) announced that it has concluded that the risk of hepatoxicity with oral ketoconazole products was greater than the benefits in treating fungal infections and recommended that these products no longer be marketed in the European Union.

Creams, shampoos, and other topical ketoconazole formulations have not been associated with these problems, according to the FDA.

The updated label is available here. Serious adverse events associated with ketoconazole should be reported to the FDA at 800-332-1088 or MedWatch.