对乙酰氨基酚与罕见但致死性严重皮肤反应相关

8月1日，美国食品药品管理局(FDA)宣布，使用对乙酰氨基酚与Stevens-Johnson综合征(SJS)和其他严重、潜在致死性皮肤反应相关，这可能是某些患者服用含有对乙酰氨基酚的产品后出现这些反应的原因。

FDA在公告中指出，使用对乙酰氨基酚还与中毒性表皮坏死松解症(TEN)和急性全身发疹性脓疱病(AGEP)相关。患者在首次用药和治疗期间均有报告发生上述3种皮肤反应。虽然难以确定这些反应的发生频次，但这些事件很有可能较为罕见。



公告还指出，医疗专业人员“在评估患者潜在药物引起的皮肤反应时，应意识到这一罕见风险，并考虑到对乙酰氨基酚和其他已知存在上述关联的药物”。一旦患者出现皮疹或超敏反应迹象时，应告知患者立即停止服用对乙酰氨基酚。

FDA是基于对不良反应事件报告系统(AERS)以及1995~2011年医学文献报告的107例对乙酰氨基酚相关性严重皮肤反应的评估结果发出上述警告的。

声明指出，文献报告了少数病例的对乙酰氨基酚再激发反应呈阳性结果，支持因果关系。

其中包括1例7岁女孩，她在服用3次对乙酰氨基酚(每次剂量为10 mg/kg)后发生TEN而住院治疗。6个月后，再次服用250 mg对乙酰氨基酚30分钟后出现弥散性红斑和荨麻疹，再次住院治疗。
 
另一病例为83岁男性患者，髋关节置换术后因服用对乙酰氨基酚和其他药物出现反应而住院，确诊为AGEP。在静脉注射对乙酰氨基酚的前药——丙帕他莫后复发皮疹。

1969~2012年，AGEP共收到因服用对乙酰氨基酚(多为单活性成分产品)导致的91例SJS/TEN和16例AGEP报告，其中包括67例住院病例和12例死亡病例。这些病例的用药剂量(有资料可利用者)多数在推荐剂量范围之内。

在91例SJS/TEN病例中，6例被判断为“很可能”与对乙酰氨基酚有关，其余为“可能”。在16例 AGEP病例中，1例为“很可能”，余者为“可能”。

有关上述风险的警告(NSAID药物标签中已含有)将被添加至含有对乙酰氨基酚的处方药物的标签中。FDA还将要求含对乙酰氨基酚OTC药物(如泰诺)的生产商在其产品标签中也添加这一警告。

应将与使用对乙酰氨基酚有关的严重不良事件报告至FDA的MedWatch不良事件报告系统或致电800-332-1088。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

The use of acetaminophen has been linked to cases of Stevens-Johnson syndrome and other serious, potentially fatal skin reactions, and should be considered as a possible cause in patients who develop these reactions after taking any product containing acetaminophen, the Food and Drug Administration announced on August 1.

Use of acetaminophen also has been associated with toxic epidermal necrolysis (TEN) and acute generalized exanthematouspustulosis (AGEP). All three types of skin reactions have been reported with the first dose and at other times during treatment. Although it is difficult to determine the frequency of these reactions, "it is likely" that these events are rare, the FDA statement said.

Health care professionals "should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions," and should advise patients that acetaminophen should be stopped immediately with the first sign of a skin rash or hypersensitivity, the FDA said in the announcement.

The warning is based on the FDA’s review of 107 serious skin reactions associated with acetaminophen products reported to the Adverse Event Reporting System (AERS) and reports in the medical literature between 1995 and 2011.

A small number of cases in the literature describe positive rechallenges with acetaminophen, "supporting causality," according to the statement.

They include the case of a 7-year-old girl who developed TEN and was hospitalized after taking three doses of acetaminophen at a 10 mg/kg dose. Six months later, she developed diffuse erythema and urticaria 30 minutes after a rechallenge with a 250 mg dose and was hospitalized again.

Another case was an 83-year-old man, diagnosed with AGEP after being hospitalized for a reaction that occurred after taking acetaminophen, along with other medications after hip replacement. The rash recurred when he received intravenous propacetamol, a prodrug of acetaminophen.

From 1969 to 2012, 91 cases of SJS/TEN and 16 cases of AGEP were reported to AERS in people who took acetaminophen (most were single-ingredient products), and included 67 hospitalizations and 12 deaths. In most of these cases, the doses reported (when the information was available) were within recommendations.

Of the 91 SJS/TEN cases, 6 were determined to be probable cases associated with acetaminophen and the rest were considered possible. One of the 16 AGEP cases was considered a probable case and the rest were considered possible.

Warnings about these risks –which are already in the labels of NSAIDs – will be added to the labels of prescription drugs that contain acetaminophen. The agency will request that manufacturers of OTC acetaminophen-containing products, such as Tylenol, add a warning to those products as well.

Serious adverse events associated with acetaminophen should be reported to the FDA’s MedWatch program or by calling 800-332-1088.