FDA发布阿奇霉素致心律失常风险的警告

美国食品药品管理局(FDA)3月12日发布警告称，使用抗生素阿奇霉素与致死性心律失常风险增高相关。

FDA已开始加强药品说明书中关于QT间期延长和尖端扭转型心律失常的现有警告。通常，风险最大的人群是有已知危险因素的患者，如已有QT间期延长、血钾或血镁水平降低、心率低于正常或使用某些用于治疗心脏节律异常或心律失常的药物的患者。医生可能认为，大环内酯类或非大环内酯类抗生素(如氟喹诺酮类药物)可替代阿奇霉素，但对于有危险因素的患者，选择抗生素的使用并不是如此简单，因为这些药物本身也有使QT间期延长的风险。

FDA的声明是基于其对一项研究的回顾。这项研究显示，与接受阿莫西林、环丙沙星、左氧氟沙星或未接受药物治疗的患者相比，接受5天疗程阿奇霉素治疗的患者发生心血管源性死亡、任何原因死亡的风险增高(N. Engl. J. Med. 2012;366:1881-90)。研究者发现阿奇霉素相关的心血管源性死亡风险与左氧氟沙星相似。当与未接受抗生素治疗的患者相比时，发现接受阿奇霉素治疗患者心血管源性死亡风险增加1.88倍，任何原因死亡风险增加了0.85倍，均有统计学意义。尽管这项研究具有局限性，但“方法是正确的，并且支持总体结果的有效性”，此外，心血管源性死亡风险增加，“尤其是猝死风险，与药物相关的QT间期延长所致心律失常一致”。另外，FDA还考虑了由生产商进行的一项临床QT研究的结果，这一结果已被加入药品说明书，提示阿奇霉素可使QTc间期延长。

FDA的声明中包含一个特定的尖端扭转型心律失常风险增高人群的清单，包括已知有QT间期延长、尖端扭转型心律失常病史、先天性长QT综合征、心动过缓或失代偿心力衰竭以及接受已知可延长QT间期的药物治疗的患者。此外，正处于致心律失常状况的患者的风险也有所增高，包括未经纠正的低钾血症或低镁血症；有临床意义的心动过缓和接受ⅠA类(奎尼丁、普鲁卡因酰胺)或Ⅲ类(多非利特、胺碘酮、甲磺胺心定)抗心律失常药物治疗的患者。老年患者以及心脏病患者“可能对致心律失常药物延长QT间期的效应更敏感”。

上述信息已被增补进阿奇霉素产品(商品名为希舒美和Zmax)说明书中的警告和注意事项部分，阿奇霉素经核准的适应证包括细菌性COPD急性加重、急性细菌性鼻窦炎、社区获得性肺炎、咽炎/扁挑体炎、无并发症的皮肤或皮肤附属器感染以及尿道炎和宫颈炎。

与阿奇霉素使用相关的严重不良事件应报告至FDA的MedWatch不良事件报告系统，可拨打电话800-332-1088或登录网址www.fda.gov/medwatch/报告。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

Use of the antibiotic azithromycin is associated with an increased risk for fatal arrhythmia, according to a warning issued by the Food and Drug Administration on Mar. 12.

The FDA has taken the step to strengthen the existing warning on the drug’s label about the risk of QT interval prolongation and torsades de pointes. In general, the people at greatest risk are those with known risk factors such as existing QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or use of certain drugs used to treat abnormal heart rhythms or arrhythmias, according to the FDA.
 
Macrolides or nonmacrolides such as fluoroquinolones are among the antibiotics that physicians might consider using as alternatives to azithromycin, but there is no easy answer to which antibiotic to use in at-risk patients since these agents carry their own increased risk for QT prolongation, according to the FDA.

The FDA’s statement is a result of the agency’s review of a study showing that the risk of cardiovascular deaths, and the risk of death from any cause, was increased among those treated with a 5-day course of azithromycin, compared with people treated with amoxicillin, ciprofloxacin, levofloxacin, or no drug (N. Engl. J. Med. 2012;366:1881-90).

When compared with levofloxacin, the risk of cardiovascular death associated with azithromycin was similar. When compared with those who took no antibiotic, the risk of cardiovascular death was increased by 2.88 and the risk of death from any cause was increased by 1.85 among those treated with azithromycin, both statistically significant effects.

Although this study had limitations, it was "methodologically sound and supports the validity of the overall findings," and the excess risk of cardiovascular death, "especially of sudden death, is consistent with arrhythmias from drug-related QT prolongation," the FDA said.

In formulating its warning, the FDA also considered findings from a clinical QT study conducted by the manufacturer. The results of the manufacturer’s study, which have been added to the drug label, indicated that azithromycin prolonged the QTc interval, according to the FDA statement.

The FDA statement includes a list of specific groups at increased risk for torsades de pointes, including those with known prolongation of the QT interval, history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure, as well as those who are on drugs known to prolong the QT interval.

Also at risk are people with ongoing proarrhythmic conditions, including uncorrected hypokalemia or hypomagnesemia; those with clinically significant bradycardia; and patients treated with class IA (quinidine, procainamide) or class III (dofetilide, amiodarone, sotalol) antiarrhythmic drugs. Elderly patients and those with cardiac disease "may be more susceptible to the effects of arrhythmogenic drugs on the QT interval," the statement adds.

This information has been added to the warnings and precautions section of the labels for azithromycin products – marketed as Zithromax and Zmax – which are approved for indications that include acute bacterial exacerbations of COPD, acute bacterial sinusitis, community-acquired pneumonia, pharyngitis/tonsillitis, uncomplicated skin and skin structure infections, and urethritis and cervicitis.

Serious adverse events associated with azithromycin should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch/.